EASL: Having Only Wild-type Hepatitis B Virus Predicts Response to Interferon

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Published on Friday, 04 May 2012 00:00        Written by Liz Highleyman

Milan Sonneveld (Photo: Liz Highleyman)

Chronic hepatitis B patients who do not have 2 common HBV mutations are more likely to achieve undetectable viral load and HBsAg loss when treated with pegylated interferon, according to study findings presented at the 47th International Liver Congress (EASL 2012) last month in Barcelona.

Hepatitis B virus (HBV) may carry variations in the "precore" and "core promoter" regions of its genome, which affect production of hepatitis B "e" antigen (HBeAg). Prior research has shown that these mutations are associated with more severe disease progression and poorer response to treatment compared with wild-type, or non-mutated, virus.

HBeAg loss in people who start out HBeAg positive is a measure of treatment success, along with undetectable HBV DNA viral load and hepatitis B surface antigen (HBsAg) loss; 1 study saw an HBeAg loss rate of 30% among patients treated with pegylated interferon. However, people who experience HBeAg loss still often have detectable HBV DNA and positive HBsAg, indicating that they are not cured.


Milan Sonneveld from Erasmus Medical Center in Rotterdam and colleagues performed a study to look at the relationship between the presence of precore/core promoter mutations and HBV DNA, HBeAg, and HBsAg persistence during interferon treatment.


The analysis included 214 HBeAg positive chronic hepatitis B patients treated with pegylated interferon alfa-2b (PegIntron); about half also received lamivudine (3TC; Epivir) for 52 weeks. Most (78%) were men, three-quarters were white, 19% were Asian, and the mean age was 34 years. Approximately one-third had HBV genotype A, 9% had genotype B, 14% had genotype C, and 40% had genotype D.


Participants were classified at baseline as having either only wild-type HBV or non-wild-type virus with detectable precore and/or core promoter mutations. Treatment response was evaluated 6 months after completion of therapy (week 78), with long-term follow-up at 3 years.

Results

• Precore and/or core promoter mutations were detected in 64% of patients, with frequencies varying substantially across different genotypes:
  
  • Genotype A: 69% wild-type, 7% precore, 24% core promoter, 0% both mutations;
  • Genotype B: 26%, 68%, 0%, and 5%, respectively;
  • Genotype C: 24%, 7%, 45%, and 24%, respectively;
  • Genotype D: 11%, 40%, 18%, and 32%, respectively.
    
• At baseline, participants with only wild-type virus had significantly higher levels of HBV DNA (9.20 vs 8.86 log copies/mL), HBeAg (2.81 vs 2.33 log IU/mL), and HBsAg (4.53 vs 4.28 log IU/mL) than those with precore/core promoter mutations.
• Participants with only wild-type HBV were significantly more likely than those with mutations to respond to treatment by all measures at 78 weeks:
  
  • Undetectable HBV DNA (<400 copies/mL): 20% vs 2%, respectively;
  • HBsAg loss: 18% vs 2%, respectively;
  • HBeAg loss: 42% vs 32%, respectively;
  • Combined response of HBeAg loss + HBV DNA < 10,000 copies/mL: 34% vs 11%, respectively.
    
• After 3 years of follow-up, response rates were higher overall, and wild-type virus still predicted better response:
  
  • Undetectable HBV DNA: 78% vs 25%, respectively;
  • HBsAg loss: 61% vs 13%, respectively;
  • Sustained HBeAg loss: 87% vs 80% (no longer significant).
    
• In a multivariate analysis, exclusively wild-type HBV at baseline was the strongest pre-treatment predictor of 78-week outcomes:
• HBV DNA undetectability: odds ratio (OR) 7.93, or about 8-fold higher likelihood;
• HBsAg clearance: OR 4.64, or nearly 5-fold higher;
• Combined response: OR 2.90, or about triple likelihood.
• Alanine aminotransferase (ALT) level had a minimal effect on treatment response among patients with wild-type virus compared with a nearly linear association for those with precore/core promoter mutations.
  

"Precore and core promoter mutants may be detected in a majority of HBeAg positive chronic hepatitis B patients," the investigators concluded. "Presence of mutants before [pegylated interferon treatment] is association with treatment failure."


"Patients with only wild-type virus have a high probability of virological response and HBsAg clearance through long-term follow-up," they continued. "Assessment of presence of mutants can help select patients with the highest probability of response [to pegylated interferon]."


During the question period, Sonneveld suggested that these findings may indicate that HBV with precore/core promoter mutations survive better in cells, and are perhaps less targeted by T-cells.


In a related study, Sonneveld's group also analyzed the relationship between precore/core promoter mutations and HBeAg levels and seroconversion in 138 HBeAg positive chronic hepatitis patients treated the nucleoside/nucleotide analogs lamivudine, adefovir (Hepsera), entecavir (Baraclude), and/or tenofovir (Viread).


They found that the presence of precore/core promoter mutations was associated with lower HBeAg levels and higher probability of HBeAg seroconversion. However, these mutations also predisposed patients to persistent HBV replication or HBeAg relapse after seroconversion, as was the case with pegylated interferon.


5/4/12
References
M Sonneveld, V Rijckborts, S Zeuzem, et al. Title Presence of Only Wildtype Virus is the Strongest Determinant of HBV DNA Undetectability and HBsAg Clearance in HBeAg-positive Chronic Hepatitis B Patients Treated with Peginterferon. 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012). Barcelona, April 18-22, 2012. Abstract 54.
R Zoutendijk, M Sonneveld, J Reijnders, et al. Relationship between Precore/Core Promoter Mutants, HBeAg Levels and Serological Response in HBeAg-positive Chronic Hepatitis B Treated with Nucleos(t)ide Analogues. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 551.