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Hepatitis delta is the most severe form of chronic viral hepatitis. HDV is a defective virus that can only complete its lifecycle in the presence of hepatitis B virus (HBV). HDV and HBV are transmitted in similar ways, and an estimated 15 million people are coinfected with both, with the highest prevalence in regions where hepatitis B epidemics are primarily related to injection drug use, including Russia, Romania, and the Mediterranean countries. Antiviral drugs such as tenofovir or entecavir (Baraclude) that suppress HBV viral load do not stop HDV replication, so coinfected people remain at risk for complications such as liver cirrhosis.

Heiner Wedemeyer from Hannover Medical School and fellow investigators with HIDIT-2 (the Hep Net International Delta Intervention Trial 2) evaluated the efficacy and tolerability of prolonged treatment of hepatitis delta using pegylated interferon with or without tenofovir.

The HIDIT-1 study previously showed that pegylated interferon for 1.0 to 1.5 years is effective in 25% to 30% of treated patients, but HBV polymerase inhibitors do not suppress HDV RNA, the researchers noted as background. HIDIT-2 aimed to determine if extending treatment to 2 years could improve response rates, in particular sustained response as measured 24 weeks after the end of therapy.

HIDIT-2 was actually 2 parallel trials with identical protocols and a combined analysis. One study included 70 patients with detectable HDV RNA recruited in Germany, Greece, and Romania, while the other enrolled 50 patients in Turkey. A majority were men, the mean age was 40 years, about 15% were hepatitis "e" antigen (HBeAg) positive, and 40% had cirrhosis; people with decompensated liver diseases were excluded, as this is a contraindication for interferon. People triply infected with hepatitis C or HIV also were not included. About half had previously been treated with interferon.

Participants were randomly assigned to receive 180 mcg weekly pegylated interferon alfa-2a (Pegasys) injections plus once-daily oral tenofovir or placebo for 96 weeks. Pegylated interferon stimulates the body's immune response against viruses, while tenofovir directly interferes with viral replication.

Results

• At the end of 96 weeks of treatment, 47% of patients taking pegylated interferon plus tenofovir had undetectable HDV RNA, compared with 33% of those taking interferon plus placebo -- a numerical advantage but not statistically significant (p=0.10).
• In a per protocol analysis of those who completed treatment, the corresponding rates were 54% and 41%, respectively, also not significant (p= 0.19).
• After finishing treatment, 44% of patients in the combination arm and 40% in the placebo arm relapsed; however, 1 and 3 patients, respectively, reached undetectable HDV RNA after stopping therapy.
• 24-week post-treatment sustained response rates were 30% in the combination arm and 23% in the placebo arm -- again not a significant difference (p=0.34).
• Just over 30% of patients in the combination arm and about 25% in the placebo arm experienced an HBsAg decline of >0.5 log IU/mL by week 96; this fell to about 22% in the combination arm and remained stable in the placebo arm at week 120.
• Lower HDV RNA and lower HBsAg levels at baseline were associated with HDV sustained virological response.
• People with cirrhosis also had a higher HDV virological response rate compared with non-cirrhotics (51% vs 25%, respectively).
• Prolonged pegylated interferon plus tenofovir was difficult to tolerate, and 20 patients -- about equally distributed between the 2 arms -- did not complete at least 80 weeks of treatment.
• All participants had at least 1 adverse event, and one-third had serious adverse events.

"96 weeks of [pegylated interferon alfa-2a] and tenofovir therapy is possible but associated with frequent serious adverse events," the researchers concluded. "Combination treatment showed numerically higher rates of on-treatment HDV RNA suppression but similar effects on HBsAg reductions as compared to [pegylated interferon alfa-2a] alone."

"Patients with hepatitis delta and compensated liver cirrhosis should be treated with [pegylated interferon alfa-2a]," they recommended. However, they added, "combination therapy with tenofovir des not provide obvious benefits in hepatitis delta patients with low baseline HBV DNA levels" and "96 weeks of [pegylated interferon alfa-2a] treatment does not provide higher post-treatment HDV RNA responses (compared to 48 weeks in the HIDIT-1 study)."

Speaking from the audience, Mario Rizzetto from the University of Torino, whose team discovered HDV in 1977, said that this study "confirms what we already know" -- that relapse usually occurs after stopping treatment.

The researchers concluded that, "Alternative treatment options are urgently needed for HDV-infected patients." Wedemeyer noted that EASL will help fund the Hepatitis Delta International Network to enable more research on this difficult-to-treat virus.

4/17/14

Reference

H Wedermeyer, C Yurdaydin, S Ernst, et al. Prolonged therapy of hepatitis delta for 96 weeks with pegylated-interferon-a-2a plus tenofovir or placebo does not prevent HDV RNA relapse after treatment: the HIDIT-2 study.49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O4.