Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

Bloom, Kristie; Maepa, Mohube Betty; Ely, Abdullah; Arbuthnot, Patrick

Viral hepatitis accounts for up to 1.34 million deaths per year and remains the major cause of morbidity and mortality from cirrhosis and hepatocellular carcinoma [1]. Hepatitis B virus (HBV) infections contribute significantly to the global health problem and, with an estimated 257 million people chronically infected, it is a major health priority. More than 50 years have passed since the discovery of the Australia antigen [2] , and while valuable progress has been made in vaccine and antiviral development, there is still no reliable cure for HBV infection. Worldwide prophylactic vaccination programs have reduced the prevalence of HBV in children under the age of five, but inadequate coverage in hyper-endemic African countries means that prevalence remains high in some countries [1] . Management of chronic HBV infection involves use of immune modulators or direct-acting antivirals, in the form of interferons or nucleoside/nucleotide analogs (NAs). The rationale for combining these therapies is to manage both immune dysregulation as well as viral pathogenesis. Currently, approved therapeutics include interferon α, pegylated interferon α, lamivudine, telbivudine, adenovir dipivoxil, entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide. Recommendations for first-line monotherapies are pegylated interferon α and the NAs with high barriers to resistance, which are entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide [3] [4] [5] . Guidelines for administration of combination therapies sometimes vary as a result of conflicting opinions about long-term efficacy, influence of patient selection, and whether simultaneous or sequential administration is favored (reviewed by [6, 7] ).