HIV suppression with stavudine 30 mg versus 40 mg in adults over 60 kg on antiretroviral therapy in South Africa
Hoffmann, Christopher Ja,b; Charalambous, Salomea; Fielding, Katherine Ld; Innes, Craiga; Chaisson, Richard Eb; Grant, Alison Dd; Churchyard, Gavin Ja,c,d
aAurum Institute for Health Research, Johannesburg, South Africa
bJohns Hopkins School of Medicine, Baltimore, USA
cCentre for AIDS Research in South Africa, University of KwaZulu-Natal, Durban, South Africa
dLondon School of Hygiene and Tropical Medicine, London, UK.
Received 3 December, 2008
Revised 1 May, 2009
Accepted 5 May, 2009
In 2007, the WHO recommended a maximum stavudine dose of 30 mg. We compared virologic suppression among patients weighing more than 60 kg and receiving stavudine 30 mg (n = 110) versus 40 mg (n = 508) in community HIV clinics in South Africa, before and after guidelines changed. At 6 months, HIV RNA less than 400 copies/ml was achieved in 79% and 81% receiving 30 and 40 mg stavudine, respectively (χ2, P = 0.6). In regression modeling, including baseline HIV RNA and nonnucleoside reverse transcriptase inhibitor agent, stavudine dose remained unassociated with suppression.
Combination antiretroviral therapy (cART) including stavudine, lamivudine, and nevirapine is the most widely used regimen in Africa . This regimen achieves good virologic response but troubling long-term complications (usually starting after >6 months cART) [2–5]. In response to the high rates of adverse events, in 2007, the World Health Organization (WHO) recommended using stavudine 30 mg twice daily for all adults, replacing the 40 mg dose for adults over 60 kg . This was based on results of short-term dose ranging studies [7–9] and retrospective cohort analyses. A recent meta-analysis  also suggested the similar performance of 30 mg and 40 mg stavudine. However, evaluation of outcomes of ART naïve patients weighing more than 60 kg initiated on stavudine 30 mg is lacking from Africa. In our community-based ART programmes, we changed from use of 40 mg to 30 mg for individuals weighing more than 60 kg in mid-2007. We compared virologic suppression and CD4 cell response at 6 months among individuals weighing more than 60 kg who received a stable dose of either 30 or 40 mg of stavudine.
Patients in this study were enrolled in community HIV care programmes, followed 6 months from cART initiation, and fulfilled the following criteria: initiated cART including stavudine of either 40 mg or 30 mg between 1 January 2006 and 1 January 2008; received a stable dose of stavudine; weighed more than 60 kg at cART initiation and during observation; received a nonnucleoside reverse transcriptase inhibitor (NNRTI); were cART naïve and had a known date of cART initiation, had at least 150 days follow-up after cART initiation, and were at least 18 years old. Patients within these HIV clinics received care through a standard algorithm that included HIV RNA monitoring (Versant HIV bDNA; Bayer Diagnostics, Pittsburgh, Pennsylvania, USA) at 6 weeks and 6 months after cART initiation. CART eligibility was based on WHO criteria using a CD4 cell count less than 200 cells/ml or WHO stage four condition. Starting in June 2007, clinics switched to use of 30 mg stavudine, twice daily, for all patients.
Baseline factors were compared between individuals receiving 30 mg and 40 mg stavudine using chi-square and Wilcoxon rank sum tests, as appropriate. HIV RNA response was based on the lowest HIV RNA obtained within 6 months of cART initiation. If no HIV RNA test result was available, the subject was considered to have HIV RNA more than 400 copies/ml to avoid excluding individuals without HIV RNA results because of discontinuation due to intolerance. We assessed the impact of classifying these individuals as treatment failures in a sensitivity analysis. The chi-square test was used to compare the proportion achieving HIV RNA less than 400 copies/ml or less than 50 copies/ml by stavudine group. Logistic regression was used to assess associations between covariates and HIV RNA suppression and to adjust for confounding; a multivariate model was built by including covariates with P ≤ 0.1. CD4 cell change from cART initiation to 6 months was compared, by stavudine group, using the Wilcoxon rank sum test. Ethical approval was obtained from the University of KwaZulu-Natal and the London School of Hygiene and Tropical Medicine.
Six hundred and ninety-one patients were evaluated for analysis: 618 were included, 73 were excluded because of a change in stavudine dose or because stavudine dose was not recorded at a visit. Sex, age, and HIV RNA less than 400 copies/ml at 6 months were similar between included and excluded patients. Of the included cART naïve individuals (all weighed more than 60 kg at baseline and initiated cART between January 2006 and January 2008 at 51 community ART clinic sites), 110 received 30 mg and 508 received 40 mg stavudine. The two stavudine dose groups were different with respect to WHO stage, proportion receiving efavirenz, weight, and median log10 HIV RNA and CD4 cell count at cART initiation (Table 1). Nine (8.1%) in the 30 mg group and 46 (9.1%) in the 40 mg group had no HIV RNA measurement during the observation period and were counted as treatment failures.
We observed similar virologic suppression using less than 400 copies/ml and less than 50 copies/ml at 6 months by stavudine group: suppression to less than 400 copies/ml for 30 mg was 87/110 [79%, 95% confidence interval (CI) = 71–87%] and for 40 mg was 413/508 (81%, 95% CI = 78–85%) (P = 0.6); less than 50 copies/ml for 30 mg was 66/110, (60%, 95% CI = 51–69%) and for 40 mg was 297/508, (58%, 95% CI = 54–63%) (P = 0.8). Completing sensitivity analysis excluding individuals without follow-up HIV RNA testing, we found 86% (95% CI = 0.79–0.93) and 89% (95% CI = 0.86–0.92) were suppressed with stavudine 30 mg or 40 mg groups, respectively (P = 0.3). Using logistic regression we found no association between HIV RNA suppression and sex, weight, or WHO stage at cART initiation (Table 1). On univariate analysis, log10 HIV RNA at cART initiation, NNRTI agent, and weight all had P values less than 0.1 for odds of achieving an HIV RNA less than 400 copies/ml. On multivariate analysis adjusting for NNRTI agent, weight, and HIV RNA at cART initiation, stavudine dose remained unassociated with suppression (Table 1). CD4 cell change from cART initiation to 6 months on cART increased with a median of 126 cells/mm3 (interquartile range = 87–206) for the 30 mg group and 110 cells/mm3 (interquartile range = 50–170) for the 40 mg group (P = 0.02).
In an African operational cohort, we found that HIV RNA suppression at 6 months was similar between the two-stavudine doses in patients weighing more than 60 kg. Although the recipients were not randomized to dose, the dose decisions were made based on a change in guidelines and not as a result of individualization of patient management, reducing the chance of selection bias. However, our two stavudine groups did differ in some characteristics: the group receiving 30 mg of stavudine had a lower CD4 cell count and higher WHO clinical stage at HAART initiation and was more likely to receive nevirapine. These are factors sometimes associated with poorer HAART response [11–13], yet our outcomes were similar. On the basis of virologic outcomes at 6 months, our results provide additional support for the WHO recommendations for use of 30 mg stavudine among individuals weighing more than 60 kg. Long-term (>18 months) evaluation of side effects is essential to compare tolerance of stavudine 30 mg versus 40 mg.
This work was supported by the Aurum Institute. C.J.H. was supported by NIH DK074348, REC by NIH AI5535901 and AI016137, and A.D.G. by a UK Department of Health Public Healthcareer Scientist Award. Individuals in this study were enrolled in treatment programs supported by the United States President's Emergency Plan for AIDS Relief and by Cooperative Agreement Number PS024055 from the Department of Health and Human Services/Centers for Disease Control and Prevention (CDC), National Center for HIV, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Global AIDS Program (GAP). The content of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of CDC.
Role of Authors: C.J.H. study design, analysis, and manuscript preparation, S.C. study design, manuscript preparation, K.L.F. data analysis, C.I. data collection, manuscript preparation; R.E.C. study design, manuscript preparation; A.D.G. analysis, manuscript preparation, G.J.C. analysis, manuscript preparation.
1. Renaud-Thery F, Nguimfack BD, Vitoria M, Lee E, Graaff P, Samb B, et al
. Use of antiretroviral therapy in resource-limited countries in 2006: distribution and uptake of first- and second-line regimens. AIDS 2007; 21(Suppl 4):S89–S95.
2. Geddes R, Knight S, Moosa MY, Reddi A, Uebel K, Sunpath H. A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context. S Afr Med J 2006; 96:722–724.
3. Songa PM, Castelnuovo B, Mugasha EB, Ocama P, Kambugu A. Symptomatic hyperlactatemia associated with nucleoside analogue reverse-transcriptase inhibitor use in HIV-infected patients: a report of 24 cases in a resource-limited setting (Uganda). Clin Infect Dis 2007; 45:514–517.
4. van Griensven J, De Naeyer L, Mushi T, Ubarijoro S, Gashumba D, Gazille C, 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.
5. Forna F, Liechty CA, Solberg P, Asiimwe F, Were W, Mermin J, et al
. Clinical toxicity of highly active antiretroviral therapy in a home-based AIDS care program in rural Uganda. J Acquir Immune Defic Syndr 2007; 44:456–462.
7. Murray HW, Squires KE, Weiss W, Sledz S, Sacks HS, Hassett J, et al
. Stavudine in patients with AIDS and AIDS-related complex: AIDS clinical trials group 089. J Infect Dis 1995; 171(Suppl 2):S123–S130.
8. Petersen EA, Ramirez-Ronda CH, Hardy WD, Schwartz R, Sacks HS, Follansbee S, et al
. Dose-related activity of stavudine in patients infected with human immunodeficiency virus. J Infect Dis 1995; 171(Suppl 2):S131–S139.
9. Anderson RE, Dunkle LM, Smaldone L, Adler M, Wirtz C, Kriesel D, et al
. Design and implementation of the stavudine parallel-track program. J Infect Dis 1995; 171(Suppl 2):S118–S122.
10. Hill A, Ruxrungtham K, Hanvanich M, Katlama C, Wolf E, Soriano V, et al
. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opin Pharmacother 2007; 8:679–688.
11. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al
. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine. Lancet 2004; 363:1253–1263.
12. DART Virology Group and Trial Team. Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa
13. Kamya MR, Mayanja-Kizza H, Kambugu A, Bakeera-Kitaka S, Semitala F, Mwebaze-Songa P, et al
. Predictors of long-term viral failure among ugandan children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr 2007; 46:187–193.
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