Optimizing treatment regimens for adults with chronic hepatitis B

In adults with chronic hepatitis B participating in NIDDK-funded Hepatitis B Research Network (HBRN) studies across North America, investigators tested whether a combination treatment regimen could increase long-term clearance of the virus. Chronic hepatitis B, a form of viral hepatitis, is a global problem that disproportionately affects people living in or originating from certain geographic areas, such as Asia and sub-Saharan Africa. If not appropriately treated, the disease can lead to cirrhosis, liver failure, and liver cancer. Effective treatments for chronic hepatitis B include interferon-based therapy, which targets immune cell function, and a class of drugs called nucleoside analogues that inhibit viral enzyme activity. However, these drugs’ effectiveness varies across individuals, in terms of reliably clearing the virus and ultimately preventing development of severe liver disease. In addition, these drugs often must be taken lifelong to prevent recurrence of disease; therefore, better treatments that clear the virus long-term are needed.

The NIDDK-funded HBRN conducted clinical trials of treatment approaches for chronic hepatitis B in a study population that was primarily men, women, and children of Asian descent. Though the Network studies concluded in 2022, data analysis and publication of results has continued, with study samples available for additional research through the NIDDK Central Repository. One HBRN clinical trial in adults, results of which were recently published, assessed the safety and efficacy of combining two treatments—a long-lasting form of interferon called peginterferon and the nucleoside analogue tenofovir—to increase the currently low or variable rates of viral clearance. Two hundred people with hepatitis B were treated, all of whom had active disease with high levels of viral DNA and elevations in serum liver enzymes, which indicate liver inflammation or disease. Half of the study participants’ samples contained the hepatitis B e antigen (HBeAg), a protein produced by the hepatitis B virus that signals an active infection. All study participants were treated with tenofovir for approximately 4 years; half also received peginterferon, but only for the first 6 months. After 4 years, those individuals who had received combination therapy had a higher rate of clearing the viral proteins and viral DNA, though nearly all study participants had an excellent clinical and biochemical response. The overall complete response with clearance of all hepatitis B proteins, however, was uncommon. Furthermore, almost all responses occurred in people with HBeAg and a single type of hepatitis B virus called genotype A2, found mostly in White and Black populations and rarely among those of Asian ancestry. At the 4-year point, study participants were eligible to continue or to stop tenofovir therapy, based on withdrawal of therapy being one approach to increasing the rate of complete viral clearance. One year after withdrawal of tenofovir therapy, slightly more of the participants who stopped treatment had complete clearance than those who continued therapy. Furthermore, a proportion of the study participants who elected to withdraw from further tenofovir therapy had a severe flare of hepatitis and had to be restarted on treatment.

These results indicate that the addition of peginterferon to tenofovir therapy for hepatitis B leads to an increased rate of response, but only in people with the viral protein HBeAg. Withdrawal of therapy after 4 years did not seem to increase the rate of complete response and could be followed by worsening of the hepatitis requiring restarting of therapy. Future studies will continue to build on these findings to develop more effective, individualized approaches to treating people with hepatitis B.