Reductions in Stavudine Dose Might Ameliorate Mitochondrial-Associated Complications Without Compromising Antiviral Activity

Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
HIV Clinical Trials (Impact Factor: 2.63). 07/2005; 6(4):197-202. DOI: 10.1310/ED57-EU48-RK6A-E5U0
Source: PubMed


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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    • "Thus the majority of children treated for HIV in South Africa remain on stavudine. The effect of stavudine in causing lipoatrophy appears to be strongly dose-related [20-23]. The current standard pediatric dose of stavudine was determined by extrapolation from the pharmacokinetic parameters of the adult dose of 40 mg twice daily using data from pediatric pharmacokinetic studies [24,25]. "
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    ABSTRACT: Background Despite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown. Methods In this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants. Results Among 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%–45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008). Conclusions The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.
    Full-text · Article · Nov 2012 · BMC Pediatrics
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    • "However, using 30 mg of stavudine may reduce adverse events and toxicities without reducing efficacy regardless of body weight. In addition to the studies noted, small-scale randomized trials have suggested a trend towards a decrease in plasma lipids and improvements in peripheral wasting with lower-dose stavudine [17,24]. However, in order to be a useful strategy, the optimal dose of stavudine that limits drug-induced toxicity while maintaining virologic potency needs to be investigated in large populations in resource-limited settings where the clinical and economic pressure to continue stavudine use is high. "
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    ABSTRACT: As stavudine remains an important and widely prescribed drug in resource-limited settings, the effect of a reduced dose of stavudine (from 40 mg to 30 mg) on outcomes of highly active antiretroviral therapy (HAART) remains an important public health question. We analyzed prospectively collected data from the Themba Lethu Clinic in Johannesburg, South Africa. We assessed the relationship between stavudine dose and six- and/or 12-month outcomes of stavudine substitution, failure to suppress viral load to below 400 copies/ml, development of peripheral neuropathy, lipoatrophy and hyperlactatemia/lactic acidosis. Since individuals with a baseline weight of less than 60 kg were expected to have received the same dose of stavudine throughout the study period, analysis was restricted to individuals who weighed 60 kg or more at baseline. Data were analyzed using logistic regression. Between 1 April 2004 and 30 September 2009, 3910 patients were initiated on antiretroviral therapy (ART) with a recorded stavudine dose and were included in the analysis. Of these, 2445 (62.5%) received a 40 mg stavudine dose while 1565 (37.5%) received 30 mg. In multivariate analysis, patients receiving a 40 mg dose were more likely to discontinue stavudine use (adjusted odds ratio, OR 1.71; 95% confidence limits, CI 1.13-2.57) than those receiving 30 mg by 12 months on ART. Additionally, patients receiving 40 mg doses of stavudine were more likely to report peripheral neuropathy (OR 3.12; 95% CI 1.86-5.25), lipoatrophy (OR 11.8; 95% CI 3.2-43.8) and hyperlactatemia/lactic acidosis (OR 8.37; 95% CI 3.83-18.29) in the same time period. Failure to suppress HIV viral load within 12 months of HAART initiation was somewhat more common among those given 40 mg doses (OR 1.62; 95% CI 0.88, 2.97) although this result lacked precision. Sensitivity analyses accounting for death and loss to follow up generally supported these estimates. Lower stavudine dosage is associated with fewer reports of several stavudine-associated adverse events and also a lower risk of stavudine discontinuation within the first year on ART.
    Full-text · Article · Mar 2012 · Journal of the International AIDS Society
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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. "
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    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.
    Full-text · Article · Aug 2011 · Antiviral research
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