DeCure for Hepatitis B virus infection

The hepatitis B virus infects more than 350 million people worldwide and is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, accounting for 1 million deaths annually. A 1997 review noted that a vaccine and treatments capable of eradicating chronic infection had been developed. By 2003, researchers observed that the virus uses reverse transcription to copy its DNA genome, producing enormous viral loads during active replication without directly killing the infected cell, and that mutant viral genomes are frequently selected by host immune clearance, vaccines, and antivirals. It remained unknown which specific mutations affect clinical presentation, viral persistence, or the course of chronic infection.

A 2017 human clinical trial of the RNA interference-based therapeutic ARC-520, which targets HBV transcripts, found that HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for hepatitis B e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors. Investigation in chronically infected chimpanzees showed that HBsAg was expressed not only from episomal covalently closed circular DNA but also from HBV DNA integrated into the host genome, which was the dominant source in HBeAg-negative chimpanzees. Many of the integrants lacked target sites for the small interfering RNAs in ARC-520, explaining the reduced response in HBeAg-negative chimpanzees and, by extension, in HBeAg-negative patients. The authors concluded that these results could alter trial design and endpoint expectations of new therapies for chronic HBV.

A 2011 review analysed the role of combination therapy for chronic hepatitis B, noting that the success of combination therapy in HIV infection had stimulated studies on various drug combinations, but did not report any definitive efficacy results from those studies. A 2016 review stated that the pathogenesis of HBV depends on the critical interplay between viral and host factors, and highlighted genotypes and mutations associated with disease progression and immune response. A 2017 Chinese review noted that optimal clinical outcomes for antiviral treatment include liver histopathological changes, occurrence of cirrhosis and hepatocellular carcinoma, mortality and survival rates, survival time, life quality, and prevention rates of mother-to-child transmission and HBV reinfection after liver transplantation, but that these indicators usually require prolonged follow-up.

What is still missing is a clear understanding of which viral mutations directly affect clinical outcomes, as noted in 2003. The 2017 ARC-520 trial revealed that integrated HBV DNA can be a dominant source of HBsAg in HBeAg-negative patients, meaning therapies that only target episomal cccDNA may fail to reduce antigen load in that population. No trial has yet shown that any RNAi-based or combination regimen can eliminate integrated HBV DNA or achieve consistent HBsAg loss across all patient subgroups. Adequately powered trials that stratify patients by HBeAg status, prior nucleos(t)ide exposure, and integration profile are needed, as is funding for long-term follow-up to capture cirrhosis and hepatocellular carcinoma endpoints.