Hepatitis Drug May Generate HIV Resistance

BALTIMORE, June 20 -- When treating hepatitis B and HIV co-infection, physicians should use caution with the antiviral drug entecavir (Baraclude), researchers here said.

Unless a patient is already on a fully suppressive anti-HIV regimen, treating with entecavir runs the risk of generating HIV resistance to reverse transcriptase inhibitors, according to Chloe Thio, M.D., of Johns Hopkins, and colleagues.

The recommendation emerged from three case studies and a series of in vitro experiments, Dr. Thio and colleagues reported in the June 21 issue of the New England Journal of Medicine.

Earlier studies had indicated that entecavir had no effect on HIV replication, Dr. Thio and colleagues noted, but in the three patients the investigators found significant changes in both HIV levels and CD4 cell counts.

In all three patients -- whose HIV infections were not being treated at the time -- HIV levels fell by a factor of 10, with a concomitant rise in the number of CD4 cells, the researchers found.

In one of the patients, entecavir treatment led to the accumulation of HIV variants with the M184V mutation, which confers resistance to the nucleoside reverse transcriptase inhibitors lamivudine (3TC) and emtricitabine (Emtriva).

The patient had not been recently treated with either drug, and the researchers said genetic evidence indicated the mutations were newly evolved, presumably as a result of the use of entecavir.

In addition, the investigators obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication.

The "full extent of HIV-1 reverse-transcriptase mutations selected by entecavir monotherapy is not known," the researchers said, urging caution in the use of the drug unless a patient is also being effectively treated for HIV.

They suggested they found the anti-HIV effect - while earlier studies had not - because they used more sensitive tests.

Preliminary reports in February immediately prompted the drug's manufacturer, Bristol-Myers Squibb, to warn doctors of the possibility of generating resistance. (See CROI: HIV Resistance Linked to Hepatitis Drug)

In April, the Department of Health and Human Services changed its treatment guidelines for hepatitis B to recommend against the use of the drug "without concomitant treatment for HIV."

Co-infected patients "should consult with their physician to see whether entecavir is the right drug to treat their hepatitis B in the first place," Dr. Thio said.

She noted that the drug, which inhibits hepatitis B viral polymerase, is still effective against the liver disease, but "many co-infected patients and their physicians are justifiably concerned about whether to use the drug."

But the point may become moot, as more and more doctors and patients opt for early treatment of HIV, commented Martin Hirsch, M.D., of Massachusetts General Hospital in Boston, in an accompanying editorial,

"The need for isolated (hepatitis B) therapy in co-infected patients should continue to shrink," Dr. Hirsch said and, for the remaining cases other hepatitis drugs are available, including pegylated interferon alfa and adefovir (Hepsera).

He said the studies provide "rather convincing evidence" that entecavir has anti-HIV activity by inhibiting the viral reverse transcriptase enzyme.

The study was supported by the NIH. The authors reported no potential conflicts.