Toxicity Associated with Stavudine Dose Reduction from 40 to 30 mg in First-Line Antiretroviral Therapy (original) (raw)
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Transactions of the Royal Society of Tropical Medicine and Hygiene, 2010
Please cite this article in press as: van Griensven J, et al. Stavudine-and nevirapine-related drug toxicity while on generic fixed-dose antiretroviral treatment: incidence, timing and risk factors in a three-year cohort in Kigali, Rwanda. Trans R a b s t r a c t This cohort study was conducted to report on the incidence, timing and risk factors for stavudine (d4T)-and nevirapine (NVP)-related severe drug toxicity (requiring substitution) with a generic fixed-dose combination under program conditions in Kigali, Rwanda. Probability of 'time to first toxicity-related drug substitution' was estimated using the Kaplan-Meier method and Cox-proportional hazards modeling was used to identify risk factors. Out of 2190 adults (median follow-up: 1.5 years), d4T was replaced in 175 patients (8.0%) for neuropathy, 69 (3.1%) for lactic acidosis and 157 (7.2%) for lipoatrophy, which was the most frequent toxicity by 3 years of antiretroviral treatment (ART). NVP was substituted in 4.9 and 1.3% of patients for skin rash and hepatotoxicity, respectively. Use of d4T 40 mg was associated with increased risk of lipoatrophy and early (<6 months) neuropathy. Significant risk factors associated with lactic acidosis and late neuropathy included higher baseline body weight. Older age and advanced HIV disease increased the risk of neuropathy. Elevated baseline liver tests and older age were identified as risk factors for NVP-related hepatotoxicity. d4T is associated with significant long-term toxicity. d4T-dose reduction, increased access to safer ART in low-income countries and close monitoring for those at risk are all relevant strategies. (J. van Griensven). role in the scale-up of ART in these countries and still remains the pillar of many national ART programs in sub-Saharan Africa.
Journal of AIDS and …, 2010
This study compared the efficacy and tolerability of stavudine at two dose levels in patients attending a HIV Comprehensive Care Centre in Kenya. Data were collected retrospectively from the records of 810 adult patients. Fewer stavudine related adverse effects were seen in patients 60 kg treated with 30 mg stavudine compared to those who received 40 mg (4.2 vs 16.7%, p < 0.001). Patients < 60 kg were more likely to experience drug toxicity than those 60 kg when given 30 mg stavudine (12.8 vs 4.2%, p < 0.001). Occurrence of any adverse drug reaction was significantly associated with severe immunosuppression (HR =1.45, CI: 0.86 -2.45, p < 0.001), co-morbidities (HR = 2.16, CI: 1.06 -4.38, p < 0.001) and treatment with isoniazid (HR = 2.07, CI: 1.09 -3.96, p < 0.001). The onset of drug related toxicities was principally in the first year of commencing therapy. Similar immunologic outcomes were demonstrated across all the treatment groups with median CD4 cell counts after 12 months of treatment more than doubling for patients in all the study cohorts. The findings support the use of combination antiretroviral therapy regimens containing low dose stavudine in Kenya.
Journal of Virology and Emerging Diseases ( ISSN 2471-822X ), 2016
Stavudine at a dose of 30mg has been in use for more Thana decade. Its toxicity remains a challenge and phase out has picked up. However, the information about viral load suppression (VLS) at once-a-day dosing is lacking. A prospective open-label randomized controlled study was conducted. Methods: Naïve HIV infected patients were equally randomized either to receive stavudine 30mg once-daily or zidovudine standard dose regimens. Viral load, hemoglobin (Hb), alanine amino transferase (ALT), Body Mass Index (BMI), opportunistic infections (OIs) at baseline and six months were determined. Changes at baseline and six months were compared within and between-groups. Our outcome was the proportion of patients who attained VLS< 400 copies/mL at six months. Results: Four hundred and eighty three patients aged ≥ 18 years were analyzed. The overall mean standard deviation (SD) age was of 39 (9) years, 41 (9) and 38 (9) for males and females respectively. The two groups were similar in demographic, clinical and other laboratory indices at baseline. At six months, VLS< 400 copies/mL was 73.2%, there was no statistically significant differences been groups. There was no statistically significant differences been males and females. Patients with age >40 years were more likely to have VLS by 8% compared to young ones, risk ratio (95% CI) being 0.921 (0.829, 1.023; p=0.1275) Conclusion: Viral load suppression for stavudine 30 mg once-a-day was similar to zidovudine standard regimen. However, long follow up period is recommended to determine efficacy and long term side effects at our recommended dose.
Antiretroviral therapy in resource-limited settings: is there still a role for stavudine?
Antiviral Therapy, 2012
Phanuphak et al. compared three strategies for first-line antiretroviral therapy in 150 Thai patients: initiating therapy with zidovudine (AZT), tenofovir disoproxil fumarate (TDF), or a 24-week lead-in phase with stavudine (d4T) followed by a switch to AZT. Those taking d4T had higher haemoglobin levels and CD4 + T-cell counts without an increase in neuropathic symptoms, peripheral neuropathy or lipoatrophy compared with those on AZT. Because AZT is associated with more short-term side effects and toxicity than d4T, and because most d4T toxicity occurs only after long-term use, this approach may have advantages over initial use of AZT. However, TDF-based regimens, while more expensive, are more effective, better tolerated, less toxic, less likely to lead to cross-resistance, and possibly more cost-effective. The goal in resource-limited settings should be to move away from use of thymidine analogues in first-line regimens.
Stavudine Toxicity in Adult Longer-Term ART Patients in Blantyre, Malawi
PLoS ONE, 2012
Background: Stavudine is an effective and inexpensive antiretroviral drug, but no longer recommended by WHO for firstline 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. Methods: 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. Results: 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 personyears (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. Conclusion: 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.
Journal of HIV and AIDS ( ISSN 2380-5536 ), 2015
Objectives: To compare the immunological and clinical effects of a further reduction of stavudine dose to 30 mg once-daily with that of a standard zidovudine containing antiretroviral therapy (ART) regimen in a prospective, open-label randomized controlled study. Methods: Naïve HIV infected patients were equally randomized to receive either stavudine 30 mg once-daily or a standard dose zidovudine containing regimen. CD4+ T-cell counts, Haemoglobin (Hb), alanine aminotransferase (ALT), Body Mass Index (BMI), WHO stage and patients' morbidity at baseline, three and six months were determined. Changes between baseline and three as well as six months follow-up were compared within-and between-groups. Results: Five hundred and twenty patients aged ≥ 18 years were included. Males were 159 (30.6%), with the mean (SD) age of 39 (9) years. Within group comparison indicated that there were statistically significant increases in mean CD4+ cell counts, BMI, and Hb (p<0.0001) at 3 and 6 months from the values at baseline in both groups, but there were not significantly different between groups. Furthermore, there was no statistically significant difference between groups in terms of occurrence of opportunistic infections (OIs) however, there was significant decrease of OIs for subsequent follow up time points compared to baseline status. The overall median adherence rate was 94% (IQR 94%, 98%) in both groups, but patients in the stavudine group had better adherence compared to those in the zidovudine group, p<0.0001. Additionally, liver damage at 6 months, as indicated by elevated ALT, was more likely with the zidovudine based regimen, p <0.0001. There was no statistically significant difference in ALT elevations between the groups at 3 months. Conclusion: The immunological and clinical outcomes following a regimen employing a reduced dose of stavudine to 30 mg once-daily were similar to those of a standard zidovudine-based antiretroviral regimen.