Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis.

INTRODUCTION: Since 2002, the WHO has recommended either nevirapine (NVP) or efavirenz (EFV) as part of first-line antiretroviral therapy. These two drugs are known to have differing toxicity profiles, but the risk of these toxicities overall is not well established. METHODS: We systematically reviewed adverse events among treatment-naive HIV-positive adults and children receiving either NVP or EFV as part of first-line antiretroviral therapy. The primary outcome was drug discontinuation as a result of any adverse event; specific toxicities were evaluated as secondary outcomes. Point estimates and 95% confidence intervals (95% CIs) were calculated and proportions and odds ratios (ORs) pooled using fixed-effects meta-analysis. RESULTS: We reviewed data on 26,446 adults and 3975 children from eight randomized trials and 26 prospective cohorts. Overall, adults on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95% CI 1.9-2.6). Severe hepatotoxicity (OR 3.3, 95% CI 2.5-4.2), severe skin toxicity (OR 3.9, 95% CI 2.5-5.4), and severe hypersensitivity reactions (OR 2.4, 95% CI 1.9-2.9) were more likely to occur among patients on NVP. Patients receiving EFV were more likely to experience severe central nervous system events (OR 3.4, 95% CI 2.1-5.4). Similar associations were seen in children. DISCUSSION: Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations. This finding supports a move toward EFV-based therapy as the preferred first-line treatment regimen for HIV treatment within a public health approach.

Utilization patterns and projected demand of antiretroviral drugs in low- and middle-income countries.

Background. The rapid scale-up of antiretroviral therapy in resource-limited settings has greatly increased demand for antiretroviral medicines and raised the importance of good forward planning, especially in the context of the new 2010 WHO treatment guidelines. Methods. Forecasting of the number of people receiving antiretroviral therapy from 2010 to 2012 was produced using three approaches: linear projection, country-set targets, and a restricted scenario. Two additional scenarios were then used to project the demand for various antiretroviral medicines under a fast and slower phase-out of stavudine. Results. We projected that between 7.1 million and 8.4 million people would be receiving ART by the end of 2012. Of these, 6.6% will be on second-line therapy. High variation in forecast includes reductions in the demand for d4T and d4T increases in the demand for tenofovir, emtricitabine followed by efavirenz, ritonavir, zidovudine and lopinavir; lamivudine, atazanavir, and nevirapine. Conclusion. Despite the global economic crisis and in response to the revised treatment guidelines, our model forecasts an increasing and shifting demand for antiretrovirals in resource-limited settings not only to provide treatment to new patients, but also to those switching to less toxic regimens.

Use of antiretroviral therapy in resource-limited countries in 2006: distribution and uptake of first- and second-line regimens.

OBJECTIVE: To address the information gap on current use of antiretroviral drugs (ARTs) in developing countries. METHODS: The AIDS Medicines and Diagnostics Service of the World Health Organization (WHO) carried out a multi-country survey in early 2006. Questionnaires covered the use of first- and second-line regimens in adults and children, and the rates of switching from first-line to second-line regimen. Weighted percentages of use of ARTs across the cohort of adults and children were calculated and correlated with 2006 WHO guidelines. A second analysis compared demand for ARTs with rates of production of active pharmaceutical ingredients. RESULTS: Twenty-three countries (96%) returned the questionnaires, representing 53% of relevant patients in developing countries as of June 2006, and comprising 92% adults and 8% children receiving ARTs. Response rates were highest for questions regarding first-line use and lowest for those regarding pediatric regimens. The distribution of first-line: second-line use was 96%: 4% among adults and 99%: 1% among children. For adults, 95% of those receiving first-line treatment, but only 25% of those receiving second-line treatment, were on regimens consistent with those preferred by the WHO. Among first-line users, the most common regimen (61%) was stavudine+lamivudine+nevirapine. Among second-line users, abacavir+didanosine+lopinavir/ritonavir was the most common regimen (24%). Among children, compliance with WHO guidelines was high among the respondents, with zidovudine+lamivudine+nevirapine reported as the main option. Estimates of first-year switching rate were highly variable, ranging from 1% to 15%, with only ten responses. Comparison of supply and demand showed that the stated production capacity for active pharmaceutical ingredients is sufficient to meet current demands for ARTs. CONCLUSION: This survey has provided valuable information on the uptake of ARTs in developing countries and will help forecast future demand. Reporting for second-line and pediatric antiretroviral therapy should improve as national programs gain more experience. The current availability of active pharmaceutical ingredients appears to be sufficient to meet current demand. Further work is needed for an understanding of switching rates.

Forecast of demand for antiretroviral drugs in low and middle-income countries: 2007-2008.

BACKGROUND: Middle and low-income countries have scaled up HIV treatment in the past 5 years. To maintain this effort, information regarding the amounts and types of drugs is needed. Shortages or overstock of active pharmaceutical ingredients make the scale-up efforts more difficult and costly. To inform global planning and implementation, we estimate the volume of current and future demand for active pharmaceutical ingredients for first and second-line antiretroviral drugs. METHODS: Using regression analysis and documented assumptions, we estimated the number of individuals receiving antiretroviral drugs to 2008. The volume of active pharmaceutical ingredients was calculated using two methods: a normative approach modelling implementation of country-specific guidelines, and an empirical model projecting current trends in drug use estimated by a survey of country HIV programmes. RESULTS: The number of patients treated was estimated to reach 3.38 million by the end of 2008, of which 94.6% would be on first-line and 5.4% on second-line treatment. The largest estimated absolute demand volumes for 2008 were for nevirapine, lamivudine, and zidovudine using either approach; the largest proportional increases in 2007-2008, were observed for emtricitabine, tenofovir, indinavir, and nelfinavir. The gap between normative and empirical estimates was greatest (most positive) for tenofovir, zidovudine, didanosine, and smallest (most negative) for saquinavir and nelfinavir. CONCLUSION: A comparison of the results from the normative and empirical demand quantities suggests that more tenofovir, zidovudine and didanosine would be required if national treatment guidelines were fully implemented, whereas the countries seem to be using more saquinavir and nelfinavir than would be required by their current guidelines.