Stavudine in First-Line Antiretroviral Regimens in Resource-Limited Settings: Time for a Better Solution

HIV TherapyVol. 3, No. 2 EditorialFree AccessStavudine in first-line antiretroviral regimens in resource-limited settings: time for a better solutionJohn A Bartlett and Venance P MaroJohn A Bartlett† Author for correspondenceBox 3238, Duke University Medical Center, Durham, NC 27710, USA and, Kilimanjaro Christian Medical Centre, Kilimanjaro Christian Medical College, Tanzania. and Venance P MaroKilimanjaro Christian Medical Centre, Kilimanjaro Christian Medical College, TanzaniaPublished Online:6 Mar 2009https://doi.org/10.2217/17584310.3.2.109AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail By the end of 2007, an estimated 3 million HIV-infected individuals had received antiretroviral treatment (ART) in resource-limited settings (RLS) [101]. This represents a remarkable achievement through the cooperative efforts of international donors, such as the President's Emergency Plan for AIDS Relief (PEPFAR), the WHO, the Global Fund to Fight AIDS, Tuberculosis and Malaria, in-country Ministries of Health, and non-governmental organizations. The benefits of ART in RLS are clear with dramatic improvements in survival and fewer HIV-associated complications [1]. Despite these heroic efforts, many HIV-infected persons do not have access to ART; WHO estimates that in late 2007 approximately 30% of HIV-infected persons in need globally were actually receiving ART [101]. The number of individuals in need of ART may expand even further given the results of recent studies which demonstrate survival benefit at higher CD4+ cell counts [2]. Therefore, massive scale-up efforts must continue to meet the WHO goal of universal access by 2015 [101], and millions of HIV-infected persons will initiate first-line ART in the next 6 years. As leaders in clinical research and HIV medicine, we have an obligation to identify and provide the most effective and least toxic treatment regimens for those initiating ART.The mainstay of first-line ART is a fixed-dose combination of stavudine, lamivudine and nevirapine, and this combination has provided outstanding responses in suppressing plasma HIV RNA levels and increasing CD4+ cell counts. With the availability of generic products, the cost of this fixed-dose combination may be as low as US$100 per year [3]. The low manufacturing cost of stavudine itself has assisted in keeping the fixed-dose combination price at a minimal level (<3 US cents per 30 mg capsule) (see pages 29–30 in [102])Despite the antiretroviral effectiveness, low cost and wide availability of stavudine, there are reasons for concern relating to its considerable toxicity profile. In 2006, WHO recommended a decrease in dosage from 40 to 30 mg twice daily owing to drug-related peripheral neuropathy [103]. In addition to peripheral neuropathy, stavudine use has been associated with lipoatrophy [4], lactic acidosis [5], triglyceride elevations [4] and pancreatitis [5]. Peripheral neuropathy may be reported in up to 36% of persons in RLS receiving stavudine 40 mg twice daily (9% severe) [6], and despite the recent recommendations for a lower stavudine dose of 30 mg twice daily, peripheral neuropathy remains a common complication of treatment [7]. Lipoatrophy is increasingly prevalent among patients receiving fixed-dose stavudine, lamivudine and nevirapine in RLS, and in one Rwandan study 52% of patients had lipoatrophy, the majority being severely affected [8]. Lipoatrophy is stigmatizing through its alteration in physical appearance [9,10], and fat loss in the face may give treated patients the appearance of being ill, in contrast with their laboratory responses of virologic suppression and immunologic recovery. Ultimately, the body habitus changes associated with ART can lead to decreased adherence and the possibility of treatment failure and drug resistance [11,12]. Use of stavudine during pregnancy has been associated with cases of fatal lactic acidosis and hepatic steatosis [5]. Owing to these observations, stavudine has largely disappeared from use in first-line regimens in resource-rich settingsAs a consequence of these stavudine-related toxicities, alternative medications must be considered in first-line ART for use in RLS. Zidovudine has a record of extensive use in RLS, but can exacerbate prevalent pre-treatment anemia and is also associated with lipoatrophy, (albeit slightly delayed in comparison to stavudine) [13]. Other alternatives in RLS could include abacavir, didanosine and tenofovir. A randomized trial of zidovudine, lamivudine and efavirenz versus tenofovir, emtricitabine and efavirenz demonstrated improved virologic outcomes and better tolerability for the tenofovir and emtricitabine-containing combination [13]. A recently completed randomized trial suggested that in subjects with baseline plasma HIV RNA levels greater than 100,000 copies/ml, tenofovir and emtricitabine were associated with better virologic suppression than abacavir and lamivudine [14]. In resource-rich settings, tenofovir and emtricitabine are prescribed most commonly as components of first-line regimens, and now represent the preferred nucleoside or nucleotide reverse transcriptase inhibitors in the latest DHHS Guidelines [104]. Tenofovir is not a panacea, and can be associated with drug-related toxicities including renal failure, Fanconi's syndrome, changes in bone-mineral density, body habitus changes, lactic acidosis and hepatic steatosis, and post-treatment discontinuation flares of hepatitis B [15]. Its safety has not been established during pregnancy, and there is very limited data on its use in HIV-infected children. There are drug interactions between tenofovir, didanosine and atazanavir which require dose adjustments. However, there are clinical trial results that suggest that tenofovir-containing regimens are well-tolerated in RLS [16]. In the Development of Anti-Retroviral Therapy (DART) study, 2469 subjects from Uganda and Zimbabwe received zidovudine, lamivudine and tenofovir as first-line ART, and renal insufficiency with severe impairment of the glomerular filtration rate was infrequent [17]. In a modeling study examining the toxicities associated with stavudine and tenofovir-containing regimens in South Africa, the results suggested that after 2 years 82.5% of those beginning stavudine-containing regimens and 97.5% of those beginning tenofovir-containing regimens would be on their original treatments [18]. The costs associated with the 15% difference between the regimens and subsequent toxicity management may be considerable when applied to large populationsWhy then is tenofovir not currently being employed as a component of first-line ART in RLS? The simple answers are cost and slow increases in access. In countries which are eligible for Gilead's (Foster City, CA, USA) lowest price for tenofovir, its use in first-line ART would increase cost by four- to six-times (see pages 31–32 in [102]). In addition, as of February 2009, Gilead had registered tenofovir in only 71 of the 97 countries eligible for their preferred pricing program [Venkat Ramanan, Gilead Sciences, Inc., February 2009, Pers. Comm.], up from 25 countries in June 2007 [102]. Gilead has offered voluntary licenses to Indian generic manufacturing companies, but they are limited in their ability to export only to the least developed countries. Although four companies are now producing generic tenofovir, the competition has not yet reached a level where dramatic cost savings have been realized. A cost–effectiveness analysis of replacing stavudine with tenofovir in first-line ART suggested that at a tenofovir cost of US$17 per month, the cost savings of avoiding stavudine-related toxicity management would cover approximately 20% of the increased cost for tenofovir acquisition [18]. However, this model was very sensitive to declines in tenofovir cost, and if the cost fell to US$12.94 per month, it would be judged to be highly cost effective to incorporate tenofovir into all first-line regimens [18]. A recent update suggests that the sale price of tenofovir produced by Matrix Laboratories LTD is US$12–13.66 per month, crossing the threshold of cost-effectiveness [Venkat Ramanan, Gilead Sciences, Inc., February 2009, Pers. Comm.].The need for replacing stavudine in first-line ART regimens is high, and the time is now. The consideration of tenofovir as a substitute is justified, and it is likely that competition in generic tenofovir production will increase availability and decrease cost. It is our responsibility to advocate with policy makers for the optimal treatment first-line treatment for all in need.Financial & competing interests disclosureJA Bartlett has received research funding, consulting fees and speaking honoraria from Abbott Laboratories. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosedThe authors acknowledge and appreciate the assistance of Kelly Deal, MPH in researching background information for this editorial.No other writing assistance was utilized in the production of this manuscriptBibliography1 Weidle P, Malamba S, Mwebaze R et al.: Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival and drug resistance. Lancet360,34–40 (2002).Crossref, Medline, CAS, Google Scholar2 Kitahata M: Initiating rather than deferring HAART at a CD4+ count betwen 351–500 cells/mm3 is associated with improved survival. Presented at: 48th Interscience Conference on Antimicrobial Agents and Chemotherapy. 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Synr.48,334–344 (2008).Crossref, Medline, Google Scholar101 UNAIDS: Report on the global AIDS epidemic (2008). www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global_report.aspGoogle Scholar102 Medecins sans frontieres. www.accessmed-msf.orgGoogle Scholar103 Addendum to 2006 WHO guidelines on antiretroviral therapy HIV infection for adults and adolescents. www.who.int/entity/hiv/art/ARTadultsaddendum.pdfGoogle Scholar104 DHHS guidelines for treatment-naive patients. www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdfGoogle ScholarFiguresReferencesRelatedDetailsCited ByTargeting of the Purine Biosynthesis Host Cell Pathway Enhances the Activity of Tenofovir Against Sensitive and Drug-Resistant HIV-16 August 2013 | Journal of Infectious Diseases, Vol. 208, No. 12The K65R mutation in HIV-1 reverse transcriptase: genetic barriers, resistance profile and clinical implicationsBluma G Brenner & Dimitrios Coutsinos30 October 2009 | HIV Therapy, Vol. 3, No. 6 Vol. 3, No. 2 Follow us on social media for the latest updates Metrics Downloaded 162 times History Published online 6 March 2009 Published in print March 2009 Information© Future Medicine LtdFinancial & competing interests disclosureJA Bartlett has received research funding, consulting fees and speaking honoraria from Abbott Laboratories. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosedThe authors acknowledge and appreciate the assistance of Kelly Deal, MPH in researching background information for this editorial.No other writing assistance was utilized in the production of this manuscriptPDF download

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