Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study).

BACKGROUND & AIMS: The phase 2, FOURward study (NCT02175966) investigated short-duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1. METHODS: Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice-daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks. RESULTS: Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 106  IU/mL). Most patients had undetectable HCV-RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV-RNA (<2 million IU/mL, 71% [n=5/7]; ≥2 million IU/mL, 33% [n=7/21]). None of the 16 non-SVR12 patients had NS3 or NS5B resistance-associated substitutions (RAS) detected at failure. All 15 patients retreated with DCV-TRIO + RBV for 12 weeks achieved SVR12. All regimens were well tolerated. CONCLUSIONS: Short-duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype-1 infection and high baseline viraemia. Non-SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV-TRIO + RBV for 12 weeks led to SVR in all patients.

The Optimal Timing of Hepatitis C Therapy in Transplant Eligible Patients With Child B and C Cirrhosis: A Cost-Effectiveness Analysis.

BACKGROUND: Ledipasvir (LDV)/sofosbuvir (SOF) has demonstrated high efficacy, safety, and tolerability in hepatitis C virus (HCV)-infected patients. There is limited data, however, regarding the optimal timing of therapy in the context of possible liver transplantation (LT). METHODS: We compared the cost-effectiveness of 12 weeks of HCV therapy before or after LT or nontreatment using a decision analytical microsimulation state-transition model for a simulated cohort of 10 000 patients with HCV Genotype 1 or 4 with Child B or C cirrhosis. All model parameters regarding the efficacy of therapy, adverse events and the effect of therapy on changes in model for end-stage liver disease (MELD) scores were derived from the SOLAR-1 and 2 trials. The simulations were repeated with 10 000 samples from the parameter distributions. The primary outcome was cost (2014 US dollars) per quality adjusted life year. RESULTS: Treatment before LT yielded more quality-adjusted life year for less money than treatment after LT or nontreatment. Treatment before LT was cost-effective in 100% of samples at a willingness-to-pay threshold of US $100 000 in the base-case and when the analysis was restricted to Child B alone, Child C, or MELD > 15. Treatment before transplant was not cost-effective when MELD was 6-10. In sensitivity analyses, the MELD after which treatment before transplant was cost-effective was 13 and the maximum cost of LDV/SOF therapy at which treatment before LT is cost-effective is US $177 381. CONCLUSIONS: From a societal perspective, HCV therapy using LDV/SOF with ribavirin before LT is the most cost-effective strategy for patients with decompensated cirrhosis and MELD score greater than 13.

Secondary IgA nephropathy presenting as nephrotic syndrome with glomerular crescentic changes and acute renal failure in a patient with autoimmune hepatitis.

Patients with end-stage liver disease are prone to hemodynamic and immunologic renal injury, the latter at times manifesting as glomerulonephritis. Elevated serum immunoglobulin A (IgA) levels and mesangial IgG-IgA deposits are common in these patients, but are often clinically silent. We report a patient with autoimmune hepatitis and secondary IgA nephropathy (IgAN) who presented with nephrotic syndrome, acute renal failure (ARF), with 30% of the renal glomeruli having undergone crescentic change, and with IgA2 deposits in the glomerular mesangium. This article discusses secondary IgAN pathogenesis and its therapeutic management.