By using an established stochastic simulation of HIV disease progression and therapy we have explored the impact of using different NRTI drugs (namely ZDV versus TDF) on resistance emergence and its consequences in terms of response to available second-line regimens and associated costs. Owing to uncertainty with respect to the influence of prolonged exposure to failing regimens and the effect of non-B subtype infection on NRTI-cross resistance we tested two pathways for resistance emergence while receiving TDF therapy. The base scenario assumed a rapid and frequent emergence of the TDF signature mutation K65R but only a very limited degree of NRTI cross-resistance. The second, pessimistic scenario was derived from analyses of genotypic resistance tests performed after failure of first-line combination treatment with D4T and was characterized by a more limited emergence of K65R, but a considerable risk for NRTI-cross resistance by the emergence of Q151M.
Our analyses suggest that first-line TDF use is a cost-effective treatment strategy compared with first-line ZDV use when considering quality adjusted life years as outcome, although dominance of the TDF strategy was only observed in 11% to 46% of comparisons (). The use of TDF instead of ZDV also led to a reduction in treatment failures on the basis of WHO criteria by approximately 1% (pessimistic scenario) to 4% (base scenario). Consequently, fewer individuals in the TDF group had to switch to more costly second-line therapy compared with ZDV starters, although the magnitude of this difference was dependent on assumptions regarding the TDF resistance pathway. Our study results are line with those from a modelling analysis by Bendavid et al., who obtained an ICER estimate of US$ 1045 for first-line regimens consisting of TDF, 3TC and NVP when compared with first-line ZDV, 3TC and NVP 
. Other published cost-effectiveness analyses are not directly comparable to our study, because their reference scenarios involved receiving no cART 
or receiving D4T 
. Nevertheless, both studies also reached the conclusion that the TDF first strategy may be cost-effective when compared with the ZDV first strategy because of better tolerability. Further support for this conclusion stems from analyses of antiretroviral treatment programs in southern Africa, which observed fewer drug related toxicity events among first-line TDF users when compared with individuals starting therapy with ZDV 
. In particular, severe TDF-associated renal toxicity was shown to be rare and often transient, and therefore does not seem to pose a major obstacle for widespread TDF implementation in settings without creatinine clearance monitoring 
. In comparison, life-threatening anaemia or lipoatrophy occur frequently in association with ZDV-use, especially in malnourished populations 
. All these are drug side effects, which are not caused by TDF.
Depending on the actual rate of NRTI multidrug resistance emergence, first-line TDF use may increase emergence of extensively NRTI class-resistant HIV by 8.5-fold (17/1000 first-line TDF users in the pessimistic scenario compared with 2/1000 first-line ZDV users). Observational studies have reported associations of K65R mutations with Q151M, possibly pointing towards a co-selection of these mutations 
. However, these studies were performed among patients with extensive antiretroviral drug histories-including exposure to D4T or didanosine, but not necessarily TDF-, and the drugs responsible for selection of K65R and Q151M could not be determined with certainty. In contrast, currently available resistance data from individuals undergoing long-term therapy with TDF support the more optimistic scenario 
. If true, the limited degree of cross-resistance even after extended exposure to failing treatment would make TDF a valid option for second-line therapy, in which EFV is replaced by LPV/r. A recent observational study suggests that in salvage settings staying on TDF may be preferable over switching to ZDV due to better tolerability and similar viral load reductions 
Some limitations should be noted about this study. Like any model, our simulation involves simplifications of reality and is based on assumptions regarding input parameters. In particular, given the lack of real data we had to make assumptions regarding rates and extent of drug resistance following immunological failures in resource-limited settings, as shown in . Given these limitations, we subjected several important parameters to sensitivity analyses and repeated the simulation for different settings. We observed that the pessimistic simulation scenario with regards to drug resistance emergence reduces TDF cost-effectiveness, and so did changes to settings or other input parameters of interest (adherence levels, switch rates, and potency of LPV/r). But these results did not alter our conclusions, because TDF remained very cost effective by WHO standards (). These analyses further revealed that a strategy of first-line TDF use in settings with virological monitoring would further enhance cost effectiveness relative to first-line ZDV use ( and ). It should also be noted that measures of treatment outcomes in our analysis such as the proportion of individuals with undetectable viral loads or the increase in CD4 cell counts from baseline tend to be somewhat lower than those observed in clinical trials and observational studies, although this finding has no direct impact on the cost-effectiveness analyses.
In summary, taking into account the possibility of more extensive drug resistance or possible long term renal toxicity by TDF use we conclude that first-line TDF use is likely to be a very cost-effective treatment strategy in resource-limited settings even in the absence of virological monitoring, because of the better tolerability and the small cost difference.