Entecavir + tenofovir works well for people with hepatitis B who have had prior treatment failure

A dual regimen of entecavir (Baraclude) plus tenofovir (Viread) for 48 weeks led to virological response and was generally well-tolerated among people with chronic hepatitis B who had experienced treatment failure with previous nucleoside/nucleotide analogue treatment, according to a poster presented earlier this month at The Liver Meeting 2013, the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD), in Washington, DC.

Chronic hepatitis B virus (HBV) infection is treated with oral nucleoside/nucleotide analogues including lamivudine (Epivir), adefovir (Hepsera), entecavir (Baraclude), telbivudine (Sebivo or Tyzeka) and tenofovir (Viread). While these drugs can reduce HBV viral load to an undetectable level while on therapy, they typically do not lead to post-treatment sustained virological response or hepatitis B antigen loss.

HBV can develop resistance mutations that compromise long-term efficacy of treatment – especially of the oldest drug, lamivudine – and limit future treatment options, but entecavir and tenofovir have a higher barrier to resistance.

Maciej Jablkowski of the Medical University of Lodz in Poland and colleagues conducted the ENTEBE study (AI463203) to evaluate the safety and efficacy of entecavir plus tenofovir in people with chronic hepatitis B who had experienced treatment failure with previous nucleoside/nucleotide therapy.

This multicentre phase 3b trial enrolled 92 participants. Three-quarters were men, 76% were white and the median age was 43 years. A majority (62%) were hepatitis B 'e' antigen (HBeAg)-positive and 76% had normal alanine aminotransferase (ALT) at baseline. People with decompensated liver disease were excluded.

Most participants had previously been treated with entecavir (53%) or lamivudine (22%) monotherapy; 12% had taken tenofovir and a few had used adefovir (4%) or telbivudine (2%). About 5% had tried dual combinations that included lamivudine or adefovir.

The patients had experienced prior treatment failure as defined by European Association for the Study of the Liver (EASL) guidelines. Nearly 10% had primary non-response (<1 log₁₀ decline in HBV DNA after 12 weeks of treatment), 57% had partial virological response (decline of >1 log₁₀ but still detectable at week 24 or 48) and 33% experienced viral breakthrough while on treatment (>1 log₁₀ increase over the lowest level). At baseline, 52% had evidence of lamivudine resistance, 25% had entecavir resistance and 7% had adefovir resistance. About one-quarter had no resistance mutations and 16% had viral load too low for sequencing.

All participants in this ongoing, open-label, single-arm study were re-treated with 1mg entecavir plus 300mg tenofovir, both once daily, for up to 96 weeks. After 96 weeks, study participants and investigators could elect to pursue further treatment using commercially available hepatitis B drugs. Those who discontinued study treatment at or before week 96 entered a post-treatment follow-up phase of up to 24 weeks.

More than half of participants (54%) had HBV DNA <50 IU/ml at week 12 of re-treatment, rising to 64% at week 24. The primary analysis at week 48 found that 76% had viral load <50 IU/ml. Looking at the lower limit of detection of 6 IU/ml, response rates were 13, 12 and 19%, respectively, at these three time points.

Prior partial responders had the highest likelihood of undetectable HBV viral load at week 48 (83%), followed by prior breakthroughs (73%) and primary non-responders (56%). People who had previously taken tenofovir were least likely to respond to re-treatment (55%) compared to those previously taking entecavir (77%), lamivudine (85%) or adefovir (100%).

Five people who experienced virological failure on re-treatment – all of whom had primary non-response to prior treatment – met the criteria for resistance testing, but no treatment-emergent genotypic resistance mutations were detected.

Serological response rates were much lower than virological response. Only 5% of participants achieved HBeAg loss, 4% showed HBeAg seroconversion, and none experienced hepatitis B surface antigen (HBsAg) loss or seroconversion.

Entecavir/tenofovir combination therapy was generally safe and well-tolerated. Only 3% of participants in the study experienced serious adverse events, none of which were considered treatment-related, and just one person discontinued therapy early for this reason. The most common side-effects were gastrointestinal symptoms, fatigue and nausea. No serious kidney-related adverse events were reported.

Based on these findings the researchers concluded, "48 weeks of combination therapy with entecavir + tenofovir is a highly effective second-line chronic hepatitis B therapy", regardless of the type of prior nucleoside/nucleotide analogue treatment.