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Professor of Medicine
Chief, Section of Hepatology
Associate Director, Solid Organ Transplantation
Richard B. Capps Chair of Hepatology
Rush University Medical Center
Nancy Reau, MD, has disclosed that she has received consulting fees from AbbVie, Arbutus, Gilead Sciences, Intercept, and Salix and funds for research support (paid to her institution) from AbbVie and Gilead Sciences.
Hepatitis D (or “delta”) virus (HDV) is an RNA virus that usually depends on the presence of hepatitis B surface antigen (HBsAg) for propagation. HDV affects nearly 65 million people worldwide and significantly increases the risk for developing cirrhosis and hepatocellular carcinoma.
Although healthcare professionals may have little experience with HDV, in my location, I care for many patients coinfected with hepatitis B virus (HBV) and HDV owing to the large Mongolian population near Chicago. Mongolia is unfortunately a high prevalence location for viral hepatitis, including HDV. It is not uncommon to diagnose cirrhosis or liver cancer in these individuals, many of whom I’ve watched progress under my care owing to the lack of effective treatment options.
The exciting news is that several presentations at the recent virtual International Liver Congress suggest new therapeutic options may be available in the near future.
In vitro Insight Into Combination Therapies
In an in vitro study, Zhang and colleagues showed that HDV persists through cell division–mediated spread. This is an important observation as it makes HDV independent of HBV: HDV will escape strategies that only target de novo infection.
They also showed that interferon affects cell division–mediated HDV spread. Drug combinations targeting both spreading pathways act synergistically with the best viral suppression occurring in cell cultures treated with both interferon and either bulevirtide (HDV entry inhibitor) or lonafarnib (farnesyltransferase inhibitor).
This presentation was important for a few reasons: It highlights that HDV is not solely reliant on HBsAg. It also suggests that interferon might retain a pivotal role in HDV therapy until treatment strategies that target both cell division and de novo infection are formulated.
New Clinical Studies on Bulevirtide
Bulevirtide is an HDV entry inhibitor that is administered by daily subcutaneous injection, and there were several reports on its use.
The phase III MYR301 trial evaluated either low-dose (2-mg) or high-dose (10-mg) bulevirtide monotherapy in patients with chronic HDV infection. Nucleos(t)ide analogues were allowed but not required. At the 24-week interim report, both the 2-mg and 10-mg doses were safe and demonstrated excellent virologic response. There was no clear dose effect and no HBV flares were seen. Bulevirtide 2 mg/day subcutaneous injection has been given conditional authorization in Europe for treatment of chronic HDV infection.
Asselah and colleagues presented Week 24 data of a phase IIb study comparing the same 2 doses of bulevirtide (2 mg or 10 mg subcutaneous once daily), both in combination with peginterferon alfa-2a, and also comparing them with peginterferon alone and bulevirtide 10 mg alone. Combination treatment was superior to monotherapy for the endpoint of HDV RNA suppression; however, bulevirtide monotherapy was associated with higher rates of alanine aminotransferase (ALT) normalization. It is important to realize that these are interim data with an intended treatment duration of 96 weeks for bulevirtide and 48 weeks of peginterferon alfa-2a.
Real-world Experience With Bulevirtide
To help add context to these reports, Loglio published a small case series of patients with chronic HDV infection who had received bulevirtide for 24 weeks or longer with ongoing treatment with tenofovir DF. In this report, the investigators showed not just viral suppression and normalization of ALT but also improvement in portal hypertension in one patient. Adverse events were minimal; increase in bile acids was reported but caused no symptoms that led to dose reduction or discontinuation.
Although HDV is an uncommon etiology of liver disease, it is not rare and is often unrecognized. Now that treatment options are on the horizon, we need to concentrate on identifying our infected patients and preparing them for treatment.
Do you see patients with HDV in your practice? How do you anticipate these new therapies fitting into your practice? Please leave comments below for discussion.