A total of 379,865 patients from 23 countries were included in the regression models, including 86,390 patients from 9 LIC (23%), 176,858 from 4 LMIC (47%), 82,152 from 4 UMIC (22%), and 34,465 from 6 HIC (9%). The Democratic Republic of the Congo, Kenya, Malawi, and Mali were overrepresented when compared with the WHO estimates of the number of patients on cART in the LIC included in our study. In contrast, Tanzania and Zimbabwe were underrepresented. The group of LMIC countries was dominated by Zambia and that of UMIC countries by South Africa. Among HIC, France contributed almost half of all patients, whereas the United States and Italy were underrepresented (see Table S1, Supplemental Digital Content,http://links.lww.com/QAI/A446).
The annual increase in median CD4 cell counts at the start of cART initiation from 2002 to 2009, estimated through linear regression (model 1), varied within and across World Bank country groups and tended to be greater among women than men (Table 2). Among LIC, the annual change in median CD4 cell counts ranged from −14 cells/μL [95% confidence interval (CI): −37 to +9 cells/μL] among women in the Democratic Republic of the Congo to +32 cells/μL (95% CI: +22 to +42 cells/μL) among Rwandan women. For LMIC, the corresponding range was from −2 cells/μL (95% CI: −14 to +9 cells/μL) among Nigerian men to +13 cells/μL (95% CI: +8 to +19 cells/μL) among women in Côte d’Ivoire. In UMIC, the range was from −1 cells/μL (−17 to +15 cells/μL) in Botswana men to +15 cells/μL (95% CI: 0 to +29 cells/μL) among Brazilian men. Finally, in HIC, the range was from −3 cells/μL (95% CI: −12 to +7 cells/μL) in Australian men to +16 cells/μL (95% CI: +12 to +20 cells/μL) in Canadian men. Crude (unweighted) and weighted pooled estimates of annual increases in CD4 cell count at cART initiation by country group were generally similar (Table 2). Also, results were similar in the complete case analysis (see Table S3, Supplemental Digital Content, http://links.lww.com/QAI/A446).
In LIC, the percentage of patients starting cART below 200 cells/μL declined from 85% in 2002 to 81% in 2009 in women and from 88% to 70% in men. Corresponding figures for LMIC were from 78% to 59% in women and from 79% to 67% in men and for UMIC from 86% to 65% in women and from 78% to 71% in men. In HIC, the decline was from 46% to 31% in women and from 49% to 35% in men. For threshold below 100 cells/μL, the declines were from 50% to 28% in women and from 57% to 36% in men in LIC, from 47% to 27% in women and from 51% to 36% in men in LMIC, from 54% to 31% in women and from 49% to 40% in men in UMIC, and from 22% to 15% in women and from 27% to 17% in men in HIC. Trends were similar in the complete case analysis (see Figure S2, Supplemental Digital Content, http://links.lww.com/QAI/A446).
This global analysis of CD4 cell counts at cART initiation between 2002 and 2010 was conducted in 2 HIV cohort collaborations, which together span 6 continents.7,18–21 We found that median CD4 cell counts at cART initiation were substantially higher in HIC, with only small differences between LIC and MIC. Median CD4 cell counts at the start of cART increased over the study period in most countries. These increases were greater in LIC and MIC than in HIC, and greater in women than in men. Among LIC and MIC, median CD4 cell counts at the start of cART were substantially higher in the few countries with national cART coverage of 80% or above.
In LIC and MIC, the median CD4 cell count remained well below 200 cells/μL between 2002 and 2009, despite the 2001 WHO recommendation to start when the CD4 gets near or falls below 200 cells/μL or, in persons with advanced clinical disease (WHO stage IV), irrespective of the CD4 cell count.26 Following a 2006 recommendation to consider treatment at CD4 cell counts below 350 cells/μL for patients in WHO stage III, WHO indicated in 2009 that cART should be initiated at 350 cells/μL irrespective of clinical symptoms.27 National guidelines in resource-limited settings generally echoed WHO guidelines,28 whereas HIC have more rapidly increased the CD4 cell count threshold for initiation. Of note, North American guidelines recently converged in their recommendation that cART should be offered to all HIV-positive individuals, irrespective of the CD4 cell count.29,30
A substantial rise in HIV testing in many countries, supported by Global Fund for Tuberculosis, AIDS and Malaria, PEPFAR, national or state/provincial level governments, and other donors, may have contributed to increasing CD4 cell counts at the start of cART. A monitoring and evaluation analysis of PEPFAR-supported HIV care clinics in 8 sub-Saharan African countries found that CD4 cell counts at cART initiation increased with HIV testing coverage in the region.31 In sub-Saharan Africa, PEPFAR supported over 140 million testing and counseling sessions between 2004 and 2011, with the number of sessions increasing from 1.9 million in 2004 to over 40 million in 2011.32 Two Demographic and Health Surveys from 7 PEPFAR countries conducted between 2003 and 2010 showed a dramatic increase in population level coverage of HIV testing and counseling.32 In Kenya, for example, the percentage of men reporting testing in the last 12 months increased from 7.5% to 22.7%. The corresponding increase was even greater in women, from 6.7% to 29.3%. Similarly, in Lesotho, testing increased from 6.3% to 42.0% in women and from 4.8% to 24.0% in men. Provider-initiated testing and counseling may not, however, be sufficient to prevent late HIV diagnosis. Uganda adopted provider-initiated HIV testing in the health care setting in 2005, but in a recent randomized controlled trial, half of HIV-positive patients screened had CD4 cell counts below or equal to 250 cells/μL.33
The steeper increase of HIV testing coverage among women compared with men may be explained by scale-up of programs to PMTCT. More frequent testing leads to earlier diagnosis and then earlier initiation of cART in eligible women. The scale-up of PMTCT could thus also account for the greater increases of CD4 cell counts at the start of cART in women than men observed in the present study. A review of national program data for 2004 to 2005 showed that the scale-up of PMTCT had gained momentum in many countries and that provider-initiated (opt-out) HIV testing had become nearly universal in some regions (eg, in East and Southern Africa) but not in others (eg, in West Africa).34 A systematic review and meta-analysis of 44 studies of pregnant women who attended PMTCT programs in sub-Saharan Africa showed that uptake at antenatal care services was 94% for opt-out testing compared with 58% for opt-in testing.35 Coverage with any type of antiretroviral prophylaxis was 70%, and 62% of pregnant women eligible for cART received treatment.35 Similarly, a meta-analysis of 6 studies that reported on numbers of adults followed up between HIV diagnosis and start of cART showed that of every 100 patients with a positive HIV test, 72 had a CD4 cell count measured, 40 were eligible for cART, and 25 started cART. Of note, men were more likely to be lost to program and less likely to start cART than women.36
Our study has several limitations. We could only examine information up to 2010 because more recent data were not yet available from many sites participating in the IeDEA and ART cohort collaborations. CD4 cell counts at the start of cART were missing in approximately 1 quarter of patients, who were more likely to be from LIC and MIC and in a more advanced stage of disease than patients with measured CD4 cell counts. It is thus likely that our estimates of median CD4 cell counts at cART initiation are biased upward for these countries. Data from some countries were limited to a small number of patients from a single clinic. We decided to include these in descriptive analyses, but because the data are probably not representative of all patients on cART in those countries, we excluded them from analyses of time trends and predictors of CD4 cell count at the start of cART. In sensitivity analyses, we weighted individual country data, with the aim of creating a data set that was representative, within each income group, of the number of patients on cART in each country, as estimated by WHO.5 Some of the data included in these sensitivity analyses may, however, not be representative of all patients on cART in the country. In particular, the clinics from LIC and MIC participating in IeDEA are mainly urban and capture data in electronic databases, indicating a higher level of resources. They may more closely reflect best practice in urban settings than in the country as a whole. Nevertheless, our study is a unique source of information on trends and determinants of the CD4 cell count in adult patients starting cART across the globe.
In conclusion, our results illustrate the enormous challenges that lie ahead. Despite the massive scale up of cART in LIC, from 300,000 patients on cART in 2002 to 6.6 million by the end of 2010, the increases in median CD4 cell count at the start of cART during this period have been modest. In 2009, most patients in LIC and MIC and many patients in HIC started cART with CD4 cell counts below 200 cells/μL, which means that they were already at high risk of complications and had spent years at high risk of HIV transmission. Substantial efforts and resources are needed to achieve earlier implementation of cART globally. Finally, continued monitoring of the CD4 cell count at which HIV-positive patients start cART in LIC, middle-income countries, and HIC is needed to evaluate the results of these efforts.
The IeDEA and ART cohort collaborations are grateful to all patients, care givers, and data managers involved in the participating cohorts and treatment programs.
The African regions of the International epidemiological Databases to Evaluate AIDS (IeDEA) are supported by the National Cancer Institute (NCI), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Allergy And Infectious Diseases (NIAID) as part of IeDEA (Grants 5U01-AI069919-04, 5U01-AI069924-05, 1U01-AI069927, U01-AI069911-01, 5U01-AI096299). The Caribbean, Central and South America network of IeDEA is supported by NIAID Grant 5U01-AI69923-06. The North American AIDS Cohort Collaboration on Research and Design of IeDEA is supported by Grants U01-AI069918, U10-AA13566, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI35043, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-HD32632, U10-EY08057, U10-EY08052, U10-EY08067, UL1-RR024131, UL1-RR024131, M01-RR-00052, M01-RR00071, M01-RR00079, M01-RR00083, M01-RR00722, M01-RR025747, P30-AI27757, P30-AI27767, P30-AI27763, P30-AI50410, P30-AI54999, R01-DA04334, R01-DA12568, R01-DA11602, R01-AA16893, R24-AI067039, Z01-CP010176, AHQ290-01-0012, N02-CP55504, AI-69432, AI-69434, K01-AI071725, K23-AI610320, K23-EY013707, K24-DA00432, K01-AI093197, U10-AA13566, R01-AG029154, and K23 AG024896 from the National Institutes of Health; contract CDC200-2006-18797 from the Centers for Disease Control and Prevention; Grants TGF-96118, HCP-97105, CBR-86906, CBR-94036, KRS-86251, and 169621 from the Canadian Institutes of Health Research; the Canadian HIV Trials Network, project 24; and the Government of British Columbia. The TREAT Asia HIV Observational Database, TREAT Asia Studies to Evaluate Resistance, and the Australian HIV Observational Database are initiatives of TREAT Asia, a program of amfAR, The Foundation for AIDS Research, with support from the Dutch Ministry of Foreign Affairs through a partnership with Stichting Aids Fonds, and the US National Institutes of Health's NIAID, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and NCI, as part of IeDEA (U01AI069907). Queen Elizabeth Hospital and the Integrated Treatment Center received additional support from the Hong Kong Council for AIDS Trust Fund. The Kirby Institute is funded by the Australian Government Department of Health and Ageing and is affiliated with the Faculty of Medicine, The University of New South Wales. The ART Cohort Collaboration is supported by UK Medical Research Council and the Department for International Development (DFID), (grants G0700820 and MR/J002380/1). The content of this publication is solely the responsibility of the authors and does not represent the official views of any of the institutions and funders mentioned.
Dorita Avila,1 Keri N. Althoff,2 Catrina Mugglin,1 Kara Wools-Kaloustian,3 Manuel Koller,1 François Dabis,4 Denis Nash,5 Thomas Gsponer,1 Somnuek Sungkanuparph,6 Catherine McGowan,7 Margaret May,8 David Cooper,9 Cleophas Chimbetete,10 Marcelo Wolff,11 Ann Collier,12 Hamish McManus,9 Mary-Ann Davies,13 Dominique Costagliola,14 Brenda Crabtree-Ramirez,15 Romanee Chaiwarith,16 Angela Cescon,17 Morna Cornell,13 Lameck Diero,18 Praphan Phanuphak,19 Adrien Sawadogo,20 Jochen Ehmer,21 Serge P. Eholie,22 Patrick C.K. Li,23 Matthew P. Fox,24,25 Neel R. Gandhi,26 Elsa González,27 Christopher K.C. Lee,28 Christopher J. Hoffmann,29,30 Andrew Kambugu,31 Olivia Keiser,1 Rossana Ditangco,32 Hans Prozesky,33 Fiona Lampe,34 Nagalingeswaran Kumarasamy,35 Mari Kitahata,12 Emmanuel Lugina,36 Rita Lyamuya,37 Saphonn Vonthanak,38 Valeria Fink,39 Antonella d'Arminio Monforte,40 Paula Mendes Luz,41 Yi-Ming A. Chen,42 Albert Minga,43 Jordi Casabona,44,45 Albert Mwango,46 Jun Y. Choi,47 Marie-Louise Newell,48 Elizabeth A. Bukusi,49 Kapella Ngonyani,50 Tuti P. Merati,51 Juliana Otieno,52 Mwebesa B. Bosco,53 Sam Phiri,54 Oon T. Ng,55 Kathryn Anastos,56 Jürgen Rockstroh,57 Ignacio Santos,58 Shinichi Oka,59 Geoffrey Somi,60 Christoph Stephan,61 Ramon Teira,62 Deo Wabwire,63 Gilles Wandeler,64 Andrew Boulle,13 Peter Reiss,65 Robin Wood,66 Benjamin H. Chi,67 Carolyn Williams,68 Jonathan A. Sterne,9 Matthias Egger.1,13
(1) Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland; (2) Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; (3) Indiana University School of Medicine, Indianapolis, IN; (4) Institut de Santé Publique, Epidémiologie et Développement (ISPED), Université Bordeaux Segalen, Bordeaux, France; (5) CUNY School of Public Health, New York; (6) Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; (7) Vanderbilt University School of Medicine, Nashville, TN; (8) School of Social and Community Medicine, University of Bristol, United Kingdom; (9) The Kirby Institute, The University of New South Wales, Sydney, Australia; (10) Newlands Clinic, Harare, Zimbabwe; (11) Fundación Arriarán, Universidad de Chile, Santiago, Chile; (12) University of Washington School of Medicine Center, Seattle, WA; (13) Centre for Infectious Disease Epidemiology & Research and Division of Epidemiology & Biostatistics, School of Public Health & Family Medicine, University of Cape Town, South Africa; (14) 1-UPMC Univ Paris 06, UMR_S 943, Paris, France; (15) Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, México D.F., México; (16) Research Institute for Health Sciences, Chiang Mai, Thailand; (17) British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada; (18) Academic Model Providing Access to Health Care (AMPATH), School of Medicine, College of Health Sciences, Moi University, Eldoret, Kenya; (19) HIV-NAT/Thai Red Cross AIDS Research Centre, Bangkok, Thailand; (20) CHU Sourô Sanou, Bobo-Dioulasso, Burkina Faso; (21) SolidarMed African HIV prevention and treatment program, Lucerne, Switzerland; (22) Service de Maladies Infectieuses et Tropicales (SMIT), CHU de Treichville, Abidjan, Côte d’Ivoire; (23) Queen Elizabeth Hospital, Hong Kong SAR, China; (24) Center for Global Health and Development and Department of Epidemiology, Boston University and Boston University School of Public Health, Boston, MA; (25) Health Economics and Epidemiology Research Office, University of the Witwatersrand, Johannesburg, South Africa; (26) Departments of Epidemiology, Global Health & Infectious Diseases, Emory University Rollins School of Public Health, Atlanta, GA; (27) Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru; (28) Hospital Sungai Buloh, Sungai Buloh, Malaysia; (29) Aurum Institute, Johannesburg, South Africa; (30) John Hopkins University School of Medicine, Baltimore, MD; (31) Infectious Diseases Institute (IDI), Kampala, Uganda; (32) Research Institute for Tropical Medicine, Manila, Philippines; (33) Division of Infectious Diseases, University of Stellenbosch and Tygerberg Hospital, Cape Town, South Africa; (34) Research Department of Infection and Population Health, University College London, United Kingdom; (35) YRG Center for AIDS Research and Education, Chennai, India; (36) Ocean Road Cancer Institute (ORCI), Dar-es-Salaam, Tanzania; (37) Morogoro Regional Hospital, Morogoro, Tanzania; (38) National Center for HIV/AIDS, Dermatology & STDs, Phnom Penh, Cambodia; (39) Fundación Huésped, Buenos Aires, Argentina; (40) Clinic of Infectious Diseases & Tropical Medicine, San Paolo Hospital, University of Milan, Italy; (41) Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; (42) Taipei Veterans General Hospital and AIDS Prevention and Research Center, National Yang-Ming University, Taipei, Taiwan; (43) Centre Médical de Suivi de Donneurs de Sang/CNTS/PRIMO-CI, Abidjan, Cote d'Ivoire; (44) Centre d’Estudis Epidemiològics sobre ITS/VIH/SIDA de Catalunya, Badalona, Spain; (45) CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; (46) Zambian Ministry of Health, Lusaka, Zambia; (47) Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; (48) Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Mtubatuba, South Africa; (49) Family AIDS Care and Education Services (FACES), Kisumu, Kenya; (50) Tumbi Regional Hospital, Kibaha, Tanzania; (51) Faculty of Medicine Udayana University & Sanglah Hospital, Bali, Indonesia; (52) Nyanza Provincial Hospital, MTCT-plus, Kisumu, Kenya; (53) Mbarara University of Science and Technology (MUST), ISS Clinic, Mbarara, Uganda; (54) Lighthouse Trust, Lilongwe, Malawi; (55) Tan Tock Seng Hospital, Singapore; (56) Departments of Medicine and Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY; (57) Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany; (58) Hospital La Princesa, Madrid, Spain; (59) National Center for Global Health and Medicine, Tokyo, Japan; (60) National AIDS Control Program, Dar es Salaam, Tanzania; (61) HIVCENTER am Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; (62) Hospital Sierrallana, Torrelavega, Spain; (63) Makerere University Johns Hopkins University Research Collaboration (MUJHU Research collaboration), Kampala Uganda; (64) Department of Infectious Diseases, Bern University Hospital and University of Bern, Switzerland; (65) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, The Netherlands; (66) Desmond Tutu HIV Center, University of Cape Town, South Africa; (67) Center for Infectious Disease Research in Zambia, Lusaka, Zambia; (68) Epidemiology Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD.
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