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EASL 2015: 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. Other researchers reported that adding 48 weeks of 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 analogs 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 long-term 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 analogs 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.

Tenofovir + Pegylated Interferon

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

This international study (GS-US-174-0149) included 740 hepatitis B patients 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).

Results

• HBV viral load initially declined in all groups after starting treatment; however, while it fell by -6 log IU/mL by week 48 in all the tenofovir-containing arms, the decline was only about -3 log 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 log with tenofovir alone, -0.8 log with interferon alone, -0.5 log with tenofovir plus interferon for 16 weeks, and -1.1 log 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 log IU/mL 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 log 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 + 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 + pegylated interferon] combination if they have HBsAg decline <1 log IU/mL at week 12," they added. "Future research to identify patient subpopulations who may derive the most benefit from combination therapy is warranted."

Add-on Pegylated Interferon

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

This Phase 3 trial included 185 chronic hepatitis B patients at multiple centers 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). Patients were stratified according whether their HBsAg level at study entry was above or below 2.25 log IU/mL.

Participants had been on stable nucleoside/nucleotide therapy for at least 1 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 analogs alone or to continue these drugs and add 180 mcg/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.

Results

• At week 48, a total of 7 patients (8%) in the add-on interferon group experienced HBsAg loss and 4 (4%) had HBs seroconversion, compared with none in the nucleoside/nucleotide monotherapy group -- a significant difference.
• By week 96, the HBsAg loss rate in the interferon group remained at 8% and 2 additional patients had HBs seroconversion (for a total of 7%).
• By week 96, the HBsAg loss rate in the nucleoside/nucleotide monotherapy group had risen to 3% -- no longer significantly different from the interferon group -- and 1 person (1%) had HBs seroconversion.
• HBsAg levels fell more in the add-on interferon group compared to the monotherapy group (-0.89 vs -0.35 log IU/mL from week 0 to week 96).
• However, within the interferon group, patients could be divided into a good responder subgroup (HBsAg decline -3.74 log IU/mL) and a non-responder subgroup (-0.62 log IU/mL).
• 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 log IU/mL at baseline, 33% of patients 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 log IU/mL, and 4% and 0% among those with >3 log IU/mL.
• HBsAg decline usually occurred early, during the first 24 weeks of combination treatment, but 1 person had a slow decline and did not achieve HBsAg loss until week 96.
• Combination treatment with pegylated interferon was generally safe, but side effects were common.
• 20 participants either stopped interferon or had their dose reduced, mostly due to adverse events (an additional 5 people refused to start interferon after randomization).
• There were about 4 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 1 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 analogs] 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 patients with undetectable HBV DNA who were invited to join the study agreed to do so, mostly due to the expected poor tolerability of pegylated interferon.

Switching to 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/nucleotides and began treatment with pegylated interferon alfa-2a for 48 or 96 weeks.

At week 48, 16% 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, patients who saw their HBsAg decrease to <200 IU/mL by week 24 after switching also had a 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 a 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 analogs 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.

6/9/15

References

HL Chan, SH Ahn, WL Chuang, et al. Predictors of clinical response: results from a large, randomized controlled study with tenofovir disoproxil fumarate (TDF) plus peginterferon 
alfa-2a (PEG) combination for chronic hepatitis B (CHB). 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O117.

M. Bourlière, P Rabiega, N Ganne-Carrie, et al. HBsAg clearance after addition of 48 weeks of 
PEGIFN in HBeAg negative CHB patients on nucleos(t)ide therapy with undetectable HBV DNA for at least
 one year: final results from ANRS-HB06 PEGAN study: a multicenter randomized controlled phase III trial
. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O112.

P Hu, J Shang, W Zhang, H Fan, H Ren, et al. Predictive value of baseline and on-treatment qHBsAg level in HBeAg positive CHB patients who switched from NUCs to pegylated interferon a-2a: a further analysis from NEW SWITCH study. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O116.