Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study. METHODS: Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study. RESULTS: Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable. CONCLUSIONS: Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS. GOV NUMBER: NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy.

Efficacy and Safety of Ledipasvir/Sofosbuvir With and Without Ribavirin in Patients With Chronic HCV Genotype 1 Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ION Trials.

BACKGROUND: Interferon-based hepatitis C virus (HCV) therapy is safe and effective among people receiving opioid substitution therapy (OST), but treatment uptake remains low. Our aim was to evaluate the impact of OST and drug use during therapy on completion, adherence, sustained virologic response (SVR12), and safety of ledipasvir/sofosbuvir ± ribavirin. METHODS: The phase 3 ION studies evaluated a fixed-dose combination of ledipasvir/sofosbuvir ± ribavirin administered for 8, 12, or 24 weeks in patients with chronic HCV genotype 1. People with clinically significant drug use (prior 12 months) or noncannabinoids detected at screening by urine drug tests (not explained by prescriptions) were ineligible. Stored samples were available from ION-1 for retrospective testing for illicit drugs by enzyme-linked immunosorbent assay. RESULTS: Among 1952 patients enrolled in the ION studies, 4% (n = 70) were receiving OST. Among those receiving (n = 70) and not receiving OST (n = 1882), there was no difference in treatment completion (97% vs 98%; P = .40), ≥80% adherence (93% vs 92%; P = 1.00), SVR12 (94% vs 97%; P = .28), and serious adverse events (4% vs 3%; P = .43), respectively. Among participants in the ION-1 trial, 23% (n = 196) used illicit drugs during therapy (15% cannabinoids alone; 8% other illicit drugs ± cannabinoids). There was no difference in treatment completion, ≥80% adherence, SVR12, or serious AEs in those with no drug use during treatment compared with those who used cannabinoids and/or other illicit drugs. No cases of HCV reinfection were observed in the 24 weeks following treatment. CONCLUSIONS: OST and drug use during HCV therapy did not impact treatment completion, adherence, SVR12, or safety. CLINICAL TRIALS REGISTRATION: ION-1 (NCT01701401); ION-2 (NCT01768286); and ION-3 (NCT01851330).

Efficacy and Safety of Sofosbuvir/Velpatasvir in Patients With Chronic Hepatitis C Virus Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ASTRAL Trials.

In this analysis of the ASTRAL trials (non-opioid substitution therapy [OST], n = 984; OST, n = 51) evaluating the once-daily, pan-genotypic regimen of sofosbuvir/velpatasvir for hepatitis C virus infection, OST did not impact completion, adherence, sustained virologic response (SVR12), or safety. SVR12 was 96% (95% confidence interval, 87%, >99%) in those receiving OST.

Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir.

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.