ritonavir and Hepatitis-C

Hepatitis C virus (HCV) is the primary contributor to chronic hepatic diseases. A rapid change in the situation took place with the advent of oral direct-acting antivirals (DAAs). However, a comprehensive review of the adverse event (AE) profile of the DAAs is lacking. This cross-sectional study aimed to analyze the reported Adverse Drug Reactions (ADRs) with DAA treatment using data from VigiBase, the WHO Individual Case Safety Report (ICSR) database.. All ICSRs reported to VigiBase with sofosbuvir (SOF), daclatasvir (DCV), sofosbuvir /ledipasvir (SOF/LDV) and ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) in Egypt were extracted. Descriptive analysis was performed to summarize patients' and reactions' characteristics. Information components (ICs) and proportional reporting ratios (PRRs) for all reported ADRs were calculated to identify signals of disproportionate reporting. Logistic regression analysis was performed to identify the DAAs association with serious events of concern while adjusting for age, gender, pre-existing cirrhosis, and ribavirin use.. Out of 2925 reports, 1131 (38.6%) were serious. The most commonly reported reactions; anaemia (21.3%), HCV relapse (14.5%) and headache (14%). For the disproportionality signals; HCV relapse was reported with SOF/DCV (IC 3.65, 95% CrI 3.47-3.79) and SOF/RBV (IC 3.69, 95% CrI 3.37-3.92), while anaemia (IC 2.85, 95% CrI 2.26-3.27) and renal impairment (IC 2.12, 95% CrI 0.7-3.03) were reported with OBV/PTV/r.. The highest severity index and seriousness were reported with SOF/RBV regimen. A significant association was found for OBV/PTV/r with renal impairment and anaemia although being the superior regimen in terms of efficacy. The study findings call for further population-based studies for clinical validation.

Topics: Anilides; Antiviral Agents; Cross-Sectional Studies; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Pharmacovigilance; Recurrence; Ribavirin; Ritonavir; Sofosbuvir; Sustained Virologic Response

Hepatitis C virus (HCV) infection is an independent risk factor associated with adverse outcomes in patients with end-stage renal disease (ESRD). Due to the wide variety of direct-acting antiviral regimens (DAAs) and the factor of renal insufficiency, careless selection of anti-hepatitis C treatment can lead to treatment failure and safety problems. The integrated evidence for optimized therapies for these patients is lacking. This study would conduct comparisons of different DAAs and facilitate clinical decision-making.. We conducted a systematic literature search in multiple databases (PubMed, Ovid, Embase, Cochrane Library, and Web of Science) up to 7 August 2023. Study data that contained patient characteristics, study design, treatment regimens, intention-to-treat sustained virologic response (SVR), and adverse event (AE) data per regimen were extracted into a structured electronic database and analyzed. The network meta-analysis of the estimation was performed by the Bayesian Markov Chain Monte Carlo methods.. Our search identified 5,278 articles; removing the studies with duplicates and ineligible criteria, a total of 62 studies (comprising 4,554 patients) were included. Overall, the analyses contained more than 2,489 male individuals, at least 202 patients with cirrhosis, and no less than 2,377 patients under hemodialysis. Network meta-analyses of the DAAs found that receiving ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (R) plus dasabuvir (DSV), glecaprevir (G)/pibrentasvir (P), and sofosbuvir (SOF)/ledipasvir (LDV) ranked as the top three efficacy factors for the HCV-infected ESRD patients. Stratified by genotype, the G/P would prioritize genotype 1 and 2 patients with 98.9%-100% SVR, the SOF/DCV regimen had the greatest SVR rates (98.7%; 95% CI, 93.0%-100.0%) in genotype 3, and the OBV/PTV/R regimen was the best choice for genotype 4, with the highest SVR of 98.1% (95% CI, 94.4%-99.9%). In the pan-genotypic DAAs comparison, the G/P regimen showed the best pooled SVR of 99.4% (95% CI, 98.6%-100%). DAA regimens without Ribavirin or SOF showed the lowest rates of AEs (49.9%; 95% CI, 38.4%-61.5%) in HCV-infected ESRD patients.. The G/P could be recommended as the best option for the treatment of pan-genotypic HCV-infected ESRD patients. The OBV/PTV/R plus DSV, SOF/Velpatasvir (VEL), SOF/Ledipasvir (LDV), and SOF/DCV would be reliable alternatives for HCV treatment with comparable efficacy and safety profiles.. https://www.crd.york.ac.uk/prospero/#searchadvanced, PROSPERO: CRD42021242359.

Topics: Antiviral Agents; Bayes Theorem; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Kidney Failure, Chronic; Male; Network Meta-Analysis; Ritonavir; Treatment Outcome

Topics: Adult; Drug Combinations; Hepatitis C; Humans; Lung Diseases, Interstitial; Macrocyclic Compounds; Male; Middle Aged; Respiration, Artificial; Respiratory Function Tests; Ritonavir; Sulfonamides; Tomography, X-Ray Computed; Uracil

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

The pharmacology, pharmacokinetics, clinical efficacy, and safety of Viekira, as well as its place in hepatitis C virus (HCV) therapy, are reviewed.. Ombitasvir 25 mg-paritaprevir 150 mg-ritonavir 100 mg plus dasabuvir 250 mg (Viekira) is approved in the United States as a combination direct-acting antiviral agent for treatment-naive or treatment-experienced patients with HCV genotype 1 infection, including those with compensated cirrhosis. It is the first coformulated direct-acting antiviral that targets different stages of the virus's life cycle. Viekira is administered as an oral, interferon-free regimen. Phase III clinical trials demonstrated that Viekira administered with or without ribavirin can achieve sustained virological response rates of ≥90%. These results are notable because they show that high virological cure rates can be achieved without peginterferon and ribavirin. Viekira is also effective for special patient populations, such as individuals coinfected with HIV, liver transplant recipients, and those with advanced renal disease. The most frequently reported adverse effects among patients associated with Viekira without ribavirin were nausea, pruritus, and insomnia. During clinical trials, the most common adverse effects among patients receiving Viekira with ribavirin were fatigue, nausea, pruritus, insomnia, and weakness.. Viekira, the first coformulated direct-acting antiviral that targets different stages of the HCV life cycle, is an interferon-free treatment for HCV genotype 1 infection. It is associated with a virological cure rate of ≥90% and treatment durations of 12 and 24 weeks. Viekira is also effective and safe for patients who have undergone liver transplantation, are coinfected with HIV, or have advanced kidney disease.

Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Drug Combinations; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Macrocyclic Compounds; Ritonavir; Sulfonamides; Treatment Outcome; Uracil

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

Hepatitis C virus (HCV) therapy continues to evolve rapidly. ABT-450 is a novel potent inhibitor of the non-structural 3/4A protease that has been studied in combination with several agents, allowing shorter duration of therapy and interferon-free/ribavirin-free all-oral regimens. Preliminary data from studies evaluating these new regimens are impressive with sustained virological response (SVR) rates of 88 - 100% after 12 weeks of therapy in patients with previously untreated HCV genotype 1 infection. SVR rates in treatment-experienced patients are also encouraging.. Efficacy and tolerability of antiviral regimens containing ABT-450 boosted with ritonavir (ABT-450/r). Results from published studies and abstracts from recent meetings are presented.. Newer direct-acting antiviral agents such as ABT-450 promise effective and durable suppression of HCV with interferon/ribavirin-free all-oral regimens. This agent also allows for shorter duration of treatment and has tolerable side effects. Results of clinical trials including a broader spectrum of individuals with HCV infection are eagerly awaited.

Topics: Antiviral Agents; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Ribavirin; Ritonavir; Sulfonamides; 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

Topics: Adult; Amides; Antiviral Agents; Atazanavir Sulfate; Benzofurans; Carbamates; Cyclopropanes; Darunavir; Drug Interactions; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; Lopinavir; Male; Middle Aged; Quinoxalines; Ritonavir; Sulfonamides; Viral Nonstructural Proteins; Young Adult

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 light of the advances in HCV therapy, simplification of diagnosis confirmation, pre- treatment diagnostic workup and treatment monitoring is required to ensure broad access to interferon-free therapies. HCV core antigen (HCV cAg) testing is rapid, giving results in approximately 60min, and less expensive than HCV RNA methods. While extensive data on the analytical performance of HCV cAg relative to RNA or comparisons in longitudinal studies of patients on interferon based (response guided) therapy there is very limited data on the relative performance of HCV cAg in diagnosis and monitoring patients receiving all-oral interferon free regimens. Furthermore, there is no data in the literature that describes the specificity of HCV cAg in patients with resolved HCV infection i.e. anti-HCV positive/HCV RNA negative. In this study a total of 1201 plasma samples from the 411 HCV genotype 1 subjects with a HCV RNA viral load >50,000IU/ml who enrolled in a clinical trial with ombitasvir, ritonavir-boosted paritaprevir and dasabuvir, with or without ribavirin were retrospectively tested in a blinded fashion with HCV cAg test and results were compared to HCV RNA levels. The specificity of the HCV cAg test was also evaluated in anti-HCV positive but HCV RNA negative samples. Overall concordance between HCV cAg and HCV RNA was 98.6% while concordance in pre-treatment samples was 99.5% (409/411; n=2 HCV RNA pos. with viral loads>3 Mill IU/ml but HCV cAg neg.) and 99.24% in post treatment week 12 samples (391/394; n=2 HCV RNA pos.<25IU/ml and n=1 HCV RNA pos. 2180IU/ml). Specificity in anti-HCV positive HCV RNA negative samples tested was 100%.

Topics: 2-Naphthylamine; Administration, Oral; Adult; Aged; Antiviral Agents; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C Antigens; Hepatitis C, Chronic; Humans; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Retrospective Studies; Ribavirin; Ritonavir; RNA, Viral; Sensitivity and Specificity; Sulfonamides; Uracil; Viral Load

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

Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis.. An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18-35 kg/m(2). Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24).. In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred.. Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.

Topics: Antiviral Agents; Cyclopropanes; Drug Administration Schedule; Female; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Isoindoles; Lactams; Lactams, Macrocyclic; Liver Cirrhosis; Male; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; Ribavirin; Ritonavir; Sulfonamides; Treatment Failure

To report the 96 week results on efficacy, safety and bone mineral density (BMD) in subjects with HIV-1 that were virologically suppressed and treated with atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy.. MODAt is a prospective, multicentre, open-label, non-inferiority, randomized, 96 week trial (NCT01511809) comparing efficacy of atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy. Treatment success was defined as no occurrence of confirmed viral rebound (two consecutive HIV-RNA >50 copies/mL) or discontinuation for any cause of the ongoing regimen.. The 96 week treatment success was 64% in the atazanavir/ritonavir monotherapy arm and 63% in the triple-therapy arm (difference 1.3%, 95% CI: -17.5 to 20.1). In the atazanavir/ritonavir monotherapy arm, no PI- or NRTI-associated resistance mutations were observed at virological failure and all patients re-suppressed after re-intensification. In the monotherapy arm, treatment failure was more frequent in patients coinfected with hepatitis C virus [64% versus 28% (difference 35.4%, 95% CI: 3.7-67.2)]. Drug-related adverse events leading to discontinuation were 3 (6%) in the atazanavir/ritonavir monotherapy arm and 11 (21.5%) in the triple-therapy arm (P = 0.041). The 96 week adjusted mean percentage change in total proximal femur (not at lumbar spine) BMD was +1.16% and -1.64% in the atazanavir/ritonavir monotherapy arm and the triple-therapy arm, respectively (P = 0.012).. The 96 week analyses suggested that long-term efficacy of atazanavir/ritonavir monotherapy was inferior as compared with atazanavir/ritonavir triple therapy, particularly when administered in subjects coinfected with hepatitis C virus. In the atazanavir/ritonavir monotherapy arm, reintroduction of nucleosides, as needed, was always effective with no new resistance mutation; monotherapy was also associated with a lower incidence of adverse events and improvement in femur BMD.

Topics: Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Bone Density; Coinfection; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Prospective Studies; Ritonavir; RNA, Viral; Treatment Failure; Treatment Outcome; Viral Load

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

Paritaprevir is a direct-acting antiviral agent that is a component of approved multidrug regimens used in the treatment of hepatitis C virus (HCV) infection. A population pharmacokinetic model for paritaprevir was developed using data from formulation, bioavailability, and drug-drug interaction studies that evaluated the pharmacokinetics of paritaprevir (coadministered with ritonavir to enhance exposure) with or without ombitasvir and/or dasabuvir at different paritaprevir dose levels.. A non-linear mixed-effects modeling approach was applied to data from 12 phase I, single- and multiple-dose studies that enrolled a total of 369 healthy volunteers. Age, sex, race, ethnicity, body weight, body surface area, body mass index, and baseline creatinine clearance were evaluated as covariates during model development. In addition, the influences of dose, formulation, and concomitant medications (e.g. ombitasvir and dasabuvir) on paritaprevir bioavailability were included in the model.. A two-compartment model with first-order absorption and elimination optimally described paritaprevir plasma concentration-time data. Paritaprevir bioavailability was formulation- and dose-dependent, and increased supraproportionally. The accumulation of paritaprevir was 1.57-fold on repeated dosing compared with the first dose. Coadministration of dasabuvir increased paritaprevir bioavailability by 59 %; however, ombitasvir coadministration did not affect the pharmacokinetic profile of paritaprevir. No subject-specific covariate influenced the paritaprevir pharmacokinetics. The pharmacokinetic model was robust in bootstrap evaluations and was consistent with observed data based on diagnostic goodness-of-fit plots and visual predictive checks.. The complex pharmacokinetics of paritaprevir were well described by the model, which can be used as a basis for clinical trial dosing and further evaluations in patients with HCV.

Topics: Adolescent; Adult; Antiviral Agents; Biological Availability; Cyclopropanes; Drug Compounding; Drug Interactions; Drug Therapy, Combination; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Models, Biological; Proline; Protease Inhibitors; Ribavirin; Ritonavir; Sulfonamides; Young Adult

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

Danoprevir is a hepatitis C virus (HCV) protease inhibitor with activity against genotypes (G)1/G4, which is maintained at lower doses by ritonavir-boosting. We report results of a large, randomized, active-controlled phase IIb study of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a/ribavirin (P/R) in treatment-naive patients with HCV G1/4 infection.. Treatment-naive patients with HCV G1/4 infection were randomized to twice-daily danoprevir/r 200/100 mg (A, n = 92); 100/100 mg (B, n = 93); or 50/100 mg (C, n = 94) plus P/R for 24 weeks; twice-daily danoprevir/r 100/100 mg (D, n = 94) plus P/R for 12 or 24 weeks; or P/R alone (E, n = 44) for 48 weeks. Patients in the response-guided therapy arm (D) with an extended rapid virological response (eRVR2: HCV RNA <15 IU/ml during Weeks 2-10) stopped all therapy at Week 12; non-eRVR2 patients continued all treatment to Week 24. The primary efficacy endpoint was sustained the virological response (SVR24: HCV RNA <15 IU/ml after 24 weeks of untreated follow-up).. SVR24 rates in Arms A, B, C, D and E were 89.1%, 78.5%, 66.0%, 69.1% and 36.4%, respectively, in the overall population; 83.6%, 69.6%, 60.3%, 59.2% and 38.5% in G1a-infected patients, 96.6%, 93.1%, 73.1%, 78.4% and 28.6% in G1b-infected patients and 100%, 87.5%, 100%, 100% and 66.7% in G4-infected patients. Danoprevir/r plus P/R was generally well tolerated compared with P/R alone. There was a higher incidence of serious adverse events in danoprevir-treatment arms, but most were associated with P/R.. The combination of danoprevir/r plus P/R is efficacious in treatment-naïve patients with HCV genotype 1 or 4 infection.

Topics: Adult; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Isoindoles; Lactams; Lactams, Macrocyclic; Male; Polyethylene Glycols; Proline; Recombinant Proteins; Ritonavir; RNA, Viral; Sulfonamides

Safety and tolerability of peginterferon-based hepatitis C virus (HCV) infection therapy remains suboptimal, even when direct-acting antiviral agents are added. This study assessed the efficacy, safety and tolerability of mericitabine combined with ritonavir-boosted danoprevir (danoprevir/r) ± ribavirin for up to 24 weeks in treatment-naïve HCV genotype (G)1 infected patients.. Patients received twice daily mericitabine (1000 mg) and danoprevir/r (100 mg/100 mg) plus either ribavirin (1000/1200 mg/day; Arm A) or placebo (Arm B) for 12 or 24 weeks. Patients with HCV RNA <43 IU/ml between Weeks 2 and 8 and HCV RNA <15 IU/ml at Week 10 were rerandomized (1:1) at Week 12 to discontinue/continue assigned regimens until Week 24. Because of unacceptable relapse rates in both 12-week arms and in ribavirin-free Arm B, treatment was extended to 24 weeks and patients in Arm B received peginterferon alfa-2a/ribavirin. The primary outcome was sustained virological response 24 weeks after end of treatment (SVR24).. In Arm A, the SVR24 rate in patients receiving 24 weeks of therapy was 37.9% (25/66); 63.6% (14/22) in G1b and 25.0% (11/44) in G1a patients. Virologic breakthrough and relapse were associated with danoprevir-resistant virus in most cases. The mericitabine-resistance mutation (NS5BS282T) was detected in two patients bearing dual resistant virus NS3 R155K/NS5B S282T and dual resistance mutation L159F/L320F in one patient. Treatment was safe and well tolerated.. Mericitabine, danoprevir/r plus ribavirin for 24 weeks were safe and well tolerated. However, SVR rates were poor, achieving rates of only 25.0% in G1a and 63.6% in G1b patients.

Topics: Adult; Aged; Cyclopropanes; Deoxycytidine; Electrocardiography; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Isoindoles; Lactams; Lactams, Macrocyclic; Male; Middle Aged; Proline; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides

Lopinavir/ritonavir plus nucleoside reverse transcriptase inhibitors is one standard antiretroviral therapy regimen, both in patients with HIV alone and coinfected with hepatitis B or C. Our objective was to investigate whether hepatitis coinfection without clinical signs of hepatic impairment is a cofactor altering lopinavir pharmacokinetics and influencing therapy outcome.. Steady-state 12-hour pharmacokinetic profiles of lopinavir/ritonavir were assessed in patients with (group 1, n = 20) or without (group 2, n = 36) hepatitis coinfection, taking lopinavir/ritonavir 400/100 mg twice a day plus nucleoside reverse transcriptase inhibitors, measured by means of high-performance liquid chromatography-tandem mass spectrometry. Demographic (sex, age, weight), pharmacological (formulation, comedication), clinical, and virological/immunologic parameters (HIV-RNA PCR, CD4(+) cell count) were compared between the groups and included in regression analyses for correlations with lopinavir pharmacokinetic parameters (C(min), C(max), AUC, CL, and t(1/2)) and viral load evolution over 48 weeks on therapy. Patient pairs were matched 1:2 for the parameters sex, age, weight, ethnicity, and drug formulation.. None of the hepatitis-related cofactors (aspartate aminotransferase, alanine aminotransferase, γGT, HBe Ag, HBsAg, HCV-RNA PCR, HCV-therapy) had an influence on lopinavir pharmacokinetics in this group of patients. Lopinavir C(min) (P = 0.039) and area under the curve (P = 0.038) and ritonavir C(max) (P = 0.049) were significantly enhanced in hepatitis-coinfected patients, but correlated only with drug formulation (ie, soft gel capsule or Meltrex tablet formulation, multivariate regression analysis, P = 0.001), not hepatitis coinfection.. Despite moderately enhanced lopinavir/ritonavir plasma concentrations, regular therapeutic drug monitoring is not to be considered in hepatitis-coinfected patients without hepatic impairment. Antiviral efficacy is comparable between both groups, a less-pronounced CD4(+) cell increase in hepatitis-coinfected patients is in line with previously published data.

Topics: Adult; Case-Control Studies; Chemistry, Pharmaceutical; Coinfection; Drug Combinations; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver; Lopinavir; Male; Middle Aged; Ritonavir; Treatment Outcome; Viral Load

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

Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients.. In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated.. Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined.. No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).

Topics: Adenine; Adult; Alkynes; Aminoisobutyric Acids; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Coinfection; Cyclopropanes; Darunavir; Drug Interactions; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Leucine; Male; Middle Aged; Oligopeptides; Organophosphonates; Proline; Protease Inhibitors; Quinolines; Ritonavir; Sulfonamides; Tenofovir; Thiazoles; Young Adult

Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy.. Three open-label studies were conducted in healthy subjects to assess potential interactions between the investigational first-in-class HCV NS5A replication complex inhibitor daclatasvir and representative antiretrovirals atazanavir/ritonavir, efavirenz and tenofovir disoproxil fumarate.. Target exposure was that of 60 mg daclatasvir alone. Dose-normalized (60 mg) geometric mean ratios of daclatasvir AUCτ for 20 mg ± atazanavir/ritonavir (2.10 [90% CI 1.95, 2.26]) and 120 mg ± efavirenz (0.68 [0.60, 0.78]) showed less than the three-fold elevation and two-fold reduction, respectively, in systemic exposure predicted by prior interaction studies with potent inhibitors/inducers of CYP3A4. Daclatasvir dose adjustment to 30 mg once daily with atazanavir/ritonavir and 90 mg once daily with efavirenz is predicted to normalize AUCτ relative to the target exposure (geometric mean ratios 1.05 [0.98, 1.13] and 1.03 [0.90, 1.16], respectively). Atazanavir exposure (Cmax, AUCτ and C24 trough) and efavirenz Ctrough under coadministration were similar to historical data without daclatasvir. No clinically relevant interactions between daclatasvir and tenofovir disoproxil fumarate were observed for either drug, and no dosing adjustments were indicated. Daclatasvir was well tolerated in all three studies.. The pharmacokinetic data support coadministration of daclatasvir with atazanavir/ritonavir, efavirenz and/or tenofovir. A Phase III study in HIV-HCV coinfection has commenced using the described dose modifications.

Topics: Adenine; Adolescent; Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Carbamates; Coinfection; Cyclopropanes; Drug Interactions; Female; Hepatitis C; HIV Infections; Humans; Imidazoles; Male; Middle Aged; Oligopeptides; Organophosphonates; Pyridines; Pyrrolidines; Ritonavir; Tenofovir; Valine; Viral Nonstructural Proteins; Young Adult

The aim of this randomised, prospective, open-label, multicentre pilot clinical trial was to compare the 48-week toxicity profile of lopinavir/ritonavir (LPV/r) monotherapy with LPV/r-based HAART (KaMon = Kaletra monotherapy) in HIV/HCV patients undergoing HCV treatment. The study involved 30 HIV/HCV co-infected patients naive to anti- HCV therapy. One patient in each arm (6.7%) discontinued anti-HCV therapy because of adverse events. There were no significant between-group differences in terms of the proportion of patients experiencing AEs (p=0.999) or the number of grade 3-4 AEs (p=0.146). No HIV failure was observed. The safety profile of LPV/r monotherapy was similar to that of LPV/r-based HAART, thus encouraging HAART simplification in patients receiving anti-HCV treatment.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Coinfection; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Ritonavir; Young Adult

Abstract Our objective was to evaluate the liver toxicity of antiretroviral regimens including fosamprenavir plus ritonavir (FPV/r) 1400/100 mg once daily (QD) in HIV/hepatitis C virus (HCV)-coinfected patients. This was a prospective cohort study that included 117 HIV/HCV-coinfected patients who started FPV/r 1400/100 mg QD-based antiretroviral therapy (ART) and who neither had received a previous antiretroviral regimen containing FPV nor had a past history of virologic failure while receiving protease inhibitors (PI). The primary end point of the study was the occurrence of grade 3-4 liver enzymes elevations (LEE) within 1 year after starting FPV/r QD. Factors potentially associated with grade 3-4 LEE, including baseline liver fibrosis, were analyzed. Eleven (9%) patients had a grade 3-4 LEE during the follow-up, resulting in an incidence of severe liver toxicity of 9% (95% confidence interval 4.1-14.6%). None of these cases led to FPV/r discontinuation. Baseline liver fibrosis could be assessed in 97 (83%) patients. Six of 71 patients (8%) with significant fibrosis had a grade 3-4 LEE versus 2 of 26 (8%) without significant fibrosis (p=1.0). Twenty (21%) patients had cirrhosis at baseline. There were no cases of LEE among cirrhotics. In conclusion, the incidence of severe liver toxicity after 1 year of therapy with FPV/r QD-based ART in HIV/HCV-coinfected patients is similar to what has been reported with other boosted PIs. In addition, the presence of significant fibrosis or cirrhosis was not associated with the emergence of liver toxicity. Thus, ART regimens containing FPV/r QD may be considered safe in HIV/HCV-coinfected patients, including those with cirrhosis.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Cohort Studies; Drug Therapy, Combination; Female; Furans; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver Cirrhosis; Male; Middle Aged; Organophosphates; Ritonavir; RNA, Viral; Sulfonamides

Liver disease may alter the pharmacokinetics of antiretrovirals and produce changes in plasma protein binding. The aim was to evaluate the pharmacokinetics of total and unbound lopinavir (LPV) in HIV-infected patients with and without hepatitis C virus (HCV) coinfection. Fifty-six HIV+ patients receiving lopinavir/ritonavir (LPV/r) (group I = 24 controls; II = 23 HIV/HCV-coinfected; III = 9 cirrhotic HIV/HCV-coinfected) were included. Total (n = 56) and unbound (n = 36) LPV pharmacokinetic parameters were determined at steady-state using validated high-performance liquid chromatography with ultraviolet detection and high-performance liquid chromatography-tandem mass spectrometry methods, respectively. Pharmacokinetic parameters (plasma concentration just before drug administration, peak concentrations in plasma, times to maximum plasma concentration, areas under the plasma concentration-time curve from 0 to 12 hours, and CL/F/kg) of both total and unbound LPV were calculated by standard noncompartmental methods and differences among groups evaluated (Kruskal-Wallis test).LPV apparent oral clearance normalized to body weight (median, interquartile range) was 55 (40-68), 59 (44-69), and 71 (53-78) mL/h/kg for groups I, II, and III, respectively (II vs. I, P = 0.52; III vs. I, P = 0.16). The areas under the plasma concentration-time curve from 0 to 12 hours were 110.4 (80.9-135.2), 103.4 (85.5-131.3), and 92.8 (87.4-116.3) microg h/mL for groups I, II, and III, respectively (II vs. I, P = 0.68; III vs. I, P = 0.71). Chronic liver impairment produced a slight, although not significant, decrease in plasma protein binding. The free-fraction of LPV increased ( approximately 21%) from 0.97% (0.80-1.06) in HIV+/HCV- patients to 1.18% (0.89-1.65) in HIV/HCV+ cirrhotic patients. The apparent oral clearance of unbound LPV (CLu/F/kg) in cirrhotic patients did not change significantly, supporting the concept that the clearance of unbound LPV in liver disease is not affected after being inhibited by low-dose ritonavir co-administration.LPV total and unbound pharmacokinetics were not affected by hepatic impairment, suggesting that no adjustment of LPV/r dose is required for HIV/HCV-coinfected patients with and without cirrhosis and moderate impairment of liver function.

Topics: Adult; Area Under Curve; Body Weight; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver Cirrhosis; Liver Function Tests; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Risk Factors; Ritonavir; Spectrophotometry, Ultraviolet; Ultrafiltration; Ultrasonography

To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant.. An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods.. Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced.. When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required.. The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

Topics: Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Area Under Curve; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dose-Response Relationship, Drug; Female; Graft Rejection; Half-Life; Hepatitis C; HIV; HIV Infections; Humans; Liver Transplantation; Lopinavir; Male; Middle Aged; Nelfinavir; Pyrimidinones; Ritonavir; Tacrolimus; Viral Load

The effect of hepatic impairment on lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.

Topics: Adult; Area Under Curve; Biological Availability; Drug Combinations; Drug Monitoring; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Male; Middle Aged; Pyrimidinones; Radioligand Assay; Ritonavir

The aim of this study was to evaluate the frequency, characteristics and risk factors of lipid changes associated with lopinavir/ritonavir treatment in antiretroviral-naive patients.. A prospective cohort of 107 antiretroviral-naive HIV-infected patients was followed for 12 months after starting lopinavir/ritonavir-based highly active antiretroviral therapy.. At 12 months, percentages of patients with hypercholesterolaemia and hypertriglyceridaemia were 17.4% and 40%, respectively. Mean increases in total cholesterol and triglycerides were 40.7 and 73.3 mg/dL. There was a significant increase in both low-density and high-density (HDL) cholesterol, and no increase in the total cholesterol/HDL ratio (from 4.16 at baseline to 4.49 after 12 months). Baseline cholesterol > 200 mg/dL and triglycerides > 150 mg/dL were independent risk factors for dyslipidaemia, while hepatitis C coinfection appeared to be protective.. Patients with elevated lipid values at baseline have the greatest risk of developing hypercholesterolaemia and hypertriglyceridaemia after starting lopinavir/ritonavir. Antiretroviral-naive patients coinfected with hepatitis C have a low risk of developing hyperlipidaemia after starting lopinavir/ritonavir.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Cholesterol, HDL; Cholesterol, LDL; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Risk Factors; Ritonavir; Triglycerides

Highly active antiretroviral therapy (HAART) initiation in patients coinfected with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) has been associated with transaminase and HCV viral load flares. Previous studies have included highly variable antiretroviral regimens. We compared effects of 2 protease inhibitor-based regimens on alanine aminotransferase (ALT) levels and HCV loads in HCV-HIV-coinfected patients initiating HAART.. Seventy HIV-infected patients with positive baseline results of HCV enzyme-linked immunosorbant assay from a treatment trial comparing lopinavir-ritonavir with nelfinavir were evaluated during a 48-week period. HCV and HIV titers were analyzed at baseline, at weeks 24 and 48 of treatment, and during flares in the ALT level of >5 times the upper limit of normal.. A total of 57 of 70 patients tested positive for HCV RNA at baseline. HCV titers for patients in lopinavir-ritonavir and nelfinavir groups, respectively, were as follows: baseline, 6.07 and 6.22 log IU/mL; week 24 of treatment, 6.68 and 6.48 log IU/mL; and week 48 of treatment, 6.32 and 6.44 log IU/mL. Of patients with a CD4+ cell count of <100 cells/mm3 at baseline, 5 of 11 in the nelfinavir group and 0 of 10 in the lopinavir-ritonavir group had an increase in the HCV load of >0.5 log IU/mL from baseline to week 48. The mean ALT level increased by 45 U/L at 24 weeks and 18 U/L at 48 weeks in the nelfinavir group but decreased by 18 U/L at 24 weeks and 7 U/L at 48 weeks in the lopinavir-ritonavir group. Eight patients in the nelfinavir group and 2 patients in the lopinavir-ritonavir group had grade 3 or 4 flares in the ALT level.. HAART initiation is associated with increased HCV loads and ALT levels. A low baseline CD4+ cell count is associated with persistent increases in the HCV RNA load in nelfinavir-treated patients. These results warrant careful interpretation of abnormalities in the ALT load after HAART initiation in HCV-HIV-coinfected patients to prevent premature discontinuation of treatment.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver; Lopinavir; Male; Middle Aged; Nelfinavir; Pyrimidinones; Ritonavir; RNA, Viral; Viral Load

Topics: Adult; Drug Therapy, Combination; Hemophilia A; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Liver Cirrhosis; Ritonavir; Saquinavir; Stavudine

The impact of human immunodeficiency virus (HIV) protease inhibitors on hepatitis C (HCV) viremia was assessed in 19 patients infected with both HIV and HCV. HIV and HCV RNA levels were measured before and during treatment with protease inhibitors. Before treatment, mean levels of HCV RNA were 5.3 log for HCV RNA and 5.0 log for HIV RNA. CD4 lymphocyte counts were 63/mm3. After 6 weeks of treatment, a mean reduction of 2.1 log10 in HIV RNA (P < .001) and a mean (+/-SE) increase of 73 (+/-21) CD4 and 296 (+/-70) CD8 cells were observed (P < .05). In contrast, both HCV viremia (+0.4 log +/- 0.1) and alanine aminotransferase increased (P < .04). HCV RNA levels returned to baseline after 17 and 32 weeks of treatment. Thus, potent anti-HIV regimens with protease inhibitors may temporarily worsen HCV status despite improvement of HIV parameters.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Viremia

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

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

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

Topics: Aged; Animals; Anti-HIV Agents; Antiviral Agents; Atazanavir Sulfate; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzimidazoles; Caco-2 Cells; Carbamates; Drug Interactions; Female; Fluorenes; Hepatitis C; HIV Infections; Humans; Imidazoles; Intestines; Lopinavir; Male; Maraviroc; Middle Aged; Pyrrolidines; Rats; Rats, Wistar; Ritonavir; Saquinavir; Valine; Zidovudine

Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new direct-acting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofosbuvir+Daclatasvir± Ribavirine, Sofosbuvir+Ledispavir±Ribavirine, Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. Therapy outcomes, hematochemical parameters, viral replication, genotype, and resistance-associated-mutations were analyzed retrospectively. Sustained virological response was 90.4% in the whole population, 83.2% in cirrhotics, 85% in patients with previous virological failure, 93.6% in patients >60 years, and 95.6% in liver transplant recipients. SVR24 for each drug regimen was 75% Sofosbuvir+Ribavirine, 80.4% Sofosbuvir+Simeprevir±Ribavirine, 94.3% Sofosbuvir+Daclatasvir±Ribavirine, 98.7% Sofosbuvir+Ledispavir±Ribavirine, 100% Ombitasvir/ Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. The highest sustained virological response rates were obtained with genotype-1b (95.9%). Twenty-five patients, mostly cirrhotics or suffering from severe liver complications, manifested relapse (84%), breakthrough (12%), or non-response (4%). Mild side effects were observed in 41.1% of patients. Model-for-End-Liver- Disease score <10 and alanine aminotransferase ≤20 U/L at week 8 of therapy proved positive predictors of sustained virological response. Direct-acting antiviral therapy is efficacious and safe even in patients with advanced liver disease and/ or previous virological failure; Model-for-End-Liver-Disease <10 and alanine aminotransferase reduction during therapy were found to be reliable predicting markers of sustained-virological-response.

Topics: 2-Naphthylamine; Antiviral Agents; Biomarkers, Pharmacological; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Middle Aged; Proline; Retrospective Studies; Ribavirin; Ritonavir; Simeprevir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil

The warfarin management strategy for a mechanical mitral valve patient initiated on a ritonavir-based hepatitis C treatment regimen is described. A 62-year-old male with a past medical history of hepatitis C genotype 1a and stable warfarin dose history was initiated on a concomitant Viekira Pak® (VP) regimen containing ritonavir. Prior to initiation of the VP for hepatitis C treatment, the patient was stable on a warfarin dose of 40 mg/wk for 5 months. During treatment with VP, the patient experienced a markedly decreased international normalized ratio (INR) and warfarin requirements ultimately increased 125% from baseline (90 mg/wk). Effective anticoagulation management throughout and surrounding the treatment period for hepatitis C involved frequent warfarin dose adjustments, including preemptive changes, close monitoring, and repeated use of enoxaparin to ensure adequate thrombotic prophylaxis. This is believed to be the first reported case describing the management of warfarin in a patient with hepatitis C who received VP and required a drastically increased weekly warfarin dose. The possible mechanisms suggestive of this interaction and similar case reports in the literature are discussed.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Monitoring; Heart Valve Prosthesis; Hepatitis C; Humans; International Normalized Ratio; Macrocyclic Compounds; Male; Middle Aged; Mitral Valve; Ritonavir; Sulfonamides; Uracil; Warfarin

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

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

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

The renal function is a key-issue in HIV/HCV co-infected patients, nevertheless, it has not established so far whether HCV treatment with new direct acting agents could impact on estimated glomerular filtration rate (eGFR) variations. In the present work, we examined the real-life data on renal function that have been prospectively collected in the SIMIT compassionate-use program of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) in 144 HIV/HCV genotype 1 co-infected patients. The population was 74% male, 30.5% in CDC stage C, with median age of 52 years (48.0-56.5) and median liver stiffness of 7.8 kPa (6.7-9.2). Median baseline eGFR was 102.0 (90.8-108.1), changing to 99.8 (83.5-104.8) at the end of treatment (EoT), and 100.0 (87.3-105.6) 12 weeks after the EoT (FU12), p<0.0001. No patient had grade 3-4 increase of creatinine. At EoT 60/144 (41.7%) patients had ≥ 5% reduction in their eGFR, confirmed at FU12 in 39/60 (65.0%) cases. Longer duration of HCV infection (cut-off 12.9 years), lower HCV-RNA viral load (cut-off 1,970,160 IU/ml) and lower platelet count (cut-off 167,000 x106/L) were significantly associated with eGFR decline at logistic analysis (adjOR 2.9, 95%CI 1.0-8.8, p = 0.05; adjOR 3.5, 95%CI 1.2-10.4, p = 0.02; adjOR 2.8, 95%CI 1.1-6.8, p = 0.03, respectively). After repeating the analysis throughout a mixed model, a higher eGFR decline was highlighted in patients concomitantly treated with tenofovir (p = 0.0001), ribavirin (p = 0.0001), or integrase inhibitors (p <0.0001), with longer duration of HIV (p = 0.0002) and HCV infection (p = 0.035), lower baseline HCV RNA (p <0.0001), previous HCV treatment (p<0.0001), and older age (p<0.0001). In conclusion, our study confirms a good renal safety profile of OBV/PTV/r + DSV treatment in HIV/HCV patients, and the median decline of 2 ml/min in eGFR, albeit statistically significant, is of doubtful clinical significance. The role of aging, concomitant therapies and duration of HIV/HCV infection needs to be further investigated.

Topics: 2-Naphthylamine; Antiviral Agents; Cyclopropanes; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hepatitis C; HIV Infections; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil

The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.. When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7-21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).. Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.. DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Coinfection; Drug Therapy, Combination; Female; Germany; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Ribavirin; Ritonavir; Sofosbuvir; Treatment Outcome

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

The effect of hepatitis C virus (HCV) coinfection on CD4 T cell recovery in treated HIV-infected children is poorly understood.. To compare CD4 T cell recovery in HIV/HCV coinfected children with recovery in HIV monoinfected children.. We studied 355 HIV monoinfected and 46 HIV/HCV coinfected children receiving antiretroviral therapy (ART) during a median follow-up period of 4.2 years (interquartile range: 2.7-5.3 years). Our dataset came from the Ukraine pediatric HIV Cohort and the HIV/HCV coinfection study within the European Pregnancy and Paediatric HIV Cohort Collaboration. We fitted an asymptotic nonlinear mixed-effects model of CD4 T cell reconstitution to age-standardized CD4 counts in all 401 children and investigated factors predicting the speed and extent of recovery.. We found no significant impact of HCV coinfection on either pre-ART or long-term age-adjusted CD4 counts (z scores). However, the rate of increase in CD4 z score was slower in HIV/HCV coinfected children when compared with their monoinfected counterparts (P < 0.001). Both monoinfected and coinfected children starting ART at younger ages had higher pre-ART (P < 0.001) and long-term (P < 0.001) CD4 z scores than those who started when they were older.. HIV/HCV coinfected children receiving ART had slower CD4 T cell recovery than HIV monoinfected children. HIV/HCV coinfection had no impact on pre-ART or long-term CD4 z scores. Early treatment of HIV/HCV coinfected children with ART should be encouraged.

Topics: Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Cohort Studies; Coinfection; Drug Combinations; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Interferon-alpha; Lamivudine; Lopinavir; Male; Models, Immunological; Polyethylene Glycols; Recombinant Proteins; Recovery of Function; Ribavirin; Ritonavir; Time-to-Treatment; Zidovudine

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

To describe the use of nonantiretroviral comedication and combination antiretroviral therapy (cART) in patients coinfected with HIV/hepatitis C virus (HCV) and to predict the potential for drug-drug interactions (DDIs) with direct-acting antivirals (DAAs) against HCV.. This is a retrospective, cross-sectional study, using the Dutch, nationwide ATHENA observational HIV cohort database. All patients with a known HIV/HCV coinfection on January 1, 2015, were included. Comedication and cART registered in the database were listed. The potential for DDIs between DAAs and comedication/cART were predicted using http://hep-druginteractions.org. DDIs were categorized as: (1) no clinically relevant DDI; (2) possible DDI; (3) contraindication; or (4) no information available.. We included 777 patients of whom 488 (63%) used nonantiretroviral comedication. At risk for a category 2/3 DDI with nonantiretroviral comedications were 299 patients (38%). Most DDIs were predicted with paritaprevir/ritonavir, ombitasvir ± dasabuvir (47% of the drugs) and least with grazoprevir/elbasvir (11% of the drugs). Concerning cART, daclatasvir/sofosbuvir is the most favorable combination as no cART is contraindicated with this combination. In genotype 1/4 patients, grazoprevir/elbasvir is least favorable as 75% of the patients must alter their cART.. This study showed that comedication use in the aging HIV/HCV population is frequent and diverse. There is a high potential for DDIs between DAAs and comedication/cART.

Topics: Adult; Aged; Aged, 80 and over; Amides; Anti-Retroviral Agents; Antiviral Agents; Benzofurans; Carbamates; Coinfection; Combined Modality Therapy; Cross-Sectional Studies; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepacivirus; Hepatitis C; HIV; HIV Infections; Humans; Imidazoles; Middle Aged; Quinoxalines; Retrospective Studies; Ritonavir; Sulfonamides; Young Adult

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

Topics: Antiviral Agents; Drug Combinations; Drug Therapy, Combination; Hepatitis C; Humans; Kidney Transplantation; Macrocyclic Compounds; Male; Middle Aged; Ribavirin; Ritonavir; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil

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

New Direct-acting Antiviral Agents (DAA)-based anti-HCV therapies currently provide extraordinary opportunities to cure patients. Drug-drug interactions are however a real challenge during treatment. In particular, in HIV-infected patients in cART, DAA choice is limited by such interactions, which can result both in reduced efficacy and toxicity. We report the case of a HIV-infected patient on cART with atazanavir/ritonavir/abacavir/lamivudine, who presented kidney and biliary lithiasis, the latter treated with endoscopic retrograde cholangiopancreatography and endoscopic biliary sphincterotomy, after beginning anti-HCV treatment with daclatasvir/sofosbuvir/ribavirin. Hyperbilirubinemia with or without jaundice is a well known side effect of atazanavir, because of its inhibition of uridine diphosphate-glucuronosyl transferase. We speculate that in this case hyperbilirubinemia worsening was due to atazanavir/ribavirin co-administration. However, pharmacokinetic data are lacking about atazanavir/daclatasvir concomitant administration in real life setting.

Topics: Adult; Anti-HIV Agents; Antiviral Agents; Atazanavir Sulfate; Biliary Tract Diseases; Carbamates; Coinfection; Dideoxynucleosides; Drug Combinations; Drug Interactions; Genotype; Hepacivirus; Hepatitis C; HIV Infections; Humans; Imidazoles; Kidney Calculi; Lamivudine; Lithiasis; Male; Pyrrolidines; Ribavirin; Ritonavir; Sofosbuvir; Valine

Simeprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, displays nonlinear pharmacokinetics (PK) at therapeutic doses. Using physiologically based PK modeling, various drug-drug interactions were simulated with simeprevir as victim drug to identify whether saturation of the predominant metabolic enzyme (CYP3A4) or the active hepatic transporters (organic anion-transporting polypeptide (OATP)1B1/3) could account for the nonlinear PK. Interactions with ritonavir, a strong CYP3A4 inhibitor that does not affect OATP (at 100 mg dose), erythromycin, a moderate CYP3A4 inhibitor, and efavirenz, a moderate CYP3A inducer that does not affect OATP, demonstrated the involvement of CYP3A4. Interaction studies with low-dose cyclosporine confirmed the role of OATP. The interplay between hepatic uptake and CYP3A4 metabolism was verified by simulations with rifampicin, a potent CYP3A4 inducer and OATP1B1/3 inhibitor, and maintenance doses of cyclosporine. Saturation of gut and liver metabolism by CYP3A4, and saturation of hepatic uptake by OATP1B1/3, seem to account for the observed nonlinear PK of simeprevir.

Topics: Alkynes; Antiviral Agents; Benzoxazines; Cyclopropanes; Cyclosporine; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Erythromycin; Hepatitis C; Humans; Liver; Liver-Specific Organic Anion Transporter 1; Nonlinear Dynamics; Organic Anion Transporters; Rifampin; Ritonavir; Simeprevir; Viral Nonstructural Proteins

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cognitive Dysfunction; Coinfection; Cyclopropanes; Drug Therapy, Combination; Executive Function; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Lopinavir; Male; Memory; Middle Aged; Neuropsychological Tests; Ritonavir; Verbal Learning

The aim of this study was to assess whether hepatitis C virus (HCV) coinfection would affect the clinical and immunological outcome of HIV-infected patients following a simplification strategy. A prospective cohort of HIV-infected patients starting a ritonavir boosted darunavir monotherapy (mtDRV/rtv) was followed for 24 months. HCV infection was evaluated by HCV viremia and hepatic fibrosis. Immune activation was studied as HLA-DR CD38 coexpression on CD4(+) and CD8(+) T cells and also the quantification of plasma sCD14 levels. Microbial translocation was studied by the plasma levels of 16S rDNA and lipopolysaccharide (LPS). A total of 150 HIV-infected patients were enrolled in this study, including 46 individuals also infected with HCV (30.6%). HIV/HCV coinfection did not decrease mtDRV/rtv efficacy, since similar rates of HIV-1 intermittent viremia (HCV: 26.6% vs. no-HCV: 34.7%) and episodes of virological failure (HCV: 22.2% vs. no-HCV: 11.2%, p-value = 0.381) were found. No major differences were found between both groups at baseline, although higher HLA-DR(+)CD38(+)CD4(+) T cell counts were found in the coinfected group (HCV: 6.65% vs. no-HCV: 4.55%, p-value = 0.032); this difference was maintained in the 24 months of follow-up. After the 24-month follow-up, both groups, HIV-monoinfected patients and HIV/HCV-coinfected patients, presented similar immune activation and microbial translocation profiles. In conclusion, the use of a simplified mtDRV/rtv strategy compromises neither HIV nor HCV viremic control in coinfected patients, although a higher immune activation of CD4(+) T cells was found.

Topics: ADP-ribosyl Cyclase 1; Adult; Antiviral Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Coinfection; Darunavir; Female; Gene Expression; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; HLA-DR Antigens; Humans; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Ritonavir; Viral Load

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

Although different factors have been implicated in the CD4/CD8 T-cell ratio recovery in HIV-infected patients who receive effective antiretroviral therapy (ART), limited information exists on the influence of the regimen composition. A longitudinal study carried out in a prospective, single-center cohort of HIV-infected patients. ART regimens including non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), or integrase strand transfer inhibitors (INSTI) from patients who achieved long-term (≥6-month duration) virological suppression (HIV-RNA < 400 copies/mL) from January 1998 to June 2014 were analyzed. The impact of ART composition on the changes of the CD4/CD8 T-cell ratio was modeled using a mixed linear approach with adjustment for possible confounders. A total of 1068 ART regimens from 570 patients were analyzed. Mean (SD) age of the patients was 42.15 (10.68) years and 276 (48.42%) had hepatitis C virus (HCV) coinfection. Five hundred fifty-eight (52.25%) regimens were PI-based, 439 (40.10%) NNRTI-based, and 71 (6.65%) INSTI-based; 487 (45.60%) were initial regimens, 476 (44.57%) simplification, and 105 (9.83%) salvage regimens. Median (IQR) number of regimens was 1 (1-2) per patient, of 29 (14-58) months duration, and 4 (3-7) CD4/CD8 measurements per regimen. The median baseline CD4/CD8 ratio was 0.42, 0.50, and 0.54, respectively, with the PI-, NNRTI-, and INSTI-based regimens (P = 0.0073). Overall median (IQR) increase of CD4/CD8 ratio was 0.0245 (-0.0352-0.0690) per year, and a CD4/CD8 ratio ≥1 was achieved in 19.35% of the cases with PI-based, 25.97% with NNRTI-based, and 22.54% with INSTI-based regimens (P = 0.1406). In the adjusted model, the mean CD4/CD8 T-cell ratio increase was higher with NNRTI-based regimens compared for PI-based (estimated coefficient for PI [95% CI], -0.0912 [-0.1604 to -0.0219], P = 0.009). Also, a higher CD4/CD8 baseline ratio was associated with higher CD4/CD8 increase in the adjusted model (P = 0.001); by contrast, higher age (P = 0.020) and simplification of ART regimen (P = 0.003) had a negative impact on the CD4/CD8 ratio. Antiretroviral regimen composition has a differential impact on the CD4/CD8 T-cell ratio; NNRTI-based regimens are associated with enhanced CD4/CD8 T-cell ratio recovery compared to PI-based antiretroviral regimens.

Topics: Adult; Age Factors; Alkynes; Atazanavir Sulfate; Benzoxazines; CD4-CD8 Ratio; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Interferon Type I; Male; Middle Aged; Oligopeptides; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ribavirin; Ritonavir

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

Topics: Drug Combinations; Drug Costs; Hepatitis C; Insurance, Health; Macrocyclic Compounds; Ritonavir; Sofosbuvir; Sulfonamides; United States; Uracil

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

Determination of paritaprevir and ritonavir in rat liver tissue samples.. We successfully validated a UPLC-MS/MS method to measure paritaprevir and ritonavir in rat liver using deuterated internal standards (d8-paritapervir and d6-ritonavir). The method is linear from 20 to 20,000 and 5 to 10,000 pg on column for paritaprevir and ritonavir, respectively, and is normalized per milligram tissue. Interday and intraday variability ranged from 0.591 to 5.33% and accuracy ranged from -6.68 to 10.1% for quality control samples. The method was then applied to the measurement of paritaprevir and ritonavir in rat liver tissue samples from a pilot study.. The validated method is suitable for measurement of paritaprevir and ritonavir within rat liver tissue samples for PK studies.

Topics: Animals; Antiviral Agents; Chromatography, High Pressure Liquid; Cyclopropanes; Hepacivirus; Hepatitis C; Lactams, Macrocyclic; Limit of Detection; Liver; Macrocyclic Compounds; Male; Pilot Projects; Proline; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Ritonavir; Sulfonamides; Tandem Mass Spectrometry

We aimed to determine the association between the stepwise increase in the sustained viral response (SVR) and Swiss and United States (US) market prices of drug regimens for treatment-naive, genotype 1 chronic hepatitis C virus (HCV) infection in the last 25 years. We identified the following five steps in the development of HCV treatment regimens: 1) interferon (IFN)-α monotherapy in the early '90s, 2) IFN-α in combination with ribavirin (RBV), 3) pegylated (peg) IFN-α in combination with RBV, 4) the first direct acting antivirals (DAAs) (telaprevir and boceprevir) in combination with pegIFN-α and RBV, and 5) newer DAA-based regimens, such as sofosbuvir (which is or is not combined with ledipasvir) and fixed-dose combination of ritonavir-boosted paritaprevir and ombitasvir in combination with dasabuvir.. We performed a linear regression and mean cost analysis to test for an association between SVRs and HCV regimen prices. We conducted a sensitivity analysis using US prices at the time of US drug licensing. We selected randomized clinical trials of drugs approved for use in Switzerland from 1997 to July 2015 including treatment-naïve patients with HCV genotype 1 infection.. We identified a statistically significant positive relationship between the proportion of patients achieving SVRs and the costs of HCV regimens in Switzerland (with a bivariate ordinary least square regression yielding an R2 measure of 0.96) and the US (R2 = 0.95). The incremental cost per additional percentage of SVR was 597.14 USD in Switzerland and 1,063.81 USD in the US.. The pricing of drugs for HCV regimens follows a value-based model, which has a stable ratio of costs per achieved SVR over 25 years. Health care systems are struggling with the high resource use of these new agents despite their obvious long-term advantages for the overall health of the population. Therefore, the pharmaceutical industry, health care payers and other stakeholders are challenged with finding new drug pricing schemes to treat the entire population infected with HCV.

Topics: Antiviral Agents; Cost-Benefit Analysis; Drug Discovery; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Interferons; Oligopeptides; Ribavirin; Ritonavir; Sofosbuvir; Switzerland; United States

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

The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection.. Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus.. A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA-positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis.. Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug Therapy, Combination; Female; Hepatitis B; Hepatitis C; HIV Infections; Humans; Italy; Liver; Male; Middle Aged; Protease Inhibitors; Risk Factors; Ritonavir

The objective of the study was to assess plasma concentrations of efavirenz, darunavir/ritonavir and raltegravir in patients with human immunodeficiency virus-hepatitis C virus (HIV-HCV)-coinfection without liver cirrhosis.. In this observational, open-label study, adult HIV-infected outpatients treated with tenofovir/emtricitabine plus efavirenz (600 mg daily), darunavir/ritonavir (800/100 mg daily) or raltegravir (400 mg twice daily) for at least 4 weeks were asked to participate. Subjects with liver cirrhosis were excluded. The trough concentration (C trough) of darunavir/ritonavir and raltegravir and the mid-dose concentration (C12h) of efavirenz were assessed at steady state by a validated high-performance liquid chromatography (HPLC)-tandem mass spectrometry method.. A total of 96 HIV-positive patients were enrolled into the study. Thirty-four patients were treated with efavirenz, 33 with darunavir/ritonavir and 29 with raltegravir. The geometric mean plasma C trough [coefficient of variation (%)] of darunavir was comparable between HIV+/HCV+ and HIV+/HCV- subjects: 2644 ng/ml (155%) and 2491 ng/ml (139%), respectively (geometric mean ratio (GMR) = 0.81; 95% confidence interval (CI) = 0.79-1.56; p = 0.69). These values were comparable for raltegravir: 108 ng/ml (149%) in the HIV+/HCV+ group and 96 ng/ml (161%) in the HIV+/HCV- group (GMR = 0.84; 95% CI = 0.61-1.44; p = 0.72). On the contrary, the geometric mean plasma C12h of efavirenz was significantly higher among the 15 HIV+/HCV+ patients (1915 ng/ml, 159%) than among the 19 HIV+/HCV- patients (1505 ng/ml, 167%; GMR = 1.41; 95% CI = 1.19-1.71; p = 0.009).. The mean plasma concentration of efavirenz was significantly higher in HCV-positive than in HCV-negative patients without liver cirrhosis, while the mean plasma levels of darunavir/ritonavir and raltegravir were comparable in both groups.

Topics: Adult; Alkynes; Analysis of Variance; Anti-HIV Agents; Benzoxazines; Coinfection; Cyclopropanes; Darunavir; Female; Hepatitis C; HIV Infections; Humans; Liver Function Tests; Male; Middle Aged; Raltegravir Potassium; Ritonavir

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

The impact of drug-drug interactions (DDIs) between interferon-free direct acting antiviral (DAA) regimens and antiretrovirals (ART) among HIV/HCV co-infected individuals in clinical practice settings is unknown. A single-center, retrospective chart review of co-infected patients was conducted from June 2014 to February 2015. Significant interactions between simeprevir (SMV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (3D regimen) with ART were identified based on available literature. SMV had the largest number of DDIs and was further investigated to determine the feasibility of ART switch to allow for DAA use. Of 127 subjects, 23% had advanced liver disease; 86% of those with known HCV genotype were HCV genotype 1. An ART switch allowing use of SMV, LDV, and 3D regimen was recommended in 97/127 (76%), 81/127 (64%), and 91/127 (72%) patients, respectively. Subjects on PI/r regimens had limited options for ART switch, with 40% of these patients unable to be switched to an ART regimen that avoided the use of a PI. In conclusion, the majority of HIV/HCV co-infected patients will be recommended to switch ART prior to use of interferon-free, DAA regimens, and an ART switch may not be feasible for more than a third of patients on a boosted PI. DDIs between ART and DAAs represent an additional barrier to treatment efficacy in clinical practice settings that are unaccounted for in clinical trials.

Topics: Anti-HIV Agents; Antiviral Agents; Coinfection; Drug Interactions; Female; Hepacivirus; Hepatitis C; HIV Infections; Humans; Male; Middle Aged; Protease Inhibitors; Retrospective Studies; Ribavirin; Ritonavir

Our objective was to describe the pharmacokinetic (PK) parameters of total and unbound darunavir and ritonavir concentrations in HIV-hepatitis C virus (HCV)-coinfected patients with cirrhosis, as ritonavir-boosted darunavir is mainly metabolized in the liver, and hepatic cirrhosis might modify darunavir-ritonavir concentrations. This was a prospective, case-control, and unicenter study. HIV-HCV-coinfected patients with compensated cirrhosis (cases) and HIV-monoinfected patients with normal liver function (controls) were included. Darunavir-ritonavir was given at 800/100 mg once daily. Patients were followed for 24 weeks to assess safety and efficacy. A steady-state 12-h PK study was performed. Total and unbound concentrations were determined by liquid chromatography-tandem mass spectrometry. The unbound fraction was obtained by ultrafiltration. The plasma area under the concentration-time curve (AUC) and oral clearance (CL/F) were assessed by noncompartmental models. Thirty patients (20 cases and 10 controls) were included. Among cirrhotic patients, the Child-Pugh score was C in 4 cases, B in 1 case, and A in 15 cases; the median (interquartile range) transient elastography values were 20 kPa (14 to 26 kPa), and 5 patients had prior clinical decompensations. There were no significant differences in the darunavir PK parameters between cases and controls except for longer time to maximum plasma concentrations (Tmax) and half-lives in the cirrhotic patients. There were no significant differences in ritonavir total concentrations, but the unbound concentrations were higher in cirrhotic patients. There were significant correlations between the darunavir total and unbound concentrations in both cirrhotic patients and controls. There were no differences in PK parameters based on Child-Pugh score, liver elasticity, gender, or use of concomitant medications. In conclusion, in HIV-HCV-coinfected patients with clinically compensated cirrhosis receiving darunavir-ritonavir at 800/100 mg once daily, the darunavir total and unbound concentrations are similar to those observed in noncirrhotic patients, and dose adjustments are not necessary.

Topics: Adult; Case-Control Studies; Coinfection; Darunavir; Female; Hepatitis C; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Ritonavir

The main objective is to evaluate the efficacy and durability of lopinavir-ritonavir monotherapy (LPV/r-MT) in virologically controlled HIV-positive individuals switching from combination antiretroviral therapy (cART).. Criteria to be included in this observational study were to have initiated for the first time LPV/r-MT after ≥2 consecutive HIV RNA≤50 copies/ml achieved on a ≥3-drug-including regimen. The main end points were time to virological rebound (VR; defined in two ways: time of first of two consecutive viral load [VL]>50 and >200 copies/ml), time to discontinuation/intensification and time to experience either a single VL>200 copies/ml or discontinuation/intensification (treatment failure [TF]). Individuals' follow-up accrued from the date of starting LPV/r-MT to event or last available VL. Kaplan-Meier curves and Cox regression analyses were used.. A total of 228 individuals were included: median age 46 years (IQR 40-50), 36% females, 36% intravenous drug users and 25% HCV-coinfected. Median CD4(+) T-cell count at nadir was 215 cell/mm(3) (IQR 116-336) and at baseline was 615 cell/mm(3) (IQR 436-768). By 36 months after switching to LPV/r-MT, the proportion of individuals with VR (confirmed VL>200 copies/ml) was 11% and with TF was 35%. In the multivariable Cox model the factors associated with a lower risk of TF was the duration of viral suppression <50 copies/ml prior to baseline (ARH=0.92; 95% CI 0.85, 0.99; P=0.024, per 6 months longer) and having LPV/r as part of last cART (ARH=0.45; 95% CI 0.21, 0.95; P=0.037).. In daily clinical practice, we confirm a relatively safe approach of treatment simplification to LPV-MT in a selected population with long-lasting virological control.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Ritonavir; RNA, Viral; Substance-Related Disorders; Time Factors; Viral Load

Topics: Female; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Lactams; Male; Polyethylene Glycols; Ritonavir; Sulfonamides

Topics: Anticonvulsants; Antiviral Agents; Atazanavir Sulfate; Carbamazepine; Cytochrome P-450 CYP3A; Drug Dosage Calculations; Drug Interactions; Drug Monitoring; Enzyme Activation; Epilepsy; Hepatitis C; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome

Among patients with hepatitis C virus (HCV) monoinfection, 25-hydroxyvitamin D [25(OH)D] concentrations are positively associated with a response to peg-interferon/ribavirin. Data on the relation between 25(OH)D concentrations and HCV treatment response in HIV-infected patients are limited.. The objective was to determine whether baseline 25(OH)D concentrations predict virologic response in HIV/HCV co-infected patients and to examine variables associated with 25(OH)D concentrations ≥30 ng/mL.. Data and samples from 144 HCV genotype 1, treatment-naive patients from a completed HCV treatment trial were examined in this retrospective study. Early virologic response (EVR) was defined as ≥2 log10 reduction in HCV RNA and/or HCV RNA <600 IU/mL at week 12 of peg-interferon/ribavirin treatment. Baseline 25(OH)D was measured by liquid chromatography/tandem mass spectrometry.. Compared with the non-EVR control group (n = 68), the EVR group (n = 76) was younger, had fewer cirrhotic subjects, had a higher proportion with the IL28B CC genotype, had a higher albumin concentration, and had a lower HCV viral load at baseline (P ≤ 0.05). The difference in baseline 25(OH)D concentrations between EVR and non-EVR patients was not statistically significant (median: 25 ng/mL compared with 20 ng/mL; P = 0.23). Similar results were found for sustained virologic response (SVR). In multivariable analysis, white and Hispanic race-ethnicity (OR: 6.26; 95% CI: 2.47, 15.88; P = 0.0001) and ritonavir use (OR: 2.68; 95% CI: 1.08, 6.65; P = 0.033) were associated with higher 25(OH)D concentrations (≥30 ng/mL).. Baseline 25(OH)D concentrations did not predict EVR or SVR. Because ritonavir impairs the conversion of 25(OH)D to the active metabolite, utilization of 25(OH)D may have been impaired in subjects taking ritonavir. This trial was registered at www.clinicaltrials.gov as NCT00078403.

Topics: Adult; Antiviral Agents; Coinfection; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; HIV; HIV Infections; Humans; Interferon-alpha; Logistic Models; Male; Middle Aged; Retrospective Studies; Ribavirin; Ritonavir; RNA, Viral; Viral Load; Vitamin D

Liver enzyme elevations (LEE) were investigated in 2717 episodes of initiation of antiretroviral therapy since January 2010 in 1982 HIV patients. Serum hepatitis C virus (HCV)-RNA was positive in 24%. Any grade of LEE was recognized in 9% of episodes, being 6% in HCV-negative and 17% in HCV-positive patients (P < 0.001). Grades 3-4 LEE only occurred in 0.4% of patients. Overall, LEE were more frequent with ritonavir-boosted darunavir and atazanavir than with raltegravir and etravirine.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Coinfection; Cyclopropanes; Darunavir; Female; Follow-Up Studies; Hepatitis C; HIV Infections; Humans; Liver; Male; Nevirapine; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment.

Topics: Animals; Antiviral Agents; Benzimidazoles; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Evaluation, Preclinical; Drug Interactions; Enzyme Inhibitors; Half-Life; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microsomes, Liver; Predictive Value of Tests; Rats; Ritonavir; Species Specificity; Transplantation Chimera; Virus Replication

In the combination antiretroviral therapy (cART) era, renal dysfunction remains common. The Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN) (ClinicalTrials.gov number, NCT00146419) is a prospective observational cohort study of HIV-infected adults. At baseline, comprehensive data were collected, including cystatin C and measures of renal function. Univariate and multivariate regression analyses were performed to identify factors associated with baseline renal dysfunction [estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m(2) calculated using the simplified Modification of Diet in Renal Disease equation] and elevated cystatin C (>1.0 mg/liter) in a cross-sectional analysis. Among 670 subjects with complete data (mean age 41 years, mean CD4 cell count 530 cells/mm(3), 79% prescribed cART), the mean eGFR was 96.8 ml/min/1.73 m(2). Forty percent of subjects had renal dysfunction; 3.3% had chronic kidney disease (eGFR < 60 ml/min/1.73 m(2)). Elevated cystatin C was present in 18% of subjects. In multivariate analysis, renal dysfunction was associated with older age, non-Hispanic white race/ethnicity, higher body mass index (BMI), hypertension, higher cystatin C levels, and current prescription of ritonavir. Factors associated with elevated cystatin C included hepatitis C coinfection, hypertension, current smoking, older age, current tenofovir use, detectable plasma HIV RNA, and elevated microalbuminuria. The prevalence of chronic kidney disease (CKD) was low in this contemporary HIV cohort. However, mild to moderate renal dysfunction was common despite the widespread use of cART.

Topics: Adenine; Adult; Anti-HIV Agents; Body Mass Index; CD4 Lymphocyte Count; Cohort Studies; Cross-Sectional Studies; Cystatin C; Female; Glomerular Filtration Rate; Hepatitis C; HIV Seropositivity; Humans; Hypertension; Male; Organophosphonates; Prospective Studies; Renal Insufficiency; Ritonavir; Tenofovir

Most antiretrovirals are metabolized in the liver, and overexposure could be more common in human immunodeficiency virus (HIV)-infected patients with hepatic impairment. Careful monitoring of potential drug-related liver injury in clinical practice is necessary. The aim of our study was to analyze the trough concentrations (C (trough)) of atazanavir (ATV) in the plasma of HIV/hepatitis C virus (HCV)-co-infected patients and to compare the values with those of a HIV-infected control population. C (trough) values (22-26 h after last intake) of atazanavir, following the administration of atazanavir/ritonavir 300/100 mg once daily as part of antiretroviral therapy, were assessed by HPLC. We also collected data on dosing of atazanavir, and on demographic (age, gender, and ethnicity), physiological (weight and body mass index), and clinical parameters (CD4+ cell count, HIV-RNA viremia, co-medication, and hepatitis C co-infection). A total of 28 Caucasian HIV-infected adults were studied, of whom 13 were HIV/HCV co-infected. No baseline characteristics differed between the two cohorts, except statistically significant differences regarding ALT, AST, and total bilirubin. The median (range) plasma ATV C (trough) levels were 0.62 (0.05-3.22) μg/ml in HIV patients and 0.32 (0.04-3.37) μg/ml in HIV/HCV patients. Thus, there was no significant difference in plasma trough levels of atazanavir in the two cohorts. In our patients with mild impairment of hepatic function caused by HCV infection, atazanavir C (trough) was comparable in HIV-infected and HIV/HCV-co-infected patients.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Cohort Studies; Coinfection; Drug Interactions; Drug Monitoring; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Viral Load

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; C-Reactive Protein; Darunavir; Female; Hepatitis C; HIV Infections; Humans; Interleukin-6; Male; Ritonavir; Sulfonamides; Time Factors

To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART.. Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes.. Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from -2.18 to -1.37 ml/min per 1.73 m per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m: 3.35 (95% confidence interval (CI) = 1.40-8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type.. ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.

Topics: Adenine; Adult; AIDS-Associated Nephropathy; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Creatinine; Female; Glomerular Filtration Rate; Hepatitis C; HIV Seropositivity; HIV-1; Humans; Incidence; Male; Middle Aged; Organophosphonates; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; Ritonavir; Tenofovir; United States; Viral Load

Topics: Antidepressive Agents, Second-Generation; Aryl Hydrocarbon Hydroxylases; Citalopram; Coinfection; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Darunavir; Depression; Drug Interactions; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Middle Aged; Polymorphism, Single Nucleotide; Ritonavir; Serotonin Syndrome; Sulfonamides

Adequate plasma trough concentrations (Ctrough) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection.. We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 μg/mL, based on the proposed therapeutic range (0.15-0.85 μg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV-, HIV+/HCV+, and HIV+/HCV+ with cirrhosis.. In the whole study population, we observed a large variability and found suboptimal Ctrough levels (<0.15 μg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) μg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median Ctrough of 0.70 (0.43-1.0) μg/mL, with no statistical difference when compared with HIV+/HCV- infected patients. For the 400ATV OD (n=90) dosage regimen, the total median ATV Ctrough was 0.40 (0.23-1.0) μg/mL. In this group, we found a statistically significant difference between HIV+/HCV- and HIV+/HCV+-infected patients: median Ctrough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) μg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the Ctrough median value was 0.42 (0.13-0.75) μg/mL, and there was a significant difference when compared with HIV patients without coinfection.. Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIV-infected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure.

Topics: Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug Monitoring; Female; Fibrosis; Hepacivirus; Hepatitis C; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Retrospective Studies; Ritonavir

The hepatic safety profile of ART including DRV/r was retrospectively evaluated in antiretroviral-experienced HIV-infected patients (18 HIV/HCV coinfected, group A and 29 infected with HIV alone, group B) during a 72 week study. During the study, liver enzyme values were higher in group A, but in the case of abnormal transaminase levels, the median values did not exceed 1.6xULN. This study showed evidence of long-lasting hepatic safety of ART including PI DRV/r in HIV/HCV coinfected and in HIV monoinfected persons.

Topics: Adult; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver; Male; Middle Aged; Retrospective Studies; Ritonavir

To compare the frequency of grade 3 or 4 transaminase elevations (TEs) in HIV/hepatitis C virus (HCV) co-infected patients who started a three-antiretroviral drug regimen including efavirenz or a ritonavir-boosted protease inhibitor (PI/r) and the influence of pre-existing significant hepatic fibrosis or cirrhosis.. All pre-treated or treatment-naive HIV/HCV co-infected patients who started an antiretroviral regimen including two nucleos(t)ide reverse transcriptase inhibitors along with efavirenz or a PI/r in seven Spanish centres from January 2007 to December 2009 were included in this prospective study.. Of 262 patients included in this study, 76 (29%) individuals began antiretroviral therapy (ART) including efavirenz and 186 (71%) a PI/r-based combination. The median (interquartile) follow-up was 14.0 (6.2-23.7) months. A total of 20 (7.6%) patients presented grade 3-4 TEs. Four (1.5%) subjects discontinued ART due to this adverse event. Grade 3-4 TEs were observed in 5 (6.6%) subjects receiving efavirenz and 15 (8.1%) treated with PI/r (P = 0.681). Three (6.5%) patients in the efavirenz group with significant fibrosis developed grade 3-4 TEs versus 2 (8.7%) without pre-existing significant fibrosis (P = 0.743). In the PI/r group, the corresponding figures were 10 (8.8%) and 5 (9.3%), respectively (P = 0.931).. The frequency of grade 3-4 TEs associated with efavirenz-based ART combinations under clinical practice conditions is low and similar to that found in patients receiving PI/r currently used in HIV/HCV co-infected patients. The baseline fibrosis stage does not have an impact on the development of TEs caused by these antiretroviral drugs in this population.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver; Liver Cirrhosis; Male; Middle Aged; Ritonavir; Transaminases

Danoprevir (ITMN-191; RG-7227), under development by InterMune Inc and Roche Holding AG, is a promising, potent NS3/4A protease inhibitor for the oral treatment of HCV infection. Preclinical data demonstrated that danoprevir binds with high affinity and dissociates slowly from the HCV NS3 protease, allowing high liver drug exposure with only modest plasma drug exposure. A phase Ib, 'IFN-free' clinical trial demonstrated that danoprevir, combined with the HCV polymerase inhibitor RG-7128 (Pharmasset Inc/Roche Holding AG), was effective in reducing HCV-RNA levels in a large proportion of treatment-naïve patients with HCV infection and in approximately half of previously non-responsive patients with HCV-1 infection, without resistance or safety concerns. In a phase IIb trial in treatment-naïve patients with HCV-1 infection, danoprevir plus pegylated IFNalpha2a and ribavirin resulted in undetectable levels of HCV-RNA in the majority of patients, without any evidence of viral resistance; however, the high-dose danoprevir arm was prematurely terminated because of grade 4 ALT elevations. Phase I trials have also demonstrated that ritonavir boosting improved the pharmacokinetic profile of danoprevir; therefore, at the time of publication, a phase IIb trial to evaluate ritonavir-boosted, low-dose danoprevir in combination with RG-7128 was planned.

Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Cyclopropanes; Dogs; Drug Evaluation, Preclinical; Drug Therapy, Combination; Haplorhini; Hepacivirus; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Isoindoles; Lactams; Lactams, Macrocyclic; Polyethylene Glycols; Proline; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Ribavirin; Ritonavir; Sulfonamides; Viral Nonstructural Proteins

Although the mechanism of atazanavir (ATV)-related hyperbilirubinemia is well identified, its prevalence, risk factors, and association with transaminase flares have rarely been assessed in a large population from the "real life" setting.. Prospectively collected data on 2,404 patients from the Italian MASTER Cohort and the Italian ATV expanded access program database were examined. Uni- and multivariable Cox proportional hazards regression models were conducted to identify risk factors for grade >or= III hyperbilirubinemia during the administration of ATV. The risk of increased levels of serum alanine aminotransferase (ALT) was compared between patients with or without grade >or= III hyperbilirubinemia in a Cox regression analysis stratified by hepatitis C virus (HCV) serostatus.. Grade III and IV hyperbilirubinemia were observed in 1,072 (44.6%) and 174 (7.2%) of the patients, respectively. Higher CD4+ T-cell counts, abnormal bilirubinemia at baseline, and ritonavir co-administration were associated with a higher risk of developing grade >or= III hyperbilirubinemia. In contrast, female gender, clinical class C, and non-nucleoside reverse transcriptase co-administration appeared to be protective. Higher bilirubinemia at baseline and the use of ritonavir were associated with a higher risk of grade IV hyperbilirubinemia. The occurrence of grade >or= III hyperbilirubinemia was not associated with severe hepatotoxicity (hazard ratio 1.00, 95% confidence interval 0.64-1.57; p = 0.997).. Hyperbilirubinemia is a common side effect of an ATV pharmacotherapeutic regimen. However, grade IV increase in bilirubin was rarely found. In most cases, ATV hyperbilirubinemia appeared to be an innocent phenomenon as far as the risk of a subsequent increase in liver enzyme level is concerned.

Topics: Adult; Alanine Transaminase; Analysis of Variance; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; CD4 Lymphocyte Count; Cohort Studies; Female; Hepatitis C; HIV Infections; Humans; Hyperbilirubinemia; Liver; Male; Multivariate Analysis; Oligopeptides; Prevalence; Proportional Hazards Models; Pyridines; Risk Factors; Ritonavir; Severity of Illness Index

To appraise the rate of grade 3-4 transaminase elevations (TEs) and grade 4 total bilirubin elevation (TBE) in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C or hepatitis B virus (HCV or HBV, respectively) who receive atazanavir/ritonavir. Moreover, the relationship between these events and the degree of prior liver fibrosis was evaluated.. A cohort of 189 HIV-infected patients, 175 co-infected with HCV, 4 with HBV and 10 with both, receiving atazanavir/ritonavir, was analysed. Baseline liver fibrosis was assessed in 113 (60%) patients. Twenty-four patients had cirrhosis, whereas such a diagnosis was ruled out in 58 patients.. Twelve (6%) and 28 (15%) patients developed grade 3-4 TEs and grade 4 TBE, respectively. Eight (10%) of 84 patients with fibrosis >/=F2 versus 1 of 29 (3%) with F0-F1 (P = 0.51) developed grade 3-4 TEs. The frequencies of grade 3-4 TEs in patients with and without cirrhosis were 8% and 5% (P = 0.63), respectively. Grade 4 TBE was more common among patients with cirrhosis (35% versus 13%, P = 0.05) in the univariate analysis. In the multivariate study, the only predictor of grade 3-4 TEs was baseline CD4 cell count <300 cells/mm(3) [adjusted OR (AOR) (95% CI) = 8.77 (1.07-71.42), P = 0.04]. The factors independently associated with grade 4 TBE were baseline total bilirubin >1 mg/dL [AOR (95% CI) = 3.2 (1.21-8.45), P = 0.01] and age >40 years [AOR (95% CI) = 2.98 (1.19-7.47), P = 0.02].. Prior significant liver fibrosis or cirrhosis do not increase substantially the risk of severe TE associated with atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses.

Topics: Adult; Age Factors; Atazanavir Sulfate; Bilirubin; CD4 Lymphocyte Count; Female; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver Cirrhosis; Male; Oligopeptides; Pyridines; Ritonavir; Transaminases

To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment.. Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach.. Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively).. Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Topics: Area Under Curve; Chromatography, High Pressure Liquid; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver; Liver Function Tests; Lopinavir; Pyrimidinones; Ritonavir

To describe a case of exacerbated mania potentially related to an interaction between lopinavir/ritonavir and valproic acid (VPA) and propose a mechanism of action for this interaction.. A 30-year-old man with bipolar disorder and HIV initiated treatment with lopinavir/ritonavir, zidovudine, and lamivudine. Prior to beginning therapy with these antiretrovirals, he was receiving VPA 250 mg 3 times daily, with his most recent VPA concentration measured at 495 micromol/L. Twenty-one days after starting antiretroviral treatment, he became increasingly manic. His VPA concentration at admission was 238 micromol/L, a 48% decrease. The daily VPA dose was increased to 1500 mg, and olanzapine was introduced. The VPA concentration following this dose escalation was 392 micromol/L, and the patient improved clinically.. Fifty percent of VPA is metabolized by glucuronidation, 40% undergoes mitochondrial beta-oxidation, and less than 10% is eliminated by the cytochrome P450 isoenzymes. Ritonavir can induce glucuronidation of several medications including ethinyl estradiol, levothyroxine, and lamotrigine. We believe that ritonavir-mediated induction of VPA glucuronidation resulted in a decrease in VPA concentrations and efficacy. An objective causality assessment suggested that the increased mania was probably related to the decrease in VPA concentration and that a possible interaction exists between lopinavir/ritonavir and VPA.. A potential interaction exists between VPA and all ritonavir-boosted antiretroviral regimens. Clinicians should monitor patients closely for a decreased VPA effect when these medications are given concomitantly.

Topics: Adult; Antiretroviral Therapy, Highly Active; Bipolar Disorder; Dose-Response Relationship, Drug; Drug Interactions; Hepatitis C; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Valproic Acid

Topics: Adult; Aged; Female; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

The objective of this study was to find predictive factors of lopinavir/ritonavir (LPV/r) discontinuation for drug-related toxicities in highly pre-treated human immunodeficiency virus (HIV)-infected subjects. The study was an observational study of HIV patients starting LPV/r with HIV RNA > 3log10 copies/mL and a follow-up > or = 6 months. Parameters studied were HIV RNA, CD4+ cell counts, metabolic parameters and drug-related adverse events. Acquired immune deficiency syndrome (AIDS) events and deaths were recorded. The Kaplan-Meier (KM) model was used to estimate time-dependent probability, and the multivariable Cox model to identify predictors of LPV/r discontinuation for adverse events. The study evaluated 416 HIV-infected patients. Seventy-seven patients (18.5%) discontinued LPV/r for toxicities. Adverse events leading to LPV/r discontinuation were gastrointestinal symptoms in 40 cases, hyperlipidaemia in 27 and increase of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in 10 patients. Nineteen patients (4.6%) developed an AIDS event during observation and 15 (3.6%) died. The KM probability of LPV/r discontinuation for toxicities was 5.3% (range 3.1-7.5%) at month 12 and 15.7% (range 12.1-19.3%) at month 24. Subjects with hepatitis C virus (HCV)-HIV co-infection (odds ratio (OR) 7.40; 95% confidence interval (CI) 3.73-14.66 versus HCV-negative; P = 0.001) and receiving LPV/r plus nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitor (PI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) (OR 1.74; 95% CI 1.04-2.91 versus LPV/r plus only NRTIs; P = 0.04) showed a higher risk of LPV/r discontinuation by a Cox analysis, whereas non-intravenous drug abusers (IVDUs) (OR 0.40; 95% CI 0.24-0.67 versus IVDUs; P = 0.001) had a lower risk. The rate of discontinuation for toxicity decreased by 17% for each additional month of LPV/r exposure (OR 0.83; 95% CI 0.80-0.86 for each additional month; P < 0.001). LPV/r was substantially well tolerated. Diarrhoea was the most frequent adverse event leading to discontinuation. HCV-HIV co-infected patients and patients with a short exposure to LPV/r have a higher risk of discontinuing LPV/r and should be strictly monitored.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Cohort Studies; Drug Administration Schedule; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Odds Ratio; Prospective Studies; Pyrimidinones; Risk Factors; Ritonavir

Topics: Drug Therapy, Combination; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir

Topics: Drug Combinations; Europe; Hepatitis C; HIV Protease Inhibitors; Humans; Liver; London; Lopinavir; Mitochondria, Liver; Pyrimidinones; Ritonavir

To evaluate the occurrence of hepatotoxicity in patients during antiretroviral therapy (ART) that contains protease inhibitors and the role of hepatitis viruses in its development, we performed a retrospective study including 1325 HIV-infected patients treated with ART for at least 6 months. Presence or absence of hepatitis viruses, alanine aminotransferase (ALT), total bilirubin, CD4 cell count, and plasma HIV RNA levels were evaluated. Hepatotoxicity developed in a few study subjects without coinfection, whereas it was significantly higher in coinfected patients. Univariate logistic regression analysis showed that viral hepatitis coinfections are independent risk factors for hepatotoxicity. After 6 months of treatment, ritonavir was associated with higher rates of severe hepatotoxicity in the coinfected group; in fact, ritonavir seems to be the most strongly hepatotoxic agent among coinfected patients. After 12 months of therapy, hepatotoxicity occurred more frequently in patients with hepatitis C virus who did not respond to antiretroviral therapy (ART), whereas patients who did respond to ART showed decreased ALT levels. Hepatotoxicity is not exclusively an effect of drug toxicity, and the presence of hepatitis coinfection is an independent risk factor. Moreover, chronic hepatotoxicity mainly occurs in patients who did not respond to therapy. Conversely, patients who did respond to ART seemed to show improvement of chronic liver infection.

Topics: Adult; Alanine Transaminase; Antiviral Agents; Bilirubin; Chemical and Drug Induced Liver Injury, Chronic; Female; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Italy; Male; Prevalence; Regression Analysis; Retrospective Studies; Risk Factors; Ritonavir; Time Factors; Viral Load

This retrospective cohort study investigated whether particular antiretroviral agents are associated with a higher risk for developing grade 4 liver enzyme elevations (LEEs) in patients with human immunodeficiency virus (HIV) type 1 infection who are starting to receive highly active antiretroviral therapy (HAART). Grade 4 LEE was defined as aminotransferase levels >10 times the upper limit of normal and >200 U above baseline levels. A multivariate Cox model was used to identify risk factors. The incidence of LEE was 6.3%. No patients died of LEE consequences. Risk factors were higher baseline alanine aminotransferase levels, chronic hepatitis B or C virus infection, antiretroviral therapy-naive patients undergoing their first HAART regimen, recent start of a regimen of nevirapine or high-dose ritonavir, and female sex. In hepatitis B virus (HBV)-coinfected patients, discontinuing lamivudine (3TC) use was a risk factor. In 97% of cases, >or=1 risk factor was present. In HBV-coinfected patients using 3TC, continued use of 3TC should be considered, even if 3TC-resistant HIV strains develop.

Topics: Adult; Alanine Transaminase; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Hepatitis B; Hepatitis C; HIV Infections; HIV-1; Humans; Incidence; Lamivudine; Liver Function Tests; Male; Nevirapine; Proportional Hazards Models; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Sex Factors; Transaminases

Ten severely immunocompromised HIV-HCV co-infected patients were enrolled in a quantifiable HCV-RNA assay. Serum alanine aminotransferase, HCV-RNA levels and HIV viral loads were determined at baseline, at month three and at month six after initiation of a highly active antiretroviral therapy including an HIV protease inhibitor. HCV genotypes were determined using a line probe assay kit. Our results suggested that this therapy did not result in lower HCV viraemia, whatever the HCV genotypes, and probably had no effect on the outcome of chronic viral hepatitis C. As our patients were severely immunocompromised and their mean increase of CD4 cell counts was less than 50/mm(3), we cannot reach any conclusions about the impact of the improvement of immune status on the HCV-RNA load.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Hepacivirus; Hepatitis C; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load; Viremia; Virus Replication

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Follow-Up Studies; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Liver Function Tests; Male; Ritonavir

Topics: AIDS-Related Opportunistic Infections; Hepacivirus; Hepatitis C; HIV Protease Inhibitors; Humans; Immunity; Indinavir; Retrospective Studies; Ritonavir; Saquinavir

To report observations from case studies on the pathogenic mechanisms underlying the acute hepatitis that sometimes occurs in hepatitis C virus (HCV) and HIV coinfected patients following treatment with potent antiretroviral therapy that includes a HIV protease inhibitor.. Cases of acute hepatitis were identified from a group of 133 patients enrolled in a retrospective study of pathogen-associated inflammatory disease following the use of potent antiretroviral therapy. Data on serum alanine aminotransferase concentrations, clinical events, HCV antibodies, and liver biopsies were collected from medical records. HCV RNA assays and additional HCV antibody assays were undertaken on stored plasma or sera.. Three of the 133 patients (2%) developed symptomatic hepatitis. One was HCV antibody-positive prior to commencing antiretroviral therapy and developed hepatitis subsequent to an episode of Mycobacterium avium complex disease associated with immune restoration. However, the other two patients had previously undiagnosed HCV infection for up to 2 years prior to antiretroviral therapy, with HCV RNA detected but anti-HCV antibody repeatedly undetectable in stored plasma or sera. HCV antibody was only detectable after antiretroviral therapy-induced decrease in plasma HIV RNA and immunological reconstitution. Plasma HCV RNA increased after therapy in one of these patients, but in the other the level was not increased at a time of active hepatitis demonstrated by liver biopsy.. Hepatitis in HCV-HIV-coinfected patients following treatment with potent antiretroviral therapy may reflect restoration of anti-HCV immune responses rather than increased HCV replication or a hepatotoxic effect of antiretroviral therapy.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Female; Hepacivirus; Hepatitis C; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine

Some reports have suggested that drug-induced hepatotoxicity can be associated with antiretroviral therapy in HIV-positive people coinfected with chronic hepatitis C virus (HCV). Several presentations at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) examined this possible interaction. The impact of highly active antiretroviral therapy (HAART) on persons coinfected with HCV was described. There is increasing clinical recognition that HCV can lead to significant liver-related morbidity and mortality among HIV-infected persons.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Ritonavir; RNA, Viral