At the annual Digestive Disease Week (DDW 2009) meeting this week in Chicago, a panel of experts discussed the prevention and management of antiviral drug resistance in patients receiving long-term treatment for chronic hepatitis B virus (HBV) infection, according to DDW Daily News, the official conference newspaper.

Anna Lok, MD, MSc, MPH

The clinical symposium entitled "Avoiding HBV Drug Resistance: How Many Drugs?" featured a panel consisting of moderator George Lau, MD, from the University of Hong Kong; Anna Lok, MD, MSc, MPH, from the University of Michigan Health System in Ann Arbor; Daryl Lau, MD, from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston; and Marc Ghany, MD, from the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health.

Newer, more potent nucleoside analogs have demonstrated much lower rates of antiviral resistance than older agents such as lamivudine (Epivir-HBV), according to the panel members. Speaking during the discussion, Dr. Ghany said, "The panel consensus is entecavir (Baraclude) and tenofovir (Viread) should be first-line [treatment]."

The incidence of viral resistance to lamivudine -- the former standard of care -- rises from 24% after 1 year of treatment to 67% in year 4, reported Dr. Daryl Lau. "It is no longer best for long-term therapy of chronic HBV," he said.

Several factors contribute to development of resistance, said Dr. Lok. These include viral factors, such as the rate of HBV replication and the number of pre-existing viral mutations; the drug's potency and genetic barriers to resistance; and factors relating to the host, such as prior treatment, adherence, pharmacogenetics, and body size. Adverse consequences of drug resistance include hepatitis flares and hepatic decompensation due to ongoing viral replication.

The frequency of viral resistance depends on the patient population, definitions of drug resistance, and measurement techniques. Dr. Lok defined viral resistance -- characterized by virological breakthrough -- as an increase in serum HBV DNA of greater than or equal to 1 log above the nadir (lowest-ever) level or reappearance of detectable HBV DNA.

Predictors of Viral Resistance

The GLOBE Trial showed that a high HBV DNA level at week 24 of treatment predicts viral resistance, Dr. Ghany said, "The take-home message is: if your patient has a high viral load at week 24, you better do something, because these patients have a high risk of developing resistance."

Dr. Ghany recommended changing therapy if treatment response is suboptimal, and listed other ways to prevent viral resistance include avoiding inappropriate antiviral treatment, using a potent agent that has a high genetic barrier to resistance, reinforcing patient adherence, and starting treatment with a combination regimen.

To prevent multidrug resistance, he suggested avoiding sequential monotherapy -- adding a single new drug after the previous one fails -- and choosing agents that do not share a cross-resistance profile. For instance, a patient with viral resistant to lamivudine is less likely to respond to telbivudine (Tyzeka).

Jury Still Out on Combination Therapy for Hepatitis B

Dr. George Lau also spoke about combination therapy for chronic hepatitis B. The rationale for combination therapy, he noted, is to enhance viral potency and increase the genetic barrier to resistance.

There are conflicting results in the medical literature on differences in HBV DNA suppression between monotherapy and combination therapy. Some randomized clinical trials found that antiviral efficacy is enhanced with the use of combination regimens.

"The first virologic breakthrough should be managed with combination therapy, not by switching to another [single-agent] treatment," he said.

An exception, he added, is lamivudine plus adefovir (Hepsera), since a study last year showed no greater antiviral effect with the combination versus lamivudine alone.

In considering combination therapy, a clinician must weigh the potential benefits against the drawbacks, including potentially higher treatment costs, more difficult adherence, and additive side effects that include an increased risk of peripheral neuropathy with telbivudine and pegylated interferon (Pegasys).

Patients that may especially benefit from combination therapy, he concluded, include those with liver cirrhosis, HIV-HBV coinfection, suboptimal response to an initial drug, and established resistance to antiviral medications.

Drs. Lok and Daryl Lau remarked that because extensive data are only available for the older nucleoside analogs, more research using the newer drugs is needed to determine the benefits of combination therapy.

6/05/09

Source
Hepatitis B antiviral drug resistance common but avoidable. DDW Daily News. Digestive Disease Week (DDW 2009). June 2, 2009.