Why is Zerit still being used in developing countries?

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From Clinical Care OptionsThe Evolving Role of Stavudine as Part of Initial Antiretroviral Therapy in Resource-Constrained SettingsArnaldo D. Casiró, MDHead, Department of Infectious Diseases Teodoro Alvarez HospitalBuenos Aires, ArgentinaDespite long-standing evidence of its adverse effects, stavudine has remained a common component of antiretroviral therapy regimens prescribed where healthcare resources are scarce. In 2010, the World Health Organization (WHO) recommended new measures to scale up HIV treatment programs in resource-constrained settings, including earlier initiation of antiretroviral therapy and the use of simpler and less toxic antiretrovirals.[1] Chief among the latter was the advice that stavudine be phased out of first-line therapy regimens, to be replaced by either

tenofovir or zidovudine.Use of stavudine is associated with increased risk of lipid abnormalities as well as a number of toxicities believed to result from the drug’s effects on mitochondria, including lipoatrophy, peripheral neuropathy, lactic acidosis, and pancreatitis.[2]Data from randomized trials of first-line HAART indicate that stavudine-containing therapy is less well tolerated than regimens that include either tenofovir or zidovudine, although they provide comparable virologic efficacy. Metabolic abnormalities have been the key differentiator. In the GS 903 study, tenofovir was associated with improved lipid profiles and less lipodystrophy than stavudine when each was combined with lamivudine and efavirenz.[3] In A5005S, a metabolic substudy of ACTG 384, use of zidovudine/lamivudine was superior to stavudine and didanosine regarding limb fat loss[4]; significantly greater increases in total cholesterol, non–high density lipoprotein (HDL) cholesterol, and HDL cholesterol also occurred with stavudine and didanosine regimens.[5] Research conducted in resource-limited settings supports this picture. Studies from India, Rwanda, and Senegal have reported high rates of lipoatrophy in patients receiving stavudine-containing therapy,[6-8] whereas a recent report from Lesotho found that in patients treated with stavudine, the risk of a toxicity-driven regimen change was almost 6-fold higher

than in those receiving tenofovir.[9]The low cost of stavudine has enabled the scale-up of HIV treatment programs in underresourced settings, and the drug continues to be an important component of antiretroviral therapy prescribed in this context. A fixed-dose triple-drug regimen of stavudine/lamivudine/nevirapine has been used as standard first-line therapy in many developing countries. Although usage has declined significantly, the WHO estimates that 56% of adults receiving antiretroviral therapy in low- and middle-income countries in December 2008 were receiving stavudine compared with 8% receiving tenofovir-containing therapy.[10] This headline figure disguises substantial

geographical variations. The ART in Lower Income Countries collaboration reported that in 2005-2006, 82% of patients who initiated antiretroviral therapy in sub-Saharan Africa started with a stavudine-containing regimen compared with 66% in Asia and 15% in South America.[11]For those countries where the extent of stavudine use remains significant, what are the likely practical challenges of adopting the WHO recommendations? The WHO acknowledges that the feasibility of phasing out stavudine use within individual countries will be influenced by the size of the population that becomes candidates for treatment, given the parallel recommendation that therapy be started earlier. Patient comorbidities and pregnancy status will influence whether providers opt for tenofovir

or zidovudine; tenofovir is preferred in patients with hepatitis B virus coinfection or anemia whereas zidovudine is the first choice for pregnant women. In addition, the availability of fixed-dose combination treatments should be considered, as this varies between countries. The once-daily dosing of tenofovir or tenofovir/emtricitabine may be an advantage over zidovudine, which is dosed twice daily. There is also the potential for once-daily nevirapine to be coformulated with tenofovir/emtricitabine in a fixed-dose regimen.Clearly, the cost of therapy is a central concern. Zidovudine is, of course, off patent but its manufacturer reports providing fixed-dose zidovudine/lamivudine at low cost in more than 80 of the world’s poorest countries.[12] The

manufacturer of tenofovir has developed a system of tiered pricing that discounts price in low- and middle-income countries.[13] However, these prices may not be low enough to drive uptake in some of the poorest settings. A cost-effectiveness model developed for a hypothetical South African HIV cohort estimated incremental cost and cost-effectiveness of replacing stavudine with tenofovir in first-line therapy.[14] At a tenofovir price of $17.00/month, savings on management of stavudine toxicity would offset approximately 20% of the higher price of tenofovir. The change to tenofovir became cost neutral at a price of $6.17/month and was cost effective by World Health Organization standards[15] (ie, incremental cost

< 3 times the per capita gross domestic product) at a price of $12.94/month. A model constructed based on an Indian HIV-positive population found that initiating therapy with tenofovir was more economically efficient than either stavudine or zidovudine and cost-effective by international standards.[16]The global HIV epidemic needs less expensive drugs. The challenge for all sectors of society is to work together to expand antiretroviral access programs and enable lowering of drug prices. All antiretrovirals present a risk of toxicity but some are better tolerated than others. At this time, we have enough information—and enough treatment options—to allow us to choose those drugs we know to be the safest.Arnaldo Casiró, MD, has disclosed that he has received funds for research support from Abbott Laboratories, Gilead Sciences, Jannsen, Pfizer, and Schering-Plough. He has received funds for non-CME services from Bristol-Myers Squibb, Gilead Sciences, Jannsen, Merck Sharp & Dohme, Pfizer, and ViiV and consulting fees from Merck Sharp & Dohme. Poppa (Contributing Writer) has disclosed that she has served as a consultant to ViiV.References1. World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach—2010 rev. Available at: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. Accessed April 27, 2011.2. McComsey G, Lonergan JT. Mitochondrial dysfunction: patient monitoring and toxicity management. J Acquir Immune Defic Syndr. 2004;37(suppl

1):S30-S35.3. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191-201.4. Dubé MP, Komarow L, Mulligan K, et al. Long-term body fat outcomes in antiretroviral-naive participants randomized to nelfinavir or efavirenz or both plus dual nucleosides. Dual X-ray absorptiometry results from A5005s, a substudy of Adult Clinical Trials Group 384. J Acquir Immune Defic Syndr. 2007;45:508-514.5. Dubé MP, RA, Tebas P, et al. Glucose metabolism, lipid, and body fat changes

in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS. 2005;19:1807-1818.6. Pujari SN, Dravid A, Naik E, et al. Lipodystrophy and dyslipidemia among patients taking first-line, World Health Organization-recommended highly active antiretroviral therapy regimens in Western India. J Acquir Immune Defic Syndr. 2005;39:199-202.7. van Griensven J, De Naeyer L, Mushi T, et al. High prevalence of lipoatrophy among patients on stavudine-containing first-line antiretroviral therapy regimens in Rwanda. Trans R Soc Trop Med Hyg. 2007;101:793-798.8. Mercier S, Gueye NF,

Cournil A, et al. Lipodystrophy and metabolic disorders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal: a case-control study. J Acquir Immune Defic Syndr. 2009;51:224-230.9. Bygrave H, Ford N, van Cutsem G, et al. Implementing a tenofovir-based first-line regimen in rural Lesotho: clinical outcomes and toxicities after two years. J Acquir Immune Defic Syndr. 2011;56:e75-78.10. World Health Organization. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector: progress report 2009. Available at: http://www.who.int/hiv/pub/tuapr_2009_en.pdf. Accessed April 27, 2011.11. ART-LINC Collaboration of International Databases to Evaluate AIDS (IeDEA), Keiser O, Anastos K, et al. Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America. Trop Med Int Health. 2008;13:870-879.12. ViiV Healthcare Web site. Not-for-profit pricing. Available at: http://www.viivhealthcare.com/access/not-for-profit-pricing.aspx. Accessed

April 27, 2011.13. Gilead Web site. Enabling access to treatment. Available at: http://www.gilead.com/enabling_access. Accessed April 27, 2011.14. Rosen S, Long L, Fox M, Sanne I. Cost and cost-effectiveness of switching from stavudine to tenofovir in first-line antiretroviral regimens in South Africa. J Acquir Immune Defic Syndr. 2008;48:334-344.15. World Health Organization. CHOosing Interventions that are Cost Effective

(WHO-CHOICE). Available at: http://www.who.int/choice/costs/CER_thresholds/en/index.html. Accessed April 28, 2011.16. Bender MA, Kumarasamy N, Mayer KH, et al. Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India. Clin Infect Dis. 2010;50:416-425. Regards, VergelPoWeRUSA.org