When to start antiretroviral therapy in resource-limited settings

Abstract

Background: The results of international clinical trials that are assessing when to initiate antiretroviral therapy (ART) will not be available for several years.

Objective: To inform HIV treatment decisions about the optimal CD4 threshold at which to initiate ART in South Africa while awaiting the results of these trials.

Design: Cost-effectiveness analysis by using a computer simulation model of HIV disease.

Data sources: Published data from randomized trials and observational cohorts in South Africa.

Target population: HIV-infected patients in South Africa.

Time horizon: 5-year and lifetime.

Perspective: Modified societal.

Intervention: No treatment, ART initiated at a CD4 count less than 0.250 x 10(9) cells/L, and ART initiated at a CD4 count less than 0.350 x 10(9) cells/L.

Outcome measures: Morbidity, mortality, life expectancy, medical costs, and cost-effectiveness.

Results of base-case analysis: If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 x 10(9) cells/L would reduce severe opportunistic diseases by 22,000 to 221,000 and deaths by 25,000 to 253,000 during the next 5 years compared with ART initiation at 0.250 x 10(9) cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 10(9) cells/L. Compared with an initiation threshold of 0.250 x 10(9) cells/L, a threshold of 0.350 x 10(9) cells/L has an incremental cost-effectiveness ratio of $1200 per year of life saved.

Results of sensitivity analysis: Initiating ART at a CD4 count less than 0.350 x 10(9) cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%.

Limitation: This model does not consider the possible benefits of initiating ART at a CD4 count greater than 0.350 x 10(9) cells/L or of reduced HIV transmission.

Conclusion: Earlier initiation of ART in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 x 10(9) cells/L, earlier than is currently recommended.

Primary funding source: National Institute of Allergy and Infectious Diseases and the Doris Duke Charitable Foundation.

Figure 1

Decision tree outlining the ART strategy options over the next five years while awaiting “when to start” trial results. The payoffs in terms of both clinical outcomes and costs are delineated to the right of the tree. The probability, “p”, represents the chance that the trial will demonstrate a clinical benefit to ART at <350/μl. Using a cost-effectiveness willingness-to-pay threshold of 3 × the per capita GDP in South Africa ($16,200/YLS), the tree suggests an optimal policy of ART at <350/μl now for values of p such that: $$\$\mathrm{16,200}\ge \frac{[\text{pCosts}(\text{Branch A})+(1-\mathrm{p})\text{Costs}(\text{Branch B})-\text{Costs}(\text{Branch C})]}{[\text{pOutcomes}(\text{Branch A})+(1-\mathrm{p})\text{Outcomes}(\text{Branch B})-\text{Outcomes}(\text{Branch C})]}$$ As described in the Results section, values of p ≥ 0.17 satisfy this decision rule.

Figure 2

Model-based projections over the next five years, under an ART at <350/μl (in white) and an ART at <250/μl (in black) initiation strategy. Total deaths are indicated by squares and total opportunistic diseases by diamonds for the two strategies (left vertical axis). The excess total costs of ART at <350/μl compared to ART at <250/μl over a 5-year horizon are indicated by bars (right vertical axis). The x-axis represents results at varying proportions of HIV cases identified and linked to care in the population. (OD: opportunistic disease)

Figure 3

The incremental cost-effectiveness of ART at <350/μl vs. ART at <250/μl at alternative values of “p”, the probability that the trial will confirm model-based results indicating a benefit for earlier therapy (see Methods and Figure 1). The incremental cost-effectiveness is provided for the 5-year time horizon and reported in dollars per year of life saved. (YLS: years of life saved, GDP: per capita gross domestic product in South Africa (US$5,400)). The height of the bar provides the cost-effectiveness ratio of ART at <350/μl vs. ART at <250/μl for alternative values of p; bars that remain below the horizontal dashed line (<3× GDP) are considered to be “cost-effective” and those that remain below the horizontal dotted-dashed line (<1× GDP) are considred to be “very cost-effective.”

Figure 4

Model-generated survival curves for ART starting at <350/μl, <250/μl, or no ART (co-trimoxazole alone). The annual mortality hazard two years after entry into care was 0.01 for ART at <350/μl, 0.05 for ART at CD4 <250/μl, and 0.06 with no ART. Two years after entry into care, the composite annual hazard of severe opportunistic disease, tuberculosis, or death was 0.06 for ART at <350/μl, 0.16 for ART at CD4 <250/μl, and 0.17 with no ART (data not shown).