Toward a pharmacogenetic understanding of nucleotide and nucleoside analogue toxicity.

Antiretroviral therapies for HIV-1 infection have become progressively more potent and better tolerated. An important milestone was the 2001 Food and Drug Administration approval of tenofovir di-soproxil fumarate (TDF), a once-daily nucleotide analogue reverse-transcriptase in-hibitor that is available commercially as a single agent (Viread; Gilead Sciences), co-formulated with emtricitabine (Truvada; Gilead Sciences), and coformulated with emtricitabine and efavirenz (Atripla; Gil-ead Sciences and Bristol-Myers Squibb). Compared with some nucleoside analogues , TDF is notable for less mitochon-drial toxicity in vitro and in animal models [1, 2] and for lower rates of nucleoside analogue–associated toxicities, such as li-poatrophy and peripheral neuropathy [3, 4]. As with all antiretroviral agents, however , TDF use has been associated with serious toxicity in some individuals. In particular, TDF has been infrequently associated with renal tubular injury. This was not completely unexpected in light of prior experience with structurally related compounds. The nucleotide antiviral drug adefovir diprovoxil is safe at low doses for the treatment of hepatitis B virus infection but was associated with proximal renal tubular injury when studied at higher doses [5], precluding its use for treatment of HIV infection. The anti-cytomegalovirus nucleotide cidofovir also causes renal toxicity [6, 7]. On the basis of the adefovir experience, there was enhanced monitoring for renal adverse events during clinical trials of TDF in HIV-infected volunteers. These trials [3, 4, 8] and at least one postmarketing observational study [9] did not demonstrate increased rates of renal dysfunction with TDF. Subsequent case series and cohort studies, however, have implicated TDF as a cause of renal dysfunction that ranges from mild, reversible renal insufficiency [10] and Fanconi syndrome [11, 12] to more-severe renal failure [13]. Characteristic features include decreased creatinine clearance with increased urinary wasting of phosphate, glucose, calcium, uric acid, and, in some cases, protein. Factors that may increase an individual's risk for this toxicity include preexisting renal impairment , lower body weight, and concomi-tant use of nephrotoxic drugs or HIV pro-tease inhibitors, in particular ritonavir [14–16]. Exclusion of individuals with pre-existing renal impairment from clinical trials of TDF [3, 4] may, in part, explain the infrequency of TDF-associated renal dysfunction in these studies. There is considerable interindividual variability in the likelihood, character, and severity of renal dysfunction with TDF, suggesting a possible influence of host genetics on susceptibility. In this issue of the Journal, Izzedine et al. [17] provide the first report of a possible association between a …