| Abstract |
Efavirnez (EFV) is a potent and highly
effective antiretroviral agent, a key component of one of
the preferred regimen in the initial treatment of human immunodeficiency
virus (HIV) infection. In addition, it is available in generic
form in developing countries, constituting a major option
for the treatment of HIV-infection in resource poor settings.
EFV is primarily metabolized through the CYP2B6 isoform in
the liver, an enzyme whose activity is induced by rifampin
and may also be affected by genetic polymorphisms. Tuberculosis
(TB) is the most common and serious complication of HIV infection
in sub-Saharan Africa. Patients with HIV and TB coinfection
often have low CD4 counts, and indication for immediate initiation
of highly active antiretroviral therapy (HAART). However,
concurrent HAART is limited by the pharmacokinetic (PK) interactions
between rifampin and some of the antiretroviral agents. PK
studies have demonstrated that rifampin decreases the exposure
to EFV by 22-26% during concomitant administration. Recent
studies have shown that EFV plasma concentrations are 24-32%
higher in higher in African-Americans compared white non-Hispanics
because of lower clearance of EFV in blacks. Thus, it is possible
that the decrease in EFV clearance in blacks may compensate
for the induction effect of rifampin on its metabolism, maintaining
effective EFV plasma exposure during concomitant therapy.
The proposed pilot study will evaluate the PK, virologic
response and toxicity of EFV-based regimen in HIV-infected
TB patients receiving rifampin-based therapy in Ghana, West
Africa. HIV-infected patients with AFB-smear positive or clinical
TB and CD4 counts = 250 cells/uL presenting to Korle-bu Teaching
Hospital, Accra will be enrolled. HAART consisting of two
nucleoside reverse transcriptase inhibitors and EFV 600 mg
will be initiated within 2 to 8 weeks of starting TB treatment.
HAART will be initiated as soon as TB therapy is tolerated.
All patients will be followed up until the completion of TB
treatment and/or 6 months of concurrent HAART. The primary
study end points will include: (1) PK parameters (Cmax, Cmin,
and AUC) of EFV. (2) Correlation of virologic response and
central nervous system side effects of EFV with plasma concentrations.
Secondary endpoints will include: (1) Correlation of plasma
EFV concentrations with body weight, body mass index and gender
and (2) Comparison of the 12-hour EFV plasma concentration
in the African patients with established levels in Thai patients.
The results of this study will provide important data about
the PK interaction between rifampin and EFV in Africans with
HIV/TB coinfection and will better characterize the relationship
between EFV exposure and efficacy/toxicity. In addition, the
secondary analysis will increase our understanding of the
effect of race on the metabolism of EFV in the presence of
rifampin.
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