As
a result of these findings, until more is known about HIV resistance patterns
and their selection by entecavir, caution is needed when the drug is used by HIV-HBV
coinfected individuals who are not receiving fully suppressive combination
antiretroviral regimens. The U.S. Food and Drug Administration (FDA) has warned
against the use of entecavir as monotherapy in such patients, and the latest U.S.
HIV treatment guidelines recommend that all
HIV-HBV patients who need treatment for hepatitis B should receive combination
antiretroviral therapy.
In a case report published last year in the
journal AIDS, Spanish researchers described a patient triply infected with
HIV, hepatitis B, and hepatitis delta who was treated with oral entecavir (1 mg
daily) and did not show any significant fluctuation in plasma HIV RNA or selection
of M184V in HIV during the first 24 weeks of entecavir monotherapy [1]. This observation
conflicted with the findings
reported by U.S. researchers at the 2007 Retrovirus conference, followed by other
similar reports.
As they followed their patient over a longer period,
the Spanish investigators reported that, in this individual, the M184V mutation
in HIV was later selected in spite of having evidence of significant reductions
or rebounds in plasma HIV RNA. Their follow up report appeared in the April 23,
2008 issue of AIDS. Following are excerpts from their correspondence:
"This
43-year-old man with hepatitis delta and CD4 counts above 350 cells/mm3 began
treatment with entecavir (1 mg/day) in an attempt to ameliorate his liver disease,
as recent evidence has suggested that potent new anti-HBV nucleos(t)ide analogues
might be efficacious against the delta virus.
"As in many subjects
with chronic hepatitis B superinfected with delta virus, serum hepatitis B virus
DNA was undetectable in our patient. He did not show any significant fluctuation
in plasma HIV RNA after introducing entecavir, with plasma levels remaining around
20 000 copies/mL. HIV-1 genotyping before and every 2 months after beginning entecavir
did not show evidence of selection of M184V.
"However, one further
specimen collected at month 8, which was repeated in a separate sample collected
3 weeks later, confirmed the selection of mutation M184V in HIV-1. The patient
was then recommended to switch to tenofovir, emtricitabine, and efavirenz [the
drugs in the Atripla combination pill]. One month later, he had undetectable plasma
HIV RNA [while] the liver enzymes remained slightly elevated.
"In
a regular control made after 6 months of triple antiretroviral therapy, signs
of severe tubular [kidney] dysfunction, including glucosuria, aminoaciduria and
phosphaturia, developed. Serum creatinine remained normal. Removal of tenofovir
was then considered, but controversy arose about the most appropriate alternative
treatment.
"Reintroduction of entecavir alone with an abacavir-based
triple antiretroviral regimen was put on hold because of concern about the lack
of information on potential interactions between entecavir and abacavir, as both
are guanosine analogues. A recent experience suggesting a deleterious interference
between abacavir and ribavirin in HIV patients with chronic hepatitis C treated
with pegylated interferon plus ribavirin [2,3] was the reason for this concern,
as ribavirin is similarly a guanosine analogue.
"Finally, a decision
was taken to resume entecavir alone with raltegravir [Isentress] and efavirenz
[Sustiva]. Three months later, the patient had undetectable plasma HIV RNA and
hepatitis delta viremia continued to decline.
"This report highlights
the risk of using entecavir without concomitant antiretroviral therapy in HIV-HBV
coinfected patients. Although the lack of significant changes in plasma HIV RNA
in our patient argue against a potent antiretroviral activity of entecavir, the
slow selection of mutation of M184V indirectly confirms that enough drug pressure
is made. Recent in vitro findings support this view [4].
"While the
warning of the Food and Drug Administration against the use of entecavir as monotherapy
in HIV/HBV-coinfected patients is rather appropriate, it opens the discussion
about which antiretroviral drugs are the most convenient to use alone with entecavir
in this population."
Department
of Infectious Diseases, Hospital Carlos III, Madrid, Spain. Correspondence to
Dr Vincent Soriano, Department of Infectious Diseases, Hospital Carlos III, Madrid,
Spain.
5/16/08
Reference V
Soriano, E Vispo, P Labarga, and P Barreiro. A low antiretroviral activity of
the anti-hepatitis B drug entecavir may be enough to select for M184V in HIV-1
(Correspondence). AIDS 22(7): 911-912. April 23, 2008.
Other Citations
1.
V Soriano, J Sheldon, P Garcia-Gasco, and others. E. Lack of anti-HIV activity
of entecavir in an HIV patient coinfected with hepatitis B and delta viruses.
AIDS 18: 2253-2254. 2007.
2.
F Bani-Sadr, L Denoeud, P Morand, and others. Early virologic failure in HIV-coinfected
hepatitis C patients treated with the peginterferon-ribavirin combination: does
abacavir play a role? Journal of Acquired Immune Deficiency Syndromes 45:123-125.
2007.
3.
E Vispo, P Barreiro, JA Pineda, and others. Low response to pegylated interferon
plus ribavirin in HIV-infected patients with chronic hepatitis C treated with
abacavir. Antiviral Therapy (in press).
4.
R Domaoal, M McMahon, C Thio, and others. Pre-steady state kinetic studies establish
entecavir 5'-triphosphate as a substrate for HIV-1 reverse transcriptase. Journal
of Biological Chemistry 283: 5452-5459. 2008.
