abt-267 and Hepatitis-C

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

Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.

Topics: Animals; Antiviral Agents; DNA-Directed RNA Polymerases; Enzyme Inhibitors; Hepatitis C; Humans; Molecular Structure; Molecular Targeted Therapy; Protease Inhibitors

Topics: 2-Naphthylamine; Adrenal Cortex Hormones; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Eruptions; Drug Therapy, Combination; Female; Follow-Up Studies; Hepacivirus; Hepatitis C; Histamine Antagonists; Humans; Incidence; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Proline; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

The direct-acting antiviral regimen of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r)±dasabuvir (DSV)±ribavirin (RBV) demonstrated high rates of sustained viral response at post-treatment week 12 (SVR12) in clinical trials for treatment of hepatitis C virus (HCV) genotypes (GT) 1 and 4. To confirm the effectiveness of this regimen in the real world, we conducted meta-analyses of published literature on 30 April 2016. Freeman-Tukey transformation determined the SVR rate within GTs 1a, 1b and 4, as well as specific SVR rates by cirrhosis or prior treatment experience status. Rates of virologic relapse, hepatic decompensation, drug discontinuation and serious adverse events were also analysed. In total, 20 cohorts across 12 countries were identified, totalling 5158 patients. The overall SVR12 rates were 96.8% (95% CI 95.8-97.7) for GT1 and 98.9% (95% CI 94.2-100) for GT4. For GT1a patients, the SVR rates were 94% and 97% for those with or without cirrhosis, and 94% overall. For GT1b patients, the SVR rates were 98% and 99% for those with or without cirrhosis, and 98% overall. The virologic relapse rate of GT1 patients was 1.3%, across 3524 patients in nine studies that reported this parameter. The rate of hepatic decompensation was less than 1% across five studies, including 3440 patients, 70% of which had cirrhosis.. Real-world SVR12 rates for OBV/PTV/r±DSV±RBV were consistently high across HCV GT1 and four irrespective of cirrhosis status or prior HCV treatment experience, confirming effectiveness within a diverse patient population across multiple cohorts and countries.

Topics: Anilides; Antiviral Agents; Carbamates; Comorbidity; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Valine; Viral Load

AbbVie's 3 direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with and without ribavirin is approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Safe and efficacious antiviral regimens resulting in minimal to no drug-drug interactions (DDIs) with antiretrovirals are needed to ensure that patients coinfected with HCV and the human immunodeficiency virus (HIV) achieve 12-week sustained virologic response rates similar to HCV-monoinfected patients. Also, the prevalence of injection drug use history is high in both monoinfected and HIV/HCV-coinfected patients. This review summarizes results from phase 1 DDI studies of the 3D regimen and antiretrovirals or drugs to treat substance abuse. Data suggest the 3D regimen is a viable option for HIV/HCV-coinfected patients on antiretroviral therapy containing tenofovir/emtricitabine, abacavir/lamivudine, dolutegravir, raltegravir, or atazanavir. HCV-infected patients receiving medications for substance abuse, particularly methadone or buprenorphine/naloxone, can also be treated with the 3D regimen.

Topics: 2-Naphthylamine; Anilides; Anti-Retroviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepatitis C; HIV Infections; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Protease Inhibitors; Ritonavir; Substance-Related Disorders; Sulfonamides; Uracil; Valine

The development of direct-acting antiviral (DAA) agents has reinvigorated the treatment of hepatitis C virus infection. The availability of multiple DAA agents and drug combinations has enabled the transition to interferon-free therapy that is applicable to a broad range of patients. However, these DAA combinations are not without drug-drug interactions (DDIs). As every possible DDI permutation cannot be evaluated in a clinical study, guidance is needed for healthcare providers to avoid or minimize drug interaction risk. In this review, we evaluated the DDI potential of the novel three-DAA combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir (the 3D regimen) with more than 200 drugs representing 19 therapeutic drug classes. Outcomes of these DDI studies were compared with the metabolism and elimination routes of prospective concomitant medications to develop mechanism-based and drug-specific guidance on interaction potential. This analysis revealed that the 3D regimen is compatible with many of the drugs that are commonly prescribed to patients with hepatitis C virus infection. Where interaction is possible, risk can be mitigated by paying careful attention to concomitant medications, adjusting drug dosage as needed, and monitoring patient response and/or clinical parameters.

Topics: Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Drug Interactions; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Valine

Hepatitis B virus (HBV) and hepatitis C virus (HCV), discovered as causative viruses of post-transfusion hepatitis, become persistent infections, leading to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). For HCV, recent IFN-free direct-acting antiviral (DAA) therapies have increased sustained virological response (SVR) rates and reduced adverse events. IFN-based therapies, still the standard of care in Asian countries, are influenced by IL28B genetic variants and the liver fibrosis stage, but the DAA combinations obscure the influence of these factors. These new therapies can eradicate HCV and prevent HCC development. On the other hand, it is difficult to eradicate HBV completely. Although HBV infection can be prevented by vaccination, reactivation of HBV following anti-cancer chemotherapy and immunosuppressive therapy is a well-known complication. HBV reactivation has been reported to be associated with anti-CD20 monoclonal antibody rituximab-containing chemotherapy and TNF-α inhibitor-containing immunosuppressive therapy in HBV-resolved patients. Our prospective observational study revealed that monthly monitoring of HBV DNA was useful for preventing HBV reactivation-related hepatitis among B-cell non-Hodgkin lymphoma patients with resolved HBV infection following rituximab-steroid-chemo, suggesting that preemptive therapy guided by serial HBV DNA monitoring should be recommended. Recently, highly sensitive HBsAg detection by Lumipulse HBsAg-HQ may be useful for several clinical applications. The sensitivity of this assay (5 mIU/mL) was approximately 10-fold higher than Abbott ARCHITECT, but still lower than HBV-DNA assays. The convenient HBsAg-HQ may be useful for detecting occult HBV infection and HBV reactivation in relatively low-risk groups except for those receiving rituximab-steroid-chemo. [

Topics: Anilides; Antineoplastic Agents; Antiviral Agents; Biomarkers; Carbamates; Cyclopropanes; DNA, Viral; Drug Therapy, Combination; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B virus; Hepatitis C; Humans; Imidazoles; Immunoassay; Immunosuppressive Agents; Interferons; Interleukins; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Pyrrolidines; Ritonavir; Rituximab; Sensitivity and Specificity; Sulfonamides; Transfusion Reaction; Valine; Virus Activation

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

An estimated 184 million people worldwide have hepatitis C virus (HCV) infection. Chronic infection can ultimately result in liver cirrhosis and hepatic failure. Eradication of the virus by antiviral treatment can hinder the development of the aforementioned complications. Historically, the combination therapy of PEGylated interferon/ribavirin was considered the standard-of-care therapy for HCV. Such therapy did not demonstrate satisfactory cure rates and had significant side effects that precluded its widespread use among HCV patients. In view of this situation, scientific advances have led to the development of new interferon-free regimens that are better tolerated, more effective and with shorter duration of therapy. One of the newest members of this family is the all-oral regimen (ombitasvir/paritaprevir/ritonavir co-packaged with dasabuvir) that has recently received FDA approval for the treatment of adult patients with genotype 1 HCV infection, including those with compensated cirrhosis. This new combination was found to be safe and well tolerated with high rates of sustained virologic response of up to 100%. An overview of the current knowledge about this regimen is reviewed herein.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Molecular Structure; Proline; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

Topics: Anilides; Animals; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Randomized Controlled Trials as Topic; Ritonavir; Sulfonamides; Valine

About 2% of the world's population is estimated to be chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of developing liver cirrhosis and its complications. Successful treatment of HCV infection is associated with improved quality of life and increased survival. Antiviral approaches were formerly based on interferon and therefore all patients with a contraindication to interferon were excluded from treatment (e.g., patients with decompensated disease, severe impairment of other organs). Very recently, interferon-free combinations have become available for genotypes 2 and 3. This review focuses on the most recently reported data on the various interferon-free combinations used (namely, sofosbuvir-based combinations, the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination, and the MK-5172/MK-8742 combination). All these combinations yielded amazing results in terms of efficacy (90-100%), tolerability and safety. If the problem of the high cost is overcome, interferon-free therapies will lead to what has long been a chimera, namely, an HCV-free world.

Topics: 2-Naphthylamine; Amides; Anilides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials as Topic; Cyclopropanes; Disease Eradication; Drug Combinations; Hepacivirus; Hepatitis C; Humans; Imidazoles; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Pyrrolidines; Quinoxalines; Ribavirin; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine

Hepatitis C virus (HCV) chronically infects about 150,000,000 people worldwide and is a relevant cause of liver cirrhosis, hepatocellular carcinoma and death. Antiviral treatment is rapidly moving from interferon (IFN)-based therapy to IFN-free approaches. This review focuses on the mechanism of action, pharmacokinetics, efficacy, tolerability, safety and resistance of ombitasvir, which is an inhibitor of the HCV nonstructural protein 5A. The pharmacokinetics of ombitasvir enables its once daily administration. In vivo, in combinations with other oral direct acting antivirals, ombitasvir achieves very high rates of sustained virological response (about 95%) in patients with HCV genotype 1 infection with a good tolerability. Resistance profiling revealed a low barrier to resistance when given as monotherapy. However, coadministration of ombitasvir and other antivirals enhances its barrier to resistance. In conclusion, ombitasvir is a good drug to be used in IFN-free combinations for the treatment of chronic hepatitis C.

Topics: Anilides; Animals; Antiviral Agents; Carbamates; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Viral; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Proline; RNA, Viral; Valine; Viral Nonstructural Proteins

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

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

The 3-DAA regimen consisting of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) has shown high sustained virologic response rates (~95%) in phase 3 clinical trials including >2300 HCV genotype 1-infected patients. Real-world evidence studies have confirmed the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with chronic HCV genotype 1 infection and are consistent with clinical trial results. TOPAZ-I and TOPAZ-II are ongoing phase 3b trials, assessing safety, efficacy and long-term progression of liver disease and clinical outcomes for up to 5 years post-treatment in patients treated with OBV/PTV/r + DSV ± RBV. High rates of sustained virologic response (SVR) were achieved regardless of presence or absence of cirrhosis.In this report, we assessed the long-term progression of liver disease and incidence of clinical outcomes up to 3 years of post-treatment follow-up in patients with chronic HCV GT1 infection who were treated with (OBV/PTV/r + DSV) ± RBV in the TOPAZ-I and TOPAZ-II studies. Improvements were observed in liver disease markers including FIB-4, METAVIR and Child-Pugh scores as well as platelet counts. Clinical outcomes related to long-term progression of liver disease such as liver decompensation were infrequent (<1%). Hepatocellular carcinoma (HCC) occurred in 1.4% of cirrhotic patients.

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

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs.. An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants.. Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m. 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment.. NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

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

The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.

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

This study analyses health-related quality of life data from 8 randomized clinical trials using ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin to investigate: (i) the impact of the treatment vs placebo during treatment on health-related quality of life; (ii) the sustainability of such treatment effect after 12-week treatment period; and (iii) if results from (i) and (ii) differ in subgenotypes 1a vs 1b.. Six registration trials and 2 post-approval trials were pooled and analysed using longitudinal mixed models to estimate the effect of ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin on health-related quality of life outcomes adjusting for baseline scores, as well as patient demographics and clinical characteristics.. Patients treated with ribavirin-free ombitasvir/paritaprevir/ritonavir and dasabuvir regimen reported statistically significant increase in health-related quality of life outcomes as compared to placebo patients. While ombitasvir/paritaprevir/ritonavir and dasabuvir + ribavirin treatment saw statistically significant decline in health-related quality of life outcomes during treatment vs baseline and placebo, effect on health-related quality of life outcomes associated with ribavirin did not persist in the post-treatment period for ombitasvir/paritaprevir/ritonavir and dasabuvir patients followed for up to 52 weeks. The analysis also found Genotype 1b patients reported greater improvements in health-related quality of life as compared to genotype 1a patients.. During the active treatment period, small but statistically significant decrements in health-related quality of life outcomes were observed potentially driven by ribavirin, which were not sustained during the post-treatment follow-up period. Differences were observed by patient subgenotype, where health-related quality of life improvements were consistently higher for genotype 1b patients as compared to genotype 1a patients.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; Humans; Internationality; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Quality of Life; Regression Analysis; Ribavirin; Ritonavir; Severity of Illness Index; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin.. We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials. Multivariate stepwise logistic regression models assessed predictors associated with ribavirin dose adjustments and with developing anaemia.. Of 1548 patients, 100 (6.5%) modified ribavirin dose due to haemoglobin declines, of which 99% achieved sustained virological response at 12 weeks post-treatment. Median time to first ribavirin dose reduction was 37 days. Low baseline haemoglobin was significantly associated with an increased risk of requiring ribavirin dose modification (odds ratio: 0.618 [0.518, 0.738]; P < .001) and developing anaemia (odds ratio: 0.379 [0.243, 0.593]; P < .001).. Ribavirin dose reductions were infrequent, occurred early in treatment, and did not impact sustained virological response at 12 weeks post-treatment. Patients with low baseline haemoglobin should be monitored for on-treatment anaemia.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; Humans; Internationality; Lactams, Macrocyclic; Logistic Models; Macrocyclic Compounds; Male; Middle Aged; Multivariate Analysis; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

Background Data on the efficacy, safety, and concomitant use with other drugs of the combination ritonavir-boosted paritaprevir/ombitasvir plus dasabuvir (PrOD) in HIV/HCV-coinfected patients in real life are limited. The objectives of this study were to analyze these topics in HIV/HCV-coinfected subjects bearing HCV genotype 1 (GT1). Methods One hundred and eighty-two HIV/HCV-coinfected patients with GT1 (87 1a, 71 1b, 23 other) treated with PrOD, plus ribavirin (RBV) in 119 cases, in routine clinical practice were analyzed. The main variable of efficacy was sustained virological response (SVR) 12 weeks after completing therapy in an intention-to-treat (ITT) analysis and that of safety treatment discontinuation because of adverse effects. Factors associated with SVR were analyzed with a modified ITT (mITT) strategy. Results One hundred and seventy-two (94%) patients attained SVR, 3 (2%) experienced a relapse and two (1%) discontinued therapy due to adverse events. The rates of SVR in subjects with GT 1a and 1b by mITT were, respectively, 97% and 98%. Sixty-five (98%) out of 66 patients with cirrhosis and 107 (98%) out of 110 (p = 1) non-cirrhotics achieved SVR. Fifty-five (95%) patients on concomitant darunavir therapy developed SVR vs. 117 (99%) (p = 0.105) of those without DRV. RBV dose was reduced in 13 (11%) patients and permanently discontinued in 2 (2%), with no impact on SVR. Conclusions PrOD is highly effective and well tolerated in HIV/HCV-coinfected patients with GT1 in routine clinical practice. RBV is often required. However, RBV dose reduction or discontinuation is uncommonly needed and do not impair the SVR rate.

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

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Australia; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; England; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Intention to Treat Analysis; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; New Zealand; Proline; Prospective Studies; Ribavirin; Ritonavir; RNA, Viral; Safety; Sulfonamides; Treatment Outcome; Uracil; Valine

Ombitasvir/paritaprevir/ritonavir with dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) is approved for hepatitis C virus (HCV) genotype 1 (GT1) treatment in HIV-1 coinfected patients. In healthy controls, coadministration of OBV/PTV/r + DSV + darunavir (DRV) lowered DRV trough concentration (Ctrough) levels. To assess the clinical significance of this change, TURQUOISE-I, Part 1b, evaluated the efficacy and safety of OBV/PTV/r + DSV + RBV in coinfected patients on stable, DRV-containing antiretroviral therapy (ART).. Patients were HCV treatment-naive or interferon-experienced, had CD4+ lymphocyte count ≥200 cells/µL or ≥14%, and plasma HIV-1 RNA suppression on once-daily (QD) DRV-containing ART at screening. Patients were randomized to maintain DRV 800 mg QD or switch to twice-daily (BID) DRV 600 mg; all received OBV/PTV/r + DSV + RBV for 12 weeks.. Twenty-two patients were enrolled and achieved SVR12. No adverse events led to discontinuation. Coadministration had minimal impact on DRV maximum observed plasma concentration and area under the curve; DRV Ctrough levels were slightly lower with DRV QD and BID. No patient experienced plasma HIV-1 RNA >200 copies/mL during treatment.. HCV GT1/HIV-1 coinfected patients on stable DRV-containing ART achieved 100% SVR12 while maintaining plasma HIV-1 RNA suppression. Despite DRV exposure changes, episodes of intermittent HIV-1 viremia were infrequent.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Anti-Retroviral Agents; Body Mass Index; Carbamates; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Darunavir; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; HIV-1; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine; Young Adult

In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection.. Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients.. A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5-99.5%) and 75.0% (36/48; 95% confidence interval 62.8-87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis.. OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile.. ClinicalTrials.gov identifier, NCT02023112.. AbbVie.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Japan; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Valine

Treatment of HCV genotype 1b (GT1b)-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) in studies M12-536 and GIFT-I demonstrated high sustained virologic response (SVR) rates. The virologic failure rate was 3% (13/436) across the two studies. Analyses were conducted to evaluate the impact of baseline resistance-associated variants (RAVs) on treatment outcome and the emergence and persistence of RAVs in patients experiencing virologic failure. Baseline paritaprevir resistance-conferring variants in NS3 were infrequent, while Y93H in NS5A was the most prevalent ombitasvir resistance-conferring variant at baseline. A comparison of baseline prevalence of polymorphisms in Japanese and western patients showed that Q80L and S122G in NS3 and L28M, R30Q, and Y93H in NS5A were significantly more prevalent in Japanese patients. In the GIFT-I study, the prevalence of Y93H in NS5A varied between 13% and 21% depending on the deep-sequencing detection threshold. Among patients with Y93H comprising <1%, 1 to 40%, or >40% of their preexisting viral population, the 24-week SVR (SVR24) rates were >99% (276/277), 93% (38/41), and 76% (25/33), respectively, indicating that the prevalence of Y93H within a patient's viral population is a good predictor of treatment response. The predominant RAVs at the time of virologic failure were D168A/V in NS3 and Y93H alone or in combination with other variants in NS5A. While levels of NS3 RAVs declined over time, NS5A RAVs persisted through posttreatment week 48. Results from these analyses are informative in understanding the resistance profile of an ombitasvir- plus paritaprevir/ritonavir-based regimen in Japanese GT1b-infected patients.

Topics: Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Genetics, Population; Hepacivirus; Hepatitis C; Humans; Japan; Lactams, Macrocyclic; Macrocyclic Compounds; Polymorphism, Genetic; Proline; Ritonavir; Sulfonamides; Treatment Failure; Valine; Viral Nonstructural Proteins

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

Although hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct-acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD).. We performed a single-arm, multicenter study of treatment-naïve adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15-30 mL/min/1.73 m(2)) or stage 5 (estimated glomerular filtration rate, <15 mL/min/1.73 m(2) or requiring hemodialysis). Twenty patients were given ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir for 12 weeks. Patients with HCV genotype 1a infections also received ribavirin (n = 13), whereas those with genotype 1b infection did not (n = 7). The primary end point was sustained virologic response (serum HCV RNA <25 IU/mL) 12 weeks after treatment ended (SVR12). We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities.. All 20 patients completed 12 weeks of treatment. Eighteen of the 20 patients achieved SVR12 (90%; 95% confidence interval: 69.9-97.2). One patient death after the end of the treatment (unrelated to the treatment) and 1 relapse accounted for the 2 non-SVRs. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an AE. Four patients experienced serious AEs; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients due to anemia; 4 received erythropoietin. No blood transfusions were performed.. In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088.

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

Interactions between tacrolimus and cyclosporine (CSA) and the 3 direct-acting antiviral regimen (3D) of ombitasvir, paritaprevir/ritonavir, and dasabuvir necessitate a priori dose adjustments for the immunosuppressants to achieve desired levels. Modeling and simulations based on data in healthy subjects predicted that tacrolimus 0.5 mg every 7 days or 0.2 mg every 3 days, and CSA at one-fifth the total daily dose administered once daily, would achieve desired trough concentrations (Ctrough) during 3D treatment. The success of these dosing recommendations was evaluated by analyzing pharmacokinetic data from liver transplant recipients in the CORAL-I study.. A population pharmacokinetic model was developed using tacrolimus dosing and Ctrough data before and during 3D treatment (n = 29). The model was used to simulate various tacrolimus dosing regimens and predict tacrolimus concentration-time profiles during 3D treatment. CSA Ctrough data before and during 3D treatment (n = 5) were also summarized.. A one-compartment model with first-order absorption adequately described tacrolimus pharmacokinetic profiles during the first 4 weeks of 3D treatment. Estimated tacrolimus Ctrough values (median; interquartile range) before and during 3D treatment were comparable (5.7 ng/mL; 4.9-6.5 ng/mL versus 5.2 ng/mL; 4.2-6.3 ng/mL, respectively). Based on simulations, in a patient with a starting Ctrough of 6 ng/mL, 0.5 mg tacrolimus every 7 or 14 days or 0.2 mg tacrolimus every 3 days will result in Ctrough levels of 6-9 ng/mL, 4-6 ng/mL, and 6-10 ng/mL, respectively, during 3D treatment. For CSA, Ctrough values (median; interquartile range) before and during 3D treatment were comparable (126 ng/mL; 94-140 ng/mL versus 104 ng/mL; 82-140 ng/mL).. Observed data for tacrolimus and CSA in liver transplant recipients confirm that the recommended dosing strategies are valid and therapeutic levels of immunosuppression can be maintained during 3D treatment.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cyclosporine; Drug Dosage Calculations; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Models, Biological; Proline; Ritonavir; Sulfonamides; Tacrolimus; Uracil; Valine; Young Adult

ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.

Topics: 2-Naphthylamine; Adolescent; Adult; Anilides; Antiviral Agents; Area Under Curve; Carbamates; Cyclopropanes; Cyclosporine; Drug Administration Schedule; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Sulfonamides; Tacrolimus; Uracil; Valine; Young Adult

The interferon-free regimen of ABT-450 (a protease inhibitor), ritonavir, ombitasvir (an NS5A inhibitor), dasabuvir (a non-nucleoside polymerase inhibitor), and ribavirin has shown efficacy in patients with hepatitis C virus (HCV) genotype 1b infection-the most prevalent subgenotype worldwide. We evaluated whether ribavirin is necessary for ABT-450, ritonavir, ombitasvir, and dasabuvir to produce high rates of sustained virologic response (SVR) in these patients.. We performed a multicenter, open-label, phase 3 trial of 179 patients with HCV genotype 1b infection, without cirrhosis, previously treated with peginterferon and ribavirin. Patients were assigned randomly (1:1) to groups given ABT-450, ritonavir, ombitasvir, and dasabuvir, with ribavirin (group 1) or without (group 2) for 12 weeks. The primary end point was SVR 12 weeks after treatment (SVR12). We assessed the noninferiority of this regimen to the rate of response reported (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin.. Groups 1 and 2 each had high rates of SVR12, which were noninferior to the reported rate of response to the combination of telaprevir, peginterferon, and ribavirin (group 1: 96.6%; 95% confidence interval, 92.8%-100%; and group 2: 100%; 95% confidence interval, 95.9%-100%). The rate of response in group 2 was noninferior to that of group 1. No virologic failure occurred during the study. Two patients (1.1%) discontinued the study owing to adverse events, both in group 1. The most common adverse events in groups 1 and 2 were fatigue (31.9% vs 15.8%) and headache (24.2% vs 23.2%), respectively. Decreases in hemoglobin level to less than the lower limit of normal were more frequent in group 1 (42.0% vs 5.5% in group 2; P < .001), although only 2 patients had hemoglobin levels less than 10 g/dL.. The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or without ribavirin, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b infection. Both regimens are well tolerated, as shown by the low rate of discontinuations and generally mild adverse events. ClinicalTrials.gov number: NCT01674725.

Topics: 2-Naphthylamine; Adult; Aged; Anilides; Antiviral Agents; Biomarkers; Carbamates; Cyclopropanes; Drug Therapy, Combination; Europe; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Puerto Rico; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides; Time Factors; Treatment Outcome; United States; Uracil; Valine; Viral Load

The clinical guidelines suggest that the dosing of cyclosporine (CsA), during combination therapy with paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD), would be only one-fifth of the pre-PrOD total daily dose to be administered once daily. However, this dosing may not be applicable to all patients depending on their clinical condition. This study focuses on the pharmacokinetic dynamics of PrOD with CsA in Asian organ transplant recipients with severe liver fibrosis or cirrhosis who undergo concurrent treatment with PrOD treatment and CsA. The efficacy and safety of PrOD treatment was also evaluated.. Data from 7 patients obtained between January 2017 and September 2017 were retrospectively analyzed. Determinations of the blood concentrations of CsA were made, whether used as a single treatment or in combination therapy with PrOD.. The combination regimen compared with CsA administered alone resulted in a 4.53-fold and 5.52-fold increase in the area under the concentration-time curve from time 0-12 hours (AUC0-12 h) of CsA on days 1 and 15, respectively. In addition, the maximal concentration, time to maximum concentration, and terminal phase elimination half-life (t1/2) of CsA were increased during the combined treatment of PrOD and CsA. The authors proposed reducing the CsA dosage during PrOD treatment to one-seventh of that of the pre-PrOD treatment of the total daily dose to maintain target CsA levels. All patients achieved sustained virologic responses at week 12. There were no episodes of serious adverse events or graft rejections observed.. Although the combination with PrOD significantly affects the pharmacokinetics of CsA, it is effective and safe with regular monitoring of the CsA blood concentrations and appropriate CsA dose adjustment.

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

Although persistent sustained viral response rates are increased in hepatitis C infection following administration of direct-acting antiviral (DAA) agents, the pre-use predictive parameters of these antivirals and the clinical progression in patients post-treatment remain unknown. To obtain data pertaining to the predictive parameters prior to the use of ombitavir/paritaprevir/ritonavir + dasabuvir and the clinical progression in patients following antiviral treatment. The expression profiles of miR-223-3p, miR-17-5p, miR-24-3p, and TLR2 - 196 to - 174 del/ins polymorphisms from the blood/serum of 34 hepatitis C virus (HCV)-infected patients pre- and post-ombitavir/paritaprevir/ritonavir + dasabuvir treatment were determined by RT-qPCR. The expression levels of miR-17-5p (P < 0.001) and miR-24-3p (P = 0.011) were significantly downregulated post-treatment as compared with those pre-treatment; however, there was no significant difference between these two groups in terms of miR-223-3p expression. In addition, there was no significant difference in TLR2 genotype or allele distribution between pre-and post-treatment (P > 0.05); nevertheless, the TLR2 del allele was decreased post-treatment (16.2%) as compared with that pre-treatment (19.1%), although the difference was not statistically significant. Moreover, a significant difference was found between the mRNA levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and HCV RNA pre-and post-treatment (P < 0.05). Further, miR-17-5p expression correlated with both ALT and AST mRNA levels post-treatment (P.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; MicroRNAs; Proline; Ribavirin; Ritonavir; RNA, Messenger; Sulfonamides; Toll-Like Receptor 2; Treatment Outcome; Uracil; Valine

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

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

Since 2017 treatment-naïve patients infected with genotype 1b of hepatitis C virus and minimal or moderate fibrosis can be treated with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir (OPrD) for 8 weeks according to updated Summary of Product Characteristics. The aim of our study was to assess the comparative efficacy of 8 and 12-weeks therapy with OPrD in large cohort of patients eligible for 8 weeks regimen treated in real-world setting.. We analysed data of 3067 HCV genotype 1b infected patients treated with OPrD between 2015 and 2017. Final analysis included patients with none, minimal or moderate fibrosis (F0-F2).. A total of 771 patients were enrolled in the study, including 197 (26%) treated for 8-weeks and 574 patients fulfilling criteria for 8-weeks but assigned to 12-weeks regimen. Majority of patients had no or minimal fibrosis (F0-F1). Longer treatment duration was more often administered in patients with moderate fibrosis, comorbidities, concomitant medications. SVR was achieved in 186 (94%) patients treated for 8 weeks and 558 (97%) for 12 weeks (p = 0.07). After exclusion of lost to follow-up patients, sustained virological response (SVR) rate reached 95% and 99%, respectively (p = 0.01). We were not able to identify factors associated with non-response.. This real-word experience study confirmed similar, high effectiveness of 8 and 12-weeks regimens of OPrD in genotype 1b HCV infected patients with non-advanced fibrosis. Despite of reduced SVR rate after 8-weeks regimen, there is no need to extend therapy to 12-weeks in vast majority of such patients and no need to add ribavirin.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Male; Middle Aged; Prognosis; Proline; Retrospective Studies; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Young Adult

The combination of pegylated-interferon and ribavirin (PegIFN+RBV) is currently the gold standard in treating chronic hepatitis C virus (HCV) patients in Malaysia and is reimbursed by the Malaysian authorities. This analysis evaluated the cost-effectiveness (CE) of the ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin (OBT/PTV/r+DSB±RBV) regimen as compared with the PegIFN+RBV or no treatment in chronic HCV Genotype 1 (GT1) treatment-naïve and treatment-experienced cirrhotic and noncirrhotic patients in Malaysia.. A Markov model based on previously published CE models of HCV was adapted for the Malaysian public healthcare payer perspective, based on good modeling practices. Treatment attributes included efficacy, regimen duration, and EQ-5D treatment-related health utility. Transitional probabilities and health state health utilities were derived from previous studies. Costs were derived from Malaysian data sources. Costs and outcomes were discounted at 3.0% per year. Deterministic and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainties around key variables.. Based on the analysis, patients treated with the OBT/PTV/r+DSB±RBV showed less frequent progression to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths when compared with standard care (ie, PegIFN+RBV or no treatment). At a price of MYR 1846/day, the OBT/PTV/r+DSB±RBV regimen is cost-effective over PegIFN+RBV and yields better outcomes in terms of life-years (LYs) gained and quality-adjusted life-years (QALYs) at a higher cost, which is still well below the implied willingness to pay threshold of MYR 384 503/QALY.. The OBT/PTV/r+DSB±RBV regimen is cost-effective for treatment naïve, treatment experienced, cirrhotic, and noncirrhotic GT1 chronic HCV patients in Malaysia.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cost-Benefit Analysis; Cyclopropanes; Genotype; Hepatitis C; Humans; Lactams, Macrocyclic; Malaysia; Proline; Ribavirin; Ritonavir; Sulfonamides; Treatment Outcome; Uracil; Valine

In England, choice of hepatitis C therapy is determined by national contracts that change with time, facilitating comparisons between different regimens. England has a diverse population with hepatitis C including large proportions of uncommon viral genotypes.. To evaluate efficacy of directly acting anti-viral treatments for hepatitis C in England using real-world data from the national treatment registry.. Sustained virological response (SVR) rates 12 weeks after treatment completion for patients treated between 2014 and August 2018 who attended for SVR tests were analysed in univariate subgroups using Chi-squared tests. Multivariate models were constructed with clinically relevant variables to determine predictors of SVR and evaluate the impact of treatment regimens.. SVR data were available on 14,603 treated patients. The overall SVR rate was 95.59% [95% CI 95.25%-95.91%]. Multivariable regression modelling in patients with genotype 1 infection showed that the odds of SVR with elbasvir/grazoprevir were higher than for those treated with sofosbuvir/ledipasvir (OR 1.891, 95% CI 1.072-3.336, P = 0.028). For genotype 3, we found no significant difference between any of the treatment regimens. Patients who completed at least one third of the planned treatment duration achieved SVR rates in excess of 80%.. All of the currently licensed hepatitis C direct-acting anti-viral regimens had similar efficacy (>95%) in an unselected population. Noncompletion of planned treatment duration still resulted in over 80% SVR rates provided that more than one third of treatment was completed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Combinations; England; Female; Fluorenes; Hepatitis C; Humans; Imidazoles; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Quinoxalines; Registries; Ribavirin; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uridine Monophosphate; Valine; Young Adult

The Social Security System of our country reimburses only paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD) regime in treatment-naive patients with hepatitis C regardless of kidney disease. Most of our renal transplant (RT) recipients were treated with PrOD. The aim of the present study was to investigate the efficacy and safety of PrOD in RT patients with hepatitis C virus (HCV) infection in a single center real-life experience.. RT recipients with a post-transplant follow-up of at least 1 year were included in the study. The patients were treated and monitored according to the guidelines. Blood levels of immunosuppressive patients were closely followed up and adjusted.. A total of 21 (12 male and nine female) patients were assessed. The age of the patients was 50.8±8.5 years. Ten patients were infected with G1a, 10 patients with G1b, and one patient with G4 HCV. Two patients had compensated cirrhosis. Eighteen patients were treatment-naive, and three were peginterferon+ribavirin-experienced. Sustained virologic response (SVR12) was achieved in all patients. None of the patients discontinued the treatment. Cyclosporine (Csa) and tacrolimus (Tac) doses were reduced to once a day to once a week to maintain the blood level within normal range. The most common adverse effect was anemia in patients receiving ribavirin. Renal functions did not change during the treatment period.. In this real-life experience, all of the 21 PrOD-treated RT recipients reached SVR12. Tac or Csa serum levels were maintained within the normal range with close monitoring. PrOD regime can be successfully and safely used in RT recipients with HCV infection with close follow-up.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cyclosporine; Female; Hepacivirus; Hepatitis C; Humans; Kidney Transplantation; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Postoperative Complications; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Tacrolimus; Uracil; Valine

In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes.. This is a prospective, interventional, single-center study at Hospital Clínic de Barcelona. All HCV-RNA positive patients who received antiviral therapy with DAAs within a 3-year period (2014-2017) were analyzed (n=20). Data on virologic response, adverse events, and biochemical and hematological parameters during and after DAA therapy were analyzed.. All patients achieved sustained virologic response (SVR) and only 40% of patients presented with mild AEs. None of the patients presented with HCV reinfection after a 1-year follow-up period, and thus HCV was eliminated from our HD unit. SVR was associated with a significant increase in hemoglobin and hematocrit, and a tendency toward the need for lower doses of iron supplementation with no changes in darbepoetin dose.. HCV infection can be safely eliminated from HD units with the use of DAAs, preventing new infections in patients and healthcare staff. In the short term, the achievement of SVR is associated with an improvement in the control of anemia.

Topics: 2-Naphthylamine; Anemia; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Darbepoetin alfa; Female; Hematinics; Hematocrit; Hemoglobin A; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Ritonavir; Sulfonamides; Sustained Virologic Response; Uracil; Valine

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Chemical and Drug Induced Liver Injury; Creatinine; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Function Tests; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sodium; Sulfonamides; Uracil; Valine

The study was performed to evaluate cerebral volume changes in HCV-infected subjects before and after interferon-free therapy with direct-acting antiviral agents (DAA). We aimed also to estimate the impact of successful DAA therapy on the neuropsychological state of patients. Eleven HCV genotype 1 (GT1) patients treated with ombitasvir/paritaprevir (boosted with ritonavir) and dasabuvir, with or without ribavirin underwent brain magnetic resonance (MR) before and 24 weeks after completion of therapy. All patients achieved sustained viral response. Precise automatic parcellation was made using the fully-available software FreeSurfer 6.0. Statistically significant volume deceleration six months after treatment was found in the subcallosal cingulate gyrus, transverse frontopolar gyri and sulci, anterior segment of the circular sulcus of the insula and horizontal ramus of the anterior segment of the lateral sulcus. After DAA therapy we found statistically significant improvement in the performance of all three tasks of the Rey Complex Figure Test that permits the evaluation of different functions (attention, planning, working,memory). Additionally, significant amelioration in Percentage Conceptual Level Responses in The Wisconsin Card Sorting Test (a neurocognitive test for assessing intellectual functioning) was also discovered. Successful interferon-free therapy may lead to transient cerebral atrophy, probably by reducing neuroinflammation and oedema. This is the first pilot study of the alterations in brain volume after successful interferon-free therapy in chronic HCV patients. Longitudinal follow-up study is needed to observe further effects of therapy on cerebral structures volume changes.

Topics: Adult; Aged; Anilides; Antiviral Agents; Attention; Brain; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Magnetic Resonance Imaging; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Organ Size; Pilot Projects; Proline; Ritonavir; Sulfonamides; Valine

Data regarding the efficacy and safety of paritaprevir/ritonavir, ombitasvir plus dasabuvir (PrOD) for East Asian non-cirrhotic hepatitis C virus genotype 1b (HCV GT1b) patients receiving hemodialysis were limited.. Forty-six HCV GT1b non-cirrhotic patients receiving hemodialysis who received PrOD for 12 weeks were prospectively enrolled in seven academic centers in Taiwan. The primary efficacy endpoint was sustained virologic response 12 weeks off-therapy (SVR. Treatment with PrOD for 12 weeks is efficacious and well-tolerated for East Asian non-cirrhotic HCV GT1b patients receiving hemodialysis.

Topics: Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Middle Aged; Proline; Renal Dialysis; Ritonavir; Sulfonamides; Valine; Young Adult

Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available.. GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded.. A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin.. In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited.. Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.

Topics: Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Lactams, Macrocyclic; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Retreatment; Ribavirin; Ritonavir; Sofosbuvir; Spain; Sulfonamides; Sustained Virologic Response; Valine; Viral Nonstructural Proteins

Modification of a HCV NS5A inhibitor, ombitasvir, led to the identification of 10d with improved pan-genotype NS5A inhibition and better pharmacokinetic properties. The key structural changes to ombitasvir include bioisosteric replacement of carbon with silicon atom. Compared with ombitasvir, the activity of anti-HCV genotypes (GT 1 to 6) of 10d is increased to some extent, especially the inhibitory activity against genotype 3a and 6a is increased by more than seven times, and the dog's in vivo pharmacokinetics properties were also superior to ombitasvir. Further drug evaluation showed that 10d was similar to ombitasvir on plasma protein binding and liver distribution profiles, with no cytotoxicity and no inhibitory effect on both CYP 450 and hERG ligand binding. However, permeability assay results indicated that 10d was not the substrate of P-gp or BCRP transporter, which is different from that of ombitasvir. The results of a 14-day repeat-dose toxicity study identified no toxicity with 10d. Our findings in preclinical tests suggest that the silicon-containing compound 10d could be worthy of continued study as a potential drug candidate.

Topics: Anilides; Animals; Antiviral Agents; Carbamates; Dogs; Drug Design; Enzyme Inhibitors; Genotype; Hepacivirus; Hepatitis C; Humans; Proline; Silicon; Valine; Viral Nonstructural Proteins

Treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin (OPrD ± RBV), was the first interferon-free direct-acting antiviral for hepatitis C virus (HCV) introduced to Israel's national basket of health services in February 2015. Patients with HCV genotype 1 (GT1) and advanced fibrosis (F3-F4) were eligible for treatment in 2015. This study aimed to characterize patients initiating OPrD ± RBV and assess sustained virological response (SVR). A retrospective cohort study was performed using the database of Maccabi Healthcare Services (MHS), a 2-million-member health plan in Israel. The study population included adults who initiated OPrD ± RBV through December 2015 per health basket criteria. A gap in medication fills (>14 days between a fill's run-out and the next fill) was used to estimate adherence. SVR was defined by the viral tests at least 12-week post-treatment. The study population consisted of 403 patients (56.3% male), with a mean age of 60.7 years (SD 11.0). Overall, 71.0% were naïve to prior HCV treatment, and 95.6% were treated with a 12-week regimen. A total of 348 patients (86.4%) completed the regimen in the usual time frame (highly adherent), whereas 8.2% completed with a gap, and 4.7% purchased less than the recommended dose. SVR rates overall and among highly adherent patients were 395/403 (98.0%; 95% CI 96.1-99.1) and 346/348 (99.4%; 95% CI 97.9-99.9), respectively. GT1b patients on 12-week regimens attained SVR rates of 194/196 (fibrosis F3) and 170/176 (cirrhosis). After a first year of provision of OPrD ± RBV with good adherence, high SVR rates were achieved in various patient subgroups and comorbidities.

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

Hepatitis C virus (HCV) is a highly divergent virus currently classified into seven major genotypes and 86 subtypes (ICTV, June 2017), which can have differing responses to therapy. Accurate genotyping/subtyping using high-resolution HCV subtyping enables confident subtype identification, identifies mixed infections and allows detection of new subtypes. During routine genotyping/subtyping, one sample from an Equatorial Guinea patient could not be classified into any of the subtypes. The complete genomic sequence was compared to reference sequences by phylogenetic and sliding window analysis. Resistance-associated substitutions (RASs) were assessed by deep sequencing. The unclassified HCV genome did not belong to any of the existing genotype 1 (G1) subtypes. Sliding window analysis along the complete genome ruled out recombination phenomena suggesting that it belongs to a new HCV G1 subtype. Two NS5A RASs (L31V+Y93H) were found to be naturally combined in the genome which could limit treatment possibilities in patients infected with this subtype.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Drug Resistance, Viral; Equatorial Guinea; Female; Fluorenes; Gene Expression; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Microbial Sensitivity Tests; Middle Aged; Mutation; Phylogeny; Proline; Pyrrolidines; Sequence Analysis, DNA; Sulfonamides; Uracil; Valine; Viral Nonstructural Proteins

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

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

BACKGROUND The introduction of direct-acting antivirals (DAAs) has considerably improved therapeutic outcomes for patients with chronic hepatitis C virus (HCV) infections. The AMBER-CEE study aimed to assess real-world efficacy and safety of ombitasvir/paritaprevir/ritonavir/+ dasabuvir ±ribavirin (OBV/PTV/r/ +DSV±RBV) in the treatment of post-transplant recurrence of HCV infection. MATERIAL AND METHODS Liver transplant recipients with recurrent HCV genotype 1 infection, scheduled for OBV/PTV/r/+DSV±RBV according to therapeutic guidelines, were eligible. The primary efficacy endpoint was sustained virologic response (SVR) 12 weeks after the end of treatment (FU12). Clinical and laboratory adverse events (AEs) were recorded from baseline to FU12. RESULTS A total of 35 patients were included: 91.4% genotype 1b-infected, 94.3% treatment-experienced, and 77.1% at fibrosis stage ≥F2. SVR12 was achieved by all patients (35/35, 100%) including one patient with genotype 1a, one patient with detectable HCV RNA at the end of treatment, two patients with a history of first-generation DAA therapy, and two patients who prematurely discontinued the regimen. AEs were experienced by 22 patients (62.9%) and were mostly mild. No death, graft loss, or acute graft rejections were reported during the therapy. On-treatment hepatic decompensation occurred in three patients (8.6%). Anemia was observed in 29 patients (83.9%), with 21 (60%) requiring RBV dose reduction or discontinuation. CONCLUSIONS OBV/PTV/r/+DSV±RBV has excellent efficacy in post-transplant recurrence of HCV genotype 1-infection treated under real-world conditions. Excellent virologic outcomes were observed irrespective of prior treatment history or the degree of fibrosis, and AEs were mostly mild and transient.

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

Limited data exist on the outcomes of ritonavir-boosted paritaprevir with ombitasvir and dasabuvir (PrOD) ± ribavirin in a real-world setting. The aim of this study was to compare the efficacy and safety of PrOD-based therapy in hepatitis C genotype 1 patients with and without cirrhosis, and to explore pre-treatment factors predictive of sustained viral response (SVR) and serious adverse events (SAEs) on treatment.. 451 patients with hepatitis C genotype 1 treated in 20 centres across Australia were included. Baseline demographic, clinical and laboratory information, on-treatment biochemical, virological and haematological indices and details on serious adverse events were collected locally.. Cirrhosis was present in 340 patients (75.4%). Overall SVR was 95.1% with no differences in SVR between the cirrhosis and non-cirrhosis groups (94.7% versus 96.4%). SVR in subgenotypes 1a and 1b was 93.1% and 99.2%, respectively. On multivariate analysis, baseline bilirubin level and early treatment cessation predicted SVR. SAEs occurred in 10.9% of patients including hepatic decompensation (2.7%) and hepatocellular carcinoma (1.8%). On multivariate analysis of factors predictive of SAEs in the overall group, Child-Turcotte-Pugh (CTP) B was the only significant factor, while in those with cirrhosis, baseline albumin and creatinine levels were significant.. In this large real-world cohort of HCV genotype 1 subjects, treatment with PrOD was highly effective and similar to clinical trials. Important determinants of reduced SVR include early cessation of therapy and baseline bilirubin concentration. SAEs were not infrequent with CTP B patients being at greatest risk.

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

A fixed-dose formula that combines Ombitasvir (OBV), Paritaprevir (PTV) and Ritonavir (RTV) has been launched into the field of anti-HCV therapy in Japan for patients infected with HCV genotypes 1 and 2 in 2015. However, little is yet known as to the efficacy and safety of this novel therapy in patients on maintenance haemodialysis (HD). The present report describes a preliminary experience in 10 patients (five males and five females) who underwent maintenance HD. All of them had HCV genotype 1b, without having the resistance-associated variants at Y93 or L31 in the nonstructural proteins 5A (NS5A) region. After the treatment, eight patients successfully achieved virus eradication and sustained a virological response at 12 weeks (SVR12). In addition, mac-2 binding protein glycosylation isomer (M2BPGi), a biomarker for liver fibrosis, was reduced after the therapy. Two patients withdrew from the therapy due to the development of erythema multiforme and a strong drowsiness, respectively. These results suggest that triple therapy combining OBV, PTV and RTV is effective in achieving SVR12 in most of the HCV-infected patients on HD. In addition, this combination therapy contributed to retard the progression of liver fibrosis. However, we suggest that further trial will be required to establish its clinical efficacy and safety.

Topics: Aged; Aged, 80 and over; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Disease Progression; Drug Combinations; Drug Compounding; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Japan; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Renal Dialysis; Renal Insufficiency, Chronic; Ritonavir; RNA, Viral; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Valine; Viral Load

No drug-drug interaction study has been conducted to date for the combination of ombitasvir, paritaprevir/ritonavir, dasabuvir (3D), and mycophenolic acid (MPA). We here report the case of a hepatitis C virus-infected patient treated with 3D and MPA for vasculitis. In light of the threat of drug-drug interaction, the concentration of MPA was measured before, during, and 15 days after the end of the 3D treatment. Similar values were found at all 3 time points, thus indicating that there is probably no need to adapt MPA dosage to 3D.

Topics: 2-Naphthylamine; Aged; Anilides; Antibiotics, Antineoplastic; Antiviral Agents; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A Inhibitors; Disease Management; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Mycophenolic Acid; Proline; Ritonavir; Sulfonamides; Uracil; Valine

We are presenting the case study of the patient diagnosed at the age of 37 with liver cirrhosis due to genotype 1b hepatitis C virus infection. At the age of 46, he was diagnosed with hepatocellular carcinoma with subsequent resection of the tumour in May 2015. In December 2015, the treatment was started with ombitasvir, paritaprevir/ritonavir and dasabuvir (3D) with ribavirin (RBV) 1000 mg per day. After 24 days of this treatment, the patient received a deceased donor liver transplantation, followed by 18-day interruption of 3D therapy. Due to the anaemia, RBV dose was reduced to 600 mg per day for the rest of the treatment. At the 11th week of 3D+RBV treatment, there was another 8-day long discontinuation of therapy due to the postoperative wound infection. In total, the patient received 24 weeks of 3D+RBV treatment, achieving sustained virological response at week 24 post-treatment.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Drug Therapy, Combination; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine

Ombitasvir/Paritaprevir/ritonavir/Dasabuvir (OBV/PTV/r+DSV) is one of the elective direct-acting antivirals (DAAs) recommended by international guidelines and the only one covered by the National Insurance System in Romania until November 2016. Our aim was to present the first prospective Romanian cohort evaluating the effectiveness and safety in clinical practice of this 3DAA combination in patients with HCV genotype-1b Child A liver cirrhosis.. 681 patients received OBV/PTV/r+DSV+RBV for 12 weeks and were assessed clinically and biologically at baseline, week 4, 8, 12 (end of treatment, EOT), and 12 weeks after therapy (sustained viral response, SVR).. Per protocol, EOT virological response was 99.8% and SVR12 rate was 99.4%. Adverse events were present in 36.4% of patients. Permanent discontinuation of 3DAA regimen due to side effects was reported in 11 patients (1.6%). In 47.6% (185/389) of patients, Transient Elastography values were >20kPa (defined as clinically significant portal hypertension, CSPH) at baseline. Independent variables associated with CSPH were: baseline cholesterol level (p=0.003), platelet count <120,000/mm³ (p=0.02), MELD score (p=0.01). Liver stiffness measurement has significantly improved between baseline (26.6+/-12.7kPa) and SVR12 (21.6+/-11.8kPa) (p<0.0001). The same was true for APRI score (2.66+/-0.15 at baseline vs 0.85+/-0.02 at SVR12, p<0.0001) and FIB4 score (5.53+/-0.28 vs 3.24+/-0.08, p<0.0001), but not for Lok score (0.57+/-0.01 vs 0.63+/-0.01, p<0.0001).. We report a high efficacy of the 3DAA regimen in a homogeneous compensated HCV genotype-1b liver cirrhosis population, in a real-life setting. Noninvasive fibrosis scores significantly improved at SVR12.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Elasticity Imaging Techniques; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Ritonavir; Romania; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine

The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection.. Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations.. The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin (n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance.. The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen.

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

Hepatitis C virus (HCV) infection is highly prevalent among patients on hemodialysis (HD) and is associated with poor prognosis. Treatment with interferon and ribavirin is poorly tolerated, and few data are available on the impact of new direct-acting antivirals (DAAs). This study was intended to analyze the efficacy and safety of treatment with a combination of ombitasvir/paritaprevir/ritonavir and dasabuvir with/without ribavirin in HCV-infected patients on HD from 3 hospitals.. This is a multicentric study. We analyze the clinical course of all patients on HD with HCV infection who had been treated with the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir in 3 hospitals in Madrid, Spain. All patients under treatment had undergone Transient elastography (FibroScan®) and HCV RNA (PCR) and HCV genotype were determined simultaneously.. Thirty-five patients aged 53.3 ± 8.9 years (68.6% males) and with genotypes 1 and 4 were treated with the DAA regimen, and 17 were also given ribavirin. The most common etiology was glomerular disease. Sustained viral response was achieved in 100% of patients. Adverse effects were negligible, and no patient had to discontinue treatment. The most significant side effect was anemia, which led to a significant increase in the dose of erythropoiesis-stimulating agents. Anemia was more marked in patients receiving ribavirin. No patients required transfusions.. A combination of ombitasvir/paritaprevir/ritonavir and dasabuvir with/without ribavirin for the treatment of HCV in patients on HD is highly effective and causes minimal side effects. This regimen represents a major advance in disease management. A considerable improvement in prognosis seems likely.

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

Large cohorts are needed to assess human immunodeficiency virus (HIV)/hepatitis C virus (HCV) real-world treatment outcomes. We examined the effectiveness of ledipasvir/sofosbuvir with or without ribavirin (LDV/SOF ± RBV) and ombitasvir/ paritaprevir/ritonavir plus dasabuvir (OPrD) ± RBV in HIV/HCV genotype 1 (GT1)-coinfected patients initiating HCV therapy in clinical practice.. Observational intent-to-treat cohort analysis using the Veterans Affairs Clinical Case Registry to identify HIV/HCV GT1-coinfected veterans initiating 12 weeks of LDV/SOF ± RBV or OPrD ± RBV. Multivariate models of sustained virologic response (SVR) included age, race, cirrhosis, proton pump inhibitor (PPI) prescription, prior HCV treatment, body mass index, genotype subtype, and HCV treatment regimen.. Nine hundred ninety-six HIV/HCV GT1-coinfected veterans initiated therapy: 757 LDV/SOF, 138 LDV/SOF + RBV, 28 OPrD, and 73 OPrD + RBV. Overall SVR was 90.9% (823/905); LDV/SOF 92.1% (631/685), LDV/SOF + RBV 86.3% (113/131), OPrD 88.9% (24/27), and OPrD + RBV 88.7% (55/62). SVR was 85.9% (176/205) and 92.4% (647/700) in those with and without cirrhosis (P = .006). SVR was similar between African Americans (90.5% [546/603]) and all others (91.7% [277/302]). PPI use with LDV/SOF ± RBV did not affect SVR (89.7% [131/146] with PPI and 91.5% [613/670] without PPI). Cirrhosis was predictive of reduced SVR (0.51 [95% confidence interval {CI}, .31-.87]; P = .01). Median creatinine change did not differ among patients receiving LDV/SOF and tenofovir disoproxil fumarate (TDF) without a protease inhibitor (PI) (0.18 [interquartile range {IQR}, 0.08-0.30]; n = 372), LDV/SOF and TDF/PI (0.17 [IQR, 0.04-0.30]; n = 100), and LDV/SOF without TDF (0.15 [IQR, 0.00-0.30]; n = 423).. SVR rates in HIV/HCV GT1-coinfected patients were high. African American race or PPI use with LDV/SOF ± RBV was not associated with lower SVR rates, but cirrhosis was. Renal function did not worsen on LDV/SOF regimens with TDF.

Topics: Administration, Oral; Aged; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cohort Studies; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; HIV Infections; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Practice Patterns, Physicians'; Proline; Registries; Ribavirin; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uridine Monophosphate; Valine; Veterans

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Therapy, Combination; Genotype; Graft Survival; Hepacivirus; Hepatitis C; HIV Infections; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Recurrence; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Uracil; Valine

Orthotopic liver transplant patients with recurrent hepatitis C (HCV) historically have had limited treatment options. Ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin (3D+R) was approved by the FDA in December 2014 for liver transplant recipients with recurrent genotype 1 HCV, in whom it is effective and well-tolerated.. Using a two-phase Markov model, we analysed the cost-effectiveness of 3D+R in liver transplant recipients, the only HCV treatment with FDA approval in this population. As a sensitivity analysis, we also considered the cost-effectiveness of pegylated interferon plus ribavirin, the only other therapy with data from Phase III trials in this population. Patients were given one of three options: 3D+R for 24 weeks, pegylated interferon and ribavirin for 48 weeks (PR48) or no treatment (NT). Patients were then followed through subsequent disease progression until death. Outcome measures analysed were: lifetime risks of liver morbidity and mortality, treatment costs, non-treatment medical expenditures, and quality-adjusted life years.. Treatment with 3D+R was associated with a significantly lower lifetime risk of liver-related morbidity and mortality than treatment with PR48 or NT. 3D+R also was associated with a higher gain in quality-adjusted life years (11.3 compared to 8.25 with NT) and lower discounted overall costs ($423,585 compared to $724,757 with NT).. The use of 3D+R for liver transplant recipients with recurrent HCV is an outcome-improving and cost-effective regimen for this population with limited treatment options and large unmet need.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cost-Benefit Analysis; Cyclopropanes; Drug Costs; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Markov Chains; Middle Aged; Models, Economic; Phenotype; Proline; Recurrence; Ribavirin; Risk Factors; Ritonavir; Sulfonamides; Time Factors; Treatment Outcome; United States; Uracil; Valine; Viral Load; Virus Activation

The combination of ombitasvir, dasabuvir, and paritaprevir/ritonavir (considered as the 3D regimen) has proven to be associated with high sustained virologic response and optimal tolerability in hepatitis C virus-infected patients. Here, we describe an HIV-HCV-coinfected patient who experienced a grade 4 hyperbilirubinemia and a 2.5-fold increase in the atazanavir plasma trough concentrations few days after the start of 3D-based antiviral therapy who benefited from an atazanavir dose reduction guided by therapeutic drug monitoring.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Atazanavir Sulfate; Carbamates; Coinfection; Cyclopropanes; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Lactams, Macrocyclic; Macrocyclic Compounds; Middle Aged; Proline; Ritonavir; Sulfonamides; Uracil; Valine

We observed a sustained viral response (SVR) of ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin therapy, for 12 wk, in two cases with compensated liver cirrhosis and fully destroyed early hepatocellular carcinoma (HCC). Patients were infected with hepatitis C virus (HCV) genotype 1b and were previous null responders/relapsers to interferon-alpha/ribavirin (IFN/RBV). There was a rapid suppression of HCV RNA to undetectable levels within the first two treatment weeks. SVR was achieved even after marked reduction of the RBV dose. The treatment was well tolerated. Both subjects experienced worsening of liver disease during therapy, in different patterns: severe, transient, predominantly direct hyperbilirubinemia without cytolysis (case 1) or progressive increase of aminotransferases (grade 4) without severe hyperbilirubinemia (case 2). Adverse events spontaneously resolved. The patients remained in a good clinical condition without hepatic decompensation. There was no re-occurrence of HCC. This is the first report for treatment of HCV cirrhosis after complete HCC destruction.

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

Topics: 2-Naphthylamine; Anilides; Carbamates; Coinfection; Cyclopropanes; Darunavir; Hepatitis C; HIV Infections; HIV-1; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Uracil; Valine

We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4.. We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 ± 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment.. An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%-93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%-87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%-77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%-93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80.2% with genotype 2; 69.2% with genotype 3; and 93.5% with genotype 4 achieved SVR12. Among treatment-naive patients, 92.8% with genotype 1; 88.0% with genotype 2; 77.5% with genotype 3; and 88.3% with genotype 4 achieved SVR12. Eight-week regimens of ledipasvir/sofosbuvir produced an SVR12 in 94.3% of eligible patients with HCV genotype 1 infection; this regimen was underused.. High proportions of patients with HCV infections genotypes 1-4 (ranging from 75% to 93%) in the Veterans Affairs national health care system achieved SVR12, approaching the results reported in clinical trials, especially in patients with genotype 1 infection. An 8-week regimen of ledipasvir/sofosbuvir is effective for eligible patients with HCV genotype 1 infection and could reduce costs. There is substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Retrospective Studies; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; United States; United States Department of Veterans Affairs; Uracil; Uridine Monophosphate; Valine

Interferon-free hepatitis C treatment regimens are effective but very costly. The cost-effectiveness, budget, and public health impacts of current Medicaid treatment policies restricting treatment to patients with advanced disease remain unknown.. To evaluate the cost-effectiveness of current Medicaid policies restricting hepatitis C treatment to patients with advanced disease compared with a strategy providing unrestricted access to hepatitis C treatment, assess the budget and public health impact of each strategy, and estimate the feasibility and long-term effects of increased access to treatment for patients with hepatitis C.. Using a Markov model, we compared two strategies for 45- to 55-year-old Medicaid beneficiaries: 1) Current Practice-only advanced disease is treated before Medicare eligibility and 2) Full Access-both early-stage and advanced disease are treated before Medicare eligibility. Patients could develop progressive fibrosis, cirrhosis, or hepatocellular carcinoma, undergo transplantation, or die each year. Morbidity was reduced after successful treatment. We calculated the incremental cost-effectiveness ratio and compared the costs and public health effects of each strategy from the perspective of Medicare alone as well as the Centers for Medicare & Medicaid Services perspective. We varied model inputs in one-way and probabilistic sensitivity analyses.. Full Access was less costly and more effective than Current Practice for all cohorts and perspectives, with differences in cost ranging from $5,369 to $11,960 and in effectiveness from 0.82 to 3.01 quality-adjusted life-years. In a probabilistic sensitivity analysis, Full Access was cost saving in 93% of model iterations. Compared with Current Practice, Full Access averted 5,994 hepatocellular carcinoma cases and 121 liver transplants per 100,000 patients.. Current Medicaid policies restricting hepatitis C treatment to patients with advanced disease are more costly and less effective than unrestricted, full-access strategies. Collaboration between state and federal payers may be needed to realize the full public health impact of recent innovations in hepatitis C treatment.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cost-Benefit Analysis; Cyclopropanes; Drug Combinations; Female; Fluorenes; Health Services Accessibility; Hepacivirus; Hepatitis C; HIV Protease Inhibitors; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Markov Chains; Medicaid; Middle Aged; Proline; Ritonavir; Severity of Illness Index; Sofosbuvir; Sulfonamides; United States; Uracil; Uridine Monophosphate; Valine

Topics: Anilides; Antiviral Agents; Breast Diseases; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C; Humans; Hypertrophy; Lactams, Macrocyclic; Macrocyclic Compounds; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Valine

Topics: 2-Naphthylamine; Accidental Falls; Anilides; Antiviral Agents; Bronchodilator Agents; Carbamates; Cushing Syndrome; Cyclopropanes; Drug Therapy, Combination; Fluticasone; Hepatitis C; Humans; Hydrocortisone; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ritonavir; Salmeterol Xinafoate; Sulfonamides; Uracil; Valine

A 40-year-old man, diagnosed with decompensated liver cirrhosis because of hepatitis C virus, was on the wait list for a liver transplant when he began treatment with the direct-acting antivirals simeprevir 150 mg and sofosbuvir 400 mg. The patient demonstrated end of treatment virologic response at week 12, normal bilirubin, and alanine aminotransferase levels, resolution of ascites, with downgrading to subcompensated liver cirrhosis, and was removed from the liver transplant wait list. However, the patient did not comply with the recommended duration of the antiviral treatment of at least 16 weeks, which resulted in hepatitis C virus relapse at posttreatment week 12. Later, the patient started an alternative regimen that included a combination of ombitasvir 12.5 mg, paritaprevir 75 mg, ritonavir 50 mg, and dasabuvir 250 mg for 24 weeks and achieved a sustained virologic response. However, despite undetectable hepatitis C virus, the patient began to deteriorate again and was again put on the liver transplant wait list. This first described clinical case in Kazakhstan of successful antiviral therapy with 2 consecutive directacting agents demonstrates the importance of virus eradication of pretransplant survival extension and delaying the need for liver transplant.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Hepatitis C; Humans; Kazakhstan; Lactams, Macrocyclic; Liver Cirrhosis; Liver Transplantation; Macrocyclic Compounds; Male; Medication Adherence; Proline; Recurrence; Retreatment; Ritonavir; Simeprevir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine; Waiting Lists

Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.).

Topics: Anilides; Antiviral Agents; Carbamates; Cell Line; Drug Resistance, Viral; Hepacivirus; Hepatitis C; Humans; Proline; Valine

Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) has revolutionized the care of infected patients. Among these novel compounds are non-nucleoside analogs, which bind viral RNA-dependent RNA polymerase resulting in a conformational change inhibiting RNA synthesis.. Efficacy and tolerability of treatment regimens containing the non-nucleoside analog polymerase inhibitor dasabuvir (ABT-333).. Dasabuvir-containing regimens achieve high rates of sustained virologic response in HCV genotype 1a and 1b-infected patients when combined with other DAAs, namely paritaprevir (ABT-450), ritonavir and ombitasvir (ABT-267). In the populations studied, dasabuvir seems to be well tolerated and safe. The major limitations of this novel drug are its genotype-restricted activity, the necessity to include ribavirin for HCV genotype 1a and the emergence of resistance if not combined with other DDAs.

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Hepatitis C; Humans; Interferon-alpha; Lactams, Macrocyclic; Macrocyclic Compounds; Polyethylene Glycols; Proline; Ribavirin; RNA-Dependent RNA Polymerase; Sulfonamides; Uracil; Valine

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A Inhibitors; Drug Combinations; Drug Interactions; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ritonavir; Sulfonamides; Uracil; Valine