Reductions in stavudine dose might ameliorate mitochondrial-associated complications without compromising antiviral activity
ABSTRACT Stavudine (d4T) is a nucleoside analogue approved for the treatment of HIV infection. Concern has risen due to its association with mitochondrial toxicity. Given that the toxicity might be dose-dependent, we explored prospectively whether lowering d4T doses might improve the safety profile of the drug without compromising its antiviral activity.
All HIV-infected patients seen at our institution during the first semester of year 2003 who were receiving a d4T-containing regimen and had plasma HIV RNA below 50 copies/mL for the previous 3 months were invited to participate in a trial in which half of patients reduced the dose of d4T from 40 to 30 mg bid (cases) and the other half continued with the same d4T dose (controls).
A total of 92 patients were recruited in the study: 47 cases and 45 controls. A total of 9 patients experienced virological failure during the following 12 months: 4 cases and 5 controls. No significant differences between groups were recognized for mean transaminase levels, cholesterol, triglycerides, and lactate at baseline nor over the 12-month follow-up period. Lipodystrophy was recognized in 20% of patients at baseline, without significant differences between groups, and no significant improvements were recognized in the d4T 30 mg bid arm after 12 months follow-up. However, a median significant increase of 2.23-fold in the mitochondrial DNA content in peripheral blood mononuclear cells (PBMCs) was recognized in a subset of 11 patients who reduced the d4T dose, whereas it remained unchanged in 10 controls.
A reduction in the d4T dose from 40 to 30 mg bid may ameliorate mtDNA depletion in PBMCs without compromising the antiviral activity of the drug. However, significant improvements on surrogate laboratory markers of mitochondrial toxicity or in lipoatrophy could not be recognized over 12 months follow-up.
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ABSTRACT: Background and objective Stavudine (d4T) has shown a favourable short and long-term tolerability profile. Nevertheless, its usage is currently decreasing due to some safety concerns. We aimed to evaluate the efficacy and safety of d4T low-dose-based regimens. Patients and method This was a multicenter and retrospective review chart of patients receiving standard doses of d4T for ≥ 6 months (weight > 60 kg: 40 mg/12 h; weight < 60 kg: 30 mg/12 h) and having undetectable viral load for at least 3 months before the d4T dose reduction (weight > 60 kg: 30 mg/12 h; weight < 60 kg: 20 mg/12 h). Immunological and viral parametres, lipid profile and side effects were determined. Results A total of 982 patients were included. The main reason for reducing the dose was prevention of tocixity (76%). After 6 months of follow-up, 97% and 84% patients had less than 400 and 50 cp/ml, respectively, and the CD4 cell count increased by 38 cel/ml. Lipids, lipodystrophy and peripheral polineuropathy improved but there was no statistical significance. Conclusions A d4T dose reduction in an immuno-virologically stable population does not affect treatment efficacy. Longer follow-ups are required to confirm improvements in the safety profile.Medicina Clínica 09/2007; 129(10):361-365. DOI:10.1157/13110209 · 1.25 Impact Factor
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ABSTRACT: The antiviral efficacy of stavudine depends on the trough concentration of its intracellular metabolite, stavudine-triphosphate (d4T-TP), while the degree of stavudine's mitochondrial toxicity depends on its peak concentration. Rates of mitochondrial toxicity are high when stavudine is used at the current standard pediatric dose (1 mg/kg twice daily [BID]). Evidence from adult work suggests that half of the original standard adult dose (i.e., 20 mg BID) may be equally effective, with markedly less mitochondrial toxicity. We present a population pharmacokinetic model to predict intracellular d4T-TP concentrations in pediatric HIV-infected patients administered a dose of 0.5 mg/kg BID. Our model predicted that the reduced pediatric dose would result in a trough intracellular d4T-TP concentration above that of the reduced 20-mg adult dose and a peak concentration below that of the 20-mg adult dose. The simulated pediatric intracellular d4T-TP at 0.5 mg/kg BID resulted in median peak and trough values of approximately 23.9 fmol/106 cells (95% prediction interval [PI], 14.2 to 41 fmol/106 cells) and 14.8 fmol/106 cells (95% PI, 7.2 to 31 fmol/106 cells), respectively. The peak and trough concentrations resulting from a 20-mg BID adult dose were 28.4 fmol/106 cells (95% PI, 17.3 to 45.5 fmol/106 cells) and 13 fmol/106 cells (95% PI, 6.8 to 28.6 fmol/106 cells), respectively. Halving the current standard pediatric dose should therefore not compromise antiviral efficacy, while markedly reducing mitochondrial toxicity.Antimicrobial Agents and Chemotherapy 02/2014; 58(2). DOI:10.1128/AAC.01717-13 · 4.57 Impact Factor
European Neuropsychopharmacology 08/2010; 20. DOI:10.1016/S0924-977X(10)70756-2 · 5.40 Impact Factor