Stavudine

Abstract: ContextTenofovir disoproxil fumarate (DF) is a once-daily nucleotide analogue reverse transcriptase inhibitor.ObjectiveTo evaluate the efficacy and safety of tenofovir DF compared with stavudine in antiretroviral-naive patients.Design, Setting, and ParticipantsA prospective, randomized, double-blind study conducted at 81 centers in the United States, South America, and Europe from June 9, 2000, to January 30, 2004. A total of 753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study.InterventionPatients were randomized to receive either tenofovir DF (n = 299) or stavudine (n = 303), with placebo, in combination with lamivudine and efavirenz.Main Outcome MeasureProportion of patients with HIV RNA levels of less than 400 copies/mL at week 48.ResultsIn the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures, the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval, −10.4% to 1.5%), exceeding the predefined −10% limit for equivalence. However, equivalence was demonstrated in the secondary analyses (HIV RNA <50 copies/mL) at week 48 and through 144 weeks. Virologic failure was associated most frequently with efavirenz and lamivudine resistance. Through 144 weeks, the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups, respectively (P = .06). A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n = 170] vs +134 mg/dL for stavudine [n = 162], P<.001), total cholesterol (+30 mg/dL [n = 170] vs +58 mg/dL [n = 162], P<.001), direct low-density lipoprotein cholesterol (+14 mg/dL [n = 169] vs +26 mg/dL [n = 161], P<.001), and high-density lipoprotein cholesterol (+9 mg/dL [n = 168] vs +6 mg/dL [n = 154], P = .003). Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58 [19%] of 301, P<.001). The number of bone fractures and the renal safety profile were similar between the 2 groups.ConclusionsThrough 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine, lamivudine, and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy.

Abstract: Background In countries with a high seroprevalence of human immunodeficiency virus type 1 (HIV-1), HIV infection contributes significantly to infant mortality. We investigated antiretroviral-treatment strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial. Methods HIV-infected infants 6 to 12 weeks of age with a CD4 lymphocyte percentage (the CD4 percentage) of 25% or more were randomly assigned to receive antiretroviral therapy (lopinavir–ritonavir, zidovudine, and lamivudine) when the CD4 percentage decreased to less than 20% (or 25% if the child was younger than 1 year) or clinical criteria were met (the deferred antiretroviral-therapy group) or to immediate initiation of limited antiretroviral therapy until 1 year of age or 2 years of age (the early antiretroviral-therapy groups). We report the early outcomes for infants who received deferred antiretroviral therapy as compared with early antiretroviral therapy. Results At a median age of 7.4 weeks (interquartile range, 6.6 to 8....

Abstract: After zidovudine (ZDV), a 3′-azido analogue of thymi-dine, was found to be an effective antiretroviral drugagainst HIV [1,2], other nucleoside analogues inhibit-ing reverse transcriptase (RT) soon followed: didano-sine (ddI), zalcitabine (ddC), lamivudine (3TC),stavudine (D4T), and recently abacavir (1592U89)[3–7]. These drugs have demonstrated efficacy inreduction of morbidity and mortality, especially incombination therapy [8–10]. A special feature of someof these drugs is the protection against AIDS dementiacomplex, which appears to be related to good penetra-tion of the blood–brain barrier [11–13]. Although theintroduction of protease inhibitors has changed themanagement of HIV infection drastically, this cerebro-protective property will assert the role of these nucleo-side RT inhibitors (NRTI) as a cornerstone ofantiretroviral therapy [9,10].More than 10 years of experience with NRTI therapyhas revealed important adverse effects ranging frommild (myopathy) to fatal in some cases (pancreatitis,liver failure and lactic acidosis). Behind most of theseside-effects there appears to be a common mechanism:a decreased mitochondrial energy-generating capacity.In this review we will summarize the literature inwhich this mechanism is analysed and will emphasizethe importance of acquired mitochondrial dysfunctionthat will accumulate during long-term treatment withantiretroviral nucleoside analogues.