Patient- and population-level health consequences of discontinuing antiretroviral therapy in settings with inadequate HIV treatment availability

While international initiatives to combat HIV have facilitated major increases in antiretroviral therapy (ART) availability, coverage remains limited [1]. The treatment gap relates to inadequate HIV detection and linkage to care [2], as well as drug stock-outs, funding constraints, and staff and space shortages, contributing to treatment suspensions and waiting lists [3–5]. These obstacles persist when international HIV treatment guidelines call for earlier ART initiation and consideration of additional antiretroviral regimens, which suggest an increasing demand for ART [6]. Changing political priorities and the global financial crisis have also jeopardized external financial commitments to HIV treatment and care [7].

Understanding the range of different treatment alternatives, as well as their associated benefits, costs, and uncertainty, can make trade-offs in clinical policy decisions more explicit. To understand the implications of one area — ART after treatment failure — our objective was to assess a policy of ART discontinuation after failure by creating a stylized depiction of antiretroviral therapy allocation. In so doing, we aimed to highlight trade-offs among competing policy goals of optimizing health outcomes for treated patients, health outcomes for treated and untreated patients, and the number receiving treatment when treatment availability is inadequate.

With evidence of recent funding shortfalls, continued obstacles to treatment provision, and flattening donor funding across resource-limited settings, we sought to assess the consequences and identify the trade-offs associated with one HIV treatment policy decision — antiretroviral discontinuation after treatment failure. To do so, we evaluated life expectancy for individual treated patients; life expectancy for an HIV-infected population, including treated and untreated individuals; and the number receiving treatment when discontinuing ART compared to the current standard of care (i.e., lifelong ART).

Results confirm that among treated individuals only, treatment discontinuation results in lower life expectancy and decreased treatment resource consumption. Among both treated and untreated individuals, however, discontinuing treatment among those who have failed it increases the total number of individuals receiving therapy, and thereby increases life expectancy per cohort among all newly detected HIV-infected individuals. This relationship holds across a variety of different assumptions, including many levels of treatment capacity, ART initiation criteria, number of treatment regimens, and timing of antiretroviral failure detection.

This research highlights concerns regarding the responsibility health care providers feel to patients directly under their care compared to those in the wider community. In this analysis, more deaths occur over the analytic time horizon for treated individuals under the Status Quo compared to the Alternative strategy. This finding underscores both clinical and ethical concerns in resource-limited settings. First, some fraction of deaths among treated individuals are deaths which would likely be avoidable with less misclassification of ART failure [28]. Out of concern for and responsibility to patients under their care, many health care providers would choose not to implement, or even consider, a treatment discontinuation policy unless a treated patient was not receiving any ART-related health benefits. In settings where HIV RNA and/or genotype tests are not available, a discontinuation policy implies ART may be withdrawn while it is still effective, due to discordance between immunologic and virologic failure and uncertainty regarding the underlying cause of virologic failure (e.g., non-adherence). Given the lack of adequate diagnostic surrogates for both HIV RNA and genotype tests, a discontinuation policy might only be feasible in settings with access to these tests.

Further, the increased number of deaths under the Alternative strategy, compared to the Status Quo, are deaths for which a health care provider would feel immediately responsible. Indeed, health care providers, as providers, would oppose a policy of treatment discontinuation because of their sense of obligation to offer the best treatment to patients under their care. This opposition might well continue even if another person could potentially benefit more from the discontinued treatment. Therefore, even if misclassification of antiretroviral failure were eliminated, concerns about patient abandonment and, for physicians, mindfulness of the Hippocratic Oath may well persist even if fewer deaths occurred in the overall HIV-infected population under the Alternative strategy compared to the Status Quo. For these reasons, when conflict exists between the health outcomes of individual patients in care and those of the larger community, it is important for clinicians and public health authorities to work closely together, so that policy discussions consider both the best interests of individual patients as well as the wider population.

Increasing treatment capacity over time highlights trade-offs associated with the goals of different treatment policies. With more modest capacity increases over time, discontinuing treatment not only maximizes life expectancy per cohort, but also allows more individuals to receive treatment, improving both efficiency and equity. With greater capacity increases over time, however, the Status Quo (i.e., not discontinuing treatment) maximizes life expectancy per cohort, yet does not allow more individuals to receive treatment. In this case, the greater health benefits associated with lifelong treatment outweigh the increased numbers of individuals who initiate, but later discontinue, ART. Therefore, efficiency improves but at the expense of equity. This illustrates the tension, given a specific treatment capacity, between keeping individuals on treatment longer and treating more people. While this model was developed to address efficiency concerns and maximize life expectancy per cohort, instances could arise in which concerns about equity override efficiency. This might occur, for example, if society values certain distributions of services (i.e., more individuals receiving ART under a discontinuation policy) more highly than overall population benefit resulting from a particular treatment policy.

While obstacles exist to implementing an antiretroviral discontinuation policy when treatment failure has occurred and treatment availability is inadequate, political challenges may limit the broader discussion and formulation of clearly articulated prioritization policies. Indeed, the adoption of such policies can be influenced by the prospect of far-reaching influence (e.g., a majority vote); targeted impact (e.g., interest groups, such as funding agencies, health authorities, or activists); political reward (e.g., media or public opinion polling, legacy, or mandates); or individual reward (e.g., seeking policies that will increase personal advantage at the expense of societal benefit), all of which policy makers may consider in the policy acceptance and/or implementation process [29–31].

While this study suggests greater public health benefits could be realized through implementation of the Alternative strategy when treatment availability is inadequate, additional challenges exist regarding explicit priority setting even when resources are severely constrained. Given the complexity of resource allocation decisions, Mechanic, while acknowledging the role of explicit rationing decisions in providing a framework for medical care, has cautioned against formal rationing in the doctor-patient relationship and the process of care provision [32]. He argues that the process of providing medical care develops both personally and iteratively, relying on patient trust and diverse preferences rather than the implementation of rigid standards and a one-size-fits-all approach. These personal relationships result in exceptions to the rule in the process of providing care. However, explicit rules or standards of care may lack flexibility in their implementation, may be subject to political manipulation, and may lag behind the changing reality of clinical care and uncertainty in the evidence base. In the current climate, he later argues, these challenges can begin to be met through several mechanisms, including patient advocacy within frameworks of procedural justice and fair process, expanded responsibility for population health, more collaborative and participatory partnerships with patients, and practicing of medicine that has transparent rationales and a clear evidence base [33]. Ham and Coulter propose an integrated approach to priority setting that they believe captures the complexity of allocation decisions in practice [34]. Recognizing that while explicit priority setting can enhance fairness, political accountability, and transparency, they cite the need for an improved informational and institutional base to inform decision making. Continued quantification and articulation of priority decisions by experts complemented by strengthened institutions that can better incorporate input from both experts and, in particular, the public are recommended [34].

This study has several limitations. First, we assume the number of treatment regimens available and antiretroviral regimen efficacy is fixed over time. We found, however, that the results hold with fewer as well as more antiretroviral regimens, though the impact is mitigated if more regimens are available. Second, similar to treatment slots, time on treatment was chosen as a proxy for the consumption of HIV treatment resources. Third, this analysis relied mainly on data available from Côte d’Ivoire, which may limit the generalizability of results. However, parameter estimates generally fall within the confidence intervals of data from other resource-limited settings, including first- and second-line ART effectiveness at 24 weeks and 18-month loss from care [27, 35–38]. While this allows drawing of broad policy conclusions about antiretroviral discontinuation after treatment failure, context-specific analyses that rely on sound, local data should be conducted in settings where complete treatment availability may be inadequate.

Fourth, while the population model implicitly includes costs in the treatment slot constraint, the analysis does not explicitly account for ART costs, a key driver of policy decisions in this context [39]. However, it is unlikely that policy conclusions would change were ART and opportunistic infection costs included in the analysis. This is because the higher cost of continued second-line ART after first-line antiretroviral failure under the Status Quo strategy would outweigh the combined costs of: (a) newly enrolled patients on less expensive first-line ART, including transaction or start-up costs associated with treatment enrollment, and (b) treatment for opportunistic infections among those discontinuing treatment under the Alternative strategy. Therefore, at the population level, the comparative advantage of the Alternative strategy compared to the Status Quo would remain similar or be strengthened if costs related to treatment and care were included.

Fifth, in the population model, we assume a steady state situation, in which there is a constant incidence of newly detected cases, distribution of patient characteristics of detected cases, and availability of treatment. In the short-term, as in the 5-year time horizon in this analysis, steady state assumptions may be plausible. For example, recent reports suggest that the HIV epidemic has stabilized in some sub-Saharan African countries [40], indicating that HIV incidence, and potentially, the incidence of newly detected patients, could remain relatively stable in the short-term in some settings. However, prevention effects of ART, which evidence shows decrease the risk of HIV transmission [41, 42], may result in lower numbers of newly HIV-infected individuals annually, lower numbers of newly detected cases annually, and potentially decreased demand for HIV treatment in the longer term. In addition, a larger fraction of treated individuals would have effective viral suppression under the Alternative strategy, which would increase the population health advantage of the Alternative strategy compared to the Status Quo. In the current economic climate of flat or decreasing HIV treatment budgets, it is also reasonable to assume that capacity, in the form of treatment slots, might remain constant over a fixed time horizon. However, if voluntary counseling and testing efforts and/or treatment scale-up efforts continue, it is unlikely that treatment demand, in the form of newly detected patients, and treatment capacity will remain fixed over time.

Finally, in the population-level model, we assume individuals could initiate ART only upon HIV case detection. In settings where HIV case detection occurs late in the course of disease (typically CD4 <200 cells/μL) [43], as in this analysis, the vast majority of individuals entering a treatment program are already ART eligible. Thus, precluding later treatment initiation once the eligibility criterion is met has little effect on the results. If individuals eligible to initiate treatment upon detection, but for whom no treatment slot was available were able to subsequently initiate ART, the health benefit achieved by these individuals would likely be less than among individuals initiating ART immediately upon detection. Therefore, in this model, which maximizes life expectancy per cohort, the remaining fraction of a previous cohort would not be selected to receive ART if competing with newly detected individuals who could achieve higher life expectancy.

As obstacles to providing HIV treatment persist in resource-limited settings, questions regarding resource allocation and priority setting necessarily emerge. Assessment of antiretroviral discontinuation policies can highlight the trade-offs associated with policy goals of maximizing life expectancy of treated individuals only, life expectancy of the entire population, and the number of individuals receiving treatment. While individuals receiving ART may continue to derive some treatment benefit even after virologic failure, the aggregate public health benefit is maximized by providing effective therapy to the greatest number of people. Individual- and population-level health trade-offs should be debated and discussed, with these trade-offs made explicit and more transparent in treatment policy decisions.

Preliminary results for this manuscript were presented in part at the Annual Meeting of the Society for Medical Decision Making [abstract 5218], October 24–27, 2010, Toronto, Canada.