Antiretroviral therapy has significantly improved the prognosis of individuals with HIV-1 disease in the developed world [1–9]. Therapy has evolved from treatment with a single nucleoside to highly active antiretroviral therapy (HAART), which is presently the standard of care. The potency of HAART has been shown by comparison with dual nucleoside therapy in the ACTG 320 study  and other trials [11–13], together with a temporal association with sustained decreases in AIDS-related morbidity and mortality [1–9]. However, placebo-controlled studies of HAART have not been conducted for underlying ethical considerations.
The initial ‘hit early hit hard’ strategy has been moderated following increased recognition of long-term adverse events associated with HAART to one of defering treatment to a later stage of HIV immune suppression . In recent years, there has been some convergence of the European and North American treatment guidelines, but precise CD4 cell count and viral load thresholds for therapy initiation still vary and undergo regular revision [15–17]. Benefits of HAART demonstrated in the developed world may differ for populations in sub-Saharan Africa because of the varying spectrum of opportunistic infections and the level of immune suppression at which they occur . However, determination of the accurate threshold for HAART initiation is of particular economic relevance to large-scale programmes as it defines the proportion of the HIV-infected population eligible for treatment.
The World Health Organization (WHO) has set a target of treating three million individuals in the developing world with HAART by 2005 . The 2002 WHO guidelines for scaling up antiretroviral therapy in resource-limited settings recommended initiation of HAART for those with AIDS and WHO stages I, II or III with CD4 cell counts < 200 × 106 cells/l . The 2003 guidelines revision recommended extending treatment to those with WHO stage III disease with CD4 cell counts of 200–350 × 106 cells/l . In sub-Saharan Africa, frequent manifestations of WHO stage III disease include pulmonary tuberculosis, oral hairy leukoplakia and mucosal candidiasis [22–27], which have been independently associated with progressive immune suppression [24–33] and occur in more than 30% of African patients at a CD4 cell count > 200 × 106 cells/l [22,23,27]. In addition, laboratory capacity may not be routinely available in primary health-care sites in resource-limited settings. Therefore, it would be relevant to explore low-cost strategies based on clinical parameters to identify and refer eligible patients to HAART programmes.
The present study is a comparative stratified analysis to assess the utility of the revised WHO criteria relative to other possible scenarios of HAART initiation, comparing the rates of disease progression to AIDS and death in a group of indigent patients accessing HAART and a group attending the same institution in Cape Town, South Africa who did not have access to HAART.
Setting and patients
The setting and methods of enrolment into the prospective Cape Town AIDS Cohort (CTAC) have been described previously . In brief, the study site was a specialized HIV clinic at New Somerset Hospital, a major public health-care provider for HIV-infected patients in Cape Town. Antiretroviral therapy was not provided by the public health services during the study period. Patients presenting to the HIV clinic between 1995 and 2001 had limited access to HAART by participation in clinical trials. Informed consent was obtained from all participants, and studies were approved by the University of Cape Town Research Ethics Committee. Study inclusion criteria were age > 16 years but specific entry CD4 cell counts and viral loads differed between studies . Exclusion criteria included clinically significant laboratory abnormalities, acute opportunistic disease, substance abuse, pregnancy, lactation or recent use of systemic chemotherapeutic agents or immune-modulating agents. All patients treated with HAART received at least three antiretroviral drugs: a non-nucleoside reverse transcriptase inhibitor or protease inhibitor together with two nucleoside analogues or three nucleoside analogues. Patients were followed every 2–3 months or more frequently if deemed clinically necessary. A prospective log of medication dispensed at each attendance was maintained. Adherence was monitored by clinic-based tablet refills. Viral load was determined by reverse transcriptase polymerase chain reaction (Amplicor; Roche Molecular Systems, Branchburg, New Jersey, USA).
A comparison group (no-HAART group) who did not access HAART was identified. This group included all patients who presented to the HIV clinic between 1992 and 2000 and did not participate in the clinical trials or access HAART privately. Patients in the no-HAART cohort were followed-up approximately 3–6 monthly or when clinically indicated. Viral load was not available in publicly funded health-care facilities and, therefore, was not measured in this group.
For both groups, HIV-1 infection was confirmed by enzyme-linked immunosorbent assay or Western blot on two different blood specimens. CD4 cell counts were measured by flow cytometry (Beckman Coulter, Miami, Florida, USA). At each attendance, clinical information was recorded, and HIV disease staged using the WHO staging criteria . Socioeconomic status of each patient was defined using the Cape Metropolitan Council suburbs composite index, which has been described previously .
The primary end-points in this study were AIDS and death. Time to these events was defined, respectively, as time from the initial clinic visit (or from starting treatment for the HAART group) to the date of first AIDS-defining illness, and/or date of death, date of last known clinic visit or end of study period. Death events were identified from patients’ records and hospital or municipality death registry. Patients switching from the no-HAART group to the HAART group contributed survival time to the no-HAART group from their initial clinic visit till the date of initiating HAART, and subsequently to the HAART group until the date of onset of AIDS (or death), the last follow-up visit or study end-point.
The Kaplan–Meier technique and the generalized log-rank test were used to plot and compare AIDS-free and death-free survival probabilities curves of the two groups. Because the WHO guidelines utilize a combination of clinical stage plus CD4 cell count for treatment initiation , analyses were further stratified by baseline CD4 cell count, WHO stage and a combination of WHO stage III with CD4 cell count < 200, 200–350 or > 350 × 106 cells/l.
Cumulative incidence rate of AIDS and death was defined as the number of events occurring in each group per 100 patient-years (PY) of follow-up. Patients presenting with prior AIDS-defining illness were excluded from the calculation of incidence rate of AIDS. The analyses were further stratified by baseline CD4 cell count and WHO stage. In addition, relative hazards from Cox multivariate proportional hazards regression models, described below, were used to calculate number of AIDS or death events averted by HAART. Binomial distribution was used to calculate the 95% confidence (CI) for incidence rates and number of AIDS and death averted. The chi-square test was used to compare differences in proportions. All calculated P values were two sided.
Cox proportional hazard regression analysis was used to identify variables associated with the likelihood of AIDS or death using SAS software version 8.2 (SAS, Cary, North Carolina, USA). A number of baseline prognostic variables were examined in analysis, including CD4 cell count, WHO stage, prophylactic cotrimoxazole, age, socioeconomic status, gender, and year of initial care. The assumption of proportional hazards was examined by plotting the log [−log (survival function)] estimates against log time. Interaction terms were not included in the final models as they were not significant and did not impact on the fit of the models.
The relative utility of the 2003 revised WHO treatment guidelines was assessed by comparing the projected number of patients eligible for HAART and the resulting number of deaths averted applying five different scenarios of initiating HAART in the 974 no-HAART group: scenario I the revised WHO treatment guidelines (treating patients with stage IV irrespective of CD4 cell count enumeration, with stage III plus CD4 cell count < 350 × 106 cells/l, with stage I or II plus CD4 cell count < 200 × 106 cells/l); scenario II the previous WHO treatment guidelines (treating patients with stage IV irrespective of CD4 cell count enumeration, with WHO stages I–III with CD4 cell count cell count < 200 × 106 cells/l); scenario III treating symptomatic patients (WHO stages III and IV); scenario IV treating patients with AIDS only; scenario V treating patients with CD4 cell count < 200 × 106 cells/l only.
As of December 2001, 292 patients had received HAART who met our inclusion criteria and constituted the treated arm of this study. The no-HAART group comprised 981 patients. Of these, seven patients did not have clinical or laboratory data and were, therefore, excluded from the analysis. Baseline demographic and clinical characteristics of the two groups are shown in Table 1. Age, gender, ethnicity and WHO stage did not differ in the two groups. More patients in the HAART group had a higher socioeconomic status. Prophylactic cotrimoxazole was used more frequently in the no-HAART group than in the HAART group. The HAART group had lower CD4 cell counts than did the no-HAART group. Mean follow-up was longer in the HAART group (17.4 months) than in the no-HAART group (14.4 months) (P =0.0005). The 415 baseline stage III diagnoses in this cohort consisted of 154 (37%) with pulmonary tuberculosis [median CD4 cell count 168 × 106 cells/l; interquartile range (IQR), 68–279], 206 (50%) with oral candidiasis or hairy leukoplakia (median CD4 cell count 166 × 106 cells/l; IQR, 61–276) and 55 (13%) with other stage III diagnoses (severe bacterial infections, weight loss > 10% of body weight, unexplained prolonged fever, unexplained chronic diarrhoea) (median CD4 cell count 201 × 106 cells/l; IQR 74–301).
In patients without prior AIDS, 10 new AIDS-defining illnesses occurred in the HAART group (2.8/100 PY) compared with 125 (12.9/100 PY) in the no-HAART group [unadjusted rate ratio (ARR), 0.22; 95% CI, 0.11–0.41; P < 0.0001]. Overall, AIDS-free survival proportion in the Kaplan–Meier analysis was significantly higher in the HAART compared with the no-HAART group (P < 0.0001), and remained significant when the analysis was stratified by baseline WHO stage, CD4 cell count or the different combinations of CD4 cell count and WHO stage (Fig. 1). After adjusting simultaneously for baseline differences in a Cox multivariate analysis, HAART conferred an independent protective benefit against risk of AIDS (ARR, 0.16; 95% CI, 0.08–0.31; P < 0.0001). Other variables associated with risk of AIDS were baseline WHO stage plus CD4 cell count (Table 2).
An analysis was carried out to calculate and compare the incidence of AIDS in the two groups, and to calculate the adjusted number of AIDS cases averted by HAART, stratifying patients by CD4 cell count, WHO stage, and the different combinations of WHO stages plus CD4 cell counts. Overall, adjusted number of AIDS cases averted was 10.8/100 PY (95% CI, 7.5–14.0), and this increased by advancing clinical stage of disease or immune suppression, with the largest number of adjusted cases averted in patients with WHO stage III (22.0/100 PY; 95% CI, 6.1–26.9) and CD4 cell count < 200 × 106 cells/l (15.4/100 PY; 95% CI, 8.6–21.3) (Table 3).
A similar trend was observed when the analysis was carried out using death as an end-point. During the follow-up period, 15 deaths occurred in the HAART group (3.6/100 PY) compared with 302 (26.4/100 PY) in the no-HAART group (ARR, 0.13; 95% CI, 0.08–0.23; P < 0.0001). Survival proportion was consistently significantly better in the HAART group than in the no-HAART group in the WHO stratified Kaplan–Meier analyses (Fig. 2). HAART was independently associated with significant reduction in death (ARR, 0.10; 95% CI, 0.06–0.18; P < 0.0001). Prophylactic cotrimoxazole, baseline CD4 cell count and WHO stage were also independently associated with risk of death (Table 2). The overall adjusted number of deaths averted was 23.8/100 PY (95% CI, 19.6–27.4) and, as in the AIDS analysis, also increased by advancing clinical stage of disease or immune suppression (Table 4).
In the analysis carried out to compare the relative impact of applying the WHO revised criteria and the other three scenarios defined above, the percentage of patients eligible for treatment from the total 974 no-HAART patients applying the revised WHO guidelines (56.7; 95% CI, 53.5–59.8) was significantly higher (P < 0.05) than that calculated for symptomatic WHO stage III or IV patients (44.5; 95% CI, 41.3–47.6), AIDS patients (12.9; 95% CI, 10.9–15.2) or patients with < 200 × 106 cells/l CD4 cell counts (45.9; 95% CI, 42.7–49.1) (Table 5). However, the number of deaths averted per 100 PY using the WHO revised criteria (30.0/100 PY; 95% CI, 23.1–35.9) was not statistically different from that calculated applying other scenarios, except for patients with AIDS (cases averted 74.0/100 PY; 95% CI, 50.2–84.5). There was no significant advantage in terms of number of AIDS cases averted in treating symptomatic patients in comparison with treating patients meeting the revised WHO criteria (Table 3).
This study is unique in that it compares the outcome of HIV disease in a group of patients receiving HAART with a comparison group without access to treatment, controlling for measurable confounding factors. Our findings address the identification of those at greatest need of immediate access to HAART in sub-Saharan Africa and are of practical relevance for the cost-effective use of scarce medical resources. HAART substantially reduced both progression to AIDS and deaths across all WHO stages plus CD4 cell counts. The magnitude of therapeutic benefit increased with advancing HIV disease progression. WHO clinical stage was a stronger predictor than CD4 cell count for both risk of AIDS and death.
Our comparative analysis of HAART initiation strategies demonstrated that a treatment threshold of clinical stage IV only would identify the lowest number (12.9%) of patients eligible for treatment but achieve the highest deaths/100 PY averted (74.0%). These patients would represent an appropriate target population for HAART where resources are severely constrained. Targeting those with symptomatic HIV disease (WHO stages III and IV) would have resulted in a significantly lower number of individuals eligible for treatment (44.5%) than with implementation of the revised WHO criteria (56.7%) but would have resulted in comparable numbers of deaths/100 PY averted [40.8 (95% CI, 32.0–48.5) and 30.0 (95% CI, 23.1–35.9), respectively]. Implementation of therapy at a threshold of CD4 cell count < 200 × 106 cells/l would also result in a significantly lower eligible proportion (45.9%) but would result in less deaths averted per 100 PY (29.6; 95% CI, 21.7–36.0) than treatment of symptomatic disease.
The decision of when to initiate HAART is multifaceted and depends on many factors, including available resources, the untreated prognosis, benefits of therapy, drug toxicity, and the need for long-term adherence. North American and European HIV treatment guidelines recommend initiating HAART for all patients with symptomatic disease, together with various CD4 cell count and viral load thresholds for asymptomatic individuals [15–17]. The WHO guidelines for scaling-up antiretroviral therapy in resource-poor settings included a CD4 cell count threshold of 200 × 106 cells/l for asymptomatic patients but excluded stage III disease with > 200 × 106 cells/l, which was revised in 2003 to exclude stage III with a CD4 cell count > 350 × 106 cells/l. In our cohort, 43% of stage III disease occurred at CD4 cell counts > 200 × 106 cells/l. Individuals with stage III disease, regardless of their CD4 cell counts, had more AIDS events and deaths than those with stage I or II disease with a CD4 cell count of < 200 × 106 cells/l. Oral candidiasis and oral hairy leukoplakia were the commonest stage III diagnoses (50%), with pulmonary tuberculosis (37%) and other stage III conditions (13%) occurring less frequently. CD4 cell counts did not differ significantly between these conditions, and comparable survival of patients with these conditions has been previously reported in our cohort . Application of the initial WHO guidelines would have excluded 43% , and the revised WHO guidelines 21% , of stage III patients who would benefit from HAART. However, when CD4 cell count < 200 × 106 cells/l is not used for access to HAART, and only symptomatic patients are treated, 41% of the patients with CD4 cell count < 200 × 106 cells/l who may benefit from HAART would be excluded.
Several points should be considered in interpretation of our analysis. The observational design of our study is a limitation but, because of the undoubted benefits of HAART, a randomized placebo-controlled trial would not be a feasible alternative. In this none-randomized cohort study, there were some recognized but unavoidable confounders. The HAART group was largely self-selected and this may have resulted in a selection bias; however, each group had a broad spectrum of immune suppression and clinical disease, which allowed for stratification of outcomes, and controlling for well-established prognostic indicators of disease progression. The median follow-up time was lower in those not receiving HAART, but this could not explain the higher event frequency noted in this group. The study population was attending a public sector health facility and may not be representative of the total South African HIV-infected population; however, it would resemble those who are most likely to access HAART in a national treatment programme. We did not adjust our results for viral load, as it was not available for the no-HAART group. However, while baseline CD4 cell count and clinical stage were predictive of on-HAART progression in a large multicentre analysis, only viral loads > 105 copies/ml were associated with increased progression rate . Survival of our untreated cohort was not dissimilar from that of the US Multi-Center AIDS Cohort Study , and better than elsewhere in Africa [22,23,37,38], probably because of the availability of rifampicin-based tuberculosis therapy, cotrimoxazole prophylaxis and treatment of common opportunistic infections. Death rates in our on-HAART group were comparable to those reported by Egger et al. ; however, cause-specific mortality was not available, and, therefore, it was not possible to ascertain whether all deaths reported in both cohorts studied were HIV related. The clinical benefits of HAART in this indigent African population appear to be of similar magnitude to those in developed world settings. Low socioeconomic status is not a predictor of poor adherence to HAART , and indigent African patients have been shown to be able to adhere to therapy and achieve high rates of viral suppression [39–49]. The low number of individuals accessing HAART in resource-poor settings is a consequence of economic factors, particularly the prohibitive cost of drugs, rather than any medical rationale.
We have quantified the impact of HAART initiated at various thresholds and shown a graded response: greatest in those with AIDS and lowest in asymptomatic disease with preserved CD4 cell counts. The combination of the number of AIDS and deaths averted by varying strategies and the proportion of individuals eligible for treatment at different initiation thresholds are useful data for HAART programme planning and cost-effectiveness modelling. Where medical resources are limited, it is appropriate to treat first those who would benefit most from HAART. The superiority of WHO clinical stage over CD4 cell count for identifying those who will benefit most from HAART allows therapy to be targeted to symptomatic individuals who are already likely to be seeking care within the health system. Where resources are less constrained, CD4 cell counts can be utilized to identify asymptomatic patients at high risk of progression to AIDS and death, who may also benefit from HAART. Implementation of the 2003 revised WHO guidelines in sub-Saharan Africa could result in a significantly larger number of eligible individuals but with lower impact on mortality than an alternative strategy based on clinical parameters.
The authors acknowledge the valuable assistance of Douglas Wilson, Katherine Stuve, Elizabeth Fielder, Roasalind Maynier and Salome de Kock of the Desmond Tutu HIV Research Centre, of Ria Kirsten (medical superintendent), Mustufah Goliath, Richard Solomons and Jennette du Preez of Somerset Hospital and Mahomed Hassan and Johan Daniels of the Cape Town Metropolitan Council.
Sponsorship: This study was partially funded by unrestricted academic research grant from Secure the Future, Bristol-Myers and Squibb Co.
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Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
HAART; AIDS; mortality; sub-Saharan Africa; WHO guidelines