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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- "Pilot and retrospective studies suggested that reduction in d4T dosage from 40 to 30 mg twice daily (bid), in individuals weighing less than 60 kg and possibly heavier individuals as well, may decrease the incidence of side effects, without compromising antiviral efficacy (Ait-Mohand et al., 2008; Hoffmann et al., 2009; Karara et al., 2010; Pedrol et al., 2007; Sanchez-Conde et al., 2005). However, d4T dose reduction to control toxicity remains controversial. "
ABSTRACT: Stavudine (d4T) is used extensively as part of HAART in resource poor settings, despite its toxicities. The revised WHO guidelines specify replacement of d4T with less toxic but more expensive drugs when feasible, and that d4T doses be standardized to 30 mg twice daily (bid) (irrespective of body-weight), from the approved 40 mg bid in adults (body-weight ≥60 kg). Therefore, an in silico population pharmacokinetic and biochemical model was utilized to compare relative efficacies of the two doses in humans. Assessment of predicted quartile ranges of simulated concentrations of the triphosphate of d4T suggested sufficient trough concentrations to inhibit wild type HIV-1 reverse transcriptase at the reduced dose, lending support to the revised WHO recommendations.Antiviral research 08/2011; 92(2):372-7. DOI:10.1016/j.antiviral.2011.08.004 · 3.94 Impact Factor
Article: Ayurveda[Show abstract] [Hide abstract]
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ABSTRACT: A panel of leading Italian specialists in infectious diseases, virologists and immunologists met in Rome in 2005 to review critical data and discuss recommendations for each of the key questions in antiretroviral therapy today: When to start treatment? How to start? When to switch? What to switch to? Whether to stop or not to stop treatment, and how? The method of a nominal group meeting was used and recommendations were graded for their strength and quality using a system based on the one adopted by the Infectious Diseases Society of America. Main conclusions are summarized and critically discussed in this consensus statement, as well as some of the most recent data supporting these recommendations are provided.Journal of Antimicrobial Chemotherapy 07/2006; 57(6):1055-64. DOI:10.1093/jac/dkl113 · 5.44 Impact Factor