Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase

Abstract

Background and aims: Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80-90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data.

Patients and methods: Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg.

Results: The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p(overall)=0.01).

Conclusions: The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race.

Figures

Figure 1

Cumulative percentage of sustained hepatitis B e antigen (HBeAg) seroconversion (A) and hepatitis B virus (HBV) DNA negativity (B) for the total study population. HBeAg relapse at one year of follow up was observed in 42% of lamivudine (LAM), in 21% of interferon (IFN), and in 23% of combination therapy (IFN+LAM) treated patients, increasing to 54%, 32%, and 23% respectively after three years (poverall=0.01).

Figure 2

Cumulative percentage of relapse for the three therapies, corrected for the baseline factors pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and race, can be calculated for a specific patient using the results of the Cox regression (the estimated relative risks and baseline hazard). Here, the risk is illustrated for a male Caucasian patient with a mean pretreatment HBV DNA level of 4×108 g eq/ml after lamivudine (LAM), interferon (IFN), and IFN-lamivudine (IFN+LAM) combination therapy for three different ALT values: (A) ALT <2×upper limit of normal (ULN), (B) ALT 2–5×ULN, (C) >5×ULN. Relapse rates are particularly high in patients with a baseline ALT <2×ULN.