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Are People With HIV at Increased Risk for Breakthrough COVID-19?

  • Authors: News Author: Marcia Frellick; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 7/29/2022
  • Valid for credit through: 7/29/2023
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    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

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Target Audience and Goal Statement

This activity is intended for primary care physicians, infectious disease specialists, nurses, physician assistants, pharmacists, and other members of the healthcare team who care for people living with HIV.

The goal of this activity is for learners to be better able to evaluate the association between HIV infection and the risk for breakthrough COVID-19 among adults.

Upon completion of this activity, participants will:

  • Assess COVID-19 efficacy against the Omicron variant
  • Evaluate the association between HIV infection and the risk for breakthrough COVID-19 among adults
  • Outline implications for the healthcare team


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News Author

  • Marcia Frellick

    Freelance writer, Medscape


    Marcia Frellick has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Editor/Compliance Reviewer

  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC



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Nurse Planner

  • Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC



    Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Are People With HIV at Increased Risk for Breakthrough COVID-19?

Authors: News Author: Marcia Frellick; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 7/29/2022

Valid for credit through: 7/29/2023


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to the approved COVID-19 vaccines are provided in this activity in an effort to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

Vaccination is one of the most valuable tools against COVID-19, but there is evidence that the efficacy of vaccination may not be as strong with the advent of the Omicron variant. A study of more than 2 million vaccinated residents of Qatar examined this issue, and the results of this study by Abu-Raddad and colleagues were published in the May 12, 2022 issue of the New England Journal of Medicine.[1]

Rates of symptomatic COVID-19 among patients who received the 2-dose BNT 162b2 (Pfizer-BioNTech) series alone were 4.5% compared with a rate of 2.4% among patients who received 2 doses of BNT 162b2 plus a booster. Overall vaccine effectiveness of the booster against Omicron was 49.4%, but booster effectiveness against hospitalization for COVID-19 was 76.5%.

The rate of breakthrough infection after receipt of 2 doses of the mRNA-1273 vaccine (Moderna) was 1.9%, and this rate fell to 1% after the booster dose. Effectiveness of the mRNA-1273 booster vs the 2-dose series alone was 47.3%.

People with HIV infection are considered to be at higher risk for complications of COVID-19. The current study by Coburn and colleagues examines vaccine efficacy in this important population.

Study Synopsis and Perspective

People with HIV have an increased risk for breakthrough SARS-CoV-2 infections, a new study finds, and the authors said an additional primary vaccine dose should be considered for all who are living with the disease.

Currently, an additional primary dose administered 28 days after a second dose of the messenger RNA (mRNA) (Moderna or Pfizer) vaccines or after the first dose of the Johnson & Johnson (J&J) vaccine is recommended only for persons with advanced or untreated HIV.

The Centers for Disease Control and Prevention (CDC) recommends boosters for all adults with or without HIV.

Sally B. Coburn, PhD, MPH, with the department of epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, led the study, which was published June 1 in JAMA Network Open.[2]In their study, the researchers estimated the risk for breakthrough infections among fully vaccinated adults on the basis of HIV status in the United States.

Adults with HIV who were fully vaccinated before June 30, 2021 were matched with adults without HIV with regard to date of full vaccination, age, race/ethnicity, and sex. The researchers followed all through December 31, 2021.

Patients were considered fully vaccinated either 14 days after the second dose of the Pfizer or Moderna shots or 14 days after the single dose of the J&J shot.

Breakthrough Risk 28% Higher

In the study of 113,994 patients, researchers found that risk for breakthrough SARS-CoV-2 infection was low overall (3.8%) but was 28% higher among people with HIV in comparison with people without HIV (adjusted HR [aHR] 1.28 [95% CI: 1.19, 1.37]).

The breakthrough rate was also higher in the HIV group (55 cases/1000 person-years [PY] vs 43 cases/1000 PY in people without HIV).

Patients were drawn from 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, which involves 4 cohorts.

Among people with HIV, individuals aged younger than 45 years (vs persons aged 45-54 years) and individuals with a history of COVID-19 were more likely to experience breakthrough infections. In addition, persons who did not get any additional shots after the primary vaccination were more likely to have breakthrough infections, amplifying the need to get boosters, the authors wrote.

The authors noted that there was no link between breakthrough infections and HIV viral load suppression, but high cluster of differentiation (CD)4 counts (≥ 500 cells/mm3) were associated with fewer breakthrough cases among people with HIV.

Monica Gandhi, MD, professor of medicine and associate division chief of HIV, infectious diseases, and global medicine at the University of California San Francisco, praised the study, noting that until now, large studies have not examined the rate of breakthrough infections among vaccinated people with HIV and people without HIV in the United States.

She agrees with the authors that a third dose for all who are living with HIV is needed because rates of breakthrough infections were high across all populations during the Omicron surge (which largely occurred after the period of this study).

She said she was not convinced the third shot was needed before Omicron because breakthrough rates in both HIV and non-HIV groups were low.

"However, the most interesting part of this study for me was how well the vaccines worked in people with HIV with generally higher CD4 counts and virologic suppression, again telling us as HIV providers how well the HIV medicines work and how our patients with HIV have relatively normal immune systems if treated," she said.

One limitation of the study was that the study population was 92% male. Also, persons without regular access to health care (who may be at greater risk for COVID-19) were less likely to be included in the study. People engaged in care may seek more frequent COVID-19 testing, which could lead to higher detection of breakthrough infections than in the general population.

"Future analyses should account for testing practices and include a larger proportion of women with HIV," the authors wrote. "Ultimately, policy makers must determine the appropriate balance between preventing further COVID-19 infections and possibly unnecessary additional vaccinations."

Co-author Keri Althoff, PhD, MPH, told Medscape that there is one unanswered question that would strengthen the call to action by the CDC: Do people with HIV have more severe postvaccination COVID-19 breakthrough illness?

"We have a second paper[3] that is a preprint and currently under peer review," she said. "In this paper, we found that people with HIV with a CD4 count < 350 cells/mm3 were more likely to be hospitalized with post-vaccination COVID-19 breakthrough illness compared to similar people without HIV."

At a minimum, Althoff said, policymakers should consider including people with HIV with a CD4 < 350 cells/mm3 (loosening the restriction to < 200 cells/mm3) in their recommendations for people who are moderately or severely immunocompromised.

The research was funded with supplemental funds to the North American AIDS Cohort Collaboration on Research and Design. Coburn reports no relevant financial relationships. A co-author has received grants from the Canadian Institutes of Health Research, Alberta Innovates, and Cumming School of Medicine, University of Calgary/Alberta Health Services.

Study Highlights

  • The study was conducted within 4 large US health systems. Study patients were aged ≥ 18 years and had received ≥ 2 doses of an mRNA-based COVID-19 vaccine or 1 dose of an adenovirus-based COVID-19 vaccine.
  • Researchers identified persons living with HIV (PWH) from diagnosis codes and matched with up to 3 persons living without HIV (PWoH). The study period ran through the end of 2021.
  • The main study outcome was the rate of breakthrough cases of COVID-19, as defined by a positive molecular test or a clinical diagnosis code.
  • The study analysis was adjusted for demographic factors, provision of a third dose of vaccine, calendar period, and patients’ history of COVID-19.
  • Researchers compared 33,029 PWH with 80,965 PWoH. 70% of patients were aged ≥ 55 years, and 92.1% were male. 41.3% of the cohort was Black, and 37.9% were White.
  • 90.5% of the PWH had viral suppression, and the median CD4 count was 636 cells/mm3.
  • 51% of patients received the BNT162b2 vaccine, and 42% received mRNA-1273. 7% received Ad26.COV2.S (J&J).
  • Rates of receiving a booster vaccine dose were 56% and 45% among PWoH and PWH, respectively.
  • The rates of breakthrough cases were 55/1000 PY and 43/1000 PY in the PWH and PWoH cohorts, respectively (aHR 1.28 [95% CI: 1.19, 1.37]).
  • Regarding individual vaccines, breakthrough infection rates were 70, 54, and 34 cases/1000 PY for the Ad26.COV2.S, BNT162b2, and mRNA-1273 vaccines, respectively.
  • CD4 count and HIV viral load were not significantly associated with the risk for breakthrough COVID-19. PWH had higher rates of breakthrough infection than PWoH across the spectrum of CD4 and viral concentration levels.
  • Among PWH, age ≥ 55 years was associated with a lower risk for breakthrough infections whereas age < 44 years was associated with a higher risk.
  • The HR for breakthrough infection in comparing the mRNA-1273 vs BNT 162b2 vaccines was 0.66 (95% CI: 0.57, 0.77).

Clinical Implications

  • A previous study by Abu-Raddad and colleagues found that booster doses with either BNT162b2 or mRNA-1273 were nearly 50% more effective than the 2-dose series alone in the prevention of COVID-19 during the Omicron surge. Booster efficacy against severe infection was even stronger. mRNA-1273 was more effective than BNT162b2 overall.
  • The current study by Coburn and colleagues finds higher rates of breakthrough COVID-19 among vaccinated adults with HIV compared with adults without HIV. This result was independent of CD4 count and HIV viral load, and breakthrough infections in the cohort with HIV were more common among adults younger than age 44 years.
  • Implications for the healthcare team: The healthcare team should provide education on COVID-19 booster vaccination and risk reducing mitigation strategies, especially for PWH.


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