Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis

Abstract

Background: The new 2010 World Health Organization (WHO) HIV treatment guidelines recommend earlier antiretroviral therapy (ART) initiation (CD4<350 cells/µl instead of CD4<200 cells/µl), multiple sequential ART regimens, and replacement of first-line stavudine with tenofovir. This paper considers what to do first in resource-limited settings where immediate implementation of all of the WHO recommendations is not feasible.

Methods and findings: We use a mathematical model and local input data to project clinical and economic outcomes in a South African HIV-infected cohort (mean age = 32.8 y, mean CD4 = 375/µl). For the reference strategy, we assume that all patients initiate stavudine-based ART with WHO stage III/IV disease and receive one line of ART (stavudine/WHO/one-line). We rank-in survival, cost-effectiveness, and equity terms-all 12 possible combinations of the following: (1) stavudine replacement with tenofovir, (2) ART initiation (by WHO stage, CD4<200 cells/µl, or CD4<350 cells/µl), and (3) one or two regimens, or lines, of available ART. Projected life expectancy for the reference strategy is 99.0 mo. Considering each of the guideline components separately, 5-y survival is maximized with ART initiation at CD4<350 cells/µl (stavudine/<350/µl/one-line, 87% survival) compared with stavudine/WHO/two-lines (66%) and tenofovir/WHO/one-line (66%). The greatest life expectancies are achieved via the following stepwise programmatic additions: stavudine/<350/µl/one-line (124.3 mo), stavudine/<350/µl/two-lines (177.6 mo), and tenofovir/<350/µl/two-lines (193.6 mo). Three program combinations are economically efficient: stavudine/<350/µl/one-line (cost-effectiveness ratio, US$610/years of life saved [YLS]), tenofovir/<350/µl/one-line (US$1,140/YLS), and tenofovir/<350/µl/two-lines (US$2,370/YLS).

Conclusions: In settings where immediate implementation of all of the new WHO treatment guidelines is not feasible, ART initiation at CD4<350 cells/µl provides the greatest short- and long-term survival advantage and is highly cost-effective.

Figure 1. Clinical and policy decisions yield 12 implementation strategies.

Clinical and policy decisions result in 12 possible implementation strategies. These strategies are listed in Text S1. Squares represent decision points. The reference strategy is bolded. d4t, stavudine; TDF, tenofovir.

Figure 2. Model-projected survival curves.

Model-projected survival curves (undiscounted) of the reference strategy (stavudine/WHO/one-line) and the three strategies projected to maximize life expectancy in stepwise progression toward the 2010 WHO guidelines (see Results and Table 2 for details). Curves highlighting outcomes over the next 5 y are provided in Figure S4. The 20-y horizon is presented here, not to imply that HIV treatment will remain unchanged over this time horizon, but rather to demonstrate when different interventions will have meaningful survival impacts. Median survival increases from 90 mo with stavudine/WHO/one-line (reference strategy) to 121 mo with the addition of CD4 monitoring and ART initiation at CD4<350 cells/µl (stavudine/<350/µl/one-line, step 1) to 177 mo with the addition of a second-line ART regimen (stavudine/<350/µl/two-lines, step 2). A subsequent switch from stavudine to tenofovir results in a comparatively modest survival advantage, with a median survival increase to 196 mo (tenofovir/<350/µl/two-lines, step 3). The survival curve of step 3 represents what might be expected when allthe 2010 WHO treatment guidelines are fully implemented.

Figure 3. Clinical and economic outcomes of each of the scale-up interventions.

The clinical and economic outcomes of all combinations of scale-up interventions are examined. The efficient frontier (marked by the line) connects the non-dominated strategies in the cost-effectiveness plane. Strategies below and to the right of the efficient frontier are those that are either strongly or weakly dominated by other options (see Methods). As illustrated in the upper panel, strategies based on clinical criteria (WHO stage III/IV) alone fall far below the efficient frontier (lower right oval), indicating their relatively high cost for the comparative benefit gained. Strategies in the upper left oval are those representing CD4 monitoring and one line of ART. Strategies incorporating a second-line regimen (upper right oval) all confer large survival benefits but at increased costs. The lower panel examines potential country situations. For instance, a country with a current stavudine/WHO/one-line policy could switch to a tenofovir/<350/µl/one-line policy (open arrow) and both decrease projected per-person lifetime costs and improve survival. A country with a stavudine/<200/µl/one-line policy could decrease per-person costs and also improve outcomes by changing to a stavudine/<350/µl/one-line policy (solid arrowhead). Countries with a stavudine/<200/µl/two-lines policy would require increased per-person expenditures to achieve the survival benefits associated with tenofovir/<350/µl/two-lines (dotted arrow). To illustrate the impact of a policy requiring that all persons receive the same intervention, we examine the arbitrary affordability threshold of US$11,500 per person. The bracket (upper right) denotes the per person survival loss (14.5 mo) attributable to a policy requiring that all persons receive the same intervention.