Two recent studies reported in the same journal compared treatment using lamivudine (Epivir-HBV) alone versus lamivudine in combination with adefovir (Hepsera) [Sung and others]; and adefovir monotherapy versus adefovir plus emtricitabine (Emtriva) for the treatment of HBeAg-positive chronic hepatitis B [Hui and others].

Although Dr. Jacobson stated that these studies serve as "prototypes for the work still needed in this field," he wrote, "They nonetheless fall short of establishing a definitive role for routine combination therapy in all patients when potent monotherapies with robust long-term resistance profiles are available."

As an example, Dr. Jacobson said that 4-year data on the antiviral drug entecavir (Baraclude) show rates of HBV DNA undetectability greater than 90% in HBeAg-positive patients after four years and a cumulative resistance rate of less than 1%.

He added that, "The recently presented pivotal trial data on tenofovir (Viread) demonstrate potent suppression [of HBV]." After 1 year of tenofovir monotherapy, 93% and 76% of HBeAg-negative and HBeAg-positive patients experienced undetectable HBV DNA, and there was no evidence of genotypic resistance.

Dr. Jacobson believes that these and other similar data -- including experience in HIV-HBV coinfected patients -- make it clear that "tenofovir has a robust long-term resistance profile."

He notes that although the nucleoside analog telbivudine (Tyzeka) has shown potent suppression of HBV, "[the drug] has a less robust resistance profile than entecavir or the nucleotides, but is associated with 2-year resistance rates of 2% or less in patients who, after 24 weeks of treatment, have undetectable HBV DNA and meet certain criteria for baseline viral load and/or ALT."

Dr Jacobson believes that results from more clinical trials of combination therapy are needed prior to expansion of its use with currently available anti-HBV agents. He also stated, "Even though prevention of resistance is a cornerstone of this concept [combination therapy], the practical design of trials with this as the primary endpoint is problematic when monotherapies that have high barriers to resistance and excellent proven long-term resistance profiles are already available."

He surmised that before combination anti-HBV therapy comes into widespread use, it may be necessary to have available other drugs with novel mechanisms of action, such as immunomodulatory agents (including those that restore specific immune responses), small interfering RNAs (siRNAs), entry inhibitors (e.g., pre-S peptides), or assembly inhibitors.

Trials evaluating the combination of pegylated interferon (Pegasys or PegIntron) and lamivudine for hepatitis B have demonstrated a more profound decrease in HBV DNA than that seen with either drug alone. However, Dr. Jacobson points out that post-treatment endpoints (viral suppression, HBeAg seroconversion, and HBsAg clearance) "have not been significantly different from those noted with peginterferon alone, which is superior to lamivudine alone." In addition, he wrote, "These trials entailed the discontinuation of lamivudine, like peginterferon, after 1 year, which is not done in practice."

Dr. Jacobson suggests that while the search for and development of alternative approaches to combination anti-HBV therapy continues, including the potential for combining peginterferon with other nucleoside/nucleotide analogs entailing longer administration of oral agents, more studies combining nucleoside/nucleotide analogs would be worthwhile. These would include combinations such as tenofovir plus emtricitabine (Emtriva), tenofovir plus entecavir, tenofovir plus telbivudine, and entecavir plus adefovir.

In the meantime, Dr. Jacobson said that results from recent trials, despite their limitations, provide support for the use of oral combination therapy -- albeit off-label -- in selected situations such as the following:

• Patients with cirrhosis who can least afford the emergence of resistance;

• Patients who have experienced suboptimal response to initial monotherapy at a specified time point, such as 24 weeks using a drug with a low genetic barrier to resistance, or 1 year using an agent with a high barrier;

• Patients coinfected with HBV and HIV;

• Patients who, for any reason, have established resistance to an anti-HBV drug.

In conclusion, Dr. Jacobson wrote, "[T]he universal application of combination therapy to all patients undergoing treatment for chronic hepatitis B requires a firmer foundation in comparative trials with potent agents used as monotherapy before it goes from the controversial to the routine."