Review of hepatitis D virus describes “unique” biologic characteristics and “ominous” medical effect, but constrained as HBV treatments affect HDV life cycle.
A recent
Tarik Asselah, MD, Université de Paris–Cité, Hôpital Beaujon, Department of Hepatology, Assistance Publique–Hôpitaux de Paris, France and Mario Rizzetto, MD, Department of Medical Sciences, University of Turin, Turin, Italy, describe HDV as a defective, hepatotropic pathogen with a life cycle that relies on HBV for its viral packaging, infectivity, transmission, and inhibition of host immunity.
“Clinical studies have shown that chronic hepatitis D is the most severe and progressive form of viral hepatitis in humans,” Asselah and Rizzetto observe.
HDV requires the presence of hepatitis B surface antigen (HBsAG), which, in the period from 2011 to 2016, had a prevalence of only approximately 0.36% in the US. Of these carriers, however, 42% had antibodies to HDV. "Most of these carriers were persons who inject drugs or were from areas with a high prevalence of HDV,” the reviewers noted.
Asselah and Rizzetto find that HDV screening remains low in both developed and developing countries; with only 6.7% of 157,333 patients with chronic HBV in the US between 2010 to 2020 having had HDV screening. They suggest “reflex testing” strategy for HDV in all persons who test positive for HBsAG.
“This would prevent health care providers who are not familiar with hepatitis D from overlooking a diagnosis of HDV infection,” they remark, noting that such reflex testing in Spain recently led to a 5 factor increase in the number of HDV diagnoses.
The management of HDV infection will be different, according to the reviewers, depending on whether it presents as coninfection in persons without previous HBV exposure, or as superinfection in those with chronic HBV.The course in coinfection is often self-limited, acute hepatitis, with treatment of HBV serving against HDV as well.
Superinfections account for approximately 90% of cases of chronic HDV infection and chronic hepatitis D.The course of chronic HDV is more severe and progressive than with HBV, according to the reviewers. In one cited study, histologic deterioration occurred in 77% of a cohort who were positive for anti-HDV antibodies, compared with 30% of HBsAG carriers without anti-HDV antibodies. In another study, HDV increased the risk of hepatocellular carcinoma by a factor of 3.
There is not yet an approved therapy for chronic HDV in the US, although the reviewers find that pegylated interferon has been used off label.Among therapeutic strategies in development are measures to deprive HDV from gaining critical functions from HBsAG.Investigational agents include lonaferon lambda and bulevirtide; and the latter was conditionally approved by the European Medicines Agency in July, 2020.
Although a sustained viral response (SVR), with absence of detectable HDV RNA in serum for 6 months after treatment, would be an optimal therapeutic endpoint, the reviewers note that this has been achieved in less than 30% of patients treated with interferon, and long-term relapses have been common.To facilitate treatment development, the FDA has endorsed a decrease of 2 log10 IU per ml in the HDV RNA level from the original viremic titer as a likely predictor of clinical benefit, with expectation that further development and clinical testing will target viral clearance.
“Combination therapy with these agents, possibly administered with newly developed inhibitors of HBsAg synthesis, hold promise as a cure for chronic hepatitis D,” Asselah and Rizzetto indicate.
