Treatment of hepatitis B virus with combination therapy now and in the future.

Chronic Hepatitis B continues as a significant public health problem despite the availability of safe and effective antivirals and a highly effective protective vaccine. Current therapy, however rarely leads to cure and lifelong therapy is often required, contributing to poor uptake and ongoing morbidity. New insights into the hepatitis B viral life cycle and the host immune response have expanded the potential targets for drug therapies with interesting antiviral candidates and novel immunotherapeutic approaches in early stage development. Yet, HBV persistence is multifactorial - due to an intrahepatic reservoir and ongoing HBV-mediated immune dysregulation, making "cure" unlikely to be realized through even the most efficacious monotherapy. Building on the success seen in the treatment of hepatitis C (HCV) and human immunodeficiency virus (HIV), combination therapy may be an essential strategy to improve efficacy and decrease viral breakthrough. Combinations acting on immune and viral targets are particularly attractive. However, creating synergy while balancing efficacy and safety remains a clear challenge. Various approaches to combination therapy are reviewed, highlighting strengths and challenges of each potential strategy. Overall, combination therapies are attractive as the next step towards cure and are a key strategy for achieving treatment with finite durations and durable endpoints.

Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia.

OBJECTIVES: Mixed cryoglobulinemia is strongly associated with hepatitis C virus (HCV) infection and ranges from being asymptomatic to causing life-threatening vasculitis. In those with symptoms, treatment with pegylated interferon (pegIFN) and ribavirin (RBV) reduces mortality. However, few data are available on the safety and efficacy of antiviral therapy with direct acting antivirals (DAAs) in the treatment of HCV-related cryoglobulinemia. METHODS: Patients treated for HCV-related cryoglobulinemia with DAA±pegIFN were retrospectively evaluated at a tertiary care center. Primary outcomes were virological, immunological, and clinical response. Complete (normalization), partial (>50% reduction), or non-response (<50% reduction) were used to describe change in cryocrit or vasculitic manifestations at week 12 post treatment. Side effects, hospitalizations, and decompensating events were recorded. RESULTS: Eighteen symptomatic and 65 asymptomatic patients were reviewed (61% male, median age 58 years) including 10 with severe/life-threatening vasculitis. Sixty-six (79.5%) patients received pegIFN-free therapy. Sustained virological response (SVR) was attained in 16 (88.9%) symptomatic and 59 (90.8%) asymptomatic patients. Cryoglobulins disappeared in 5 (29.4%) symptomatic and 27 (52.9%) asymptomatic patients. Of symptomatic patients with SVR, clinical response was complete in 7 (38.8%) and partial response in 4 (22.2%). Of the 5 viral relapsers, 1 had a complete response during therapy with no symptomatic recurrence, while the other patients had no clinical response. Among 7 with severe vasculitis, 6 achieved SVR but only 1 had a complete clinical response, with 3 showing a partial response and 2 showing no improvement. All four with life-threatening vasculitis required plasmapheresis and three received rituximab. All achieved SVR leading to partial clinical response in two, but no response in two. Skin manifestations (39% reduction) were most likely to completely resolve with lower responses seen in renal (11.2% reduction) and neurological symptoms (11.1%). Eighty-two (98.8%) patients completed therapy, with 19 (22.8%) reporting adverse events. Hospitalization for decompensation or worsening vasculitis occurred in five (6.0%) and four (22.2) patients respectively. CONCLUSIONS: DAAs resulted in high rates of SVR in patients with cryoglobulinemia. Safety and tolerability were excellent; however, most patients did not have a complete clinical or immunological response, suggesting a delay to clinical response particularly in those with severe/life-threatening vasculitis. Further follow-up will be required to determine if clinical improvement continues after viral clearance.