The public health approach for combination antiretroviral therapy (cART) in resource-limited settings includes the use of one standard first-line and one standard second-line regimen . According to World Health Organization 2010 treatment guidelines, first-line therapy should consist of a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI), one of which should be zidovudine (ZDV) or tenofovir (TDF). Second-line ART should consist of a ritonavir-boosted protease inhibitor (PI/r) plus two NRTIs, one of which should be ZDV or TDF, based on what was used in first-line therapy. Ritonavir-boosted atazanavir (ATV/r) or lopinavir/ritonavir (LPV/r) are the preferred PIs.
The choice of using TDF or ZDV in first-line treatment is determined at country level. Randomized clinical trials have demonstrated superiority of TDF over ZDV , , ,  and over stavudine (D4T) ,  in combination therapy with regards to virological suppression, as well as a tendency for less toxicity-related discontinuations and improved adherence in industrialized  and resource-limited settings . In contrast, the somewhat lower costs favour the use of ZDV, although considerable price reductions for TDF have been achieved more recently so differences are now small .
One particular concern regarding the widespread use of TDF in settings without virological monitoring is the potential for development of extensive nucleoside and nucleotide analogue cross-resistance via the emergence of the reverse transcriptase mutation K65R, and possibly also multidrug resistance patterns such as Q151M, although the latter has not been detected in well-controlled clinical trials in resource-rich settings , , . Moreover, some in vitro data point to more rapid selection of K65R emergence in subtype C viruses, owing to a specific nucleotide motif at reverse transcriptase position 65 that facilitates the amino acid switch from lysine to arginine , . Indeed, recent surveys from resource-limited settings suggest a comparatively high prevalence of high-level NRTI cross-resistance resistance associated with K65R (23%) or Q151M (0–19%) amongst patients with clinical or virological treatment failure , .
Previous cost effectiveness analyses have already pointed towards better clinical outcomes of TDF use compared with other NRTIs in industrialized  and resource-limited settings , , , . These studies, however, mainly focused on HIV-1 and treatment related morbidities, and did not investigate the impact of the emergence of drug resistance mutations on future therapy options. In the present simulations, we aimed to re-assess the cost effectiveness of TDF over ZDV for settings using the public health approach for ART with one standard first-line and one standard second-line regimen, and without virological monitoring, which is the reality in most resource-poor settings. For this purpose, an established individual-based stochastic model of HIV transmission and treatment in a resource-limited country was adapted to reflect possible mutation patterns leading to and after first-line treatment failures and to predict costs of treatment for HIV-1 and tuberculosis-(TB) and HIV-related morbidity and mortality , . We specifically considered the impact of the different resistance patterns generated by the use of TDF or ZDV in first-line cART on efficacy of second-line therapy and subsequent morbidity and mortality.
The most recent World Health Organization (WHO) antiretroviral treatment guidelines recommend the inclusion of zidovudine (ZDV) or tenofovir (TDF) in first-line therapy. We conducted a cost-effectiveness analysis with emphasis on emerging patterns of drug resistance upon treatment failure and their impact on second-line therapy.
We used a stochastic simulation of a generalized HIV-1 epidemic in sub-Saharan Africa to compare two strategies for first-line combination antiretroviral treatment including lamivudine, nevirapine and either ZDV or TDF. Model input parameters were derived from literature and, for the simulation of resistance pathways, estimated from drug resistance data obtained after first-line treatment failure in settings without virological monitoring. Treatment failure and cost effectiveness were determined based on WHO definitions. Two scenarios with optimistic (no emergence; base) and pessimistic (extensive emergence) assumptions regarding occurrence of multidrug resistance patterns were tested.
In the base scenario, cumulative proportions of treatment failure according to WHO criteria were higher among first-line ZDV users (median after six years 36% [95% simulation interval 32%; 39%]) compared with first-line TDF users (31% [29%; 33%]). Consequently, a higher proportion initiated second-line therapy (including lamivudine, boosted protease inhibitors and either ZDV or TDF) in the first-line ZDV user group 34% [31%; 37%] relative to first-line TDF users (30% [27%; 32%]). At the time of second-line initiation, a higher proportion (16%) of first-line ZDV users harboured TDF-resistant HIV compared with ZDV-resistant viruses among first-line TDF users (0% and 6% in base and pessimistic scenarios, respectively). In the base scenario, the incremental cost effectiveness ratio with respect to quality adjusted life years (QALY) was US$83 when TDF instead of ZDV was used in first-line therapy (pessimistic scenario: US$ 315), which was below the WHO threshold for high cost effectiveness (US$ 2154).
Using TDF instead of ZDV in first-line treatment in resource-limited settings is very cost-effective and likely to better preserve future treatment options in absence of virological monitoring.