key: cord-0024521-fyk10ae2
authors: Coburn, Sally B.; Humes, Elizabeth; Lang, Raynell; Stewart, Cameron; Hogan, Brenna C; Gebo, Kelly A.; Napravnik, Sonia; Edwards, Jessie K.; Browne, Lindsay E.; Park, Lesley S.; Justice, Amy C.; Gordon, Kirsha; Horberg, Michael A.; Certa, Julia M.; Watson, Eric; Jefferson, Celeena R; Silverberg, Michael; Skarbinski, Jacek; Leyden, Wendy A; Williams, Carolyn F.; Althoff, Keri N.
title: COVID-19 infections post-vaccination by HIV status in the United States
date: 2021-12-05
journal: medRxiv
DOI: 10.1101/2021.12.02.21267182
sha: 0afb41a0a99da25d0eef478eb0a754398848d6a2
doc_id: 24521
cord_uid: fyk10ae2

IMPORTANCE: Recommendations for additional doses of COVID vaccine are restricted to people with HIV who have advanced disease or unsuppressed HIV viral load. Understanding SARS-CoV-2 infection risk post-vaccination among PWH is essential for informing vaccination guidelines. OBJECTIVE: Estimate the risk of breakthrough infections among fully vaccinated people with (PWH) and without (PWoH) HIV in the US. DESIGN, SETTING, AND PARTICIPANTS: The Corona-Infectious-Virus Epidemiology Team (CIVET)-II cohort collaboration consists of 4 longitudinal cohorts from integrated health systems and academic health centers. Each cohort identified individuals ≥18 years old, in-care, and fully vaccinated for COVID-19 through 30 June 2021. PWH were matched to PWoH on date fully vaccinated, age group, race/ethnicity, and sex at birth. Incidence rates per 1,000 person-years and cumulative incidence of breakthrough infections with 95% confidence intervals ([,]) were estimated by HIV status. Cox proportional hazards models estimated adjusted hazard ratios (aHR) of breakthrough infections by HIV status adjusting for demographic factors, prior COVID-19 illness, vaccine type (BNT162b2, [Pfizer], mRNA-1273 [Moderna], Jansen Ad26.COV2.S [J&J]), calendar time, and cohort. Risk factors for breakthroughs among PWH, were also investigated. EXPOSURE: HIV infection OUTCOME: COVID-19 breakthrough infections, defined as laboratory evidence of SARS-CoV-2 infection or COVID-19 diagnosis after an individual was fully vaccinated. RESULTS: Among 109,599 individuals (31,840 PWH and 77,759 PWoH), the rate of breakthrough infections was higher in PWH versus PWoH: 44 [41, 48] vs. 31 [29, 33] per 1,000 person-years. Cumulative incidence at 210 days after date fully vaccinated was low, albeit higher in PWH versus PWoH overall (2.8% versus 2.1%, log-rank p<0.001, risk difference=0.7% [0.4%, 1.0%]) and within each vaccine type. Breakthrough infection risk was 41% higher in PWH versus PWoH (aHR=1.41 [1.28, 1.56]). Among PWH, younger age (18–24 versus 45–54), history of COVID-19 prior to fully vaccinated date, and J&J vaccination (versus Pfizer) were associated with increased risk of breakthroughs. There was no association of breakthrough with HIV viral load suppression or CD4 count among PWH. CONCLUSIONS AND RELEVANCE: COVID-19 vaccination is effective against infection with SARS-CoV-2 strains circulating through 30 Sept 2021. PWH have an increased risk of breakthrough infections compared to PWoH. Recommendations for additional vaccine doses should be expanded to all PWH.

As vaccines for COVID-19 continue to be distributed in the United States (US), in both clinical trials 1-3 and observational settings. [4] [5] [6] [7] [8] [9] Characterizing breakthrough infections is 1 3 5 critical for efforts to curb the pandemic and to deepen our understanding of the scope of 1 3 6 population immunity conferred by vaccination. Additionally, the rate of breakthrough infections is Immunocompromised individuals may be particularly at risk for breakthrough infections and generalizability to the broader population of PWH in the US. 10, 13 These studies also did not 1 4 9

address differences in breakthrough rates among PWH by vaccine type or by clinically relevant The US Centers for Disease Control and Prevention's (CDC's) guidance for PWH is 1 5 3 specific to those with advanced or untreated HIV and includes the recommendation of an . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. Study (VACS) which is a sample of all PWH receiving care within the National US Veterans The CIVET-II cohort collaboration participants include PWH and PWoH observed during 1 8 6 the COVID-19 pandemic. Adults (≥18 years old) "in-care" (determined by unique criteria for 1 8 7 each site; see Supplement Table S1 ) and fully vaccinated against COVID-19 between 1 8 8

December 11, 2020 (date of Emergency Use Authorization of the first COVID-19 vaccine) and were excluded from the study population if they received a vaccine that was not authorized in 1 9 3 the US. Each fully vaccinated PWH was matched to three PWoH on the date considered fully 1 9 5 vaccinated (+/-14 days), 10-year age group (18-24, 25-34, 35-44, 45-54, 55-64, 65-74, ≥ 75 1 9 6 years), race/ethnicity (Black/African American, white, Hispanic, Asian, other, unknown) , and sex 1 9 7 at birth (female or male). When necessary, PWH could be matched to individuals either one age 1 9 8 group above or below their category. If three matches were not available, PWH could be 1 9 9 matched to one or two PWoH to maximize the study population size. All cohorts completed this 2 0 0 matching schema except for VACS (N=65,440), which has its own long-standing schema to 2 0 1 match each veteran with HIV to two veterans without HIV on age, race/ethnicity, sex, and 2 0 2 clinical site at the establishment of the cohort and during its dynamic enrollment as veterans irrespective of HIV status, including matching factors described above, were abstracted from 2 0 5 electronic medical records. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted December 6, 2021. The first infection with SARS-CoV-2 or COVID-19 illness diagnosed after the date an 2 0 9

individual is fully vaccinated (14 days after the last required dose) was defined as a 2 1 0 breakthrough case (Supplemental Figure S1 ). Incident COVID-19 cases were identified using: 2 1 1 1) positive or detectable SARS-CoV-2 nucleic acid amplification assay (NAAT) or antigen test; For each patient, all positive SARS-CoV-2 laboratory tests were identified. Any to their greater specificity. This same process was completed for ICD-10 diagnoses that did not 2 2 7 occur within +/-90 window of another laboratory test. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ; https://doi.org/10.1101/2021.12.02.21267182 doi: medRxiv preprint PWH were identified using HIV registries or ICD diagnosis codes for HIV, depending on 2 3 1 the participating cohort (see Supplemental Table S1 ). PWoH were classified as such if there 2 3 2 was no evidence of infection using these same sources as of December 11, 2020 (including no 2 3 3 positive ELISA or Western blot tests, no HIV RNA measurements, no ICD diagnosis codes, and 2 3 4 not found in an HIV registry). In addition to demographics used to match fully vaccinated PWH to PWoH (i.e., age, any vaccination and those that occurred in the window between the first dose but before full 2 4 3 vaccination (partial breakthrough). These were identified using the approach used to identify our 2 4 4 main outcome. close to date full vaccination as possible (within a window of 1 Jan 2020 to full vaccination) and 2 4 7 at antiretroviral therapy (ART) initiation (within a window of 12 months prior to 1 month after).

HIV viral suppression was defined as <50 copies/mL, which was the highest lower limit of 2 4 9 quantification used across the health systems. History of AIDS diagnosis (clinical diagnosis 20 or 2 5 0 CD4 count <200 cells/mm 3 , depending on the cohort) prior to date fully vaccinated was 2 5 1 included. All analyses were conducted in R and a p-value<0.05 was considered statistically 2 8 7 significant. Of the 109,719 fully vaccinated patients, 120 (40 PWH and 80 PWoH) were excluded 2 9 1 due to mixing of vaccine type within the primary series, resulting in a study population of 2 9 2 109,599 patients (31,840 PWH and 77,759 PWoH) ( Table 1) . Most patients were 55 years and Pfizer (51%) or the Moderna (43%) vaccines. A small minority received J&J (6%). Although we 2 9 5 did not match on vaccine type, the distribution of vaccine type by HIV status did not differ by 2 9 6 more than 2 percentage points. Twenty-six percent of PWH received an additional COVID-19 2 9 7 vaccine dose after their primary series compared to 12% of PWoH. Differences in the 2 9 8 characteristics of PWH who did and did not receive an additional vaccine dose after their 2 9 9 primary series can be found in Supplementary Table S2 ). Among PWH, 15% had a history of The overall incidence rate of breakthrough infections was 35 [33, 36] per 1,000 person- . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. remained after stratifying by calendar time, especially in July and August of 2021 (Figure 1) .

There was a bimodal distribution of breakthrough infections by calendar month which was The cumulative incidence of breakthrough infections regardless of vaccine type at 210 3 1 4 days (i.e., 7 months) after date fully vaccinated was 2.3% [2.2%, 2.5%] (Figure 2a) difference between the cumulative incidence of breakthrough infections was 0.68% (95% CI 3 1 7 0.38, 0.98) higher in PWH. When stratified by CD4 count, PWH with lower CD4 counts at full 3 1 8 vaccination had higher cumulative incidence of breakthroughs, although this was not statistically 3 1 9 significant (log-rank p=0.18 after excluding PWoH, Figure 2b) . Similarly, PWH with 3 2 0 unsuppressed HIV viral load had a higher risk of breakthrough infection those with suppressed 3 2 1 viral load, but this was not statistically significant (log-rank p=0.47 after excluding PWoH, Figure   3 2 2 2c). PWH had higher cumulative incidence of breakthrough, regardless of CD4 count or HIV 3 2 3 viral load suppression, as compared to PWoH (Figures 2b and 2c) .

The risk of breakthrough infection differed by vaccine type (Figure 3) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ; https://doi.org/10.1101/2021.12.02.21267182 doi: medRxiv preprint PWH had a significantly higher risk of breakthrough infection compared to PWoH 3 2 9 (aHR=1.41 [1.28, 1.56]) after adjusting for covariates of interest (described above) ( Table 2) .

The association was robust in subgroup analyses where: a) individuals with of history of COVID- Among PWH (25,478 after exclusion for missing risk factor data), older age (55-74 3 3 4 years) was associated with decreased risk of breakthrough, and younger age (18-24 years) was breakthrough decreased with increasing CD4 count, but this was not statistically significant.

There was a near three-fold increase in the risk of breakthrough among those with evidence of a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ;  consistent with studies that implicate other immunocompromising conditions (e.g., solid-organ 3 7 9 transplant, use of immune suppressing medications, active cancer diagnosis) have increased 3 8 0 risk of breakthrough. 10-12 Regardless of CD4 count, the cumulative incidence of breakthroughs 3 8 1 was higher among PWH versus PWoH, which is suggestive of residual immune function 3 8 2 abnormalities despite CD4 count recovery. Among PWH, the finding that older age was associated with lower risk of breakthrough 3 8 8

infections are likely not representative of a biological association, but rather behavioral increased breakthrough risk among PWH may be a reflection of increased exposure and/or 3 9 4 adoption (or lack thereof) of prevention measures. For example, PWH with increased exposure 3 9 5 (perhaps occupational) prior to being fully vaccinated may have had persistent increased 3 9 6 exposure post-full vaccination, leading to increased breakthroughs. This may also reflect the 3 9 7 increased burden of underlying comorbidities among people aging with HIV that increased their 3 9 8 vulnerability to COVID-19. Detecting COVID-19 prior to, and after, being fully vaccinated may 3 9 9 also be a function of lower barriers to accessing care and regularly seek care. These . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ;

Our findings are not necessarily reflective of all PWH in the US, as we were only able to 4 0 4 assess individuals with access to care. We may not have captured those who had less regular 4 0 5 access to health care, who may also be at greater risk for infection. For instance, one study 4 0 6

showed that individuals with substance use disorders have a higher risk of breakthrough We will continue to monitor breakthroughs monthly to accrue more follow-up time and assess 4 2 2 breakthrough risk among PWH through December 2021. This will become especially relevant as For PWH, the CDC recommends an additional primary series dose 28 days after the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ; recommendation as the risk of breakthrough was higher in PWH than PWoH regardless of CD4 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Questions. www.hivma.org. www.hivma.org. Accessed November 15, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. ; https://doi.org/10.1101/2021.12.02.21267182 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021.

; https://doi.org/10.1101/2021.12.02.21267182 doi: medRxiv preprint Figure 3 : Cumulative incidence of SARS-CoV-2 vaccine breakthrough infection (and 95% confidence intervals represented by the shading), stratified by HIV status and primary vaccination series type Footnotes: J&J was authorized for emergency use in February 2021. Therefore, the maximum follow-up time for the majority of individuals who received J&J in these analyses is 180 days, except for a few a individuals who received the J&J vaccine prior to February 2021 (e.g. vaccination clinical trial participants)

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 6, 2021. Abbreviations: HR=crude hazard ratio. aHR=adjusted hazard ratio. 95% CI=95% confidence interval. a Adjusted for age, sex, race and ethnicity, primary vaccination series type, COVID-19 prior to fully vaccinated, 3-month calendar period, an interaction of COVID-19 prior to fully vaccinated and 3-month calendar period, and cohort. b N=6,362 (20% of all PWH) were excluded due to missing CD4 or HIV RNA measurements. Adjusted for the covariates in the table and cohort.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted December 6, 2021. ;

0%) 6,595 (8.5%) 3,232 (10.2%) 45-54 17,791 (16.2%) 12,275 (15.8%)

6%) 7,963 (10.2%) 3,640 (11.4%)

Primary vaccination series type Pfizer

5%) 5,218 (6.7%) 1,946 (6.1%) Additional dose after primary series

CD4 at ART initiation (cells/mm 3 )

22. Wang L, Wang QQ, Davis PB, Volkow ND, Xu R. Increased risk for COVID-19