At
last year's Conference on Retroviruses and Opportunistic Infections, researchers
presented data demonstrating that entecavir (Baraclude), a drug approved for the
treatment of hepatitis B, also has unexpected
activity against HIV.
These findings led manufacturer Bristol-Myers
Squibb and the Food and Drug Administration to warn that entecavir
should not be used alone by HIV-HBV coinfected people, due to the potential
for HIV to develop an entecavir-resistance mutation (M184V) that can also confer
resistance to 3TC (lamivudine; Epivir)
and emtricitabine (Emtriva).
The latest U.S. treatment guidelines recommend that all HIV-HBV coinfected patients
being treated for hepatitis B should also be on HAART.
At
this year's Retrovirus conference, held last week in Boston, 2 research teams
gave oral presentations describing further work to characterize entecavir's activity
against HIV.
Entecavir
Interferes with Reverse Transcriptase Activity
Investigators
conducting the first analysis (abstract 62) hypothesized that because entecavir
is a guanosine nucleoside analog that contains a 3'-hydroxyl group, it may exert
its inhibitory effects following incorporation and/or later during synthesis of
the second DNA strand when entecavir-5'-monophpsphate (ETV-MP) is part of the
template. In a laboratory study, they used site-specific foot-printing tools in
combination with enzyme kinetics and binding studies to understand the anti-HIV
mechanism of entecavir.
They found that incorporation of ETV-MP at position
n causes strong "pausing" at positions n and n+3. However, increasing
concentrations of natural dNTP pools at positions n+1 and n+4 can overcome this
pausing, which indicates an immediate effect of ETV-MP on rates of incorporation
of the next nucleotide and later at n+4.
They added that steady-state
kinetic measurements revealed an 8-fold decrease in the efficiency of nucleotide
incorporation at position n+1 when entecavir-terminated primers are compared with
their natural counterpart. Site-specific foot-printing showed that the incorporation
of ETV-MP prevents reverse transcriptase (RT) translocation; in this pre-translocational
conformation, the nucleotide binding site is blocked, and chain termination occurs.
The
investigators concluded that, "The results of this study delineate 3 interlinked
mechanisms of inhibition of HIV-1 RT by entecavir. DNA synthesis is compromised
at positions n+1 and n+4, and, during synthesis of the second DNA strand, at position
n+1. The combined data provide a rational for mechanism-based approaches in the
development of more potent non-obligate chain-terminators."
Risk
Factors for Resistance
In
the second study (abstract 63), the research team that initially reported the
anti-HIV action of entecavir aimed to further characterized this activity and
determine risk factors associated with the development of the mutation M184V.
To
this end, they conducted a multi-center cohort study of 17 HIV-HBV
coinfected individuals in the U.S. and Australia who had received entecavir
in the absence of other antiretroviral agents. HIV RNA and HBV DNA levels, HIV
reverse transcriptase polymerase sequencing, and clinical data were abstracted
from medical records prior to receiving (earliest data July 2004) and while on
entecavir monotherapy
(through July 2007).
Results
•
10 study subjects were antiretroviral-naive
and 7 were antiretroviral-experienced.
•
Naive individuals had a median HIV RNA reduction
of 1.0 log10 (range 0.5 to 2.0) after a median of 113 days (range 17 to 291) on
entecavir.
•
Experienced individuals had a median HIV RNA
reduction of 1.1 log10 (range 0.1 to 2.3) after a median of 96 days (range 75
to 215) on entecavir.
•
Of the 17 patients, 12 (71%) demonstrated
an HIV RNA reduction of 0.5 log10 or greater, including 7 of the 10 naive individuals
(70%) and 5 of the 7 experienced patients (71%).
•
4 patients (24%) experienced HIV viral load
rebound of 0.5 log10 or greater after achieving their nadir (lowest-ever) HIV
RNA level.
•
Reverse transcriptase polymerase sequencing
was confirmed for 12 of the cohort (8 naive and 4 experienced), of whom 3 naive
and 3 experienced individuals demonstrated emergence of the M184V mutation.
•
In a univariate analysis, significant risk
factors for selection of M184V were reduction in HBV viral load and total duration
of entecavir monotherapy.
•
All 3 treatment-experienced individuals who
demonstrated selection of M184V had previously been treated with 3TC.
Based
on these findings, the investigators concluded, "Entecavir
monotherapy results in a clinically significant reduction in HIV RNA in the
majority but not all HIV-HBV coinfected individuals and can select for the M184V
mutation, even in HIV treatment-naive individuals. HIV-HBV coinfected individuals
should not receive entecavir monotherapy."
2/12/08
References
E
Tchesnokov, A Obikhod, R Schinazi, and others. 3 Interlinked Mechanisms of Inhibition
of HIV-1 Reverse Transcriptase by the HBV Drug Entecavir. 15th Conference on Retroviruses
and Opportunistic Infections (CROI). Boston, MA. February 3-6, 2008. Abstract
62.
J Audsley,
J Sasadeusz, A Mijch, and others. The Anti-HIV Activity of Entecavir: Serum HIV
RNA Decreases and Selection of the M184V Mutation Occurs in both ART-naïve
and -experienced HIV/HBV-co-infected Individuals. 15th CROI. Abstract 63.
Two
Studies Look at Anti-HIV Activity of Entecavir (Baraclude)
Results
