Antiretroviral Therapy–Associated Toxicities in the Resource‐Poor World: The Challenge of a Limited Formulary (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.
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.
Scaling Up Antiretroviral Therapy in Resource-Limited Settings
World Health, 2002
Annex 3. Characteristics of NNRTI-based regimens ___ Annex 4. Characteristics of triple NsRTI-based regimens _______________________________ Annex 5. Characteristics of PI-based regimens _______ Annex 6. Characteristics of NNRTI-, triple NsRTI-and PI-based regimens in special populations ____ Annex 7. Antiretroviral dosage regimens for adults and adolescents ___________________ Annex 8A. Antiretroviral drug interactions ____________ Annex 8B. Drug interactions between non-nucleoside reverse transcriptase inhibitors and protease inhibitors _______________________ Annex 8C. Drug interactions involving non-nucleoside reverse transcriptase inhibitors and protease inhibitors of relevance to poor countries ____ Annex 9. Choice of antiretroviral drugs in HIV-infected pregnant women _____________ Annex 10. Summary of paediatric drug formulations and doses ______________________________ Annex 11A. Antiretroviral drug toxicity ________________ Annex 11B. Monitoring and management of antiretroviral drug toxicity ________________ References _________________________________________ Interim WHO Antiretroviral Treatment Working Group, Geneva, 19
Management of antiretroviral drug toxicity
Current Opinion in HIV and AIDS, 2006
Purpose of review With the emergence of very potent antiretroviral regimens, the major limitation to the success of treatment is now the tolerability of drugs, which can ultimately affect adherence. It is important, therefore, to review the current understanding on antiretroviral drug toxicity, and examine key recent data that can inform the successful avoidance or management of such toxicities. Recent findings A common theme of recent research has focussed on the genetic predisposition to important immediate side-effects, such as abacavir hypersensitivity, nevirapine hepatotoxicity, efavirenz neurotoxicity and hyperbilirubinemia with atazanavir. Long-term toxicities such as body-composition changes and hyperlipidemia have been more closely linked to thymidine analogues and certain protease inhibitors. The management of these toxicities has also been clarified by studies addressing switching antiretroviral drugs or specific treatments for metabolic syndromes. Summary Recent data emphasize the need for the prevention of antiretroviral toxicity by the avoidance of some drugs in certain genetically predisposed populations or by the avoidance of entire classes if possible. In addition, recent studies emphasize the importance of ongoing research to determine the emergence of additional toxicities, as new drugs emerge and achieve widespread use.
Obstacles and Opportunities to Improve Antiretroviral Regimen Access in Low-Income Countries
Current HIV/AIDS Reports, 2010
Increasing evidence suggests that dramatically increasing access to effective and well-tolerated antiretroviral medications is key to reversing the HIV pandemic. Currently used first-line therapies in developing countries have multiple toxicities that cause significant morbidity and mortality. New World Health Organization HIV treatment guidelines support earlier treatment initiation and the use of less toxic first-line therapies. Adoption of these guidelines requires political and financial commitment from multiple stakeholders including country governments and donors. This review summarizes the major adverse effects associated with commonly used ARV regimens in low-income countries and also analyzes some of the barriers and potential solutions that affect the ability of low-income countries to implement the new World Health Organization guidelines.
PLoS ONE, 2013
Background: Tenofovir (TDF) is part of the WHO recommended first-line antiretroviral therapy (ART); however, there are limited data comparing TDF to other nucleoside reverse transcriptase inhibitors in resource-limited-settings. Using a routine workplace and community-based ART cohort in South Africa, we assessed single drug substitution, HIV RNA suppression, CD4 count increase, loss-from-care, and mortality between TDF, stavudine (d4T) 30 mg dose, and zidovudine (AZT). Methods: In a prospective cohort study we included ART naïve patients aged $17 years-old who initiated ART containing TDF, d4T, or AZT between 2007 and 2009. For analysis of single drug substitutions we used a competing-risks time-to-event analysis; for loss-from-care, mixed-effect Poisson modeling; for HIV RNA suppression, competing-risks logistic regression; for CD4 count slope, mixed-effects linear regression; and for mortality, proportional hazards modeling. Results: Of 6,196 patients, the initial drug was TDF for 665 (11%), d4T for 4,179 (68%), and AZT for 1,352 (22%). During the first 6 months of ART, the adjusted hazard ratio for a single drug substitution was 2.3 for d4T (95% confidence interval [CI]: 0.27, 19) and 5.2 for AZT (95% CI: 1.1, 23), compared to TDF; whereas, after 6 months, it was 10 (95% CI: 5.8, 18) and 4.4 (95% CI: 2.5, 7.8) for d4T and AZT, respectively. Virologic suppression was similar by agent; however, CD4 count rise was lowest for AZT. The adjusted hazard ratio for loss-from-care, when compared to TDF, was 1.5 (95% CI: 1.1, 1.9) for d4T and 1.2 (95% CI: 1.1, 1.4) for AZT. The adjusted hazard ratio for mortality, when compared to TDF, was 2.7 (95% CI: 2.0, 3.5) and 1.4 (95% CI: 1.3, 1.5) and for d4T and AZT, respectively. Discussion: In routine care, TDF appeared to perform better than either d4T or AZT, most notably with less drug substitution and mortality than for either other agent.