This study tested the hypothesis that biological consequences of genetic variants will, if significant or severe, lead to treatment discontinuation, a well defined clinical outcome. Among 23 genetic variants included in the study, those in CYP2B6, 2A6, and 3A4 previously associated with plasma levels of efavirenz, and those in UGT1A1 previously associated with atazanavir-induced hyperbilirubinemia were also associated with early treatment discontinuation. The retrospective study was not designed to assess other clinical endpoints such as specific toxicities; however, assessment of the codes used in routine care to indicate the reasons for treatment discontinuation convincingly associated genetic risk to toxicity for those 2 drugs.
Thus, the study suggests that assessment of the genetic markers could lead to improved prescription of atazanavir and efavirenz. Unconjugated hyperbilirubinemia, the main adverse effect of atazanavir, is widely considered as irrelevant in clinical care [29
]. However, despite the reversibility and the absence of clinical consequences of hyperbilirubinemia, 2 of 3 individuals homozygous for the UGT1A1
promoter variant discontinued atazanavir in the present study. Differences in rates of discontinuation across centers reflected the frequency of homozygous individuals receiving the drug. Overall, 10% of Caucasians carry this genetic risk, but its frequency varies across ethnic groups [30
The basis of treatment discontinuation of efavirenz is more complex. While the genetic determinants of efavirenz blood levels are by now well understood [10
], there is no consensus as to whether high drug levels are associated with neuropsychotoxicity, or on the usefulness of therapeutic drug monitoring and dose adjustment [31
]. These considerations notwithstanding, the study suggests that treatment discontinuation correlates with decreased metabolism of efavirenz, and that the loss of the primary metabolic pathway, CYP2B6
, is necessary but not sufficient [32
] for an increased rate in efavirenz discontinuation. Extremely high plasma drug levels of efavirenz results from loss of both primary (CYP2B6
) and accessory (CYP3A4
) metabolic pathways [10
]. Consistent with such pharmacokinetic data, individuals that have loss of accessory metabolisms in the context of homozygous loss of function of CYP2B6
present the highest risk of treatment discontinuation. As pointed out for atazanavir, these data question the interest to initiate efavirenz in individuals with the genetic risk if two-thirds of them will subsequently discontinue the drug.
The study included tenofovir despite the paucity of genetic data associated with toxicity for this drug. We analyzed the genetic variants as proposed by Izzedine et al. [19
] in a study of 13 individuals with tubular dysfunction on tenofovir, and by Rodriguez-Novoa et al. [20
] in a study of 115 HIV-infected patients of whom 19 had tubular dysfunction. The current study suggests a possible association of rs2273697 G>A variant in ABCC2
with higher rates of drug discontinuation. The SHCS database did not allow for detailed analysis of the reasons for discontinuation in these individuals; in particular, for renal function (see below). Thus, the data on rs2273697 G>A should be considered preliminary; additional discovery efforts on the genetics of tenofovir are needed.
The case of lopinavir is a pertinent example of how a well-documented association of genetic variants and a laboratory phenotype (dyslipidemia) with potential long-term consequences—cardiovascular disease—may not translate into short-term clinical decisions. We did not document an association between the proposed risk score and treatment discontinuation or introduction of a lipid-lowering agent. However, the most appropriate clinical endpoint here would have been the actual laboratory data (reaching clinically relevant cut-offs of dyslipidemia) [12
]. The patient carrying the genetic risk could be prescribed an alternative drug on that basis. Prediction of dyslipidemia will improve with the increasing availability of genetic markers [13
This study did not include abacavir hypersensitivity because clinical testing for HLA*B5701 was introduced during the study period. We did, however, notice that the allelic frequency for the risk marker was lower in patients that received abacavir than among those that did not (data not shown)—confirming that the patients were increasingly screened before treatment initiation. Another relevant observation of the present study is that although genetic predisposition to toxicity might lead, through poor adherence, to virological treatment failure, there were few (n = 15) instances coded as virological treatment failure, and none among participants with the genetic risk marker. The current analysis did not consider drug adherence; its inclusion would have been informative.
This study should be considered as a pilot analysis that can provide data for power calculation, and support further discovery efforts toward identification of additional genetic markers. Thereafter, a prospective clinical trial should ideally formalize the analysis, and provide the basis for measuring the cost effectiveness of this approach [34