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: (1) it supports the decision by the WHO to eliminate stavudine/lamivudine/nevirapine from the guidelines for first-line regimens; (2) 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 (3) 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 suggests stavudine is similar to tenofovir while 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 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 cost as much 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, although our ability to extrapolate beyond South Africa is limited.[5
] 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, lamivudine, and nevirapine, by comparison, is relatively unfamiliar and understudied, but increasing recent data supports its efficacy compared with established regimens.[24
] Previous studies suggest that nevirapine can be used in once-daily drug combinations.[26
] 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 was 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.[27
] However, toxicity rates are less reliable: a recent study suggested that zidovudine-related anemia in African settings was more frequent than in developed countries.[18
] In addition, while 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 are derived from a US-based catalog.[16
] 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 health care are generally above average for the region. We attempted to account for this in our probabilistic sensitivity where 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 where 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.