The most common adverse effects of tenofovir in patients with HBV infection are nausea, abdominal pain, diarrhea, dizziness, and fatigue. Chronic renal insufficiency secondary to a proximal tubulopathy may occur, and may progress to renal failure. Decreases in bone mineral density and Fanconi’s syndrome, as observed in HIV-infected patients treated with tenofovir, have not been described in patients with HBV infection receiving tenofovir disoproxil. Tenofovir alafenamide fumarate (TAF) is an orally bioavailable prodrug of tenofovir that enables enhanced delivery of the parent nucleotide and its active diphosphate metabolite into lymphoid cells and hepatocytes, so that the dose of tenofovir can be reduced and toxicities minimized.
The nucleoside analog emtricitabine (see HIV) is under clinical investigation for treatment of HBV infection. The entry inhibitors Myrcludex B and cyclosporine, as well as cccDNA inhibitors, are being evaluated. Research is also ongoing to develop and test new agents that can “cure” HBV by eliminating all replicative forms, including covalently closed circular DNA (cccDNA). Broadly curative antiviral strategies include agents that could directly target infected cells as well as novel immunotherapeutic strategies that boost HBV-specific adaptive immune responses or activate innate intrahepatic immunity. New molecules under investigation include entry inhibitors and short-interfering RNAs (siRNAs), and capsid inhibitors
In contrast to the treatment of patients with chronic HBV infection, the primary goal of treatment in patients with HCV infection is viral eradication. In clinical trials, the primary efficacy end point is typically achievement of sustained viral response (SVR), defined as the absence of detectable viremia 24 weeks after completion of therapy. SVR is associated with improvement in liver histology, reduction in risk of end-stage liver disease and hepatocellular carcinoma, and, occasionally, with regression of cirrhosis as well. Late relapse occurs in less than 5% of patients who achieve SVR.
In acute hepatitis C, the rate of clearance of the virus without therapy is estimated at 20–35%. Therefore, most practitioners choose to delay therapy for a minimum of 6 months after the initial infection. If treatment is initiated thereafter due to persistent HCV RNA viremia, the regimens are the same as those administered or chronic HCV infection.
The advent of the first-generation direct-acting antiviral agents (DAAs) boceprevir and telaprevir dramatically altered the landscape for the optimal treatment of chronic HCV infection, which was previously treated with the combination of interferonalfa (replaced by pegylated interferon-alfa) and ribavirin. Since interferon-containing regimens tend to be associated with higher rates of serious adverse events (including anemia and rash), longer treatment durations, more frequent dosing, and clinically significant drug-drug interactions, they are gradually being replaced by combination regimens of DAAs (see Table 49–7). Moreover, while the first-generation HCV protease inhibitors (ie, boceprevir, telaprevir) markedly improved the effectiveness of pegylated interferon plus ribavirin, they have been replaced by newer DAAs over the past 2 years, which can be administered in all-oral, interferon-free combinations—with or without ribavirin—with improved efficacy and tolerability, improved dosing schedules, lesser genotype specificity, and fewer potential drug-drug interactions. However, the DAA regimens are expensive.