Pharmacogenetic markers led to discontinuation of ART in treatment-naive patients

Lubomirov R. J Infect Dis. 2011;203:246-257.

Issue: February 2011

Researchers have identified various pharmacogenetic markers associated with the risk for early treatment discontinuation during the first year of antiretroviral therapy in treatment-naive patients. Therefore, researchers recommend these markers to be considered for validation in the clinical setting.

Of the 23 genetic variants included in the study, CYP2B6, CYP2A6 and CYP3A4 variants assigned efavirenz (Sustiva, Bristol Myers Squibb), and UGT1A1 variant assigned atazanavir/ritonavir were associated with early treatment discontinuation, according to the results published in The Journal of Infectious Diseases.

“Up to one-third of patients initiating [ART] interrupt treatment — mostly due to poor tolerance/toxicity,” Rubin Lubomirov, PhD, of the Institute of Microbiology at the University of Lausanne, Switzerland told Infectious Disease News. “The present study indicates that some of currently available pharmacogenetic markers can identify patients that will likely interrupt therapy. While poor tolerance is not considered as relevant as severe toxicity, [such as] abacavir hypersensitivity, it does contribute significantly to life quality and to medical costs.”

Lubomirov and colleagues assessed the association between pharmacogenetic markers and time to treatment discontinuation during the first year of ART in 577 treatment-naive patients. Patients initiated treatment with either tenofovir (n=500) or abacavir (n=77) in combination with efavirenz (n=272), lopinavir/ritonavir (n=184), or atazanavir/ritonavir (n=121).

Cox regression models were used to assess rates of ART discontinuation between groups with and without genetic risk markers.

Compared with 14% of patients who discontinued treatment with tenofovir, 30% of those assigned efavirenz, 34% of those assigned lopinavir, and 25% of those assigned atazanavir discontinued treatment. Overall, 33% of patients stopped one or more therapies during the first year of ART.

In addition, patients assigned efavirenz and atazanavir with genetic risk markers had higher discontinuation rates vs. patients without genetic risk markers (71.15% vs. 28.10%, and 62.5% vs. 14.6%, respectively). The HR for efavirenz discontinuation was 3.14 (95% CI, 1.35–7.33) and 9.13 for atazanavir (95% CI, 3.38–24.69).

Conversely, researchers observed no definite genetic risk for discontinuation of tenofovir or lopinavir.

“[The data] should make the medical system more attentive to lesser manifestations of toxicity, and increase the interest for personalized prescription based on pharmacogenetic markers — even when the predictive power of the markers are not as elevated as that offered by HLA-B5701 and abacavir,” Lubomirov said.

Lubomirov noted a formal prospective study is needed to assess the value and cost effectiveness of pharmacogenetic testing for the prescription of efavirenz and atazanavir and boosted protease inhibitors. – by Ashley DeNyse

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