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Associate Professor of Medicine
Medicine, Division of Gastrointestinal and Liver Diseases
Keck School of Medicine of USC
University of Southern California
Los Angeles, California
Takeshi Saito, MD, PhD, has no relevant conflicts of interest to report.
Hepatitis delta virus (HDV), a satellite virus of hepatitis B virus (HBV), requires the hepatitis B surface antigen for the production of infectious particles. Therefore, its life cycle is entirely dependent on the coexistence of active HBV replication. The unique relationship between these 2 pathogens is exploitable to broaden available antiviral strategies against HDV infection. Given that HDV is reliant on active HBV replication, any anti-HBV compound leading to the functional cure would also eradicate HDV. Numerous novel anti-HBV compounds are currently in preclinical or early clinical trials, raising hope that some of these will be available for use in therapeutic strategies for HBV/HDV superinfection in the future.
Why Are New Treatments for HDV Needed?
Chronic coinfection of HBV and HDV, referred to as HDV superinfection, was previously considered a rare condition owing to insufficient epidemiologic information, impeded by multiple factors such as the lack of sensitive and specific diagnostic methods and global disparities in healthcare infrastructure. However, recent epidemiologic studies with improved detection methods reveal that approximately 10% of HBV carriers, perhaps 65 million people worldwide, have HDV superinfection. Diagnosing people with HDV and linking them to care is, therefore, a pressing need in viral hepatitis management.
HDV infection is recognized as the most aggressive form of viral hepatitis, substantially accelerating the progression of liver disease. Consequently, individuals with HDV superinfection develop cirrhosis in 5-10 years, whereas in chronic HBV monoinfection, cirrhosis typically takes considerably longer to emerge. Therefore, HDV superinfection substantially increases the risk of end-stage liver disease development compared with that seen in HBV monoinfection. These observations collectively point to the urgent need to establish a definitive antiviral strategy that eradicates HDV infection.
What Is the Current Approach to Treating HDV?
To date, the FDA has not approved any antiviral therapies for use in the treatment of HDV infection. Instead, current management in the United States involves off-label use of peginterferon α-2a. This approach has limited efficacy, as only 20% of patients achieve sustained viral clearance. Low efficacy is compounded by the fact that a significant proportion of individuals with HDV superinfection have already progressed to end-stage liver disease at the time of diagnosis.
Because the use of peginterferon α-2a in patients with decompensated cirrhosis is contraindicated, the number of patients with HDV who are candidates for peginterferon α-2a treatment is likely to be limited.
Emerging Therapies for HDV Infection
Bulevirtide is a viral entry inhibitor that prevents HBV and HDV entry into hepatocytes. This emerging therapeutic is approved for use in patients with chronic HDV infection and compensated liver disease in the European Union, and it is expected to be submitted to the FDA for approval later in 2021.
Recent interim reports from the phase IIb MYR204 trial and the phase III MYR301 trial are encouraging. In the phase III trial, the proportion of patients achieving an antiviral response (defined as undetectable HDV RNA or a decrease by ≥2 log10 IU/mL from baseline) after 24 weeks of treatment was significantly greater with bulevirtide vs placebo. Alanine aminotransferase normalization was also more common in treated patients.
Lonafarnib is an investigational anti-HDV compound that inhibits prenylation of large hepatitis delta antigen, which is required for the packaging of the HDV genome into the viral envelope. Lonafarnib has been shown to reduce HDV RNA in phase I/II studies. The combination with peginterferon appears to enhance antiviral efficacy, and ritonavir boosting has been shown to allow lower lonafarnib dosing, resulting in improved antiviral efficacy and tolerability.
Lonafarnib is currently being evaluated in the phase III D-LIVR study, which compares lonafarnib/ritonavir with or without peginterferon α-2a in patients with chronic HDV infection who are maintained on anti-HBV nucleos(t)ide therapy (NCT03719313). This study is recruiting at multiple sites worldwide.
Based on these insights, it is anticipated that the range of therapeutic options available for the treatment of HDV will expand in the near future, improving our ability to manage patients with HDV infection.
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