Initiating highly active antiretroviral therapy in sub-Saharan Africa

Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World

Health Organization scaling-up guidelines

Motasim Badri, Linda-Gail Bekker, Catherine Orrell, Jennifer Pitt,

Francois Cilliers and Robin Wood

Objectives: To assess the utility of the 2003 revised World Health Organization(WHO) criteria [initiating highly active antiretroviral therapy (HAART) in stage IV, instage III plus CD4 cell count , 350 3 106 cells/l, or in stage I or II plus CD4 cell count, 200 3 106 cells/l] relative to other scenarios of HAART initiation.

Methods: Progression to AIDS and death in 292 patients taking HAART and 974 nottaking HAART in a South African institution in 1992–2001, stratifying patients bybaseline CD4 cell count and WHO stage.

Results: HAARTwas associated with decreased AIDS [adjusted rate ratio [ARR], 0.16;95% confidence interval (CI), 0.08–0.31) and death (ARR, 0.10; 95% CI, 0.06–0.18).Benefit of HAART was significant across all WHO stages plus CD4 cell counts. Thegreatest number of deaths averted was in stages IV [74.0/100 patient-years (PY); 95%CI, 50.2–84.5) and III (32.8/100 PY; 95% CI, 22.4–40.9). AIDS cases averted in stageIII (22.0/100 PY; 95% CI, 6.1–26.9) were higher than in stage I and II with CD4 cellcount , 200 3 106 cells/l (8.9/100 PY 95% CI, 5.6–13.3). Treatment initiation forsymptomatic disease resulted in greater benefits than using any CD4 cell thresholds.Application of WHO criteria increased the treatment-eligible proportion from 44.5%to 56.7% (P , 0.05) but did not prevent more death (P. 0.05) than treating sympto-matic disease.

Conclusion: Implementation of the revised WHO guidelines in sub-Saharan Africamay result in a significantly increased number of individuals eligible for treatment butwould not be as effective a strategy for preventing death as treating symptomaticdisease. & 2004 Lippincott Williams & Wilkins

AIDS 2004, 18:1–10

Keywords: HAART, AIDS, mortality, sub-Saharan Africa, WHO guidelines

Introduction

Antiretroviral therapy has significantly improved theprognosis of individuals with HIV-1 disease in the devel-oped world [1–9]. Therapy has evolved from treatmentwith a single nucleoside to highly active antiretroviraltherapy (HAART), which is presently the standard of

care. The potency of HAART has been shown bycomparison with dual nucleoside therapy in theACTG 320 study [10] and other trials [11–13], togetherwith a temporal association with sustained decreases inAIDS-related morbidity and mortality [1–9]. However,placebo-controlled studies of HAART have not beenconducted for underlying ethical considerations.

From the Desmond Tutu HIV Centre, Institute of Infectious Diseases and Molecular Medicine, Department of Medicine,University of Cape Town, South Africa.

Correspondence to Professor Robin Wood, Desmond Tutu HIV Centre, Werner Beit North Building, Ground Floor MedicalSchool, University of Cape Town, Anzio Rd, Observatory 7925. South Africa.

Received: 18 December 2003; revised: 6 February 2004; accepted: 17 February 2004.

DOI: 10.1097/01.aids.0000125941.58195.95

Article number = 1549

ISSN 0269-9370 & 2004 Lippincott Williams & Wilkins 1

The initial ‘hit early hit hard’ strategy has beenmoderated following increased recognition of long-term adverse events associated with HAART to one ofdefering treatment to a later stage of HIV immunesuppression [14]. In recent years, there has been someconvergence of the European and North Americantreatment guidelines, but precise CD4 cell count andviral load thresholds for therapy initiation still vary andundergo regular revision [15–17]. Benefits of HAARTdemonstrated in the developed world may differ forpopulations in sub-Saharan Africa because of the vary-ing spectrum of opportunistic infections and the levelof immune suppression at which they occur [18].However, determination of the accurate threshold forHAART initiation is of particular economic relevanceto large-scale programmes as it defines the proportionof the HIV-infected population eligible for treatment.

The World Health Organization (WHO) has set atarget of treating three million individuals in thedeveloping world with HAART by 2005 [19]. The2002 WHO guidelines for scaling up antiretroviraltherapy in resource-limited settings recommended in-itiation of HAART for those with AIDS and WHOstages I, II or III with CD4 cell counts , 200 3 106

cells/l [20]. The 2003 guidelines revision recom-mended extending treatment to those with WHO stageIII disease with CD4 cell counts of 200–350 3 106

cells/l [21]. In sub-Saharan Africa, frequent manifesta-tions of WHO stage III disease include pulmonarytuberculosis, oral hairy leukoplakia and mucosal candi-diasis [22–27], which have been independently asso-ciated with progressive immune suppression [24–33]and occur in more than 30% of African patients at aCD4 cell count . 200 3 106 cells/l [22,23,27]. Inaddition, laboratory capacity may not be routinelyavailable in primary health-care sites in resource-limitedsettings. Therefore, it would be relevant to explorelow-cost strategies based on clinical parametersto identify and refer eligible patients to HAARTprogrammes.

The present study is a comparative stratified analysis toassess the utility of the revised WHO criteria relative toother possible scenarios of HAART initiation, compar-ing the rates of disease progression to AIDS and deathin a group of indigent patients accessing HAART anda group attending the same institution in Cape Town,South Africa who did not have access to HAART.

Methods

Setting and patientsThe setting and methods of enrolment into theprospective Cape Town AIDS Cohort (CTAC) havebeen described previously [34]. In brief, the study site

was a specialized HIV clinic at New Somerset Hospital,a major public health-care provider for HIV-infectedpatients in Cape Town. Antiretroviral therapy was notprovided by the public health services during the studyperiod. Patients presenting to the HIV clinic between1995 and 2001 had limited access to HAART byparticipation in clinical trials. Informed consent wasobtained from all participants, and studies were ap-proved by the University of Cape Town ResearchEthics Committee. Study inclusion criteria were age. 16 years but specific entry CD4 cell counts and viralloads differed between studies [34]. Exclusion criteriaincluded clinically significant laboratory abnormalities,acute opportunistic disease, substance abuse, pregnancy,lactation or recent use of systemic chemotherapeuticagents or immune-modulating agents. All patientstreated with HAART received at least three antiretro-viral drugs: a non-nucleoside reverse transcriptase in-hibitor or protease inhibitor together with twonucleoside analogues or three nucleoside analogues.Patients were followed every 2–3 months or morefrequently if deemed clinically necessary. A prospectivelog of medication dispensed at each attendance wasmaintained. Adherence was monitored by clinic-basedtablet refills. Viral load was determined by reversetranscriptase polymerase chain reaction (Amplicor;Roche Molecular Systems, Branchburg, New Jersey,USA).

A comparison group (no-HAART group) who did notaccess HAART was identified. This group included allpatients who presented to the HIV clinic between1992 and 2000 and did not participate in the clinicaltrials or access HAART privately. Patients in the no-HAART cohort were followed-up approximately 3–6monthly or when clinically indicated. Viral load wasnot available in publicly funded health-care facilitiesand, therefore, was not measured in this group.

For both groups, HIV-1 infection was confirmed byenzyme-linked immunosorbent assay or Western bloton two different blood specimens. CD4 cell countswere measured by flow cytometry (Beckman Coulter,Miami, Florida, USA). At each attendance, clinicalinformation was recorded, and HIV disease staged usingthe WHO staging criteria [35]. Socioeconomic statusof each patient was defined using the Cape Metropoli-tan Council suburbs composite index, which has beendescribed previously [34].

Statistical analysisThe primary end-points in this study were AIDS anddeath. Time to these events was defined, respectively,as time from the initial clinic visit (or from startingtreatment for the HAART group) to the date of firstAIDS-defining illness, and/or date of death, date of lastknown clinic visit or end of study period. Death eventswere identified from patients’ records and hospital or

AIDS 2004, Vol 18 No X2

municipality death registry. Patients switching from theno-HAART group to the HAART group contributedsurvival time to the no-HAART group from theirinitial clinic visit till the date of initiating HAART, andsubsequently to the HAART group until the date ofonset of AIDS (or death), the last follow-up visit orstudy end-point.

The Kaplan–Meier technique and the generalized log-rank test were used to plot and compare AIDS-free anddeath-free survival probabilities curves of the twogroups. Because the WHO guidelines utilize a combi-nation of clinical stage plus CD4 cell count fortreatment initiation [21], analyses were further stratifiedby baseline CD4 cell count, WHO stage and acombination of WHO stage III with CD4 cell count, 200, 200–350 or . 350 3 106 cells/l.

Cumulative incidence rate of AIDS and death wasdefined as the number of events occurring in eachgroup per 100 patient-years (PY) of follow-up. Patientspresenting with prior AIDS-defining illness were ex-cluded from the calculation of incidence rate of AIDS.The analyses were further stratified by baseline CD4cell count and WHO stage. In addition, relative hazardsfrom Cox multivariate proportional hazards regressionmodels, described below, were used to calculate num-ber of AIDS or death events averted by HAART.Binomial distribution was used to calculate the 95%confidence (CI) for incidence rates and number ofAIDS and death averted. The chi-square test was usedto compare differences in proportions. All calculated Pvalues were two sided.

Cox proportional hazard regression analysis was used toidentify variables associated with the likelihood ofAIDS or death using SAS software version 8.2 (SAS,Cary, North Carolina, USA). A number of baselineprognostic variables were examined in analysis, includ-ing CD4 cell count, WHO stage, prophylactic cotri-moxazole, age, socioeconomic status, gender, and yearof initial care. The assumption of proportional hazardswas examined by plotting the log [�log (survivalfunction)] estimates against log time. Interaction termswere not included in the final models as they were notsignificant and did not impact on the fit of the models.

The relative utility of the 2003 revised WHO treat-ment guidelines was assessed by comparing the pro-jected number of patients eligible for HAART and theresulting number of deaths averted applying five differ-ent scenarios of initiating HAART in the 974 no-HAART group: scenario I the revised WHO treatmentguidelines (treating patients with stage IV irrespectiveof CD4 cell count enumeration, with stage III plusCD4 cell count , 350 3 106 cells/l, with stage I or IIplus CD4 cell count , 2003 106 cells/l); scenario IIthe previous WHO treatment guidelines (treating pa-

tients with stage IV irrespective of CD4 cell countenumeration, with WHO stages I–III with CD4 cellcount cell count , 200 3 106 cells/l); scenario IIItreating symptomatic patients (WHO stages III andIV); scenario IV treating patients with AIDS only;scenario V treating patients with CD4 cell count, 200 3 106 cells/l only.

Results

As of December 2001, 292 patients had receivedHAART who met our inclusion criteria and consti-tuted the treated arm of this study. The no-HAARTgroup comprised 981 patients. Of these, seven patientsdid not have clinical or laboratory data and were,therefore, excluded from the analysis. Baseline demo-graphic and clinical characteristics of the two groupsare shown in Table 1. Age, gender, ethnicity andWHO stage did not differ in the two groups. Morepatients in the HAART group had a higher socio-economic status. Prophylactic cotrimoxazole was usedmore frequently in the no-HAART group than in theHAART group. The HAART group had lower CD4cell counts than did the no-HAART group. Mean

Table 1. Baseline demographic and clinical characteristics of thegroups taking and not taking highly active antiretroviral therapy.

HAART[No. (%)]

No HAART[No. (%)] P valuea

No. in group 292 974Age (years) 0.19, 33) 145 (49.7) 441 (45.3)> 33 147 (50.3) 533 (54.7)

Gender 0.35Male 159 (54.5) 502 (51.5)Female 132 (45.5) 472 (48.5)

Population group 0.97Black 170 (58.2) 573 (58.8)Mixed race 67 (23) 224 (23)White 55 (18.8) 177 (18.)

Socioeconomic status , 0.0001High 149 (51) 346 (35.5)Low 143 (49) 628 (64.5)

Year of initial care , 0.0001**1992–1996 0 588 (60.4)1997–2000 292 (100) 386 (39.6)

Cotrimoxazole , 0.0001Yes 98 (33.6) 506 (52)No 194 (66.) 468 (48)

WHO stage 0.09I and II 157 (53.8) 541 (55.5)III 108 (37) 307 (31.5)IV 27 (9.2) 126 (13)

CD4 cell count (3 106 cells/l) , 0.0001, 200 102 (34.9) 447 (45.9)200–350 111 (38) 229 (23.5). 350 79 (27.1) 298 (30.6)

HAART, highly active antiretroviral therapy; WHO, World HealthOrganization.*By chi-square test; **by Fisher exact test.

Initiating HAART in sub-Saharan Africa Badri et al. 3

follow-up was longer in the HAART group (17.4months) than in the no-HAART group (14.4 months)(P ¼0.0005). The 415 baseline stage III diagnoses inthis cohort consisted of 154 (37%) with pulmonarytuberculosis [median CD4 cell count 168 3 106 cells/l;interquartile range (IQR), 68–279], 206 (50%) withoral candidiasis or hairy leukoplakia (median CD4 cellcount 166 3 106 cells/l; IQR, 61–276) and 55 (13%)with other stage III diagnoses (severe bacterial infec-tions, weight loss . 10% of body weight, unexplainedprolonged fever, unexplained chronic diarrhoea) (med-ian CD4 cell count 201 3 106 cells/l; IQR 74–301).

In patients without prior AIDS, 10 new AIDS-definingillnesses occurred in the HAART group (2.8/100 PY)compared with 125 (12.9/100 PY) in the no-HAARTgroup [unadjusted rate ratio (ARR), 0.22; 95% CI,0.11–0.41; P , 0.0001]. Overall, AIDS-free survivalproportion in the Kaplan–Meier analysis was signifi-cantly higher in the HAART compared with the no-HAART group (P, 0.0001), and remained significantwhen the analysis was stratified by baseline WHOstage, CD4 cell count or the different combinations ofCD4 cell count and WHO stage (Fig. 1). After

adjusting simultaneously for baseline differences in aCox multivariate analysis, HAART conferred an in-dependent protective benefit against risk of AIDS(ARR, 0.16; 95% CI, 0.08–0.31; P , 0.0001). Othervariables associated with risk of AIDS were baselineWHO stage plus CD4 cell count (Table 2).

An analysis was carried out to calculate and comparethe incidence of AIDS in the two groups, and tocalculate the adjusted number of AIDS cases averted byHAART, stratifying patients by CD4 cell count,WHO stage, and the different combinations of WHOstages plus CD4 cell counts. Overall, adjusted numberof AIDS cases averted was 10.8/100 PY (95% CI, 7.5–14.0), and this increased by advancing clinical stage ofdisease or immune suppression, with the largest numberof adjusted cases averted in patients with WHO stageIII (22.0/100 PY; 95% CI, 6.1–26.9) and CD4 cellcount , 2003 106 cells/l (15.4/100 PY; 95% CI,8.6–21.3) (Table 3).

A similar trend was observed when the analysis wascarried out using death as an end-point. During thefollow-up period, 15 deaths occurred in the HAART

Patients with CD4 cells � 350

Pro

port

ion

with

AID

S-f

ree

surv

ival

0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48Months Months Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P � 0.008

Patients with stage 1 or 21.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P � 0.0001

Patients with stage 3

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P � 0.01

1.00.90.80.70.60.50.40.30.20.1

P � 0.0001

Patients with stage 3 and CD4 cells � 350

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P 5� 0.01

Patients with CD4 cells 200–350

1.00.90.80.70.60.50.40.30.2

0.1

P � 0.03

Patients with stage 3 and CD4 cells 200–350

0.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P � 0.0001

Overall

1.00.90.80.70.60.50.40.30.20.1

P � 0.0008

Patients with stage 3 and CD4 cells � 200

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P � 0.005

Patients with CD4 cells � 200

Fig. 1. Kaplan–Meier probabilities of AIDS-free survival for the group taking highly active antiretroviral therapy (solid line)and those not taking such therapy (dotted line). Stages are World Health Organization staging; CD4 cell counts given as3 106 cells/l.

AIDS 2004, Vol 18 No X4

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 consistentlysignificantly better in the HAART group than in theno-HAART group in the WHO stratified Kaplan–Meier analyses (Fig. 2). HAART was independentlyassociated with significant reduction in death (ARR,0.10; 95% CI, 0.06–0.18; P , 0.0001). Prophylacticcotrimoxazole, baseline CD4 cell count and WHOstage were also independently associated with risk ofdeath (Table 2). The overall adjusted number of deathsaverted was 23.8/100 PY (95% CI, 19.6–27.4) and, asin the AIDS analysis, also increased by advancing clin-ical stage of disease or immune suppression (Table 4).

In the analysis carried out to compare the relativeimpact of applying the WHO revised criteria and theother three scenarios defined above, the percentage ofpatients eligible for treatment from the total 974 no-HAART patients applying the revised WHO guide-lines (56.7; 95% CI, 53.5–59.8) was significantly higher(P , 0.05) than that calculated for symptomatic WHOstage III or IV patients (44.5; 95% CI, 41.3–47.6),AIDS patients (12.9; 95% CI, 10.9–15.2) or patientswith , 200 3 106 cells/l CD4 cell counts (45.9; 95%CI, 42.7–49.1) (Table 5). However, the number ofdeaths averted per 100 PY using the WHO revisedcriteria (30.0/100 PY; 95% CI, 23.1–35.9) was notstatistically different from that calculated applying otherscenarios, except for patients with AIDS (cases averted74.0/100 PY; 95% CI, 50.2–84.5). There was no

significant advantage in terms of number of AIDS casesaverted in treating symptomatic patients in comparisonwith treating patients meeting the revised WHOcriteria (Table 3).

Discussion

This study is unique in that it compares the outcomeof HIV disease in a group of patients receivingHAART with a comparison group without access totreatment, controlling for measurable confounding fac-tors. Our findings address the identification of those atgreatest need of immediate access to HAART in sub-Saharan Africa and are of practical relevance for thecost-effective use of scarce medical resources. HAARTsubstantially reduced both progression to AIDS anddeaths across all WHO stages plus CD4 cell counts.The magnitude of therapeutic benefit increased withadvancing HIV disease progression. WHO clinical stagewas a stronger predictor than CD4 cell count for bothrisk of AIDS and death.

Our comparative analysis of HAART initiation strate-gies demonstrated that a treatment threshold of clinicalstage IV only would identify the lowest number(12.9%) of patients eligible for treatment but achievethe highest deaths/100 PY averted (74.0%). Thesepatients would represent an appropriate target popu-lation for HAART where resources are severely con-

Table 2. Coxproportional hazards regression models for predictors of AIDS and death.

Predictors of AIDS Predictors of death

Univariate analysis RR(95% CI)

Multivariate analysis RR(95% CI)

Univariate analysis RR(95% CI)

Multivariate analysis RR(95% CI)

HAARTYes 0.23 (0.12–0.44) 0.16 (0.08–0.31) 0.14 (0.08–0.23) 0.10 (0.06–0.18)No 1 1 1 1

CotrimoxazoleYes 0.65 (0.47–0.97) 0.96 (0.66–1.39) 1.00 (0.80–1.25) 0.67 (0.53–0.85)No 1 1 1 1

WHO stageI and II 0.22 (0.15–0.32) 0.23 (0.16–0.35) 0.14 (0.11–0.20) 0.15 (0.11–0.21)III 1 1 0.45 (0.34–0.59) 0.48 (0.36–0.64)IV – – 1 1

CD4 cell count (3 106 cells/l), 200 2.52 (1.61–3.95) 1.82 (1.13–2.91) 2.44 (1.80–3.30) 1.86 (1.36–2.55)200–350 0.98 (0.57–1.71) 0.98 (0.56–1.72) 1.34 (0.94–1.91) 1.56 (1.09–2.26). 350 1 1 1 1

Initial year of care1992–1996 1.16 (0.81–1.65) 0.69 (0.47–1.01) 1.57 (1.24–1.99) 0.85 (0.66–1.09)1997–2000 1 1 1 1

Age (years), 33 0.88 (0.63–1.24) 0.96 (0.67–1.36) 0.78 (0.63–0.97) 0.84 (0.67–1.05)> 33 1 1 1 1

Socioeconomic statusHigh 1.02 (0.72–1.45) 1.17 (0.81–1.69) 1.09 (0.87–1.36) 0.95 (0.75–1.20)Low 1 1 1 1

HAART, highly active antiretroviral therapy; WHO, World Health Organization.

Initiating HAART in sub-Saharan Africa Badri et al. 5

strained. Targeting those with symptomatic HIV dis-ease (WHO stages III and IV) would have resulted in asignificantly lower number of individuals eligible fortreatment (44.5%) than with implementation of therevised WHO criteria (56.7%) but would have resultedin 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 thresholdof CD4 cell count , 200 3 106 cells/l would alsoresult in a significantly lower eligible proportion(45.9%) but would result in less deaths averted per100 PY (29.6; 95% CI, 21.7–36.0) than treatment ofsymptomatic disease.

The decision of when to initiate HAART is multi-faceted and depends on many factors, including avail-able resources, the untreated prognosis, benefits oftherapy, drug toxicity, and the need for long-termadherence. North American and European HIV treat-ment guidelines recommend initiating HAART for allpatients with symptomatic disease, together with var-ious CD4 cell count and viral load thresholds forasymptomatic individuals [15–17]. The WHO guide-lines for scaling-up antiretroviral therapy in resource-poor settings included a CD4 cell count threshold of200 3 106 cells/l for asymptomatic patients but ex-cluded stage III disease with . 200 3 106 cells/l,which was revised in 2003 to exclude stage III with aCD4 cell count . 350 3 106 cells/l. In our cohort,43% of stage III disease occurred at CD4 cell counts. 2003 106 cells/l. Individuals with stage III disease,regardless of their CD4 cell counts, had more AIDSevents and deaths than those with stage I or II diseasewith a CD4 cell count of , 2003 106 cells/l. Oralcandidiasis and oral hairy leukoplakia were the com-monest stage III diagnoses (50%), with pulmonarytuberculosis (37%) and other stage III conditions (13%)occurring less frequently. CD4 cell counts did notdiffer significantly between these conditions, and com-parable survival of patients with these conditions hasbeen previously reported in our cohort [27]. Applica-tion of the initial WHO guidelines would haveexcluded 43% [20], and the revised WHO guidelines21% [21], of stage III patients who would benefit fromHAART. However, when CD4 cell count , 200 3106 cells/l is not used for access to HAART, and onlysymptomatic patients are treated, 41% of the patientswith CD4 cell count , 200 3 106 cells/l who maybenefit from HAART would be excluded.

Several points should be considered in interpretation ofour analysis. The observational design of our study is alimitation but, because of the undoubted benefits ofHAART, a randomized placebo-controlled trial wouldnot be a feasible alternative. In this none-randomizedcohort study, there were some recognized but unavoid-able confounders. The HAART group was largely self-selected and this may have resulted in a selection bias;Ta

ble

3.AID

Sinciden

cean

dca

sesaverted.

HAART

NoHAART

No.

patients

AID

Sca

ses

PY

Inciden

ce(per

100PY)

No.

patients

AID

Sca

ses

PY

Inciden

ce(per

100PY)

Adjusted

arate

ratio

(95%

CI)

Pvalue

Adjusted

aNo.ca

ses

averted(95%

CI)

Overall

264

10

357.5

2.8

(1.3–5.1)

848

125

967.4

12.9

(10.9–15.2)

0.16(0.08–0.31)

10.8

(7.5–14.0)

WHO

stag

eIan

dII

156

1215.2

0.5

(0.01–2.6)

541

42

675.7

6.2

(4.5–8.3)

0.05(0.01–0.41)

0.005

5.9

(2.7–8.2)

III

108

9142.3

6.3

(2.9–11.7)

307

83

291.7

28.5

(23.3–34.0)

0.23(0.11–0.49)

0.0002

22.0

(6.1–26.9)

CD4ce

llco

unt(3

106cells/l)

,200

81

8115.2

6.9

(3.1–13.3)

361

76

395.8

19.2

(15.4–23.4)

0.20(0.09–0.44)

,0.0001

15.4

(8.6–21.3)

200–350

110

2145.1

1.4

(0.2–4.9)

206

24

272.0

8.8

(5.7–12.8)

0.14(0.03–0.72)

0.02

7.6

(1.6–12.4)

.350

73

–97.2

–281

25

299.6

8.0

(5.5–12.1)

––

WHO

stag

eplusCD4ce

llco

unt(3

106cells/l)

Stag

eIan

dIIplusCD4ce

ll,

200

24

–33.5

–186

21

235.7

8.9

(5.6–13.3)

––

Stag

eIan

dIIplusCD4ce

ll200–350

72

1103.8

1.0

(0.02–5.2)

139

12

201.4

6.0

(3.1–10.2)

0.25(0.02–0.48)

0.004

4.5

(1.6–10.00)

Stag

eIan

dIIplusCD4ce

ll.

350

60

–77.9

–216

9238.6

3.8

(1.7–7.0)

–Stag

eIIIplusCD4ce

ll,

200

57

881.7

9.8

(4.3–18.3)

175

55

160.1

34.4

(27.1–42.3)

0.31(0.13–0.72)

0.006

23.7

(7.6–36.8)

Stag

eIIIplusCD4ce

ll200–350

38

141.2

2.4

(0.1–12.9)

67

12

70.7

17.0

(9.1–27.7)

0.08(0.01–0.83)

0.03

15.6

(1.6–27.4)

Stag

eIIIplusCD4ce

ll.

350

13

–19.4

–65

16

60.9

26.3

(15.8–39.1)

––

HAART,highlyac

tive

antiretroviraltherap

y;W

HO,WorldHea

lthOrgan

ization;PY,person-yea

rs;CI,co

nfiden

ceinterval.

aAdjusted

forvariab

lesin

Table

2.

AIDS 2004, Vol 18 No X6

however, each group had a broad spectrum of immunesuppression and clinical disease, which allowed forstratification of outcomes, and controlling for well-established prognostic indicators of disease progression.

The median follow-up time was lower in those notreceiving HAART, but this could not explain thehigher event frequency noted in this group. The studypopulation was attending a public sector health facility

1.00.90.80.70.60.50.40.30.20.10.0

Overall

P � 0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Patients with stage 1 or 2

P � 0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Patients with stage 3

P � 0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Patients with stage 4

P � 0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Patients with CD4 cells �200

P � 0.0001

0 6 12 18 24 30 36 42 48Months

1.00.90.80.70.60.50.40.30.20.1

Patients with CD4 cells 200–350

P � 0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Patients with CD4 cells �350

P � 0.0003

1.00.90.80.70.60.50.40.30.20.10.0

Patients with stage 3 and CD4 cells �200

P � 0.0001

1.00.90.80.70.60.50.40.30.20.1

Patients with stage 3 and CD4 cells 200–350

P � 0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Patients with stage 3 and CD4 cells �350

P � 0.0001

0 6 12 18 24 30 36 42 48Months

Fig. 2. Kaplan–Meier probabilities of survival of the group taking highly active antiretroviral therapy (solid line) and those nottaking such therapy (dotted line). Stages are World Health Organization staging; CD4 cell counts given as 3 106 cells/l.

Initiating HAART in sub-Saharan Africa Badri et al. 7

Table 4. Death incidence and deaths averted.

HAART No-HAART

No.patients Deaths PY

Incidence(per 100 PY)

No.patients Deaths PY

Incidence(per 100 PY)

Adjusteda rate ratio(95% CI) P value

Adjusteda No. casesaverted (95%CI)

Overall 292 15 422.5 3.6 (1.9–5.8) 974 302 1,142.6 26.4 (23.9–29.1) 0.10 (0.06–0.18) , 0.0001 23.8 (19.6–27.4)WHO stageI and II 157 – 226.0 – 541 89 704.0 12.6 (10.3–15.3) – –3 108 9 153.9 5.9 (2.7–10.8) 307 133 340.1 39.1 (33.9–44.5) 0.16 (0.08–0.34) , 0.0001 32.8 (22.4–40.9)4 27 6 42.6 14.1 (5.3–27.9) 126 80 98.5 81.2 (71.7–88.0) 0.10 (0.04–0.30) , 0.0001 74.0 (50.2–84.5)

CD4 cell count (3 106 cells/l), 200 102 14 156.9 8.9 (4.96–14.5) 447 177 502.7 35.2 (31.0–39.5) 0.16 (0.09–0.30) , 0.0001 29.6 (21.7–36.0)200–350 111 – 158.0 – 229 73 300.7 24.3 (19.5–29.5) – –. 350 79 1 107.6 0.9 (0.02–5.1) 298 52 339.2 15.3 (11.7–19.6) 0.03 (0.004–0.26) 0.0012 14.8 (8.7–19.5)

WHO stage plus CD4 cell count (3 106 cells/l)Stage I and II plus CD4 cell, 200 24 – 34.6 – 186 38 247.1 15.4 (11.1–20.5) – –Stage I and II plus CD4 cell 200–

35072 – 110.5 – 139 32 209.3 15.3 (10.7–20.9) – –

Stage I and II plus CD4 cell. 350 61 – 80.9 – 216 19 247.6 7.7 (4.7–11.7) – –Stage III plus CD4 cell, 200 57 8 87.4 9.2 (4.1–17.3) 175 83 190.9 43.5 (36.3–50.8) 0.24 (0.11–0.56) 33.1 (16.0–45.2)Stage III plus CD4 cell 200–350 38 – 46.2 – 67 26 74.3 35.0 (24.4–47.1) – –Stage III plus CD4 cell. 350 13 1 20.3 4.9 (0.1–24.9) 65 24 74.9 32.0 (21.7–43.8) 0.15 (0.01–0.61) 0.012 27.2 (8.5–43.4)Stage IV plus CD4 cell , 200 21 6 34.8 17.2 (6.6–33.7) 86 56 64.7 86.6 (75.3–93.5) 0.11 (0.04–0.34) , 0.0001 77.0 (49.7–89.8)Stage IV plus CD4 cell 200–350 1 – 1.3 – 23 15 17.2 87.2 (63.6–98.5) – –Stage IV plus CD4 cell . 350 5 – 6.5 – 17 9 16.6 54.2 (27.8–77.0) – –

HAART, highly active antiretroviral therapy; WHO, World Health Organization; PY, person-years; CI, confidence interval.aAdjusted for variables in Table 2.

AID

S2004,Vol18NoX

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and may not be representative of the total SouthAfrican HIV-infected population; however, it wouldresemble those who are most likely to access HAARTin a national treatment programme. We did not adjustour results for viral load, as it was not available for theno-HAART group. However, while baseline CD4 cellcount and clinical stage were predictive of on-HAARTprogression in a large multicentre analysis, only viralloads . 105 copies/ml were associated with increasedprogression rate [8]. Survival of our untreated cohortwas not dissimilar from that of the US Multi-CenterAIDS Cohort Study [36], and better than elsewhere inAfrica [22,23,37,38], probably because of the availabilityof rifampicin-based tuberculosis therapy, cotrimoxazoleprophylaxis and treatment of common opportunisticinfections. Death rates in our on-HAART group werecomparable to those reported by Egger et al. [8];however, cause-specific mortality was not available,and, therefore, it was not possible to ascertain whetherall deaths reported in both cohorts studied were HIVrelated. The clinical benefits of HAART in thisindigent African population appear to be of similarmagnitude to those in developed world settings. Lowsocioeconomic status is not a predictor of poor adher-ence to HAART [39], and indigent African patientshave been shown to be able to adhere to therapy andachieve high rates of viral suppression [39–49]. Thelow number of individuals accessing HAART inresource-poor settings is a consequence of economicfactors, particularly the prohibitive cost of drugs, ratherthan any medical rationale.

We have quantified the impact of HAART initiated atvarious thresholds and shown a graded response: great-est in those with AIDS and lowest in asymptomaticdisease with preserved CD4 cell counts. The combina-tion of the number of AIDS and deaths averted byvarying strategies and the proportion of individualseligible for treatment at different initiation thresholdsare useful data for HAART programme planning andcost-effectiveness modelling. Where medical resourcesare limited, it is appropriate to treat first those who

would benefit most from HAART. The superiority ofWHO clinical stage over CD4 cell count for identify-ing those who will benefit most from HAART allowstherapy to be targeted to symptomatic individuals whoare already likely to be seeking care within the healthsystem. Where resources are less constrained, CD4 cellcounts can be utilized to identify asymptomatic patientsat high risk of progression to AIDS and death, whomay also benefit from HAART. Implementation of the2003 revised WHO guidelines in sub-Saharan Africacould result in a significantly larger number of eligibleindividuals but with lower impact on mortality than analternative strategy based on clinical parameters.

Acknowledgements

The authors acknowledge the valuable assistance ofDouglas Wilson, Katherine Stuve, Elizabeth Fielder,Roasalind Maynier and Salome de Kock of the Des-mond Tutu HIV Research Centre, of Ria Kirsten(medical superintendent), Mustufah Goliath, RichardSolomons and Jennette du Preez of Somerset Hospitaland Mahomed Hassan and Johan Daniels of the CapeTown Metropolitan Council.

Sponsorship: This study was partially funded by unrest-ricted academic research grant from Secure the Future,Bristol-Myers and Squibb Co.

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