RPW, XA, and RW participated in the World Health Organization Guidelines 2009 revision process, including the Peer Review Panel (XA) and Review Meeting 14–16 October, 2009, Geneva, Switzerland (RPW and RW).
Rochelle Walensky and colleagues use a model-based analysis to examine which of the 2010 WHO antiretroviral therapy guidelines should be implemented first in resource-limited settings by ranking them according to survival, cost-effectiveness, and equity.
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.
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).
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.
Since 1981, acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people, and about 33 million people (30 million of them in low- and middle-income countries) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections (so-called opportunistic infections). Early in the AIDS epidemic, most people with HIV died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART)—a combination of several powerful antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians care for people with HIV by prescribing ART regimens tailored to each individual's needs. They also regularly measure the amount of virus in their patients' blood, test for antiretroviral-resistant viruses, and monitor the health of their patients' immune systems through regular CD4 cell counts. As a result, the life expectancy of patients with HIV in developed countries has dramatically improved.
Initially, resource-limited countries could not afford to provide ART for their populations, and the life expectancy of HIV-positive people remained low. Now, through the concerted efforts of governments, the World Health Organization (WHO), and other international agencies, more than a third of the people in low- and middle-income countries who need ART are receiving it. However, many without access are still in need of ART, and ART programs in developing countries follow a public-health approach rather than an individualized approach. That is, drug regimens, clinical decision-making, and disease monitoring are all standardized and follow recommendations in the 2006 WHO ART guidelines. This year (2010), these guidelines were revised. The guidelines now recommend the following: earlier ART initiation—when the CD4 count falls below 350/µl of blood, instead of below 200/µl as in the 2006 guidelines; the provision of sequential ART regimens instead of a single regimen; and the replacement of the antiretroviral drug stavudine with tenofovir, a less toxic but more expensive drug, in first-line ART regimens. However, many resource-limited countries are still struggling to implement the 2006 guidelines, so which of these new recommendations should be prioritized? Here, the researchers use a mathematical model to address this question.
The Cost Effectiveness of AIDS Complications (CEPAC)–International model simulates the natural history and treatment of HIV disease. The researchers entered South African clinical and cost data for HIV treatment into this model and then used it to project survival and costs in a hypothetical group of South African HIV-positive patients under alternative guideline prioritization scenarios. The reference strategy for the simulations (denoted as “stavudine/WHO/one-line”) assumed that patients (with a mean CD4 count of 375/µl) began a single stavudine-based ART regimen when they developed WHO stage III/IV HIV disease (i.e., when patients develop multiple opportunistic infections such as tuberculosis and pneumonia). When the new guideline recommendations were considered separately, ART initiation at CD4<350/µl (stavudine/<350/µl/one-line) maximized five-year survival. Stepwise adjustment from the reference strategy (which had a life expectancy 99.0 months) through strategies of stavudine/<350/µl/one-line (a projected life expectancy of 124.3 months), stavudine/<350/µl/two-lines (177.6 months), and tenofovir/<350/µl/two-lines (193.6 months) produced the greatest improvements in life expectancy. Finally, strategies of stavudine/<350/µl/one-line, tenofovir/<350/µl/one-line, and tenofovir/<350µl/two-lines produced incremental cost-effectiveness ratios of US$610, US$1,140, and US$2,370 per year of life saved, respectively.
As with all mathematical models, the accuracy of these findings are dependent on the assumptions included in the model and on the data populating it. Nevertheless, these findings suggest that, where resources are limited and immediate implementation of all the new WHO recommendations is impossible, ART initiation at a CD4 count of less than 350/µl would provide the greatest survival advantage and would be very cost-effective. In countries that are already initiating ART at this threshold and that have access to CD4 monitoring, a switch from stavudine to tenofovir would further increase survival and would also be cost-effective. Finally, although access to second-line ART regimen would provide more clinical benefits than access to tenofovir, the cost of this change in strategy would be substantially greater. Importantly, these findings should help to avoid the complete dismissal of the revised WHO guidelines on the basis of cost and should help policy makers adjust their ART program strategies to maximize their clinical benefits and cost effectiveness.
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The 2006 World Health Organization (WHO) guidelines on antiretroviral therapy (ART) established a worldwide standard of care for patients with HIV infection
As WHO expands treatment recommendations, many countries in resource-limited settings still struggle to implement 2006 guidelines
The Cost Effectiveness of AIDS Complications (CEPAC)–International model is a Monte Carlo simulation model of the natural history and treatment of HIV disease (see
Clinical and policy decisions result in 12 possible implementation strategies. These strategies are listed in
When reporting clinical outcomes alone (per-person life expectancy), we provide undiscounted results. When clinical and economic results are used to create cost-effectiveness ratios, we adhere to established convention in discounting both at 3% per annum
Costs are converted to 2008 US dollars using the South African gross domestic product deflators and the 2008 mean exchange rate between the South African rand and the US dollar (8.23 rand = US$1)
The CEPAC-International model simulates the progression of disease in a hypothetical cohort of patients infected with HIV as a sequence of monthly transitions between health states. Health states are defined to be clinically and economically representative of the disease course and are stratified by current CD4 count, current HIV RNA level, and history of opportunistic disease. A graphical representation of a patient trace in South Africa is presented in
In strategies without available CD4 monitoring, decisions regarding ART initiation and switching are made based upon observation of any of the following severe opportunistic diseases representative of WHO stage III/IV disease: severe bacterial infection, severe fungal infection, tuberculosis, toxoplasmosis, nontuberculous mycobacteriosis,
The frequency of clinical and laboratory assessments in the model is user-defined. For this analysis, we have chosen clinical assessments to occur every 3 mo; in strategies where CD4 counts are available, they are modeled as being performed biannually. ART is initiated when one of two criteria is met: falling below a defined CD4 count threshold or the development of WHO III/IV disease (i.e., severe opportunistic disease). Effective ART in the model results in actual virologic suppression (independent of gender), a CD4 count increase, and a CD4-independent reduction in risk of opportunistic diseases and chronic AIDS death
Stavudine- or tenofovir-related toxicity occurs with a one-time probability, distributed over time since drug initiation. Depending on the nature of the toxicity, toxicity results in a one-time cost and/or a duration of costs spanning the time of increased need for care. Certain types of toxicity—including lactic acidosis, lipodystropy, neuropathy, and nephrotoxicity—also result in a single drug switch to zidovudine.
To converge on stable model output, we run a simulated cohort of 1 million patients infected with HIV. Because the cohort size can be varied in the simulation—i.e., we might also simulate 2 million or 5 million patients—95% confidence intervals and standard deviations (SDs) do not adequately capture uncertainty in simulation modeling. Instead, we adhere to the guidance of the US Panel on Cost-Effectiveness in Health and Medicine for reporting uncertainty in deterministic methods
Data sources for individual input parameters are referenced in
Variable | Estimate | Reference |
Age, mean years ± SD | 32.8±9.2 | |
Male (%) | 54.6 | |
Distribution of initial CD4, mean cells/µl (SD) | 375 (25) | Assumption |
HIV RNA distribution (%) | ||
>100,000 copies/ml | 42.5 | |
30,001–100,000 copies/ml | 28.3 | |
10,001–30,000 copies/ml | 17.9 | |
3,001–10,000 copies/ml | 7.8 | |
501–3,000 copies/ml | 2.3 | |
<500 copies/ml | 1.2 | |
Mean monthly CD4 decline (cells/µl) by HIV RNA stratum (copies/ml) | ||
>30,000 | 6.4 | |
10,001–30,000 | 5.4 | |
3,001–10,000 | 4.6 | |
501–3,000 | 3.7 | |
Monthly risk of severe opportunistic infections (%) |
||
Bacterial | 0.08–0.71 | |
Fungal | 0.02–2.22 | |
Tuberculosis | 0.21–1.96 | |
Toxoplasmosis | 0.00–0.06 | |
Nontuberculosis mycobacteriosis | 0.00–0.30 | |
|
0.00–0.12 | |
Other severe opportunistic infections | 0.25–2.57 | |
Monthly risk of mild opportunistic diseases (%) |
||
Fungal | 0.59–3.51 | |
Other | 2.51–3.10 | |
Severe bacteria | 49.8 | |
Mild fungal infections | −46.4 |
|
Toxoplasmosis | 83.2 | |
97.3 | ||
Other WHO stage IV defining diseases | 17.9 | |
First line: stavudine-based regimen | ||
HIV RNA suppression | 75% at 24 wk | |
CD4 count increase | 136 cells/µl at 48 wk | |
Probability of later failure (monthly, after 24 wk) | 0.02 |
|
First line: tenofovir-based regimen | ||
HIV RNA suppression | 85% at 24 wk (85%–95%) | |
CD4 count increase | 136 cells/µl at 48 wk | |
Probability of later failure (monthly, after 24 wk) | 0.01 |
|
Second line: lopinavir/ritonavir-based regimen | ||
HIV RNA suppression | 78% at 24 wk (40%–88%) | |
CD4 count increase | 151 cells/µl at 48 wk | |
Probability of later failure (monthly, after 48 wk) | 0.03 |
|
Stavudine-based regimen (range examined) | ||
Severe lactic acidosis | 1.7 (1.7–3.4) | |
Lipodystrophy | 1.3 (1.3–2.6) | |
Neuropathy | 2.6 (2.6–5.2) | |
Tenofovir-based regimen (range examined) | ||
Nephrotoxicity | 1.6 (1.6–3.2) | |
Anemia | 0.4 (0.4–0.8) | |
3% | ||
Co-trimoxazole prophylaxis (monthly) | 1.03 | |
Stavudine-based first-line ART (monthly) | 8.33 | |
Tenofovir-based first-line ART (monthly) | 17.00 (10.00–17.00) | |
Lopinavir/ritonavir second-line ART (monthly) | 55.75 (8.36–55.75) | |
Routine care (range by CD4, monthly) |
9.99–131.23 | |
Inpatient hospital care, per day | 224.25 | |
Outpatient hospital care, per visit | 10.87 | |
CD4 count test | US$25 (25–75) |
“Range examined” indicates that we examined both extreme and intermediate values within the specified ranges.
Range indicated by CD4 count; details by CD4 strata are presented in the
The percent monthly risk of mild fungal infections is increased by 46.4% in the presence of co-trimoxazole
Projected using published 24-wk data
Estimated from published 24- and 48-wk data
Estimated from published 24- and 48-wk data
We define an ART-naïve cohort of patients with HIV in South Africa, with mean age 32.8 y
All patients at model entry are provided co-trimoxazole prophylaxis, conferring protection against mild and severe bacterial infections,
When second-line ART is available, it is a lopinavir/ritonavir-based regimen with a 24-wk suppressive efficacy of 78%, a resultant CD4 count increase of 151 cells/µl, and a 0.03 monthly probability of virologic failure after 48 wk
We consider HIV-associated direct medical costs, including inpatient days, outpatient visits, medication costs, and laboratory tests, when available (
An untreated HIV-infected South African cohort starting with a mean CD4 count of 375 cells/µl (SD, 25 cells/µl) has a mean undiscounted life expectancy of 47.9 mo. A single-line stavudine-based ART regimen, initiated on development of WHO stage III/IV disease (“reference strategy”; stavudine/WHO/one-line) increases life expectancy to 99.0 mo.
Step | 5-y Survival (%) | Projected Life Expectancy (Months) | Δ Projected Life Expectancy (months) |
65 | 99.0 | — | |
(1) Switch from stavudine to tenofovir, or | 66 | 112.9 | 13.9 |
(2) Add CD4 monitoring capacity, initiate ART at CD4<200 cells/µl, or | 80 | 115.6 | 16.6 |
(3) Add second-line ART regimen, or | 66 | 121.4 | 22.4 |
87 | 124.3 | — | |
(1) Switch from stavudine to tenofovir, or | 89 | 144.8 | 20.5 |
91 | 177.6 | — | |
We use the following nomenclature to define the strategies: nucleoside analog used in first line/ART initiation criterion/number of available regimens. All strategies with initiation criteria indicated by a CD4 count threshold assume availability of CD4 count monitoring. For each step, the option that maximizes survival is shown in bold.
Model-generated survival curves are provided for no ART, the reference strategy, and the three steps in
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
Incremental cost-effectiveness analysis (
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
Strategy |
Discounted Cost | Discounted Per-Person Life Expectancy (Undiscounted) Months | Incremental Cost-Effectiveness Ratio (US$/YLS) |
No ART | 2,540 | 44.9 (47.9) | |
Stavudine/<200/µl/one-line | 5,740 | 97.3 (115.6) | Dominated |
Tenofovir/<350/µl/one-line | 6,870 | 118.3 (144.8) | 1,140 |
Tenofovir/<200/µl/one-line | 6,930 | 109.9 (133.9) | Dominated |
Tenofovir/WHO/one-line | 8,400 | 93.9 (112.9) | Dominated |
Stavudine/WHO/two-lines | 10,140 | 98.8 (121.4) | Dominated |
Tenofovir/WHO/two-lines | 10,640 | 105.0 (131.2) | Dominated |
Stavudine/<200/µl/two-lines | 11,460 | 127.0 (161.3) | Dominated |
Tenofovir/<200/µl/two-lines | 11,930 | 135.3 (175.5) | Dominated |
The reference strategy and the strategies selected in the stepwise progression in
We use the following nomenclature to define the strategies: nucleoside analog used in first line/ART initiation criterion/number of available regimens. All strategies with initiation criteria indicated by a CD4 count threshold assume availability of CD4 count monitoring; WHO indicates WHO stage III/IV disease.
Strongly dominated (more expensive but confer less clinical benefit than some other strategy)
Weakly dominated (more expensive but confer less clinical benefit than some combination of other strategies)
Thus, a country with a current stavudine/WHO/one-line policy (
Of the three efficient programs (
In sensitivity analyses, we examine changes in clinical input data required to alter the stepwise ordering of program additions. Modest reductions in the mean CD4 count of the cohort (to 250 cells/µl) show decreased clinical benefits to earlier ART initiation but no substantial changes in cost-effectiveness. When the mean CD4 count of the cohort is less than 100 cells/µl, the benefits of a policy change to earlier ART initiation are largely irrelevant (
Holding efficacy constant, results are very sensitive to the price of tenofovir; a decrease in the cost of tenofovir from US$135 to US$51 per person per year would make tenofovir both more effective and less costly than stavudine. Results are less sensitive to the costs of second-line regimens (15% of base case) and CD4 monitoring (three times base case), neither of which produced meaningful changes in cost-effectiveness results (
Further sensitivity analyses are detailed in the
The new 2010 WHO ART guidelines aim to promote public health interventions that “secure the greatest likelihood of survival and quality of life for the greatest number” of individuals with HIV. The reported guiding principles in the revision process include: (1) do no harm, (2) ensure access and equity, (3) promote quality and efficiency, and (4) ensure sustainability. Motivated by these tenets, the new guidelines recommend a single CD4-based ART initiation criterion for all populations, a switch from stavudine to tenofovir, and universally available second-line regimens
The additional outlays implied by the new guidelines stand in stark contrast to the resource-constrained reality encountered on the ground. Many countries are still striving to meet goals set by the now-superseded 2006 guidelines. The WHO estimates the current ART coverage rate across low- and middle-income countries to be 42%
Based on projected short- and long-term survival and cost-effectiveness results, we identify three critical messages. First, countries with very limited resources and still only one line of ART available should focus first on access to CD4 count monitoring and ART initiation at CD4<350 cells/µl. These should be implemented before switching from stavudine to tenofovir and prior to providing second-line ART. Although advising to use stavudine in the first-line regimen—with its inherent toxicities—may be seen as conflicting with the primary WHO principle “first, do no harm,” the switch from stavudine to tenofovir is the recommendation that provides the least overall increase in survival, according to the results presented here. Initiating stavudine-based ART at CD4<350 cells/µl, compared with clinically based ART initiation, provides immediate and substantial short-term survival benefits, yields the greatest life expectancy compared to other guideline components, and is cost-effective by international standards. In cases where most patients present to care with CD4 counts far below the ART initiation threshold (e.g., CD4<100 cells/µl), a policy of earlier ART initiation is neutral at worst—both in terms of cost and clinical outcomes—as it serves only to increase life expectancy among patients with less advanced disease.
Second, countries with currently one line of ART available but more resources should ensure access to CD4 count monitoring with ART initiation at CD4<350 cells/µl and then switch from stavudine to tenofovir, before making second-line ART available. Indeed, some countries have already responded to the 2010 WHO guidelines and have made plans to phase out stavudine
Third, in countries with sufficient budgets to provide second-line ART, it is neither effective nor cost-effective to maintain stavudine in first-line regimens. Second-line ART may offer additional efficiencies by decreasing the prevalence of resistant virus and leaving future drug regimen options available.
Once countries have the capacity to provide early ART initiation, tenofovir, and second-line regimens, there will be additional clinical and policy questions. Policy makers will be addressing what to do upon second-line failure; optimal third-line regimens will be in question. Expanded ART regimen availability leads to clinical need for timely ART switches and forces the issue of HIV RNA laboratory availability. Finally, timely ART initiation is currently limited by late presentation to care
It is important to highlight that full and immediate implementation of the comprehensive set of new guidelines is cost-effective by South African standards. But, while it is helpful to critically examine the survival and economic efficiency of alternative programmatic choices, “cost-effective” does not mean “affordable.” In the setting of clear budget constraints, the question of affordability may conflict with the political imperative that all persons receive the same care package. In this case, prioritization of equity over efficiency decreases mean life expectancy—sometimes by more than 1 y per person—for the same healthcare expenditure (
This analysis has several limitations. We report results from a cohort of HIV-infected individuals initiating ART. Although we believe the overall results would be consistent, this analysis does not specifically address ART programs with patients already in alternative stages of care, including some on first-line regimens, some on second-line regimens, and some who have previously accumulated drug-related toxicities. Such diversity within a cohort would require more individualized analyses. Additionally, a full budget impact analysis would be required to examine the number of patients in need of care, and to project the implications of each component of the WHO recommendation on program budgets over alternative time horizons.
Despite its limitations, this analysis represents the only systematic, scientific effort we are aware of that marshals the evidence base in support of implementing the WHO guidelines. The most unfortunate outcome upon release of the revised WHO guidelines would be either their complete dismissal on cost grounds alone, or the execution of more expensive—though easier to implement—interventions that offer less overall health benefit than other interventions.
In cases where the simultaneous implementation of all components of the 2010 WHO ART guidelines is beyond the reach of programs or countries, important prioritization questions emerge. This analysis suggests that CD4 count monitoring and ART initiation at CD4<350 cells/µl are the critical initial priorities. Replacing stavudine with tenofovir would further increase survival and would also be cost-effective. Adding a second-line ART regimen would provide large survival benefits, but with substantial increases in the necessary budgets.
ART scale-up strategies.
(0.62 MB DOC)
Course of disease.
(0.22 MB TIF)
Validation of South African natural history data in the CEPAC model.
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Patient survival in the first 5 y after model entry.
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WHO priorities: Technical appendix.
(0.27 MB DOC)
WHO priorities; sensitivity analyses addendum, part 1.
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WHO priorities; sensitivity analyses addendum, part 2.
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The authors thank Ji-Eun Park and Erin Rhode for their technical assistance.
antiretroviral therapy
Cost Effectiveness of AIDS Complications
standard deviation
World Health Organization
years of life saved