HIV - Can Genetic Testing Predict Antiretroviral Drug Side Effects?

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HIV - Can Genetic Testing Predict Antiretroviral Drug Side Effects?

SUMMARY: Genetic variations can help identify which HIV patients are most likely to prematurely stop certain antiretroviral drugs due to adverse events, according to study findings reported in the January 15, 2011 Journal of Infectious Diseases. Researchers looking at a mostly European population found genetic markers significantly associated with early discontinuation of efavirenz (Sustiva) and atazanavir (Reyataz).

A substantial proportion of people with HIV manage only suboptimal adherence or stop taking antiretroviral therapy (ART) altogether due to poor tolerance and adverse drug reactions. Researchers hope that identifying factors that predict ART discontinuation may help patients stay on life-saving treatment.To explore the link between genetic factors and ART use, Rubin Lubomirov and fellow investigators with the Swiss HIV Cohort Study Team performed a retrospective genetic association study to assess the relationship between pharmacogenetic markers (genetic markers associated with response to drugs) and time to treatment discontinuation during the first year on ART. The analysis included 577 treatment-naive participants who started therapy between 2004

and 2008, with regimens consisting of tenofovir (Viread, also in the Truvada and Atripla coformulations) or abacavir (Ziagen), in combination with efavirenz (Sustiva, also in the Atripla pill), lopinavir/ritonavir (Kaletra), or ritonavir-boosted atazanavir (Reyataz). A majority (73%) were men, most (80%) were Caucasian/white, and the median age was 44 years.The researchers examined 23 genetic marker variations, or alleles, of 15 genes associated

with drug toxicity or pharmacokinetics of the study medications.Results

During the first year on ART, 190 individuals, or 33%, stopped taking 1 or more drugs.

Among 500 patients receiving tenofovir, 70 (14%) discontinued treatment during the first year;

Among 272 patients receiving efavirenz, 81 discontinued during the first year (30% cumulative);

Among 184 patients receiving lopinavir/ritonavir, 60 discontinued in the first year (34% cumulative);

Among 121 patients receiving atazanavir/ritonavir, 30 discontinued in the first year (25% cumulative).

Individuals with specific genetic markers were significantly more likely to discontinue efavirenz and atazanavir:

Efavirenz: 71.15% with markers of decreased CYP2B6/CYP2A6/CYP3A4 function vs 28.10% without (hazard ratio

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3.14. or about 3 times higher risk);

Atazanavir: 62.5% with double marker of decreased UGT1A1 function vs 14.6% without (HR 9.13, or about 9 times higher risk).

Significant links between genetic markers and treatment discontinuation were not observed for tenofovir or lopinavir/ritonavir.

"Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation," the study authors concluded. "These markers should be considered for validation in the clinical setting."Genetic markers related to cytochrome P450 enzymes (including CYP2B6, CYP2A6, and CYP3A4) responsible for processing drugs in the liver -- which have previously been shown to influence blood levels of efavirenz -- were associated with early efavirenz discontinuation, the researchers explained in their discussion. For atazanavir, variations associated with decreased function of UGT1A1, an enzyme that processes bilirubin -- thereby predisposing patients to hyperbilirubinemia -- were associated with premature discontinuation. The authors noted that while elevated bilirubin, which can lead to jaundice (yellowing of the skin and eyes), is reversible and often considered clinically

harmless, 2 out of 3 patients with 2 copies of the relevant UGT1A1 variation discontinued atazanavir.The researchers were not able to establish significant links between genetic markers and tenofovir toxicity, but suggested that gene variations associated with kidney tubular dysfunction (e.g., the rs2273697 G>A variant in ABCC2) may play a role and warrant further study.

They also did not see a clear association between genetic variations linked to abnormal lipid levels and discontinuation of lopinavir/ritonavir or use of cholesterol-lowering medications. Nevertheless, they suggested that patients with genetic risk could be prescribed alternative drugs.

The well-known link between the HLA*B5701 gene variation and abacavir hypersensitivity reactions was not studied in this analysis because in that case genetic testing to avoid adverse drug events has already been widely adopted as standard practice.

Investigator affiliations: Institute of Microbiology and Infectious Diseases Service, University Hospital Center, University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland; Infectious Disease/HIV Unit, Division of Infectious Diseases, University Hospital, Geneva, Switzerland; Ospedale Regionale, Lugano, Switzerland; University Hospital, Basel, Switzerland; Kantonsspital, St. Gallen, Switzerland; University Clinic for Infectious Diseases, Bern University Hospital and University of Bern, Switzerland.

1/18/11

ReferenceR Lubomirov, S Colombo, J di Iulio, and others (Swiss HIV Cohort Study Team). Association of Pharmacogenetic Markers with Premature Discontinuation of First-line Anti-HIV Therapy: An Observational Cohort Study. Journal of Infectious Diseases 203(2): 246-257 (Abstract). January 15, 2011.

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