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Outcomes of the South African national antiretroviral treatment programme for children: the IeDEA Southern Africa collaboration.

South Africa's paediatric antiretroviral treatment (ART) programme is the largest in the world, with an estimated 32 000 children <15 years of age on treatment at the end of 2007. (1) Nevertheless the programme reaches less than half of the children estimated to need ART according to national guidelines, (2) and an even lower proportion if need is defined using revised 2008 World Health Organization (WHO) guidelines for early treatment of HIV-infected infants. (3)

Despite the size of the national programme, few individual cohorts have published treatment outcomes, with follow-up limited to 1 year. (4-6) Similar to other African countries, these cohorts have demonstrated good short-term outcomes. (7,8) However, the small size of any individual South African cohort has limited statistical power to robustly describe associations with mortality for all markers of disease severity. (9-14) Furthermore, the lack of routinely collected national monitoring data means that South Africa has lagged behind other southern African countries in publishing programme outcomes, and more importantly, has no mechanism to assess the effectiveness of this enormous health service intervention. (9,15) South Africa could potentially generate valuable paediatric ART data, not only because of the size of the programme but also due to the uniform approach to treatment shaped by national guidelines, as well as good access to laboratory testing facilities, particularly viral load.

The International epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa Collaboration includes 8 sites in South Africa providing paediatric ART at different levels of care in 3 provinces. More than 6 000 children had commenced ART at these sites by the end of 2007, representing >20% of children in the national programme at that time. This collaboration therefore provides a unique opportunity to examine the effectiveness of the South African paediatric ART programme and the extent to which national guidelines are being followed.

Our objectives were to describe for this combined cohort the outcomes of children receiving ART, factors associated with these outcomes, and the extent to which national programme guidelines are being followed.

Methods

Study, design, setting and population

Data for this cohort analysis were collected prospectively at sites and transferred anonymously to the IeDEA data centre in a standard format between May 2007 and February 2008. Each site has institutional ethical approval for contribution of data to IeDEA collaborative analyses.

HIV-infected, ART-naive children with known gender and date of birth who initiated treatment with at least 3 antiretroviral drugs at age [less than or equal to] 16 years on a documented date between 1 June 1999 and 29 February 2008 were included. Sites where less than 25 children met these criteria were excluded.

Key variables

Information describing ART programmes was provided on standardised questionnaires by site representatives. Child characteristics included measures of disease severity (WHO stage, weight, height, haemoglobin (Hb), CD4 percentage or count, viral load) at ART initiation and at 6-monthly follow-up intervals, together with initiating regimen. CD4 percentage and absolute counts are reported, with the worst of these being used to determine whether the child was severely immunosuppressed according to WHO criteria. (16) Primary caregiver and exposure to prevention of mother-to-child transmission (PMTCT) regimens were recorded.

As sites changed from the WHO 3-stage to WHO 4-stage classification of disease severity during the latter half of 2004, all children with stage 3 or 4 disease under either system were considered to have clinically advanced disease. (17) Viral loads and CD4 counts were performed by local laboratories using standard methods. A viral load <400 copies/ml was considered undetectable. Sex- and age-standardised z-scores for weight and height were calculated for children [less than or equal to] 10 years at time of measurement using WHO 2007 growth reference standards. (18)

Sites provided data on known deaths and transfers out (TFO). Children were deemed lost to follow-up (LFU) if the last visit date was more than 6 months before date of closure of the site database, with the last visit date used as date of LFU.

Analysis

Kaplan-Meier estimates of mortality, LFU and TFO were determined. Cox proportional hazards models stratified by site were used to assess associations between baseline characteristics and mortality. Multivariate models were built by sequentially adding the next most significant predictor variable from univariate analysis, and variables with a p-value <0.1 after adjustment for those already in the model, or that changed the hazard ratio (HR) for variables in the model by more than 10%, were retained. Separate models were generated excluding the weight-for-age z-score (WAZs) as this could only be calculated for children [less than or equal to] 10 years of age, and viral load, as this is not routinely available in most resource-limited settings. Since Hb at ART initiation was only available for a third of children, this was excluded from the main model, but a separate model was generated to assess the effect of anaemia on mortality. Age was categorised as <12 months, 12-35 months and [greater than or equal to] 36 months. WAZs were categorised as <-3, -3 to -2 and [greater than or equal to] -2, according to United Nations Children's Fund (UNICEF) definitions. (19) Viral load was categorised as [less than or equal to] 100 000, 100 000 to 1 million and >1 million copies/ml, and year of starting ART as [less than or equal to] 2005 and [greater than or equal to] 2006 as these thresholds explained the largest amount of variability in mortality. Anaemia was defined as Hb <8 g/dl.

As these data include a substantial proportion of children who received ART through donor-funded programmes before commencement of National Department of Health provision on 1 April 2004, a sensitivity analysis was performed on descriptions of baseline characteristics and survival models with data limited to those children who started ART after 31 March 2004. All statistical analyses were performed using Stata version 10 (STATA Corporation, College Station, TX).

Results

Exclusions

Of the 8 South African IeDEA sites, 1 was excluded because the cohort comprised <25 children. The remaining data included 6 266 children on ART. Of these, 85 did not meet inclusion criteria due to missing or inconsistent baseline data. Non-naive patients (N=39) and those commenced on <3 drugs (N=64) were excluded. The final data-set therefore comprised 6 078 children (49.1% female) from 7 sites with 9 368 child-years of follow-up, and median (interquartile range (IQR)) follow-up duration of 16 (6-29) months.

Contributing sites

Site characteristics are shown in Table I. Of note, sites are all urban and represent major centres in 3 provinces (Western Cape, Gauteng and KwaZulu-Natal); however, all levels of care are represented. There is a wide variation in the number of children being treated with ART at different sites, from >2 000 at a site providing all levels of care in Gauteng to <300 at a smaller primary care clinic in Cape Town. The median age of children from tertiary care sites is less than that of children from sites providing other levels of care (18.4 v. 51.9 months; p<0.0001).

Characteristics at ART start

Most children were severely ill with advanced clinical disease, immunosuppression, high viral load and impaired growth at the start of ART (Table II). The median (IQR) age of children commencing ART was 42.7 (14.7-82.5) months, with nearly 30% of children less than 18 months of age. The starting regimen included stavudine (d4T) and lamivudine (3TC) with either efavirenz or lopinavir/ritonavir (Kaletra) as the third drug for 81% of children.

Data were incomplete for many key variables. In particular, WHO stage was unknown for nearly a third of children, while caregiver and PMTCT exposure information was provided by only a few sites at which exposure status was still unknown for nearly 50%. Characteristics at start of ART were not substantially different when the data were limited to those initiating treatment after formal commencement of the national programme (N=5 601, results not shown).

Survival and retention in care

Mortality at 3 years was 7.7% (95% confidence interval (CI) 7.0-8.6%), and 81.4% (95% CI 80.1-82.6%) of children were alive and in care at 3 years (Fig. 1, a, b). There was rapid transfer from sites providing exclusively tertiary care to lower levels after the first 6 months of ART, with the tertiary cohort reduced by nearly 50% at 2 years (Fig. 1, c). LFU at 1 year increased from 2.2% (95% CI 1.1-4.7%) in those who commenced ART before 2004 to 8.2% (95% CI 7.1-9.4%) in those who commenced during or after 2006.

Mortality was higher for younger children, those with more advanced disease and those who were more severely immunosuppressed (Fig. 1). All markers of disease severity were independent predictors of mortality in multivariate analysis (Table III). Use of a protease inhibitor versus a non-nucleoside reverse transcriptase inhibitor as the third drug had no effect on mortality (p=0.572). Similarly, Hb <8 g/dl independently predicts mortality after adjustment for disease severity, age and programme year (adjusted hazard ratio 1.65; 95% CI 1.07-2.55%; p=0.024). Models excluding WAZ and viral load as predictors yielded similar results to the full model, as did models limited to those children treated after commencement of the national programme (results not shown).

[FIGURE 1 OMITTED]

Monitoring of viral and immune response to treatment

Follow-up measurements of CD4 and viral load are shown in Fig. 2. Notably, measurements of CD4 and viral load at 6-monthly intervals were available for over 80% and 75% of children respectively through to 36 months, with [greater than or equal to] 80% of children virologically suppressed throughout (82.4% at 3 years; 95% CI 79.4-85.5%). The percentage (95% CI) of children severely immunosuppressed at 1 and 3 years dropped to 16.9% (15.4-18.3%) and 6.4% (4.2-8.6%), respectively.

Growth response to treatment

There was initial rapid weight gain from a median WAZ of -1.80 to -0.75 by 12 months, remaining relatively constant thereafter (Fig. 3). Height increased more slowly but was still increasing at 36 months, when a quarter of children still had a height-for-age z-score <-2.

Discussion

Main findings of the study

Outcomes of this cohort of ART-treated children in South Africa, the largest from a single country in Africa to date, were good with mortality of 7.7% and 81.1% of children alive and in care at 3 years. As expected, young age together with all markers of disease severity were independent predictors of mortality. These findings are strikingly similar to those of a similar combined cohort analysis of sub-Saharan paediatric ART programmes, the Kids' Antiretroviral Treatment in Lower-Incomes Countries (KIDS-ART-LINC) Collaboration. (8) Furthermore, follow-up monitoring of laboratory parameters was excellent, with more than 75% of children tested 6-monthly according to national guidelines. Although comparisons with rich countries are difficult owing to the older age of ART commencement in the South African children and inherent survival bias, the high level of virological suppression is encouraging and compares favourably with cohorts from Europe (20) and North America (21) and other African studies. (7,14) Similarly, children remaining in care experienced dramatic improvements in growth and immune status. While the proportion and absolute number of nearly 2 000 very young children accessing ART are much greater than in most other African studies, across the country older children are still preferentially accessing treatment with more than 70% of the cohort being over 18 months of age. (7,8,22)

Strengths and generalisablity of findings

This study is valuable because of the large number of children and length of follow-up, but particularly because of the high absolute number of those under 18 months of age. With new WHO guidelines encouraging early ART initiation in infants, a better understanding of clinical outcomes in this age group is required. (3) In addition, the availability of regular viral load information is unusual in the African context. Inclusion of children from a number of different sites in 3 provinces and at different levels of care enhances representivity, while uniformity of treatment protocols lends itself to collation into a single analysis.

Limitations

Although the study includes some of the busiest routine public sector clinics, it should be acknowledged that IeDEA collaboration sites must have capacity for electronic collection of routine data, which is not the norm. Some high-burden provinces are not included in the study, and there is disproportionate representation of sites with tertiary care capacity. The thorough monitoring and high number of infants on ART therefore probably represent best-practice examples in well-resourced clinics.

While LFU in this study is relatively low compared with adult publications of routine cohort data, (23) there is variation in LFU at different sites. This is of concern as many of those who are LFU are likely to have died, resulting in under-ascertainment of mortality. Indeed, while there are various plausible explanations for the apparent protective effect on mortality of starting ART after 2005 (including that children starting earlier are 'sicker' in ways not captured by markers of disease severity available for this analysis), the contribution of increasing LFU in later years as programmes expand should not be underestimated. In this respect, the effect of choice of first drug (zidovudine v. stavudine) on mortality could not be definitively assessed owing to changes in prescribing patterns after the introduction of national treatment guidelines in 2004 and increasing LFU over time. The high transfer rate from tertiary sites to lower levels of care limits duration of follow-up for these patients. Systems of data collection integrated across sites are needed to ascertain outcomes for transferred patients.

Poor integration of health information systems is also reflected in the paucity of PMTCT exposure data. This reflects poor integration of antenatal, routine child care and HIV services themselves within the health system, a major barrier to timeous HIV diagnosis and referral for care of those infants infected despite PMTCT exposure. (7,22,24) Completeness and accuracy of other exposure variables is also limited, while historical changes in the WHO staging system limit its value as a measure of disease advancement.

Reflections on the South African national paediatric ART programme

This study indicates that the programme is successful for those children who access it. The latter caveat is important, as the fact that 20% of all children are treated at a handful of sites, all in large urban centres, suggests that considerable inequities in access are likely. Nevertheless the fastidious monitoring, utilisation of first-line regimens recommended in national guidelines, good survival, high proportions of children with viral suppression and favourable immune and growth responses--at least at these sites--are encouraging. The Western Cape has the specific aim of treating children at their nearest health centre whenever possible, with only those warranting specialist care remaining at tertiary facilities. (24) In this respect, the rapid transfer of children from exclusive tertiary to primary care sites, together with the difference in ages of children starting ART at different levels of care, indicate that children are indeed receiving care at the appropriate level.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Although the cohort includes several infants, the number is negligible compared with the estimated 64 000 new infections that occur perinatally and through breastfeeding every year. (25) Together with lack of integration of antenatal PMTCT and paediatric HIV services, perceived and actual lack of expertise in the care of young HIV-infected infants pose significant barriers to access for infants, who are still largely cared for at tertiary sites. These problems need to be addressed urgently if South Africa seeks to implement revised WHO guidelines recommending early ART for infants irrespective of disease severity. (3)

In this respect it should be noted that the relatively poor outcomes for infants in this study would not necessarily be the scenario should infant ART initiation be prioritised. Disease progression is rapid in HIV-infected infants, and in this study children commencing ART at a young age are those whose disease progressed rapidly enough to meet previous WHO disease severity criteria while they were still young and who were able to access treatment before otherwise inevitable early death. (26) Better outcomes for older children represent a survivor effect, with older age at ART initiation being a proxy for slower disease progression. In contrast, other South African studies have shown excellent outcomes for infants commencing ART before disease progression. (27,28)

Conclusion

This study of a substantial proportion of the South African national ART programme for children demonstrates the dramatic clinical benefit for those accessing the programme. The higher mortality in infants and young children and those with advanced disease highlights the need to identify HIV-infected infants and commence ART before disease progression.

We thank all the children whose data were used in this analysis, their caregivers and all staff at participating sites for preparation of data contributed to the IeDEA Southern Africa collaboration. Many thanks to Nicola Maxwell for preparing the combined data for analysis, Morna Cornell and Claire Graber for project management, and Eugene Zwane, Landon Myer, Martin Brinkhof, Lukas Fenner and Mar Pujades who provided valuable advice on the analysis and final manuscript.

Funding. This study was supported by the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant 1 U01 AI069924-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest. The authors declare that they have no conflict of interest.

IeDEA Southern Africa Steering Group

Member sites: Anna Coutsoudis, PMTCT Plus, Durban, South Africa; Diana Dickinson, Gabarone Independent Hospital, Gaborone, Botswana; Brian Eley, Red Cross Children's Hospital, Cape Town, South Africa; Lara Fairall, Free State provincial ARV roll-out, South Africa; Tendani Gaolathe, Princess Marina Hospital, Gaborone, Botswana; Janet Giddy, McCord Hospital, University of KwaZulu-Natal, Durban, South Africa; Timothy Meade, CorpMed Clinic, Lusaka, Zambia; Patrick MacPhail, Themba Lethu Clinic, Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Lerato Mohapi, Perinatal HIV Research Unit, Johannesburg, South Africa; Margaret Pascoe, Newlands Clinic, Harare, Zimbabwe; Hans Prozesky, Tygerberg Academic Hospital, Stellenbosch, W Cape, South Africa; Harry Moultrie, University of the Witwatersrand Paediatric HIV Clinics (Harriet Shezi Clinic, Chris Hani Baragwanath Hospital), Johannesburg, South Africa; Karl Technau, University of the Witwatersrand Paediatric HIV Clinics (Rahima Moosa Mother and Child Hospital), Johannesburg, South Africa; Gilles van Cutsem, Khayelitsha ART Programme and Medecins Sans Frontieres, Cape Town, South Africa; Paula Vaz, Paediatric Day Hospital, Maputo, Mozambique; Ralf Weigel, Lighthouse Clinic, Lilongwe, Malawi; Robin Wood, Gugulethu and Masiphumelele ART Programmes, Cape Town, South Africa.

Central team: Martin Brinkhof, Matthias Egger, Beatrice Fatzer, Claire Graber, Fritz Kaesar and Olivia Keiser, Institue of Social and Preventive Medicine, University of Bern, Switzerland; Andrew Boulle, Morna Cornell, Mary-Ann Davies, Nicola Maxwell and Landon Myer, School of Public Health and Family Medicine, University of Cape Town.

Accepted 3 June 2009.

References

(1.) World Health Organization, UNICEF, UNAIDS. Towards Universal Access: scaling up priority HIV/AIDS interventions in the health sector. WHO 2008. http://www.who.int/hiv/mediacentre/2008progressreport/en/index.html (accessed 5 December 2008).

(2.) National Department of Health SA. Progress report on declaration of commitment on HIV and AIDS. WHO 2008. http://data.unaids.org/pub/Report/2008/south_africa_2008_ country_progress_report_en.pdf (accessed 24 February 2009).

(3.) World Health Organization. Report of the WHO Technical Reference Group, Paediatric HIV/ ART Care Guideline Meeting. WHO 2008. http://www.who.int/hiv/pub/meetingreports/art_meeting_april2008/en/index.html (accessed 27 October 2008).

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(5.) Jooste JP, Van Zyl AJM, Baker A, Crawford W, Jassen A. Antiretroviral treatment in the Northern Cape. S Afr Med J 2008; 95: 812.

(6.) Reddi A, Leeper SC, Grobler AC, et al. Preliminary outcomes of a paediatric highly active antiretroviral therapy cohort from KwaZulu-Natal, South Africa. BMC Pediatrics 2007; 7: 13.

(7.) Sutcliffe CG, van Dijk JH, Bolton C, Persaud D, Moss WJ. Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa. Lancet Infectious Diseases 2008; 8: 477-489.

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(9.) Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA 2007; 298(16): 1888-1899.

(10.) Fassinou P, Elenga N, Rouet F, et al. Highly active antiretroviral therapies among HIV-1infected children in Abidjan, Cote d'Ivoire. AIDS 2004; 18(14): 1905-1913.

(11.) Nyandiko WM, Ayaya S, Nabakwe E, et al. Outcomes of HIV-infected orphaned and nonorphaned children on antiretroviral therapy in western Kenya. J Aquir Immune Defic Syndr 2006; 43(4): 418-425.

(12.) O'Brien DP, Sauvageot D, Zachariah R, Humblet P. In resource-limited settings good early outcomes can be achieved in children using adult fixed-dose combination antiretroviral therapy. AIDS 2006; 20(15): 1955-1960.

(13.) O'Brien DP, Sauvageot D, Olson D, et al. Treatment outcomes stratified by baseline immunological status among young children receiving nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in resource-limited settings. Clin Infect Dis 2007; 44(9): 1245-1248.

(14.) Rouet F, Fassinou P, Inwoley A, et al. Long-term survival and immuno-virological response African HIV-1-infected children to highly active antiretroviral therapy regimens. AIDS 2006; 20(18): 2315-2319.

(15.) The Malawi Antiretroviral Treatment Group. Antiretroviral therapy for children in the routine setting in Malawi. Transcripts of the Royal Society of Tropical Medicine and Hygiene 2007; 101(5): 511-516.

(16.) World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. WHO 2007. www.who.int/hiv/pub/guidelines/hivstaging/en/index.html (accessed 28 December 2008).

(17.) World Health Organization. Interim WHO clinical staging of HIV/AIDS and HIV/AIDS case definitions for surveillance. WHO 2005. www.who.int/hiv/pub/guidelines/clinicalstaging. pdf (accessed 5 August 2008).

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(20.) Judd A, Doerholt K, Tookey PA, et al. Morbidity, mortality, and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996-2006: planning for teenage and adult care. Clin Infect Dis 2007; 45(7): 918-924.

(21.) Van Rossum AMC, Fraaij PLA, De Groot R. Efficacy of highly active antiretroviral therapy HIV-1 infected children. Lancet Infect Dis 2002; 2: 93-102.

(22.) Meyers T, Moultrie H, Naidoo K, Cotton M, Eley B, Sherman G. Challenges to pediatric HIV care and treatment in South Africa. J Infect Dis 2007; 196 Suppl 3: S474-S481.

(23.) Rosen S, Long L, Sanne I. The outcomes and outpatient costs of different models of antiretroviral treatment delivery in South Africa. Trop Med Int Health 2008; 13(8): 1005-1015.

(24.) Eley B, Nuttall J. Antiretroviral therapy for children: challenges and opportunities. Ann Trop Paediatr 2007; 27: 1-10.

(25.) Actuarial Society of Southern Africa. Results extracted from the AIDS and Demographic Model of the Actuarial Society of Southern Africa (ASSA). ASSA 2003. http://www.actuarialsociety.org.za (accessed 15 November 2008).

(26.) Little K, Thorne C, Luo C, et al. Disease progression in children with vertically-acquired HIV infection in sub-Saharan Africa: reviewing the need for HIV treatment. Curr HIV Res 2007; 5(2): 139-153.

(27.) Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359(21): 2233-2244.

(28.) Mphatswe W, Blanckenberg N, Tudor-Williams G, et al. High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis. AIDS 2007; 19(10): 1253-1261.

Mary-Ann Davies, Olivia Keiser, Karl Technau, Brian Eley, Helena Rabie, Gilles van Cutsem, Janet Giddy, Robin Wood, Andrew Boulle, Matthias Egger, Harry Moultrie, for the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration

Mary-Ann Davies, MB ChB

Andrew Boulle, MB ChB, MSc, FCPHM (SA)

School of Public Health and Family Medicine, University of Cape Town

Olivia Keiser, MSc

Matthias Egger, MD, MSc, FFPH, DTM&H

Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland

Karl Technau, MB ChB, DCH, Dip HIV Man

Harry Moultrie, MB BCH, MSc (Epidemiology)

University of the Witwatersrand Paediatric HIV Clinics (Harriet Shezi Clinic, Chris Hani Baragwanath Hospital, Soweto and Empilweni Clinic, Rahima Moosa Mother and Child Hospital, Johannesburg), and School of Public Health, University of the Witwatersrand, Johannesburg

Brian Eley, MB ChB, FCP (Paed) (SA), BSc (Hons)

Red Cross War Memorial Children's Hospital, Cape Town, and School of Child and Adolescent Health, University of Cape Town

Helena Rabie, MB ChB, FCP (Paed) (SA), MMed (Paed)

Tygerberg Academic Hospital and Stellenbosch University, Tygerberg, W Cape

Gilles van Cutsem, MD, DTM&H, MPH

School of Public Health and Family Medicine, University of Cape Town, Medecins Sans Frontieres, Khayelitsha, W Cape, and Khayelitsha ART Programme

Janet Giddy, MB ChB, DipPHCEd, MFamMed

McCord Hospital, Durban

Robin Wood, BSc, BM, MMed, FCP (SA)

Gugulethu Community Health Centre and Desmond Tutu HIV Centre, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town

Corresponding author: M-A Davies (Mary-Ann.Davies@uct.ac.za)
Table I. Characteristics of facilities providing ART

 Main level
Cohort name of care Type of clinic
and location provided and payment

Harriet Shezi Clinic, All levels Public and
Soweto research, free ART

Rahima Moosa, All levels Public, free ART
Mother and
Child Hospital
Johannesburg

Red Cross Children's Tertiary Public and
Hospital, Cape Town research, free ART

Tygerberg Hospital, Tertiary Public and,
Cape Town research free ART

Khayelitsha Primary Public, free ART
Community Health
Centre, Cape Town

Gugulethu Primary Public and,
Community Health research free ART
Centre, Cape Town

McCord Hospital, Secondary Government-
Durban subsidised mission
 hospital, small co-
 payment

 Total

 No. of
Cohort name Target First year of children
and location population ART provision on ART

Harriet Shezi Clinic, 2001 2 183
Soweto Children only

Rahima Moosa, Children and 1999 1 023
Mother and pregnant women
Child Hospital
Johannesburg

Red Cross Children's Children only Tertiary 2001 839
Hospital, Cape Town

Tygerberg Hospital, Adults and 2000 690
Cape Town children, separate
 clinics

Khayelitsha Adults and 2001 650
Community Health children, separate
Centre, Cape Town clinics

Gugulethu Adults and 2001 262
Community Health chil dren, separate
Centre, Cape Town clinics

McCord Hospital,
Durban Adults and 2003 431
 children, separate
 clinics

 Total 6 078

 Median (IQR) Number of
 age (mo.) of children (%)
Cohort name children at <1 yr of age
and location ART initiation at ART initiation

Harriet Shezi Clinic, 55.9 328 (15.0)
Soweto (21.9-90.3)

Rahima Moosa, 44 202 (19.8)
Mother and (15.9-84.4)
Child Hospital
Johannesburg

Red Cross Children's 16.1 351 (41.8)
Hospital, Cape Town (6.3-50.2)

Tygerberg Hospital, 21.6 240 (34.8)
Cape Town (8.5-59.0)

Khayelitsha 41.7 94 (14.5)
Community Health (20.3-74.2)
Centre, Cape Town

Gugulethu 47.1 42 (16.0)
Community Health (18.3-82.4)
Centre, Cape Town

McCord Hospital,
Durban 72.4 33 (7.7)
 (33.0-109.2)

 Total

Table II. Characteristics of children at ART initiation
(N = 6 078)

Year of ART start (%)
 [less than or equal to] 2003 321 (5.3)
 2004 1 076 (17.7)
 2005 1 809 (29.8)
 2006 1 707 (28.1)
 [greater than or equal to] 2007 1 165 (19.2)

Female (%) 2 981 (49.1)
Age
 Median (IQR) age (mo.) 42.7 (14.7 - 82.5)
 Less than 18 mo. (%) 1 758 (28.9)

WHO stage (%)
 1 263 (4.3)
 2 745 (12.3)
 3/4 3 073 (50.1)
WHO stage unknown 1 997 (32.9)

PMTCT exposure (%) (N=4 695) *
 Known exposed 596 (12.7)
 Known unexposed 1 764 (37.6)
 Exposure status unknown 2 335 (49.7)

Primary caregiver (%) (N=4 045) ([dagger])
 Mother 2 449 (60.5)
 Father 141 (3.5)
 Grandmother 204 (5.0)
 Other family 712 (17.6)
 Other 123 (3.0)
 Institution 225 (5.6)
 Unknown 191 (4.7)

Laboratory measurements
 Median (IQR) CD4% by age group (N = 4 592)
 [less than or equal to] 11 mo.
 (N = 1 045) 16.4 (10.0-23.6)
 12 - 35 mo. (N=1 089) 13.0 (9.0-18.1)
 36 - 59 mo. (N=712) 12.0 (7.2-16.5)
 [greater than or equal to] 5 yrs
 (N = 1 746) 10.0 (4.7-15.0)
 Median (IQR) CD4 absolute count
 (cells/[micro]l) by age group
 (N = 4 852)
 [less than or equal to] 11 mo.
 (N = 1 062) 642 (280-1 132)
 12 - 35 mo. (N=1 145) 636 (345-1 014)
 36 - 59 mo. (N=750) 437 (251-691)
 [greater than or equal to] 5 yrs
 (N = 1 895) 435 (81-241)
 Severely immunosuppressed (%)
 (N = 4 934) ([double dagger]) 4 024 (81.6)
 Median (IQR) log viral load (N = 4 063) 5.36 (4.74-5.89)
 Viral load >1million copies/ml
 (%) (N = 4 063) 850 (20.9)
 Haemoglobin <8 g/dl (%) (N = 1 803) 220 (12.2)

Anthropometry ([section])
 z-scores
 Median (IQR) weight-for-age z-score
 (N = 3 892) -1.89 (-3.20 - -0.93)
 Median (IQR) height-for-age z-score
 (N = 3 690) -2.39 (-3.37 - -1.44)
 Median (IQR) weight-for-height z-score
 (N = 3 186) -0.46 (-1.73 - 0.55)
 Weight-for-age z-scores (N = 3 892)
 -3 - -2 (%) 747 (19.1)
 <-3 (%) 1 096 (28.2)
 Height-for-age z-score (N = 3 690)
 -3 - -2 (%) 1 011 (27.4)
 <-3 (%) 1 242 (33.7)
 Weight-for-height z-score (N = 3 186)
 -3 - -2 (%) 312 (9.8)
 <-3 (%) 365 (11.5)
Regimen (%) (N=5 484)
 Most common regimens
 d4T+3TC+efavirenz 2 839 (51.8)
 d4T+3TC+lopinavir/ritonavir
 ([paragraph]) 1 603 (29.2)

 First NRTI
 d4T-based regimen 4 856 (88.5)

 Third drug
 Lopinavir/ritonavir-based regimen
 ([parallel]) 1 808 (33.0)
 Ritonavir-based regimen 191 (3.5)

Regimen not recorded 594

* Data only available for Rahima Moosa, Harriet Shezi,
Khayelitsha and Red Cross.

([dagger]) Data only available for Rahima Moosa, Harriet
Shezi and Red Cross; for Harriet Shezi caregiver information
was collected at first visit--may be different from caregiver
at ART start.

([double dagger]) WHO criteria for severe immune suppression
(CD4% <25 or CD4 count <1 500/[micro]l if age [less than or
equal to] 11months; CD4% <20 or CD4 count <750/[micro]l if age
between 12 and 35 months; CD4% <15 or CD4 count <350/[micro]l
if age between 36 and 59 months; CD4% <15 or CD4 count <200/
[micro]l if age [greater than or equal to] 60 months.

([section]) Only calculated for children ?120 months (N=5 535).

([paragraph]) Includes 201 children with additional ritonavir
boosting.

([parallel]) Includes 214 children with additional ritonavir
boosting.

Table III. Predictors of mortality using Cox-proportional
hazards model stratified by site (adjusted for year of ART
start)

Characteristic at ART start Crude HR 95% CI

WAZ
 >-2 1
 -3 - -2 1.93 1.29 - 2.89
 < -3 5.23 3.84 - 7.12

Viral load (copies/ml)
 <100 000 1
 100 000 to 1 million 1.75 1.24 - 2.45
 >1 million 3.30 2.32 - 4.70

Severe immunosuppression
(WHO definition) 4.23 2.55 - 7.00
WHO stage 3 or 4 (v. 1 or 2) 3.01 2.00 - 4.54

Age
 >3 yrs 1
 1 -3 yrs 1.31 0.98 - 1.74
 <1 yr 3.38 2.65 - 4.31

ART commenced before 2006 1.28 1.02 - 1.60

 Adjusted HR
 Full model
Characteristic at ART start p-value (N=2 449)

WAZ <0.001 *
 >-2 1
 -3 - -2 1.13
 < -3 2.44

Viral load (copies/ml) <0.001 *
 <100 000 1
 100 000 to 1 million 1.68
 >1 million 2.22

Severe immunosuppression
(WHO definition) <0.001 3.83
WHO stage 3 or 4 (v. 1 or 2) <0.001 2.16

Age <0.001 *
 >3 yrs 1
 1 -3 yrs 1.17
 <1 yr 2.00

ART commenced before 2006 0.036 1.68

Characteristic at ART start 95% CI p-value

WAZ <0.001 *
 >-2
 -3 - -2 0.69 - 1.87
 < -3 1.65 - 3.59

Viral load (copies/ml) 0.010 *
 <100 000
 100 000 to 1 million 1.02 - 2.76
 >1 million 1.31 - 3.77

Severe immunosuppression
(WHO definition) 1.68 - 8.72 0.001
WHO stage 3 or 4 (v. 1 or 2) 1.28 - 3.62 0.004

Age 0.002 *
 >3 yrs
 1 -3 yrs 0.76 - 1.84
 <1 yr 1.30 - 3.07

ART commenced before 2006 1.18 - 2.39 0.004

p-values derived from likelihood ratio tests.
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Title Annotation:Original Articles
Author:Davies, Mary-Ann; Keiser, Olivia; Technau, Karl; Eley, Brian; Rabie, Helena; van Cutsem, Gilles; Gid
Publication:South African Medical Journal
Geographic Code:6SOUT
Date:Oct 1, 2009
Words:5448
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