Evaluating Combination Therapy vs. Monotherapy in Hepatitis B

Is combination therapy of peginterferon alpha-2a (Peg-IFN alpha-2a) with a nucleos(t)ide analogue (NA) more effective than Peg-IFN alpha-2a alone for the treatment of chronic hepatitis B (HBV)?

Wei-Wen Su, MD, of Changhua Christian Hospital in Changhua, Taiwan, explored this question during a general session Saturday at the 2014 EASL International Liver Conference in London, UK, when he presented results from the NA bEforE aDministration of PEG-IFN alpha-2a (NEED) study.

Peg-IFN alpha-2a is associated with serious treatment-limiting adverse effects. Nucleos(t)ide analogues such as entecavir and adeforvir markedly suppress HBV DNA levels in patients with chronic hepatitis B when compared with interferon-based therapies. However, satisfactory seroconversion of the hepatitis B ‘e’ antigen (HBeAg)‑‑which circulates in infected blood when the virus is actively replicating‑‑is often not achieved with treatment with these agents.

The NEED study‑‑a large phase 4 randomised, double-blind, multicenter, placebo-controlled trial conducted in Taiwan‑‑evaluated HBeAg seroconversion rate in HBeAg-positive HBV patients who received a 6-week regimen of either of two nucleos(t)ide analogues (adeforvir 10 mg daily or entecavir 0.5 mg). A total of 280 patients were randomised 1:1:1 into three study arms: placebo (n=94), entecavir (n=95), or adeforvir (n=91).

Treatment with Peg-IFN alpha-2a (100 micrograms subcutaneously once per week) was started in all groups after the initial 4-week NA therapy. The NA treatment was continued for a further 2 weeks and then stopped. Peg-IFN alpha-2a treatment ran for a total of 48 weeks (ie, there was a 2-week overlap in NA and Peg-IFN alpha-2a treatments). Patients were followed for a further 48 weeks after Peg-IFN alpha-2a therapy.

According to Su, “patients included in the trial were mostly young males (approximately 38 years of age), with a high viral load and an alanine aminotransferase level of approximately 200 IU/mL. Most of the patients in the study were treatment-naïve (57% in Arm A, 62% in arm B, and 50% in arm C), and had been HBsAg-positive and HBeAg-positive for greater than 6 months and greater than 3 months, respectively, prior to the trial.” HBV patients with poorly controlled co-morbid medical conditions or co-infection with hepatitis C or D and/or HIV were excluded, as were HBV patients with decompensated liver disease or hepatocellular carcinoma. HBeAg seroconversion, loss of HBeAg, and presence of anti-HBeAg were the primary endpoints. Safety was also an important endpoint.

Su said, “Overall, this study shows that this kind of sequential combination strategy does not increase the HBeAg seroconversion rate compared to Peg-IFN alpa-2a monotherapy at the end of treatment or at 24 weeks post-treatment follow-up.” The results show that although HBeAg seroconversion increased steadily in all groups throughout the 48 weeks of treatment and continued even after the treatment had been stopped, HBeAg seroconversion had only been achieved in 35.9%, 28.4%, and 22.7% of patients in the placebo + Peg-IFN alpha-2a, entecavir + Peg-IFN alpha-2a, and adeforvir + Peg-IFN alpha-2a groups, respectively.

“The results show that a short course of NA treatment followed by Peg-IFN alpha-2a is safe and well tolerated by patients,” said Su. Between 88% and 93% of patients experienced some side effects, “but these were mild to moderate and consisted mainly of hairloss, headache, fever, and myalgia).” Between 8% and 13% of patients experienced serious side effects (mainly from the entecavir + Peg-IFN alpha-2a treatment arm), and one patient withdrew from the study.

“The results also suggest that a treatment strategy of initial combination treatment with NA for a longer period to achieve lower HBV DNA level before starting Peg-IFN requires further study,” said Su.