Hepatitis B antiviral drug resistance common but avoidable

Hepatitis B antiviral drug resistance common but avoidable -
by 'using tenofovir or entecavir firstline'



A panel of experts discussed the management and prevention of antiviral drug resistance in the long-term treatment of chronic hepatitis B virus (HBV) infection during Sunday's AASLD Clinical Symposium at DDW May 30-June 3 2009, Avoiding HBV Drug Resistance: How Many Drugs?

The panel consisted of moderator George Lau, MD, honorary clinical professor at the University of Hong Kong, Anna Lok, MD, MSc, MPH, professor of internal medicine and director of clinical hepatology, University of Michigan Health System, Ann Arbor, Daryl Lau, MD, associate professor of medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, and Marc Ghany, MD, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD.

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

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

Hepatitis flares and hepatic decompensation are among the adverse consequences of viral resistance.

Resistance develops because of several factors, Dr. Lok said. They include viral factors - the rate of HBV replication and 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, compliance with treatment, pharmacogenetics and patient's body size.

The frequency of viral resistance depends on the patient population, the definition of drug resistance used and the measurement technique. Dr. Lok defined viral resistance, also called virologic breakthrough, as an increase in serum HBV DNA of greater than or equal to 1 log above the nadir or redetection of HBV DNA.

Predictors of viral resistance

The GLOBE Trial showed that a high HBV DNA level at treatment week 24 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 the treatment response is suboptimal, and listed other ways to prevent viral resistance. They include avoiding inappropriate antiviral treatment, using a potent agent that has a high genetic barrier to resistance, reinforcing patient compliance with the prescribed regimen and initiating treatment with a combination regimen.

To prevent multidrug resistance, he suggested avoiding sequential monotherapy and choosing a drug that does not share a cross-resistance profile. For instance, a patient who is resistant to lamivudine should not receive telbivudine.

"Patients with multidrug resistance should be managed by experts," Dr. Ghany said.

Jury is out on combination therapy

Dr. George Lau spoke about combination therapy for HBV. The rationale for combination therapy is to enhance viral potency and increase the genetic barrier to drug resistance, he said.

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

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

An exception is that a study last year showed no greater antiviral effect between the lamivudine-plus-adefovir combination versus lamivudine alone, Dr. Lau said.

In considering combination therapy, the clinician must weigh the risks and costs, including potentially higher treatment costs, more difficult patient adherence to treatment, and side effects that include an increased risk of peripheral neuropathy with the use of telbivudine and pegylated interferon.

Potential patient populations in which to consider using combination therapy, according to Dr. George Lau, include those with cirrhosis, HIV/HBV co-infection, suboptimal response to an initial drug and established resistance to antiviral medications.

Drs. Lok and Daryl Lau remarked that because data are available only for old nucleosides, more research is needed to determine the benefit of combination therapy.