abt-267 and Hepatitis-C--Chronic

Hepatitis C virus (HCV) has caused a considerable threat to human health. To date, no treatments are without side effects. The proteins and RNA associated with HCV have specific functions during the viral life cycle. The vulnerabilities to virus are associated with those proteins or RNA. Thus, targeting these proteins and RNA is an efficient strategy to develop anti-HCV therapeutics. The treatment for HCV-infected patients has been greatly improved after the approval of direct-acting antivirals (DAAs). However, the cost of DAAs is unusually high, which adds to the economic burden on patients with chronic liver diseases. So far, many efforts have been devoted to the development of small molecules as novel HCV inhibitors. Investigations on the inhibitory activities of these small molecules have involved the target identification and the mechanism of action. In this mini-review, these small molecules divided into four kinds were elaborated, which focused on their targets and structural features. Furthermore, we raised the current challenges and promising prospects. This mini-review may facilitate the development of small molecules with improved activities targeting HCV based on the chemical scaffolds of HCV inhibitors.

Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; RNA

The World Health Organization has called for the elimination of hepatitis C virus (HCV) as a public health threat by 2030. Highly effective direct-acting antiviral agents provide the therapeutic tools required for elimination. In the absence of a vaccine, HCV elimination will require enhanced primary prevention and an increase in the proportions of people diagnosed and treated. Given that globally only 20% of people with chronic HCV are diagnosed, and around 5% have initiated HCV treatment, the task ahead is enormous. But, global public health needs optimism, and countries currently on track for HCV elimination provide a pathway forward.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzofurans; Carbamates; Drug Therapy, Combination; Global Health; Health Care Costs; Hepatitis C, Chronic; Humans; Imidazoles; Proline; Pyrrolidines; Sofosbuvir; Sulfonamides; Uracil; Valine; World Health Organization

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance-associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1-4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next-generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs, we observed genome-wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments.

Topics: 2-Naphthylamine; Aminoisobutyric Acids; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Denmark; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Male; Prognosis; Proline; Protease Inhibitors; Pyrrolidines; Quinoxalines; Sulfonamides; Uracil; Valine

With the advent of the direct-acting antiviral agents (DAAs) for chronic hepatitis C infection, the treatment paradigm has dramatically changed, especially the duration, tolerability, and response to therapy. The DAAs fall into several classes and are variously indicated in the treatment of one or more genotypes of infection. All these agents are orally administered and, as they are largely renally eliminated (with exceptions), do not require adjustment in mild to moderate renal insufficiency. Most of these agents demonstrate a high barrier to resistance and are extremely well-tolerated by patients. Overall efficacy rates are ≥90%.

Topics: Anilides; Antiviral Agents; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Mutation; Proline; Sulfonamides; Valine

Hepatitis C treatment has changed considerably in recent years, and many interferon (IFN)-free therapies are now available. Considering the high rates of sustained virological response (SVR) presented by clinical trials for these treatments, high rates of effectiveness are also expected in real-world clinical practice. Hence, this study aimed to conduct a systematic review and meta-analysis of observational cohort studies to evaluate the clinical effectiveness and safety of IFN-free therapies for hepatitis C.. The search was performed in four electronic databases and included cohort studies that evaluated IFN-free schemes and provided data on SVR at 12 weeks after the end of treatment (SVR12) as the primary outcome. Overall and subgroup meta-analyses of patients' clinical conditions (e.g. co-infection with human immunodeficiency virus (HIV), cirrhosis, liver transplant, specific genotypes, and other conditions) were performed.. Sixty-eight studies encompassing a total of 24,151 patients were included for quantitative and qualitative analyses, evaluating six treatments: sofosbuvir with ledipasvir, daclatasvir, or simeprevir; daclatasvir with asunaprevir; paritaprevir/ritonavir in combination with ombitasvir and dasabuvir; and sofosbuvir with ribavirin. The overall analysis showed SVR rates of 88-96% for all treatments except sofosbuvir combined with ribavirin, which had SVR rates of approximately 80%. The results of subgroup analyses showed that the genotype 3 virus appears to be the most difficult to treat.. In order to choose the best treatment option, it is necessary to consider the patients' conditions and characteristics. In conclusion, the use of IFN-free therapies meets the high expectations created by clinical trials, including patients in special clinical conditions.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Simeprevir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

Chronic HCV infection is a non-traditional (but modifiable) risk factor for chronic kidney disease and has been implicated in glomerular injury and nephrosclerotic disease. Three HCV direct-acting antiviral regimens are available for patients with severe kidney impairment: ombitasvir, paritaprevir with the pharmacokinetic enhancer ritonavir, and dasabuvir; glecaprevir plus pibrentasvir; and elbasvir plus grazoprevir. In patients with severe kidney impairment, sofosbuvir-free regimens are preferred because sofosbuvir accumulation has been associated with a progressive worsening of renal function. In this Review, we provide our expert opinion on the current HCV treatment paradigm and highlight the remaining issues that need to be overcome to improve the treatment of HCV in this population.

Topics: 2-Naphthylamine; Amides; Aminoisobutyric Acids; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Disease Management; Drug Therapy, Combination; Expert Testimony; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Practice Guidelines as Topic; Proline; Pyrrolidines; Quinoxalines; Renal Insufficiency, Chronic; Risk Factors; Ritonavir; Sulfonamides; Uracil; Valine

The recently approved interferon-free DAA (direct antiviral agents) regimens have shown not only to be effective in terms of sustained virological response (SVR) rates (> 90%) but also well tolerated in most hepatitis C virus (HCV) infected patients. Nevertheless HCV genotypes are different and only a small percentage of trials consider genotype 4 (GT4), which was associated with lower rates of SVR compared with other genotypes before the arrival of the DAA's. In this review, we discuss the efficacy of DAA therapy in GT4 HCV infection with specific reference to more recent studies, including those conducted in a 'field-practice' scenario. Overall, DAA-based regimens appear more effective also in the poorly-explored setting of patients with HCV GT4 infection. Despite an overall limited number of patients was evaluated, favorable results are being derived from studies on ombitasvir/paritaprevir/ritonavir, sofosbuvir and velpatasvir, whether or not in association with voxilaprevir, and with the new combined therapy glecaprevir + pibentasvir.

Topics: Aminoisobutyric Acids; Anilides; Antiviral Agents; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Interferons; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Quinoxalines; Ribavirin; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Valine

Since 2014, the United States and Europe has approved all oral, interferon free- regimens that combine with direct-acting antiviral agents. Hence, the sustained virological response rate of patients with chronic HCV genotype 1 infection has improved over 90%, and the treatment modalities has introduced a new era. These drugs, ombitasvir and dasabuvir, received customary authorization of Food and Drug Administration in 2015 and are the first combined direct-acting antiviral agents for treating HCV genotype 1 infection. It has superior application prospects in China because of its high-sustained virological response rate and safety profile. This article reviews the pharmacokinetics, drug interactions, efficacy and safety of this therapeutic regimen.. 自2014年全口服不含干扰素的直接抗病毒方案在美国、欧洲陆续获批准，基因1型丙型肝炎病毒感染患者的持续病毒学应答率提高到90%以上，慢性丙型肝炎基因1型的治疗进入了一个新的时代。作为第一个全新的直接抗病毒药物组合，奥比帕利联合达塞布韦于2015年经食品和药品管理局批准治疗基因1型慢性丙型肝炎患者，其持续病毒学应答率高、安全性好，在我国具有较好的应用前景。现对该治疗方案的药代动力学、药物相互作用、疗效及安全性等方面进行综述。.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Proline; Sulfonamides; United States; Uracil; Valine

Hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma responsible for almost 700,000 deaths worldwide annually. Until 2014, management of HCV infections was based on interferon alfa containing regimens, with efficacy of 40-70% and a high adverse event rate. Interferon-free therapeutic options improved sustained viral response (SVR) rate to >90% and safety profile to placebo-like levels. Areas covered: This article describes all-oral regimen consisting of three direct acting antivirals (DAA) - ombitasvir (OBV), paritaprevir (PTV) and dasabuvir (DSV), which in clinical practice is boosted with ritonavir (r) and sometimes with ribavirin (RBV). This combination is registered for treatment of patients infected with HCV genotype 1 and 4. We focused on the regimen characteristics, pharmacokinetics, risk of resistance as well as efficacy and safety in clinical trials and real world studies. Expert commentary: Combination of OBV/PTV/r±DSV±RBV provides SVR rate of about 95% and good safety profile even in patients with compensated liver cirrhosis and failure with previous therapy. Currently it should be of particular value in areas with a predominance of genotype 1b infections. Due to the complexity and risk of drug to drug interactions, it will probably be replaced in coming few years with pangenotypic combinations of next generation DAAs.

Topics: 2-Naphthylamine; Administration, Oral; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis.. Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r±ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV±RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported.. In 1,066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2).. This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r±DSV±RBV in this population. These results support the use of OBV/PTV/r±DSV±RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients.

Topics: 2-Naphthylamine; Administration, Oral; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Young Adult

Interferon-free regimens are rapidly evolving for patients with chronic hepatitis C virus (HCV) infection. We performed this meta-analysis to investigate the safety and efficacy of a combination regimen (ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r] ± dasabuvir [DSV]) for the treatment of patients with HCV genotype 1 infection.. A computerized literature search for relevant clinical trials was conducted during May 2017. Data on sustained virological response (SVR), virological relapse, and safety outcomes were extracted and calculated as pooled proportion (PP) or risk ratio (RR) with their 95% confidence interval (CI), using StatsDirect and RevMan software.. The final analysis included 13 studies for HCV genotype 1 (3115 patients). The pooled effect estimate showed that 12-week treatment of genotype 1 patients with the OBV/PTV/r regimen achieved a high SVR rate (PP = 94%, 95% CI 92-96) that increased to (PP = 97%, 95% CI 96-98) upon the addition of DSV. These results were consistent when independent subgroup analyses were conducted based on viral subgenotypes, the presence of cirrhosis, or former treatment failure. Adding ribavirin (RBV) to this regimen was not associated with increased SVR rates (risk ratio = 1, 95% CI 0.98-1.02), while it increased the risk of serious adverse events (p = 0.02), insomnia (p = 0.001), and pruritus (p < 0.001).. The current meta-analysis showed a high efficacy for the OBV/PTV/r regimen in the treatment of HCV genotype 1 (with DSV) infection, regardless of the presence of cirrhosis or former treatment failure. Adding RBV to this regimen slightly decreased the relapse rate. Future studies with larger sample sizes are required to investigate the efficacy of this regimen in other HCV genotypes and to establish the evidence about the effect of adding RBV to OBV/PTV/r + DSV.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Mixed Cryoglobulinemia (MC) is the most frequent extrahepatic manifestation of Hepatitis C virus (HCV) infection. MC is an autoimmune /B-cell lymphoproliferative disorder characterized by circulating immune-complexes, named cryoglobulins. MC patients exhibit symptoms due to a systemic vasculitis of small/medium size vessels (mixed cryoglobulinemia syndrome, MCS) in a percentage going from 5 to 30%. The first-line therapeutic option in MCS patients is the etiologic treatment and, in the past fifteen years, antiviral therapy with Pegylated-Interferon (Peg-IFN) plus Ribavirin (RBV) represented the standard of care. Lately, the arrival of direct acting antivirals (DAAs) significantly modified the cure of HCV infection, consenting the use of IFN-free regimens. Here we report a review of the literature about the role of antiviral treatment, following its evolution, in treating HCVrelated MC. Furthermore, we report the results, after 8 weeks of treatment, of a preliminary pilot prospective study, counting 17 patients with HCV-related MC with or without MCS, treated with new generation DAAs in IFN-free regimens. After 8 weeks of DAA administration, all the subjects were HCV RNA negative. Moreover, in 6/17 (35%) patients cryoglobulins disappeared and, on the whole, in all patients a decrease of the cryocrit values was observed (p<0.05). Furthermore, three MCS-HCV patients (30%) resulted to be complete clinical responders and 5 subjects (50%) partial clinical responders. Therefore, IFN-free anti-HCV treatment appears to be safe and effective in MC patients from virological and clinical points of view, thus supporting the importance of HCV eradication in leading MC remission.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Cryoglobulinemia; Cyclopropanes; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Pilot Projects; Proline; Prospective Studies; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Valine

Ombitasvir, paritaprevir (given with low-dose ritonavir), and dasabuvir are direct-acting antivirals (DAAs) used with or without ribavirin for the treatment of chronic hepatitis C virus (HCV) infection. The objective of this analysis was to evaluate the effect of renal function as determined by creatinine clearance (CrCL) on the pharmacokinetics of the DAAs, ritonavir, and ribavirin in HCV genotype 1-infected patients with or without cirrhosis.. Total exposure, measured by area under the plasma concentration-time curve (AUC), was generated for the DAAs, ritonavir, and ribavirin using population pharmacokinetic modeling of data (N = 2093 patients) from 6 Phase 3 studies and 1 Phase 2 study. The effect of CrCL on the AUC values of each DAA, ritonavir, and ribavirin was separately evaluated and adjusted for any significant patient-specific covariates including, age, sex, body weight, cirrhosis, and Asian race in multiple linear regression analysis. Using the final models, AUC values were predicted for patients with normal renal function (CrCL = 105 mL/min), mild renal impairment (CrCL = 75 mL/min) and moderate renal impairment (CrCL = 45 mL/min).. CrCL was not a statistically significant predictor of DAA or ritonavir AUC values. Age, sex, and cirrhosis were significant covariates for the AUC values of all the DAAs and body weight was a significant covariate for the AUC values of ombitasvir and dasabuvir. Asian race was significant only for dasabuvir. Only age and sex were statistically significant predictors for the AUC values of ritonavir. CrCL showed a significant relationship with the ribavirin AUC values, consistent with ribavirin's renal excretion. Age, sex, body weight, and cirrhosis were also significant covariates for the AUC values of ribavirin. The DAA and ritonavir AUC values were comparable (≤10 % difference) among different levels of renal function, while ribavirin AUC values were up to 17 % higher in mild/moderate renal impairment compared with normal renal function.. No dose adjustments are needed for the 3D regimen in HCV genotype-1 infected patients with mild or moderate renal impairment. Ribavirin doses should be adjusted for renal impairment as recommended in the ribavirin label.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Area Under Curve; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney Function Tests; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Models, Biological; Proline; Renal Insufficiency; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine; Young Adult

Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that ombitasvir has a low potential for drug interactions.

Topics: Anilides; Animals; Antiviral Agents; Carbamates; Drug Interactions; Drug Therapy, Combination; Food-Drug Interactions; Hepacivirus; Hepatitis C, Chronic; Humans; Proline; Valine

There has been a revolution in the treatment of chronic hepatitis C. Several oral regimens combining direct-acting antivirals (DAAs) from different families [NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors (PI)] have been developed. These regimens result in an increase in sustained virological response (SVR) rates to above 90% and reduce the duration of treatment to 12 weeks or less. As of 2016 several regimens will be approved with additive potencies, without cross-resistance and with a good safety profile. Remaining issues will include increasing screening and access to care so that HCV may become the first chronic viral infection eradicated worldwide. This review summarizes results obtained with oral DAA combinations that have been approved and/or have completed phase 3 clinical trials for HCV infection and discusses future perspectives.

Topics: 2-Naphthylamine; Amides; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Protease Inhibitors; Quinoxalines; Sofosbuvir; Sulfonamides; Uracil; Valine; Viral Nonstructural Proteins

A fixed-dose tablet comprising the NS5A inhibitor ombitasvir, the NS3/4A inhibitor paritaprevir and ritonavir (ombitasvir/paritaprevir/ritonavir) (Technivie(®), Viekirax(®)) is available for use, in combination with ribavirin, for the treatment of chronic hepatitis C virus (HCV) genotype 4 infection. High sustained virological response rates at 12 weeks post-treatment (SVR12) were achieved in treatment-naive or -experienced patients with chronic HCV genotype 4 infection, including patients without cirrhosis who received ombitasvir plus paritaprevir and ritonavir in combination with ribavirin for 12 weeks (SVR12 100 %) (PEARL-I trial), patients with compensated cirrhosis who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 or 16 weeks (SVR12 97 and 98 %) (AGATE-I trial), or Egyptian patients without cirrhosis who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 weeks (SVR12 94 %) or with compensated cirrhosis who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 or 24 weeks (SVR12 97 and 93 %) (AGATE-II trial). Ombitasvir/paritaprevir/ritonavir was generally well tolerated in patients with chronic HCV genotype 4 infection without cirrhosis or with compensated cirrhosis in clinical trials. There have been postmarketing reports of hepatic decompensation and hepatic failure, which mainly occurred in patients with advanced cirrhosis who received regimens containing ombitasvir/paritaprevir/ritonavir. In conclusion, ombitasvir/paritaprevir/ritonavir is a valuable option for use in patients with chronic HCV genotype 4 infection without cirrhosis or with compensated cirrhosis.

Topics: Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Valine

Chronic hepatitis C (CHC) constitutes a major health concern. Hepatitis C virus eradication by antiviral treatment can markedly reduce the risk of developing cirrhosis, hepatocellular carcinoma and liver-related death. A plethora of new direct antiviral agents have been developed and are being explored in clinical trials. One of the newest members of this family is the NS3/4A protease inhibitor ABT-450. The multi-targeted approach combining ritonavir-enhanced ABT-450 with ombitasvir and dasabuvir has been evaluated for the treatment of CHC Gt1 in treatment-naïve and treatment-experienced adults. In this article, we sought to discuss the current knowledge on ABT-450-containing regimens, with special emphasis on treatment-experienced CHC Gt1 patients. This new combination was found to be potent, safe and well tolerated. Future Phase III trials with larger sample size in patients with decompensated cirrhosis, non-Gt1, end-stage renal disease and liver transplant recipients are eagerly awaited.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Proline; Protease Inhibitors; Randomized Controlled Trials as Topic; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Uracil; Valine

To review the data with ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection.. Phase I, II, and III trials and review articles were identified through MEDLINE (1996-January 2015) and PubMed (1996-January 2015), conference abstracts, and US national clinical trials registry, using the keywords NS3/4A protease inhibitor, NS5A inhibitor, NS5B polymerase inhibitor, ABT-450, ABT-267, ABT-333, paritaprevir, ombitasvir, and dasabuvir.. Preclinical, phase I, II, and III studies describing pharmacology, pharmacokinetics, efficacy, safety, and tolerability were identified.. Noncirrhotic patients with HCV genotype 1b experienced sustained virological response 12 weeks after completion of therapy (SVR12) rates of 96% to 100% when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered for 12 weeks, regardless of inclusion of ribavirin. SVR12 rates of 95% to 97% were seen in noncirrhotic patients with HCV genotype 1a infection who received ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 weeks. Patients with Child-Pugh Class A cirrhosis also experienced high SVR12 rates (91.8%) when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered with ribavirin for 12 weeks. Cirrhotic patients with HCV genotype 1a and a history of prior null response to peginterferon/ribavirin have higher SVR12 rates when ombitasvir/paritaprevir/ritonavir and dasabuvir and ribavirin are administered for 24 instead of 12 weeks (94.2% vs 88.6%). Adverse events are typically mild, most commonly consisting of fatigue, headache, nausea, and diarrhea.. The regimen consisting of ombitasvir/paritaprevir/ritonavir and dasabuvir is highly efficacious in the treatment of HCV genotype 1 infection, with minimal adverse events. It is expected to play an important role in the armamentarium of novel agents that have a high chance of curing HCV infection.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Combinations; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Proline; Ribavirin; Ritonavir; Sulfonamides; Tablets; Uracil; Valine

The global prevalence of chronic hepatitis C virus (HCV) is estimated to be 80 - 115 million and currently viremic infections account for 350,000 deaths annually. As the knowledge about HCV evolves, new anti-viral treatments have been developed. The primary goal of antiviral therapies has been to eradicate HCV virus from serum and achieve sustained virologic response (SVR). Historically, interferon has been a staple of nearly all HCV treatment regimens, despite significant toxic effects.. In recent years, HCV treatment has changed rapidly and significantly. All-oral treatment regimens show promise for treatment with shorter duration and more manageable side effects. New antivirals aimed at improving SVR may provide a cure to nearly all HCV-infected patients. The unique combination of ABT-450 (paritaprevir) and ABT-267 (ombitasvir) provides highly effective treatment for patients with genotype 1 HCV. This review will examine the antiviral properties, pharmacokinetics, pharmacodynamics, and side effects of these agents.. The combination of ABT-450/r and ABT-267 has improved potency, favorable side effect profile, and low risk of resistance compared to the first-generation protease inhibitors. This combination is likely to be a major part of novel upcoming HCV treatment regimens and is likely to be widely used by clinicians. Additional data is awaited in additional patient populations, and with possible shorter treatment durations.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Time Factors; Treatment Outcome; Uracil; Valine

Interferon-based regimens with first-generation protease inhibitors have a limited efficacy and an unfavorable safety profile. Combination therapies with two or more second-generation direct-acting antivirals plus/minus ribavirin revolutionized treatment strategies in patients chronically infected with hepatitis C virus. In this rapidly evolving era, patients in the transplant setting benefit from interferon-free treatment regimens. Scientific societies can barely keep up with this development, making it necessary to update the clinical guidelines by the American and European Associations for the Study of Liver Diseases within short periods. This review presents and discusses the currently available data of the use of interferon-free treatment in the setting of liver transplantation. However, costs, different reimbursement strategies, and health-care options cannot be answered by guidelines and recommendations from scientific societies. Further investigator-initiated trials are needed to individualize treatment concepts.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cholestasis, Intrahepatic; Clinical Trials as Topic; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Fibrosis; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferons; Lactams, Macrocyclic; Liver Cirrhosis; Liver Transplantation; Macrocyclic Compounds; Proline; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Valine

Chronic hepatitis C, without treatment, can cause liver cirrhosis, liver failure and liver cancer. The availability of new oral direct acting antivirals, such as the protease inhibitors simeprevir, asunaprevir and paritaprevir, the NS5A inhibitors daclatasvir, ledipasvir, and ombitasvir, the polymerase inhibitors Sofosbuvir and dasabuvir have resulted an enormous progress in the treatment of chronic hepatitis C, leading to >90% sustained viral response rates. Even the hard-to-treat or previously treatment ineligible patients can be cured with the combination of these drugs. Furthermore the treatment duration is much shorter, and the side effects are minimal. Today, treatment of all hepatitis C virus infected patients is recommended, and the best choices are the interferon-free options. Eradication of hepatitis C virus has become realistic, however, appropriate screening programs are mandatory to achieve this goal.

Topics: 2-Naphthylamine; Administration, Oral; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Interferons; Isoquinolines; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Nucleic Acid Synthesis Inhibitors; Proline; Protease Inhibitors; Pyrrolidines; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine; Viral Load; Viral Nonstructural Proteins; Virus Replication

A fixed-dose tablet comprising ombitasvir (an NS5A replication complex inhibitor), paritaprevir (an NS3/4A protease inhibitor) and ritonavir (a cytochrome P450 inhibitor) taken in combination with dasabuvir (an NS5B polymerase inhibitor) is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in several countries, including the USA (copackaged as Viekira Pak(™)) and those of the EU (Viekirax(®) and Exviera(®)). In phase II and III trials, this interferon-free regimen, taken ± ribavirin, provided high rates of sustained virological response 12 weeks post-treatment in adults with chronic HCV genotype 1a or 1b infection, including those with compensated cirrhosis, liver transplants or HIV-1 co-infection. The regimen was generally well tolerated, with nausea, insomnia, asthenia, pruritus, other skin reactions and fatigue being among the most common tolerability issues. Thus, ombitasvir/paritaprevir/ritonavir plus dasabuvir is an effective interferon-free, direct-acting antiviral regimen for use ± ribavirin in a broad range of adults chronically infected with HCV genotype 1.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepatitis C, Chronic; HIV Infections; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Transplantation; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Uracil; Valine

Failure to respond to the approved combinations of multiple direct-acting antiviral agents is relatively low in hepatitis C virus treatment registration studies, with rates of 1% to 7%, depending on the patients' baseline characteristics. In real life, failure is slightly higher, likely because of lower compliance. Treatment failures are usually related to relapse and less often to on-treatment viral breakthrough. Hepatitis C drug-resistant variants are detected in most patients who do not achieve viral eradication. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry resistance-associated variants may not obtain benefits from treatment and are at risk of disease progression and transmission of the variants. Whether hepatitis C resistance-associated variants persist depends on their type: NS3-4A variants often disappear gradually after therapy is stopped, whereas NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent antivirals with genetic barriers to resistance. In patients failing first-generation protease inhibitors, combination therapies with sofosbuvir and NS5 inhibitors have proven effective. Some salvage regimens can be shortened to 12 weeks by addition of ribavirin. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Protease Inhibitors; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Treatment Failure; Uracil; Uridine Monophosphate; Valine

Over the last several years, many advances have been made in the treatment of chronic hepatitis C virus (HCV) infection with the development of direct-acting antivirals. Paritaprevir/ritonavir/ombitasvir with dasabuvir (PrOD) is a novel combination of a nonstructural (NS) 3/4A protein inhibitor boosted by ritonavir, an NS5A protein inhibitor, and an NS5B nonnucleoside polymerase inhibitor. This review aims to discuss the pharmacology, efficacy, safety, drug interactions, and viral drug resistance of PrOD in the treatment of HCV genotype 1 infections. Phase I, II, and III human and animal studies that describe the pharmacology, pharmacokinetics, efficacy, and safety of PrOD for HCV were identified and included. Studies that evaluated patients without cirrhosis (n=2,249) and with cirrhosis (n=422) demonstrated that PrOD for 12 or 24 weeks was effective at achieving sustained virologic response rates (>90%) in patients with genotype 1a or 1b HCV infection. Although indicated for the treatment of HCV genotype 1 infection, PrOD is also recommended for the treatment of HCV in patients coinfected with HIV. Additionally, promising data exist for the use of PrOD in liver-transplant recipients. The most common adverse drug events associated with PrOD included nausea, pruritus, insomnia, diarrhea, asthenia, dry skin, vomiting, and anemia. The high efficacy rates seen coupled with a favorable side effect profile seen with PrOD with or without ribavirin have led to its addition as a recommended treatment regimen for HCV genotype 1 infection.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Carrier Proteins; Cyclopropanes; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Intracellular Signaling Peptides and Proteins; Lactams, Macrocyclic; Macrocyclic Compounds; Molecular Targeted Therapy; Proline; Protease Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine; Viral Nonstructural Proteins

Chronic hepatitis C therapy using Directly Acting Antivirals (DAA) has high efficacy (till 100 %), minimum contra-indications and extraordinarily favorable safety profile. Primarily, it is necessary to pay attention to drug-drug interactions. However they are well documented and successfully resolvable already in general clinical practice. Current possibilities of interferon-free therapy represent combinations of sofosbuvir with other DAA or with ribavirin and combination of paritaprevir boosted by ritonavir+ombitasvir±dasabuvir (3D combination).

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

Chronic hepatitis C infection is a global disease with 160 million people infected worldwide. Until recently, therapy was characterized by long duration, suboptimal success rates and significant adverse drug reactions. The development of direct-acting antivirals initiated a dramatic change in the treatment of hepatitis C.. This review covers the development of the novel NS5A inhibitor ombitasvir (ABT-267) and its clinical evaluation in Phase I to III trials as monotherapy and in combination with the NS3/4A inhibitor ABT-450/r and the non-nucleoside NS5B inhibitor dasabuvir (ABT-333) ± ribavirin.. Ombitasvir (ABT-267) is a potent inhibitor of the hepatitis C virus protein NS5A, has favorable pharmacokinetic characteristics and is active in the picomolar range against genotype 1 - 6. In patients with genotype 1 and 4, 12-week combination treatment with ombitasvir, dasabuvir and ABT-450/r plus ribavirin was highly effective and resulted in 12-week sustained virological response rates higher than 95% in treatment-naöve and treatment-experienced patients. In liver transplant recipients with genotype 1 hepatitis C, success rates in the same range can be expected after 24 weeks of treatment according to preliminary trial results. Genotype 1a patients with compensated cirrhosis who were prior nonresponders benefit from a treatment duration of 24 weeks.

Topics: Anilides; Animals; Antiviral Agents; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Proline; Ribavirin; Valine; Viral Nonstructural Proteins

Topics: 2-Naphthylamine; Administration, Oral; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Combinations; Fluorenes; Genotype; Germany; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Liver Cirrhosis; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine

Hepatitis C virus infection is a major health problem worldwide and no vaccine has yet been developed against this virus. In addition, currently approved pharmacotherapies achieve suboptimal cure rates and have side effects that result in non-compliance and premature treatment discontinuation. Significant research has been devoted to developing direct-acting antiviral agents that inhibit key viral functions. In particular, several novel drug candidates that inhibit the viral non-structural protein 5A (NS5A) have been demonstrated to possess high potency, pan-genotypic activity, and a high barrier to resistance. Clinical trials using combination therapies containing NS5A inhibitors have reported results that promise high cure rates and raise the possibility of developing interferon-free, all-oral regimens.

Topics: Administration, Oral; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Proline; Pyrrolidines; Valine; Viral Nonstructural Proteins

Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable.. We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12.. This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

Topics: 2-Naphthylamine; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Female; Fluorenes; Follow-Up Studies; Genotyping Techniques; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Lactams, Macrocyclic; Male; Middle Aged; Proline; Quinoxalines; Ribavirin; RNA, Viral; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine; Young Adult

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8

Topics: 2-Naphthylamine; Anilides; Antigens, Viral; Antiviral Agents; CD8-Positive T-Lymphocytes; Chromatin; Cyclopropanes; Epigenesis, Genetic; Hepacivirus; Hepatitis C, Chronic; High Mobility Group Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunologic Memory; Lactams, Macrocyclic; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight-based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized.. Adults living with HIV/HCV coinfection receiving steady-state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV.. Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration-time curve of raltegravir with vs without HCV therapy were 0.68 (0.38-1.19) and 0.82 (0.58-1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration-time curve values by 41-82% and 4-73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV.. The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide.

Topics: 2-Naphthylamine; Acquired Immunodeficiency Syndrome; Adult; Anilides; Antiviral Agents; Coinfection; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV-1; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Raltegravir Potassium; Ritonavir; Sulfonamides; Uracil; Valine

Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection.. We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S.. Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4.. We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.

Topics: 2-Naphthylamine; Acquired Immunodeficiency Syndrome; Adult; Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Female; Hepatitis C, Chronic; Humans; Kinetics; Lactams, Macrocyclic; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; United States; Uracil; Valine; Viral Load

The aim of this work was assessment of the efficacy and tolerability of two different regimens for retreatment of hepatitis C virus (HCV) patients who failed to respond to SOF/DCV-based therapy. This prospective study included 104 HCV patients who failed to respond to SOF/DCV-based therapy. Patients were randomly allocated to two groups. Efficacy and tolerability were assessed. The 12-week sustained virological response (SVR12) rates were 96% and 94.4% in groups B and A, respectively, with no significant difference (p = 1.000). Most adverse events reported were mild to moderate, with no deaths during the study. Multi-target direct-acting antiviral (DAA) combinations are efficient for retreatment of HCV patients after failure of SOF/DCV-based therapy in real-world management.ClinicalTrials.gov identifier: NCT02992457.

Topics: Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Ribavirin; Ritonavir; Simeprevir; Sofosbuvir; Sulfonamides; Treatment Outcome; Valine

Hepatitis C virus (HCV) direct-acting antivirals are highly effective. Less is known about changes in markers of immune activation in persons with human immunodeficiency virus (HIV) in whom a sustained virologic response (SVR) is achieved.. We conducted a nonrandomized clinical trial of 12 or 24 weeks of paritaprevir-ritonavir-ombitasvir plus dasabuvir (PrOD) with or without ribavirin in persons with HCV-1/HIV coinfection suppressed with antiretroviral therapy. Plasma HCV, soluble CD14 (sCD14), interferon-inducible protein 10, soluble CD163 (sCD163), interleukin 6 (IL-6), interleukin 18, monocyte chemoattractant protein (MCP-1), autotaxin (ATX), and Mac2-binding protein (Mac2BP) were measured over 48 weeks.. Participants were treated with PrOD for 12 (n = 9) or 24 (n = 36) weeks; the SVR rate at 12 weeks was 93%. At baseline, cirrhosis was associated with higher ATX and MCP-1, female sex with higher ATX and IL-6, older age with higher Mac2BP, higher body mass index with higher ATX, and HIV-1 protease inhibitor use with higher sCD14 levels. In those with SVR, interferon-inducible protein 10, ATX, and Mac2BP levels declined by week 2, interleukin 18 levels declined by the end of treatment, sCD14 levels did not change, and sCD163, MCP-1, and IL-6 levels changed at a single time point.. During HIV/HCV coinfection, plasma immune activation marker heterogeneity is in part attributable to age, sex, cirrhosis, body mass index, and/or type of antiretroviral therapy. HCV treatment with paritaprevir-ritonavir-ombitasvir plus dasabuvir is highly effective and is associated with variable rate and magnitude of decline in markers of immune activation.. NCT02194998.

Topics: 2-Naphthylamine; Adult; Anilides; Anti-HIV Agents; Antiviral Agents; Biomarkers; Carbamates; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Immunologic Factors; Lactams, Macrocyclic; Liver Cirrhosis; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations.. Participants received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily plus dasabuvir 250 mg twice daily for 14 days (healthy subjects, n = 36) or 12 weeks (HCV patients, n = 754). Patients with compensated cirrhosis also received ribavirin 1000 or 1200 mg divided twice daily, per the local label. Intensive or sparse pharmacokinetic sampling was performed for assessments of plasma drug concentrations.. The exposures [maximum plasma concentration (C. Collectively, the results of these pharmacokinetic analyses support the use of the same dose of the 3D regimen for Asian and Western patients. CLINICALTRIALS.GOV: NCT02534870, NCT02517515, NCT02517528.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Asian People; Carbamates; China; Cyclopropanes; Female; Healthy Volunteers; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Republic of Korea; Ritonavir; Sulfonamides; Taiwan; Uracil; Valine

Despite high efficacy of current direct-acting antiviral agents (DAAs) in treating chronic hepatitis C virus (HCV) infection, a small portion of patients fail treatment. QUARTZ-I was a phase 2, open-label, multicenter, two-part study that assessed the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) with dasabuvir (DSV) with or without the addition of sofosbuvir (SOF) and/or ribavirin (RBV) in DAA treatment-experienced adults with chronic HCV GT1 infection.. Genotype 1 HCV-infected patients with or without compensated cirrhosis had prior treatment failure to any DAA (part 1) or ledipasvir/SOF (part 2). Patients received OBV/PTV/r + DSV ± SOF with or without RBV for 12 or 24 weeks. The primary endpoint of this study is the percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12).. In part 1 of the study, 95.5% (21/22) of patients achieved SVR12, and in part 2, the SVR12 rate was 85.7% (6/7). Most adverse events (AEs) were mild and moderate in severity. Two serious AEs occurred and were assessed as not being related to study drug, of which one resulted in study drug discontinuation. Two patients experienced grade 3 elevations of serum alanine aminotransferase, and no other grade ≥3 laboratory abnormalities were observed.. The multi-targeted regimen of OBV/PTV/r + DSV ± SOF with or without RBV was effective in the treatment of patients who failed previous DAA regimens including NS3/4A protease and NS5A and NS5B polymerase inhibitors. These results provide a promising outcome for patients that traditionally had limited treatment options.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Patients infected with hepatitis C virus (HCV) treated with interferon-free direct-acting antivirals may still require ribavirin. However, ribavirin is associated with adverse events that can limit its use. This open-label, multicentre, Phase 3 study evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) with low-dose ribavirin for 12 weeks in genotype 1a-infected patients without cirrhosis. The primary efficacy endpoint was sustained virologic response at post-treatment Week 12 (SVR12). The primary safety endpoint was haemoglobin <10 g/dL during treatment and decreased from baseline. Overall, 105 patients enrolled. The SVR12 rate was 89.5% (n/N = 94/105; 95% CI, 83.7-95.4). The study did not achieve noninferiority versus the historic SVR12 rate for OBV/PTV/r + DSV plus weight-based ribavirin. Five patients experienced virologic failure, four discontinued, and two had missing SVR12 data. Excluding nonvirologic failures, the SVR12 rate was 94.9% (n/N = 94/99). One patient met the primary safety endpoint. OBV/PTV/r + DSV plus low-dose ribavirin offers an alternative option for patients in whom full-dose ribavirin may compromise tolerability, although noninferiority to the weight-based ribavirin regimen was not met.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks.

Topics: Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Japan; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Polymorphism, Genetic; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Failure; Treatment Outcome; Valine

The once-daily, all oral, RBV-free, pangenotypic direct-acting anti-viral regimen consisting of co-formulated NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (G/P), demonstrated high rates of sustained virologic response (SVR) in phase 2 and 3 studies outside Japan.. CERTAIN-1 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in Japanese patients with chronic HCV GT1 infection. Patients without cirrhosis received 8 weeks of G/P or 12 weeks of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r, 25/150/100 mg); patients with cirrhosis received G/P for 12 weeks. The primary efficacy endpoint was non-inferiority of G/P compared to OBV/PTV/r by assessing SVR at post-treatment week 12 (SVR12) among non-cirrhotic patients without the NS5A Y93H polymorphism.. SVR12 was achieved by 128/129 (99.2%; one patient lost to follow-up) non-cirrhotic patients in the 8-week G/P Arm (including 23/23 patients with the NS5A Y93H polymorphism) and 52/52 (100%) patients in the 12-week OBV/PTV/r Arm. No patients from the G/P Arm prematurely discontinued the study drug or experienced a treatment-emergent serious adverse event (TESAE). Three patients from the OBV/PTV/r Arm experienced five TESAEs and one of these patients discontinued the study drug due to TESAEs. All 38 (100%) patients with compensated cirrhosis achieved SVR12; in this group, no TESAEs were reported and one patient discontinued treatment due to an AE.. CERTAIN-1 study results demonstrate high efficacy and favorable tolerability of G/P in GT1-infected Japanese patients including those with the NS5A Y93H polymorphism, with no virologic failures observed.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Aminoisobutyric Acids; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Pyrrolidines; Quinoxalines; Ritonavir; RNA, Viral; Sulfonamides; Sustained Virologic Response; Valine; Viral Nonstructural Proteins

The current standard of care for patients with chronic hepatitis C virus (HCV) infection is a combination of direct-acting antiviral agents (DAAs). However, rare clinical trials have been reported on the combination regimen of sofosbuvir (SOF) with ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) plus ribavirin (RBV) for treated patients with HCV genotype 4 (GT4) infection.. To clarify the retreatment efficacy and safety of the recent regimen, SOF with OBV/PTV/r + RBV, for chronic HCV GT4-experienced patients who failed treatment with DAA-based regimens.. A total of 113 treatment-experienced patients were allocated for the completion of their treatment period. The enrolled patients were treated orally with SOF plus a fixed dose combination of OBV/PTV/r + RBV, which was administered orally based on the patients' tolerability. The primary end point was a sustained virological response (HCV RNA < 15 IU/mL), observed 12 weeks after the end of the treatment (SVR12).. Among all patients, the treatment-experienced patients with SOF plus OBV/PTV/r + RBV had a higher SVR12 rate (97%; 109/113). Further, SVR12 was achieved by 98% (81/83) of non-cirrhotic patients and 93% (28/30) of cirrhotic patients. Additionally, the most common adverse events reported included fatigue, headache, insomnia, nausea, and dyspnea.. The recent multi-targeted regimen of SOF plus OBV/PTV/r + RBV was well tolerated and achieved excellent SVR rates among retreatment-experienced Egyptian patients with prior DAA treatments failure, thus providing an alternative regimen for the retreatment of difficult-to-cure HCV GT4 patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Retreatment; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Valine; Young Adult

Hepatitis C virus (HCV) genotype 4 (GT4) is genetically diverse with 17 confirmed and 4 provisional subtypes. In this report, HCV GT4-infected patient samples from Phase 2/3 clinical studies were analysed to characterize global demographics and genetic diversity of GT4 infection among patients treated with ombitasvir (OBV, NS5A inhibitor) plus paritaprevir/r (NS3/4A inhibitor codosed with ritonavir). Among 17 subtypes isolated from GT4-infected patients in the PEARL-I and AGATE-I studies, subtype prevalence by country of enrolment and country of origin suggested that subtypes 4a and 4d were likely circulating in Europe, while heterogeneous GT4 subtypes and a portion of GT4a detected in European and North American countries were likely due to immigration of HCV-infected patients from Africa. The distributions of birth cohort and race were also significantly different across GT4 subtypes 4a, 4d, and non-4a/4d. In addition, phylogenetic analyses of NS5A sequences revealed clustering within subtype 4a which segregated by the patient-reported country of origin and the presence of the L30R/S polymorphism. HCV NS5A sequences derived from GT4a-infected patients who originated from Europe and the United States clustered separately from sequences derived from patients who originated from Egypt, suggesting that genetically distinct strains of subtype 4a may be circulating globally. Finally, NS5A baseline polymorphisms were frequently detected at amino acid positions of interest for the inhibitor-class and OBV retained activity against 37 of 39 NS5A GT4 clinical isolates, with no impact on treatment outcome in the PEARL-I and AGATE-I studies.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cluster Analysis; Cyclopropanes; Demography; Europe; Female; Genetic Variation; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Molecular Epidemiology; North America; Phylogeny; Prevalence; Proline; Ritonavir; Sequence Analysis, DNA; Sulfonamides; Treatment Outcome; Valine; Viral Nonstructural Proteins

An estimated 336 per 100 000 people in Russia are infected with hepatitis C virus, including up to 75% with genotype (GT) 1b. In the TURQUOISE-II/-III trials, a 12-week regimen of the direct-acting antiviral agents ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) in GT1b-infected patients with compensated cirrhosis resulted in 12-week sustained virologic response (SVR) rates of 100%.. In TURQUOISE-IV, GT1b-infected patients (n=36) from Russia and Belarus with compensated cirrhosis, who were treatment naive or previously treated with pegylated interferon/ribavirin (RBV), received OBV/PTV/ritonavir+DSV+RBV for 12 weeks. The primary efficacy end point was SVR at 12 weeks. Safety assessments included adverse event (AE) monitoring and laboratory testing.. At baseline, patients had Child-Pugh scores of 5 (92%) or 6 (8%). Overall, 69% were treatment experienced (44% prior null responders, 32% relapsers, and 16% partial responders). All patients achieved SVR at 12 weeks (36/36; 100%). No patient experienced a serious AE or discontinued treatment prematurely. Treatment-emergent AEs possibly related to study drugs occurring in greater than or equal to 10% of patients were asthenia (19%), anemia (14%), cough (14%), and headache (11%); most events were mild in severity. Clinically significant laboratory abnormalities were infrequent.. In Russian and Belarusian patients with hepatitis C GT1b infection and compensated cirrhosis, 100% achieved SVR at 12 weeks after 12 weeks' treatment with OBV/PTV/ritonavir+DSV+RBV. The treatment was well tolerated.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Republic of Belarus; Ribavirin; Ritonavir; Russia; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine

In AGATE-II, treatment with ombitasvir coformulated with paritaprevir/ritonavir plus ribavirin (RBV) in Egyptians infected with hepatitis C virus genotype 4 resulted in high rates of sustained virologic response at post-treatment week 12. This subanalysis examined the effects of treatment in AGATE-II on liver biomarkers in patients with compensated cirrhosis. AGATE-II was a phase 3, open-label, partly randomized trial of ombitasvir/paritaprevir/ritonavir with weight-based RBV daily once in treatment-naive or treatment-experienced patients. Patients without cirrhosis received treatment for 12 weeks and patients with compensated cirrhosis were randomized 1:1 to the same regimen for either 12 or 24 weeks. Sixty patients with compensated cirrhosis were randomized to treatment for 12 weeks (n = 31) or 24 weeks (n = 29). In the 12-week arm, significant improvements were observed in biomarkers of liver injury (alanine aminotransferase: -53.7 U/L, P < 0.001; aspartate aminotransferase: -35.9 U/L, P < 0.001) and liver fibrosis (aspartate aminotransferase to platelet ratio index: -0.987, P < 0.001; fibrosis-4 index: -1.165, P < 0.001). Similar results were reported in the 24-week arm. Treatment with ombitasvir/paritaprevir/ritonavir plus RBV in hepatitis C virus genotype, 4-infected Egyptians with compensated cirrhosis resulted in improvements in certain biomarkers of liver synthetic function, injury, and fibrosis, independent of treatment duration.

Topics: Adult; Aged; Alanine Transaminase; Anilides; Antiviral Agents; Aspartate Aminotransferases; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Valine

New potent direct-acting antiviral (DAA) regimens against hepatitis C virus have been approved in recent years. However, information about the rate of adverse events (AEs) across different DAA regimens is limited. We aimed to evaluate differences in AEs and treatment efficacy in patients with chronic hepatitis C (CHC), genotype (GT) 1 or 3, randomized to two different treatment arms, correspondingly.. We randomly assigned 96 patients in a 1 : 1 ratio, to treatment for 12 weeks with either paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin (RBV) or ledipasvir/sofosbuvir (SOF)/RBV if infected with GT1 (72 patients) or to daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks, if infected with GT3 (24 patients). Data on AEs were collected throughout the entire study period.. A total of 70 (97%) patients with CHC with GT1 and 20 (83%) patients with GT3 achieved cure. The GT3 treatment arm was prematurely terminated, owing to change in national treatment guidelines. Thus, only AEs for GT1 patients are described. AEs occurred in 70 (97%) GT1 patients, and most common AEs were anemia (n=56/78%), fatigue (n=53/74%), and headache (n=33/46%). No difference was observed in relation to treatment group (P=1.0), anemia (P=1.0), or liver cirrhosis (P=0.53). In seven (11%) patients, AEs assessed by the investigator to be possibly related to the DAA regimen were still present 12 weeks after treatment.. We found no difference in AEs possibly related to the DAA regimen in patients with CHC, but surprisingly, AEs possibly related to the DAA regimen persisted in a significant number of patients after treatment. This finding can be of importance for clinicians in relation to patient information concerning AEs possibly related to DAA treatment.

Topics: 2-Naphthylamine; Adult; Anemia; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Fluorenes; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil; Valine; Viral Load

Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an openlabel multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection.. All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR12).. The study enrolled 222 patients, 214 achieved an SVR12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR12 was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event.. The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Brazil; Carbamates; Cyclopropanes; Drug Combinations; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine; Viral Load

Clinical studies have shown high rates of sustained virological response (hepatitis C virus [HCV] RNA <15 IU/mL) at post-treatment week 12 (SVR12) in patients with genotype 1b infection with and without cirrhosis who received coformulated ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin, for 12 weeks. In this study, we aimed to assess 8-week treatment with ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin in patients infected with HCV genotype 1b without cirrhosis.. We did a multicentre, open-label, single-arm, phase 3b study (GARNET) in 20 hospitals or clinics in Australia, Canada, France, Germany, Israel, Italy, Spain, and the UK, to assess the safety and efficacy of an 8-week treatment duration of once-daily oral ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, plus twice-daily oral dasabuvir 250 mg in previously untreated patients with chronic HCV genotype 1b infection without cirrhosis (as assessed by liver biopsy, transient elastography, or serum markers). Eligible patients were aged at least 18 years, with more than 1000 IU/mL HCV RNA, and a laboratory result at screening indicating infection with HCV genotype 1b subtype only. Patients were excluded if they had evidence of HCV genotype or subtype other than genotype 1b, if they tested positive for hepatitis B surface antigen or anti-HIV antibody at screening, or if they had previously been treated for HCV. The primary endpoint was the proportion of patients with SVR12; the primary endpoint and safety were assessed in all patients who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, number NCT02582632.. Patients were screened between Nov 24, 2015, and March 1, 2016, and 166 patients were enrolled. 163 (98%) of 166 enrolled patients had HCV genotype 1b infection, and three (2%) of 166 had other genotypes or subtypes (genotype 1a, genotype 1d, and genotype 6). All enrolled patients received at least one dose of study drugs. 162 (98% [95% CI 95·3-99·9]) of 166 patients achieved SVR12. One patient discontinued treatment on day 45 due to adverse events. Most adverse events were mild in severity, and the most common adverse events were headache (35 [21%] of 166) and fatigue (28 [17%] of 166). Two (1%) of 166 patients had serious adverse events; neither were considered related to study drug treatment.. Treatment with ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin, for 8 weeks was efficacious and well tolerated. 8-week treatment options for previously untreated patients with HCV genotype 1b infection without cirrhosis are limited; shortening the treatment duration might reduce the burden associated with medical visits and procedures, thereby improving access to care and enabling the treatment of more patients.. AbbVie.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Polymorphism, Genetic; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Failure; Uracil; Valine

Hepatitis C virus (HCV) infection is of considerable clinical concern in Japan. We modeled the population pharmacokinetics of an oral interferon-free, direct-acting antiviral agent (DAA) regimen (i.e., the 2D regimen) recently approved for the treatment of chronic HCV genotype 1 infection as a new option for affected Japanese patients.. Using data from a phase III clinical trial (GIFT-I) that enrolled Japanese patients with HCV genotype 1b infection, population pharmacokinetic models were developed for the drugs that comprise the 2D regimen: paritaprevir, ombitasvir, and ritonavir. Demographic and clinical covariates with potential to influence 2D pharmacokinetics were evaluated for their effects on drug exposures. Proposed models were assessed using goodness-of-fit plots, visual predictive checks, and bootstrap evaluations.. One-compartment models with first-order absorption and elimination adequately described the population pharmacokinetics of paritaprevir, ombitasvir, and ritonavir. On average, patients with cirrhosis had approximately 95-145 % higher, 19-24 % lower, and 58-68 % higher exposures of paritaprevir, ombitasvir, and ritonavir, respectively. Female patients had 58-81 % higher ombitasvir exposures, whereas patients with mild renal impairment (creatinine clearance 75 mL/min) had 9-14 % higher ombitasvir exposures than did patients with normal renal function (creatinine clearance 105 mL/min). The DAA exposure values were comparable between responders and non-responders.. Population pharmacokinetic modeling did not reveal any patient-related or clinical parameters that would require dose adjustment of the 2D regimen when used for the treatment of HCV genotype 1b infection in Japanese patients.

Topics: Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; Fibrosis; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Japan; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Proline; Renal Insufficiency; Ritonavir; Sex Factors; Sulfonamides; Valine; Young Adult

The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles.. The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens.. Overall, 24 subjects, six in each of four renal function groups (normal, mild, moderate, and severe), received a single dose of the 3D and 2D regimens in separate dosing periods. Plasma and urine were analyzed to assess the effect of renal impairment on drug exposure.. DAA exposures changed by up to 21, 37, and 50 % in subjects with mild, moderate, and severe renal impairment, respectively, versus subjects with normal renal function. Ritonavir exposure increased with the degree of renal impairment (maximum 114 %). The half-lives of DAAs and ritonavir in subjects with renal impairment were generally comparable with those in healthy subjects. No safety or tolerability concerns arose in this study.. The 3D and 2D regimens do not require dose adjustment for patients with HCV infection and concomitant renal impairment.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney Diseases; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

Hepatitis C virus (HCV) genotype 4 infection is most commonly reported in sub-Saharan Africa and the Middle East; however, prevalence is increasing worldwide through immigration. HCV genotype 4 accounts for 20% of all infections, but clinical trial data for treatment remain limited. We assessed the combination of two direct-acting antivirals, ombitasvir (NS5A inhibitor) and paritaprevir (NS3/4A protease inhibitor; co-dosed with ritonavir) plus ribavirin in patients with HCV genotype 4 infection and compensated cirrhosis.. In this multicentre, randomised, open-label phase 3 trial (AGATE-I), treatment-naive and interferon or pegylated interferon and ribavirin treatment-experienced patients with HCV genotype 4 infection and compensated cirrhosis were recruited from academic, public, and private hospitals in Austria, Belgium, Canada, France, Germany, Greece, Italy, and the USA. Key eligibility criteria were age 18 years or older, with chronic HCV infection assessed by the presence of anti-HCV antibodies or HCV RNA. Patients were randomly assigned (1:1) to receive 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir once daily, with weight-based ribavirin dosed twice daily for either 12 weeks or 16 weeks. Randomisation was stratified by HCV treatment history (treatment-experienced vs treatment-naive patients) and further stratified by type of non-response to previous HCV treatment (null responders, partial responders, or relapsers) for treatment-experienced patients. Treatments were assigned by an interactive response technology system with computer-generated randomisation lists prepared by personnel from the study's funding sponsor who were not involved with the conduct of the study or with data analysis. The primary outcome was the proportion of patients with a sustained virological response (HCV RNA <25 IU/mL) at post-treatment week 12 (SVR12) in the intention-to-treat population, with the lower 97·5% CI compared with a clinically relevant threshold (67%; based on SVR reported for pegylated interferon and ribavirin) to achieve superiority. The safety population included all patients who received at least one dose of study drug, and safety analyses were done by the treatment duration received (12 weeks or 16 weeks). Data presented are from the planned primary interim analysis of part one of the study when all patients enrolled in part one had reached post-treatment week 12 or prematurely discontinued from the study. This trial is registered with ClinicalTrials.gov, number NCT02265237, and part two of the trial is ongoing but closed to new participants.. Between Nov 18, 2014, and May 19, 2015, we enrolled 120 eligible patients, with 59 patients assigned to receive 12 weeks of treatment and 61 patients assigned to receive 16 weeks of treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. One patient in the 12-week group experienced virological breakthrough and one discontinued prematurely after the first day of treatment. One patient missed the post-treatment week 12 visit in the 16-week group. SVR12 was achieved in 57 (97%; 97·5% CI 86·7-99·2) of 59 patients in the 12-week group and 60 (98%; 89·6-99·8) of 61 in the 16-week group. Adverse events in more than 10% of all patients were asthenia (11 [18%] of 60 in the 12-week group; 19 [32%] of 60 in the 16-week group), fatigue (ten [17%] in the 12-week group; 20 [33%] in the 16-week group), headache (14 [23%] in the 12-week group; 14 [23%] in the 16-week group), anaemia (nine [15%] in the 12-week group; 12 [20%] in the 16-week group), pruritus (five [8%] in the 12-week group; 14 [23%] in the 16-week group), nausea (six [10%] in the 12-week group; eight [13%] in the 16-week group), and dizziness (four [7%] in the 12-week group; nine [15%] in the 16-week group).. With SVR12 achieved in a high proportion of patients, no post-treatment relapses, and a similar adverse event profile for the 12-week and 16-week treatment groups, extending treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin beyond 12 weeks seems to have no additional benefit for patients with HCV genotype 4 infection and compensated cirrhosis and might not be necessary for this patient group.. AbbVie.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Valine; Young Adult

In Egypt, chronic hepatitis C virus (HCV) infection occurs in around 10% of the population (about 8 million individuals), and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and mortality. Although HCV genotype 4 constitutes about 20% of HCV infections worldwide, the prevalence in Egypt is more than 90%. We assessed the efficacy and safety of the two direct-acting antiviral drugs ombitasvir, an NS5A inhibitor, and paritaprevir, an NS3/4A protease inhibitor dosed with ritonavir, plus ribavirin in treatment of chronic HCV infection in Egypt.. AGATE-II was a phase 3, open-label, partly randomised trial in patients with chronic HCV genotype 4 infection recruited from five academic and hepatology centres in Egypt. Patients were HCV treatment-naive or treatment-experienced with interferon-based regimens. Eligible patients were aged 18 years or older, and had been chronically infected with HCV genotype 4 for at least 6 months with a plasma HCV RNA concentration of more than 1000 IU/mL at screening. Patients without cirrhosis were assigned to receive 12 weeks of 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir orally once daily plus weight-based ribavirin. Patients with compensated cirrhosis were randomly assigned (1:1) to receive the same treatment for either 12 weeks or 24 weeks. Randomisation was stratified by previous pegylated interferon and ribavirin treatment experience using a web-based interactive response technology system and computer-generated schedules prepared by personnel from the funder's statistics department. Investigators were masked to randomisation schedules and were informed of each patient's assigned treatment by the interactive response technology system immediately after allocation. The primary endpoint was the proportion of patients with a sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the last dose of study drug (SVR12). All patients who received at least one dose of study drugs were included in the primary and safety analysis. This study is registered with ClinicalTrials.gov, number NCT02247401.. Between Nov 4, 2014, and March 16, 2015, we screened 182 patients with HCV infection, of whom 160 were eligible for inclusion; 100 patients were assessed as not having cirrhosis and were given 12 weeks of treatment, and 60 patients assessed as having cirrhosis were randomly assigned to the 12-week treatment group (n=31) or the 24-week treatment group (n=29). 94 (94%; 95% CI 88-97) of 100 patients in the without cirrhosis group, 30 (97%; 84-99) of 31 patients in the cirrhosis 12-week treatment group, and 27 (93%; 78-98) of 29 patients in the cirrhosis 24-week treatment group achieved SVR12. The most common adverse events in patients without cirrhosis were headache (41 [41%]) and fatigue (35 [35%]). Fatigue occurred in nine (29%) patients in the cirrhosis 12-week treatment group and 11 (38%) patients in the cirrhosis 24-week treatment group, and headache occurred in nine (29%) patients in the cirrhosis 12-week treatment group and in 10 (35%) patients in the cirrhosis 24-week treatment group. Adverse events were predominantly mild or moderate in severity, and laboratory abnormalities were not clinically meaningful. No patients discontinued treatment because of an adverse event. One serious adverse event in the group without cirrhosis was attributed to study drugs by the investigators; the patient had deep venous thrombosis.. Ombitasvir, paritaprevir, and ritonavir plus ribavirin for 12 weeks achieved SVR12 in a high proportion of patients and was well tolerated in Egyptian patients with HCV genotype 4 infection with or without compensated cirrhosis. Extension of treatment to 24 weeks in patients with cirrhosis did not improve the proportion of patients achieving SVR12. A shorter duration regimen could be useful to address the significant burden of HCV genotype 4 infection in patients with compensated cirrhosis.. AbbVie.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Egypt; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Valine; Young Adult

Telaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV.. Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.. Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0-4% and 34-47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV.. Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66-82% with 24-48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; Sulfonamides; Uracil; Valine

Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR-122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct-acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1-infected treatment-naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment-naïve genotype (GT)1-3-infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR-122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR-122 showed an average four-fold reduction between baseline and week 2, and remained below baseline through post-treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR-122 levels began to return to baseline levels after the second week of treatment. The change in miR-122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1-3 subjects treated with IFN-free combinations of DAAs. The results suggest that serum levels of miR-122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Biomarkers; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; MicroRNAs; Proline; Sulfonamides; Uracil; Valine; Virus Replication

Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12weeks in patients with HCV genotype 1b infection and compensated cirrhosis.. Treatment-naïve and peginterferon/ribavirin treatment-experienced patients received 12weeks of ombitasvir/paritaprevir/ritonavir (25/150/100mg once daily) and dasabuvir (250mgtwicedaily). Key inclusion criteria were hemoglobin ⩾10g/dl, albumin ⩾2.8g/dl, platelet count ⩾25×10(9)/L, creatinine clearance ⩾30ml/min, and Child-Pugh score ⩽6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA <25IU/ml) 12weeks post-treatment (SVR12). Efficacy and safety were assessed in all patients receiving study drug.. Sixty patients with HCV genotype 1b infection and cirrhosis received treatment. The study population comprised 62% male, 55% treatment-experienced, 83% with IL28B non-CC genotype, 22% with platelet count <90×10(9)/L, and 17% with albumin <3.5g/dl. All 60 patients completed treatment, and SVR12 was achieved in 100% (95% CI, 94.0-100%) of patients. The most common adverse events were fatigue (22%), diarrhea (20%), and headache (18%). Only one patient (1.7%) experienced a serious adverse event. Laboratory abnormalities were infrequently observed and not clinically significant.. The HCV regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12weeks achieved 100% SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that this 12-week ribavirin-free regimen is sufficient in this population.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Combinations; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.).

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Ritonavir; Sofosbuvir; Sulfonamides; Uracil; Valine

Guidelines for the treatment of human immunodeficiency virus (HIV) infection consistently recommend initiation of antiretroviral therapy in patients with hepatitis C virus (HCV)/HIV-1 coinfection. Therefore, potential drug interactions between antiretroviral drugs and HCV direct-acting antiviral agents (DAAs) must be carefully considered. The objective of this investigation was to evaluate the compatibility of a novel combination of DAAs (the 3D regimen) with commonly prescribed HIV-1 protease inhibitors (PIs).. Five phase 1, multiple-dose, open-label pharmacokinetic studies were performed in 144 healthy volunteers. Participants in each study were randomly assigned 1:1 into cohorts assessing the effects of the steady-state 3D regimen on steady-state HIV-1 PIs or vice versa. The 3D regimen comprised ombitasvir (25 mg once daily), paritaprevir/ritonavir (150/100 mg once daily), and dasabuvir (250 or 400 mg twice daily). The HIV-1 PIs assessed included atazanavir, darunavir, and lopinavir (administered with ritonavir). Safety, tolerability, and pharmacokinetic parameters were assessed to evaluate the compatibility of the drug regimens.. Coadministration of the 3D regimen with the evaluated HIV-1 PIs was generally well tolerated in healthy volunteers. Morning administration of atazanavir (300 mg once daily) and darunavir regimens exhibited no clinically meaningful drug interactions with the 3D regimen. However, owing to higher paritaprevir and/or ritonavir exposures, evening administration of atazanavir (300 mg) plus ritonavir (100 mg) or lopinavir/ritonavir (800/200 mg) with the 3D regimen is not recommended.. The 3D regimen can be coadministered with morning atazanavir and darunavir regimens. However, evening atazanavir plus ritonavir and lopinavir/ritonavir regimens are not recommended in combination with the 3D regimen.

Topics: 2-Naphthylamine; Adolescent; Adult; Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Uracil; Valine; Young Adult

The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments.. Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC).. Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP.. Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose adjustment is necessary for the 3D regimen.

Topics: 2-Naphthylamine; Adolescent; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Healthy Volunteers; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Pharmacokinetics; Proline; Ritonavir; Sulfonamides; Uracil; Valine; Young Adult

The all-oral 2 direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once a day has been evaluated in hepatitis C virus subgenotype 1b-infected Japanese adults in the GIFT-I study. The aim of this analysis was to evaluate potential relationships between DAA exposures and laboratory abnormalities/adverse events of peripheral edema in patients in GIFT-I.. The GIFT-I study consisted of a randomized, double-blind, placebo-controlled substudy in patients without cirrhosis and an open-label substudy in patients with compensated cirrhosis. Patients received ombitasvir/paritaprevir/ritonavir for 12 weeks. Exposure-response relationships between individual components of the ombitasvir/paritaprevir/ritonavir regimen and clinical parameters of interest were explored using pharmacokinetic and clinical data from patients in the study. Graphical analyses were performed. For events that occurred in at least 10 patients (total bilirubin elevation ≥grade 2 and peripheral edema ≥grade 1), multivariate logistic regression analyses were used to identify significant relationships between predictor variables (drug exposures) and response variables (probability of adverse events or laboratory abnormalities), with consideration for the effect of potential covariates and baseline status of response variables.. Data from 321 noncirrhotic and 42 compensated cirrhotic patients were analyzed. There were 14 events of peripheral edema (10 at grade 1 and 4 at grade 2) in patients who received concomitant administration of calcium channel blockers and ombitasvir/paritaprevir/ritonavir. There was no apparent relationship between the incidences of peripheral edema and exposures of paritaprevir, ombitasvir, or ritonavir. There was a shallow relationship between total bilirubin elevation and exposures of paritaprevir which is an inhibitor of bilirubin transporter organic anion-transporting polypeptide 1B. Based on graphical analyses, exposures of paritaprevir, ombitasvir, or ritonavir were weakly associated with hemoglobin decrease, but not associated with post baseline alanine aminotransferase or aspartate aminotransferase elevations.. In Japanese patients, there were no associations or only shallow relationships between DAA exposures and peripheral edema or laboratory abnormalities. Consequently, therapeutic drug monitoring is not expected to be beneficial in managing patients on the 2-DAA regimen.. ClinicalTrials.gov identifier, NCT02023099.. AbbVie Inc.

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Genes, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Japan; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Treatment Outcome; Valine

The three-direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir (coadministered with ritonavir [paritaprevir/ritonavir], and dasabuvir (the 3D regimen) ± ribavirin for treatment of HCV genotype 1-infected patients demonstrated efficacy and safety in Phase II and Phase III clinical trials. The relationships between the steady-state exposure (area under the concentration-time curve at steady state and trough concentration at steady state) of the three DAAs and ribavirin with sustained virologic response at 12 weeks after treatment (SVR12) following administration of the 3D regimen in six Phase II/III studies were examined.. HCV non-cirrhotic genotype 1-infected adult male and female patients (N = 1690) enrolled in the one Phase II study or one of the five Phase III studies were included for graphical analysis. HCV subgenotype 1a-infected patients who received the 3D regimen with ribavirin (approved regimen for that patient population) (N = 615) from the same studies were included in the multivariate logistic regression exposure-response analysis.. Graphical analysis suggested a shallow trend between exposure and % SVR12 for paritaprevir, ombitasvir, and ribavirin exposure but not for dasabuvir exposure. After adjusting for covariate effects, the exposure-response logistic-regression analysis indicated that ombitasvir exposure was the single significant predictor, demonstrating a 1 % change in SVR12 with up to 25 % change in ombitasvir exposure at steady state.. The results of these analyses indicate that the doses selected for the 3D regimen were optimal, achieving high SVR12 rates across the range of exposures observed in the Phase III studies.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Double-Blind Method; Drug Combinations; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine; Young Adult

The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.

Topics: 2-Naphthylamine; Adult; Anilides; Anti-HIV Agents; Anti-Retroviral Agents; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Drug Interactions; Female; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lactams, Macrocyclic; Lamivudine; Macrocyclic Compounds; Male; Middle Aged; Oxazines; Piperazines; Proline; Pyridones; Ritonavir; Sulfonamides; Uracil; Valine

Virologic and safety outcomes of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) therapy have shown high sustained virologic response (SVR) rates and good tolerability in most patient populations in pre-registration studies.. To confirm these clinical trial findings in the treatment of genotype 1 and 4 hepatitis C under real-world conditions.. Patients enrolled for treatment with OBV/PTV/r ± DSV ± RBV based on therapeutic guidelines were included, and the regimen was administered according to product characteristics. Clinical and laboratory data, including virologic response, were collected at baseline, end of treatment (EOT) and 12 weeks after EOT.. A total of 209 patients with chronic hepatitis C were enrolled, most were genotype 1b-infected (84.2%) and 119 (56.9%) had liver cirrhosis. Among these, 150 (71.7%) had failed previous anti-viral therapies and 84 (40.2%) were null-responders. At 12 weeks after EOT, SVR was achieved by 207 (99.0%) patients, ranging from 96.4% to 100.0% across subgroups. All Child-Pugh B and post-orthotopic liver transplantation patients achieved SVR. Adverse events occurred in 151 (72.2%) patients and were mostly mild and associated with the use of RBV. Serious adverse events, including hepatic decompensation, renal insufficiency, anaemia, hepatotoxicity and diarrhoea, were reported in eight (3.8%) patients. In five (2.4%) patients, adverse events led to treatment discontinuation. On-treatment decompensation was experienced by seven (3.3%) patients.. The results of our study confirm previous findings. They demonstrate excellent effectiveness and a good safety profile of OBV/PTV/r± DSV±RBV in HCV genotype 1-infected patients treated in the real-world setting.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Diarrhea; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

To examine the safety and efficacy of ombitasvir and ABT-450 with ritonavir (ABT-450/r) ± ribavirin (RBV) in treatment-naïve, non-cirrhotic adults with chronic HCV genotype 1-3 infection.. Patients in this open-label, exploratory, phase 2, multicenter study received ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ± RBV for 12 weeks. Primary efficacy endpoint was HCV RNA < lower limit of quantitation (LLOQ) from week 4 through 12. Sustained virologic response 12 weeks post-treatment (SVR12) was a secondary endpoint.. Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Sulfonamides; Treatment Outcome; Valine; Viral Load

Approximately 2 million Japanese individuals are infected with hepatitis C virus and are at risk for cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Patients in whom interferon (IFN)/ribavirin (RBV) therapy has failed remain at risk as effective therapeutic options are limited. This phase 2, randomized, open-label study evaluated an IFN- and RBV-free regimen of once-daily ombitasvir (ABT-267), an NS5A inhibitor, plus paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (paritaprevir/ritonavir), in pegylated IFN/RBV treatment-experienced Japanese patients with hepatitis C virus subtype 1b or genotype 2 infection. Patients without cirrhosis (aged 18-75 years) with subtype 1b infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 or 24 weeks; patients with genotype 2 infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 weeks. Sustained virologic response (SVR) at posttreatment week 24 (SVR24 ) was the primary endpoint. Adverse events were collected throughout the study. One hundred ten patients received ≥1 dose of study medication. In the subtype 1b cohort, SVR24 rates were high (88.9%-100%) regardless of paritaprevir dose or treatment duration. In the genotype 2 cohort, SVR24 rates were 57.9% and 72.2% with 100 mg and 150 mg of paritaprevir, respectively. The SVR24 rate was higher in patients with subtype 2a (90%) than 2b (27%). Concordance between SVR12 and SVR24 was 100%. The most common adverse events overall were nasopharyngitis (29%) and headache (14%).. In this difficult-to-treat population of patients in whom prior pegylated IFN/RBV had failed, ombitasvir/paritaprevir/ritonavir demonstrated potent antiviral activity with a favorable safety profile among Japanese patients with hepatitis C virus genotype 1b or 2a infection.

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Interferons; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Valine; Young Adult

Paritaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients.. Mechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction.. Coadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a <2-fold change in mean Cmax and AUC for most medications and the DAAs, indicating minimal to modest interactions. Carbamazepine decreased PTV, ritonavir, and DSV exposures substantially, while gemfibrozil increased DSV exposures substantially. Although coadministration with ethinyl estradiol-containing contraceptives resulted in elevated alanine aminotransferase levels, coadministration with a progestin-only contraceptive did not.. The majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated.

Topics: 2-Naphthylamine; Administration, Oral; Adolescent; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C Antibodies; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Uracil; Valine; Young Adult

Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin.. In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203.. Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia.. An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection.. AbbVie.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Anilides; Antiviral Agents; Aspartate Aminotransferases; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Valine; Young Adult

Hepatitis C virus (HCV)-infected patients with a history of injection drug use have low rates of initiation and completion of interferon-based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy.. This was a phase II, multicenter, open-label, single-arm study in treatment-naïve or peginterferon/ribavirin treatment-experienced HCV genotype 1-infected patients on methadone or buprenorphine±naloxone. Patients received 12weeks of co-formulated ombitasvir/paritaprevir/ritonavir (25mg/150mg/100mg once daily) and dasabuvir (250mg twice daily)+weight-based ribavirin. The primary efficacy endpoint was sustained virologic response 12 weeks post-treatment.. Thirty-eight non-cirrhotic patients on chronic methadone (n=19) or buprenorphine (n=19) were enrolled. A total of 37 patients (97.4%) had a sustained virologic response 12 weeks post-treatment. No patient had a viral breakthrough or relapse. One patient discontinued due to serious adverse events unrelated to study drug (cerebrovascular accident and sarcoma). The most frequent adverse events were nausea, fatigue, and headache. Eight patients had on-treatment hemoglobin concentrations <10g/dl. Pharmacokinetic analyses indicated no clinically meaningful impact of methadone or buprenorphine on ombitasvir, paritaprevir, ritonavir, dasabuvir, or dasabuvir M1 metabolite exposures. No dose adjustments of methadone or buprenorphine were required.. The interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin for 12weeks was well tolerated and achieved sustained virologic response in 97.4% of patients on opioid substitution therapy in this study. This all-oral regimen may provide an effective alternative to interferon-based therapies for HCV-infected patients with a history of injection drug use.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Analgesics, Opioid; Anilides; Antiviral Agents; Buprenorphine; Carbamates; Cyclopropanes; DNA, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Methadone; Middle Aged; Opioid-Related Disorders; Proline; Retrospective Studies; Ribavirin; Sulfonamides; Uracil; Valine; Young Adult

Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs.. HCV-negative subjects with normal hepatic function (n=7) or mild (Child-Pugh A, n=6), moderate (Child-Pugh B, n=6), or severe (Child-Pugh C, n=5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100 mg), ombitasvir (25 mg), and dasabuvir (400 mg). Plasma samples were collected through 144 hours after administration for pharmacokinetic assessments.. Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, C(max), and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line.. The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepatic Insufficiency; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Function Tests; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

GIFT-I is a phase 3 trial evaluating the efficacy and safety of a 12-week regimen of coformulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) for treatment of Japanese hepatitis C virus genotype 1b-infected patients. It consists of a double-blind, placebo-controlled substudy of patients without cirrhosis and an open-label substudy of patients with compensated cirrhosis. Patients without cirrhosis were randomized 2:1 to once-daily OBV/PTV/r (25 mg/150 mg/100 mg; group A) or placebo (group B). Patients with cirrhosis received open-label OBV/PTV/r (group C). The primary efficacy endpoint was the rate of sustained virological response 12 weeks posttreatment in interferon-eligible, treatment-naive patients without cirrhosis and hepatitis C virus RNA ≥100,000 IU/mL in group A. A total of 321 patients without cirrhosis were randomized and dosed with double-blind study drug (106 received double-blind placebo and later received open-label OBV/PTV/r), and 42 patients with cirrhosis were enrolled and dosed with open-label OBV/PTV/r. In the primary efficacy population, the rate of sustained virological response 12 weeks posttreatment was 94.6% (106/112, 95% confidence interval 90.5-98.8). Sustained virological response 12 weeks posttreatment rates were 94.9% (204/215) in group A, 98.1% (104/106) in group B (open-label), and 90.5% (38/42) in group C. Overall, virological failure occurred in 3.0% (11/363) of patients who received OBV/PTV/r. The rate of discontinuation due to adverse events was 0%-2.4% in the three patient groups receiving OBV/PTV/r. The most frequent adverse event in patients in any group was nasopharyngitis.. In this broad hepatitis C virus genotype 1b-infected Japanese patient population with or without cirrhosis, treatment with OBV/PTV/r for 12 weeks was highly effective and demonstrated a favorable safety profile.

Topics: Aged; Anilides; Antiviral Agents; Asian People; Carbamates; Cyclopropanes; Double-Blind Method; Drug Combinations; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Valine

Interferon-free treatment options are rapidly evolving for patients with chronic hepatitis C virus (HCV) genotype 1b (GT1b) infection with cirrhosis and for nonresponders to prior pegylated interferon and ribavirin therapy. We performed a phase 2b, open-label trial of the combination of ombitasvir (a NS5A replication complex inhibitor), paritaprevir, and ritonavir (an NS3/4A protease inhibitor)-an interferon- and ribavirin-free regimen-in difficult-to-treat patients, including prior null responders and patients with cirrhosis.. In an international study, 82 patients without cirrhosis (42 treatment-naive and 40 prior null responders) and 99 with cirrhosis (47 treatment-naive and 52 treatment-experienced with prior relapse or a null or partial response) with chronic HCV GT1b infection received ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis). The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12).. In treatment-naive and null responder patients without cirrhosis, rates of SVR12 were 95.2% and 90.0%, respectively. In treatment-naive and treatment-experienced patients with cirrhosis, rates of SVR12 were 97.9% and 96.2%, respectively. No clinically meaningful differences in rates of SVR12 were observed between patients with or without cirrhosis. Virologic relapse occurred in 3 null responders without cirrhosis and 1 with cirrhosis; virologic breakthrough occurred in 1 null responder without cirrhosis. Common adverse events included headache, asthenia, pruritus, and diarrhea. One patient discontinued taking the drugs because of treatment-related adverse events.. An interferon- and ribavirin-free regimen of ombitasvir, paritaprevir, and ritonavir, achieved high rates of SVR12 in patients with HCV GT1b infection with and without cirrhosis. This regimen was well tolerated and was associated with low rates of treatment discontinuation. ClinicalTrials.gov no: NCT01685203.

Topics: Administration, Oral; Aged; Anilides; Antiviral Agents; Carbamates; Carrier Proteins; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Enzyme Inhibitors; Europe; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Intracellular Signaling Peptides and Proteins; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Recurrence; Remission Induction; Ritonavir; Sulfonamides; Time Factors; Treatment Outcome; United States; Valine; Viral Nonstructural Proteins

Thrombocytopaenia and hypoalbuminaemia are surrogate markers for portal hypertension and hepatic synthetic dysfunction respectively. Patients infected with hepatitis C virus (HCV) with these surrogates have reduced likelihood of sustained virologic response and increased risk for hepatic decompensation or death when treated with peginterferon/ribavirin plus either telaprevir or boceprevir.. We conducted a post-hoc analysis of the TURQUOISE-II clinical trial in patients with cirrhosis to examine the impact of these surrogates on efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin.. Of 380 genotype 1-infected patients in TURQUOISE-II, 104 had either a platelet count <100 × 10(9)/L or albumin <3.5 g/dl. Sustained virologic response rates were 89 and 97% in patients with thrombocytopaenia, and 84 and 89% in patients with hypoalbuminaemia after 12 and 24 weeks of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin respectively. These rates were similar to those observed in the overall study population (92 and 97% for 12 and 24 weeks). HCV genotype 1a-infected patients with thrombocytopaenia or hypoalbuminaemia had higher response rates when treated for 24 weeks, whereas only 1 of 35 genotype 1b patients did not achieve a sustained virologic response. Adverse event rates and discontinuations because of adverse events were low.. The findings of these analyses support the use of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin in these subpopulations with cirrhosis. Genotype 1a-infected patients with indicators of portal hypertension may benefit from a 24-week treatment duration.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Hypertension, Portal; Hypoalbuminemia; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Sulfonamides; Thrombocytopenia; Treatment Outcome; Uracil; Valine; Young Adult

Hepatitis C virus (HCV) genotype 4 (GT4) is genetically diverse, with 17 confirmed subtypes, and comprises approximately 13% of infections worldwide. In this study, we identified GT4 subtypes by phylogenetic analysis, assessed differences in patient demographics across GT4 subtypes, examined baseline sequence variability among subtypes and the potential impact on treatment outcome, and analyzed the development of viral resistance in patients who received a regimen of ombitasvir (nonstructural protein 5A [NS5A] inhibitor) plus ritonavir-boosted paritaprevir (NS3/4A inhibitor) with or without ribavirin (RBV) for the treatment of HCV GT4 infection. Phylogenetic analysis of HCV NS3/4A, NS5A, and NS5B nucleotide sequences identified 7 subtypes (4a, 4b, 4c, 4d, 4f, 4g/4k, and 4o) among 132 patient samples. Subtype prevalence varied by country, and the distributions of patient birth cohort and race were significantly different across GT4 subtypes 4a, 4d, and non-4a/4d. Baseline amino acid variability was detected in NS5A across GT4 subtypes but had no impact on treatment outcome. Three patients experienced virologic failure and were infected with subtype 4d, and the predominant resistance-associated variants at the time of failure were D168V in NS3 and L28V in NS5A. Overall, high response rates were observed among patients infected with 7 HCV GT4 subtypes, with no impact of baseline variants on treatment outcome. GT4 subtype distribution in this study differed based on patient demographics and geography.

Topics: Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Phylogeny; Proline; Ritonavir; Sulfonamides; Treatment Outcome; Valine; Young Adult

An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.. In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.. Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.. In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.).

Topics: Administration, Oral; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Protease Inhibitors; Ribavirin; RNA, Viral; Sulfonamides; Valine; Viral Nonstructural Proteins; Young Adult

In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin.. We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin.. A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively.. Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415.).

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Double-Blind Method; Drug Combinations; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Retreatment; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Uracil; Valine; Viral Load; Young Adult

The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis.. In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B.. A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P<0.05 for all comparisons). Reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients in group A, whereas grade 1 reductions occurred in 2.5% of the patients in group B.. In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.).

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Double-Blind Method; Drug Combinations; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine; Viral Load; Young Adult

Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis.. We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [CI], 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%.. A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events.. In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.).

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Logistic Models; Macrocyclic Compounds; Male; Middle Aged; Proline; Recurrence; Ribavirin; Sulfonamides; Valine

The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis.. We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment.. The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea.. Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hemoglobins; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Recurrence; Ribavirin; RNA, Viral; Sulfonamides; Valine

Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection.. We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment.. Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study.. Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Calcineurin Inhibitors; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Uracil; Valine; Viral Nonstructural Proteins; Young Adult

Hepatitis C is one of the leading causes of death in patients with inherited bleeding disorders. Currently, direct-acting antiviral drugs used for the treatment of hepatitis C have become an effective and a reliable option for people with inherited bleeding disorders. The aim of this study is to report the efficacy and safety of ombitasvir + paritaprevir/ritonavir and dasabuvir combination in the treatment of hepatitis C in patients with inherited bleeding disorders.. In this retrospective study, we evaluated the efficacy and safety of the combination of ombitasvir + paritaprevir/ritonavir and dasabuvir in 10 adult patients with hemophilia A, 4 patients with hemophilia B, and 1 patient with von Willebrand disease who were infected with hepatitis C genotype 1.. Five patients had genotype 1a and 10 patients had genotype 1b chronic hepatitis C. One patient had Child A cirrhosis, 14 patients had chronic hepatitis C without cirrhosis. Hepatitis C virus ribonucleic acid was negative in all patients at week 4 and at the end of the treatment. Sustained virologic response was obtained in all patients. Serious side effects were detected in 3 patients, which were intra- muscular bleeding, erosive gastritis-related gastrointestinal bleeding, and pneumonia.. Ombitasvir + paritaprevir combined with ritonavir and dasabuvir ± ribavirin is an effective treatment for patients infected with genotype 1 hepatitis C who have coagulation disorders. Tolerance and side effects are similar to other treatment options.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Child; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Proline; Retrospective Studies; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

BACKGROUND In the European Union, a tablet with fixed doses of ombitasvir, paritaprevir, and ritonavir combined with dasabuvir is an authorized treatment for patients with chronic hepatitis C virus (HCV) infection. Ribavirin is a broad-spectrum antiviral used in several treatment regimens for patients with HCV infection. This real-world study aimed to compare the safety and efficacy of ombitasvir, paritaprevir, and ritonavir combined with dasabuvir, with or without ribavirin, in 587 patients with chronic hepatitis C attending the Fundeni Clinical Institute, Bucharest, Romania. MATERIAL AND METHODS This is an observational prospective study including 315 patients with F4 degree of fibrosis and compensated cirrhosis, 185 patients with F3 fibrosis, and 83 patients with F2 fibrosis. Liver fibrosis was evaluated by liver biopsy or Fibromax. Efficacy was defined as undetectable HCV-RNA at 12 weeks after the end of treatment. In terms of safety, we monitored the development of adverse reactions, liver cytolysis, cholestasis, and hematologic disorders. RESULTS Of the 587 patients, 2 patients with B-cell lymphoma died during therapy. In total, 3/585 patients (0.51%) did not achieve sustained virologic response. Common adverse effects were nausea and asthenia (especially in patients with other medical treatments; P=0.03 and P=0.04, respectively) and anemia in patients who received ribavirin (P<0.01). None of the patients discontinued antiviral treatment. Patients with kidney transplant or end-stage kidney disease did not receive or discontinued ribavirin. CONCLUSIONS Ombitasvir, paritaprevir, and ritonavir combined with dasabuvir, with or without ribavirin had an efficacy rate of over 99% in HCV genotype 1b infection. We report no serious adverse reactions.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Proline; Prospective Studies; Ribavirin; Ritonavir; Romania; Sulfonamides; Uracil; Valine

Treatment of hepatitis C virus (HCV) genotype 4 patient with fixed dose combination of ombitasvir-paritaprevir-ritonavir plus ribavirin (OBV/rPTV/RBV) has been proven efficacy and safety in many clinical trials. The current study reports the efficacy and safety of OBV/rPTV/RBV (for treatment-naïve), and OBV/rPTV/RBV/sofosbuvir (SOF) (for treatment-experienced), in chronic HCV genotype 4 patients in real life settings.. Prospective cohort study including all adult chronic HCV genotype 4 patients who were scheduled to receive OBV/rPTV/RBV ± SOF for 12 or 24 weeks in New Cairo Viral Hepatitis Treatment Center. The primary efficacy endpoint was a virologic response at posttreatment week 12 (SVR12). Changes in hematological parameters, liver biochemical profile and fibrosis-4 index (FIB-4), as well as clinical and laboratory adverse events (AEs) across follow up visits (week 4, end of treatment [EOT], and SVR12), were recorded.. Our study included 325 patients (age; 47.63 ± 12.63 years, 55.38% [n = 180] men). Most of the included patients (89.85%, n = 292) were treatment naïve and only 7% (n = 23) had liver cirrhosis. Overall, SVR12 was attained by 98.44% (316 of 321) of the patients; 97.15% (307 of 316) of patients who received 12 weeks of OBV/rPTV/RBV ± SOF and 100% (9 of 9) of patients who received 24 weeks of OBV/rPTV/RBV as assessed by modified intention to treat analysis. There was a significant improvement of baseline alanine aminotransferase, aspartate aminotransferase, hemoglobin, FIB-4 at SVR12 (P < 0.05). The most common reported AEs were anemia (n = 106), fatigue (n = 41) and elevated indirect bilirubin (n = 37).. OBV/rPTV/RBV (±SOF) is a highly effective therapy for chronic HCV patients in real life settings.

Topics: Adult; Anemia; Anilides; Antiviral Agents; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Male; Middle Aged; Proline; Prospective Studies; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Valine

To investigate the effectiveness, safety, and reasons for premature discontinuation of direct-acting antivirals (DAAs) in a diverse population of HIV/hepatitis C virus (HCV) coinfected individuals in Europe.. All HIV/HCV coinfected individuals in the EuroSIDA study that started interferon free DAA treatment between January 6, 2014, and January 3, 2018, with ≥12 weeks of follow-up after treatment stop were included in this analysis. Sustained virological response (SVR) was defined as a negative HCV-RNA result ≥12 weeks after stopping treatment (SVR12). Logistic regression was used to explore factors associated with SVR12.. 1042 individuals started interferon-free DAA treatment after 1/6/2014 and were included, 862 (82.2%) had a known response to treatment, and 789 [91.5%, 95% confidence interval (CI): 89.7 to 93.4] of which achieved SVR12. There were no differences in SVR12 across regions of Europe (P = 0.84). After adjustment, the odds of achieving SVR12 was lower in individuals that received sofosbuvir/simeprevir ± ribavirin (RBV) [adjusted odds ratio 0.21 (95% CI: 0.08 to 0.53)] or ombitasvir/paritaprevir/dasabuvir ± RBV [adjusted odds ratio 0.46 (95% CI: 0.22 to 1.00)] compared with sofosbuvir/ledipasvir ± RBV. Forty-three (4.6%) individuals had one or more components of their HCV regimen stopped early, most commonly because of toxicity (n = 14); of these 14, 11 were treated with ribavirin. Increased bilirubin was the most common grade 3 or 4 laboratory adverse event (n = 15.3%) and was related to treatment with atazanavir and ribavirin.. Our findings from real-world data on HIV/HCV coinfected individuals across Europe show DAA treatment is well tolerated and that high rates of SVR12 can be achieved in all regions of Europe.

Topics: Anilides; Antiviral Agents; Benzimidazoles; Coinfection; Cyclopropanes; Female; Fluorenes; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV Infections; Humans; Interferons; Lactams, Macrocyclic; Male; Middle Aged; Proline; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Valine

The use of direct-acting antiviral agents (DAAs) in patients with chronic HCV genotype (GT) 1 infection results in sustained virologic response (SVR) rates of 95%-97%, but 3%-5% of patients experience virologic failure. We observed 41 patients infected with HCV subtype 1b who failed previous treatment with DAAs, including 37 subjects (90.2%) with liver cirrhosis. In total, 30 (73.2%) subjects previously received NS5A inhibitors of the first generation (ledipasvir, daclatasvir, or ombitasvir) and 11 subjects (26.8%) received NS5A inhibitors of the second generation (velpatasvir). All patients received retreatment with a combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) with sofosbuvir (SOF) and ribavirin (RBV). We compared SVR12 rates depending on fibrosis stage, presence of just single or double NS5A mutation (L31M/V/I and/or Y93H), and the generation of previously used NS5A inhibitors. Observed SVR12 rates were as follows: 97.6% (40/41 patients) overall; 100% in patients without cirrhosis (n = 4) versus 97.3% in those with cirrhosis (n = 37); 100% with single L31M/V/I or Y93H mutation (n = 22) versus 94.4% with double mutations (n = 18); 100% in patients who failed previous treatment with first-generation (n = 30) versus 90.9% in those who failed previous treatment with second-generation NS5A inhibitors (n = 11). Retreatment with 3D + SOF + RBV was highly effective and safe in patients with chronic HCV GT1b infection, including those with liver cirrhosis, who failed previous treatment with DAA containing NS5A inhibitors. Fibrosis stage and single or simultaneous presence of NS5A RASs L31M/V/I and Y93H at the baseline, as well as the generation of previously used NS5A inhibitors, did not impact SVR12 rates.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Male; Middle Aged; Mutation; Proline; Retreatment; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Viral Nonstructural Proteins

The 12-week regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (OPrD) has shown high efficacy and tolerability in clinical trials for the treatment of chronic hepatitis C virus (HCV). The shorter 8-week regimen has been recently incorporated into clinical guidelines and on-label indications, but real-world evidence on its use is limited. Given this knowledge gap, the AMETHYST study aimed to evaluate the effectiveness of the 8- and 12-week regimens of OPrD in treatment-naive patients with HCV with mild to moderate liver fibrosis in Romanian clinical practice.. This was a secondary data collection study analyzing data from a 1-year Patient Support Program in HCV in Romania. Patients received OPrD treatment for 8 or 12 weeks. The effectiveness endpoint was sustained virologic response 12 weeks post-treatment (SVR12).. A total of 1,835 treatment-naive patients with HCV with mild or moderate fibrosis were included in the study. Of these, 426 and 1,375 completed the 8-week and 12-week regimens, respectively. SVR12 was 98.1% in the 8-week treatment group and 98.7% in the 12-week treatment group.. The study provides real-world evidence that 8-week and 12-week treatment regimens of OPrD are highly effective in treatment-naive patients with HCV with mild to moderate liver fibrosis.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Male; Middle Aged; Proline; Retrospective Studies; Ritonavir; Romania; Sulfonamides; Time Factors; Uracil; Valine

Hepatitis C virus genotype 4 (HCV-GT4) is a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. A combination of three new direct-acting antivirals ombitasvir, paritaprevir, and ritonavir has been recommended for treatment of HCV-GT4 infection. The current study was aimed to assess the efficacy and safety of this combination plus ribavirin in non-cirrhotic, treatment-naïve and -experienced Egyptians with HCV-GT4 infection in a real-world setting. A total of 255 Egyptians with HCV-GT4 infection were enrolled, including 82 treatment-experienced and 173 treatment-naïve patients. All of them completed 12-week treatment protocol of ombitasvir, paritaprevir and ritonavir as an oral dose combination with ribavirin. Virological response (VR) was measured, as well as the biochemical parameters related to treatment efficacy and adverse events at baseline and after treatment, at 4 (VR4) and 12 (VR12) weeks post-treatment. The results showed that the VR4 rates were 98.8% in both groups, and VR12 rates were 97.7% and 96.3% in treatment-naïve and -experienced patients, respectively, with no significant differences found between the groups concerning VR4 (P=0.9) and VR12 (P=0.3). The most common adverse events were headache and fatigue, which were significantly more common (P=0.001 and 0.003, respectively) in treatment-experienced than in treatment-naïve group. The quadruple regimen was well-tolerated, and the reported adverse events were generally mild to moderate. This real-world setting study confirms that the combination of ombitasvir, paritaprevir, ritonavir, and ribavirin is highly effective in the treatment of HCV- GT4 infection with a good safety and tolerability profile.

Topics: Adult; Anilides; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Male; Proline; Ribavirin; Ritonavir; Sulfonamides; Valine

Although direct-acting antivirals (DAAs) have significantly increased the sustained virological response (SVR) rates in chronic hepatitis C virus (HCV)-infected adult patients, the efficacy and safety for children remain unclear. We herein report three HCV-infected children who received DAA treatment. The patients were girls 10-13 years old who had been infected with genotype 1b HCV by vertical transmission based on a phylogenetic tree analysis. Two patients were treated with 12 weeks of ombitasvir/paritaprevir/ritonavir, and the other patient was treated with 8 weeks of glecaprevir/pibrentasvir. All children received DAA doses that were similar to the dosages for adult patients. None developed adverse events, and all children achieved an SVR.

Topics: Adolescent; Aminoisobutyric Acids; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Child; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Pyrrolidines; Quinoxalines; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Valine

This is a real-world evidence study that aims to analyze the efficacy, tolerability and safety profile of paritaprevir/ombitasvir/ritonavir and dasabuvir, in patients with renal impairment.. We conducted an observational prospective study, on 232 patients with chronic kidney disease, undergoing treatment with paritaprevir/ombitasvir/ritonavir and dasabuvir, for chronic hepatitis C infection - genotype 1b. Renal and liver function were assessed at the beginning of therapy, monthly during treatment and three months after therapy completion.. All patients achieved sustained virologic response. Common side effects were nausea, fatigue and headache. Close monitoring of tacrolimus blood levels and dose reduction was required in kidney transplant recipients.. HCV therapy in the setting of renal dysfunction has always been a challenging topic. Direct-acting antivirals have shown promising effects, demonstrating good tolerance and efficacy in patients with HCV infection and renal impairment. Sustained virologic response within our study population was 100%.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cryoglobulinemia; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Lupus Erythematosus, Systemic; Male; Middle Aged; Proline; Prospective Studies; Renal Insufficiency, Chronic; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Hepatitis C virus (HCV) infection is a common disease that causes liver cirrhosis, hepatocellular carcinoma, and extra hepatic manifestations with high mortality and morbidity rates. This study aimed to present real-life experiences and results of treatment of HCV infection with direct-acting antiviral agents (DAAs) from the Euro-Asian region, including Turkey and Azerbaijan.. A total of 1224 patients with chronic HCV infection were treated with DAAs in accordance with the international guidelines for the management of HCV infection. The mean age was 58.74±14.75 years, with 713 (58.25%) females. The genotypes of the patients were as follows: genotype 1b, 83.36% (n=1024); genotype 1a, 8.08% (n=99); genotype 2, 2.85% (n=35); genotype 3, 3.34% (n=41); genotype 4, 1.71% (n=21); and combined genotypes, 0.32% (n=4). Approximately 808 patients were treated with sofosbuvir-based DAAs with or without Ribavirin for 12 or 24 weeks, whereas 416 patients were treated with the Paritaprevir, Ombitasvir, Ritonavir.Dasabuvir (PROD) regimen with or without Ribavirin for 12 weeks or 24 weeks.. At the end of follow-up examinations, 1183 patients (97.93%) had sustained virological response (SVR), 17 (1.40%) died of reasons unrelated to the treatment regimen, 12 had recurrence after treatment, and 129 (10.67%) had adverse events like anemia, itching, and weakness.. In this large cohort of HCV-infected patients, treatment with DAAs yielded a high overall SVR rate of 97.93%. DAAs were safe and well-tolerated. Thus, the elimination of HCV infection is no longer a dream worldwide.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Azerbaijan; Cyclopropanes; Drug Therapy, Combination; Female; Genes, Viral; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Turkey; Uracil; Valine

mbitasvir/paritaprevir/ritonavir (OMV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) combination has demonstrated excellent rates of sustained virologic response (SVR) and a very good safety profile in patients with the chronic hepatitis C virus (HCV) genotype 1 or 4 infections. We aimed to investigate the effectiveness and safety of OMV/PTV/r ± DSV ± RBV combination regimen in a real-world clinical practice.. Data from HCV genotype 1 and 4 patients treated with OMV/PTV/r ± DSV ± RBV (n=862) in 34 centers across Turkey between April 1, 2017 and August 31, 2018 were recorded in a large national database. Demographic, clinical, and virologic data were analyzed.. The mean age of the patients was 55.63, and 430 patients (49.9%) were male. The majority had HCV genotype 1b infection (77.3%), and 66.2% were treatment-naïve. Non-cirrhosis was present at baseline in 789 patients (91.5%). SVR12 rate was 99.1% in all patients. Seven patients had virologic failure. No significant differences were observed in SVR12 according to HCV genotypes. HCV RNA was undetectable at treatment week 4 in 90.9%, at treatment week 8 in 98.5%, and at the end of treatment (EOT) in 98.9%. SVR12 ratio was significantly higher in the non-cirrhotic patients compared to that in the compensated cirrhotic patients. Rates of adverse events (AEs) in the patients was 59.7%.. The present real-life data of Turkey for the OBV/PTV/r ± DSV ± RBV treatment of patients with HCV genotype 1b, 1a, or 4 infection from 862 patients demonstrated high efficacy and a safety profile.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Cyclopropanes; Databases, Factual; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Turkey; Uracil; Valine; Young Adult

To assess the safety, efficacy, and pharmacokinetics of mini-tablet formulations of ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) with or without ribavirin for 12 weeks in children infected with chronic hepatitis C virus (HCV) genotype (GT) 1.. This is an ongoing, open-label, Phase 2/3 study in children 3-11 years old infected with HCV GT1 who were HCV treatment-naïve and non-cirrhotic. Pediatric mini-tablet formulations of OBV, PTV, ritonavir, and DSV plus ribavirin oral solution were administered for 12 weeks based on body weight. Endpoints included SVR12, adverse events (AEs), and pharmacokinetic parameters.. Overall, 26 children received OBV, PTV, ritonavir, and DSV plus ribavirin; 14 were 3-8 years old and 12 were 9-11 years old; 35% were male; and all had chronic HCV GT1a infection. The SVR12 rate was 96% (25/26; 95% CI 81.1-99.3), with 1 child failing to achieve SVR12 due to non-adherence and treatment discontinuation. Treatment-emergent AEs of Grade ≥ 3 occurred in 3 children; 2 events in 1 child were considered serious; and none were considered treatment-related. No AEs led to discontinuation of study treatment. The most common AEs were headache (27%), fatigue (23%), pyrexia (19%), and vomiting (19%). Pharmacokinetic results showed mini-tablet formulations of OBV, PTV, DSV, and ritonavir drug exposures were comparable to the adult formulation.. The mini-tablet combination of OBV, PTV, ritonavir, and DSV plus ribavirin to treat HCV GT1a infection for 12 weeks was highly effective and suitable in children 3-11 years of age.. ClinicalTrials.gov identifier, NCT02486406.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Child; Child, Preschool; Cyclopropanes; Cytochrome P-450 CYP3A Inhibitors; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Male; Proline; Ribavirin; Ritonavir; Sulfonamides; Tablets; Uracil; Valine

In previous studies that investigated the impact of direct-acting antiviral (DAA) treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients have been compared to baseline values with either end of treatment or post-treatment values. The results are inconsistent. We evaluated patients throughout the treatment and after treatment.. 121 patients were included in the study. 93 patients were treated with sofosbuvir/ledipasvir±Ribavirin (RBV), and 28 patients were treated with ombitasvir/paritaprevir/ritonavir+dasabuvir±RBV. Total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG) and homeostatic model assessment-insulin resistance (HOMA-IR) levels were measured at the onset of treatment, after the1st month of treatment, at the end of treatment, and 6 and 12 months after the end of treatment.. 117 patients were genotype 1. Sustained virological response was 98.4%. HOMA-IR values during treatment were significantly higher than at the beginning of treatment (p=0.0001). At 12 months there was a decrease in HOMA-IR, but this was not statistically significant (p=0.2048). TC and LDL levels were significantly increased in the first month of treatment (TC; 159±30, 180±34 mg/dl; LDL; 84±28, 100±30 mg/dl, respectively) (p<0.0001) and this increase was present during and after treatment. There was no statistically significant increase in TG (p=0120). Both treatment regimens showed similar effects on HOMA-IR, TC, and LDL.. Patients with HCV treated with DAAs drugs showed increased IR, TC, and LDL cholesterol levels during treatment. After the end of treatment, IR goes back to normal, while the elevated TC and LDL levels persist indefinitely.

Topics: Aged; Anilides; Antiviral Agents; Benzimidazoles; Blood Glucose; Cholesterol; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Insulin Resistance; Lactams, Macrocyclic; Lipid Metabolism; Lipoproteins, LDL; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Triglycerides; Valine

.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A Inhibitors; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactams, Macrocyclic; Middle Aged; Proline; Ritonavir; Simvastatin; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Treatment of hepatitis C virus (HCV) infection in patients with chronic kidney disease was difficult in the past because of the use of interferon (IFN). It was associated with high risk IFN-related adverse reactions due to reduced renal clearance of IFN. This study aimed to evaluate the antiviral efficacy, safety, and tolerability of ombitasvir/paritaprevir/ritonavir/ribavirin in chronic kidney disease patients infected with chronic HCV.This observational, open-label prospective study was carried out on 103 patients infected chronic HCV with different grades of renal impairment. Paritaprevir/ritonavir and ombitasvir (75/50/12.5 mg) twice daily plus ribavirin were given to the patients for 12 weeks. Dose adjustment of ribavirin was done according to degree of renal impairment.Sustained virological response (12 weeks after the end of treatment) occurred in 101 patients (98.1%). Anemia occurred in 48 patients. No serious adverse events were observed in any patient.Paritaprevir/ritonavir and ombitasvir plus ribavirin for 12 weeks was considered to be safe and effective in the treatment of chronic HCV infected patients with varying degrees of renal impairment.

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Egypt; Female; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Valine

Hepatic decompensation is a fatal on-treatment side effect during chronic hepatitis C treatment with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Prompt bilirubin testing can reveal hepatic failure in susceptible patients, and clinical parameters precipitating early elevation of bilirubin can warn clinicians to avoid PrOD prescription.. This retrospective study included 169 Hepatitis C virus (HCV)-genotype 1b patients who underwent a 12-week course of PrOD with or without ribavirin. Laboratory data underwent χ analysis with Fisher's exact test to determine the precipitating factors causing hyperbilirubinemia in patients who had received 1 week of treatment.. Sustained viral response was achieved in 164 patients (97.0%). Total bilirubin was ≥2 mg/dL (21.3%) in 36 patients after 1 week of treatment. Pretreatment white blood cell (WBC) <4500/µL and platelet <100,000/µL correlated with total bilirubin ≥2 mg/dL (relative risk [RR]: 21.64, 95% CI: 5.23-89.64, p < 0.001) after 1 week of treatment. Pretreatment platelet ≥100 000/µL and WBC <4500/µL correlated with direct bilirubin ≥0.45 mg/dL (RR: 6.56, 95% CI: 1.42-30.38, p = 0.016) and indirect bilirubin ≥0.6 mg/dL (RR: 4.77, 95% CI: 1.03-22.15, p = 0.046). Pretreatment platelet <100,000/µL with F3/F4 fibrosis correlated with first week total bilirubin ≥2 mg/dL (RR: 3.57, 95% CI: 1.35-9.09, p = 0.010).. PrOD is an effective antiviral regimen for HCV genotype 1b patients. Total bilirubin ≥2 mg/dL after 1 week of treatment serves as an early warning of irreversible progression toward hepatic decompensation, and the current study provides a guide by which to monitor chronic hepatitis C patients undergoing PrOD treatment.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Cyclopropanes; Female; Hepatitis C, Chronic; Humans; Hyperbilirubinemia; Lactams, Macrocyclic; Male; Middle Aged; Precipitating Factors; Proline; Retrospective Studies; Ribavirin; Ritonavir; Sulfonamides; Taiwan; Uracil; Valine

This study aimed to evaluate the real-life efficacy and tolerability of direct-acting antiviral treatments for patients with chronic hepatitis C (CHC) with/without cirrhosis in the Turkish population.. A total of 4,352 patients with CHC from 36 different institutions in Turkey were enrolled. They received ledipasvir (LDV) and sofosbuvir (SOF)±ribavirin (RBV) orombitasvir/paritaprevir/ritonavir±dasabuvir (PrOD)±RBV for 12 or 24 weeks. Sustained virologic response (SVR) rates, factors affecting SVR, safety profile, and hepatocellular cancer (HCC) occurrence were analyzed.. SVR12 was achieved in 92.8% of the patients (4,040/4,352) according to intention-to-treat and in 98.3% of the patients (4,040/4,108) according to per-protocol analysis. The SVR12 rates were similar between the treatment regimens (97.2%-100%) and genotypes (95.6%-100%). Patients achieving SVR showed a significant decrease in the mean serum alanine transaminase (ALT) levels (50.90±54.60 U/L to 17.00±14.50 U/L) and model for end-stage liver disease (MELD) scores (7.51±4.54 to 7.32±3.40) (p<0.05). Of the patients, 2 were diagnosed with HCC during the treatment and 14 were diagnosed with HCC 37.0±16.0 weeks post-treatment. Higher initial MELD score (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.22-2.38; p=0.023]), higher hepatitis C virus (HCV) RNA levels (OR: 1.44, 95% CI: 1.31-2.28; p=0.038), and higher serum ALT levels (OR: 1.38, 95% CI: 1.21-1.83; p=0.042) were associated with poor SVR12. The most common adverse events were fatigue (12.6%), pruritis (7.3%), increased serum ALT (4.7%) and bilirubin (3.8%) levels, and anemia (3.1%).. LDV/SOF or PrOD±RBV were effective and tolerable treatments for patients with CHC and with or without advanced liver disease before and after liver transplantation. Although HCV eradication improves the liver function, there is a risk of developing HCC.

Topics: Aged; Anilides; Antiviral Agents; Benzimidazoles; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Male; Middle Aged; Proline; Prospective Studies; Retrospective Studies; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Turkey; Valine

Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015.. Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records.. Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision.. These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Ribavirin; Ritonavir; Spain; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

Direct-acting antiviral agents (DAAs) have revolutionized treatment of chronic hepatitis C in patients with normal glomerular filtration rate (GFR). However, patients with impaired kidney function have been excluded from several clinical trials. We, therefore, investigated the use, effectiveness, and tolerability of DAAs in patients with GFR less than 30 ml/min in the real-world setting.. An analysis was done within the German Hepatitis C-Registry on 5733 patients including 46 individuals with a baseline GFR less than 30 ml/min treated with sofosbuvir-based (61%) or paritaprevir/ritonavir-based (39%) regimens.. Sustained virological response 12 rates did not differ significantly between patients with baseline GFR less than 30 versus more than 30 ml/min (91 vs. 96%). Nine individuals with a baseline GFR more than 30 ml/min presented with a GFR less than 30 ml/min at the end of treatment. GFR improvement from less than 30 ml/min to more than 30 ml/min was observed in 9/46 cases. Adverse events did not differ in patients with GFR less than 30 versus more than 30 ml/min. However, serious adverse events were significantly more frequent in individuals with GFR less than 30 ml/min and associated with ribavirin.. Different DAA therapies can be safely used with high sustained virological response rates in patients with GFR less than 30 ml/min. Ribavirin has to be avoided because of poor tolerability.

Topics: 2-Naphthylamine; Acute Disease; Adult; Aged; Anemia; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Disease Progression; Drug Therapy, Combination; Female; Fluorenes; Germany; Glomerular Filtration Rate; Hepatitis C, Chronic; Humans; Hypertension; Imidazoles; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Pleural Effusion; Proline; Pyrrolidines; Registries; Renal Insufficiency, Chronic; Ribavirin; Ritonavir; RNA, Viral; Severity of Illness Index; Simeprevir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Uridine Monophosphate; Valine

We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain.. Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded.. Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin.. Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Lactams, Macrocyclic; Logistic Models; Macrocyclic Compounds; Male; Middle Aged; Multivariate Analysis; Proline; Ribavirin; Spain; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

The recent development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of chronic hepatitis C, and interferon-based regimes have become a poor treatment choice in clinical practice. Today DAAs offer shorter, well-tolerated, highly effective curative therapies. This study aimed to evaluate the effectiveness and safety of DAAs in patients with end-stage renal disease and HCV genotype 1 infection in real clinical practice.. Thirty-six patients who attended our clinic, were diagnosed with chronic hepatitis C (CHC), undergoing hemodialysis, and fulfilled the criteria of age >18 years, genotype 1 infection, with a detectable HCV RNA level were considered for the study. Patients with GT1a infection received OBV/PTV/r plus DSV plus RBV for 12 weeks; GT1b infected patients received this regimen without RBV for 12 weeks.. The study was conducted on 33 patients. The mean age was 52.30 ±13.77 years, and 70 % of them were male. By the fourth week of treatment, HCV RNA levels decreased below 15 IU/ml in all patients. Sustained virologic response (SVR) 12 rate was 100%. Nine patients had side effects during treatment. Of the patients with side effects, 89.9% were in group 1a and 11.1% in group 1b.. In this study, treatment with OBV/PTV/r and DSV with or without RBV resulted in high rates of sustained virologic response in HCV GT1-infected patients with end-stage renal disease (ESRD). SVR was achieved in all patients with few side effects.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; RNA, Viral; Statistics, Nonparametric; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine; Young Adult

We report three cases of genotype 1b hepatitis C virus (HCV) reinfection after liver transplantation. When antiviral treatment was considered, all three patients had renal dysfunction and had been treated with immunosuppressive agents for a long time; one with tacrolimus (TAC) and the others with cyclosporine A (CyA). Therefore, the possible antiviral regimens among direct-acting antivirals (DAA) were limited and so we treated all three patients with ombitasvir/paritaprevir/ritonavir (OBV/PTV/r). Because ritonavir is known to markedly increase the blood concentration of TAC and CyA through drug-drug interactions, close monitoring of blood concentrations of TAC or CyA and dose adjustments of immunosuppressive agents were needed. Sustained virus response was achieved in all the patients treated, and there were no adverse effects or transplant rejection. OBV/PTV/r might be a useful DAA regimen for patients with genotype 1 HCV reinfection in the setting of renal dysfunction.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Monitoring; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Valine; Virus Activation

The interferon-free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8-week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8-week administration of PTV/r/OBV/DSV in a real-world cohort.. We performed a multicentre observational study from Spanish Hepa-C database including patients receiving 8 weeks of PTV/r/OBV/DSV (October 2016-November 2017). Those with advanced fibrosis, with non-genotype 1b or who were treatment-experienced were excluded.. A total of 211 patients were registered from 23 Spanish centres; eleven were excluded. At baseline, 42.5% (n = 85) were male, median (range) age was 57 (23-86), ALT was 45 (11-494) IU/mL, viral load was 6.1 (3.3-8.2) log10 IU/mL, and 74.5% had mild liver fibrosis (F0-F1) and 25.5% moderate fibrosis (F2). At the end of treatment (EOT), HCV viral load was undetectable in 100% (200/200). Seven patients relapsed after treatment discontinuation. Sustained virological response (SVR12) rates by intention-to-treat analysis were 96% (192/200). Regarding treatment safety, 2 patients developed ALT elevation >5x ULN, but there were no treatment discontinuations. One patient died 7 weeks after EOT.. Treatment with PTV/r/OBV/DSV in genotype 1b-infected treatment-naive patients with mild-moderate fibrosis shows excellent efficacy and safety in real life, similarly to clinical trials. Clinicaltrials.gov, number: NCT03122132.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Spain; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Viral Load; Young Adult

Till now, pooled data about the safety and efficacy of different direct-acting antiviral (DAAs) regimens in different renal situations are still under evaluation.. To evaluate a real-life experience of the efficacy and safety of ombitasvir/paritaprevir/ritonavir plus ribavirin (OBV/PTV/r plus RIB) in patients with end-stage kidney disease (ESKD).. Between January 2017 and January 2018, an open-label multicenter prospective study was designed to enroll all consecutive patients with proven CHC genotype 4 infections and concomitant ESKD based on estimated glomerular filtration rate (eGFR) with (HD group) or without hemodialysis (non-HD group). Patients were given a co-formula of OBV/PTV/r (25/150/100 mg) once-daily plus RIB was given for 12 weeks. Sustained virologic response (SVR 12) was the primary endpoint.. A total of 110 patients were enrolled. An overall SVR 12 was reported in 104 (94.5%) patients, and treatment failure were reported in 6 patients [2 patients (1.8%) were relapsed, and 4 patients (3.6%) patients were non-responders]. SVR12 was 96% in HD and 91.4% in non-HD patients (P = 0.286). There were no reported serious adverse events. Anemia was reported in 66.6% (n = 50) in HD group and in 31.4% (n = 11) in non-HD group.. Although it is still challenging, achievement of SVR12 in patients with chronic HCV and concomitant end-stage kidney disease in the era of DAAs became possible with a 12 weeks course of a co-formula of ombitasvir/paritaprevir /ritonavir plus ribavirin. CLINICALTRIALS.. NCT03341988.

Topics: Adult; Aged, 80 and over; Algorithms; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Valine

Topics: 2-Naphthylamine; Administration, Oral; Adult; Agammaglobulinemia; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Genetic Diseases, X-Linked; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Immunoglobulin G; Immunoglobulins, Intravenous; Lactams, Macrocyclic; Macrocyclic Compounds; Middle Aged; Proline; Pyrrolidines; Ritonavir; Sofosbuvir; Sulfonamides; Uracil; Valine

Data on the treatment of patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection remains limited. A comprehensive analysis was performed to evaluate the efficacy and safety of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir(r) ± dasabuvir (DSV) ± ribavirin (RBV) for treatment in HCV/HIV coinfected patients.. We systematically searched and included studies that enrolled patients with HIV/HCV coinfection using the OBV/PTV/r ± DSV ± RBV regimens and reported sustained virological response after 12 weeks (SVR12) end-of-treatment. Heterogeneity of results was assessed and pooled SVR rates were computed with 95% confidence intervals (95%CI). Subgroup analysis and assessment of publication bias through Egger's test were further performed.. Ten studies containing 1358 coinfected patients were included in this study. The pooled estimate of SVR12 was 96.3% (95%CI: 95.1-97.4). Subgroup analysis showed that pooled SVR12 rate was 96.2% (95% CI: 94.8-97.4) for patients with genotype (GT) 1 and 98.8% (95% CI: 95.1-100.0) for those with GT4. The SVR12 rates for the treatment-naïve (TN) and treatment-experienced (TE) patients were 96.8% (95% CI, 94.8-98.5) and 98.9% (95% CI, 96.4-100.0), respectively. Pooled SVR12 rate was 97.8(95%CI: 94.6-99.8) for patients with cirrhosis and 96.7% (95%CI: 95.3-97.8) without cirrhosis. The pooled incidence of any adverse events (AEs) and serious adverse events (SAEs) was 73.9% (95%CI: 38.1-97.6) and 2.7% (95%CI: 0.0-9.5). Publication bias did not exist in this study.. The comprehensive analysis showed high efficacy for the OBV/PTV/r ± DSV ± RBV regimen in patients coinfected with HIV and HCV, regardless of genotypes, history of treatment and the presence or absence of cirrhosis.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Clinical Trials as Topic; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; HIV; HIV Infections; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Observational Studies as Topic; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

As the most common liver disease in hemodialysis patients, chronic hepatitis C (CHC) can cause cirrhosis and hepatocellular carcinoma, even increase in renal-related mortality. In Turkey, the frequency of anti-hepatitis C virus (HCV) antibodies in hemodialysis patients ranged from 31.4% to 51%. Until recently, the mainstay of the CHC treatment for these patients was pegylated interferon with potential toxicities and low sustained virological response. The 3D regimen, a combination of four drugs (ombitasvir, paritaprevir, dasabuvir, and ritonavir), has recently been used for patients with chronic kidney disease infected with genotype 1a and 1b HCV. The aim of the present study was to present results of 3D treatment for patients with hemodialysis-dependent chronic renal failure (CRF) who were chronically infected with HCV.. Overall, 25 patients with hemodialysis-dependent CRF who were infected with genotype 1a/1b HCV have been treated using the 3D regimen in our gastroenterology clinic between July 2016 and October 2017. Three patients were administered additional ribavirin 200 mg/day. Serum HCV RNAs, blood chemistry, blood count, and side effects were recorded at 0, 4, and 12 weeks.. All 25 patients completed and well tolerated their planned treatment. At the end of 4 weeks, the viral response (defined as HCV RNA clearance) rate was 92%. At the end of 12 weeks of treatment and 3 months after treatment, viral response rates were both 100%.. We observed that the treatment with 3D regimen in hemodialysis patients infected with genotype 1 hepatitis C is highly effective and well tolerated.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Dialysis; Ritonavir; Sulfonamides; Sustained Virologic Response; Turkey; Uracil; Valine

Both hepatitis C virus infection (HCV) and chronic kidney disease (CKD) have been comorbid illnesses with increasing morbidity and mortality. The present study was conducted to present real-life experiences about treatment of HCV and CKD with a fixed-dose combination of paritaprevir 150 mg/day, ritonavir 100 mg/day as a booster, ombitasvir 25 mg/day, and dasabuvir 250 mg twice/day, the PROD regimen.. This was a multicenter, retrospective cohort study. Seventy-five patients with both HCV and CKD were treated with a PROD-based regimen with or without ribavirin. Fifty-three of 75 patients were on maintenance hemodialysis program. Seven patients had compensated liver cirrhosis. The patients with genotype 1a or compensated liver cirrhosis were treated with the PROD regimen and ribavirin in a dose of 200 mg every other day for 12 weeks. The patients with genotype 1b were treated with PROD for 12 weeks. The patients with genotype 4 were treated with a combination of paritaprevir, ritonavir, ombitasvir, and ribavirin 200 mg every other day.. All patients except one were HCV-RNA negative (98.6%) at the end of treatment. One patient had decompensated after the fourth day of therapy. She stopped the treatment, and she was exitus after 2 months. Two patients died of reasons not related to the drugs 2 months after negativity of HCV-RNA. Sustained viral rate 12 weeks after treatment was found in 96% of the patients.. The PROD regimen was very effective and safe for treatment in patients with HCV and CKD who were in stages 4 and 5.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Insufficiency, Chronic; Retrospective Studies; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

The introduction of direct-acting antiviral agents has allowed significant chances for treatment for difficult-to-treat populations. This study aimed to investigate the efficacy, tolerability, and safety of these therapies in both patients with end-stage renal disease and kidney transplant recipients with chronic hepatitis C virus infection.. This study was a retrospective analysis with prospective follow-up of patients. The antiviral combination of ombitasvir 25 mg, paritaprevir 75 mg, ritonavir 50 mg, and dasabuvir 50 mg was prescribed to patients with end-stage renal disease or kidney transplant recipients with noncirrhotic or compensated cirrhotic liver disease. The other antiviral combination consisted of sofosbuvir 400 mg and ledipasvir 90 mg, which was recommended to patients with decompensated cirrhosis or those who could not tolerate the first combination regimen. Ribavirin was given to all patients with genotype 1a hepatitis C virus infection. All clinical and laboratory data were recorded at week 4, at end of the treatment, and at 12 weeks after completion of treatment.. In terms of efficacy, sustained virologic response at 12 weeks was achieved in 94% of patients in the end-stage renal disease group and 92% of patients in the kidney transplant group. In terms of tolerability, antiviral treatment was well tolerated in both groups. Cardiac arrest and cerebrovascular accident were seen in the end-stage renal disease group; severe mucositis and glossitis were seen in the kidney transplant group. Hospitalization was needed in 2 patients for treatment of drug interactions with tacrolimus and sirolimus. Renal allograft function worsened in 2 patients, with 1 patient having biopsyproven antibody-mediated rejection.. We observed great efficacy and safety in both kidney transplant recipients and patients with end-stage renal disease with these agents in treatment of chronic hepatitis C. However, clinicians should remain aware of drug interactions and adverse events in this fragile patient population.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Retrospective Studies; Ribavirin; Risk Factors; Ritonavir; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine

Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment-naïve or -experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post-treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off-label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow-up data at post-treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2-96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b-infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro-esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post-baseline Grade 3-4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real-world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real-world setting.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Internationality; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Young Adult

The present study aimed at evaluation of changes in estimated glomerular filtration rate (eGFR) among chronic Hepatitis C virus (HCV) patients with chronic kidney disease (CKD) Stages 3-5 who were treated with 12 weeks of ritonavir-boosted paritaprevir, ombitasvir plus ribavirin.. Changes in renal functions were compared across follow up time points (baseline, SVR4, and SVR8). Data on on-treatment adverse events (AEs), serious AEs, laboratory abnormalities, treatment discontinuation were collected.. The use of ombitasvir, paritaprevir, and ritonavir for treatment of HCV-infected patients with advanced renal disease was safe and effective, moreover, it was associated with significantly improved eGFR.

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Egypt; Female; Genotype; Glomerular Filtration Rate; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Recovery of Function; Renal Dialysis; Renal Insufficiency, Chronic; Ribavirin; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Valine; Viral Load; Young Adult

Transient elastography and fibrosis-4 index (FIB-4) have been proposed to access hepatic fibrosis and steatosis for patients with chronic liver disease. This study was to determine the changes of liver stiffness (LS), controlled attenuation parameter (CAP) value and FIB-4 and their associated factors for chronic hepatitis C (CHC) patients who underwent direct-acting antivirals (DAAs).. Consecutive patients with CHC in advanced fibrosis or compensated cirrhosis undergoing paritaprevir/ritonavir/ombitasvir plus dasabuvir therapy and with LS and CAP before and 12 weeks after treatment were enrolled. The demographics, clinical characteristics and treatment outcomes were reviewed. The changes of LS, FIB-4, CAP and their associated factors were analyzed.. A total of 213 patients (mean age: 63.7 years) with complete recommended treatment were enrolled. All patients achieved sustained virological response at 12 weeks (SVR12) of follow-up. The mean values of LS, CAP and FIB-4 index before treatment were 18.5kPa, 283dB/m and 5.05 respectively. While there was no significant change in CAP, LS and FIB-4 decreased significantly at the time of SVR12 (p<0.001). Compared with follow-up period, LS and FIB-4 decreased rapidly during DDAs. Multivariate analysis showed that higher baseline LS and FIB-4 were associated with greater reductions at the time of SVR12.. For CHC patients in advanced fibrosis or compensated cirrhosis, DAAs improved LS and FIB-4 index at SVR12. Higher baseline LS and FIB-4 contributed to greater reductions. However, there was no significant change in CAP value.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Transaminases; Treatment Outcome; Uracil; Valine

Paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin shows favorable results in hepatitis C virus genotype 1 (HCV-1) patients in terms of safety and efficacy, but real-world data remain limited for those with advanced hepatic fibrosis (fibrosis 3, F3) or compensated cirrhosis (F4). A total of 941 patients treated in four hospitals (the Keelung, the Linkuo, the Chiayi and the Kaohsiung Chang Gung Memorial Hospital) through a nationwide government-funded program in Taiwan were enrolled. Patients with HCV and advanced hepatic fibrosis or compensated cirrhosis received 12 weeks of PrOD in HCV-1b and 12 or 24 weeks of PrOD plus ribavirin therapy in HCV-1a without or with cirrhosis. Advanced hepatic fibrosis or compensated cirrhosis was confirmed by either ultrasonography, fibrosis index based on 4 factors (FIB-4) test, or transient elastography/acoustic radiation force impulse (ARFI). The safety and efficacy (sustained virologic response 12 weeks off therapy, SVR

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Retrospective Studies; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs.. PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment.. Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements.. In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities.. Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Amides; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Patient Reported Outcome Measures; Proline; Prospective Studies; Quinoxalines; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Young Adult

The aim of this study was to investigate the efficacy and safety of the ombitasvir/ paritaprevir/ ritonavir and dasabuvir in patients with HCV, genotype-1b, in real clinical practice in Ukraine. The study included a total of 50 HCV infection genotype 1b patients receiving ombitasvir/ paritaprevir/ ritonavir and dasabuvir for 12 weeks. The patients were evaluated in respect of demographic, clinical and virological data, sustained virologic response (SVR) and adverse events. The mean age of patients was 52 years (40-60), 42% men, 20% treatment experienced, 42% with compensated cirrhosis. The SVR12 rate of all HCV genotype 1b patients was 96% (95%CI:86,3-99,5%). The most common adverse events were fatigue in 14 (28%) patients, diarrhea in 10 (20%) and headache in 12 (24%). In our study, the real world clinical practice data shows that ombitasvir/ paritaprevir/ ritonavir and dasabuvir for 12 weeks in HCV genotype 1b patients was well tolerated and resulted in 96% SVR12 regardless of previous treatment status and liver fibrosis stage.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Ukraine; Uracil; Valine

Recent studies have suggested a higher recurrence rate of hepatocellular carcinoma (HCC) in patients with a history of HCC and hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antiviral (DAA) agents.. We conducted a prospective analysis of 24 patients with HCV-associated cirrhosis and treated HCC who received ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin for 12 weeks. Prior therapies for HCC included resection (9/24 patients), radiofrequency ablation (RFA) (7/24) and trans-arterial chemoembolization (TACE) (8/24). All patients were eligible for treatment if they had no HCC recurrence 6 months after their last procedure. A control group was defined. All patients were followed every 6 months, with dynamic computed tomography and/or magnetic resonance imaging.. DAA therapy significantly reduced the recurrence rate of HCC and improved survival without recurrence in patients with treated HCV-associated HCC.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Cyclopropanes; Hepatectomy; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Middle Aged; Neoplasm Recurrence, Local; Proline; Prospective Studies; Radiofrequency Ablation; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

New direct-acting antiviral drugs have become the corner-stone treatment for HCV infection: they show promising results with accepted side-effects and low dropout rates. One of the available regimens is paritaprevir/ombitasvir/ritonavir (PTV/OMV/RTV). Our aim was to study the efficacy and safety of this drug regimen among HCV-positive hemodialysis patients.. This prospective single-center study was performed in the Urology and Nephrology Center, Mansoura University, Egypt. Ninety-six maintenance hemodialysis patients were screened for HCV antibodies. Positive results were found in 46 patients (47.9%). HCV PCR was assessed in all HCV-antibody-positive patients; positive results were found positive for 38 (82%); all patients were HCV genotype 4. Four patients were excluded due to advanced liver cirrhosis, liver malignancy, or metastatic breast cancer. Thirty-four patients were prescribed PTV/OMV/RTV for 3 months to treat HCV.. Mean age was 43.2 ± 11.9 years. Most patients were male (67.6%). There was a rapid response to treatment: HCV PCR became negative by 4 weeks after starting treatment. By 12 and 24 weeks post-DAA therapy, there was a sustained viral response (SVR 12, SVR 24) in 100% of patients with improved liver-enzyme levels.. The PTV/OMV/RTV regimen was safe and effectively treated Egyptian HCV-positive genotype-4 hemodialysis patients.

Topics: Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A Inhibitors; Drug Combinations; Egypt; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Renal Dialysis; Ritonavir; Sulfonamides; Treatment Outcome; Valine

The registered trial has demonstrated that paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD) with ribavirin was effective for recurrent hepatitis C virus genotype 1 (HCV-1) infection after liver transplantation in patients with mild fibrosis; however, the real-world efficacy and safety of this regimen have not been determined.. The efficacy (sustained virological response, SVR12, undetectable HCV RNA 12 weeks post-treatment) and safety were evaluated in 12 patients with recurrent HCV-1 infection after liver transplantation.. Nine patients were treated for 24 weeks, and three patients (two treatment-naïve patients and one interferon-intolerant patient) were treated for 12 weeks. HCV RNA was undetectable at treatment day 1, week 1, week 4, week 12, and at the end of treatment in 8.3% (n = 1), 25% (n = 3), 83.3% (n = 10), 100% (n = 12), and 100% (n = 12) of patients, respectively. All twelve patients achieved SVR12. Treatment was temporarily stopped in one patient because of leucopenia. The other patient with minimal fibrosis experienced an elevation in alanine aminotransferase concentration, which returned to normal levels after dose reduction. Seven (58.3%) patients required RBV dose reduction and two (16.7%) required transient RBV discontinuation during treatment. There were no serious adverse events, and most adverse events were related to ribavirin. No patient developed graft rejection or deterioration in hepatic or renal function during treatment. Treatment efficacy and safety were comparable between patients with and without advanced liver fibrosis.. PrOD plus ribavirin had a highly satisfactory real-world efficacy and safety profile in the treatment of recurrent HCV-1 infection after liver transplantation in Asian patients.

Topics: 2-Naphthylamine; Aged; Alanine Transaminase; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Postoperative Period; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Topics: Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Protease Inhibitors; Ribavirin; Ritonavir; Sulfonamides; Valine; Viral Load; Viral Nonstructural Proteins; Viremia; Virus Activation

The real-world effectiveness and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) remain limited for East Asian hepatitis C virus genotype 1b (HCV-1b) patients. The study aimed to evaluate the antiviral responses of PrOD-based regimens for HCV-1b patients in Taiwan.. The study performed a retrospective analysis of 103 HCV-1b patients receiving PrOD with or without ribavirin (RBV) for 12 weeks. Data were analyzed to assess the on-treatment and off-therapy HCV viral load and on-treatment adverse events. The pre-specified characteristics related to sustained virologic response 12 weeks off therapy (SVR. At treatment week 4, 100 of 102 patients (98.0%) had serum HCV RNA level < 25 IU/mL. The SVR. Paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without RBV are efficacious and generally well tolerated for treatment of HCV-1b patients in Taiwan.

Topics: 2-Naphthylamine; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Retrospective Studies; Ribavirin; Ritonavir; Safety; Sulfonamides; Taiwan; Treatment Outcome; Uracil; Valine; Viral Load

Drug-drug interactions (DDIs) with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin (OBV/PTV/r ± DSV ± RBV) are common in clinical trials. Our aim was to analyze the prevalence and management of potential DDIs and adverse events (AEs) related to DDIs in patients with chronic hepatitis C (CHC) receiving OBV/PTV/r ± DSV ± RBV in clinical practice.. 177 CHC patients started OBV/PTV/r ± DSV ± RBV in 4 Spanish hospitals and were screened for potential DDIs using the University of Liverpool database. Patients were classified according to the most serious potential DDIs at baseline and AEs during therapy.. At least one potential DDI was found in 110 (62.1%) patients: 100 (56.5%) had at least one manageable potential DDI and 10 (5.6%) at least one contraindicated. Patients with potential DDIs were receiving a higher number of concomitant drugs (4 vs. 2, P < 0.001). Routine medication was modified at baseline due to potential DDIs in 49 (27.7%) patients. During antiviral treatment, 67 (37.9%) patients presented at least one AE. In 9 (4.5%) patients, a DDI was suspected between OBV/PTV/r ± DSV ± RBV and the concomitant drug, requiring antiviral discontinuation in 4 patients.. Potential DDIs are frequent with OBV/PTV/r ± DSV ± RBV, although a change in baseline medication is made in only one-quarter of patients. More than half of potential DDIs were only followed, and only 5% of patients developed AEs in which the implication of DDIs could not be excluded.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

Possible drug-drug interactions (DDIs) between antiretrovirals (ARVs) and direct-acting antiviral agents (DAAs) are of some concern.. To investigate ARV plasma trough concentrations (Ctrough) before and during DAAs in patients treated in the real world.. Single-centre, prospective, observational study including HIV/HCV coinfected persons undergoing DAA treatment. Self-reported adherence was assessed and ARVs Ctrough measured by HPLC-UV. Blood samples were collected before and after 2 months of DAA treatment.. One-hundred and thirty-seven patients were included: 21.2% treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (2D/3D) and 78.8% with sofosbuvir-based regimens. Suboptimal Ctrough before and during DAA was found, respectively, in 3 (10.3%) and 3 (10.3%) cases treated with 2D/3D, and 16 (14.8%) and 11 (10.2%) with sofosbuvir-based regimens, even if self-reported ARV adherence was always ≥93%. In 2D/3D-treated patients, median darunavir Ctrough during DAAs was significantly lower than observed before DAAs [1125 ng/mL (IQR, 810-1616) versus 1903 ng/mL (IQR 1387-3983), respectively] (n = 5; P = 0.009), with a 40.9% decrease. In the same group, no differences in atazanavir or raltegravir concentrations were found. In patients treated with sofosbuvir-based regimens, Ctrough of all ARVs were similar before and during DAAs.. In the real world of HIV/HCV coinfected patients, ARV plasma concentrations during DAAs were generally not different from those found before anti-HCV treatment. Although assessed in a small number of patients, darunavir concentrations during 2D/3D showed a significant reduction when compared with those found before DAAs. ARV plasma concentrations measurement during anti-HCV treatment may give useful information for managing HIV/HCV coinfected persons receiving treatment for both infections.

Topics: 2-Naphthylamine; Anilides; Anti-Retroviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Hepatitis C, Chronic; HIV Infections; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil; Valine

Topics: Adult; Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Hepacivirus; Hepatitis C, Chronic; HIV; HIV Infections; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Plasma; Proline; Ritonavir; RNA, Viral; Sulfonamides; Valine; Viral Load

Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4β-hydroxycholesterol (4βHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4βHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4βHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4βHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4βHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Case-Control Studies; Cyclopropanes; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Female; Genotype; Hepatitis C; Hepatitis C, Chronic; Humans; Hydroxycholesterols; Imidazoles; Interferons; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Pyrrolidines; Ritonavir; Sex Factors; Sulfonamides; Treatment Failure; Valine

In this observational cohort (n = 67), we enrolled stages 4-5 CKD treatment-naïve or Peginterferon/RBV-experienced GT4-infected patients (n = 32) treated for 12-24 weeks with OBV/PTV/r ± RBV, and plus DSV in GT1 patients (n = 35, including 3 with GT1/4 co-infection). RBV was dosed by physician discretion between 200 mg weekly and 200 mg daily. Primary endpoints were SVR12, calculated on intention-to-treat (ITT) basis, and occurrence of serious adverse events.. The mean age of the cohort was 45.7 ± 12.7 years, 50.7% were females, 20.9% had cirrhosis, 35.8% were treatment-experienced and 97% were on haemodialysis. Three patients (F4) received 24-week treatment, 2 with GT4, and 1 with GT1a; and 19.4% were treated without RBV, including 9 GT1, and 4 GT4. Overall, 65 (97.1%) patients achieved SVR12, including 100% of those with a post-treatment follow-up (modified ITT analysis). Of the two patients without SVR12, one died from sepsis-related complications and the other from a myocardial infarction 2 weeks after completing therapy. Grades 3-4 anaemia occurred in 8.9%.. A 12-week regimen of OBV/PTV/r ± DSV with or without RBV is highly effective with a favourable safety profile amongst GT4 and GT1 patients with CKD stages 4-5. SVR12 rates were high regardless of patient characteristics.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Registries; Renal Insufficiency, Chronic; Ribavirin; Ritonavir; Saudi Arabia; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C (CHC), with the presence of symptoms in 10-15% of cases. There have been encouraging data regarding immunological and clinical responses in patients treated with the novel combinations of direct-acting antivirals (DAAs), but the role of ribavirin (RBV) in the treatment of MC has not yet been demonstrated. We prospectively enrolled 132 patients affected by MC and CHC, and virological, immunological and clinical responses were evaluated at 12 weeks after completion of treatment. All subjects were treated with interferon (IFN)-free regimens according to clinical guidelines, with or without RBV. All patients achieved a virological response. A complete immunological response (CR) was observed in 71 subjects (53.8%), a partial response in 44 (33.3%), and no response in 17 (12.8%). Ten patients showed a complete resolution of symptoms (7.6%), and 31 showed a significant improvement (23.5%). CR was significantly higher in patients taking RBV (71.1 vs. 44.8%, p < 0.001) and in treatment-naïve patients (62.5 vs. 43.3%, p < 0.001). In logistic regression analysis, duration of HCV infection of less than 20 years (OR 2.448; 95% IC 1.335-6.202; p = 0.019), treatment-naïve status (OR 2.885; 95% IC 1.404-9.660; p = 0.025) and the use of RBV (OR 6.961; 95% IC 3.912-26.885; p < 0.001) were predictors of CR. In MC patients, IFN-free regimens are effective and well tolerated, and RBV seems to significantly increase the immunological response and promote a decline in cryocrit.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cryoglobulinemia; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil; Valine

To explore the effectiveness and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV) for 12 weeks without ribavirin in adults with chronic HCV genotype 1b infection and compensated cirrhosis.. Observational study of a prospective cohort of adult patients with HCV genotype 1b infection and compensated cirrhosis who received 12 weeks of OBV/PTV/r and DSV without ribavirin. Effectiveness was assessed by recording the percentage of patients achieving sustained virological response at week 12 post-treatment (SVR12). Safety outcomes were based on the incidence of adverse events.. Seventy-eight patients were included. The SVR12 rate was 96.1% (95%CI 89.2-99.2). Adverse events were recorded in 78.0% of patients. Of these, 97.7% were grade 1/2. One patient discontinued treatment prematurely owing to adverse events. Eighty-six interactions were detected in 43 patients (55.1%). Overall, 81.4% of interactions required close monitoring, alteration of drug dosage, or timing of administration. In 7.0% of cases, the interactions arose from contraindications that required the suspension of the concomitant drug. In 11.6% of cases, medicinal plants or foods were withdrawn.. The simplified regimen of OBV/PTV/r+DSV administered for 12 weeks is effective and safe in patients with chronic HCV genotype 1b infection and compensated cirrhosis. No adverse reactions related to drug-drug interactions were recorded.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cohort Studies; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

Ombitasvir/paritaprevir-ritonavir (OBT/PTV-r) plus ribavirin (RBV) for 12 weeks in hepatitis C virus (HCV) genotype 4 patients with advanced fibrosis has been only investigated in clinical trials.. To assess safety and efficacy of OBT/PTV-r + RBV for 12 weeks in real-life HCV-4 patients with advanced fibrosis.. HCV-4 patients with advanced fibrosis consecutively receiving OBT/PTV-r + RBV for 12 weeks in a single center were enrolled. Fibrosis was staged by transient elastography (TE) (F3: ≥10 kPa; F4 ≥11.9 kPa) or histologically. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks post-treatment.. Between January 2016 and February 2017, 49 HCV-4 patients were included: median age 54 (39-72) years, 84% males, 59% Egyptians, 35% fibrosis F3 and 65% F4, all Child Pugh class A. Median RBV dose was 1200 (200-1200) mg/day. At ITT analysis, 47 (96%) patients achieved an SVR (100% at PP analysis). SVR was not affected by ancestry (Egyptian vs. Italian 97% vs. 95%, p = 1.0), fibrosis stage (F3 vs. F4 100% vs. 94%, p = .53), presence of baseline resistance associated substitutions (RASs) or RBV reduction.. We report 100% SVR with 12-weeks of OBT/PTV-r + RBV in HCV-4 patients with advanced liver disease, including compensated cirrhotics.

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Italy; Lactams, Macrocyclic; Liver; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Valine

No data are available on the clinical presentation and virological pattern in the case of failure of interferon (IFN)-free regimens in patients with genotype-3h. In this paper authors identified the virological and clinical characteristics of patients with genotype-3h treated with suboptimal or not indicated IFN-free regimens for the misclassification of HCV genotype.. A total of 87 consecutive patients with failure to an IFN-free regimen were re-tested for HCV genotype by HCV NS5B sequencing; the 26 patients identified as harbouring HCV-3 were enrolled.. Of the 26 patients enrolled, 4 (15.4%) harboured sub-genotype-3h and 22 (84.6%) 3a. All patients were Italian. Patients with genotype-3a infection were younger (median age 56 years, range 47-78) compared to those with genotype-3h infection (median 74 years, range 65-79; P<0.006). With regard to the failed direct-acting antiviral (DAA)-regimens, three of the four patients with genotype-3h (75%) had been treated with an ineffective​ DAA regimen (paritaprevir, ombitasvir, dasabuvir ± ribavirin for 3 months) more frequently than those with genotype-3a (13.6%; P=0.02), because of previous erroneous identification of HCV-1 genotype. NS5A resistance-associated substitutions (RASs) were observed in 10 (45.4%) genotype-3a-infected patients and in 2 (50%) with genotype-3h. NS5B RASs were observed in only two genotype-3a-infected patients and in none of the 3h-infected patients.. This is the first time genotype-3h has been identified in Italian patients failing an IFN-free regimen, in the majority of cases because of a misclassification of the HCV genotype.

Topics: 2-Naphthylamine; Aged; Amino Acid Substitution; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Gene Expression; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Isoenzymes; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Polymorphism, Genetic; Proline; Recurrence; Ribavirin; Sulfonamides; Treatment Failure; Uracil; Valine; Viral Load; Viral Nonstructural Proteins

We report a real-life 3D therapy failure in a patient treated with ombitasvir (OMV)/paritaprevir/ritonavir and dasabuvir without ribavirin (3D-R). He had therapy failure at week 12 after the end of treatment. We detected resistance-associated substitutions (RASs) plus polymorphisms on NS3, NS5A, and NS5B target regions by population sequencing (15% cut-off) at baseline, at relapse and during follow-up. About this, NS5A RASs generally persist longer than resistances in the other target genes and may impact treatment outcome. Therefore, to evaluate OMV drug-resistance mechanism, we studied the acquired RAS plus polymorphisms on NS5A phosphoprotein by computational studies. OMV showed a higher affinity towards baseline and 93H/108 K mutant structure (follow-up) with respect to 93H/R108 mutant structure (relapse) on phosphoprotein. By Molecular Dynamics simulations (MDs), structural information about the protein stability in presence of OMV were observed. According to our data, molecular modeling approach has proved to be a powerful method to evaluate the impact of these RASs plus specific amino acid (AA) changes on phosphoprotein.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Hepatitis C, Chronic; Humans; Male; Models, Molecular; Molecular Dynamics Simulation; Mutation, Missense; Polymorphism, Genetic; Proline; Recurrence; Treatment Failure; Valine; Viral Nonstructural Proteins

We report the case of a 75-year-old woman who was found to have hepatitis C virus (HCV) infection in 1987. Before treatment in 2016, she was found to have mixed cryoglobulinemia (MC). Direct-acting antiviral (DAA) treatment produced a sustained virological response 12 (SVR12). She noticed gradual muscle weakness in 2015 and the gradual development of dysarthria and dysphagia in 2017. We performed a muscle biopsy that showed inclusion body myositis (IBM). To the best of our knowledge, this is first case of a patient with HCV infection, MC, and IBM, in which MC and IBM did not improve after an SVR12 was obtained by DAA treatment.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Cryoglobulinemia; Cyclopropanes; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Myositis, Inclusion Body; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Valine

A 74-year-old Japanese man with a history of chronic hepatitis C and kidney transplant (KT) was administered pegylated-interferon plus ribavirin therapy. However, this therapy was ineffective. The patient was then hospitalized to receive ombitasvir (OBV) plus paritaprevir (PTV) plus ritonavir (r) antiviral combination therapy. He tested negative for the virus after 4 weeks, and completed 12 weeks of treatment. The patient ultimately achieved a sustained virological response after the 12 weeks of treatment. Cyclosporine (CyA) trough levels, during the OBV-PTV-r therapy, reached a peak within 5 days of initiating therapy, and increases in serum creatinine and total bilirubin were also observed. However, onset of irreversible nephropathy and hepatopathy were avoided by reducing the CyA dosage. The OBV-PTV-r therapy demonstrated a sufficient antiviral effect and could be safely administered postoperatively to patients having undergone KT. When a combination therapy with interferon-free, direct-acting antivirals is used in patients post-transplantation, consideration of drug-drug interactions with and monitoring CyA are of vital importance.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Kidney Transplantation; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Ribavirin; Ritonavir; Sulfonamides; Valine

Chronic hepatitis C (HCV) virus infection reactivates under immunosuppressive drugs and therefore has a negative impact on long-term survival of kidney transplant recipients. Treatment-induced clearance of hepatitis C virus (HCV) in kidney transplant candidates prevents virus reactivation after transplantation. Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (PrOD) represents a highly effective treatment regimen for HCV genotype 1 (GT1), also suitable for patients with end-stage renal disease (ESRD). Serious drug-drug interactions may represent a limiting factor of this regimen. The aim of this retrospective study was to evaluate safety, efficacy and drug-drug interactions management associated with PrOD treatment in the Czech real-world cohort.. Emphasizing concomitant medication adjustment, we described the treatment course with PrOD regimen in 23 patients (4 with CKD4 and 19 on maintenance haemodialysis) infected with HCV GT1 (21 GT1b, 2 GT1a), 18 males and 5 females with an average age of 53.7 years. Six patients had compensated liver cirrhosis and 3 of them were liver transplant recipients.. All 23 patients completed the 12-week treatment and achieved sustained virological response 12 weeks after the treatment (SVR12 rate 100%). None of the patients presented with a significant decrease in haemoglobin level, white blood cell and platelet count during the treatment period. The most frequent adverse events were nausea, hypotension, diarrhoea, and hyperkalemia. Four patients presented with a serious adverse event unrelated to the antiviral drugs (salmonellosis, non-functional kidney graft rejection, early gastric cancer, renal cyst infection, initiation of haemodialysis). Concomitant medication had to be modified with the treatment initiation in 10 out of 23 (43.5%) patients (calcium channel blockers, ACE inhibitors, statins, diuretics, tacrolimus); four patients required further adjustment of antihypertensive drugs or tacrolimus dosage on-treatment.. PrOD regimen demonstrated an excellent efficacy and good tolerability. Both prospective adjustment of concomitant medication and further on-treatment adjustment allowed for a safe treatment course.

Topics: 2-Naphthylamine; Anilides; Antihypertensive Agents; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Insufficiency; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

The optimum retreatment strategy for chronic hepatitis C virus (HCV) patients who failed directly-acting antiviral agents (DAA)-based therapy is unknown. We herein report the outcomes of an HCV genotype (GT) 2a-infected patient with virologic failure following treatment with sofosbuvir plus ribavirin (SOF+RBV) who was successfully retreated with ombitasvir/paritaprevir/ritonavir plus ribavirin (OBV/PTV/r+RBV).

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Retreatment; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Valine

Objective There are few reports on the outcomes of 12-week paritaprevir, ombitasvir, and ritonavir (PTV/OBV/r) treatment in real-world clinical settings. We aimed to evaluate the efficacy and safety of 12-week treatment with ritonavir-boosted paritaprevir and ombitasvir in patients with hepatitis C virus (HCV) genotype 1 infection in a real-world setting. Methods Fifty-eight patients with chronic hepatitis or compensated hepatic cirrhosis and genotype-1 HCV infection were treated with PTV/OBV/r and followed for 24 weeks after the completion of treatment in 10 centers in northern Tohoku. The efficacy and safety of this 12-week treatment regimen was analyzed. Results Among the 58 treated patients, 18 (31%) had compensated liver cirrhosis, while 11 (19%) patients had experienced treatment failure with another treatment regimen. NS5A resistance-associated variants (RAVs) were detected at baseline in 3 patients (5.2%), including Y93H in two patients and L31M in two patients. One patient had NS5A RAVs at both positions 93 and 31. The overall sustained virological response (SVR) 24 rate was 96.6%. Three patients with NS5A RAVs also achieved an SVR24. The SVR24 rate was not significantly affected by age, sex, prior treatment, prior history of HCC, or liver stiffness. The mean alanine aminotransferase (ALT) levels decreased significantly during this treatment. Adverse events occurred in 15 patients (26%), 26% of which were grade 1 or 2. No severe adverse events occurred. Conclusion In this real-world study, 12-week PTV/OBV/r treatment was effective and safe for treating patients with HCV-1 infection who had chronic hepatitis or compensated hepatic cirrhosis.

Topics: Adult; Aged; Alanine Transaminase; Anilides; Antiviral Agents; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Treatment Outcome; Valine

To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years.. We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12).. Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0-4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3-9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17-20.71, p = 0.029) as the only variable independently associated with SVR12.. Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

Topics: 2-Naphthylamine; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Biomarkers; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

The era of direct acting antivirals has revolutionised the management of chronic hepatitis C infection and improved patient outcomes. The optimal management of patients who require liver transplantation remains a matter of ongoing discussion. Treatment in the post-transplantation setting may be complicated by significant drug-drug interactions between antiviral agents and standard immune suppressive treatment regimens. We describe what we believe to be the first reported case of a patient successfully treated for CHC with ombitasvir/paritaprevir/ritonavir plus dasabuvir, while taking sirolimus following liver transplantation.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; End Stage Liver Disease; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Proline; Ritonavir; Sirolimus; Sulfonamides; Treatment Outcome; Uracil; Valine

We followed for 2 years patients treated with direct-acting agents (DAA) to assess long-term durability of virologic response, improvement of liver function, reduction in liver stiffness (LS) and risk of hepatocellular carcinoma (HCC). The study included patients from 16 hepatologic centres involved in the AMBER, investigator-initiated study on treatment of chronic hepatitis C patients within a programme preceding EU registration of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. A total of 204 patients among 209 from the primary study were enrolled, 200 with available testing at 2-year follow-up (2yFU) with undetectable HCV RNA (198 responders and 2 nonresponders retreated). During 2yFU, 4 patients died, 17 had hepatic decompensation and 3 needed liver transplantation. De novo hepatocellular carcinoma was diagnosed in 4 and its recurrence in 3 patients. Significant decreases in bilirubin, MELD, Child-Pugh scores and liver stiffness, and increases in albumin level were observed during 2yFU. Strengths of the study were a fixed period of post-treatment follow-up, prospective character of the study and high proportion of available patients from the primary study. The major weaknesses were lack of a comparative arm and relatively insufficient number of patients for subsets analysis. In conclusion, 2-year follow-up confirmed durability of virologic response after treatment of HCV infection with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. It was accompanied by significant improvement of major measures of hepatic function and reduction of hepatic stiffness. Successful therapy did not prevent hepatic decompensation, HCC or death in cirrhotics that support the need for longer than 2-year monitoring for possible disease progression.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Male; Middle Aged; Poland; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine; Viral Load

Nowadays, interferon-free therapy using new direct-acting antivirals (DAA) has dramatically increased the cure rate across different HCV-infected patient populations, including groups traditionally viewed as difficult-to-treat (patients with co-infections, cirrhosis and liver transplant - LT recipients) with marked improvement in safety and tolerability.. To present our experience with DAA therapy in LT recipients, as well as to compare pre- and post-treatment liver stiffness (LS) and noninvasive fibrosis scores.. Our cohort consisted of 89 patients with genotype 1 (GT1) recurrent hepatitis C after LT. Seventy six patients received ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin and 13 sofosbuvir/ledipasvir+/-ribavirin. Fibroscan®, FIB4 and APRI scores were performed in all patients before and 12 weeks after DAA therapy.. We analyzed 45 (50.5%) males and 44 (49.5%) females with a mean age of 55+/-7.7 years. Median time since LT was 20.9 months. At baseline, 53 (59.6%) of patients had severe necroinflammation at Fibromax®; advanced fibrosis (F3, F4) was encountered in 35 (39.4%) and grade 3 steatosis in 33 (37.1%) of LT recipients. End of therapy (EOT) virological response (VR) was 100%. Sustained virological response 12 weeks after therapy (SVR12) was 97.7% in the intention-to-treat analysis and 100% in per protocol analysis. There was a significant improvement in LS between antiviral therapy initiation and SVR12: 11.9+/-1.05kPa vs 8.8+/-0.6kPa (p<0.0001), as well as in APRI (2.7+/-0.3 vs 0.4+/-0.05, p<0.0001) and FIB4 (4.6+/-0.5 vs 2.5+/-0.2, p<0.0001) scores.. In HCV positive recipients, DAA regimens are highly effective and safe. A significant decrease of LS by transient elastography and fibrosis non-invasive scores can be observed after successful therapy.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uracil; Uridine Monophosphate; Valine

No studies have evaluated the use of sorafenib with the direct-acting antiviral ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV).. Three hepatitis C virus genotype 1b-infected patients with well-preserved liver function were included in this prospective case series. The patients were taking sorafenib for advanced hepatocellular carcinoma and received OBV/PTV/r+DSV for 12 weeks. One patient discontinued sorafenib while concomitant treatment due to grade 2 fatigue and muscular pain. The other two patients reported only grade 1 adverse effects. Sustained virologic response at 24 weeks was achieved, and no tumour recurrences were found.. The concurrent use of OBV/PTV/r+DSV with sorafenib was considered safe and effective.

Topics: 2-Naphthylamine; Aged; Anilides; Antineoplastic Agents; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ritonavir; Sorafenib; Sulfonamides; Treatment Outcome; Uracil; Valine

Hepatic decompensation is a severe on-treatment adverse event for chronic hepatitis C treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Till now, few papers regarding on-treatment hepatic decompensation have been reported. The study aims to analyze the general feature and predictive factors of on-treatment hepatic decompensation in hepatitis C virus (HCV) genotype 1b-infected patients with advanced fibrosis and compensated cirrhosis who receive treatment with PrOD.. A real-word cohort enrolled 189 HCV genotype 1b patients with advanced fibrosis and compensated cirrhosis treated with 12-week PrOD. Clinical and laboratory data were analyzed between patients with and without on-treatment hepatic decompensation.. The sustained virologic response rate at 12 weeks after treatment was 97.3% in HCV subtype 1b patients with advanced fibrosis and cirrhosis. On-treatment hyperbilirubinemia (total bilirubin >2 mg/dL) occurred in 27 (14.3%) patients, and the incidence of the increase of total and direct form bilirubin was significantly different during treatment between patients with Child-Turcotte-Pugh score 5 and score 6. Five (18.5%) hyperbilirubinemia patients progressed to hepatic decompensation. Older age (adjusted OR: 1.2, 95% CI: 1.0-1.4) and albumin ≤3.6 g/dL (adjusted OR: 10.4, 95% CI: 1.3-81.2) may be two predictors for on-treatment hepatic decompensation by multivariate analysis.. PrOD is an effective direct-acting antiviral agent for antiviral therapy in HCV genotype 1b patients with advanced fibrosis and cirrhosis. Hyperbilirubinemia is possibly the early warning feature of on-treatment hepatic decompensation. This serious adverse event of on-treatment hepatic decompensation is not common. Older age and low baseline albumin level may be predictive factors.

Topics: 2-Naphthylamine; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Hyperbilirubinemia; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Risk Factors; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Genotype; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

Direct-acting antiviral therapy for hepatitis C virus (HCV) infection is safe and effective, but there are little data among people who have recently injected drugs. This study evaluated the efficacy, and safety of paritaprevir/ritonavir, ombitasvir, dasabuvir with or without ribavirin for chronic HCV genotype (G) 1 among people with recent injecting drug use and/or receiving OST.. D3FEAT is an international open-label study that recruited treatment-naïve participants with recent injecting drug use (previous 6 months) and/or receiving OST with chronic HCV G1 infection between June 2016 and February 2017 in seven countries. Participants received paritaprevir/ritonavir, ombitasvir, dasabuvir with (G1a) or without ribavirin (G1b) administered twice daily in a one-week electronic blister pack (records timing of each dose) for 12 weeks. The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (SVR12).. Among 87 participants (median age 48 years), 23% were female, 8% had cirrhosis, and 90% had G1a. Overall, 71% were receiving OST, 61% injected in the previous six months, 45% injected in the previous month, and 15% injected > daily. Treatment completion was 97% (84 of 87). There were no virological breakthroughs, but three discontinuations (loss to follow-up, n = 1; non-adherence, n = 1; incarceration, n = 1). SVR was 91% (79 of 87, 95% CI, 83%-96%). Five participants who completed treatment did not have SVR (loss to follow-up, n = 1; death, n = 1; virologic relapse, n = 3). Drug use prior to and during treatment did not impact SVR12. Treatment-related adverse events were observed in 46 (53%) patients (six grade 3, no grade 4). Five (6%) patients had at least one serious adverse event (two possibly/probably related to therapy; nausea and myoclonus). Two cases of reinfection were observed.. Paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for 12 weeks is effective among people with HCV genotype 1 with recent injecting drug use and/or receiving OST.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Medication Adherence; Middle Aged; Opiate Substitution Treatment; Proline; Qualitative Research; Ribavirin; Ritonavir; RNA, Viral; Substance Abuse, Intravenous; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

According to the EASL and AASLD guidelines, the recommended treatment for patients who failed to achieve a sustained virologic response (SVR) on prior interferon-based triple therapy with protease inhibitors (PI), is a combination of sofosbuvir and NS5A inhibitors. Polish national recommendations also allow the use of paritaprevir/ritonavir/ombitasvir+dasasbuvir±ribavirin (PrODR) in this group of patients. The aim of the study was to evaluate the efficacy and safety of PrODR vs. ledipasvir/sofosbuvir±RBV (LSR) in PI-experienced patients in real-life setting.. Our analysis included patients registered in the nationwide, investigators initiated, multicentre EpiTer-2 database. Among 4530 patients registered, 335 with genotype 1 (93% 1b) were previously treated with IFN-based regimens with PIs: 127 with boceprevir (BOC), 208 with telaprevir (TVR). Patients with advanced fibrosis (F3/F4) were significantly predominant (BOC 28.4%/61.4%, TVR 18.8%/64.4%, respectively). Subjects were assigned to IFN-free retreatment as follows: BOC - 64 (50.4%) PrODR and 63 (49.6%) LSR; TVR- 103 (49.5%) PrODR and 105 (50.5%) LSR.. SVR rates were comparable for particular groups: BOC → PrODR- 100%; BOC → LSR - 98%; TVR → PrODR - 97%; TVR → LSR - 96% (intent-to treat analysis-ITT) and BOC → PrODR→100%; BOC → LSR - 99%; TVR → PrODR - 99%; TVR → LSR - 98% (modified intent-to treat analysis-mITT). Both treatment regimens had a favourable safety profile. Adverse events (AEs) were generally mild or moderate in severity. Three deaths were reported. The treatment was stopped due to AEs in five patients (three treated with PrODR and two with LSR).. Efficacy and safety of treatment with PrODR and LSR is comparable in BOC or TVR-experienced patients.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cohort Studies; Cyclopropanes; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Poland; Proline; Protease Inhibitors; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil; Uridine Monophosphate; Valine; Young Adult

Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Germany; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Severity of Illness Index; Sulfonamides; Treatment Outcome; Uracil; Valine; Viral Load

All-oral direct-acting antiviral regimens that include combinations of ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin were evaluated in hepatitis C virus-infected patients in phase II/III clinical studies. The objective of these analyses was to quantify the relationship between exposures of the components of the regimen and laboratory values and to determine covariates that could influence the relationship.. Exposure-safety response relationships between individual components of the direct-acting antiviral regimens and clinically important laboratory values were explored using data from 2998 patients from 11 phase II/III clinical studies. Multivariate logistic regression analyses were used to identify significant relationships between predictor variables and response variables.. No statistically significant associations were observed between ombitasvir, dasabuvir, or ritonavir exposures and maximum post-baseline alanine aminotransferase (ALT) or total bilirubin grade or minimum hemoglobin grade. A two-fold increase in paritaprevir exposure from therapeutic exposure was predicted to increase the probability of experiencing a grade 3 or higher increase in ALT by 0.5% and bilirubin by 1.1%. In the phase II/III clinical studies, ALT and bilirubin increases were reversible with continued dosing or after treatment cessation. Other correlates with adverse events of clinical importance included concomitant ribavirin treatment, sex, race, and presence of cirrhosis, consistent with previous observations.. Exposure-response analyses from phase II/III studies with the combination direct-acting antiviral regimen indicated no statistically significant relationships with ombitasvir, dasabuvir, or ritonavir exposure, but a statistically significant association was observed between paritaprevir exposure and the probability of experiencing a grade 3 or higher increase in ALT or bilirubin.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine; Young Adult

We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy.. In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study.. 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83-12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients.. Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice.. Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Compassionate Use Trials; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Longitudinal Studies; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

Hepatitis C virus (HCV) can infect extrahepatic tissues, including lymphocytes, creating reservoir of the virus. Moreover, HCV proteins can interact with DNA damage response proteins of infected cells. In this article we investigated the influence of the virus infection and a new ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) anti-HCV therapy on the PBMCs (peripheral blood mononuclear cells, mainly lymphocytes) DNA base excision repair (BER) system. BER protein activity was analyzed in the nuclear and mitochondrial extracts (NE and ME) of PBMC isolated from patients before and after therapy, and from subjects without HCV, using modeled double-strand DNA, with 2'-deoxyuridine substitution as the DNA damage. The NE and ME obtained from patients before therapy demonstrated lower efficacy of 2'-deoxyuridine removal and DNA repair polymerization than those of the control group or patients after therapy. Moreover, the extracts from the patients after therapy had similar activity to those from the control group. However, the efficacy of apurinic/apyrimidinic site excision in NE did not differ between the studied groups. We postulate that infection of lymphocytes by the HCV can lead to a decrease in the activity of BER enzymes. However, the use of novel therapy results in the improvement of glycosylase activity as well as the regeneration of endonuclease and other crucial repair enzymes.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cell Nucleus; Cyclopropanes; Deoxyuridine; DNA; DNA Breaks, Double-Stranded; DNA Glycosylases; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; Drug Therapy, Combination; Endonucleases; Gene Expression; Hepacivirus; Hepatitis C, Chronic; Host-Pathogen Interactions; Humans; Lactams, Macrocyclic; Leukocytes, Mononuclear; Macrocyclic Compounds; Mitochondria; Molecular Mimicry; Primary Cell Culture; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

Combination of sofosbuvir plus ledipasvir therapy has been expected to enhance sustained virological response (SVR) rates in hepatitis C virus (HCV) genotype 1 chronic infected patients. We analyzed the emergence of drug resistance-associated variants (RAVs) in treatment failure and changes in lipid profiles in sofosbuvir/ledipasvir-treated patients. A total of 176 patients with chronic HCV genotype 1 infection without decompensated liver cirrhosis were treated with sofosbuvir/ledipasvir for 12 weeks. NS5A and NS5B RAVs were determined by either Invader assay or direct sequencing. Serum lipid-related markers were measured at the start of treatment and at week 4 in patients who received sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir therapies. SVR was achieved in 94.9% (167 out of 176) of patients. SVR12 rate was 97.1% for patietns with low frequncy (<25%) of baseline NS5A RAVs, but 82.8% for patients with high frequency (>75%) of NS5A RAVs. In multivariate regression analysis, higher albumin (odds ratio [OR] = 0.020 for presence; P = 0.007), and NS5A-L31/Y93 RAVs with a population frequency <75% (OR = 29.860 for presence; P = 0.023) were identified as significant independent predictors for SVR12. NS5A-Y93H substitutions were detected in all nine treatment failures at HCV relapse, and three out of six patients with NS5A inhibitor-naïve patients achieved additional NS5A RAVs. Serum low-density lipoprotein cholesterol and apolipoprotein B levels were significantly elevated at week 4 in sofosbuvir/ledipasvir-treated patients. These elevations were greater than in ombitasvir/paritaprevir/ritonavir-treated patients. In conclusion, NS5A multi-RAVs are likely to develop in patients who fail to respond to sofosbuvir/ledipasvir therapy. Inhibition of HCV replication with sofosbuvir might affect lipid metabolism.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; Fluorenes; Genetic Variation; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Lipids; Macrocyclic Compounds; Male; Middle Aged; Mutation; Proline; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Failure; Uridine Monophosphate; Valine; Young Adult

Direct acting antivirals for hepatitis C virus have shown dramatic results in clinical trials. However, their effectiveness has yet to be demonstrated within observational cohorts which lack exclusion criteria found in randomized control trials.. To determine the effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir in achieving sustained virological response.. Retrospective observational cohort study of all Clalit Health Services members with hepatitis C virus genotype 1 who were dispensed dasabuvir/ombitasvir/paritaprevir/ritonavir from January 1, 2015 to-November 31, 2015.. There were 564 participants during the study period. The average age was 61.9 years, 52.0% were male, and 61.5% were born Eastern/Central Europe or Central Asia. The prevalence of diabetes was 31.7% and 70.3% were overweight/obese. Cirrhosis was present in 41.0% of participants, of whom 52.8% had stage 4 fibrosis. Of the cohort, 416 (74.8%) had follow-up viral load testing at 10 or more weeks after the end of treatment. We report a sustained virological response of 98.8% among those tested.. Treatment with dasabuvir/ombitasvir/paritaprevir/ritonavir demonstrated a near universal effectiveness in achieving a sustained virological response among HCV patients in a large cohort.

Topics: 2-Naphthylamine; Aged; Anilides; Carbamates; Cyclopropanes; Drug Combinations; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Sulfonamides; Uracil; Valine; Viral Load

Interferon-based regimens are associated with a substantial survival benefit for persons infected with hepatitis C virus (HCV). Survival data with direct-acting antiviral agents are not available. We conducted this study to quantify the effect of paritaprevir/ritonavir, ombitasvir, dasabuvir (PrOD) and ledipasvir/sofosbuvir (LDV/SOF) regimens upon mortality.. In the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans, we identified HCV-infected persons initiated on PrOD or LDV/SOF, excluding those with human immunodeficiency virus, hepatitis B surface antigen positivity, hepatocellular carcinoma, or missing HCV RNA or FIB-4 scores. For each case, we identified a propensity score-matched control never initiated on treatment. Primary outcome was survival. Outcomes were assessed using frequency of events, Kaplan-Meier curves, and Cox proportional hazards regression analyses.. We identified 1473 persons on PrOD, 5497 on LDV/SOF, and 6970 propensity score-matched untreated persons. Treated persons were more likely to be obese and have cirrhosis, but less likely to have stage 3-5 chronic kidney disease (CKD), alcohol or drug abuse or dependence diagnosis, and anemia. The proportion of persons who died was higher in the untreated group compared with either treatment group (PrOD, 0.3%; LDV/SOF, 1.4%; untreated controls, 2.5%; P < .001). A significantly larger percentage of treated patients survived to 18 months of follow-up, compared with untreated controls (P < .001). In multivariable Cox regression analysis, treatment with either regimen (hazard ratio [HR], 0.43; 95% confidence interval [CI], .33-.57) and attainment of sustained virologic response (SVR) were associated with significantly lower mortality (HR, 0.57; 95% CI, .33-.99).. Treatment with PrOD or LDV/SOF and SVR are associated with a significant mortality benefit, apparent within the first 18 months of treatment.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C, Chronic; Humans; Kaplan-Meier Estimate; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Propensity Score; Proportional Hazards Models; Ritonavir; Sofosbuvir; Sulfonamides; Survival Rate; Sustained Virologic Response; Uracil; Valine

Successful use of a 4-drug oral fixed-dose combination therapy to treat chronic hepatitis C in a patient receiving peritoneal dialysis (PD) is reported.. New highly effective treatments for chronic hepatitis C virus (HCV) infection are now available, but safety and efficacy data on the use of anti-HCV therapies in patients with renal failure, particularly those requiring PD, remain limited. A 73-year-old black man with chronic HCV genotype 1a infection and stage 5 chronic renal disease requiring daily automated PD was referred for HCV treatment prior to renal transplantation. HCV treatment was initiated with paritaprevir-ritonavir-ombitasvir- dasabuvir, or "PrOD" (a combination tablet containing paritaprevir 75 mg, ritonavir 50 mg, and ombitasvir 12.5 mg to be taken once daily and a dasabuvir sodium 250-mg tablet to be taken twice daily), in conjunction with ribavirin 200 mg once daily. After a 12-week course of PrOD therapy, during which ribavirin therapy was tapered and then discontinued at week 10 and subcutaneous epoetin alfa was administered for anemia control from weeks 4 to 12, the patient's HCV viral load was undetectable; a sustained virologic response at 12 weeks (SVR12) was noted.. A patient with end-stage renal disease requiring PD was treated successfully for HCV genotype 1a infection with PrOD fixed-dose combination therapy plus ribavirin therapy. The patient achieved an SVR12 despite withdrawal of ribavirin at treatment week 10, with minimal adverse effects reported.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Combinations; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Peritoneal Dialysis; Proline; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

Direct acting antiviral (DAA)-based treatment with ombitasvir/paritaprevir/ritonavir ± dasabuvir (OBV/PTV/r ± DSV) is highly effective in HCV genotype 1 or 4 infection and well-tolerated with only few side effects. However, pruritus has been observed in several trials in up to 20% of patients and seems to be unique for this DAA combination.. The aim of this preliminary study was to investigate the effect of OBV/PTV/r ± DSV on bile acid levels and to correlate them to the emergence of pruritus during treatment.. Twenty patients with chronic hepatitis C genotype 1 or 4 were treated for 12 or 24 weeks with OBV/PTV/r ± DSV with or without ribavirin. Side effects including pruritus were assessed every 4 weeks during treatment or on demand. Blood was collected in fasting state at baseline and at treatment week 4 for determination of bile acid concentrations by high-resolution mass spectrometry.. Pruritus developed in 5 out of 20 patients during the first 4 weeks of DAA treatment. Pruritus was self-limiting during DAA treatment in 4 patients while one patient required cholestyramine treatment and responded well. Total bile acid levels increased approximately 4‑fold by treatment week 4.. Pruritus observed during OBV/PTV/r ± DSV treatment of chronic hepatitis C is associated with increased on-treatment serum bile acid levels, possibly due to ritonavir-induced alterations of bile acid transport.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Bile Acids and Salts; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Pruritus; Ritonavir; Sulfonamides; Uracil; Valine

Direct-acting antiviral agents (DAAs) have been widely used for chronic hepatitis C (CHC) treatment recently. The characteristics of glucose abnormalities after DAAs therapy however, remain elusive. We aimed to elucidate the mutual impact between treatment response and parameters of glucose abnormalities after DAAs therapy in CHC patients. CHC patients who received DAAs therapy were recruited. The primary outcome measurements were their insulin resistance (IR) and beta-cell function assessed by the homeostasis model assessment (HOMA) method before treatment and at end-of-follow-up (EOF). Sixty-five CHC patients (19 males, mean age = 59.8 ± 10.3 years) were consecutively enrolled. They included 47 (72.3%) patients of genotype-1 infection. The treatment regimens among patients were sofosbuvir in 30 patients, paritaprevir-ritonavir/ombitasvir/dasabuvir in 23 patients, and asunaprevir/daclatasvir in 12 patients respectively. The overall sustained virological response rate was 98.5%. The mean IR at EOF was 2.6 ± 1.8, which was not significantly different from baseline level (2.7 ± 2.9, P = 0.75). There was a significant improvement of beta-cell function at EOF compared to baseline (107.7 ± 86.8 to 86.7 ± 44.5, P = 0.05). The amelioration of beta-cell function at EOF was significantly observed among 23 patients of high baseline IR (166.7 ± 111.3 of baseline vs 105.7 ± 48.2 of EOF, P = 0.04). Six (60%) of the 10 pre-diabetic patients at baseline achieved a normoglycemic state at EOF. Successful eradication of HCV by DAAs might improve glucose abnormalities in CHC patients, particularly among those who had high IR.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Glucose; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Insulin Resistance; Insulin-Secreting Cells; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Ritonavir; Sofosbuvir; Sulfonamides; Uracil; Valine

Advanced age has been a major limitation of interferon-based treatment for chronic hepatitis C virus (HCV) infection because of its poor response and tolerability. Direct-acting antiviral (DAA) drug regimens are safe and highly effective, allowing administration of treatment also in elderly. This study aims to assess the efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with ribavirin for the treatment of patients aged ≥70 years with HCV genotype 1b compensated cirrhosis.A total of 1008 patients with HCV genotype 1b compensated cirrhosis were prospectively treated with PrOD + ribavirin for 12 weeks, between December 2015 and July 2016. Sustained virologic response 12 weeks after the end of treatment (SVR12), adverse effects (AEs), comorbidities, discontinuation, and death rates were recorded. Efficacy and safety of therapy were assessed in patients aged ≥70 years and compared with data from patients <70 years.There were 117 patients aged ≥70 years, preponderantly females (58.9%), mean age 73.3 ± 2.8 years (range 70-82), and 37 (31.6%) were treatment-experienced. Comorbidities were reported in 60.6% of patients ≥70 years and in 39.8% of those <70 years (P < .001). SVR12 rates based on intention-to-treat and per-protocol analyses were 97.4% and 100%, respectively, in patients ≥70 years, compared to 97.8% and 99.6%, respectively, in patients <70 years (P = ns and P = ns). Severe AEs were reported in 4 (3.4%) patients ≥70 years, compared to 23 (2.6%) in those <70 years (P = ns). One death was recorded in a patient aged 79 years (0.9%) and 6 deaths (0.8%) in those <70 years (P = ns).Treatment with PrOD + ribavirin in patients 70 years of age or older with HCV genotype 1b compensated cirrhosis proved as effective, safe, and well tolerated, as it did in younger patients.

Topics: 2-Naphthylamine; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Proline; Prospective Studies; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

To report a case series of three patients with hepatitis C virus infection who all presented with severe type B lactic acidosis shortly after starting treatment with ombitasvir-paritaprevir-ritonavir-dasabuvir.. Case series.. ICU.. Three patients, all who had HCV cirrhosis with mild hepatic impairment (Child-Pugh A) and had started taking ombitasvir-paritaprevir-ritonavir-dasabuvir within the preceding 2 weeks, presented with similar nonspecific symptoms of lethargy, fatigue, and nausea. All had elevated lactate levels at admission without evidence of hypovolemia, cardiogenic failure, or vasodilatory shock.. All patients were given appropriate supportive intensive care for what was initially suspected to be sepsis, including a minimum of 30 mL/kg of IV fluids, infectious workup including blood cultures, broad-spectrum antibiotics, and mechanical ventilatory support. The first patient received continuous veno-venous hemofiltration. The second patient received hemodialysis. The third patient was initially started on hemodialysis despite high norepinephrine requirements and ultimately transitioned to continuous veno-venous hemofiltration.. The first patient died despite maximal intensive care. The second patient improved immediately upon starting hemodialysis and was extubated within 48 hours and discharged home. The third patient eventually became hypotensive and was treated with repeated sessions of renal replacement therapy. He ultimately was extubated and discharged home. The infectious workup was negative for all three patients, and antibiotics were discontinued after 2 days in the second and third patients.. Ombitasvir-paritaprevir-ritonavir-dasabuvir may cause type B lactic acidosis. Further study is warranted to identify risk factors and elucidate the mechanisms of excessive lactate production.

Topics: 2-Naphthylamine; Acidosis, Lactic; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Female; Fluid Therapy; Hemofiltration; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Dialysis; Respiration, Artificial; Ritonavir; Sulfonamides; Uracil; Valine

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Disease Progression; Drug Combinations; Drug Resistance, Viral; Hepacivirus; Hepatitis C, Chronic; High-Throughput Nucleotide Sequencing; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Sustained Virologic Response; Treatment Failure; Uracil; Valine; Viral Nonstructural Proteins

Paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD) is a direct-acting antiviral (DAA) approved for the treatment of chronic hepatitis C virus. We report on a probable interaction between PrOD with ribavirin and warfarin.. Two weeks after the start of PrOD with ribavirin, the patient's international normalized ratio (INR) became subtherapeutic. Eleven weeks into therapy and following a 125% total increase in the weekly warfarin dose, therapeutic INR was achieved. Thirteen days after DAA therapy was completed and discontinued, the patient's INR became critically supratherapeutic.. Patients on PrOD plus ribavirin with warfarin should have INR followed closely upon initiation and discontinuation of therapy due to a probable drug interaction.

Topics: 2-Naphthylamine; Anilides; Anticoagulants; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine; Warfarin

In registration studies, combination therapy of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with and without ribavirin for 12-24 weeks can achieve > 90% sustained virological response (SVR) for genotype 1 hepatitis C virus (HCV) infection. However, data in Asia is scanty. We aimed to study the efficacy and safety of this combination therapy in chronic hepatitis C patients in Hong Kong.. We retrospectively analyzed data from six local hospitals that have prescribed PrOD with and without ribavirin to patients with genotype 1 chronic HCV infection as part of a global compassionate program.. Among 41 patients treated, 35 (85%) patients had genotype 1b HCV infection, 6 (15%) had co-infection with human immunodeficiency virus, 35 (85%) failed previous peginterferon and ribavirin therapy, 25 (61%) had compensated liver cirrhosis, and 3 (7%) had liver transplantation. Thirty-five (85%) patients received 12-week treatment and six patients received 24-week treatment; 26 (63%) patients received ribavirin combination. Thirty-nine (95%; 95% confidence interval 88.5-100%) patients had undetectable HCV RNA at 12-week post-treatment, that is, SVR. The two patients who did not develop SVR discontinued treatment prematurely; both of them were treatment experienced with liver cirrhosis complicated by acute renal failure unrelated to the treatment of PrOD and ribavirin. No patient had hepatic decompensation.. Paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin is effective and safe in patients with genotype 1 HCV infection in real-life clinical setting in Hong Kong.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Hong Kong; Lactams, Macrocyclic; Liver Cirrhosis; Liver Transplantation; Macrocyclic Compounds; Proline; Retrospective Studies; Ribavirin; Ritonavir; Sulfonamides; Time Factors; Treatment Outcome; Uracil; Valine

High rates of sustained virologic response at post-treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA

Topics: Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Clinical Trials, Phase III as Topic; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Proline; RNA, Viral; Sustained Virologic Response; Time Factors; Treatment Outcome; Valine; Young Adult

Hepatitis C virus (HCV) infection is common in dialysis patients worldwide and nosocomial HCV spread within dialysis facilities continues to develop. Combination therapy with daclatasvir and asunaprevir (DCV/ASV) that has proven efficacy for dialysis patients infected with genotype 1b HCV (HCV/1b) has several concerns in Japan. The recently available combination therapy with ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) is not contraindicated in patients with chronic renal failure and has more safety profile and shorter treatment period than that with DCV/ASV. We evaluated the effects of combination therapy with OBV/PTV/r in four dialysis patients infected with HCV/1b, who were eligible for our study. On-treatment assessments included standard laboratory testing, serum HCV RNA and symptom-directed physical examinations. Three patients had a sustained virological response at 12 weeks after treatment, but one remaining patient had viral breakthrough. Notably, the patient with viral breakthrough had been coinfected with HCV/1b and HCV/2b; namely, HCV/2b with resistance-associated variations was not eradicated by the combination therapy. Among the three patients responsive to the combination therapy, one patient complained of appetite loss and itching, while in another patient the therapy was discontinued due to itching, exacerbation of wamble, and a falling tendency probably due to interaction with valsartan. These AEs were ameliorated or disappeared after the completion of the therapy. The significance of our study is persuasive virological evaluation associated to the combination therapy and reasonable interpretation of AEs. In conclusion, combination therapy with OBV/PTV/r may have promise as an efficacious therapy, but caution regarding AEs should be practiced.

Topics: Aged; Anilides; Carbamates; Cyclopropanes; Demography; Disease Progression; Drug Resistance, Viral; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Dialysis; Ritonavir; Sulfonamides; Valine

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Prevalence; Proline; Retreatment; Ritonavir; Sulfonamides; Uracil; Valine; Viral Load

We aimed to investigate the efficacy of interferon and ribavirin-free sofosbuvir/ledipasvir (SOF/LDV) and ritonavir boosted paritaprevir/ombitasvir with or without dasabuvir (2D/3D) regimens in a real-life cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected patients. The study focused on efficacy, need for changes in antiretroviral therapy (ART) due to drug-drug interaction (DDI), and treatment-associated changes in liver stiffness.. In this study 36 patients (n = 21 SOF/LDV and n = 15 2D/3D) were retrospectively analyzed. Depending on the genotype the following treatment regimens were used: HCV genotype (GT)-1: either SOF/LDV or 3D, no patient with HCV-GT2 was included, HCV-GT3: SOF/LDV, HCV-GT4: 2D.. Approximately one third (35.3%) of patients were treatment-experienced and 13.9% had cirrhosis. Antiretroviral therapy had to be changed in 38.1% of SOF/LDV and 60% of 2D/3D patients prior to anti-HCV treatment due to expected DDIs. We observed sustained virologic response (SVR) rates of 100% in patients treated with SOF/LDV (19/19) and 2D/3D (14/14). One 2D/3D patient was lost to follow-up, while two SOF/LDV patients died during therapy from non-treatment-related causes. They were excluded from the analysis. Between baseline and follow-up liver stiffness decreased from 11.4 to 8.3 kPa (p = 0.008) and from 8.1 to 5.7 kPa (p = 0.001) in SOF/LDV and 2D/3D patients, respectively.. We confirmed the excellent HCV eradication rates >95% in a real-life cohort of HIV/HCV coinfected patients treated with SOF/LDV and 2D/3D. We observed no HCV relapse or breakthrough. More patients treated with 2D/3D required a change in ART than patients treated with SOF/LDV. Additionally, HCV eradication led to a rapid decline in liver stiffness.

Topics: 2-Naphthylamine; Adult; AIDS-Related Opportunistic Infections; Anilides; Anti-HIV Agents; Antiviral Agents; Austria; Benzimidazoles; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C, Chronic; HIV Seropositivity; Humans; Lactams, Macrocyclic; Liver; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Retrospective Studies; Ritonavir; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine

Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice.. Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded.. The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%.. In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles.. In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Genotype; Glomerular Filtration Rate; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Male; Middle Aged; Neoplasm Recurrence, Local; Proline; Retrospective Studies; Ribavirin; Ritonavir; Sofosbuvir; Spain; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Uridine Monophosphate; Valine; Young Adult

Hepatitis C virus infection is common among patients on hemodialysis therapy and is an important cause of morbidity and mortality. We investigated the safety and effectiveness of a paritaprevir/ritonavir/ombitasvir/dasabuvir regimen in a group of 10 patients on hemodialysis therapy with genotype 1a, 1b, or 4 hepatitis C virus infection who had predictors of unfavorable response, such as compensated cirrhosis (7 patients) or advanced fibrosis and failure of previous therapy (3 patients). The treatment, with or without ribavirin, was administered daily for 12 or 24 weeks. Clinical and virologic assessment was performed every 4 weeks during the treatment and at posttreatment weeks 4 and 12. All patients achieved a sustained virologic response at posttreatment week 12. 80% of patients reported at least one adverse event: fatigue and anemia of mild intensity were the most common; a single episode of moderate liver decompensation was observed. The paritaprevir/ritonavir/ombitasvir/dasabuvir antiviral regimen is effective and well tolerated in genotype 1 or 4 hepatitis C virus-infected patients on hemodialysis therapy with compensated cirrhosis and/or failure of previous treatments.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Dialysis; Ritonavir; Severity of Illness Index; Sulfonamides; Treatment Outcome; Uracil; Valine

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepatitis C, Chronic; HIV Infections; Humans; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Raltegravir Potassium; Ritonavir; Sulfonamides; Uracil; Valine

Acid-reducing agents (ARAs) and proton-pump inhibitors (PPIs) that increase gastric pH can alter the bioavailability of antiviral drugs, particularly relevant in patients with advanced liver disease caused by chronic hepatitis C virus (HCV) infection seeking therapy. Using integrated data from six phase 3 studies, we report the safety and efficacy of the 3-direct-acting antiviral (DAA) regimen containing ombitasvir (OBV, an NS5A inhibitor), ritonavir-boosted paritaprevir (PTV/r, an NS3/4A protease inhibitor), and dasabuvir (DSV, an NS5B polymerase inhibitor) with or without ribavirin (RBV) for HCV genotype 1 patients taking concomitant ARAs and PPIs.. Treatment-naïve or peginterferon/RBV treatment-experienced patients with or without compensated cirrhosis received OBV/PTV/r and DSV with or without weight-based RBV. Rates of sustained virologic response (SVR), defined as HCV RNA below the lower limit of quantification, 12 weeks post-treatment (SVR12) and safety were evaluated in patients who were receiving concomitant ARAs.. Among 2,053 patients enrolled and dosed with study drug, 410 (20%) were receiving concomitant ARAs; of these, 308 (15%) were taking concomitant PPIs. Rates of SVR12 were 95.9% (95% confidence interval (CI) 93.5-97.4%) among patients receiving an ARA, and 96.3% (95% CI 95.3-97.2%) in patients not receiving a concomitant ARA. Similarly, among patients receiving a PPI or not, SVR12 was achieved in 95.1% (95% CI 92.1-97.0%) and 96.4% (95% CI 95.5-97.2%), respectively. Response rates were high regardless of treatment regimen (with or without RBV), and among patients receiving a standard or high dose of PPIs. Regarding safety, adverse events and serious adverse events were more frequently reported in patients taking concomitant ARAs, though baseline population differences may have played a role.. In phase 3 trials of OBV/PTV/r plus DSV and RBV in HCV genotype 1-infected patients, SVR12 rates were high regardless of ARA/PPI use or PPI dose. These data support the co-administration of this regimen with ARAs including PPIs.

Topics: 2-Naphthylamine; Anilides; Antacids; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepatitis C, Chronic; Humans; Hydrogen-Ion Concentration; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

This study compared the cost-effectiveness of direct-acting antiviral therapies currently recommended for treating genotypes (GT) 1 and 4 chronic hepatitis C (CHC) patients in the US.. A cost-effectiveness analysis of treatments for CHC from a US payer's perspective over a lifelong time horizon was performed. A Markov model based on the natural history of CHC was used for a population that included treatment-naïve and -experienced patients. Treatment alternatives considered for GT1 included ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3D ± R), sofosbuvir + ledipasvir (SOF/LDV), sofosbuvir + simeprevir (SOF + SMV), simeprevir + pegylated interferon/ribavirin (SMV + PR) and no treatment (NT). For GT4 treatments, ombitasvir/paritaprevir/ritonavir + ribavirin (2D + R), SOF/LDV and NT were compared. Transition probabilities, utilities and costs were obtained from published literature. Outcomes included rates of compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC) and liver-related death (LrD), total costs, life-years and quality-adjusted life-years (QALYs). Costs and QALYs were used to calculate incremental cost-effectiveness ratios.. In GT1 patients, 3D ± R and SOF-containing regimens have similar long-term outcomes; 3D ± R had the lowest lifetime risks of all liver disease outcomes: CC = 30.2%, DCC = 5.0 %, HCC = 6.8%, LT = 1.9% and LrD = 9.2%. In GT1 patients, 3D ± R had the lowest cost and the highest QALYs. As a result, 3D ± R dominated these treatment options. In GT4 patients, 2D + R had lower rates of liver morbidity and mortality, lower cost and more QALYs than SOF/LDV and NT.. While the results are based on input values, which were obtained from a variety of heterogeneous sources-including clinical trials, the findings were robust across a plausible range of input values, as demonstrated in probabilistic sensitivity analyses.. Among currently recommended treatments for GT1 and GT4 in the US, 3D ± R (for GT1) and 2D + R (for GT4) have a favorable cost-effectiveness profile.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Cyclopropanes; Drug Therapy, Combination; Female; Fibrosis; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Male; Markov Chains; Middle Aged; Models, Econometric; Proline; Quality-Adjusted Life Years; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Valine

Long lasting hepatocytes damage related to HCV infection stimulates liver fibrosis resulting in cirrhosis, hepatic failure and hepatocellular carcinoma. Until 2011 the only therapeutic option was 24-48 weeks of pegylated interferon alfa and ribavirin (RBV) with efficacy of 40-70%. New generation of direct-acting antivirals (DAA), available from 2014, can be combined and improve efficacy above 90% with 12 weeks of treatment.. In this article we describe the first registered all-oral regimen consisting of three DAA - ombitasvir (OBV), paritaprevir (PTV) and dasabuvir (DSV) that became available in EU in 2015 to cure patients infected with HCV genotype 1 and 4. We performed a literature search focusing on efficacy and safety data from Phase 1-3 clinical studies and few real-world data.. OBV/PTV/r±DSV±RBV provided an opportunity to cure almost all patients including cirrhotics and non-responders to previous therapy. This treatment is currently recommended as a first line regimen. However, there is still a need for real-world data. In coming years this medication will probably be replaced with the next DAA generation with improved characteristics such as a shorter treatment duration, improved safety and resistance profile.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Uracil; Valine

To estimate clinical outcomes and cost-effectiveness of ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (OMB/PTV/r + DSV ± RBV) compared with treatment regimens including pegylated interferon (PegIFN) for patients with chronic genotype 1 hepatitis C virus (HCV) infection.. An Excel spreadsheet Markov model tracking progression through stages of liver disease was developed. Costs and patient utilities for liver disease stages were taken from published studies. Rates of disease progression were based on studies of untreated HCV infection and long-term follow-up of those achieving sustained virologic response (SVR) after drug treatment. Impact of OMB/PTV/r + DSV ± RBV and other drug regimens on progression was estimated through SVR rates from clinical trials. Analyses were performed for treatment-naive and treatment-experienced patients. Impact of alternative scenarios and input parameter uncertainty on the results were tested.. For genotype 1 treatment-naive HCV patients, for OMB/PTV/r + DSV ± RBV, PegIFN + ribavirin (PegIFN/RBV), sofosbuvir + PegIFN/RBV, telaprevir + PegIFN/RBV, boceprevir + PegIFN/RBV, lifetime risk of decompensated liver disease was 5.6%, 18.9%, 7.4%, 11.7%, and 14.9%; hepatocellular carcinoma was 5.4%, 9.2%, 5.7%, 7.0%, and 7.4%; and death from liver disease was 8.7%, 22.2%, 10.4%, 14.8%, and 17.6%, respectively. Estimates of the cost-effectiveness of OMB/PTV/r + DSV ± RBV for treatment-naive and treatment-experienced patients indicated that it dominated all other regimens except PegIFN/RBV. Compared with PegIFN/RBV, the incremental cost-effectiveness ratios were £13,864 and £10,258 per quality-adjusted life-year (QALY) for treatment-naive and treatment-experienced patients, respectively. The results were similar for alternative scenarios and uncertainty analyses.. A mixed-treatment comparison for SVR rates for the different treatment regimens was not feasible, because many regimens did not have comparator arms; instead SVR rates were based on those from recent trials.. OMB/PTV/r + DSV ± RBV is a cost-effective oral treatment regimen for chronic genotype 1 HCV infection compared with standard treatment regimens and is estimated to reduce the lifetime risks of advanced liver disease.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cost-Benefit Analysis; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Markov Chains; Middle Aged; Proline; Ritonavir; Sulfonamides; Uracil; Valine

Real-world data are needed to inform hepatitis C virus (HCV) treatment decisions.. To assess the comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV) vs. ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) ± RBV in genotype 1 HCV patients treated in routine medical practice.. Observational intent-to-treat cohort of genotype 1 patients initiating 8 or 12 weeks of LDV/SOF ± RBV or 12 weeks of OPrD ± RBV. Sustained virological response (SVR) required RNA below the limit of quantification at least 10 weeks after end of treatment.. 6961 patients initiated LDV/SOF (N = 4478), LDV/SOF + RBV (N = 1269), OPrD (N = 297), and OPrD + RBV (N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/SOF, 90.0% (1098/1220) for LDV/SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/SOF were 91.7% (1223/1333) and 12 weeks of LDV/SOF 94.6% (2475/2615), LDV/SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race (OR 0.71, 95%CI 0.59-0.86, P < 0.001), body mass index (BMI) > 30 kg/m(2) (OR 0.73, 95% CI 0.60-0.89, P = 0.002), FIB4 > 3.25 (OR 0.60, 95% CI 0.49-0.72, P < 0.001), OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48-0.76, P < 0.001) and subtype 1b (OR 1.38, 95% CI 1.11-1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors.. In this robust real-world cohort, SVR rates were similar to clinical trials. FIB-4 > 3.25 and high BMI were significant negative predictors of SVR. Reduced odds of SVR in African Americans and with OPrD + RBV likely arose from excess early discontinuation as these factors were no longer significant, when limited to patients completing a 12-week course.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Black or African American; Carbamates; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; RNA, Viral; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Young Adult

New treatments for chronic hepatitis C virus (HCV) are highly effective in patients coinfected with human immunodeficiency virus (HIV). This study estimated the cost-effectiveness of treatments for genotype 1 (GT1) HCV in HIV-coinfected patients.. A Markov model based on HCV natural history was used. The base-case analysis included both treatment-naïve and -experienced patients. Alternatives were ombitasvir/paritaprevir/ritonavir, dasabuvir with or without ribavirin (3D ± R) for 12 or 24 weeks, sofosbuvir plus peginterferon and R (SOF + PR) for 12 weeks, SOF + R for 24 weeks, and no treatment (NT). A subgroup analysis restricted to treatment-naïve, non-cirrhotic patients compared 3D ± R for 12 weeks to SOF plus ledipasvir (LDV) for 12 weeks and NT. Transition probabilities, utilities, and costs were obtained from the published literature. Outcomes were measured over a lifetime horizon and included rates of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death, total costs, life-years, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).. In the base-case, SOF + R was dominated by both SOF + PR and 3D ± R. Compared to SOF + PR, 3D ± R had an ICER of $45,581. The lifetime rates of liver morbidity and mortality were lower among those treated with 3D ± R compared to SOF + PR, SOF + R, or NT. In the subgroup analysis, 3D ± R was cost-effective compared to NT at a threshold of $50,000 per QALY (ICER $27,496). SOF/LDV had an ICER of $104,489 per QALY gained compared to 3D ± R.. In the GT1 HCV population coinfected with HIV, 3D ± R was cost-effective compared to NT, SOF + R, and SOF + PR. In the treatment-naïve sub-population, 3D ± R was cost-effective compared to NT and SOF/LDV.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Cyclopropanes; Disease Progression; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Interferon-alpha; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Markov Chains; Middle Aged; Polyethylene Glycols; Proline; Quality-Adjusted Life Years; Recombinant Proteins; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; United States; Uracil; Valine

This study compared the cost-effectiveness of chronic hepatitis C virus (HCV) genotype 1b (GT1b) therapy ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) vs daclatasvir + asunaprevir (DCV/ASV) and no treatment in patients without cirrhosis. Cost-effectiveness analyses (CEAs) that compared OBV/PTV/r against DCV/ASV and sofosbuvir/ledipasvir (SOF/LDV) in Y93H mutation-negative, GT1b patients with and without cirrhosis were also included.. A health state transition model was developed to capture the natural history of HCV. A CEA over a lifetime horizon was performed from the perspective of the public healthcare payer in Japan. Costs, health utilities, and rates of disease progression were derived from published studies. Sustained virologic response (SVR) rates of OBV/PTV/r and DCV/ASV were extracted from Japanese clinical trials. Analyses were performed for treatment-naïve and -experienced patients. Alternative scenarios and input parameter uncertainty on the results were tested.. OBV/PTV/r exhibited superior clinical outcomes vs comparators. For OBV/PTV/r, DCV/ASV, and no treatment, the lifetime risk of decompensated cirrhosis in treatment-naïve patients without cirrhosis was 0.4%, 1.4%, and 9.2%, and hepatocellular carcinoma was 6.5%, 11.4%, and 49.9%, respectively. Quality-adjusted life years (QALYs) were higher in treatment-naïve and -experienced patients without cirrhosis treated with OBV/PTV/r (16.41 and 16.22) vs DCV/ASV (15.83 and 15.66) or no treatment (11.34 and 11.23). In treatment-naïve and -experienced patients without cirrhosis, the incremental cost-effectiveness ratios (ICERs) of OBV/PTV/r vs DCV/ASV were JPY 1,684,751/QALY and JPY 1,836,596/QALY, respectively; OBV/PTV/r was dominant compared with no treatment. In scenario analysis, including GT1b patients with and without cirrhosis who were Y93H mutation-negative, the ICER of OBV/PTV/r vs DCV/ASV was below the Japanese willingness-to-pay threshold of JPY 5 million/QALY, while the ICER of SOF/LDV vs OBV/PTV/r was above this threshold; thus, OBV/PTV/r was cost-effective.. OBV/PTV/r appears to be a cost-effective treatment for chronic HCV GT1b infection against DCV/ASV. OBV/PTV/r dominates no treatment in patients without cirrhosis.

Topics: Anilides; Antiviral Agents; Carbamates; Cost-Benefit Analysis; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Japan; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Models, Economic; Proline; Ritonavir; Sulfonamides; Valine

Topics: 2-Naphthylamine; Alanine Transaminase; Anilides; Antiviral Agents; Aspartate Aminotransferases; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine; Withholding Treatment

No previous studies exist examining the effectiveness and safety in real clinical practice of the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV).. To evaluate the effectiveness and safety in real clinical practice of the combination of OBV/PTV/r+DSV with or without ribavirin for 12 weeks in treatment-naïve and previously treated adult patients with chronic hepatitis C virus (HCV) genotype 1 infection.. This was an observational study of a prospective cohort of treatment-naïve and pretreated adult patients who received 12 weeks of OBV/PTV/r (25/150/100 mg once daily) and DSV (250 mg twice daily) with or without ribavirin. The primary effectiveness outcome was sustained virological response 12 weeks after the end of treatment (SVR12). Safety outcomes were presented by the incidence of adverse events.. A total of 116 of 121 patients achieved a SVR12 (95.9%, 95% CI = 90.6-98.6). The SVR12 rate was 93.8% (95% CI = 86.0-97.9) in cirrhotic patients and 100% (95% CI = 91.4-100.0) in noncirrhotic patients. Adverse events occurred in 91.7% of patients, of which 81.8% were grade 1/2, and none led to premature discontinuation. Grade 3 adverse events were reported in 9.9% of patients. The most frequent adverse event was anemia (52.1%), although only 1.6% had a hemoglobin level below 8 g/dL. The incidence of any adverse event was higher in the group of patients who received ribavirin (96.5% vs 80.0%, P = 0.002).. The combination of OBV/PTV/r+DSV with or without ribavirin for 12-week settings achieved a high rate of SVR12, with an acceptable safety profile in routine clinical care.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Industry; Drug Therapy, Combination; Fees, Pharmaceutical; Fluorenes; Health Services Accessibility; Hepatitis C, Chronic; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Public Health; Pyrrolidines; Quality Assurance, Health Care; Quality Control; Ritonavir; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine

Direct antiviral agent (DAA) has been the standard of care for patients with hepatitis C virus (HCV) infection. Twelve weeks of paritaprevir/ritonavir/ombitasvir plus dasabuvir (PROD) with or without ribavirin has shown to have a sustained virological response at post-treatment 12 weeks (SVR12) rate of >90% in HCV genotype 1 (HCV-1) patients.. We report a HCV-1b patient who received only 25 days of PROD treatment.. The patient early terminated treatment due to dengue fever but eventually achieved SVR12. It may attribute to low baseline viral loads and extraordinarily rapid suppression of HCV after treatment day1.. The finding may shed light for possible response-guided-therapy for so-called ultra-super-responders in the DAA era. Whether the dengue virus, the Flaviviridae family as with HCV, enhanced the HCV clearance remains unclear and needs further exploration.

Topics: 2-Naphthylamine; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Dengue; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Uracil; Valine; Viral Load

Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin is one of the current recommended therapies for HCV genotype 1b monoinfected patients in compensated (Child-Pugh A) cirrhosis. Whether it is known that the worsening of liver function is a rare but possible complication of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir therapy, to our knowledge no description of treatment-related acute liver failure is available in the literature.. An 84-year-old Caucasian man with chronic compensated HCV genotype 1b cirrhosis received Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy. After 13 days he developed grade 4 hyperbilirubinaemia and ascites. Even though treatment was promptly stopped, patient's clinical condition worsened, and he underwent hospitalization, several paracentheses, and developed sub-acute kidney injury. The bilirubinemia returned under three times the upper normal limit only after five months. Notably, he achieved sustained virological response despite the very short duration of therapy.. Hepatic decompensation and acute liver failure are rare but severe complications of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy in patients with compensated cirrhosis. Close monitoring for signs or symptoms of worsening of liver disease is mandatory, and further research for stratifying risk factors are required.

Topics: 2-Naphthylamine; Aged, 80 and over; Anilides; Antiviral Agents; Ascites; Carbamates; Chemical and Drug Induced Liver Injury; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Hyperbilirubinemia; Lactams, Macrocyclic; Liver Cirrhosis; Liver Failure, Acute; Liver Function Tests; Macrocyclic Compounds; Male; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine

In 247 subjects with hepatitis C virus genotype 1 infection treated with the interferon-free regimen of ABT-450/ritonavir, ombitasvir, and dasabuvir plus ribavirin, concordance of a sustained virologic response at 12 and 24 weeks supports the use of the earlier time point as a primary efficacy endpoint for trials of this interferon-free regimen.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Recurrence; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Uracil; Valine; Viral Load

Topics: Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; England; Fluorenes; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Public Health; Pyrrolidines; Simeprevir; Sofosbuvir; Sulfonamides; Uridine Monophosphate; Valine

Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon (IFN)-α monotherapy in the early 1990s to the approval of telaprevir- and boceprevir-based triple therapies with pegylated (PEG)-IFN-α and ribavirin (RBV) in 2011, the chances of curing patients infected with HCV genotype 1 have improved dramatically to reach approximately 70%. Significant further improvements that may cure virtually all HCV patients with an all-oral, IFN-free regimen are becoming progressively available. Key Messages: Historically, a PEG-IFN/RBV combination therapy of patients with liver cirrhosis was associated with lower virological rates and a worse safety profile. The advent of the first protease inhibitor-based triple therapy was long expected, but the promise fell rapidly because of the numerous side effects and the requirement for intensive clinical management in cirrhotic patients. The newer direct-acting antivirals (DAAs) target the viral polymerase with either nucleos(t)ide analogues or nonnucleosidic inhibitors, the viral protease and the viral NS5A protein. Several clinical trials have now shown that a combination of sofosbuvir (nucleosidic polymerase inhibitor) with daclatasvir or ledipasvir (NS5A inhibitors), or sofosbuvir with simeprevir (protease inhibitor), or a combination of ABT-450 (protease inhibitor) with ritonavir (ABT-450/r), the nonnucleosidic polymerase inhibitor ABT-333 and the NS5A inhibitor ABT-267, can achieve a sustained virological response in up to 95% of naive patients or previously treated patients, even in those who failed prior treatment with first-generation protease inhibitors. The best treatment regimens enable the achievement of comparable results even in cirrhotics, while other regimens still require RBV or a longer treatment duration to achieve optimal results. This improved risk/benefit ratio justifies early access programs of IFN-free regimens for cirrhotic patients. The remaining difficult-to-treat patients are cirrhotics infected with HCV genotype 3 and those with decompensated cirrhosis, for whom novel DAA combinations should be evaluated in clinical trials.. As new DAAs are becoming available in early access treatment programs, treatment strategy studies are being performed to optimize treatment regimens with respect to the choice of DAAs and treatment duration, based on viral genotypes, prior treatment response and the presence of liver cirrhosis. In the near future, this should allow: (i) a decrease in the complications of HCV-induced cirrhosis, (ii) liver transplantations to be performed in virally cured patients, and (iii) the rescue of patients in the worst clinical situation (decompensated cirrhosis and HCV recurrence on liver graft).

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferon-alpha; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Proline; Protease Inhibitors; Pyrrolidines; Ribavirin; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine

Topics: 2-Naphthylamine; Anilides; Carbamates; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Germany; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Uracil; Valine

The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for the treatment of chronic hepatitis C virus infection in Japan. Ursodeoxycholic acid (UDCA) and glycyrrhizin (GCR) are hepatoprotective agents widely used in Japan. A drug-drug interaction (DDI) study was conducted to guide dosing recommendations for UDCA and GCR when coadministered with the 2D regimen.. DDIs between the 2D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg orally once daily) and UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) were evaluated in a 2-arm, multiple-dose study in 24 Japanese healthy subjects under fed conditions. Pharmacokinetic and safety evaluations were performed when UDCA or GCR and the 2D regimen were administered alone and during coadministration. Exposures from coadministration of the 2D regimen plus UDCA or GCR versus the 2D regimen, UDCA, or GCR alone were compared using repeated-measures analyses of natural logarithms of the maximum plasma concentration (Cmax) and area under the curve (AUC).. After coadministration of the 2D regimen and UDCA, steady-state exposures (Cmax and AUC) of ombitasvir, paritaprevir, and ritonavir showed a ≤9% change, and UDCA exposures showed a ≤20% change compared with administration alone. When the 2D regimen and GCR were coadministered, steady-state exposures of ombitasvir, paritaprevir, and ritonavir were not affected (≤9% change), GCR AUC increased by 49%, and GCR Cmax was unaffected (<1% change).. No dose adjustment is needed for UDCA, GCR, or the 2D regimen when UDCA or GCR is coadministered with the 2D regimen in hepatitis C virus-infected patients under fed conditions. Clinical monitoring of patients using GCR is recommended due to an approximately 50% increase in GCR AUC when coadministered with the 2D regimen.

Topics: Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Glycyrrhizic Acid; Hepatitis C, Chronic; Humans; Japan; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Ritonavir; Sulfonamides; Ursodeoxycholic Acid; Valine; Young Adult

The use of direct-acting antiviral (DAA) agents against chronic hepatitis C virus (HCV) infections can result in the successful treatment of nearly all patients. Effective antiviral treatments can prevent the progression to cirrhosis and hepatocellular malignancy, and decrease liver-related morbidity and mortality.. Paritaprevir-ritonavir-ombitasvir and dasabuvir (PrOD), with or without ribavirin, is an all-oral regimen approved for the treatment of HCV genotype 1 infections, including patients with compensated cirrhosis. Phase 2 and 3 clinical trials demonstrated the safety and efficacy of this regimen in HCV genotype 1-infected patients who are treatment-naïve and those who have failed peginterferon/ribavirin therapy. Additional studies evaluated the use of PrOD with or without ribavirin among special populations, including patients co-infected with human immunodeficiency virus-1 and HCV, liver transplant recipients with HCV recurrence, and patients with severe renal impairment. Additionally, the combination of paritaprevir-ritonavir-ombitasvir plus ribavirin is found to be highly efficacious, and is now approved in the US, for the treatment of HCV genotype 4 infections.. The availability and use of interferon-free DAA combination regimens has resulted in a major paradigm shift in the treatment of HCV. PrOD, with or without ribavirin, is an effective, safe and tolerable treatment option.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coinfection; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine

Topics: Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Ribavirin; Sulfonamides; Valine