Relationship between HIV/Highly Active Antiretroviral Therapy (HAART)–Associated Lipodystrophy Syndrome and Stavudine‐Triphosphate Intracellular Levels in Patients with Stavudine‐Based Antiretroviral Regimens

Abstract

Intracellular levels of d4T-TP are strongly associated with the development of HALS.

Association of Thymidylate Synthase Gene Polymorphisms with Stavudine Triphosphate Intracellular Levels and Lipodystrophy

“…There is overwhelming epidemiological evidence linking d4T to the development of fat depot alterations (47). In this regard, our preliminary work, which needs further replication, suggests that a genetic mechanism may cause an alteration of nucleotide pools favoring an increase in d4T-TP levels, which we have found to be associated with the development of HALS in two different studies (11). This may explain why the TS genotype is also associated with the development of HALS (Table 2).…”

“…To our knowledge, this is the first pharmacogenetic study that has demonstrated the involvement of the metabolic folate pathway in determining the levels of d4T-TP, which in turn have been associated with the appearance of HALS (11). Not unexpectedly, TS genotypes are also associated with the appearance of HALS as well.…”

“…The presence or absence of lipoatrophy, lipohypertrophy, and mixed syndrome was determined as previously described (11). The metabolic syndrome was defined according to the U.S. National Cholesterol Education Program (NCEP) Adult Treatment Panel III Guidelines (13) and modified as recommended in the latest American Heart Association/National Heart, Lung, and Blood Institute scientific statement (20).…”

“…The TS gene was analyzed for the variable-number tandem repeat (VNTR) of a 28-bp polymorphism and the G 3 C SNP in the first and second repeats. A DNA fragment was amplified using previously described PCR conditions and primers (11) and directly sequenced using an ABI Prism 3100 genetic analyzer (Applied Biosystems, Foster City, CA). This G-to-C substitution changes a critical residue in the upstream stimulatory factor (USF) E-box consensus element, abolishes USF-1 binding, and alters transcriptional activity.…”

Estimation of Intracellular Concentration of Stavudine Triphosphate in HIV-Infected Children Given a Reduced Dose of 0.5 Milligrams per Kilogram Twice Daily

“…However, stavudine is rapidly cleared from the circulation, and the serum concentration-time curve is a poor predictor of the degree of mitochondrial toxicity and antiretroviral efficacy. Previous literature has revealed that the trough d4T-TP concentration determines the antiretroviral efficacy, while the peak d4T-TP concentration determines the degree of mitochondrial toxicity (31). A dose optimization should therefore aim to achieve an adequate d4T-TP trough (to retain efficacy) while reducing the peak d4T-TP concentration (to reduce toxicity).…”