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HIV-infected immunocompromised patients require life-long antiretroviral therapy.
To date, 26 antiretroviral drugs are approved by the US Food and Drug Administration for
the treatment of HIV. Highly Active Antiretroviral Therapy (HAART), normally a
combination of three antiretroviral drugs, has dramatically improved the prognosis of
HIV/AIDS. However, viral replication under therapy can lead to the selection of drug
resistant viruses and subsequent virologic failure. While poor adherence is likely to be the
main cause of treatment failure, individual pharmacokinetic variability can also play an
important role. Drug-drug interactions, drug-food interactions, sex, age, renal/hepatic
function and pregnancy are all sources of pharmacokinetic variability.
In recent years, host genetic polymorphisms have also been shown to explain part of
this variability and several pharmacogenetics studies have demonstrated that host genetic
polymorphisms can influence antiretroviral drug exposure, toxicity and response to treatment.
During antiretroviral drug development, drug hypersensitivity reactions have been reported
for several agents. Based on pharmacogenetic research data antiretroviral treatment decisions
based on host genetics to prevent the risk of hypersensitivity reactions are now part clinical
practice. Specifically, it is now recommended that patients initiating abacavir are screened for
the presence of the HLA-B*5701 allele as it is strongly associated with an immunologically
mediated hypersensitivity reaction to abacavir, which in rare cases can be fatal.
Antiretroviral drugs within the Non-Nucleoside Reverse Transcriptase Inhibitor
(NNRTIs) drug class are commonly used within first-line HAART regimens. Substantial
evidence exists that polymorphisms in the CYP2B6 drug metabolizing enzyme gene are
associated with higher NNRTI drug exposure, and in some studies with early drug toxicity
(mainly efavirenz related neuropsychological toxicity). The bulk of evidence concerns the
CYP2B6 516G>T polymorphism, primarily within the variant CYP2B6*6 allele that also
includes the 785A>G polymorphism, which has been shown to be associated with higher
efavirenz plasma exposure but not with time to virologic or toxicity-related failure. To date,
in the absence of drug toxicity, it is unclear the benefit of a clinical intervention for patients
identified with high NNRTI plasma drug concentrations or who are carriers of a genotype
associated with high drug concentrations.
Some antiretroviral drug toxicities do not appear until after months of treatment and
clinical and pharmacogenomics data could be combined to individualize antiretroviral
treatment. Strong evidence supports the existence of host genetic polymorphisms that predict
a higher risk of unconjugated hyperbilirubinemia in patients receiving atazanavir. Perhaps
patients with risk alleles for hyperbilirubinemia should not necessarily avoid atazanavir use
but may require closer laboratory monitoring. Similarly, the genetics of tenofovir associated
nephrotoxicity may become increasingly important as tenofovir slowly replaces zidovudine
in HAART regimens throughout the world.
To date, pharmacogenetics analyses of antiretroviral drugs have identified several
host genetic polymorphisms associated with antiretroviral drug toxicity and
pharmacokinetics. Understanding the contribution of specific polymorphisms on
antiretroviral drug efficacy and/or toxicity may lead to simple yet critical interventions to
further optimize these life-saving treatments.
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