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Sofosbuvir‐velpatasvir is approved for the treatment of chronic hepatitis C virus (HCV) infection. In this single‐arm, open‐label, phase 3, deferred treatment study, we investigated the efficacy and safety of sofosbuvir‐velpatasvir among patients randomized to the placebo group in the ASTRAL‐1 study. Patients received sofosbuvir‐velpatasvir (400/100 mg) once daily for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response 12 weeks after the end of therapy (SVR12). The primary safety endpoint was any adverse events (AEs) leading to the permanent discontinuation of study drug. Overall, 108/111 (97%, 95% confidence interval [CI], 92%‐99%) achieved SVR12, and only one patient had virological failure. SVR12 was achieved by 61/63 (97%, 95%CI, 89%‐100%) genotype 1 patients, 20/20 (100%; 95%CI, 83%‐100%) with genotype 2, 19/19 (100%; 95%CI, 82%‐100%) with genotype 4 and 8/9 (89%; 95% CI, 52%‐100%) with genotype 6. All (19/19; 95%CI, 82‐100) patients with cirrhosis and all (31/31, 95%CI, 89‐100) with prior treatment experience achieved SVR12. The safety profile during treatment was similar to that observed in patients receiving placebo treatment. The most common AEs were headache, fatigue and nausea. One patient (1%) discontinued treatment due to an AE of gallbladder carcinoma, which was not considered related to treatment. Of five reported serious AEs, none were considered related to study drug. Sofosbuvir‐velpatasvir for 12 weeks was effective and well tolerated among untreated and previously treated patients with HCV genotype 1, 2, 4 or 6 infection, including those with compensated cirrhosis (ClinicalTrials.gov NCT02346721). [ABSTRACT FROM AUTHOR]

Background and Aim: Genotype 3b hepatitis C virus (HCV) infection represents approximately 50% of patients with genotype 3 in China. We compared the efficacy of sofosbuvir (SOF) plus ribavirin (RBV) in Chinese patients with genotype 3a and 3b HCV. Methods: The analyzed data are from a phase 3, open‐label study of SOF plus RBV for 24 weeks conducted in China. The primary endpoint for the trial was sustained virologic response at 12 weeks after the end of therapy (SVR12). Results: Of 126 patients included in this analysis, 58 (46%) had genotype 3a and 68 (54%) had genotype 3b. Both the subtypes were similar in age, sex, body mass index, IL28B, and baseline HCV RNA. However, more treatment‐experienced and cirrhotic patients were in the genotype 3b group. All 100% of patients with genotype 3a (95% confidence interval [CI], 94‐100), and 91% (95% CI, 82‐97) of patients with genotype 3b achieved SVR12 (P = 0.030). For treatment‐experienced patients with genotype 3b, the SVR12 rate was 73% (95% CI, 39‐94) and 88% (95% CI, 64‐99) among patients with and without cirrhosis (P = 1.00), respectively. Conclusion: SOF plus RBV for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of SVR. However, the SVR12 rate among patients with genotype 3b was lower than that observed in patients with genotype 3a infection, particularly among treatment‐experienced patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Summary: This study evaluated 12‐week retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus (HCV) infection who did not achieve sustained virologic response after previous treatment with a sofosbuvir‐ and velpatasvir‐containing regimen. All 31 patients maintained a sustained virologic response 12 weeks after the last sofosbuvir/velpatasvir/voxilaprevir dose. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Japanese patients with chronic hepatitis C virus (HCV) genotype 2 infection have high rates of sustained virological response (SVR) following 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin, which was the standard of care at the time this study was undertaken. We assessed the efficacy of 12 weeks of treatment with a ribavirin‐free regimen of ledipasvir‐sofosbuvir. Methods: In an open‐label, Phase 3 trial we enrolled Japanese patients with chronic HCV genotype 2 infection, with or without compensated cirrhosis. In Cohort 1, participants were randomized 1:1 to receive ledipasvir‐sofosbuvir (n = 106) or sofosbuvir + ribavirin (n = 108) for 12 weeks. In Cohort 2, 25 ribavirin‐intolerant or ‐ineligible patients received ledipasvir‐sofosbuvir for 12 weeks. The primary endpoint was SVR 12 weeks after therapy (SVR12). In Cohort 1 non‐inferiority was assessed with a prespecified margin of 10%. Results: One‐third (33%) of patients were treatment experienced, and 14% had cirrhosis. In Cohort 1, SVR12 rates were 96% (95% CI, 91% to 99%) with ledipasvir‐sofosbuvir and 95% (95% CI, 90% to 98%) with sofosbuvir plus ribavirin, thus achieving non‐inferiority. Among ribavirin‐intolerant/ineligible patients in Cohort 2, SVR12 was 96% (95% CI, 80% to 100%) with ledipasvir‐sofosbuvir. Overall, the most common adverse events were nasopharyngitis, anaemia, and headache; anaemia was only observed in patients receiving ribavirin. The percentage of patients who discontinued treatment because of an adverse event was low (1%). Conclusions: Among Japanese patients with HCV genotype 2, 12 weeks of treatment with ledipasvir‐sofosbuvir resulted in high rates of SVR12 that were non‐inferior to sofosbuvir + ribavirin. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluated the effect of supratherapeutic exposure of the anti‐HCV drug ledipasvir on the QTc interval in healthy subjects. Sixty healthy volunteers were randomized to receive twice‐daily blinded ledipasvir (120 mg) or placebo, administered for 10 days each, or single doses of open‐label moxifloxacin (400 mg). Serial plasma samples for ledipasvir concentration analysis were collected after each treatment. Triplicate time‐matched electrocardiograms were collected at baseline and after each treatment. Change from baseline in the QTc for ledipasvir or moxifloxacin versus placebo was determined using several correction formulas (primary: QTcF [Fridericia's]; secondary: QTcN [population] and QTcI [individual]). Pharmacokinetics and exposure–QTc relationships were evaluated. Ledipasvir AUC0–24 and Cmax achieved approximately 3.7‐fold and 4.2‐fold, respectively, above exposures observed following administration of ledipasvir/sofosbuvir (90/400 mg) to HCV‐infected patients. There was a lack of effect of supratherapeutic ledipasvir on QTc intervals using all correction methods (upper bound of the 2‐sided 90%CIs for the mean difference in time‐matched baseline‐corrected QTc between ledipasvir versus placebo < 10 milliseconds at all times). The lower bound of the 2‐sided 96.67%CI for the mean difference in moxifloxacin versus placebo was >5 milliseconds, thereby establishing assay sensitivity. Categorical analyses did not demonstrate clinically relevant effects of ledipasvir on QTc intervals or other electrocardiogram parameters. No relationships between ledipasvir plasma concentration and QTc interval were observed. Ledipasvir does not prolong QTc interval. Based on these results and a previous TQT evaluation for sofosbuvir, the fixed‐dose combination regimen of ledipasvir/sofosbuvir is not expected to prolong the QTc interval. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aims: This study aimed to evaluate the prevalence of the hepatitis C virus intergenotype recombinant strain RF1_2k/1b in Georgia, confirm viral recombination by full genome sequencing, and determine a genetic relationship with previously described recombinant hepatitis C viruses. Methods: We retrospectively analysed data from 1421 Georgian patients with chronic hepatitis C. Genotyping was performed with the INNO‐LiPA VERSANT HCV Genotype 2.0 Assay. Results: Virus isolates were assigned to nonspecific hepatitis C genotypes 2a/2c (n = 387) as performed by sequencing of core and NS5B genes. Subsequently, sequencing results classified the core region as genotype 2k and the NS5B region as genotype 1b for 72% (n = 280) of genotype 2 patients, corresponding to 19.7% of hepatitis C patients in Georgia. Eight samples were randomly selected for full genome sequencing which was successful in 7 of 8 samples. Analysis of the generated consensus sequences confirmed that all 7 viruses were 2k/1b recombinants, with the recombination breakpoint located within 73‐77 amino acids before the NS2‐NS3 junction, similar to the previously described RF1_2k/1b virus. Phylogenetic analysis revealed clustering of the Georgian 2k/1b viruses and RF1_2k/1b, suggesting that they are genetically related. Conclusions: The 19.7% prevalence of RF1_2k/1b in Georgia patients is far higher than has generally been reported to date worldwide. Identification of recombinants in low income countries with a high prevalence of HCV infection might be reasonable for choosing the most cost‐effective treatment regimens. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir‐velpatasvir in patients with hepatitis C virus genotype 1‐6 infection and compensated cirrhosis or advanced fibrosis. Methods: This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir‐velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined. Results: Forty‐four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96‐99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment‐naïve patients and 97% (184/190) for treatment‐experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs. Conclusions: Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims In Taiwan, patients with chronic hepatitis C virus ( HCV) infection are currently treated with pegylated interferon-alpha plus ribavirin, but interferon-based regimens can be poorly tolerated, especially by those with advanced liver disease and the elderly. Sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, is approved in Europe, the USA and Japan for treating chronic HCV infection. This phase 3b study examined the efficacy and safety of sofosbuvir plus ribavirin in Taiwanese patients with chronic genotype 2 HCV infection ± compensated cirrhosis. Methods In this multicentre, open-label, phase 3b ( NCT02021643) study, 87 patients ( n = 43, treatment-naive; n = 44, treatment-experienced) received 12 weeks of treatment with sofosbuvir plus weight-based ribavirin. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after treatment discontinuation ( SVR12). Safety and pharmacokinetic data were also collected. Results All 87 patients (100%; 95% confidence interval, 92-100%) achieved SVR12, including the 13 patients with compensated cirrhosis. The most common treatment-emergent adverse events ( AEs) were insomnia (16%, 14/87) and upper respiratory tract infection (16%, 14/87). No grade 3 or grade 4 AE was reported. There was one serious AE (biliary colic), which was deemed unrelated to study treatment. Laboratory abnormalities other than ribavirin-related reductions in haemoglobin were uncommon. Conclusions The results from this phase 3b study demonstrate that 12 weeks of treatment with the interferon-free regimen sofosbuvir plus ribavirin is effective and well tolerated in both treatment-naive and treatment-experienced Taiwanese patients with chronic genotype 2 HCV infection. [ABSTRACT FROM AUTHOR]

Raltegravir is an HIV-1 integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. Data from healthy volunteers demonstrate that raltegravir is rapidly absorbed with a mean half-life of approximately 7 to 12 hours, with steady state achieved in approximately 2 days. Raltegravir is characterized by both high intra- and interindividual variabilities, although neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency has a clinically meaningful effect on raltegravir pharmacokinetics. Raltegravir lacks activity as a perpetrator of drug–drug interactions and demonstrates a low propensity to be subject to drug–drug interactions. Raltegravir is metabolized primarily by UGT1A1 and is not affected by P450 inhibitors or inducers. Inhibitors of UGT1A1 (eg, atazanavir) can increase plasma concentrations of raltegravir, although this increase has not been found to be clinically meaningful. Likewise, inducers of UGT1A1 (eg, rifampin) can reduce plasma concentrations of raltegravir, and the clinical significance of this reduction is being investigated in ongoing clinical studies. Raltegravir demonstrates favorable clinical pharmacology and a drug interaction profile that permits administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment. [ABSTRACT FROM PUBLISHER]

Raltegravir is an HIV-1 integrase strand transfer inhibitor with potent activity against HIV-1. A prior investigation of raltegravir coadministered with rifampin demonstrated a decrease in plasma concentrations of raltegravir likely secondary to induction of UGT1A1, the enzyme primarily responsible for the metabolism of raltegravir. Little is known regarding the induction of UGT1A1 by rifabutin, an alternate rifamycin. In vitro characterization of the induction potency of rifampin and rifabutin on UGT1A1 was performed. In vitro studies indicate that rifabutin is a less potent inducer of UGT1A1 messenger RNA expression than is rifampin. A fixed-sequence, 2-period, clinical crossover study was conducted to assess the effect of rifabutin on plasma levels of raltegravir: period 1, 400 mg of raltegravir every 12 hours for 4 days; period 2, 400 mg of raltegravir every 12 hours and 300 mg of rifabutin once daily for 14 days. Geometric mean ratio (GMR) (coadministration of rifabutin and raltegravir vs raltegravir alone) of raltegravir area under the concentration–time curve from 0 to 12 hours post dose (AUC0-12h) and the 90% confidence interval (CI) was 1.19 (0.86-1.63); GMR of concentration at 12 hours (C12h) and 90% CI was 0.80 (0.68-0.94); and GMR of time to maximal concentration (Cmax) and 90% CI was 1.39 (0.87-2.21). Overall, coadministration of rifabutin did not alter raltegravir pharmacokinetics to a clinically meaningful degree. [ABSTRACT FROM PUBLISHER]

The article reports on research conducted in an effort to investigate the effects that low, moderate and high fat meals had on the pharmacokinetics of the antiretroviral drug raltegravir. Researchers evaluated healthy male and female subjects between the ages of 18 and 55. They found that a low fat meal appeared to modestly decrease absorption of the drug, that a moderate fat meal appeared to have little to no effect and that a high-fat meal appeared to modestly increase absorption.