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Is Combination Therapy Most Effective for HBV Infection?

A significantly greater proportion of patients receiving a combination of tenofovir disoproxil fumarate (TDF) and pegylated interferon-α (peginterferon) for 48 weeks lost hepatitis B surface antigen (HBsAg), a marker of hepatitis B virus (HBV) DNA transcriptional activity, compared to patients given the standard care (peginterferon or TDF alone), researchers report in the January 2016 issue of Gastroenterology.

In patients with chronic HBV infection, clearance of HBsAg from serum is associated with remission and improved long-term outcomes. However, standard treatments—either a finite course of peginterferon or an oral antiviral for an indefinite duration—does not usually lead to loss of HBsAg. For example, among patients given peginterferon for 48 weeks, only 4% of hepatitis B e antigen (HBeAg)-negative and 4% of HBeAg-positive patients had lost HBsAg 6 months after the end of treatment. Only 3% in HBeAg-positive patients who received 48 weeks of treatment with the a nucleotide analogue TDF (and no HBeAg-negative patients) lost HBsAg.

Peginterferon and TDF have different antiviral mechanisms, so Patrick Marcellin et al investigated whether their combination could increase loss of HBsAg. They also tested a combination regimen that had a shorter duration (16 weeks) of peginterferon.

In an open-label trial, at 139 sites in 19 countries, of 740 patients with chronic hepatitis B were randomly assigned to groups given TDF (300 mg once daily, orally) plus peginterferon (180 μg/week, subcutaneously) for 48 weeks (group A), TDF plus peginterferon for 16 weeks followed by TDF for 32 weeks (group B), only TDF for 120 weeks (group C), or only peginterferon for 48 weeks (group D). The primary end point was the proportion of patients with serum HBsAg loss at week 72.

Effect of TDF and peginterferon as combination or monotherapy on HBsAg loss. The rate of HBsAg loss in group A was significantly higher than rates for groups C (P < .001) or D (P=.003), as well as group B (unadjusted P < .001). The rate of HBsAg loss in group B did not significantly differ from that of groups C (P = .466) or group D (P = .883)
Effect of TDF and peginterferon as combination vs monotherapy on HBsAg loss.

At week seventy-two, 9.1% of subjects in group A had HBsAg loss—a significantly higher proportion than the 2.8% of subjects in group B, none of the subjects in group C, or the 2.8% of subjects in group D.

Factors associated with loss of HBsAg included HBV genotype A, level of alanine aminotransferase (ALT) 10-fold the upper limit of normal, and a 1-log decrease in the level of HBsAg. Approximately 1 in 10 participants also reached an important secondary end point: loss of HBeAg and seroconversion to anti-HBeAg.

As the authors expected, the decrease in HBsAg in group B was similar to that in group A until peginterferon was discontinued. However, upon discontinuation of peginterferon at week 16, HBsAg levels plateaued in group B, so that few patients had achieved HBsAg loss at week 48.

Marcellin et al conclude that a peginterferon-sparing strategy is not sufficient for sustained immune control of HBV in most patients. Also, stopping peginterferon treatment increases risk of liver decompensation.

The incidence of common adverse events (including headache, alopecia, and pyrexia) and treatment discontinuation due to adverse events was similar among groups.

So, combining 2 agents with different mechanisms of action for a finite duration can significantly increase rates of serum HBsAg loss compared to standard-of-care monotherapy regimens, with no increase in adverse events compared with peginterferon alone.

But how does this combination work? Active HBV replication limits the immune response by disrupting pathways involved in antigen presentation and interferon-dependent signaling. By rapidly reducing viral replication and serum levels of viral levels, including HBsAg, TDF might increase the response of the immune system to drugs such as interferon.

The authors note that the response was not uniform and most patients did not achieve sustained immune control. Further studies are needed to identify subgroups of patients who might benefit most from combination therapy, and to determine the optimal duration of therapy.

In an editorial that accompanies the article, Brian J. McMahon writes that the best candidates for combination therapy are likely to be young, have no medical or mental health contraindications or evidence of cirrhosis, and have HBV genotype A infection with a significant increase in level of ALT. They should understand the side effects of interferon therapy and be willing to tolerate those effects for 48 weeks. They should also understand that failure to respond to this regimen might mean that he or she would still need to take TDF or a nucleoside analogue.

Although the increased rate of HBsAg loss with combination therapy vs monotherapy is encouraging, Marcellin et al admit that it is unclear whether the magnitude of this increase will be sufficient to change clinical practice.

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Kristine Novak

Kristine Novak

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About The Author:

Dr. Kristine Novak

Dr. Kristine Novak

Dr. Kristine Novak is a science writer and editor based in San Francisco. She has extensive experience covering gastroenterology, hepatology, immunology, oncology, clinical, and biotechnology research discoveries.

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