Newer ART agents, including tenofovir, are both highly effective and safer than older NRTIs, but stavudine remains the backbone of first-line ART regimens in India and many other resource-limited countries due to its lower cost [7
]. We conducted a cost-effectiveness analysis of first-line ART regimens in India, focusing on the role of tenofovir. We found that initial tenofovir increased life expectancy by about 10.4 months compared to stavudine or zidovudine. At the current price of tenofovir-containing ART ($14/person/month), the incremental cost-effectiveness ratio for initial tenofovir in India was $670/YLS compared to no ART. The alternative strategies represented a less efficient use of resources. The main determinants of these results were the cost of tenofovir, access to and cost of additional lines of ART, and mean initial CD4 count. Sensitivity analyses adjusted for quality of life increased the incremental cost-effectiveness ratio of the tenofovir-based strategy to $1,000/YLS.
Some studies suggest that tenofovir may be associated with nephrotoxicity and potentially renal failure [6
]. Moreover, renal disease is more prevalent in HIV-infected patients than the general population, regardless of ART exposure [23
]. Several US-based trials show no increase in nephrotoxicity from tenofovir with careful monitoring and minimal long-term consequences from any decline in renal function [24
]. However, renal toxicity may pose higher risks in resource-limited settings, where experience with tenofovir and access to laboratory monitoring are limited, and where death from acute renal failure may approach 90% [26
]. Sensitivity analyses on nephrotoxicity within a clinically plausible range did not offset the virologic advantages conferred by tenofovir, suggesting that the benefits would outweigh any potential harm.
In a cost-effectiveness analysis on the use of tenofovir for first-line ART in South Africa, Rosen et al
. found that tenofovir reduced toxicity and had a high incremental cost-effectiveness ratio of about $9,000/QALY compared to stavudine using monthly costs of $17 for tenofovir and $3.39 for stavudine in US$2007 [28
]. There are several important differences between the Rosen and the current study including treatment efficacy, treatment cost, and analysis time frame. The current analysis used data reflecting improved effectiveness and smaller differences in cost between initial tenofovir and other first-line alternatives, and it evaluated clinical and cost outcomes over a lifetime rather than just 2 years.
We also examined a scenario in which patients had access to only one line of ART, reflecting current limitations in ART rollout capacity, as well as a scenario anticipating access to three lines of ART. We found that the increased efficacy of first-line tenofovir over the alternatives improved its cost-effectiveness when only one line of ART was available. We observed the opposite, though modest, effect when patients had access to a costly third-line regimen. The cost-effectiveness results were stable despite changes in the cost of initial tenofovir when two lines of ART were available, likely because the higher cost of initial tenofovir was offset by the alternative with other strategies, a higher-cost, tenofovir-containing second-line regimen. When only one line of ART was available, the cost of initial tenofovir was more important. These findings together emphasize the importance of policies enhancing access to second-line, and eventually third-line, treatment in optimizing the use of limited resources for HIV treatment. Patients with better adherence may be at greater risk for developing ART toxicities, since drug exposure is a risk factor for adverse events [29
]. Toxicities such as lipodystrophy and neuropathy may decrease both adherence and the durability of first-line ART, though this is not clear [30
]. To address these uncertainties, we varied the effectiveness advantage of tenofovir [7
]. Although some have shown that tenofovir and stavudine have similar virologic outcomes, we used data that likely reflect lower adherence over time for patients on stavudine due to more chronic toxicities, and we tested this assumption in sensitivity analyses [32
A very small study suggested that tenofovir combined with nevirapine rather than efavirenz may reduce virologic suppression [33
]. If these early findings are substantiated, the selection of a non-nucleoside reverse transcriptase inhibitor (NNRTI) for use with tenofovir should take this into account [2
The discounted total lifetime costs of three of the ART strategies (initial tenofovir, initial stavudine, and initial stavudine-to-zidovudine), were similar and all around $5,600. Patients who experienced virologic failure on initial tenofovir switched to a less expensive second-line regimen containing zidovudine. Because patients spend the remainder of their lives on the second-line regimen, total costs were about the same as for those who started on a less costly initial regimen. This suggests that second-line ART costs are more important contributors to total lifetime costs than first-line ART costs.
This analysis has several limitations. First, there are limited published data comparing the effectiveness of alternative ART regimens in resource-limited settings. For stavudine- and zidovudine-based first-line ART, we used data from an observational cohort in India, but for initial tenofovir we used US clinical trials, which may reflect better outcomes. We assumed that decreased long-term adherence is implicitly included in the higher long-term virologic failure rates for initial stavudine and zidovudine, and we examined this assumption in extensive sensitivity analyses. In a sensitivity analysis examining equal effectiveness (short-term and long-term) for all first-line ART regimens, we found that tenofovir resulted in equal discounted life expectancy as initial zidovudine, but tenofovir remained the only efficient first-line ART alternative, with an incremental cost-effectiveness ratio of $740/YLS compared to initial stavudine. We did not explicitly model loss to follow-up, but we did examine the consequence of reduced adherence on treatment outcomes using the long-term failure parameter and found that it would render tenofovir more attractive.
Second, there are limited data about ART toxicities in resource-limited settings. We used published data from India on adverse events related to stavudine and zidovudine but US-based estimates for nephrotoxicity and other toxicities. Sensitivity analyses () suggest that nephrotoxicity is unlikely to alter the finding that tenofovir represents an attractive component of first-line ART in resource-limited settings.
Third, this study did not examine outcomes for individuals co infected with HIV and hepatitis B. Given the burden of hepatitis B in India, this analysis likely underestimates the benefits of tenofovir-based therapy [34
Finally, there are scant data on the quality of life impact of ART in India [36
]. We found that including plausible quality of life effects increased the cost-effectiveness ratio of tenofovir-based first-line ART to $1,000 compared to no ART from the base case ratio of $670/YLS, but this higher ratio still represents the most efficient use of resources and meets criteria for cost-effectiveness. We examined the quality of life impact for only selected health states in the model.
Determining the best use of limited resources for HIV care is challenging, because the additional expense of initial tenofovir could potentially mean that some HIV-infected patients may not receive needed treatment. Thus, while initial tenofovir may be deemed cost-effective by WHO criteria, it could challenge short-term budget constraints in some countries.
This study has several implications for guidelines on first-line ART in India. While stavudine and zidovudine are effective components of first-line ART, recent substantial price reductions in tenofovir make it a very viable treatment option. As the cost of tenofovir continues to decline, its use will become even more attractive. Incorporating tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for HIV-infected patients in India.