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The phase 2, open-label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6-or 8-week regimen of simeprevir, daclatasvir and sofosbuvir in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early-stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early-stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty-eight patients were treated (6-week group: n = 59; 8-week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early-stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6-week group was viral relapse (11.9%; 7/59). One patient had on-treatment failure due to an early withdrawal (lost to follow-up due to incarceration). One patient with SVR12 in the 6-week group had a late viral relapse at post-treatment week 24. No clinically significant drug-drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct-acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment-naïve, HCV GT1-infected patients with early-stage fibrosis or compensated cirrhosis. [ABSTRACT FROM AUTHOR]

Summary: Treatment with the direct‐acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1‐6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV‐mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo. [ABSTRACT FROM AUTHOR]

High rates of sustained virologic response at post-treatment week 12 ( SVR12) were achieved in six phase 3 trials of ombitasvir ( OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir ( PTV/r) + dasabuvir ( DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin ( RBV) in adults with chronic genotype ( GT) 1 hepatitis C virus ( HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT- PCR assay (lower limit of quantification, LLOQ =25 IU/ mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA < LLOQ. The analysis included a total of 2027 patients. Cumulative proportions of subjects with initial HCV RNA suppression < LLOQ at weeks 1, 2, 4 and 6 were 31%, 81%, 99% and 100%, respectively. SVR12 was achieved by 98%, 97%, 98% and 92% of patients with initial suppression at Weeks 1, 2, 4 and 6, respectively ( P=.42, trend test). Across six phase 3 trials of 3D ± RBV, most patients achieved viral suppression by week 2. Time to viral suppression was not associated with subsequent achievement of SVR12, suggesting that on-treatment virologic monitoring may not be necessary with this regimen. [ABSTRACT FROM AUTHOR]

A fixed-dose combination of ledipasvir and sofosbuvir ( LDV/ SOF) has been approved for treatment of HCV patients. We assessed the effect of LDV/ SOF on patient-reported outcomes ( PROs) in HIV- HCV-co-infected patients. Patient-reported outcomes data from HIV- HCV-co-infected patients who were treated with LDV/ SOF for 12 weeks were collected as a part of a clinical trial ( ION-4). Historical controls were HIV- HCV-co-infected patients treated with SOF and ribavirin ( RBV) in PHOTON-1. We included 335 HIV- HCV-co-infected patients ( SVR-12 in HCV genotype 1 was 96%) who received LDV/ SOF, while 223 patients ( SVR-12 in HCV genotype 1 was 76.3%) received SOF/ RBV. During treatment, patients receiving LDV/ SOF showed improvement in all of their PRO scores (+6.0% in activity/energy of CLDQ- HCV, +5.0% in fatigue score of FACIT-F, +6.8% in physical component of SF-36; all P < 0.0001) while those receiving SOF+ RBV showed moderate decline in some of their PRO scores (−4.8% in physical functioning of SF-36, −4.4% in fatigue score of FACIT-F, both P < 0.001). Patients who achieved sustained virologic response with LDV/ SOF also showed improvement of PROs (average +5.1%) while those treated with SOF/ RBV showed less or no improvement (average +1.4%). In a multivariate analysis, in addition to depression and fatigue, receiving SOF+ RBV ( vs LDV/ SOF) was independently associated with more PRO impairment during treatment (beta −6.1 to −12.1%, P < 0.001). Hence, HIV- HCV patients treated with LDV/ SOF show significant improvement of their health-related quality of life and other patient-reported outcomes during treatment and after treatment cessation. [ABSTRACT FROM AUTHOR]

Background and aims: Addition of a 40kD polyethylene glycol moiety to interferon-α-2a [peginterferon-α-2a (40kD)] improves pharmacokinetic properties over those of standard interferon. We conducted a phase II study to assess the safety and initial efficacy of peginterferon-α-2a (40kD) plus ribavirin combination therapy in patients with chronic hepatitis C (CHC). Methods: Twenty patients received open-label 180μg peginterferon-α-2a (40kD) subcutaneously once weekly and oral ribavirin 1000 or 1200mg daily for patients weighing <75 or ≥75kg, respectively, for a period of 24 weeks. Patients with hepatitis C virus (HCV) genotype 1 and a virological response at week 24 received study drugs for an additional 24 weeks. Results: A sustained virological response, defined as undetectable HCV RNA 24 (i.e. <100 copies/ml) weeks after completing the therapy, was achieved in 50% of patients in an intent-to-treat analysis (6/16 genotype 1 and 4/4 genotype non-1). Adverse events were similar to those reported with unmodified interferon plus ribavirin combination therapy. Anaemia led to ribavirin dose reduction in five patients. Neutropenia led to dose reduction in three patients treated with peginterferon-α-2a (40kD). Conclusions: The addition of ribavirin to a once-weekly peginterferon-α-2a (40kD) regimen should be investigated in larger clinical trials. [ABSTRACT FROM AUTHOR]

Context: Hepatitis C is the leading cause of chronic liver disease in the United States. Several trials have found that interferon and ribavirin combination therapy is more efficacious than interferon monotherapy for previously untreated patients and those who relapsed after prior interferon monotherapy, but its effectiveness for nonresponders to prior interferon monotherapy is unclear.Objective: To assess the efficacy and safety of interferon and ribavirin vs interferon alone for treatment of patients with chronic hepatitis C who previously did not respond to interferon monotherapy.Data Sources: A systematic search was performed using MEDLINE and the Science Citation Index for publications from 1966 to December 1999. A manual reference search and a manual review of relevant specialty journals also were performed, and input from clinical hepatology experts was sought.Study Selection: Included studies were randomized, controlled clinical trials comparing interferon and ribavirin with interferon alone and reporting virological and biochemical outcomes after a follow-up period. Of 50 identified studies, 12 trials (941 patients) were included in the analysis.Data Extraction: Two investigators reviewed trials independently for methods, inclusion and exclusion criteria, and outcomes. Disagreements were resolved by discussion. Abstracted data included study and patient characteristics and virological, biochemical, and histological outcomes. A quality evaluation questionnaire was used to score studies.Data Synthesis: The pooled virological response rate for combination therapy was 14% (95% confidence interval [CI], 11%-17%), with a risk difference favoring combination therapy of 7% (95% CI, 2%-13%). Use of interferon alfa-2a/2b and ribavirin, 1000 to 1200 mg/d, was associated with a pooled virological response rate of 18% and a risk difference of 16% (95% CI, 11%-21%). When interferon alfa-n/n3 and a lower dosage of ribavirin (600-800 mg/d) were used, the risk difference was 0% (95% CI, -7% to 7%). Combination therapy was associated with more adverse effects and an increased rate of discontinuation of treatment compared with interferon monotherapy.Conclusions: For chronic hepatitis C that is nonresponsive to prior interferon monotherapy, combination therapy is more effective than re-treatment with interferon alone. Response rates remain less than 20% even in the most responsive subgroups, demonstrating a need for better therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. This relationship has not been investigated at the population level, and its biological mechanism remains unknown.Objective: To examine the prevalence of type 2 diabetes among persons with HCV infection in a representative sample of the general adult population of the United States.Design: Cross-sectional national survey.Setting: The Third National Health and Nutrition Examination Survey, 1988-1994.Participants: 9841 persons older than 20 years of age for whom data on HCV infection and diabetes were complete.Measurements: The presence of diabetes was ascertained by using American Diabetes Association guidelines based on fasting plasma glucose measurement and medication history. Presence of HCV infection was assessed by testing for serum HCV-specific antibodies (anti-HCV).Results: Of the 9841 persons evaluated, 8.4% had type 2 diabetes and 2.1% were anti-HCV positive. Type 2 diabetes occurred more often in persons who were older, were nonwhite, had a high body mass index, and had low socioeconomic status. Type 2 diabetes was less common in persons who acknowledged previous illicit drug use. After adjustment for these factors, persons 40 years of age or older with HCV infection were more than three times more likely than those without HCV infection to have type 2 diabetes (adjusted odds ratio, 3.77 [95% CI, 1.80 to 7.87]). None of the 19 persons with type 1 diabetes were anti-HCV positive.Conclusion: In the United States, type 2 diabetes occurs more often in persons with HCV infection who are older than 40 years of age. [ABSTRACT FROM AUTHOR]

Context: Use of antiretroviral drugs, including protease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotally associated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus.Objectives: To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for all antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development.Design: Prospective cohort study.Setting: University-based urban HIV clinic.Patients: A total of 298 patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211 (71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days) and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronic hepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively.Main Outcome Measure: Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase, evaluated before and during therapy.Results: Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%). Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI, 17.9% -44.6%). However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir (5.9%; 95% CI, 0.15%-28.7%), and indinavir(6.8%; 95% CI, 3.0%-13.1 %). Although chronicviral hepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribed nonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or B virus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of any protease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and a CD4 cell count increase of more than 0.05 x 10(9)/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity.Conclusions: Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity. Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do not support withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus. [ABSTRACT FROM AUTHOR]

Introduction – objectifs Les patients infectés par le VHC de génotype 1 (GT1), en échec d’un traitement par PEG-IFN + RBV + IP ne disposent d’aucune option thérapeutique. L’objectif était d’évaluer l’efficacité d’un traitement par sofosbuvir (SOF) + PEG/RBV pendant 12 semaines chez les patients n’ayant pas répondu aux traitements avec 3 ou 4 médicaments. Matériels et méthodes Les patients GT1 n’ayant pas répondu à des traitements par PEG/RBV et IP (GS-9451 ou GS-9256) associés ou non à un autre antiviral (ledipasvir ou tegobuvir) ont reçu pendant 12 sem SOF + PEG-IFN (180 μg/sem) + RBV (1 000–1 200 mg/j). Les critères d’efficacité = RVS12 et RVS4. Résultats Aucun des 57 patients n’avait répondu à PEG/RBV/IP +/− inhibiteur NS5a (ledipasvir) ou inhibiteur de pol NS5b non nuc (tegobuvir). Durée moyenne traitement précédent = 202 j +/− 144. 16 patients (30 %) avaient reçu plusieurs cures de traitement. Hommes = 72 %, GT1a = 93 %, IL28B non-CC = 95 %. À ce jour, les taux de RVS4 sont de 96 % (22/23) chez les patients ayant atteint la visite 4 sem post-traitement. VRT 1 à BL Nombre (n/N ;%) RVS4 (n/N ; %) 2 0 VRT 2/57 4 %) 2/2 (100 %) 1 VRT 17/57 (30 %) 4/4 (100 %) 2 VRT 25/57 (44 %) 9/10 (90 %) 3 VRT 13/57 (23 %) 7/7 (100 %) Les données complètes de RVS12 seront présentées lors du congrès. Conclusion SOF/PEG/RBV pendant 12 sem entraîne des RVS4 élevés chez des GT1 précédemment traités en dépit d’une ou plusieurs mutations de résistance et d’autres facteurs défavorables de réponse. [ABSTRACT FROM AUTHOR]

Introduction – objectifs Évaluer la tolérance et l’efficacité de l’association sofosbuvir (SOF), inhibiteur pangénotypique de la NS5B du VHC, et ribavirine (RBV) chez des patients co-infectés VIH-VHC de génotypes (GT) 1 à 3. Matériels et méthodes Des patients VHC avec infection à VIH contrôlée ont reçu SOF 400 mg 1 fois/j et RBV 1 000–1 200mg/j ; les patients GT1 naïfs et GT2/3 prétraités ont reçu 24 semaines, les GT2/3 naïfs ont reçu 12 semaines de ttt. Le critère principal d’efficacité a été la réponse virologique soutenue 12 semaines après ttt (SVR12) ; l’évaluation de la tolérance a inclus ARN-VIH et nombre de CD4. Résultats Une SVR12 a été observée chez 88 % (23/26) des GT2 naïfs et 67 % (28/42) des GT3 naïfs. Parmi les 13 échecs virologiques survenus dans ces 2 groupes, un seul était un échappement sous ttt, lié à une non-observance. Aucune mutation de résistance S282T n’a été détectée parmi les échecs virologiques jusqu’à présent. Les résultats complets de SVR24 seront présentés pour tous les groupes. Tous groupes confondus, il y a eu peu d’arrêts de ttt pour EI (3 %) et des EI de grades 3–4 sont survenus chez 25 patients (11 %). 2 patients ont connu un rebond VIH. Conclusion Les patients co-infectés VIH-VHC GT2 ou 3 naïfs ont obtenu un taux élevé de SVR12 avec l’association SOF + RBV, sans interféron et par voie orale. Ces données suggèrent que SOF + RBV est bien toléré en cas de co-administration avec divers ARV et pourrait être aussi bien toléré et efficace, que les patients soient co-infectés ou non par le VIH. [ABSTRACT FROM AUTHOR]