Faculty Bibliography

BACKGROUND: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. METHODS: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 mug per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. FINDINGS: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. INTERPRETATION: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. FUNDING: Gilead Sciences.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNalpha-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNalpha-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 mug q4wk or Peg-IFNalpha-2a 180 mug qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (>/=15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNalpha-2a and albIFN 1500 mug; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNalpha-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNalpha/ribavirin therapy and commonly persisted for >/=6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

Background. Hepatitis C virus (HCV)-infected drug users (DUs) have largely been excluded from HCV care. We conducted a systematic review and meta-analysis of the literature on treatment completion and sustained virologic response (SVR) rates in DUs. We assessed the effects of different treatment approaches and services to promote HCV care among DUs as well as demographic and viral characteristics. Methods. Studies of at least 10 DUs treated with pegylated interferon/ribavirin that reported SVR were analyzed. Heterogeneity was assessed (Cochran test) and investigated (meta-regression), and pooled rates were estimated (random effects). Results. Thirty-six studies comprising 2866 patients were retrieved. The treatment completion rate among DUs was 83.4% (95% confidence interval [CI], 77.1%-88.9%). Among studies that included addiction-treated and untreated patients during HCV therapy, the higher the proportion of addiction-treated patients, the higher the HCV treatment completion rate (P < .0001). After adjusting for human immunodeficiency virus (HIV)/HCV coinfection, sex, and treatment of addiction, support services during antiviral therapy increased treatment completion (P < .0001). The pooled SVR rate was 55.5% (95% CI, 50.6%-60.3%). Genotype 1/4 (P = .0012) and the proportion of HIV-coinfected DUs (P = .0173) influenced the SVR rate. After adjusting for HCV genotype 1/4 and HIV/HCV coinfection, the SVR rate was positively correlated with involvement of a multidisciplinary team (P < .0001). Conclusions. Treatment of addiction during HCV therapy results in higher treatment completion. Our pooled SVR rate is similar to that obtained in registration trials in the general population. Treatment of addiction during HCV therapy will likely be important for HCV-infected DUs undergoing treatment with more complex regimens including direct-acting antivirals.

UNLABELLED: Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had >/=1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P<0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. CONCLUSION: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation.

BACKGROUND: Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. METHODS: After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (>/=2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (>/=1 unit decrease by Ishak scoring system). FINDINGS: Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0.0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (>/=1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0.0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug. INTERPRETATION: In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. FUNDING: Gilead Sciences.

Telaprevir is a recently approved direct-acting antiviral against hepatitis C virus (HCV) that works through inhibition of the NS3/4A serine protease inhibitor.Phase 2b and 3 studies have shown marked increase in sustained virological response rates in both treatment-naive and treatment-experienced patients with HCV genotype 1 treated with a telaprevir-containing regimen compared with pegylated interferon (PEG-IFN) and ribavirin alone. The most commonly observed side effects of telaprevir therapy are anaemia to a greater degree than that observed with PEG-IFN/ribavirin alone; eczematous rash, which can be severe in a minority of patients; and anorectal discomfort.

Telaprevir is a recently approved direct-acting antiviral against hepatitis C virus (HCV) that works through inhibition of the NS3/4A serine protease inhibitor. Phase 2b and 3 studies have shown marked increase in sustained virologic response rates in both treatment-naive and treatment-experienced patients with HCV genotype 1 treated with a telaprevir-containing regimen compared with pegylated interferon (Peg-IFN) and ribavirin alone. The most commonly observed side effects of telaprevir therapy are anemia to a greater degree than that observed with Peg-IFN/ribavirin alone; eczematous rash, which can be severe in a minority of patients; and anorectal discomfort.

For patients treated with telaprevir, peginterferon, and ribavirin, futility rules have been developed to prevent needless drug exposure and minimize development of drug-resistant variants for patients who have little or no chance of achieving a sustained virologic response. We performed retrospective analyses of data from phase 3 trials and validated the current futility rule. All therapy should be stopped for treatment-naive and treatment-experienced patients if hepatitis C virus RNA levels are greater than 1000 IU/mL at weeks 4 or 12, or if hepatitis C virus RNA is detectable at week 24.