Cohort Profile: The Paediatric Antiretroviral Treatment Programmes in Lower-Income Countries (KIDS-ART-LINC) Collaboration

The Paediatric Antiretroviral Treatment Programmes in Lower-Income Countries (KIDS-ART-LINC) collaboration (see Appendix for details) is an international epidemiological network in sub-Saharan Africa. The paediatric HIV burden is currently estimated at 2.3 million (1.7–3.5 million) children under 15 years of age worldwide, 90% of them living in sub-Saharan Africa.1 Anti-retroviral therapy (ART) is an essential part of the overall strategy to fight the HIV pandemic, and has, since 1996, led to substantial reduction in HIV-related morbidity and mortality in children in industrialized nations.2,,3 However, paediatric HIV care and ART programmes have not reached most resource-poor settings, particularly in Africa. Simplified models, developed to deliver drugs to large numbers of people generally focus on adults and have rarely addressed ART in children.4 An estimated 780 000 children were in need of ART in 2006 and only 10% of them received it.5 The World Health Organization (WHO) has recently updated its guidelines for ART use in resource-limited settings with a specific focus on children,6 stressing the need to build up and share local expertise in managing HIV-infected children. To date, little data is available on paediatric HIV care and treatment in Africa7–13 and furthermore, there is a lack of scientifically rigorous evaluation of the limited number of paediatric ART programmes.14,,15 Evaluating the effectiveness of ART in delaying disease progression and reducing mortality in children outside research settings deserves an urgent and wide-scale, evidence-based assessment. Built to inform health care policy and practice, the KIDS-ART-LINC Collaboration is a joint initiative of the African Network for the Care of Children Affected by HIV/AIDS (ANECCA), the Regional Centre for Quality of Health Care, Kampala, Uganda, and the Institut de Santé Publique et de Développement (ISPED) at the Université Victor Segalen, Bordeaux, France. The organizational structure includes two principal investigators from ANECCA and ISPED, a central coordinating team (project manager, epidemiologist and data manager) and a Steering Committee of representatives from all the participating sites (local principal investigators). In mid-2005, the coordinating team identified potential clinical sites and cohorts treating HIV-infected children with ART in sub-Saharan Africa from the ANECCA database of network members, by performing MEDLINE searches, screening abstracts presented at international conferences and through investigators’ contacts. A request for expression of interest to participate in the collaboration, detailing the objectives, principles and procedures, was sent to all the potential participating sites. Paediatric HIV care cohorts agreeing to participate signed a collaborative agreement. The collaboration was officially constituted in October 2005. This first phase of the KIDS-ART-LINC Collaboration was funded by the US National Institutes of Health (Office of AIDS Research) and USAID/East Africa (Office for Regional Health and HIV/AIDS Programmes), with the recent adjunct of the French Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS). All investigators agreed on the following research objectives for this first phase: To document first-line ART effectiveness or field efficacy in African children under routine circumstances, by studying annual mortality, clinical progression, immunological restoration and viral suppression (when available). To estimate the frequency of occurrence of serious adverse events (SAE) and of ART toxicities that lead to switching of drugs. To document current tuberculosis care practices in the clinical centres and estimate the frequency of occurrence of tuberculosis among ART-treated African children. To investigate potential determinants of outcomes (effectiveness and toxicity) at individual, family and programme level. To document the various models of service delivery for paediatric HIV care and treatment throughout sub-Saharan Africa and how they impact on treatment outcomes. Twenty-five sites (Figure 1) in 16 countries (eight in West, nine in East and Central and eight in Southern Africa) and the MTCT-Plus Network signed the collaborative agreement. Of the 25 individual sites, 24 were formally assessed during a site assessment survey. The median year for ART introduction in these facilities was 2003 (interquartile range [IQR]: 2002–04) (Tables 1 and 2). Eighteen (75%) centres were within public health care facilities, mainly receiving financial support through national Ministries of Health. The remaining six were either private not-for-profit centres run by non-governmental organizations or faith-based organizations (4) or research-dedicated clinics (2). Twenty-three sites (96%) were based in urban or peri-urban areas. Seven programmes (29%) exclusively treated HIV-infected children, whereas the rest were integrated into adult HIV care or general paediatric care facilities. Nineteen programmes were downstream from PMTCT programme in the same site. At the time of the survey, a minimum of 6527 HIV-infected and exposed children were registered in the 24 programmes (median 233 [IQR] 145–346). A total of 4502 children were on ART in 24 sites; with an average of 188 children per programme (median 161 [IQR] 66–293). The level of staffing varied with a median number of four (IQR 2–6) doctors per centre dedicated to care of HIV-infected/exposed children (Tables 1 and 2), corresponding to a ratio of one doctor per 56 children. Although there was a laboratory facility in 22 sites (92%), CD4 and viral load were performed in an external laboratory in 25 and 50% of cases, respectively. Thirteen of 22 centres reported to have access to virological tests for early HIV diagnosis, while the reminder had only access to antibody tests only. External quality assurance/quality control for laboratory procedures was reported in 10 (42%) facilities. With regard to the use of guidelines to provide treatment to HIV-infected children, 19 of 23 sites reported to use national Ministry of Health (MOH) guidelines and 20/24 the WHO clinical staging system. All sites had access to generic anti-retroviral (ARV) drugs, but one used branded drugs only. Eligibility criteria for ART initiation generally corresponded to the WHO or US Centers for Disease Control (CDC) criteria. The first-line ART regimens for the majority of programmes were non-nucleoside reverse transcriptase inhibitor (NNRTI) based (18 for children <10 kg and 22 for children >10 kg). Three centres prescribed lopinavir/ritonavir or nelfinavir-based regimens as first line for children weighing <10 kg. The nucleoside (NRTI) backbone drugs used were lamivudine with either zidovudine or stavudine. All centres except three offered free ARVs to patients (Tables 1 and 2). In the three sites where treatment was paid for, the families’ contribution to the cost of ARV treatment depended on income levels. All sites provided cotrimoxazole to the children, for free in 18 sites out of 22 (82%). Medical consultations were free for all children except in five sites where charges were levied on patients either as a one-time nominal fee or varied depending on the income of the parents/guardians. Twenty-one sites provided free CD4 investigation for children, while two charged a fee for this service. Most of the ARV drug costs were met through support programmes like the US President's Emergency Plan for AIDS Relief (PEPFAR), the Global Fund, other international and bilateral agencies and Ministries of Health. From this sample, nine centres with local ethics approval and data in electronic format and the MTCT-Plus network have contributed to the central KIDS-ART-LINC database (Figure 1), now comprising baseline and follow-up data from 3644 children in care, of whom 2666 have initiated ART. Geographical location of the 25 programmes participating in the KIDS-ART-LINC Collaboration, 2006–07 General characteristics of 24 treatment programmes participating in the KIDS-ART-LINC Collaboration, (Site assessment survey, 2006) ART, Antiretoviral therapy; EGPAF, Elizabeth Glaser Pediatric AIDS Foundation; MSF, Médecins sans Frontières; PEPFAR, United State President's Emergency Plan for AIDS Relief; NA, information not available. General characteristics of 24 treatment programmes participating in the KIDS-ART-LINC Collaboration, (Site assessment survey, 2006) ART, Antiretoviral therapy; EGPAF, Elizabeth Glaser Pediatric AIDS Foundation; MSF, Médecins sans Frontières; PEPFAR, United State President's Emergency Plan for AIDS Relief; NA, information not available. General characteristics of 24 treatment programmes participating in the KIDS-ART-LINC Collaboration, (Site assessment survey, 2006) aAs of April 2007. ARV, anti-retroviral; NA, not available. General characteristics of 24 treatment programmes participating in the KIDS-ART-LINC Collaboration, (Site assessment survey, 2006) aAs of April 2007. ARV, anti-retroviral; NA, not available. Children records are obtained at baseline, when they initiate HIV care in the facility, and then every 3–6 months, or in between, for any intercurrent disease. Standard operating procedures (SOP) for data transfer have been developed for the sites with electronic data already available. The sites are requested to extract from their database variables, to put them in a specific format and to export them in complete security. The SOP describes the nature and the format of the variables, how to organize the data according to a paediatric adaptation of an international standard format, the HIV Cohorts Data Exchange Protocol (HICDEP)16 and how to send the data in a secure way using compression/encryption software. The variables to be extracted were chosen in accordance with decisions taken during steering committee meetings regarding the research questions to be addressed and the key variables. Therefore, data being collected include: At baseline only Demographics: birth date, gender, mode of entry in the programme, caretaker and birth characteristics. At baseline and at each subsequent clinical assessment Clinical assessment results: tuberculosis status/history, HIV clinical stage, weight and height with dates. Medications: anti-retroviral drugs, cotrimoxazole with dates. Outcomes: death, losses to follow-up with dates. At baseline and at each subsequent biological assessment, when available Laboratory test results: CD4, haemoglobin, liver enzymes and plasma HIV RNA viral load with dates of measurement. Of 2462 children on ART with usable electronic data in the first data merger from nine centres and the MTCT-Plus network, 141 deaths were recorded and 213 children were considered lost to follow-up in the first year on ART, 14 additional deaths and 155 loss-to-follow-up were recorded in the second year of treatment. The probabilities of death or loss-to-follow-up were thus 6.0% [95% confidence interval (CI) 5.1–7.1] and 9.5% (95% CI 8.3–10.9) at 1 year and 6.9% (95% CI 5.9–8.1) and 19.2% (95% CI 17.4–21.1) at 2 years of treatment, respectively. Globally, 19 programmes reported having active follow-up procedures for tracking HIV-infected children who missed appointments, including 15 with dedicated staff and 14 conducting home visits (Tables 1 and 2). Thirteen programmes reported systematically searching for death ascertainment and recording the date of the death. Some of the participating cohorts have already published individually on their experience in HIV paediatric care and treatment.7–9,,13 The survey on the site assessments has been presented in 2006.17 Preliminary survival data from the first merger were recently presented.18 The KIDS-ART-LINC Collaboration was briefly described in a specific section of the 2007 WHO report on scaling-up priority HIV/AIDS interventions in the health sector.1 A manuscript is in progress, looking at probabilities of death or loss-to-follow-up within 2 years of treatment and to investigate their determinants (see above). KIDS-ART-LINC is a multi-centre and multi-country collaboration of paediatric HIV treatment programmes in sub-Saharan Africa. It aims, first, to build and strengthen an operational research network that describes paediatric HIV care. Treatment outcomes and their determinants are in process to be investigated by pooling individual patient data, and should thus appropriately inform policies and programmes by examining various models of care, clinical outcomes and operational issues over time. The network was based on a similar successful experience of adult treatment centres in lower income countries19 to rapidly bridge the gap on clinical and programmatic information for children on ART on the African continent. The extent to which this collaboration was representative of the whole of sub-Saharan Africa as of mid-2006 cannot be fully ascertained. It is pertinent to note that several large centres identified as providing paediatric ART services in the region did not participate. However, the total number of children on ART in the participating centres (Tables 1 and 2) account for 13.7% of the total number of children on ART in their respective country according to international statistics, when data are available.5 ART provision to children is generally quite recent in Africa, the median duration of paediatric ART services being 2 years in this first data merger. The KIDS-ART-LINC central database, comprising individual data received as of April 1, 2007, from nine centres (five in western Africa, one in central Africa and three in Southern Africa), plus the MTCT-Plus network represents one of the largest sources of data about HIV-infected children on ART in sub-Saharan Africa, with the Médecins Sans Frontières network.12 The sites with data systems not usable yet have started receiving support from the collaboration in partnership with the International epidemiological Databases to Evaluate AIDS (IeDEA) initiative (http://www.iedea-hiv.org) to improve data quality and completeness. Therefore, the KIDS-ART-LINC collaboration has the potential to contribute to human resource capacity building and networking activities required for the rolling-out of paediatric ART on the African continent and its proper evaluation. A website has been created (http://www.rcqhc.org/kids-art-linc/), presenting the collaboration and its partners, with a dedicated part where all documents produced by the collaboration are shared to the investigators who have registered. Any question or request on the data should be posted to the Central Coordinating Team through the website. It is agreed between members of the collaboration that only projects that have been approved by the Steering Committee will be conducted and presented outside of the collaboration. However, new collaborators or groups of collaborators are encouraged to propose and/or perform additional projects and analyses that have different aims and address new hypotheses. They should contact the KIDS-ART-LINC central coordinating team through the website and each request will be discussed case by case first by email exchange. Finally, the KIDS-ART-LINC Collaboration is progressively developing a scientific and technical relationship with the four regional centres of the IeDEA consortium in sub-Saharan Africa. By collecting, merging and analysing relevant data on paediatric care and ART on this continent with sound hypothesis generation and testing, it is anticipated that this African collaboration will provide the evidence needed to inform clinicians and programme managers in this rapidly evolving field. Special thanks to Jack Whitescarver (NIH/OAR) and Denis Tindyebwa (ANECCA, EGPAF) who encouraged the creation of the KIDS-ART-LINC collaboration and Chris Bailey (WHO) for encouraging the development of training in health information within the KIDS-ART-LINC network. The authors want to thank the many professionals dedicated in paediatric HIV care in the participating centres and who supported and encouraged the conduct of the survey. This work was funded by US NIH/OAR and USAID East Africa (2005–07) and French ANRS (2007), with additional support from the European and Developing Countries Clinical Trials Partnership (EDCTP). Conflict of Interest: None declared. Principal Investigators: Dorothy Mbori-Ngacha, François Dabis Central Coordinating Team: Elise Arrivé, Daniel Kyabayinze (2006), Benoit Marquis, Leticia Namale (2007), Nathan Tumwesigye Steering Committee Alain Azondékon, UPEIV/Hôpital d’Instruction des Armées, Cotonou, Bénin Alice Zougrana Kaboré, Hôpital Charles de Gaulle, Ouagadougou, Burkina Faso Andrew Boulle and David Coetzee, Khayelitsha Hospital, Cape Town, South Africa Avi Violari and Rikash Jokhan, Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital, Soweto, South Africa Christine Ondoa-Onama, Arua Regional Referral Hospital, Arua, Uganda Denis Nash, 12 MTCT Plus sites (http://www.mtctplus.org) Frida Sunjoh, Paediatric service, Provincial Hospital, Bamenda, Cameroon Haby Signaté Sy and Fatou Ly Ndiaye, Hôpital Albert Royer, Dakar, Sénégal Higgins Massawe and Augustin Massawe, Muhimbili National Hospital, Dar Es Salaam, Tanzania Julius Kiwanuka, Mbarara University, Mbarabra, Uganda Kankasa Chipapo and Mwiya Mwiya, University Teaching Hospital, Lusaka, Zambia Lorna Renner and Bamenla Goka, Korle Bu Hospital, Accra, Ghana Louise Wemin, Centre de Prise en Charge, de Recherche et de Formation (CEPREF) Enfants, Abidjan, Côte d’Ivoire Margaret Pascoe, Connaught Clinic, Harare, Zimbabwe Maria Nanyonga, Nsambya Hospital, Kampala, Uganda Mariam Sylla, Fatoumata Dicko-Traoré, Hôpital Gabriel Touré, Bamako, Mali Marie-Claude Uwurukundo, CHU Butare, Butare, Rwanda Mark Paterson, Provincial Hospital of Mutare, Mutare, Zimbabwe Mark Cotton, Helena Rabie, Hans Prozesky, Clair Edson, Heinrich Weber and Ayanda Madide, Tygerberg Children's Hospital, Cape Town, South Africa Narcisse Muganga, CHU Kigali, Kigali, Rwanda Patricia Fassinou, Centre Hospitalier Universitaire (CHU) de Yopougon, Abidjan, Côte d’Ivoire Pelagie Nimbona, Association Nationale de Soutien aux Séropositifs (ANSS), Bujumbura, Burundi Pierre Kariyo, University of Kamenge Central Hospital, Bujumbura, Burundi Ralf Weigel, Lighthouse clinic, Lilongwe, Malawi Sarah Rowland Jones and Akum Aveika, Medical Research Council, Fajara, The Gambia Tim Meade, CorpMed Clinic, Lusaka, Zambia Advisory Scientific Committee: Chewe Luo (UNICEF), Elaine Abrams (MTCT-Plus, Columbia University), Marie-Louise Newell (Ghent Group and European Collaborative Study, ICH London), Mary-Pat Kieffer (USAID), Matthias Egger (ART-LINC, University of Bern), Paolo Miotti (NIH/OAR), Ruth Nduati (ANECCA) and Valériane Leroy (Ghent Group and ISPED Bordeaux).