When to Start Antiretroviral Therapy in Resource-Limited Settings

  1. Rochelle P. Walensky, MD, MPH;
  2. Lindsey L. Wolf, SB;
  3. Robin Wood, FCP, MMed, DTM&H;
  4. Mariam O. Fofana, AB;
  5. Kenneth A. Freedberg, MD, MSc;
  6. Neil A. Martinson, MBBCh, MPH;
  7. A. David Paltiel, PhD;
  8. Xavier Anglaret, MD, PhD;
  9. Milton C. Weinstein, PhD;
  10. Elena Losina, PhD; and
  11. for the CEPAC (Cost-Effectiveness of Preventing AIDS Complications)-International Investigators*
  1. From the Massachusetts General Hospital, Brigham and Women's Hospital, Harvard University Medical School, Harvard School of Public Health, and Boston University School of Public Health, Boston, Massachusetts; University of Cape Town, Cape Town, and Perinatal HIV Research Unit, Johannesburg, South Africa; Johns Hopkins University, Baltimore, Maryland; Yale School of Medicine, New Haven, Connecticut; and Université Victor Segalen Bordeaux 2, Bordeaux, France.
     
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    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 × 109 cells/L, and ART initiated at a CD4 count less than 0.350 × 109 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 × 109 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 × 109 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 × 109 cells/L. Compared with an initiation threshold of 0.250 × 109 cells/L, a threshold of 0.350 × 109 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 × 109 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 × 109 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 × 109 cells/L, earlier than is currently recommended.

    Primary Funding Source: National Institute of Allergy and Infectious Diseases and the Doris Duke Charitable Foundation.

    Editors' Notes

    Context

    • Rapid control of HIV infection is especially important in resource-limited countries with high rates of opportunistic infections. Therapy initiation guidelines would be useful for South African physicians while awaiting the results of ongoing trials of different CD4 count thresholds for therapy initiation.

    Contribution

    • The investigators used a computer simulation of HIV disease to perform a cost-effectiveness analysis of 3 options: no treatment and thresholds of 0.250 and 0.350 × 109 cells/L. Compared with a threshold of 0.250 × 109 cells/L, starting at 0.350 × 109 cells/L was highly cost-effective, even when the probability that a trial would show its superiority was as low as 17%.

    Implication

    • Earlier antiretroviral therapy will probably prove to be superior in South Africa.

    —The Editors

    Recent data from cohort studies and mathematical models in the developed world suggest that treatment outcomes of HIV-infected patients improve when antiretroviral therapy (ART) is initiated at CD4 counts less than 0.350 × 109 cells/L or even 0.500 × 109 cells/L (1–4). The question of when to start ART in HIV-infected patients is even more critical in resource-limited settings, in the context of higher rates of mortality and opportunistic diseases—including tuberculosis and other severe bacterial infections—at CD4 counts greater than 0.200 × 109 cells/L (5). At CD4 counts between 0.200 and 0.350 × 109 cells/L, the rates of such opportunistic diseases in South Africa may be 10-fold higher than those seen in the United States (5, 6). Several international clinical trials, including one in South Africa, are currently enrolling patients. These trials will explicitly address the clinical benefits of earlier ART initiation (at CD4 counts <0.350 × 109 cells/L or <0.500 × 109 cells/L) compared with the current World Health Organization (WHO) standard of care (stage 3 or 4 disease or when CD4 counts decrease to <0.200 × 109 cells/L) (7–9).

    Although clinical trials may provide insight into the optimal timing of ART in resource-limited settings, they can only address short-term outcomes and will not be available to inform practice for several years (8, 9). Our objective is to inform crucial decisions now, until these trials are reported, by using a model-based analysis to examine treatment strategies with different ART initiation thresholds in South Africa.

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    Methods

    Analytic Overview

    Treatment Strategies

    Using a computer-based model of HIV disease, we examined the policy decision regarding when to initiate ART in South Africa. We considered 3 strategies for interim treatment until the results of the ART initiation trials are available: no treatment (for comparison purposes), initiate ART at a CD4 count less than 0.250 × 109 cells/L (or severe opportunistic disease) (7), and initiate ART at a CD4 count less than 0.350 × 109 cells/L (or severe opportunistic disease). We initiated cotrimoxazole prophylaxis at a CD4 count less than 0.500 × 109 cells/L in all strategies, in accordance with WHO recommendations (10). We examined the effect of this decision over both short-term (5-year) and lifetime horizons. We emphasize that all of these strategies would involve acting optimally on the results of the trials once they are available in 5 years.

    To report on cost-effectiveness, we adopted a modified societal perspective, considering only direct, HIV-associated use of medical resources. We reported all costs in 2006 U.S. dollars by using country-specific gross domestic product (GDP) deflators and the 2006 mean exchange rate between the South African rand and the U.S. dollar (6.8 rand = 1 U.S. dollar) (11, 12). We discounted all costs and life expectancies at 3% per year (13). The WHO guidelines designate health interventions as cost-effective if the cost per quality-adjusted life-year is less than 3 times the country's per-capita GDP, and very cost-effective if the cost per quality-adjusted life-year is less than the country's per-capita GDP (14, 15). Although our analysis computes cost-effectiveness ratios in terms of years of life saved (YLS) (rather than quality-adjusted life-years), these thresholds provide general guidance. As a reference point, we compared the results with South Africa's 2006 per-capita GDP (U.S. $5400) (11).

    Projections Over the Next 5 Years

    We first examined the policy over the next 5 years to inform decisions regarding whether it would be best to consider therapy at a CD4 count threshold of 0.350 × 109 cells/L rather than 0.250 × 109 cells/L while waiting for the clinical trial results. We did this in 2 steps. First, we projected the number of South African patients who would require ART over the 5-year time horizon and their anticipated short-term clinical outcomes (defined as deaths and opportunistic diseases) and costs under alternative ART initiation scenarios. To do so, we used model-based methods, similar to those previously described (16), to examine how many HIV-infected persons in South Africa would be eligible for ART at a CD4 count threshold of 0.350 × 109 cells/L versus 0.250 × 109 cells/L over the 5-year time horizon. This estimate assumes steady HIV incidence over the next 5 years and accounts for HIV- and non–HIV-related deaths that occur before reaching the 0.350 × 109 cells/L threshold.

    By combining data from the WHO and the President's Emergency Plan for AIDS Relief, we estimated the proportion of HIV-infected persons who were identified and linked to care in South Africa (Appendix 2) (17, 18). We estimated the effect if 10% (the proportion estimated to be receiving ART), 30% (the estimate of those receiving either ART or other, general President's Emergency Plan for AIDS Relief services), or 100% (as an upper bound) of patients were linked to care.

    Finally, we assumed that a clinical trial will provide perfect information in 5 years about whether using an ART initiation threshold of 0.350 × 109 cells/L is more efficacious than the current standard of care and developed a decision criterion under which it would be cost-effective (<3 × GDP) to invoke a policy of initiation at a CD4 count threshold of 0.350 × 109 cells/L now while awaiting clinical trial results. This criterion included a threshold value for the probability that the trials will demonstrate the superiority of starting ART at CD4 counts less than 0.350 × 109 cells/L.

    Developing a Decision Criterion

    To develop a decision criterion for earlier ART initiation now, we examined 2 potential policy scenarios (ART initiation at CD4 counts <0.350 × 109 cells/L vs. <0.250 × 109 cells/L) over the next 5 years and their associated clinical and economic outcomes (Figure 1). These outcomes excluded any long-term benefits, detriments, or costs potentially associated with either decision beyond the 5-year horizon. Although the calculated outcomes included ART-related toxicities, they also excluded any excess toxicity that might be associated with earlier ART beyond the 5-year horizon. If ART is initiated at a CD4 count less than 0.350 × 109 cells/L, the trial may demonstrate in 5 years that a 0.350 × 109 cells/L initiation threshold provides a benefit (probability P) or that it produces equivalent outcomes to a 0.250 × 109 cells/L threshold (probability 1 − P). In the latter case, the associated costs of a 0.350 × 109 cells/L initiation threshold include not only those of earlier initiation but also the HIV medical costs accrued because of the additional deaths ($536 each) and opportunistic diseases (ranging from $105 to $1006 each) anticipated with using a CD4 count threshold of 0.250 × 109 cells/L compared with those anticipated with using 0.350 × 109 cells/L (19). If ART is initiated at a CD4 count less than 0.250 × 109 cells/L over the next 5 years, clinical outcomes and costs would be those derived for the short-term strategy of initiating ART at CD4 counts less than 0.250 × 109 cells/L. Averaging out the simple tree in Figure 1, we created the decision rule under which it would be economically efficient to set the initiation threshold at 0.350 × 109 cells/L now. We defined this decision rule by examining alternative values for P and using the cost-effectiveness willingness-to-pay threshold of 3 times GDP ($16 200/YLS).

    Figure 1.
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    Figure 1. Decision tree that outlines ART strategy options over the next 5 years while trial results are pending.

    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 forthcoming trials studying ART initiation will demonstrate a clinical benefit of ART initiation at a CD4 count threshold of 0.350 × 109 cells/L. Using a cost-effectiveness willingness-to-pay threshold of 3 times the per-capita gross domestic product of South Africa ($16 200/year of life saved), the tree suggests that initiating ART at CD4 counts less than 0.350 × 109 cells/L now would be optimal for values of P such that $16 200 ≥ {[P × costs (left branch)] + [(1 − P) × costs (middle branch)] – [costs (right branch)]} ÷ {[P × outcomes (left branch)] + [(1 − P) × outcomes (middle branch)] – [outcomes (right branch)]}. As described in the Results section, values of P greater than 0.17 satisfy this decision rule. ART = antiretroviral therapy.

    Lifetime Projections

    After projecting 5-year outcomes, we then projected and compared the per-person life expectancy and mean lifetime HIV treatment costs for patients at CD4 count thresholds for ART initiation of 0.350 × 109 cells/L and 0.250 × 109 cells/L. We used these outcomes to produce incremental cost-effectiveness ratios; we used sensitivity analyses to examine the effect of key input parameters on the cost-effectiveness results.

    CEPAC International Model

    The CEPAC (Cost-Effectiveness of Preventing AIDS Complications) International model is a state-transition model of HIV disease in resource-limited settings, with data derived for several country-specific analyses, including South Africa (16, 20, 21). In brief, a cohort of hypothetical patients pass one at a time through health states, in monthly cycles, from entry into HIV care until death. Health states are defined to be both clinically and economically relevant and are stratified by current CD4 count, current HIV RNA level, and history of opportunistic disease. Opportunistic diseases are categorized into the following groups on the basis of cause, severity, and similarities in prophylaxis and treatment: mild or severe bacterial infections, mild or severe fungal infections, tuberculosis, toxoplasmosis, nontuberculous mycobacteriosis, Pneumocystis jiroveci pneumonia, and other mild and severe diseases (5). Deaths in the model occur from acute opportunistic events (within 30 days of the event), chronic AIDS (not within 30 days of an opportunistic disease), or non–HIV-related causes (22).

    Effective ART in the model functions to suppress HIV RNA level and increase CD4 count (23, 24). Beyond the beneficial effect of increased CD4 count on opportunistic diseases and chronic HIV-related death (5), ART results in an additional reduction in opportunistic diseases and chronic HIV-related death, as investigators in Côte d'Ivoire and the United States recently reported (25, 26). Clinical assessments are assumed to occur every 3 months and CD4 and HIV RNA testing every 6 months while receiving therapy, consistent with South African recommendations (27). In accordance with the current standard of care, the model uses 2 sequential lines of ART; the second line is initiated when observed CD4 count decreases by 30% from its peak observed on-treatment level or when a severe opportunistic disease is observed at least 6 months after initiation of therapy (27). In accordance with current treatment guidelines, the second regimen for each patient is continued until death (7, 28).

    Input Parameters

    Trial-Eligible Patients

    For the short-term projections, we developed a hypothetical cohort of HIV-infected patients who had the appropriate clinical attributes (Table 1). We defined both a prevalent HIV-infected cohort (to indicate those currently infected) and an incident HIV-infected cohort (to indicate those who will become infected and trial-eligible during the 5-year horizon) (see Appendix 2). We used previously described methods (16) to estimate the characteristics (CD4 count and viral load distribution) of the prevalent cohort in South Africa that might be eligible now at a CD4 count threshold for ART initiation of 0.350 × 109 cells/L. The mean CD4 count was 0.321 × 109 cells/L (SD, 0.146) for the prevalent cohort; 21% of patients in this cohort would be eligible for ART initiation at a threshold of 0.350 × 109 cells/L versus 0.250 × 109 cells/L. We also used projections from the Actuarial Society of South Africa to forecast the number of incident HIV infections anticipated over the 5-year trial horizon (29). The incident cohort had a mean CD4 count of 0.534 × 109 cells/L (SD, 0.164). In the first year after incident infection, 15% of patients in this cohort would be eligible for ART initiation at a threshold of 0.350 × 109 cells/L versus 0.250 × 109 cells/L.

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    Table 1. Model Input Parameters

    Because the CD4 counts and HIV RNA distributions of patients in the prevalent cohort and the incident cohorts differ, we derived survival data separately for each cohort. Using the CEPAC International model, we initialized the prevalent and incident cohorts to create a composite picture of the CD4 and HIV RNA distribution of each cohort, given their duration of infection (16). We projected the survival for HIV-infected patients who did not receive ART (for the no ART comparison) and those who began receiving ART at counts less than 0.350 × 109 cells/L and less than 0.250 × 109 cells/L (16). We calculated annual probabilities of survival (conditional on survival to the beginning of the year) by dividing the number of HIV-infected patients who were alive at the end of a given calendar year by the number who were alive at the end of the previous year. This reflects a patient's probability of surviving through the year, given that the patient was alive at the beginning of the year.

    Cohort Characteristics

    For the long-term projections, the simulated cohort was designed to resemble the characteristics of HIV-infected persons in South Africa. Clinical and demographic characteristics were based on data from the Cape Town AIDS Cohort (5). In the absence of specific data from South Africa, we obtained rates of CD4 count decrease, stratified by baseline HIV RNA level, from the Multicenter AIDS Cohort Study in the United States (Table 1) (30). We assumed that patients who entered the model were initiating HIV care and had a mean age of 32.8 years. For the long-term projections, we used a mean baseline CD4 count of 0.375 × 109 cells/L to simulate enrollment criteria for the ART initiation trials; 42.5% of patients had baseline HIV RNA levels greater than 100 000 copies/mL (Table 1).

    Opportunistic Disease Prophylaxis and Efficacy of Antiretroviral Therapy

    In the absence of reported data from South Africa, we derived the efficacy of cotrimoxazole prophylaxis in our model from clinical trials in Côte d'Ivoire (31, 32). In Côte d'Ivoire, cotrimoxazole confers protection against bacterial infections, P. jiroveci pneumonia, isospora and malaria, and toxoplasmosis; isospora infection and malaria are not reported in the South African data (Table 1) (20). We assumed that 2 sequential antiretroviral regimens would be available. First-line therapy was a nonnucleoside reverse transcriptase inhibitor–based regimen with which a reported 84% of patients experienced HIV RNA suppression at 48 weeks (mean CD4 count increase, 0.184 × 109 cells/L [interquartile range, 0.108 to 0.271 × 109 cells/L]) (23). Patients for whom the first-line regimen failed received a protease inhibitor–based second-line regimen. In this regimen, we incorporated the need for recycled nucleoside reverse transcriptase inhibitors, with a published estimate of 71% of patients experiencing HIV RNA suppression at 48 weeks (mean CD4 count increase, 0.151 × 109 cells/L [interquartile range, 0.105 to 0.239 × 109 cells/L]) (24).

    Costs

    We considered HIV-associated direct medical resource use, including inpatient days, outpatient visits, laboratory tests, and medication costs (19, 33–37). We excluded direct nonmedical costs and indirect costs (such as patient time and lost wages). We used a utilization analysis and unit costing approach to derive health care use from the Cape Town AIDS cohort (5, 19, 33). We derived costs on the basis of the number of inpatient hospital days and outpatient clinic visits associated with each type of opportunistic disease, or each month of routine HIV care in the absence of opportunistic disease, and the number of days and visits during the month of death.

    Role of the Funding Source

    The study was funded by the National Institute of Allergy and Infectious Diseases and the Doris Duke Foundation. The funding sources had no input in the study design, analysis and interpretation of data, writing of the report, or decision to submit for publication.

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    Results

    Outcomes Projected Over a 5-Year Horizon

    We estimated that 4.7 million HIV-infected persons in South Africa would become eligible to start ART if the CD4 count threshold is 0.350 × 109 cells/L instead of 0.250 × 109 cells/L over a 5-year time horizon. Among such persons, 1.2 million are eligible now, 1.6 million will be eligible over the next year, and 1.9 million will become eligible over the ensuing 3 years.

    For our assumptions that 10%, 30%, and 100% of these 4.7 million persons are identified and linked to care, we projected the opportunistic diseases, deaths, and costs over the next 5 years of alternative ART strategies while awaiting results of the ART initiation trials (Table 2). At the conservative HIV identification and linkage to care estimate of 10%, a CD4 count threshold of 0.350 × 109 cells/L for ART initiation would result in fewer total cases of opportunistic disease (1 599 900 vs. 1 622 000) and fewer total deaths (1 664 500 vs. 1 689 700) than a threshold of 0.250 × 109 cells/L. A threshold of 0.350 × 109 cells/L would also lead to a discounted $142 million cost increase over the next 5 years, which reflects the additional treatment costs (offset in part by the reduced incidence of opportunistic diseases). At the maximum estimate (100% identification and linkage to care), 221 000 cases of opportunistic disease and 253 000 deaths could be averted. In this situation, the additional costs of using a threshold of 0.350 × 109 cells/L would exceed $1.4 billion. Figure 2 provides results for the clinical and economic effect if between 10% and 100% of HIV-infected, eligible patients are identified and present for care. Clinical and cost results move together—the fewer patients identified, the fewer deaths and opportunistic diseases are averted and the lower the added total costs of an earlier ART initiation strategy.

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    Table 2. Clinical and Economic Outcomes of Both ART Initiation Strategies Over the Next 5 Years
    Figure 2.
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    Figure 2. Model-based projections over the next 5 years for strategies of ART initiation at CD4 count thresholds of 0.350 × 109 cells/L and 0.250 × 109 cells/L.

    Squares indicate total deaths and circles indicate total opportunistic diseases for the 2 strategies (left vertical axis). The bars indicate excess total costs of initiating ART at a threshold of 0.350 × 109 cells/L compared with 0.250 × 109 cells/L over a 5-year horizon (right vertical axis). The horizontal axis represents results at varying proportions of HIV cases identified and linked to care in the population. ART = antiretroviral therapy.

    Decision Criteria

    We then examined the probability that the data from the forthcoming trials would provide enough statistical evidence that a CD4 count threshold for ART initiation of 0.350 × 109 cells/L is superior to a 0.250 × 109 cells/L threshold—which would confirm the model-based results. If this is certain (100% probability), the incremental cost-effectiveness of a threshold of 0.350 × 109 cells/L compared with 0.250 × 109 cells/L is $2400/YLS, considering only the costs and benefits over the next 5 years. If the probability that the trials show a benefit to a threshold of 0.350 × 109 cells/L decrease to 10%, the incremental cost-effectiveness over the next 5 years would increase to $27 100/YLS. Using the established WHO cost-effectiveness guideline, a policy option to initiate ART at CD4 counts less than 0.350 × 109 cells/L should be used over the next 5 years if the probability that the trial will confirm model-based results is 17% or greater (Figure 3). In sensitivity analyses, we varied the composite increase in deaths associated with an ART initiation threshold of 0.250 × 109 cells/L versus 0.350 × 109 cells/L from 2-fold more deaths (base case) to 1.5-fold more deaths. The decreased benefits of the 0.350 × 109 cells/L threshold can simulate situations in which earlier therapy is less effective on an individual level than the model projects or linkage to care is lower at a threshold of 0.350 × 109 cells/L than at 0.250 × 109 cells/L because of the absence of clinical trial data. Under such a scenario, a policy option to initiate ART at CD4 counts less than 0.350 × 109 cells/L should be used over the next 5 years if the probability that the trial will confirm model-based results is 28% or greater (Appendix Figure).

    Figure 3.
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    Figure 3. Incremental cost-effectiveness of ART at CD4 count thresholds of 0.350 × 109 cells/L versus 0.250 × 109 cells/L at alternative probability values.

    P represents the probability that the trial will confirm model-based results indicating a benefit of earlier therapy (see Methods and Figure 1). The incremental cost-effectiveness is provided for the 5-year time horizon. The height of the bar provides the cost-effectiveness ratio of an initiation threshold of 0.350 × 109 cells/L versus 0.250 × 109 cells/L for alternative values of P; bars that remain below the horizontal solid line (<3 × GDP) are considered to be cost-effective and those that remain below the horizontal dotted line (<1 × GDP) are considered to be very cost-effective. ART = antiretroviral therapy; GDP = gross domestic product in South Africa (U.S. $5400); YLS = year of life saved.

    Appendix Figure.
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    Appendix Figure. Sensitivity analysis on the benefit of ART at a CD4 count less than 0.350 × 109 cells/L.

    Results from the model suggested a 2-fold decrease in the death rate with ART initiation at a CD4 count <0.350 × 109 cells/L. The vertical axis shows the threshold P value at which the trial will demonstrate a benefit of ART initiation at <0.350 × 109 cells/L and that also meets the cost-effectiveness threshold criterion of <$16 200 (3 times the gross domestic product of South Africa). The solid arrow indicates the 17% threshold discussed in the article; the open arrow indicates the results if the benefit of ART initiation at <0.350 × 109 cells/L were half (1.5) of what the model projected. ART = antiretroviral therapy.

    Lifetime Projections

    When we projected long-term outcomes for a cohort with a mean CD4 count of 0.375 × 109 cells/L, the no-treatment strategy resulted in a mean survival of 3.83 years (4.11 undiscounted), compared with 11.71 years (15.23 undiscounted) at a CD4 count threshold for ART initiation of 0.250 × 109 cells/L and 12.48 years (16.27 undiscounted) at a threshold of 0.350 × 109 cells/L (Table 3). The survival curves that corresponded to ART initiation thresholds of 0.350 × 109 cells/L and 0.250 × 109 cells/L diverged within about 1 year, after which time they became essentially parallel, when nearly all patients had initiated ART at a threshold of 0.250 × 109 cells/L; by year 3, initiation at CD4 counts less than 0.350 × 109 cells/L maintained a consistent 6% absolute advantage in the proportion of the cohort alive through year 10 (Figure 4). Per-person lifetime direct costs were lowest with no ART ($3930) (Table 3). Lifetime costs increased to $12 730 per person at an initiation threshold of 0.250 × 109 cells/L and $13 620 at 0.350 × 109 cells/L. The incremental cost-effectiveness ratio was $1100/YLS at a CD4 count threshold of 0.250 × 109 cells/L compared with no treatment and $1200/YLS at a threshold of 0.350 × 109 cells/L compared with 0.250 × 109 cells/L (Table 3).

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    Table 3. Life Expectancy, Cost, and Cost-Effectiveness of Strategies for HIV Care
    Figure 4.
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    Figure 4. Model-generated survival curves for ART.

    The annual mortality hazard 2 years after entry into care was 0.01 for a threshold of 0.350 × 109 cells/L, 0.05 for 0.250 × 109 cells/L, and 0.06 for no ART. Two years after entry into care, the composite annual hazard of severe opportunistic disease, tuberculosis, or death was 0.06 for a threshold of 0.350 × 109 cells/L, 0.16 for 0.250 × 109 cells/L, and 0.17 for no ART (data not shown). ART = antiretroviral therapy.

    Sensitivity Analyses on Lifetime Projections

    Because the long-term results consistently favored a CD4 count threshold for ART initiation of 0.350 × 109 cells/L, we designed the sensitivity analyses to bias against earlier initiation. Specifically, we examined large decrements in second-line antiretroviral efficacy in the earlier therapy strategies. Second-line efficacy would have to be fewer than 39% of patients achieving HIV RNA suppression at 48 weeks—a 32% relative decrease from the base case—to match the projected survival rate from using a threshold of 0.250 × 109 cells/L. To examine the effect of pill fatigue and failed retention in care (38, 39), we also considered higher rates of discontinuation of care. We assumed that some patients who started ART at CD4 counts less than 0.350 × 109 cells/L discontinued ART at the time they would have started receiving second-line regimens, thereby only realizing the benefits of first-line therapy (although they still received prophylaxis and treatment for opportunistic diseases). More than 19% of patients who received ART at a threshold of 0.350 × 109 cells/L at the time of treatment failure would need to discontinue treatment to decrease survival to that associated with a threshold of 0.250 × 109 cells/L. Finally, when we included a hypothetical third-line antiretroviral regimen, survival and costs increased for both ART treatment strategies. The incremental cost-effectiveness of using a threshold of 0.350 × 109 cells/L was largely unchanged from that of using 0.250 × 109 cells/L ($1000/YLS). Appendix 2 provides detailed results of these and other analyses.

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    Discussion

    Although the forthcoming trials in South Africa and other resource-limited settings should yield important information in the next 5 to 10 years, our analysis suggests that, until trial data are available, a CD4 count threshold of 0.350 × 109 cells/L for initiating ART would probably yield better clinical outcomes than a lower threshold. The magnitude of such benefits multiply with increased rates of HIV identification and linkage to care. A threshold of 0.350 × 109 cells/L is also expected to be highly cost-effective in the interim. Many of the clinical benefits of starting earlier occur beyond the 5-year time horizon of the trial (manifested in increased life expectancy). Even so, our results suggest that a threshold of 0.350 × 109 cells/L remains cost-effective if the probability is 17% or greater that the forthcoming trials will demonstrate improved clinical outcomes with starting ART earlier.

    When ART is initiated according to current treatment guidelines, we found that an ART initiation threshold of 0.250 × 109 cells/L is very cost-effective in the long term for HIV infection in South Africa, with a ratio of $1100/YLS (7); for a threshold of 0.350 × 109 cells/L, the cost-effectiveness ratio is $1200/YLS. That these ratios are similar suggests that if HIV treatment is worth initiating, early initiation provides similar value to later treatment. We specifically designed sensitivity analyses to see how these results might change and found that very high rates of drug resistance and pill fatigue would be required to make earlier therapy not cost-effective. Because our results depend heavily on the frequency of opportunistic diseases at higher CD4 counts, morbidity rates should be assessed carefully at high CD4 counts; initiation of therapy at a greater CD4 count threshold than 0.350 × 109 cells/L may be justified in South Africa.

    Conducting the current trials remains critically important in informing the question of when to start ART. Evidence-based guidelines continue to maintain that randomized, controlled trials are the gold standard for developing policy; modeling analyses are still considered lower levels of evidence (40, 41). As such, randomized trials will probably be used as the benchmark evidence for HIV treatment throughout the world. Meanwhile, our model-based analysis suggests that opening up the option to start ART earlier in the disease course would probably improve clinical outcomes, at least until trial results are available. Our results suggest that 25 000 lives may be at stake; waiting 5 years for trial results could be costly in human terms.

    Despite findings that a CD4 count threshold for ART initiation of 0.350 × 109 cells/L may be beneficial, a study on patient characteristics at presentation to care in South Africa suggests that a discussion of earlier versus deferred ART initiation may not be germane at present; in that study, the mean CD4 count of patients who started ART was only 0.096 × 109 cells/L (42). However, wider implementation of the WHO guidelines for using HIV testing technologies (43) and improved HIV screening and linkage to care should result in the identification of more patients who are eligible for earlier therapy initiation (7). Decisions need to be made on how best to optimize their care, and efforts to identify them must continue if a policy of earlier therapy is to have a meaningful effect. Our analysis demonstrates that a CD4 count threshold of 0.350 × 109 cells/L is highly effective and confers similar value to a threshold of 0.250 × 109 cells/L.

    However, an ART initiation threshold of 0.350 × 109 cells/L may not be optimal in some cases, such as when treatment capacity is limited—as is currently the case in many places (16). In such settings, prioritization—whether ART should be provided on a first-come, first-served basis or on a CD4 count–based policy—is already problematic (44). With inadequate treatment capacity, increasing the treatment initiation threshold for all patients to a CD4 count of 0.350 × 109 cells/L, without prioritization for the sickest patients, could result in more deaths in the near term, even if earlier therapy is associated with long-term benefits. Thus, guidelines that move toward ART initiation at higher CD4 counts should be implemented only in settings with adequate capacity to treat all of those who are eligible and at highest risk.

    Our study has limitations. First, this analysis does not represent an assessment of the estimated value of perfect information, which would examine whether the trial is worth doing. Because trials are already enrolling, we address the question of the optimal clinical strategy while awaiting the results of those trials. Second, we incorporated input data from multiple sources. Although they were uniformly derived, not all data are from similar cohorts in South Africa. Sensitivity analyses demonstrate that within reasonable reported ranges, our major conclusions are robust to these data estimates. Third, implementation of ART strategies by CD4 threshold in international settings—where CD4 testing is not universally available—may require investments in infrastructure. Fourth, our model does not account for the potential benefits of ART, unrelated to opportunistic diseases, that might be attributable to treatment at CD4 thresholds higher than the current standard of care (45). We also do not capture any additional benefits in preventing HIV transmission that earlier ART may confer because of viral load reduction (46). To the extent that these benefits occur, earlier therapy would be even more advantageous. Finally, earlier therapy may have other additional benefits in African countries that have higher rates of malaria and bacterial diseases than those documented in South Africa (5, 31).

    Ongoing randomized trials are studying the question of when to initiate ART in resource-limited settings. As these trials continue to enroll and accrue follow-up toward the primary outcomes, decisions must be made now regarding the optimal ART initiation policy in these settings. While we await trial results in settings of adequate treatment capacity, this study demonstrates that it is probably both effective and cost-effective to liberalize the opportunity for ART to be initiated at a CD4 count threshold of 0.350 × 109 cells/L in South Africa.

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    Appendix 1: CEPAC-International MembersGraphic

    We are indebted to the entire CEPAC-International team and investigators for their contributions, including Eugène Messou, Catherine Seyler, and Siaka Touré (Programme PACCI, Abidjan, Côte d'Ivoire); Yazdan Yazdanpanah (Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, EA 2694, Faculté de Médecine de Lille, and Laboratoire de Recherches Économiques et Sociales, Centre National de la Recherche Scientifique Unité de Recherche Associée 362, Lille, France); Nagalingeswaran Kumarasamy and J. and A.K. Ganesh (Y.R. Gaitonde Centre for AIDS Research and Education, Chennai, India); Glenda Gray, James McIntyre, and Lerato Mohapi (Perinatal HIV Research Unit, WITS Health Consortium, Johannesburg, South Africa); Kara Cotich, Sue Goldie, C. Robert Horsburgh, April Kimmel, Marc Lipsitch, Alethea McCormick, Chara Rydzak, George R. Seage III, and Hong Zhang (Harvard School of Public Health, Boston, Massachusetts); Heather E. Hsu (University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania); Ingrid V. Bassett, Melissa A. Bender, Sarah Chung, Andrea Ciaranello, Benjamin P. Linas, Zhigang Lu, Brandon Morris, Anjali Saxena, Caroline Sloan, Lauren Uhler, and Bingxia Wang (Massachusetts General Hospital, Boston, Massachusetts).

    We are also indebted to the CEPAC-International Scientific Advisory Board, including Richard Chaisson (Johns Hopkins University, Baltimore, Maryland); Victor De Gruttola (Harvard School of Public Health, Boston, Massachusetts); Joseph Eron (University of North Carolina, Chapel Hill, North Carolina); R.R. Gangakhedkar (National AIDS Research Institute, Pune, India); Jonathan Kaplan (Centers for Disease Control and Prevention, Atlanta, Georgia); Salim Karim (University of KwaZulu Natal, Durban, South Africa); Thérèse N'Dri Yoman (University of Cocody-Abidjan, Abidjan, Côte d'Ivoire); Douglas Owens (Stanford University, Palo Alto, California); and John Wong (Tufts Medical Center, Boston, Massachusetts).

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    Appendix 2: Technical AppendixGraphic

    We offer this technical appendix to provide supplementary data to reviewers regarding requested model input parameters and further sensitivity analyses.

     
    Next Section

    Methods

    Appendix Table 1 provides the calculations we used to project the number of persons eligible, by year, for the treatment decision of ART initiation at a CD4 count threshold of 0.350 × 109 cells/L versus 0.250 × 109 cells/L.

    View this table:
    Appendix Table 1. Calculations Used to Determine the Eligible Cohort

    Appendix Table 2 provides estimates of HIV-infected persons who were identified and linked to care in 3 countries. These estimates are obtained in part from WHO country-specific reports on the number of persons living with HIV/AIDS (17) and from the President's Emergency Plan for AIDS Relief reports on the number of HIV-infected persons who received care and support in fiscal year 2008 as well as those who received ART (18).

    View this table:
    Appendix Table 2. Estimates of HIV-Infected Persons Identified and Linked to Care in 3 African Countries

    Appendix Table 3 provides the monthly risk for opportunistic diseases, stratified by the CD4 cell counts used in the model (Table 1 provides a summary of these data).

    View this table:
    Appendix Table 3. Monthly Risk for Opportunistic Diseases, by CD4 Count
    Previous Section
     

    Results

     
    Next Section

    Sensitivity Analysis of Trial Projections

    Table 2 indicates an approximate 2-fold increase in total deaths at a CD4 count threshold for ART initiation of 0.250 × 109 cells/L compared with 0.350 × 109 cells/L over a 5-year horizon. Because this 2-fold estimate results from model output, many degrees of freedom within the model inform this estimate, including rates of opportunistic diseases, deaths associated with those events, ART efficacy, and AIDS-related mortality itself.

    We examined the composite death rates of model output from the 2 ART strategies, diminishing the benefit of a CD4 count threshold for ART initiation of 0.350 × 109 cells/L from 2.0 to 1.1. For example, if the initial death rate in year 1 was 0.03 when using a threshold of 0.350 × 109 cells/L and 0.07 when using 0.250 × 109 cells/L, then our sensitivity analysis for a benefit of 1.5 examined a new death rate for year 1 of 0.05 for a threshold of 0.350 × 109 cells/L ([(0.07 − 0.03) × 0.5] + 0.03). For each sensitivity analysis, we determined this adjusted death rate in every year of the 5-year horizon. We used a similar approach with our estimates of opportunistic diseases (decreasing the benefit of a 0.350 × 109 cells/L threshold by half) and used detailed model output to adjust the effect this would have on costs. For increasing benefits of a threshold of 0.350 × 109 cells/L (ranging from 1.0 [no benefit] to 2.0 [our results]), the Appendix Figure provides alternative values for P that meet the following 2 criteria: the trial demonstrates superiority of an ART initiation threshold of 0.350 × 109 cells/L and the cost-effectiveness ratio (over 5 years) is less than $16 200/YLS (<3 × GDP). The solid arrow indicates the threshold P value of 17%; at a value of 1.5 (half the benefit that our model suggests for a threshold of 0.350 × 109 cells/L), the value for P is 28%, indicated by the hollow arrow.

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    Sensitivity Analyses on Lifetime Projections

    Because the results of the lifetime analyses consistently favored earlier therapy, we designed sensitivity analyses to bias against earlier initiation. Specifically, we examined large decrements in second-line antiretroviral efficacy in the 0.350 × 109 cells/L strategies; presumed poorer downstream adherence in the 0.350 × 109 cells/L strategies; and included a third-line antiretroviral regimen, which potentially decreased the survival benefit of initiating ART at 0.350 × 109 cells/L.

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    Efficacy and Cost of Antiretroviral Therapy

    First-line therapy efficacy varied from 79% to 94% of patients achieving HIV RNA suppression at 48 weeks (base case, 84%), with minimal effect on the life expectancy and cost-effectiveness ratios of ART initiation at 0.350 × 109 cells/L compared with 0.250 × 109 cells/L (Appendix Table 4). Assuming that a third line of available antiretrovirals (at the same cost and efficacy as the second-line regimen) increased survival and costs in both the 0.350 × 109 cells/L and 0.250 × 109 cells/L strategies, the incremental cost-effectiveness of earlier therapy improved to $1100/YLS compared with deferred therapy. Changes in the cost of antiretroviral drugs from 50% to 200% of the base case altered the cost-effectiveness ratio of earlier compared with deferred therapy from $800 to 2400/YLS (Appendix Table 4).

    View this table:
    Appendix Table 4. Selected Sensitivity Analyses and Results for the Projected Cost-Effectiveness of Earlier ART Initiation
    Previous Section
     

    Discontinuation of Antiretroviral Therapy

    To examine the effect of pill fatigue and failed retention in care, we considered increasing rates of discontinuation of care. Specifically, we assumed that some patients discontinued antiretroviral therapy at the time they would have started receiving a different regimen, thereby only realizing the benefits of first-line therapy (although they still received prophylaxis and treatment for opportunistic diseases). More than 19% of patients who received therapy at a CD4 count threshold of 0.350 × 109 cells/L would need to discontinue treatment to decrease survival to that associated with deferred therapy. We also considered discontinuation of antiretroviral therapy at thresholds of 0.350 and 0.250 × 109 cells/L. If the rate of discontinuation at a threshold of 0.250 × 109 cells/L was similar to that at 0.350 × 109 cells/L, the benefits of earlier therapy diminished as the rates of discontinuation increased; for example, the increase in life expectancy associated with a threshold of 0.350 × 109 cells/L compared with 0.250 × 109 cells/L was 0.8 year with no discontinuation, 0.7 year with 20% discontinuation, and 0.5 year with 50% discontinuation.

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    Article and Author Information

    • Acknowledgment: The authors thank Daniel R. Kuritzkes, MD; Paul E. Sax, MD; and Bethany Morris.

    • Grant Support: By the National Institute of Allergy and Infectious Diseases (R01 AI058736, K24 AI062476, P30 AI060354, and U01 AI068634) and the Doris Duke Charitable Foundation (Clinical Scientist Development Award).

    • Potential Financial Conflicts of Interest: None disclosed.

    • Reproducible Research Statement: The authors have provided a detailed technical appendix (Appendix 2) for this and many other CEPAC papers. This appendix describes the depth of model structure and the breadth of the input parameters; for further questions, please contact Dr. Walensky.

    • Requests for Single Reprints: Rochelle P. Walensky, MD, MPH, Division of General Medicine, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.

    • Current Author Addresses: Drs. Walensky, Freedberg, and Losina; Ms. Wolf; and Ms. Fofana: Massachusetts General Hospital, Division of General Medicine, 50 Staniford Street, 9th Floor, Boston, MA 02114.

    • Dr. Wood: Institute of ID and Molecular Medicine, University of Cape Town Faculty of Health Sciences, Anzio Road, Observatory 7925, Cape Town, South Africa.

    • Dr. Martinson: WITS Health Consortium, 8 Blackwood Ridge, Parktown, Johannesburg, 2193 South Africa.

    • Dr. Paltiel: Yale University School of Medicine, 60 College Street, New Haven, CT 06520.

    • Dr. Anglaret: Unité Inserm 897, Université Bordeaux-2, 146 rue Léo-Saignat, 33076 Bordeaux, France.

    • Dr. Weinstein: Harvard School of Public Health, Department of Health Policy and Management, Program in Health Decision Science, 718 Huntington Avenue, Boston, MA 02115.

    • Author Contributions: Conception and design: R.P. Walensky, L.L. Wolf, R. Wood, K.A. Freedberg, A.D. Paltiel, M.C. Weinstein.

    • Analysis and interpretation of the data: R.P. Walensky, L.L. Wolf, R. Wood, M.O. Fofana, K.A. Freedberg, X. Anglaret, M.C. Weinstein, E. Losina.

    • Drafting of the article: R.P. Walensky.

    • Critical revision of the article for important intellectual content: R.P. Walensky, R. Wood, K.A. Freedberg, N.A. Martinson, A.D. Paltiel, X. Anglaret, M.C. Weinstein, E. Losina.

    • Final approval of the article: R.P. Walensky, L.L. Wolf, R. Wood, M.O. Fofana, K.A. Freedberg, N.A. Martinson, A.D. Paltiel, X. Anglaret, M.C. Weinstein, E. Losina.

    • Statistical expertise: M.C. Weinstein, E. Losina.

    • Obtaining of funding: R.P. Walensky, K.A. Freedberg.

    • Administrative, technical, or logistic support: L.L. Wolf, M.O. Fofana.

    • Collection and assembly of data: R. Wood, N.A. Martinson.

    • ↵* For a list of the CEPAC-International investigators, see Appendix 1.

    Previous Section
     

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