Is Combination Treatment Superior to Monotherapy?

Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are 7 approved therapies: 2 formulations of interferon (standard and pegylated) and 5 nucleos/tide analogues: lamivudine, adefovir, entecavir, telbivudine and tenofovir. In the vast majority of patients, these treatments are administered as monotherapies and a second drug is added when there is evidence of treatment failure. Many experts have advocated the use of de novo combination therapy citing the improvement in sustained virologic response rate when ribavirin is added to interferon for chronic hepatitis C and reduction in antiviral resistance rate when combination therapy is used for human immunodeficiency virus infection.

Professor Anna S. F. Lok , who came from the University of Michigan Medical Center , an editor of AASLD clinical practice guidelines for Management of chronic hepatitis B, expounded several clinical trials of de novo combination therapy today.

Ones of them have compared combination of pegylated interferon and lamivudine with pegylated interferon or lamivudine monotherapy. In each of these trials, combination therapy resulted in more marked on-treatment virus suppression compared to monotherapies but sustained virus suppression (and HBeAg seroconversion in the case of HBeAg-positive patients) after discontinuation of treatment was similar to pegylated interferon monotherapy. Combination therapy was associated with a lower rate of antiviral resistance compared to lamivudine monotherapy but this benefit should be interpreted in the context of zero resistance in patients who received pegylated interferon monotherapy. These trials demonstrated that de novo combination therapy of pegylated interferon and lamivudine does not confer an advantage over pegylated interferon monotherapy. One pilot trial reported very promising results with de novo combination therapy of pegylated interferon and adefovir but the number of patients enrolled was small and the study did not include control groups who received monotherapies.

Professor Anna S. F. Lok pointed out that there have been very few clinical trials comparing de novo combination of nucleos/tide analogues. The largest trial compared combination of lamivudine and adefovir vs. lamivudine alone. Combination therapy did not result in more rapid virus suppression. Although combination therapy was associated with a lower rate of resistance to lamivudine, a resistance rate of 15% after 2 years treatment was unacceptably high in light of resistance rates of 0-1% with entecavir or tenofovir monotherapies. Another small trial reported that combination of emtricitabine and adefovir resulted in more marked virus suppression than adefovir alone, but this trial did not include an emtricitabine alone group and the “additive” antiviral activity was likely an artifact related to the weak antiviral activity of adefovir monotherapy.

In summary, there is sound basis for de novo combination therapy of chronic hepatitis B but data to date do not support its use clinically, particularly in counties where antiviral drugs with high genetic barrier to resistance are readily available.

在过去的十年中，慢性乙型肝炎的治疗取得了实质的进展。目前，最主要的治疗方法包括2种成分的干扰素和5种核苷（酸）类似物。Anna S. F. Lok 教授总结了关于联合用药的一些试验结果。他指出聚乙二醇化干扰素与拉米夫定联合治疗比单独应用拉米夫定更加有效，但并不优于单独应用聚乙二醇化干扰素。关于核苷（酸）类似物联合用药的试验较少，已有的试验结果显示联合用药并未达到快速病毒抑制的作用。因此目前尚无明确证据支持联合用药治疗慢性乙型肝炎。