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When to Initiate Combined Antiretroviral Therapy to Reduce Mortality and AIDS-Defining Illness in HIV-Infected Persons in Developed Countries: An Observational Study

The HIV-CAUSAL Collaboration
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For a list of Writing Committee members, see end of article; for a list of the contributors to the HIV-CAUSAL Collaboration, see Appendix 1.

From Harvard School of Public Health, Boston, Massachusetts; University of Bristol, Bristol, United Kingdom; University College London Medical School and Medical Research Council, London, United Kingdom; Veterans Affairs Connecticut Healthcare System and Yale University School of Medicine, New Haven, Connecticut; University of Amsterdam, Amsterdam, the Netherlands; Universitätsspital Basel, Basel, Switzerland; University Hospital Zurich and University of Zurich, Zurich, Switzerland; Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Instituto de Salud Carlos III and Hospital Ramón y Cajal, Madrid, Spain; Hôpital de Bicêtre, Le Kremlin-Bicêtre, France; Barcelona Center for International Health Research and Hospital Clinic, Barcelona, Spain; and INSERM U943, Université Pierre et Marie Curie, and Hôpital Pitié-Salpétrière, Paris, France.

Writing Committee: Lauren E. Cain, PhD; Roger Logan, PhD; James M. Robins, MD; Jonathan A.C. Sterne, PhD; Caroline Sabin, PhD; Loveleen Bansi, MSc; Amy Justice, MD, PhD; Joseph Goulet, PhD; Ard van Sighem, PhD; Frank de Wolf, MD; Heiner C. Bucher, MD; Viktor von Wyl, PhD; Anna Esteve, PhD; Jordi Casabona, MD, MPH; Julia del Amo, MD, PhD; Santiago Moreno, MD; Rémonie Seng, MD; Laurence Meyer, PhD; Santiago Pérez-Hoyos, PhD; Roberto Muga, MD, PhD; Sara Lodi, PhD; Emilie Lanoy, PhD; Dominique Costagliola, PhD; and Miguel A. Hernán, MD, DrPH.

Grant Support: By the National Institutes of Health (grants R01-AI073127 and U10-AA013566) and the Medical Research Council (grant G0700820).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2963.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Cain (e-mail, lcain@hsph.harvard.edu).

Requests for Single Reprints: Lauren E. Cain, PhD, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115; e-mail, lcain@hsph.harvard.edu.

Current Author Addresses: Drs. Cain, Logan, Robins, and Hernán: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115.

Dr. Sterne: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, United Kingdom.

Dr. Sabin and Ms. Bansi: Research Department of Infection and Population Health, University College London Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom.

Drs. Justice and Goulet: Veterans Affairs Connecticut Healthcare System and Yale University School of Medicine, Department of Internal Medicine, 950 Campbell Avenue, 11-ACSLG, Building 35A, 2nd Floor, Room 212, New Haven, CT 06516.

Drs. van Sighem and de Wolf: Stichting HIV Monitoring, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.

Dr. Bucher: Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, CH-4031 Basel, Switzerland.

Dr. von Wyl: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Räemistrasse 100, 8091 Zurich, Switzerland.

Drs. Esteve and Casabona: CEEISCAT, Hospital Universitari Germans Trias i Pujol, Carretera Canyet s/n, 08916 Badalona, Spain.

Dr. del Amo: National Center of Epidemiology, Instituto de Salud Carlos III, Sinesio Delgado 6, 28029 Madrid, Spain.

Dr. Moreno: Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034 Madrid, Spain.

Drs. Seng and Meyer: INSERM U1018, Hôpital de Bicêtre, 82 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France.

Dr. Pérez-Hoyos: Methodological Support Unit on Biomedical Research (USMIB), Vall d'Hebron Hospital Research Institute (VHIR), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.

Dr. Muga: Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.

Dr. Lodi: Clinical Trials Unit, Medical Research Council, 222 Euston Road, London NW1 2DA, United Kingdom.

Dr. Lanoy: INSERM U943 and Université Pierre et Marie Curie, 56 boulevard V Auriol, BP 335, 75625 Paris Cedex 13, France.

Dr. Costagliola: INSERM U943, Université Pierre et Marie Curie and Hôpital Pitié-Salpétrière, 56 boulevard V Auriol, BP 335, 75625 Paris Cedex 13, France.

Author Contributions: Conception and design: L.E. Cain, J.A.C. Sterne, C. Sabin, J. Goulet, F. de Wolf, H.C. Bucher, J. Casabona, J. del Amo, D. Costagliola, M.A. Hernán.

Analysis and interpretation of the data: L.E. Cain, R. Logan, J.A.C. Sterne, C. Sabin, A. Justice, J. Goulet, F. de Wolf, J. del Amo, L. Meyer, D. Costagliola, M.A. Hemán.

Drafting of the article: L.E. Cain, J.M. Robins, J.A.C. Sterne, A. Justice, J. Goulet, S. Moreno, S. Lodi, E. Lanoy, D. Costagliola, M.A. Hernán.

Critical revision of the article for important intellectual content: L.E. Cain, J.M. Robins, J.A.C. Sterne, C. Sabin, A. Justice, J. Goulet, F. de Wolf, H.C. Bucher, V. von Wyl, J. Casabona, J. del Amo, S. Moreno, L. Meyer, S. Lodi, E. Lanoy, D. Costagliola, M.A. Hernán.

Final approval of the article: L.E. Cain, J.A.C. Sterne, C. Sabin, L. Bansi, A. Justice, J. Goulet, A. van Sighem, F. de Wolf, H.C. Bucher, V. von Wyl, A. Esteve, J. Casabona, J. del Amo, S. Moreno, R. Seng, L. Meyer, S. Pérez-Hoyos, S. Lodi, E. Lanoy, D. Costagliola, M.A. Hernán.

Provision of study materials or patients: C. Sabin, A. van Sighem, H.C. Bucher, A. Esteve, J. Casabona, J. del Amo, S. Moreno, L. Meyer, S. Pérez-Hoyos, D. Costagliola.

Statistical expertise: L.E. Cain, R. Logan, J.M. Robins, J.A.C. Sterne, J. Goulet, J. Casabona, D. Costagliola, M.A. Hernán.

Obtaining of funding: J.A.C. Sterne, J. del Amo, M.A. Hernán.

Administrative, technical, or logistic support: R. Logan, J. Casabona, M.A. Hernán.

Collection and assembly of data: I.E. Cain, C. Sabin, L. Bansi, A. Justice, J. Goulet, A. van Sighem, F. de Wolf, H.C. Bucher, V. von Wyl, A. Esteve, J. Casabona, J. del Amo, R. Seng, L. Meyer, S. Pérez-Hoyos, S. Lodi, D. Costagliola, M.A. Hernán.

Ann Intern Med. 2011;154(8):509-515. doi:10.7326/0003-4819-154-8-201104190-00001
Text Size: A A A

Background: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 109 cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate.

Objective: To identify the optimal CD4 cell count at which cART should be initiated.

Design: Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 109 cells/L.

Setting: HIV clinics in Europe and the Veterans Health Administration system in the United States.

Patients: 20 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 109 cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 109 cells/L and were included in the analysis.

Measurements: Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death.

Results: Compared with initiating cART at the CD4 cell count threshold of 0.500 × 109 cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death.

Limitations: CD4 cell count at cART initiation was not randomized. Residual confounding may exist.

Conclusion: Initiation of cART at a threshold CD4 count of 0.500 × 109 cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 109 cells/L.

Primary Funding Source: National Institutes of Health.


Grahic Jump Location
Survival (top) and AIDS-free survival (bottom) for combined antiretroviral therapy initiation at CD4 cell count thresholds ranging from 0.200 to 0.500 × 109 cells/L.
Grahic Jump Location
Grahic Jump Location
Appendix Figure.
Follow-up for 6 hypothetical persons whose data are consistent with multiple cART initiation strategies for CD4 cell count thresholds of 0.500 and 0.350 × 109 cells/L.

cART = combined antiretroviral therapy.

Grahic Jump Location




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Optimal time to initiate antiretroviral therapy: Implications for Sub-Saharan Africa
Posted on April 28, 2011
Amitabh B. Suthar
Geneva, Switzerland
Conflict of Interest: None Declared

The HIV-CAUSAL collaboration shows that initiating antiretroviral therapy (ART) once CD4 cell counts decline below 500 cells/uL prolongs AIDS-free survival (1). These findings add to the growing literature supporting a much earlier start of ART than is currently practised. Nowhere is this bold approach more needed than in sub-Saharan Africa, where 72% of the estimated 1.8 million global AIDS deaths occurred in 2009 (2). Compared with the industrialised world, patients treated in sub- Saharan Africa have much higher early mortality rates, with 8% to 26% of Africans dying during the first year of ART (3). The principal causes include undiagnosed tuberculosis (TB), bacteraemia, cryptococcal meningitis and the wasting syndrome (3).

Early start of ART has the potential to significantly reduce this mortality as well as provide other important public health advantages. Sub -Saharan Africa is gripped by a severe and continuing HIV-associated TB epidemic, particularly in the southern part of the continent, with immunodeficiency being the principal driver. At present, HIV testing and initiation of ART typically occur at low CD4 counts after the diagnosis of TB has already been made, and much of the TB preventive potential of ART is therefore squandered. Much earlier ART initiation combined with high coverage might be the most important action to combat the HIV-associated TB epidemic that currently rages in southern Africa (4). Evidence also suggests that ART reduces HIV transmission through a reduction in viral load, thus significantly decreasing the risk of HIV infection in sexual partners and in children born to infected mothers. The UNAIDS trumpet call of "zero infections" and the Global Fund's call of "Born HIV free" will not be achieved unless there is wide coverage and much earlier start of ART to protect all newborn infants during pregnancy, breast feeding and future pregnancies. Other advantages of early ART initiation include the therapeutic effects of tenofovir and lamivudine in treating hepatitis B, with which approximately 10% of HIV-infected Africans are coinfected (5).

Starting ART at higher CD4 counts in the resource-poor environment of sub-Saharan Africa will not be easy and important operational issues will need to be addressed and solved that include tolerability of drug regimens, ART adherence, prevention of drug resistance, health system and resource constraints, and assurance of adequate monitoring and reporting. However, solutions must be found as there is an opportunity to make a significant dent in both the HIV and TB epidemics.


1. The HIV-CAUSAL Collaboration. When to Initiate Combined Antiretroviral Therapy to Reduce Mortality and AIDS-Defining Illness in HIV-Infected Persons in Developed Countries. Annals of Internal Medicine. 2011;154:509-15.

2. UNAIDS. Report on the Global AIDS Epidemic. 2010 [Accessed 28 April 2011]; Available from: http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2010/20101123_globalreport_en.pdf

3. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008 Oct 1;22(15):1897-908.

4. Lawn SD, Harries AD, Williams BG, Chaisson RE, Losina E, De Cock KM, et al. Antiretroviral therapy and the control of HIV-associated tuberculosis. Will ART do it? The International Journal of Tuberculosis and Lung Disease. 2011;15(5):571-81.

5. Thio CL. Hepatitis B and human immunodeficiency virus coinfection. Hepatology. 2009 May;49(5 Suppl):S138-45.

Conflict of Interest:

None declared

Re:Optimal time to initiate antiretroviral therapy: Implications for Sub-Saharan Africa
Posted on May 9, 2011
Edward J Mills
University of Ottawa
Conflict of Interest: None Declared


The HIV-CAUSAL Collaboration provides strong inferences that earlier initiation of combination antiretroviral therapy (cART) reduces the long- term outcome of clinical events. This is consistent with the recommendations of recent peer reviewed treatment guidelines.(1) However, we question whether the continued emphasis on CD4 thresholds for initiation of cART is warranted.

The long-held debate over 'when to start' has been motivated by an attempt to balance cost versus effectiveness. These parameters have most often been assessed at the individual patient level. Even then, the focus has been on AIDS related morbidity and mortality. It is well established that inflammatory damage begins at early stages of infection, even before major immune damage has occurred.(2) Thus, the long-term effects of delayed access to cART will have an important impact on life expectancy, development of chronic diseases, and reduced long-term quality of life.(3) The slope of CD4 decline is variable, yet the period of time for a CD4 count to drop from current thresholds, say 0.500 to 0.350 x 10(9) cells/L., or 0.350 to 0.200 x 10(9) cells/L., is small (an average of 0.114 x 10(9) cells/L. cells per year (95% CI, 0.032-0.229),(4) and the short-term gains in cost and possible toxicity are importantly offset by life expectancy lost and the risk of chronic diseases.(3) For example, in the Antiretroviral Cohort Collaboration, delayed access to cART from greater than 0.200 x 10(9) cells/L. to 0.100-0.199 x 10(9) cells/L. was associated with a 7-year reduction in life expectancy.(3)

The benefits of early initiation are not just at the patient level as early cART initiation has potentially large effects at a population level on the incidence of new HIV infections.(5) Successful cART results in reduced viremia and therefore reduced infectivity.(5) Seeking out patients who are HIV infected through testing campaigns and then treating them, rather than passive systems that wait for individuals to seek HIV testing or identify infections when they present clinically, will benefit both the patients who require treatment and any of their subsequent sexual or drug using partners. The benefits of early initiation of cART are longer and better lives and the protection of others. We therefore contend that the more relevant question today should be 'why not start?' rather than 'when to start' cART.


1. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010;304:321-333.

2. Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200:749-759.

3. Antiretroviral Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. 2008;372:293-299.

4. Wolbers M, Babiker A, Sabin C, et al. Pretreatment CD4 cell slope and progression to AIDS or death in HIV-infected patients initiating antiretroviral therapy--the CASCADE collaboration: a collaboration of 23 cohort studies. PLoS Med. 2010;7:e1000239.

5. Montaner JS, Lima VD, Barrios R, et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet. 2010;376:532-539.

Conflict of Interest:

None declared

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