Using interferon with hepatitis B antivirals raises likelihood of HBsAg loss

Treating chronic hepatitis B with tenofovir plus pegylated interferon for 48 weeks resulted in a higher rate of hepatitis B surface antigen (HBsAg) clearance than either drug taken alone, though the response rate was still just 9%, according to a study presented at the recent European Association for the Study of the Liver (EASL) 50th International Liver Congress in Vienna, Austria. Other researchers reported that adding interferon to nucleoside/nucleotide therapy increased the rate of HBsAg loss to about the same level, and switching to interferon may be effective for selected patients.

Antiviral therapy using nucleoside/nucleotide analogues such as lamivudine (Epivir), entecavir (Baraclude), adefovir (Hepsera) or tenofovir (Viread) is the mainstay of chronic hepatitis B treatment. While antiviral drugs can effectively suppress hepatitis B virus (HBV) replication during treatment, they usually do not lead to a cure, as indicated by HBsAg loss and HBs antibody seroconversion.

Studies to date indicate that starting treatment with nucleoside/nucleotide analogues plus pegylated interferon, adding interferon to suppressive nucleoside/nucleotide therapy or switching from nucleosides/nucleotides to tenofovir may increase the likelihood of HBsAg loss, but the optimal treatment strategy is not yet clear.

Henry Chan of the Chinese University of Hong Kong and colleagues looked at predictors of clinical response, including HBsAg loss, among people with chronic hepatitis B treated with tenofovir and pegylated interferon.

This international study included 740 people with hepatitis B without advanced liver fibrosis or cirrhosis. About two-thirds were men, three-quarters were Asian and the mean age was approximately 38 years. At baseline, they were either hepatitis B 'e' antigen (HBeAg)-positive with HBV DNA >20,000 IU/ml (just under 60%) or HBeAg-negative with >2,000 IU/ml.

Participants in this open-label study were randomly allocated to receive tenofovir plus pegylated interferon alfa-2a for 48 weeks, combination therapy for 16 weeks followed by tenofovir alone through week 48, pegylated interferon monotherapy for 48 weeks or tenofovir monotherapy for 120 weeks. The primary endpoint was HBsAg loss at week 72 (48-week results were previously presented at the 2014 AASLD Liver Meeting).

HBV viral load initially declined in all groups after starting treatment. However, while it fell by -6 log₁₀ IU/ml by week 48 in all the tenofovir-containing arms, the decline was only about -3 log₁₀ in the interferon monotherapy arm. Predictors of viral load decline included baseline HBV DNA and HBsAg levels, HBeAg status and treatment with tenofovir.

HBsAg decline at week 48 was more variable: -0.3 log₁₀ with tenofovir alone, -0.8 log₁₀ with interferon alone, -0.5 log₁₀ with tenofovir plus interferon for 16 weeks and -1.1 log₁₀ with tenofovir plus interferon for 48 weeks. Predictors of HBsAg decline included HBV genotype (people with types A or B saw larger decreases than those with C or D), pre-treatment HBV DNA and HBsAg levels, and use of interferon.

Rates of HBsAg loss at week 72 were 0% with tenofovir alone, 2.8% with interferon alone, 2.8% with tenofovir plus interferon for 16 weeks and 9.1% with tenofovir plus interferon for 48 weeks. Predictors of HBsAg loss included HBV genotype, use of combination therapy for 48 weeks, HBsAg decline >1 log₁₀ by week 12, HBs antibody level >10 mIU/ml at week 12, and ALT >300-400 U/l. Among people who achieved HBsAg loss, 71% had a >1 log₁₀ decline in HBsAg by week 12, while 92% of people who did not experience HBsAg loss had a smaller decline.

All treatment regimens were generally safe and well-tolerated (adverse events were described in more detail in the AASLD report).

"[Tenofovir plus pegylated interferon] for 48 week induces more HBsAg decline and higher HBsAg loss than all other regimens tested in this study," the researchers concluded.

There is a "high negative predictive value for HBsAg loss among patients treated with [tenofovir plus pegylated interferon] combination if they have HBsAg decline <1 log₁₀ IU/mL at week 12," they added. "Future research to identify patient subpopulations who may derive the most benefit from combination therapy is warranted."

Marc Bourlière from Hôpital Saint Joseph in Marseille and fellow investigators with the French ANRS-HB06 PEGAN study conducted a randomised trial to evaluate the usefulness of adding pegylated interferon for people with hepatitis B on suppressive nucleoside/nucleotide therapy.

This phase 3 trial included 185 people with chronic hepatitis B at multiple centres in France. More than 80% were men, about 45% were white, 35% were black, 15% were Asian and the mean age was about 48 years. All were currently HBeAg-negative, but nearly 30% had previously been HBeAg-positive when first diagnosed with hepatitis B. About a third had advanced fibrosis or cirrhosis (stage F3-F4). Trial participants were stratified according whether their HBsAg level at study entry was above or below 2.25 log₁₀ IU/ml.

Participants had been on stable nucleoside/nucleotide therapy for at least one year with undetectable HBV DNA viral load (median 3.5 years, but ranging up to 19 years). A majority (nearly 60%) were using tenofovir, 32% were using entecavir, 22% were using lamivudine and about 12% were using adefovir; 40% had previously received interferon.

Participants in this open-label study were randomly assigned to either stay on the same nucleoside/nucleotide analogues alone or to continue these drugs and add 180mcg/week pegylated interferon alfa-2a for 48 weeks. Those with sustained HBsAg clearance for 24 weeks could stop treatment. The primary endpoint was HBsAg loss at week 96, with continuing follow-up through week 144.

At week 48, a total of seven people (8%) in the add-on interferon group experienced HBsAg loss and four (4%) had HBs seroconversion, compared with none in the nucleoside/nucleotide monotherapy group – a statistically significant difference.

By week 96, the HBsAg loss rate in the interferon group remained at 8% and two additional participants had HBs seroconversion (for a total of 7%). The HBsAg loss rate in the nucleoside/nucleotide monotherapy group had risen to 3% – no longer significantly different from the interferon group – and one person (1%) had HBs seroconversion.

HBsAg levels fell to a greater extent in the add-on interferon group compared to the monotherapy group (-0.89 vs -0.35 log₁₀ IU/ml from week 0 to week 96). However, within the interferon group, participants could be divided into a good responder subgroup (HBsAg decline -3.74 log₁₀ IU/ml) and a non-responder subgroup (-0.62 log₁₀ IU/ml). HBsAg decline usually occurred early, during the first 24 weeks of combination treatment, but one person had a slow decline and did not achieve HBsAg loss until week 96.

In a multivariate analysis, HBsAg loss was associated with lower baseline HBsAg and using the full dose and duration of pegylated interferon; duration of undetectable HBV DNA did not predict HBsAg loss.

Among people with baseline HBsAg <2 log₁₀ IU/ml at baseline, 33% of people taking add-on interferon and 16% taking nucleoside/nucleotide monotherapy achieved HBsAg loss. The corresponding rates were 23% and 8% among people with a baseline HBsAg level <3 log₁₀ IU/ml, and 4% and 0% among those with >3 log₁₀ IU/ml.

Combination treatment with pegylated interferon was generally safe, but side-effects were common. Twenty participants either stopped interferon or had their dose reduced, mostly due to adverse events (an additional five people refused to start interferon after randomisation). There were about four times as many grade 3-4 adverse events in the interferon group than in the monotherapy group, but this difference did not reach statistical significance. People over age 50 and those with more symptoms were more likely to discontinue treatment prematurely.

"Addition of [a] 48 weeks course of [pegylated interferon alfa-2a] to [nucleoside/nucleotide] therapy in HBeAg-negative chronic hepatitis B patients with undetectable HBV DNA for at least one year results in higher rates of HBsAg loss and HBs seroconversion," the researchers concluded. "Low baseline HBsAg level increase HBsAg loss and HBs seroconversion."

However, they cautioned, "acceptability of [this] regimen in patients treated with [nucleoside/nucleotide analogues] is poor and discontinuation due to adverse events occurred in 20% of the patients."

For this reason, Bourlière said, this combination should be offered to selected HBeAg-negative chronic hepatitis B patients with better predicted response.

Bourlière noted that only half of the people with undetectable HBV DNA who were invited to join this study agreed to do so, mostly due to the expected poor tolerability of pegylated interferon.

Finally, in the New Switch study, Hong Ren from Chongqing Medical University and colleagues looked at HBeAg-positive chronic hepatitis B patients on nucleoside/nucleotide therapy who switched to pegylated interferon.

This analysis included 303 Chinese patients who took lamivudine, entecavir or adefovir for 1-3 years with partial response (HBV DNA <200 IU/ml and HBeAg loss). More than 80% were men and the mean age was 34 years. They stopped their nucleosides/nucleotide analogues and began treatment with pegylated interferon alfa-2a for 48 or 96 weeks.

At week 48, 16% of participants overall had experienced HBsAg loss and 13% had experienced seroconversion. But there was a dramatic difference according to baseline HBsAg levels: people with lower HBsAg at baseline (<1500 IU/ml) were significantly more likely to achieve HBsAg loss than those with higher levels (33% vs 4.1%). In addition, people who saw their HBsAg decrease to <200 IU/ml by week 24 after switching also had a much higher rate of HBsAg loss at week 48 (48% vs 0.6%, respectively).

The researchers concluded that nucleoside/nucleotide partial responders "are likely to achieve high HBsAg loss rate by switching to pegylated interferon therapy." They added that using a combination of HBsAg levels at baseline and at week 24 might be a good way to predict who will achieve HBsAg loss.

Taken together, these studies indicate that using interferon with or after nucleoside/nucleotide analogues is associated with greater likelihood of achieving HBsAg loss and HBs seroconversion. People starting with lower HBsAg have a better chance of HBsAg clearance, which can help select which patients are most likely to be cured with the addition of interferon. But the odds of HBsAg loss remain low overall, underlining the need for new types of treatment that work by novel mechanisms.