Lifetime costs for all five strategies varied between 7711 and 9478 discounted 2009 US$ (Table 2 and Fig. 2). Using undiscounted values of costs and life expectancy, this amounts to between $713 and $810 in total direct annual costs for people living with HIV and remaining in care in South Africa. The initial regimen zidovudine/lamivudine/nevirapine was the least expensive, whereas tenofovir/lamivudine/efavirenz was the most expensive. Figure 1 shows the lifetime costs and quality-adjusted life expectancy of the primary analysis in discounted 2009 US$ and quality-adjusted life years (QALYs).
We find that only three first-line ART strategies could be considered cost-effective: zidovudine/lamivudine/nevirapine, tenofovir/lamivudine/nevirapine, and tenofovir/lamivudine/efavirenz. At least one of these strategies was more effective and less costly than the other two strategies (stavudine/lamivudine/nevirapine and zidovudine/lamivudine/efavirenz). When adjusting for quality of life, the strategy containing stavudine/lamivudine/nevirapine in initial regimen was more expensive and less effective that the strategy containing zidovudine/lamivudine/nevirapine, the increased expense primarily due to the costs of managing stavudine-associated toxicities. Compared with zidovudine/lamivudine/nevirapine, the strategy containing tenofovir/lamivudine/nevirapine in first-line provided 7.3 additional quality-adjusted months of life at an additional cost of $636, an incremental cost-effectiveness ratio of $1045 per QALY. The most effective strategy – tenofovir/lamivudine/efavirenz – was associated with additional 2.3 months of quality-adjusted months of life and an incremental cost-effectiveness ratio of $5949 per QALY compared with tenofovir/lamivudine/nevirapine. We estimated that one of the strategies recommended by the WHO – zidovudine/lamivudine/efavirenz – is more costly and less effective than a strategy with tenofovir/lamivudine/nevirapine as initial therapy. In cases in which nevirapine is not appropriate (such as simultaneous treatment of HIV and tuberculosis), the strategy with zidovudine/lamivudine/efavirenz is the least costly strategy, and the strategy with tenofovir/lamivudine/efavirenz has an incremental cost-effectiveness ratio of $1251 per QALY in comparison.
We performed sensitivity analyses to answer two important questions: do our estimates of each regimen's virologic failure change the results? And under what conditions do our estimates of the quality of life associated with toxicities matter for the outcomes? We considered these the most uncertain estimates and the ones most likely to affect our comparisons.
We first focused on our estimates of virologic failure. We varied the failure rate associated with zidovudine/lamivudine/nevirapine. This had important implications because higher failure rates associated with zidovudine/lamivudine/nevirapine could make the most common regimen in current use (stavudine/lamivudine/nevirapine) cost-effective. We found that a first-line regimen with stavudine/lamivudine/nevirapine remained more costly and less effective than a first-line regimen containing zidovudine/lamivudine/nevirapine even if the rates of virologic failure of zidovudine/lamivudine/nevirapine were twice as high (Table 1). These findings are driven by the toxicities associated with stavudine and the costs of managing these toxicities that more than offset the decreased benefits of zidovudine/lamivudine/nevirapine.
Rates of virologic failure were also important for determining the incremental cost-effectiveness of tenofovir/lamivudine/efavirenz compared with tenofovir/lamivudine/nevirapine. When we varied the rates of failure of tenofovir/lamivudine/nevirapine over a broad range (from identical to tenofovir/lamivudine/efavirenz to twice the rate), the incremental cost-effectiveness ratio ranged from $2927 per QALY when the rates of failure with tenofovir/lamivudine/nevirapine were twice that of tenofovir/lamivudine/efavirenz to $27 900 per QALY when the rates of failure were identical. At acceptable cost-effectiveness thresholds for South Africa (less than gross domestic product per capita, $5800), tenofovir/lamivudine/efavirenz remained cost-effective compared with tenofovir/lamivudine/nevirapine as long as virologic failure (at any point) was at least 1.5 times more likely with tenofovir/lamivudine/nevirapine.
We then examined when quality-of-life adjustments changed the results. We estimated that an initial regimen of stavudine/lamivudine/nevirapine could be a first-line consideration if the relative quality of life with lipoatrophy was 0.95 compared to life without lipoatrophy (up from 0.87 in the primary analysis). However, the incremental cost-effectiveness ratio of stavudine/lamivudine/nevirapine compared with zidovudine/lamivudine/nevirapine was $19 967 per QALY at that quality of life, well above established thresholds for cost-effectiveness in less developed countries. No other toxicity, when varied over a broad range of assumptions, changed the relative rank order of strategies in terms of effectiveness, suggesting the results are robust to changes in any single estimate of toxicity.
In probabilistic sensitivity analysis, we varied all parameters simultaneously to estimate the overall uncertainty in the results. During 96% of the simulations, a first-line regimen containing zidovudine/lamivudine/nevirapine provided greater benefits and cost less than stavudine/lamivudine/nevirapine. Under those assumptions when stavudine/lamivudine/nevirapine was less costly than zidovudine/lamivudine/nevirapine, the mean incremental cost-effectiveness ratio of starting with zidovudine/lamivudine/nevirapine was $200 per QALY gained (Fig. 3). We are also able to calculate an uncertainty range for the incremental cost-effectiveness ratios. In our estimates, 95% of the incremental cost-effectiveness ratios comparing a first-line regimen with tenofovir/lamivudine/nevirapine to zidovudine/lamivudine/nevirapine fell in the range of $36 per QALY gained to $2926 per QALY gained. Similarly, 95% of the time tenofovir/lamivudine/efavirenz cost between $1787 and $9449 per QALY gained compared with tenofovir/lamivudine/nevirapine. The incremental cost-effectiveness ratios for tenofovir/lamivudine/efavirenz compared with tenofovir/lamivudine/nevirapine were less than the South African gross domestic product per person in 52% of our simulations.
We present a comparison of the effectiveness and cost-effectiveness of strategies recommended by the World Health Organization for initial ART regimens in resource-constrained settings. Our analysis has three main conclusions: it supports the decision by the WHO to eliminate stavudine/lamivudine/nevirapine from the guidelines for first-line regimens; it calls into question the recommendation to have a first-line regimen that includes zidovudine/lamivudine/efavirenz when a first-line regimen that includes tenofovir/lamivudine/nevirapine is available for widespread use; and it suggests that a first-line regimen with tenofovir/lamivudine/nevirapine would be cost-effective for South Africa, while the cost-effectiveness of a first-line regimen with tenofovir/lamivudine/efavirenz is less favorable at current drug prices. Below we discuss these conclusions in detail and highlight the implications for treatment campaigns and drug development.
The finding that a first-line regimen containing stavudine/lamivudine/nevirapine is more costly and less effective than a first-line regimen containing zidovudine/lamivudine/nevirapine supports the WHO's recommendations to eliminate stavudine/lamivudine/nevirapine from the recommended first-line regimens. The removal of stavudine from all recommended first-line regimens was a primary motive for the WHO's revised guidelines. The WHO cites concerns over toxicities, and our analysis estimates the decrease in quality-adjusted life-years associated with that regimen. This was not a foregone conclusion for two reasons. First, we used efficacy data that suggest stavudine is similar to tenofovir, whereas zidovudine is inferior to tenofovir. Indeed, we find that without accounting for quality of life, stavudine/lamivudine/nevirapine is more effective than zidovudine/lamivudine/nevirapine. However, this advantage is reversed after quality-of-life adjustments for stavudine-associated toxicities. Second, we find that stavudine/lamivudine/nevirapine in initial regimen is also more expensive than zidovudine because of the higher costs associated with managing toxicities and because of the earlier switch to more expensive regimens observed after the initiation of stavudine-related toxicities.
We also find that a first-line regimen with zidovudine/lamivudine/efavirenz is not cost-effective: it is more costly and less effective than a regimen containing tenofovir/lamivudine/nevirapine. We estimated these regimens have relatively similar rates of virologic failure, but the effect of toxicities associated with zidovudine/lamivudine/efavirenz (primarily lipoatrophy and anemia) render that combination less effective. Reducing the annual cost of efavirenz can make a first-line regimen with zidovudine/lamivudine/efavirenz less expensive than tenofovir/lamivudine/nevirapine, but even if efavirenz costs as much as nevirapine, it is likely that zidovudine/lamivudine/efavirenz would remain cost-ineffective.
Our finding that a first-line regimen with tenofovir/lamivudine/nevirapine is cost-effective by WHO criteria for at least some developing countries is congruent with previous analyses [5,23]. In developed countries, the most common formulation of tenofovir is in combination with emtricitabine and efavirenz in a fixed-dose combination. The combination of tenofovir with lamivudine, by comparison, is relatively unfamiliar and understudied [24,25]. Recent observational studies, however, raise concern over its virologic efficacy. Because it is both recommended and cost-effective, a prospective trial evaluating its efficacy will provide crucial information. Previous studies suggest that nevirapine can be used in once-daily drug combinations . A fixed dose pill with that combination could be an important contribution to the current options for developing countries, especially if a head-to-head trial comparing those regimens confirms our estimates of improved effectiveness with tenofovir/lamivudine/nevirapine.
In extensive sensitivity analysis we show that one of the regimens recommended by the WHO – first line with zidovudine/lamivudine/efavirenz – remains cost-ineffective over a broad range of assumptions. A combination of zidovudine, lamivudine, and efavirenz was very popular in developed countries for several years (as Combivir and Sustiva), and the familiarity and historical reputation of this regimen may make it attractive for many settings in developing countries. However, our analysis shows that it is unlikely to be cost-effective when tenofovir is also available.
In preparing this analysis, data on virologic efficacy and toxicity rates were occasionally limited to clinical trials or experience in developed settings. Cohort and observational evidence suggests that virologic efficacy of all the drugs evaluated in this study may be similar between developed countries and sub-Saharan Africa . However, toxicity rates are less reliable: a recent study suggested that zidovudine-related anemia in African settings was more frequent than in developed countries . In addition, whereas rates of lipoatrophy on stavudine were obtained from a study that used strict case definitions in Rwanda, the quality of life of the associated symptons was derived from a US-based catalog . The generalizability of our study to other countries in southern Africa is limited since we used cost and utilization that represent the Cape Town area, where cost and access to healthcare are generally above average for the region. We attempted to account for this in our probabilistic sensitivity in which we varied cost and utilization parameters widely. Our analyses assume that patients developing toxicities on zidovudine or stavudine-containing regimens switch to a tenofovir-containing regimen. In reality, only a few African settings have guidelines in place and the capacity to switch individuals to less toxic and more expensive regimens. Finally, we focused on individuals who are followed in HIV clinics, have access to care, and adhere to their treatment regimen. We did not account for the effects of linkage to care, adherence, and loss to follow-up.
In summary, we compare the effectiveness and cost-effectiveness of the regimens recommended for first-line treatment of HIV in resource-limited settings and show that eliminating stavudine from the formulary is justifiable based on cost-effectiveness considerations, and that a regimen containing tenofovir/lamivudine/nevirapine is likely to be cost-effective in settings in which it is accessible and acceptable. We also show that one of the recommended regimens – zidovudine/lamivudine/efavirenz – is unlikely to be cost-effective, and consideration should be given to its removal from the recommendations for the general population as a way to focus attention and experience to other, preferred regimens.
1. Rapid Advice. Antiretroviral therapy for HIV infection in adults and adolescents
(November, 2009). Geneva: World Health Organization.
3. Gazzard B. British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy. HIV Med 2008; 9:563.
4. Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, et al
. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. J Am Med Assoc 2008; 300:555–570.
5. Bender M, Kumarasamy N, Mayer K, Wang B, Walensky R, Flanigan T, et al
. Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India. Clin Infect Dis 2010; 50:416–425.
6. Badri M, Cleary S, Maartens G, Pitt J, Bekker LG, Orrell C, et al
. When to initiate highly active antiretroviral therapy in sub-Saharan Africa? A South African cost-effectiveness study. Antivir Ther 2006; 11:63–72.
7. Badri M, Lawn SD, Wood R. Short-term risk of AIDS or death in people infected with HIV-1 before antiretroviral therapy in South Africa: a longitudinal study. Lancet 2006; 368:1254–1259.
8. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002; 359:2059–2064.
9. ART-LINC and ART-CC. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries
10. Arribas J, Pozniak A, Gallant J, DeJesus E, Gazzard B, Campo R, et al
. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr 2008; 47:74.
11. Haubrich R, Riddler S, DiRienzo A, Komarow L, Powderly W, Klingman K, et al
. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS 2009; 23:1109.
12. Gallant J, Staszewski S, Pozniak A, DeJesus E, Suleiman J, Miller M, et al
. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. J Am Med Assoc 2004; 292:191.
13. Hawkins C, Achenbach C, Fryda W, Ngare D, Murphy R. Antiretroviral durability and tolerability in HIV-infected adults living in urban Kenya. J Acquir Immune Defic Syndr 2007; 45:304.
14. Amoroso A. ART-associated toxicities leading to a switch in medication: experience in Uganda, Kenya, and Zambia.
. Los Angeles; 2007.
15. Nachega J, Hislop M, Dowdy D, Gallant J, Chaisson R, Regensberg L, et al
. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS 2008; 22:2117.
16. 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 Roy Soc Trop Med Hyg 2007; 101:793–798.
17. Toure S, Seyler C, Messou E, Duvignac J, Marlink R, Dabis F, et al.Main reasons of modification of the first-line antiretroviral regimen in adult patients who initiated HAART in the International Family Health Initiative (ACONDA/ISPED/EGPAF) in Abidjan, Cote d'Ivoire
. In 3rd HIV/AIDS Implementers' Meeting
. 2007: Kigali, Rwanda.
18. Mugyenyi P, Walker AS, Hakim J, Munderi P, Gibb DM, Kityo C, et al
. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised noninferiority trial. Lancet 2010; 375:123–131.
19. Bendavid E, Young SD, Katzenstein DA, Bayoumi AM, Sanders GM, Owens DK. Cost-effectiveness of HIV monitoring strategies in resource-limited settings: a Southern African analysis. Arch Internal Med 2008; 168:1910–1918.
20. Bendavid E, Wood R, Katzenstein D, Bayoumi A, Owens D. Expanding antiretroviral options in resource-limited settings: a cost-effectiveness analysis. J Acquir Immune Defic Syndr 2009; 52:106–113.
21. Holmes CB, Wood R, Badri M, Zilber S, Wang B, Maartens G, et al
. CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment. J Acquir Immune Defic Syndr 2006; 42:464–469.
22. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA 1996; 276:1253–1258.
23. 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.
24. Soriano V, Koppe S, Mingrone H, Lutz T, Opravil M, Andrade-Villanueva J. Prospective comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naive HIV-1 infected patients: ARTEN study week 48 results
[abstract LB PEB07]. In International AIDS Society
. Cape Town, South Africa; 2009.
25. Labarga P, Medrano J, Seclen E, Poveda E, Rodriguez-Novoa S, Morello J, et al.Safety and efficacy of tenofovir/emtricitabine plus nevirapine in HIV-infected patients [Letter]
26. 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: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263.
27. Kantor R, Katzenstein DA, Efron B, Carvalho AP, Wynhoven B, Cane P, et al
. Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration. PLoS Med 2005; 2:e112.
28. Dorrington R, Johnson L, Bradshaw D, Daniel T. The demographic impact of HIV/AIDS in South Africa: national and provincial indicators for 2006
. Cape Town: Centre for Actuarial Research, South African Medical Research Council and Actuarial Society of South Africa; 2006.
30. Mellors JW, Muñoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, et al
. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Internal Med 1997; 126:946–954.
31. Rodríguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, Kitahata M, et al
. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 2006; 296:1498–1506.
32. Ledergerber B, Lundgren JD, Walker AS, Sabin C, Justice A, Reiss P, et al
. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004; 364:51–62.
33. Gallant J, DeJesus E, Arribas J, Pozniak A, Gazzard B, Campo R, et al
. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354:251.
35. Smith C, Phillips A, Hill T, Fisher M, Gazzard B, Porter K, et al
. The rate of viral rebound after attainment of an HIV load< 50 copies/mL according to specific antiretroviral drugs in use: results from a multicenter cohort study. J Infect Dis 2005; 192:1387–1397.
36. John M, Moore C, James I, Nolan D, Upton R, McKinnon E, et al
. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS 2001; 15:717.
37. Boubaker K, Flepp M, Sudre P, Furrer H, Haensel A, Hirschel B, et al
. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis 2001; 33:1931–1937.
38. Cleary S, Boulle A, McIntyre D, Coetzee D. Cost-effectiveness of antiretroviral treatment for HIV-positive adults in a South African township
. Cape Town: Health Systems Trust; 2004.
39. Nyman J, Barleen N, Dowd B, Russell D, Coons S, Sullivan P. Quality-of-life weights for the US population: self-reported health status and priority health conditions, by demographic characteristics. Med Care 2007; 45:618.
40. Kimel M, Leidy N, Mannix S, Dixon J. Does epoetin alfa improve health-related quality of life in chronically ill patients with anemia? Summary of trials of cancer, HIV/AIDS, and chronic kidney disease. Value Health 2008; 11:57.
41. Badri M, Maartens G, Mandalia S, Bekker LG, Penrod JR, Platt RW, et al
. Cost-effectiveness of highly active antiretroviral therapy in South Africa. PLoS Med 2006; 3:e4.
42. Zijenah LS, Kadzirange G, Madzime S, Borok M, Mudiwa C, Tobaiwa O, et al
. Affordable flow cytometry for enumeration of absolute CD4+ T-lymphocytes to identify subtype C HIV-1 infected adults requiring antiretroviral therapy (ART) and monitoring response to ART in a resource-limited setting. J Translat Med 2006; 4:33–39.
44. Cantor S, Hudson D Jr, Lichtiger B, Rubenstein E. Costs of blood transfusion: a process-flow analysis. J Clin Oncol 1998; 16:2364.