Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study

Suzanne M Ingle, Jose M Miro*, Margaret T May, Lauren E Cain, Christine Schwimmer, Robert Zangerle, Helen Sambatakou, Charles Cazanave, Peter Reiss, Vanessa Brandes, Heiner C Bucher, Caroline A Sabin, Francesc Vidal, Niels Obel, Amanda Mocroft, Linda Wittkop, Antonella D Arminio Monforte, Carlo Torti, Cristina Mussini, Hansjakob FurrerDeborah Konopnicki, Ramon Teira, Michael S Saag, Heidi Crane, Richard D Moore, Jeffrey M Jacobson, W Chris Mathews, Elvin H Geng, Joseph J Eron, Keri N Althoff, Abigail Kroch, Raynell Lang, M John Gill, Jonathan A C Sterne

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

6 Citations (Scopus)
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Abstract

Background
Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings.

Methods
Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14–56 days after CM) ART on all-cause mortality, adjusting for potential confounders.

Results
Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33–44) years; the median CD4+ T-cell count, 19/μL (10–56/μL); and median HIV viral load, 5.3 (4.9–5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64–2.56) and 1.40 (.66–2.95), respectively.

Conclusions
We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.
Original languageEnglish
Article numberciad122
Pages (from-to)64-73
Number of pages10
JournalClinical Infectious Diseases
Volume77
Issue number1
Early online date8 Mar 2023
DOIs
Publication statusPublished - 1 Jul 2023

Bibliographical note

Funding Information:
The Antiretroviral Therapy Cohort Collaboration (ART-CC) is supported by the US National Institute on Alcohol Abuse and Alcoholism (grant U01-AA026209) and the UK Medical Research Council. The Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) is an National Institutes of Health–funded program (grant R24 AI067039) made possible by the National Institute of Allergy and Infectious Diseases. The Center for AIDS Research sites involved in CNICS include the University of Alabama at Birmingham (grant P30 AI027767), University of Washington (grant P30 AI027757), the University of California San Diego (grant P30 AI036214), University of California San Francisco (grant P30 AI027763), Case Western Reserve University (grant P30 AI036219), Johns Hopkins University (grants P30 AI094189 and U01 DA036935), Fenway Health/Harvard (grant P30 AI060354), University of North Carolina Chapel Hill (grant P30 AI50410), Vanderbilt University (grant P30 AI110527), and University of Miami (grant P30 AI073961). The North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) was supported by the National Institutes of Health (grants U01AI069918, F31AI124794, F31DA037788, G12MD007583, K01AI093197, K01AI131895, K23EY013707, K24AI065298, K24AI118591, K24DA000432, KL2TR000421, N01CP01004, N02CP055504, N02CP91027, P30AI027757, P30AI027763, P30AI027767, P30AI036219, P30AI050409, P30AI050410, P30AI094189, P30AI110527, P30MH62246, R01AA016893, R01DA011602, R01DA012568, R01 AG053100, R24AI067039, U01AA013566, U01AA020790, U01AI038855, U01AI038858, U01AI068634, U01AI068636, U01AI069432, U01AI069434, U01DA03629, U01DA036935, U10EY008057, U10EY008052, U10EY008067, U01HL146192, U01HL146193, U01HL146194, U01HL146201, U01HL146202, U01HL146203, U01HL146204, U01HL146205, U01HL146208, U01HL146240, U01HL146241, U01HL146242, U01HL146245, U01HL146333, U24AA020794, U54MD007587, UL1RR024131, UL1TR000004, UL1TR000083, Z01CP010214, and Z01CP010176; the US Centers for Disease Control and Prevention (contracts CDC-200-2006-18797 and CDC-200-2015-63931); the US Agency for Healthcare Research and Quality (contract 90047713); the US Health Resources and Services Administration (contract 90051652 ); the Canadian Institutes of Health Research (grants CBR-86906, CBR-94036, HCP-97105, and TGF-96118); the Ontario Ministry of Health and Long Term Care; and the Government of Alberta, Canada. Additional support was provided by the National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institute for Mental Health, National Institute on Drug Abuse, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Neurological Disorders and Stroke, National Institute of Nursing Research, National Institute on Alcohol Abuse and Alcoholism, National Institute on Deafness and Other Communication Disorders, and National Institute of Diabetes and Digestive and Kidney Diseases. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group has received unrestricted funding from the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS), France; the HIV Monitoring Foundation, the Netherlands; and the Augustinus Foundation, Denmark. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013; under EuroCoord grant agreement 260694P).

Funding Information:
Financial support. This work was supported by the UK Medical Research Council (S. M .I. and M. T. M.); the National Institutes of Health (L. E. C., H. M. C., R. D. M., J. J. E., M. J. G., J. A. C. S., and K. N. A.); the National Institute on Alcohol Abuse and Alcoholism (S. M. I. and M. T. M.); the University of Bristol (funding to R. T. for data extraction); ART-CC (international cohort; support to M. S. S.); Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS; personal 80:20 research grant to J. M. M.); Programa de Intensificación de Investigadores (INT20/00031)-ISCIII (support to F. V.); the National Institute for Health and Care Research (Senior Investigator award (NF-SI-0611-10168 to J. A. C. S.).

Funding Information:
The study funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Financial support. This work was supported by the UK Medical Research Council (S. M .I. and M. T. M.); the National Institutes of Health (L. E. C., H. M. C., R. D. M., J. J. E., M. J. G., J. A. C. S., and K. N. A.); the National Institute on Alcohol Abuse and Alcoholism (S. M. I. and M. T. M.); the University of Bristol (funding to R. T. for data extraction); ART-CC (international cohort; support to M. S. S.); Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS; personal 80:20 research grant to J. M. M.); Programa de Intensificación de Investigadores (INT20/00031)-ISCIII (support to F. V.); the National Institute for Health and Care Research (Senior Investigator award (NF-SI-0611-10168 to J. A. C. S.). The Antiretroviral Therapy Cohort Collaboration (ART-CC) is supported by the US National Institute on Alcohol Abuse and Alcoholism (grant U01-AA026209) and the UK Medical Research Council. The Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) is an National Institutes of Health-funded program (grant R24 AI067039) made possible by the National Institute of Allergy and Infectious Diseases. The Center for AIDS Research sites involved in CNICS include the University of Alabama at Birmingham (grant P30 AI027767), University of Washington (grant P30 AI027757), the University of California San Diego (grant P30 AI036214), University of California San Francisco (grant P30 AI027763), Case Western Reserve University (grant P30 AI036219), Johns Hopkins University (grants P30 AI094189 and U01 DA036935), Fenway Health/Harvard (grant P30 AI060354), University of North Carolina Chapel Hill (grant P30 AI50410), Vanderbilt University (grant P30 AI110527), and University of Miami (grant P30 AI073961). The North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) was supported by the National Institutes of Health (grants U01AI069918, F31AI124794, F31DA037788, G12MD007583, K01AI093197, K01AI131895, K23EY013707, K24AI065298, K24AI118591, K24DA000432, KL2TR000421, N01CP01004, N02CP055504, N02CP91027, P30AI027757, P30AI027763, P30AI027767, P30AI036219, P30AI050409, P30AI050410, P30AI094189, P30AI110527, P30MH62246, R01AA016893, R01DA011602, R01DA012568, R01 AG053100, R24AI067039, U01AA013566, U01AA02 0790, U01AI038855, U01AI038858, U01AI068634, U01AI068636, U01AI069432, U01AI069434, U01DA03629, U01DA036935, U10EY 008057, U10EY008052, U10EY008067, U01HL146192, U01HL146193, U01HL146194, U01HL146201, U01HL146202, U01HL146203, U01HL1 46204, U01HL146205, U01HL146208, U01HL146240, U01HL146241, U01HL146242, U01HL146245, U01HL146333, U24AA020794, U54MD 007587, UL1RR024131, UL1TR000004, UL1TR000083, Z01CP010214, and Z01CP010176; the US Centers for Disease Control and Prevention (contracts CDC-200-2006-18797 and CDC-200-2015-63931); the US Agency for Healthcare Research and Quality (contract 90047713); the US Health Resources and Services Administration (contract 90051652 ); the Canadian Institutes of Health Research (grants CBR-86906, CBR-94036, HCP-97105, and TGF-96118); the Ontario Ministry of Health and Long Term Care; and the Government of Alberta, Canada. Additional support was provided by the National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institute for Mental Health, National Institute on Drug Abuse, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Neurological Disorders and Stroke, National Institute of Nursing Research, National Institute on Alcohol Abuse and Alcoholism, National Institute on Deafness and Other Communication Disorders, and National Institute of Diabetes and Digestive and Kidney Diseases. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group has received unrestricted funding from the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS), France; the HIV Monitoring Foundation, the Netherlands; and the Augustinus Foundation, Denmark. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013; under EuroCoord grant agreement 260694P).

Publisher Copyright:
© 2023 The Author(s).

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