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Analysis of Postvaccination Breakthrough COVID-19 Infections Among Adults With HIV in the United States

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Are the rate and risk of COVID-19 breakthrough infections higher among vaccinated people with vs without HIV in the United States through December 31, 2021?

Findings  In this cohort study of 113 994 patients, risk of breakthrough infection was low overall (3.8%) but 28% higher in people with vs without HIV. The breakthrough rate was also higher in people with vs without HIV (55 cases per 1000 person-years vs 43 cases per 1000 person-years).

Meaning  The higher rate and risk of infection in people with HIV observed in this study suggests comprehensive inclusion of this population in recommendations for additional primary doses in immunocompromised groups.


Importance  Recommendations for additional doses of COVID-19 vaccines for people with HIV (PWH) are restricted to those with advanced disease or unsuppressed HIV viral load. Understanding SARS-CoV-2 infection risk after vaccination among PWH is essential for informing vaccination guidelines.

Objective  To estimate the rate and risk of breakthrough infections among fully vaccinated PWH and people without HIV (PWoH) in the United States.

Design, Setting, and Participants  This cohort study used the Corona-Infectious-Virus Epidemiology Team (CIVET)-II (of the North American AIDS Cohort Collaboration on Research and Design [NA-ACCORD], which is part of the International Epidemiology Databases to Evaluate AIDS [IeDEA]), collaboration of 4 prospective, electronic health record–based cohorts from integrated health systems and academic health centers. Adult PWH who were fully vaccinated prior to June 30, 2021, were matched with PWoH on date of full vaccination, age, race and ethnicity, and sex and followed up through December 31, 2021.

Exposures  HIV infection.

Main Outcomes and Measures  COVID-19 breakthrough infections, defined as laboratory evidence of SARS-CoV-2 infection or COVID-19 diagnosis after a patient was fully vaccinated.

Results  Among 113 994 patients (33 029 PWH and 80 965 PWoH), most were 55 years or older (80 017 [70%]) and male (104 967 [92%]); 47 098 (41%) were non-Hispanic Black, and 43 218 (38%) were non-Hispanic White. The rate of breakthrough infections was higher in PWH vs PWoH (55 [95% CI, 52-58] cases per 1000 person-years vs 43 [95% CI, 42-45] cases per 1000 person-years). Cumulative incidence of breakthroughs 9 months after full vaccination was low (3.8% [95% CI, 3.7%-3.9%]), albeit higher in PWH vs PWoH (4.4% vs 3.5%; log-rank P < .001; risk difference, 0.9% [95% CI, 0.6%-1.2%]) and within each vaccine type. Breakthrough infection risk was 28% higher in PWH vs PWoH (adjusted hazard ratio, 1.28 [95% CI, 1.19-1.37]). Among PWH, younger age (<45 y vs 45-54 y), history of COVID-19, and not receiving an additional dose (aHR, 0.71 [95% CI, 0.58-0.88]) were associated with increased risk of breakthrough infections. There was no association of breakthrough with HIV viral load suppression, but high CD4 count (ie, ≥500 cells/mm3) was associated with fewer breakthroughs among PWH.

Conclusions and Relevance  In this study, COVID-19 vaccination, especially with an additional dose, was effective against infection with SARS-CoV-2 strains circulating through December 31, 2021. PWH had an increased risk of breakthrough infections compared with PWoH. Expansion of recommendations for additional vaccine doses to all PWH should be considered.

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Article Information

Accepted for Publication: April 21, 2022.

Published: June 7, 2022. doi:10.1001/jamanetworkopen.2022.15934

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Coburn SB et al. JAMA Network Open.

Corresponding Author: Keri N. Althoff, PhD, MPH, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Rm E7142, Baltimore, MD 20295 (

Author Contributions: Dr Althoff and Mrs Humes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Coburn, Lang, Stewart, Napravnik, Park, Justice, Gordon, Horberg, Certa, Skarbinski, Williams, Althoff.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Coburn, Lang, Napravnik, Certa, Althoff.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Coburn, Humes, Lang, Stewart, Napravnik, Edwards, Althoff.

Obtained funding: Napravnik, Justice, Althoff.

Administrative, technical, or material support: Stewart, Hogan, Gebo, Napravnik, Edwards, Browne, Park, Justice, Horberg, Certa, Watson, Jefferson, Skarbinski, Leyden, Williams.

Supervision: Napravnik, Justice, Althoff.

Conflict of Interest Disclosures: Dr Lang reported receiving grants from the Canadian Institutes of Health Research, Alberta Innovates, and Cumming School of Medicine, University of Calgary/Alberta Health Services outside the submitted work and receiving a postdoctoral fellowship supported by a Helios UCMG Post fellowship award from the University of Calgary Cumming School of Medicine as well as a Dr Subrata Ghosh Fellowship Award from the Department of Medicine, University of Calgary. Dr Gebo reported receiving grants from the Department of Defense (paid to institution) outside the submitted work. Dr Edwards reported receiving grants from the National Institutes of Health (NIH) National Institute of Allergy and Infectious Disease (NIAID) outside the submitted work. Dr Justice reported receiving grants from NIH outside the submitted work. Dr Certa reported receiving grants from NIAID outside the submitted work. Dr Althoff reported serving as a consultant to the All of Us Research Program (NIH), TrioHealth, Kennedy Dundas, and MedIQ outside the submitted work. No other disclosures were reported.

Funding/Support: This project was funded via supplemental funds to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD, U01AI069918) from NIAID. The NA-ACCORD is supported by NIH 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, R01AG053100, R24AI067039, R34DA045592, U01AA013566, U01AA020790, U01AI038855, U01AI038858, U01AI068634, U01AI068636, U01AI069432, U01AI069434, U01DA036297, U01DA036935, U10EY008057, U10EY008052, U10EY008067, U01HL146192, U01HL146193, U01HL146194, U01HL146201, U01HL146202, U01HL146203, U01HL146204, U01HL146205, U01HL146208, U01HL146240, U01HL146241, U01HL146242, U01HL146245, U01HL146333, U24AA020794, U54GM133807, UL1RR024131, UL1TR000004, UL1TR000083, UL1TR002378, U24-AA020794, U01-AA020790, U24-AA022001, U10 AA013566-completed, UL1-TR002489, Z01CP010214, and Z01CP010176; contracts CDC-200-2006-18797 and CDC-200-2015-63931 from the US Centers for Disease Control and Prevention; contract 90047713 from the Agency for Healthcare Research and Quality; contract 90051652 from the Health Resources and Services Administration; the Grady Health System; grants CBR-86906, CBR-94036, HCP-97105, and TGF-96118 from the Canadian Institutes of Health Research; the Ontario Ministry of Health and Long-term Care; and the Government of Alberta, Canada. Additional support was provided by NIAID; the National Cancer Institute; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health & 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 & 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.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: For the Corona-Infectious-Virus Epidemiology Team (CIVETs) of the NA-ACCORD of IeDEA (International Epidemiology Databases to Evaluate AIDS).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the US Centers for Disease Control and Prevention.

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