HIV
and Hepatitis.com Coverage of the 14th
Annual Conference on Retroviruses and Opportunistic Infections (14th CROI) February
25 - 28, 2007, Los Angeles, CA
Entecavir
Active Against HIV and Selects for Antiretroviral Resistance Mutations
At
the 14th Conference on Retroviruses and Opportunistic Infections in Los Angeles
this week, researchers reported that the hepatitis B drug entecavir (Baraclude)
is also active against HIV, and can select for a mutation that confers resistance
to some antiretroviral agents.
A majority of antiviral drugs approved for
the treatment of hepatitis B virus (HBV) infection or in the development pipeline
demonstrate activity against both HBV and HIV, including:
The
only agents believed to be active against only HBV are entecavir and the recently
approved telbivudine (Tyzeka). The entecavir package insert states that the drug
"has no clinically relevant activity against HIV." These drugs are needed
by HIV-HBV coinfected patients who do not yet require antiretroviral therapy for
HIV, since using one of the dually-active drugs alone to treat HBV could select
for drug-resistant HIV strains (that is, it is equivalent to antiretroviral monotherapy).
But
according to this week's report, entecavir may have to be taken off the list of
preferred first-line agents for treating hepatitis B in coinfected individuals.
Results
•
Researchers
described 3 HIV positive patients not on antiretroviral therapy who experienced
a 1-log drop in HIV RNA after starting hepatitis B treatment with entecavir, suggesting
entecavir suppressed HIV.
•
In
a laboratory analysis using cloned HIV isolates, entecavir suppressed HIV replication,
with a 50% inhibitory concentration (IC50) between 0.1 and 1 nM.
•
Resistance
testing in vitro showed the emergence and accumulation of the M184V mutation over
time:
- 0% of clones at baseline; - 61% of clones at 4 months; -
96% of clones at 6 months.
Conclusion
and Discussion
The researchers concluded that, "entecavir is a
potent (but partial) inhibitor of HIV replication in vivo and in vitro and that
it can select for viruses bearing the M184V mutation, which confers high-level
resistance to entecavir."
In
addition, this mutation also confers resistance to the antiretroviral drugs 3TC
(approved for the treatment of both HIV and HBV) and emtricitabine (not yet approved
for HBV). These 2 drugs are popular components of NRTI backbone regimens, with
3TC being part of the Combivir, Trizivir, and Aptripla combination pills, and
emtricitabine included in the Truvada and Atripla pills.
During
a discussion after the presentation, a Bristol-Myers Squibb (BMS) representative
said that the company had extensively tested entecavir over a decade and had not
seen anti-HIV activity, although they were using less sensitive assays available
at the time. The researchers suggested that in light of their findings, "Entecavir
should not be used in HIV-HBV coinfected individuals not on a fully suppressive
HIV regimen without careful consideration of other options."
Already,
Health Canada has issued a warning to avoid the use of entecavir alone in coinfected
individuals, and the U.S. Food and Drug Administration (FDA) and BMS notified
care providers in February that the entecavir product label is being revised to
reflect the new data.
In
a recent letter, BMS advised health care providers that, "when considering
therapy with [entecavir] in an HIV-HBV coinfected patient not receiving HAART,
the risk of developing HIV resistance cannot be excluded based on current information."
03/02/07
References
M
McMahon, B Jilek, T Brennan and others. The anti-hepatitis B drug entecavir inhibits
HIV-1 replication and selects HIV-1 variants resistant to antiretroviral drugs.
14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, February
25-28, 2007. Abstract 136LB.
