Stavudine Toxicity in Adult Longer-Term ART Patients in Blantyre, Malawi

Malawi-Liverpool Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
PLoS ONE (Impact Factor: 3.23). 07/2012; 7(7):e42029. DOI: 10.1371/journal.pone.0042029
Source: PubMed


Stavudine is an effective and inexpensive antiretroviral drug, but no longer recommended by WHO for first-line antiretroviral regimens in resource-limited settings due to toxicity concerns. Because of the high cost of alternative drugs, it has not been feasible to replace stavudine in most adults in the Malawi ART programme. We aimed to provide policy makers with a detailed picture of stavudine toxicities in Malawians on longer-term ART, in order to facilitate prioritization of stavudine replacement among other measures to improve the quality of ART programmes.
Prospective cohort of Malawian adults who had just completed one year of stavudine containing ART in an urban clinic, studying peripheral neuropathy, lipodystrophy, diabetes mellitus, high lactate syndromes, pancreatitis and dyslipidemia during 12 months follow up. Stavudine dosage was 30 mg irrespective of weight. Cox regression was used to determine associations with incident toxicities.
253 patients were enrolled, median age 36 years, 62.5% females. Prevalence rates (95%-confidence interval) of toxicities after one year on stavudine were: peripheral neuropathy 21.3% (16.5-26.9), lipodystrophy 14.7% (2.4-8.1), high lactate syndromes 0.0% (0-1.4), diabetes mellitus 0.8% (0-2.8), pancreatitis 0.0% (0-1.5). Incidence rates per 100 person-years (95%-confidence interval) during the second year on stavudine were: peripheral neuropathy 19.8 (14.3-26.6), lipodystrophy 11.4 (7.5-16.3), high lactate syndromes 2.1 (0.7-4.9), diabetes mellitus 0.4 (0.0-1.4), pancreatitis 0.0 (0.0-0.2). Prevalence of hypercholesterolemia and hypertriglyceridemia increased from 12.1% to 21.1% and from 29.5% to 37.6% respectively between 12 and 24 months. 5.5% stopped stavudine, 1.3% died and 4.0% defaulted during follow up. Higher age was an independent risk factor for incident peripheral neuropathy and lipodystrophy.
Stavudine associated toxicities continued to accumulate during the second year of ART, especially peripheral neuropathy and lipodystrophy and more so at increasing age. Our findings support investments for replacing stavudine in first-line regimens in sub-Saharan Africa.

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    • "As South Africa has only recently phased out d4T, and AZT is still being used, it is not unexpected that a quarter of the women and a tenth of the men, had lipoatrophy. The prevalence of lipoatrophy found in this study is not easy to compare with other studies as studies from high-income countries focussed on men [12,24], while most studies from Africa looked at the prevalence of lipodystrophy [30-32] rather than studying the two entities of lipoatrophy and lipodystrophy separately. Our finding that tricep skinfold thickness was a predictor of lipoatrophy is supported by other studies. "
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    ABSTRACT: Background Lipohypertrophy does not appear to be an adverse ART reaction while lipoatrophy is clearly associated with the use of stavudine (d4T) and zidovudine (AZT). In low and middle income countries d4T has only recently been phased out and AZT is still widely being used. Several case definitions have been developed to diagnose lipodystrophy, but none of them are generalizable to sub-Saharan Africa where black women have less visceral adipose tissue and more subcutaneous adipose tissue than white women. We aimed to develop a simple, objective measure to define lipoatrophy and lipohypertrophy by comparing patient report to anthropometric and dual-energy X-ray absorptiometry (DXA) -derived variables. Methods DXA and anthropometric measures were obtained in a cross sectional sample of black HIV-infected South African men (n = 116) and women (n = 434) on ART. Self-reported information on fat gain or fat loss was collected using a standard questionnaire. Receiver operating characteristic (ROC) curves were used to describe the performance of anthropometric and DXA-derived variables using patient reported lipoatrophy and lipohypertrophy as the reference standard. Results Lipoatrophy and lipohypertrophy were more common in women (25% and 33% respectively) than in men (10% and 13% respectively). There were insufficient numbers of men with DXA scans for meaningful analysis. The best predictors of lipoatrophy in women were the anthropometric variables tricep (AUC = 0.725) and thigh skinfold (AUC =0.720) thicknesses; and the DXA-derived variables percentage lower limb fat (AUC = 0.705) and percentage lower limb fat/height (AUC = 0.713). The best predictors of lipohypertrophy in women were the anthropometric variable waist/hip ratio (AUC = 0.645) and the DXA-derived variable percentage trunk fat/percentage limb fat (AUC = 0.647). Conclusions We were able to develop simple, anthropometric measures for defining lipoatrophy and lipohypertrophy, using a sample of black HIV-infected South African women with DXA scans. This is of particular relevance in resource limited settings, where health professionals need simple and inexpensive methods of diagnosing patients with lipoatrophy and lipohypertrophy.
    AIDS Research and Therapy 08/2014; 11(1):26. DOI:10.1186/1742-6405-11-26 · 1.46 Impact Factor
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    • "Side effects due to ART have been previously associated with risk of becoming LTFU, particularly in the earlier stages of ART [12], [21], [26], [27]. The use of stavudine-based first line regimens in Malawi at the time of the study may have influenced the prevalence of side effects although access to second-line drugs remains limited [21], [71], [72]. While there were differences in proportions across the types reported, the highest proportion of side effects were noted in Early visits. "
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    ABSTRACT: Background Identifying follow-up (FU) visit patterns, and exploring which factors influence them are likely to be useful in determining which patients on antiretroviral therapy (ART) may become Lost to Follow-Up (LTFU). Using an operation and implementation research approach, we sought 1) to describe the timing of FU visits amongst patients who have been on ART for shorter and longer periods of time; and 2) to determine the median time to late visits, and 3) to identify specific factors that may be associated with these patterns in Zomba, Malawi. Methods and Findings Using routinely collected programme monitoring data from Zomba District, we performed descriptive analyses on all ART visits among patients who initiated ART between Jan. 1, 2007–June 30, 2010. Based on an expected FU date, each FU visit was classified as early (≥4 day before an expected FU date), on time (3 days before an expected FU date/up to 6 days after an expected FU date), or late (≥7 days after an expected FU date). In total, 7,815 patients with 76417 FU visits were included. Ninety-two percent of patients had ≥2 FU visits. At the majority of visits, patients were either on time or late. The median time to a first late visit among those with 2 or more visits was 216 days (IQR: 128–359). Various patient- and visit-level factors differed significantly across Early, On Time, and Late visit groups including ART adherence and frequency of, and type of side effects. Discussion The majority of patients do not demonstrate consistent FU visit patterns. Individuals were generally on ART for at least 6 months before experiencing their first late visit. Our findings have implications for the development of effective interventions that meet patient needs when they present early and can reduce patient losses to follow-up when they are late. In particular, time-varying visit characteristics need further research.
    PLoS ONE 07/2014; 9(7):e101875. DOI:10.1371/journal.pone.0101875 · 3.23 Impact Factor
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    • "This drug was crucial in rolling out combined antiretroviral therapy (cART) in low-income setting as in Sub-Saharan Africa (SSA) for its low price and good efficacy in suppressing replication of HIV. However, severe side effects associated with stavudine use, such as peripheral neuropathy, lactic acidosis and lipodystrophy have been shown to be frequent and accumulating over time in several African cohorts [2,3]. In the United States, stavudine was already removed in 2004 from the list of preferred first-line antiretroviral drugs recommended by the US Department of Health and Human Services (DHHS) [4]. "
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    ABSTRACT: Since 2010, World Health Organization (WHO) guidelines discourage using stavudine in first-line regimens due to frequent and severe side effects. This study describes the implementation of this recommendation and trends in usage of antiretroviral therapy combinations in a cohort of HIV-positive patients in rural Tanzania. We analyzed longitudinal, prospectively collected clinical data of HIV-1 infected adults initiating antiretroviral therapy within the Kilombero Ulanga Antiretroviral Cohort (KIULARCO) in Ifakara, Tanzania from 2007-2011. This analysis included data of 3008 patients. Median age was 38 (interquartile range [IQR] 31-45) years, 1962 (65.2%) of all subjects were female, and median CD4+ cell count at enrollment was 168 cells/mm3 (IQR 81-273). The percentage of prescriptions containing stavudine in initial regimens fell from a maximum of 75.3% in 2008 to 10.7% in 2011. TDF/FTC/EFV became available in 2009 and was used in 41.9% of patients initiating cART in 2011. An overall on-treatment analysis revealed that d4T/3TC/NVP and AZT/3TC/EFV were the most prescribed combinations in each year, including 2011 (674 [36.5%] and 641 [34.7%] patients, respectively). Of those receiving stavudine in 2011, 659 (89.1%) initiated it before 2011. Initial cART with stavudine declined to low levels according to recommendations but the overall use of stavudine remained substantial, as individuals already on cART containing stavudine were not changed to alternative drugs. Our findings highlight the critical need to exchange stavudine in treatment regimens of patients who initiated therapy in earlier years.
    BMC Infectious Diseases 02/2014; 14(1):90. DOI:10.1186/1471-2334-14-90 · 2.61 Impact Factor
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