All authors helped design the study, analyse the results, and write the paper.
SG owns shares in GlaxoSmithKline and Astra Zeneca. The other authors declare that they have are no competing interests.
The roll-out of antiretroviral treatment (ART) in developing countries concentrates on finding patients currently in need, but over time many HIV-infected individuals will be identified who will require treatment in the future. We investigated the potential influence of alternative patient management and ART initiation strategies on the impact of ART programmes in sub-Saharan Africa.
We developed a stochastic mathematical model representing disease progression, diagnosis, clinical monitoring, and survival in a cohort of 1,000 hypothetical HIV-infected individuals in Africa. If individuals primarily enter ART programmes when symptomatic, the model predicts that only 25% will start treatment and, on average, 6 life-years will be saved per person treated. If individuals are recruited to programmes while still healthy and are frequently monitored, and CD4+ cell counts are used to help decide when to initiate ART, three times as many are expected to be treated, and average life-years saved among those treated increases to 15. The impact of programmes can be improved further by performing a second CD4+ cell count when the initial value is close to the threshold for starting treatment, maintaining high patient follow-up rates, and prioritising monitoring the oldest (≥ 35 y) and most immune-suppressed patients (CD4+ cell count ≤ 350). Initiating ART at higher CD4+ cell counts than WHO recommends leads to more life-years saved, but disproportionately more years spent on ART.
The overall impact of ART programmes will be limited if rates of diagnosis are low and individuals enter care too late. Frequently monitoring individuals at all stages of HIV infection and using CD4 cell count information to determine when to start treatment can maximise the impact of ART.
Using a stochastic model based on data from Africa, Timothy Hallett and colleagues find that starting HIV treatment based on regular CD4 monitoring, rather than on symptoms, would substantially increase survival.
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first case in 1981, and about 33 million people are currently 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. Early in the AIDS epidemic, most HIV-positive individuals died within 10 years but in 1996, combination antiretroviral therapy (ART)—a mixture of powerful but expensive antiretroviral drugs—was developed. For HIV-positive people living in affluent, developed countries who could afford ART, AIDS then became a chronic disease, but for those living in low- and middle-income countries it remained a death sentence—ART was too expensive. In 2003, this lack of access to ART was declared a global health emergency and governments, international organizations, and funding bodies began to implement plans to increase ART coverage in developing countries.
The roll-out of ART in developing countries has concentrated so far on finding HIV-positive people who currently need treatment. In developing countries, these are often individuals who have AIDS-related symptoms such as recurrent severe bacterial infections. But healthy people are also being diagnosed as HIV positive during voluntary testing and at antenatal clinics. How should these HIV-positive but symptom-free individuals be managed? Should regular health-monitoring appointments be scheduled for them and when should ART be initiated? Management decisions like these will determine how well patients do when they eventually start ART, as well as the demand for ART and other health-care services. The full range of alternative patient management strategies cannot be tested in clinical trials—it would be unethical—but public-health officials need an idea of their relative effectiveness in order to use limited resources wisely. In this study, therefore, the researchers use mathematical modeling to investigate the impact of alternative patient management and ART initiation strategies on the impact of ART programs in resource-poor settings.
The researchers' mathematical model, which includes data on disease progression collected in Africa, simulates disease progression in a group (cohort) of 1,000 HIV-infected adults. It tracks these individuals from infection, through diagnosis and clinical monitoring, and into treatment and predicts how many will receive ART and their length of survival under different management scenarios and ART initiation rules. The model predicts that if HIV-positive individuals receive ART only when they have AIDS-related symptoms, only a quarter of them will ever start ART and the average life-years saved per person treated will be 6 years (that is, they will live 6 years longer than they would have done without treatment). If individuals are recruited to ART programs when they are healthy and are frequently monitored using CD4 cell counts to decide when to start ART, three-quarters of the cohort will be treated and 15 life-years will be saved per person treated. The impact of ART programs will be increased further, the model predicts, by preferentially monitoring people who are more than 35 years old and the most immunosuppressed individuals. Finally, strategies that measure CD4 cells frequently will save more life-years because ART is more likely to be started before the immune system is irreversibly damaged. Importantly for resource-poor settings, these strategies also save more life-years per year on ART.
As with all mathematical models, the accuracy of these predictions depends on the assumptions built into the model and the reliability of the data fed into it. Also, this model does not estimate the costs of the various management options, something that will need to be done to ensure effective allocation of limited resources. Nevertheless, these findings provide several general clues about how ART programs should be implemented in poor countries to maximize their effects. Early diagnosis of infections, regular monitoring of patients, and using CD4 cell counts to decide when to initiate ART should all help to improve the number of life-years saved by ART. In other words, the researchers conclude, effectively managing individuals at all stages of HIV infection is essential to maximize the impact of ART.
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Guidelines for antiretroviral therapy in adults and adolescents are provided by the
For a decade, HIV-infected persons in developed countries whose clinical course is advancing towards AIDS have been offered combination antiretroviral therapy (ART); this practice has generated a sharp decline in the rate of AIDS deaths [
Survival of HIV-infected individuals on ART depends on the state of their immune system when treatment is begun [
Whilst a great deal of work has focussed on the optimal state at which to initiate ART [
Our stochastic cohort model represents 1,000 individuals infected with HIV. Each individual is assigned particular characteristics (such as the rapidity of immune suppression and when symptoms occur), and the model calculates when the individual would be expected to die if he or she did not have HIV, had HIV but no treatment, or had HIV and treatment were available. By representing a cohort of individuals with a range of characteristics, we can estimate the mean population level outcomes, such as life-years saved by treatment, and how much variability there is in these outcomes.
The impact of treatment with different strategies for its delivery was analysed by running the cohort model under a variety of assumptions concerning (i) how and when the infection is diagnosed; (ii) how frequently individuals are monitored before they start ART and whether they are lost to follow-up; and (iii) whether CD4+ counts are used to help decide when to initiate ART. Since long-term survival on ART was not known, the simulations were repeated making different assumptions about this, based on the short-term observational data that is available [
Individuals can be diagnosed when they develop symptoms and present at a clinic, or when they are referred from an antenatal clinic (ANC), or when they voluntarily get tested for HIV (voluntary counselling and testing, VCT). For simplicity, we investigated circumstances that range from the worst-case to the achievable best-case scenario. We varied the fraction of women referred from ANC between 10% and 90%, and the fraction of infected individuals that receive VCT whilst they are still healthy between 5% and 70%. Various strategies were designed for monitoring individuals found to be infected but not yet on ART (
Possible Monitoring Strategies for HIV-Infected Patients prior to Starting ART
Possible ART Initiation Rules Used in the Model
Our analysis had three parts. First, we compared individual and population outcomes when there is no ART with the situation when ART is available but delivered suboptimally (i.e., few individuals enter care early, monitoring is infrequent, and no CD4 cell counts are taken) and with the situation when some elements of ART delivery are improved. Next, we looked at the impact of these strategies on the health-care system and identified how observed trends in survival or efficiency may be affected. Finally, we compared the different monitoring (
The mathematical model stochastically simulates disease progression in a cohort of 1,000 HIV-infected adults and tracks the services they receive and key health indicator outcomes. Each individual is realised independently and the properties of the individual and the timing of events are calculated probabilistically based on a series of rules and parametric distributions. Draws from the distributions are simulated by transforming standard uniform deviates from the pseudorandom number generator in MATLAB software (version 7.0.1.24704 (R14) Service Pack 1; Mathworks). The data used to parameterise the disease-progression part of the model were taken from several African studies, and the composition of the model cohort was based on the age and sex distribution of incident HIV infections between 1998 and 2002 in eastern Zimbabwe [
Each individual was assigned a CD4+ cell count after seroconversion and a fixed rate of CD4+ cell decline [
After the CD4+ cell count reaches 200/μl, the time until death without treatment was exponentially distributed with a median 11 mo [
A range of possible points at which an individual could be diagnosed with HIV is represented in the model. Individuals could discover they are infected when presenting at a clinic after developing symptoms. Other individuals could find they are infected when tested at an ANC or attending VCT. Age- and disease state-specific fertility rates [
Once individuals are known to be infected with HIV, they are then managed by the hypothetical “ART programme.” Immediately after diagnosis there was an “appointment” in which the need for ART was assessed. If the individual did not start ART at the first appointment, another was scheduled after a set interval; in the model there were seven possible scenarios, labelled I to VII (
In the absence of long-term follow-up studies from low-income settings, three sets of assumptions were made about survival on ART termed “best”, “medium,” and “worst”. First-year mortality was parameterised using data from the ART-LINC collaboration of cohort studies in low-income settings [
Pregnant women who were in care or attended an ANC during pregnancy were eligible to receive treatment to prevent mother-to-child transmission if they were not already on ART. The model was parameterised to reflect mother-to-child transmission in the context of treatment using a single dose of nevirapine, followed by 7–17 mo of breast-feeding [
Further details of the model and data sources are given in
The model predicts that in the absence of treatment, infected individuals will each lose, on average, ∼22 y of life (± two standard deviations from mean over 20 stochastic runs: 21.0–23.0 y) and die aged 39 y (38.2–39.8 y) years having experienced severe symptoms for ∼800 d (750–850 d) (
Key Indicator Outcomes for Alternative Initiation Decision Rules and Health-Care System Parameters
If patients are initiated on ART only when they develop symptoms of immune suppression (syndromic initiation), referral of infected women from ANC to the ART programme is low, and uptake of VCT is low, then the predicted impact of ART on these population-level indicators of mortality and morbidity is modest (model A in
Solid black line, no treatment is available. Where treatment is available, the blue line indicates that ART is available and its assumed effect is worst, the green line indicates a middle effect, and a red line indicates the effect is the best. The survival of an age and gender-matched cohort that is not infected is shown for comparison (dashed black line). The parameterisations of the ART programmes are the same as in
A CD4+ cell count can provide an early warning of immune system depletion before symptoms develop. When a CD4+ cell count is used to help decide when to initiate ART in the manner recommended by WHO [
Our model shows that the frequency with which patients are monitored also determines the impact of ART (
The effect of the ART delivery programme is further improved if referral from ANC and uptake of VCT is improved so that more individuals are diagnosed and monitored earlier in the course of infection (
Increasing opportunities for early diagnosis has two benefits: first, it allows more people to enter care and receive ART before they die; and second, it increases the chance that ART can be initiated at the right time. To isolate the second effect, alternative cohorts are compared in which either all individuals enter care through referral (from ANC or VCT) or individuals can enter care only by presenting at a clinic with symptoms. With referral, the CD4+ cell count at which ART is started tends to be higher (mean 33 cells/μl), which leads to more life-years saved by ART (∼0.5 y per person treated) (Figure B in
Altogether, these three factors—the timing with which ART is initiated, the opportunities for early diagnosis of infection, and the frequency with which patients in care are monitored (without drop-out)—combine to determine the improvement in life expectancy at infection due to the availability of ART (
In (A) only symptoms are used to initiate ART (rule 1); in (B) one CD4+ cell count measurement is used in the way WHO recommend (rule 7). In both panels, 5% yearly drop-out rate is assumed.
When more individuals are diagnosed and diagnosed at an earlier stage, the case load for the ART programme is higher (
However, the model does identify complicating factors in measuring the performance of programmes that should be considered. First, the apparent effectiveness of ART at the population level may not improve when more individuals are diagnosed earlier through VCT (Figure C[b] in
Alternative strategies for ART initiation and patient management (
Appointments are scheduled for every 6 mo. Error bars show ± 2 standard deviations from 20 stochastic runs. 5% yearly drop-out rate is assumed. Details of rules are listed in
When all strategies are compared, those that use more CD4 measurements tend to save more life-years overall and more life-years per year on ART. The advantage of CD4+ cell counts is greater when the association between CD4 level and symptoms is weak (Figure E in
The physiological variability of CD4+ cell counts means that taking two measurements instead of one could lead to better clinical decision-making for individuals. However, in the model, basing clinical decisions on the mean of two measurements does not lead to substantial improvements, because it is assumed that measurement errors are equally likely to lead to earlier initiation as to later initiation (
With more frequent monitoring, the chosen ART initiation strategy can be implemented more accurately and more life-years can be saved (Figure G[a] in
An efficient allocation of appointments is to schedule patients with high CD4+ cell counts to be monitored less frequently than those with low CD4+ cell counts (scenario IV) (Figure H in
There is great potential for ART to reduce premature deaths due to AIDS in resource-poor settings, but inadequate monitoring of HIV-infected individuals not on treatment could prevent this potential from being fully realised. Our modelling shows that using CD4+ cell counts to determine when to initiate ART could greatly increase the number of life-years saved, because it enables individuals to receive ART when the effect of therapy is greatest, before the immune system is severely weakened [
However, since individuals tend to present at clinics with advanced disease [
The CD4+ cell count is a more sensitive indication of need for ART than the presence of symptoms, so CD4+ cell count-based initiation is expected to enable more life-years to be saved and more life-years saved per year of therapy. The model shows that even making just one CD4 measurement at the first appointment, to catch those in need at ART when they first enter care, is likely to improve the impact of the programme substantially. Testing at every appointment, and basing the clinical decision on two counts for borderline cases, maximise the usefulness of the available CD4+ cell count information. Routinely starting patients with higher CD4+ cell counts than the WHO recommends would save more life-years overall, but fewer life-years per years on therapy. Avoiding CD4+ cell counts for those who have already developed symptoms could reduce the number of counts required without sacrificing impact, because few symptomatic individuals will have a CD4+ cell count higher than 350 cells/μl.
The efficiency of appointment scheduling can be improved by prioritising the more immune suppressed (CD4+ cell count ≤ 350) and older (35+ y) patients, since they probably need ART sooner. Relying on individuals to return to the clinic when they develop symptoms would reduce the number of appointments required, but is not an effective way to manage patients; symptoms unreliably predict the need for ART.
This model analysis shows that increases in rates of patient referral, earlier and more frequent monitoring of HIV-infected patients, and better rules for initiating ART could lead to increases in the number of appointments with ART providers and the amount of ART required. By evaluating the cost of providing these services, a cost-effectiveness study could determine, for a specific location, which of these changes would lead to the most efficient allocation of resources [
The substantial differences in expected ART outcomes for different programmes and modes of patient management should lead, over time, to large differences in the number in need of therapy. Projections of ART requirements will therefore need to examine how ART is initiated and how patterns of diagnosis and referral could change. Current estimates that are based on calculating the fraction of infected individuals in the last few years before death do not take the variation in strategies or their evolution over time into consideration [
The model is limited by a lack of data on the relationship between the WHO staging criteria and CD4+ cell count, which underlies the quantitative estimates of the benefit of different types of initiation. Although the average CD4+ cell count among patients with certain conditions has been reported in several studies [
In the absence of more detailed data, the model does not differentiate between WHO stage 3 and 4 disease and cannot replicate the clinical judgement that should be used to determine how soon patients with stage 3 symptoms should be started on ART [
A public-health approach to delivering ART has to consider how to initiate ART and organise the delivery programme to maximise the benefit to the population overall. According to this model, diagnosing infections earlier (through referrals from ANC or VCT), regularly monitoring patients, and using CD4+ cell counts to initiate ART will save more life-years. Unless this care is available to patients at all stages of HIV infection, the long-awaited chance to substantially reduce AIDS mortality with ART could fall far short of its full potential.
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The authors thank I. C. H. Fung, P. White, and T. D. Hollingsworth for useful discussions.
antenatal clinic
antiretroviral treatment
voluntary counselling and testing