As ART use increases in resource-limited settings and drug resistance follows, questions will arise regarding how to apply results from resistance surveillance programs. We used a simulation model of HIV infection to examine the role of sentinel resistance programs in informing national ART policies. The prevalence of primary resistance to NNRTI, within reasonably expected ranges, is not an important criterion in the selection of an optimal treatment regimen, when either one or two ART regimens are available in a country like Côte d’Ivoire. Even if PI costs decrease, we found that the increased efficacy of a boosted PI-based regimen in the face of NNRTI resistance is not enough to make it cost-effective to use initially, according to criteria described by the WHO and the Commission on Macroeconomics and Health.
In the absence of resistance, boosted PI- and NNRTI-based regimens have similar efficacy as initial regimens [21
]. When only a single regimen is available, the boosted PI-based regimen was preferable only at a fraction of its current cost (80%) or at very high rates (39%) of NNRTI resistance. In the case of two available regimens, the model inherently favors initiating with an NNRTI-based regimen and using a boosted PI-regimen subsequently. We assumed that, because NRTI options are currently limited in countries like Côte d’Ivoire, they would be ‘recycled’ in a second line of therapy. When immunological and clinical criteria are used to make ART decisions, rather than earlier switching based on HIV RNA testing, increased NRTI resistance may occur owing to ongoing viral replication and the development of thymidine analogue mutations [38
]. Therefore, when used as second line, the PI- or NNRTI-based regimen would likely have an efficacy similar to the addition of a single drug to an already resistant NRTI backbone. Since boosted PI monotherapy has greater efficacy than NNRTI monotherapy, the efficacy of a second-line boosted PI-based regimen would likely be superior to and more durable than that of an NNRTI-based regimen [32
]. Data are beginning to emerge suggesting that the efficacy of boosted PI monotherapy may, in fact, be greater than assumed in this analysis [39
]. This would move the sequencing decision toward starting with the NNRTI-based regimen followed by the PI-based regimen, regardless of the prevalence of resistance in the population. For this reason, following a boosted PI-based regimen with an NNRTI-based regimen may not seem clinically sensible; clinicians may prefer to maintain the partial suppressive benefit of the boosted PI-based regimen [32
]. If a switch is not made to the less expensive NNRTI-based regimen at the time of clinical failure of an initial boosted-PI based regimen, the results favoring starting with an NNRTI-based regimen would be further reinforced.
Despite the findings that information on the prevalence of NNRTI resistance from routine surveillance is unlikely to affect specific policies in settings similar to those in Côte d’Ivoire, there is clear value in continuing this resistance monitoring effort. The emergence of resistance is one quality measure of the ability of a public health infrastructure to deliver, and monitor adherence to, effective ART. Furthermore, the population prevalence of resistance may be helpful in developing strategies for the prevention of mother-to-child transmission [2
]. Finally, there is value in the knowledge of baseline resistance patterns in terms of HIV transmission and other population and epidemiological trends that are otherwise difficult to quantify.
This study should be interpreted within the context of its limitations. As is standard in model-based analyses, we compiled data from numerous sources to inform model input parameters. When data were not specifically from Côte d’Ivoire, we believe that they were from sources that were similar to those in Côte d’Ivoire. Because we found that the prevalence of NNRTI resistance should have little effect on treatment sequencing decisions, we anticipate that these results could be generalized to other resource-limited settings, although this would depend on the relative efficacy and cost of the particular regimens in a given setting. While the model included tuberculosis incidence and treatment costs, the advantages of using NNRTI-based therapy emerged even without considering the advantages of NNRTI therapy in the presence of concomitant tuberculosis therapy (i.e. rifampin) [40
Because of lack of available data in the general population, efficacy of the NNRTI-based regimen in the setting of nevirapine resistance was derived from women who had previously received nevirapine as part of a program to prevent mother-to-child transmission. While adherence may be better in these women than in the general population, the policy conclusions remained stable with regard to changes in this model variable. The calculation of resource use was based on clinical trial data, which may lead to an increase in follow-up visits and more detailed diagnostic work-ups, thereby overestimating true costs. Study results, however, were also robust to changes in resource use parameters. We also did not include quality adjustment, which weights years of life in proportion to their health-related quality; as such, all regimens will be even less cost-effective because more total life years are saved than quality-adjusted life years.
We restricted the analysis to the initial treatment decision, which is the most pressing question concerning primary NNRTI resistance and health outcomes for patients. While transmission of resistance and emergence of resistance to NRTI and PI will likely occur over time, we chose to focus on the challenging question of single-class resistance and its implications for drug sequencing. As data from sentinel resistance programs continue to emerge, future analyses should address the additional complexity of the possible resistance pattern combinations as well as transmitted resistance. While cost-effectiveness is only one of many criteria that help to inform policy decisions, costs remain a critical and often determining factor in settings where resources are scarce [9
]. Notably, the results of this analysis are presented with the intention of maximizing population-based health without an explicit consideration of equity. Patients with NNRTI resistance will have poorer treatment outcomes in a country where NNRTI drugs are favored. The importance of equitably distributing more costly therapies should not be understated; results of cost-effectiveness analyses may nonetheless help to inform these decisions [8
The emergence of drug resistance, both at the individual and the population level, is a complication of the life-sustaining benefits of ART. In resource-limited settings with few treatment options, among the biggest concerns is the development of resistance to the NNRTI class, especially with the widespread use of single-dose nevirapine to prevent mother-to-child HIV transmission [30
]. One of the stated goals for surveillance of resistance prevalence is to inform the rational use of ART and the revision of treatment guidelines. However, when cost-effectiveness criteria are used to inform guidelines, we found that sequencing strategies should be most influenced by other criteria, including drug costs and efficacy, rather than the prevalence of resistance.