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Analysis of Postvaccination Breakthrough COVID-19
Infections Among Adults With HIV in the United States
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JAMA Netw Open
Download the PDF here
In our analysis, with a large study population across several US geographic regions followed longitudinally to enable a time-to-event analysis, we found a 28% increased risk of breakthrough infection in PWH vs PWoH. The cumulative incidence of breakthrough infection at 275 days (9 months) after full vaccination was 3.8% (95% CI, 3.7%-3.9%) (Figure 2A), and higher among PWH vs PWoH (4.4% [95% CI, 4.2%-4.7%] vs 3.5% [95% CI, 3.4%-3.7%] log-rank P < .001), yielding a risk difference of 0.9% (95% CI, 0.6%-1.2%). PWH with lower CD4 counts at full vaccination had higher cumulative incidence of breakthroughs, although this was not statistically significant (log-rank P = .17 after excluding PWoH). Breakthrough risk was not significantly higher in PWH with unsuppressed vs suppressed HIV (log-rank P = .80 after excluding PWoH) (Figure 2C). PWH had higher cumulative incidence of breakthrough regardless of CD4 count or HIV viral load suppression compared to PWoH (Figure 2B and C).
The overall risk of breakthrough was highest with Ad26.COV2.S (5.7% [95% CI, 5.1%-6.3%]), followed by BNT162 (4.4% [95% CI, 4.2%-4.6%]) and mRNA-1273 (2.8% [95% CI, 2.6%-2.9%]). Within each primary series vaccine type, the risk was higher among PWH vs PWoH (Figure 3). Compared with patients receiving BNT162, patients who received the mRNA-1273 primary series had a reduced risk of breakthrough infection (aHR, 0.66 [95% CI, 0.57-0.77]), which strengthened for those with mRNA-1273 plus an additional dose of any type (aHR, 0.50 [95% CI, 0.38-0.67]). An additional dose following BNT162 primary vaccination was associated with lower risk than the 2 doses of BNT162 (aHR, 0.71 [95% CI, 0.58-0.88]). The risk of breakthrough infection was higher during the Delta variant (B.1.617.2) surge from July to September 2021 relative to April to June 2021 (Table 2).
![cumulative](../images/061322/061322-2/cumulative.gif)
Among 113 994 fully vaccinated patients receiving care at 4 academic or integrated health care systems across varied geographic regions in the United States, breakthroughs were uncommon in PWH and PWoH 9 months after full vaccination (3.8%), demonstrating vaccine effectiveness against SARS-CoV-2 variants circulating prior to December 31, 2021. There was a consistently higher rate of breakthrough infections among PWH (compared with PWoH), suggesting a higher risk of breakthroughs in PWH after adjustment for demographic and clinical factors and vaccine type. Breakthrough cumulative incidence was higher in PWH (vs PWoH) irrespective of CD4 count of viral suppression. Receipt of any vaccine dose after primary series conferred further protection against breakthrough infection among PWH, exhibiting the importance of boosters and additional primary doses.
Patients included adult (≥18 years old) PWH and PWoH, who were in-care (defined in eTable 1 in the Supplement) and fully vaccinated against COVID-19 with a vaccine authorized in the United States (first date of which was December 11, 2020) by June 30, 2021. Full vaccination status was defined as: (1) 14 days after the second dose of BNT162 or mRNA-1273 vaccines or (2) 14 days after the single dose of the Ad26.COV2.S viral vector vaccine.16 Patients were excluded if their primary series mRNA vaccine types were discrepant.
The breakthrough rate was highest with the Ad26.COV2.S vaccine (70 [95% CI, 63-78] cases per 1000 person-years), followed by BNT162 (54 [95% CI, 52-56] cases per 1000 person-years), and mRNA-1273 (34 [95% CI, 32-36] cases per 1000 person-years) (eTable 4 in the Supplement). Stratified by vaccine type, the rate of breakthroughs was consistently higher among PWH vs PWoH (eTable 4 in the Supplement).
Among PWH, older age (≥55 years) was associated with decreased risk of breakthrough, and younger age (<44 years) was associated with increased risk, compared with patients ages 44 to 54 (Table 2). Compared with patients receiving BNT162, patients who received the mRNA-1273 primary series had a reduced risk of breakthrough infection (aHR, 0.66 [95% CI, 0.57-0.77]), which strengthened for those with mRNA-1273 plus an additional dose of any type (aHR, 0.50 [95% CI, 0.38-0.67]). An additional dose following BNT162 primary vaccination was associated with lower risk than the 2 doses of BNT162 (aHR, 0.71 [95% CI, 0.58-0.88]). The risk of breakthrough infection was higher during the Delta variant (B.1.617.2) surge from July to September 2021 relative to April to June 2021 (Table 2).
There was no association between breakthrough risk and HIV viral suppression among PWH. CD4 count of 500 or greater (vs <200) cells/mm3 was associated with decreased breakthrough risk (aHR, 0.66 [95% CI, 0.50-0.88]). There was a 2-fold increase in the risk of breakthrough among those with evidence of a history of COVID-19 (aHR, 1.96 [95% CI, 1.65-2.33]). Excluding 24 484 patients with a history of COVID-19, the associations of age, vaccine type, 3-month calendar period, unsuppressed viral load, and CD4 count were similar (data not shown). After removing 9517 VACS patients, there was no association between history of COVID-19 and breakthrough risk (aHR, 0.80 [95% CI, 0.56-1.13]), and the associations of age, calendar period, and viral suppression were comparable with the main model; Ad26.COV2.S plus an additional dose was associated with reduced risk of breakthrough (vs 2 doses of BNT162: aHR, 0.19 [95% CI, 0.05-0.78]), and the association with a CD4 count of 500 or greater cells/mm3 (vs <200 cells/mm3) was null (aHR, 0.94 [95% CI, 0.53-1.65]).
Two prior observational studies found no association between HIV status and breakthrough infection risk.10,11 In our analysis, with a large study population across several US geographic regions followed longitudinally to enable a time-to-event analysis, we found a 28% increased risk of breakthrough infection in PWH vs PWoH. Discrepancies in findings are likely because of greater precision in our study and varying calendar periods of observation, reflecting SARS-CoV-2 variant differences in transmissibility.
A more recent analysis with larger sample size, a study period from December 10, 2020, to September 16, 2021 (prior to the uptake of boosters and emergence of Omicron), wide US geographic distribution, and also reliant on electronic health record data, reported an adjusted incidence rate ratio of breakthroughs in PWH (vs PWoH) of 1.33 (95% CI, 1.18-1.49), suggesting an increased risk of breakthrough in PWH.12 Our findings are consistent with studies that have found an increased risk of breakthroughs among those with immunocompromising conditions.10,12,19-22
Covariates
In addition to demographic factors, covariates included the type of primary series vaccine (BNT162, mRNA-1273, or Ad26.COV2.S ), additional vaccine dose after full vaccination, and evidence of SARS-CoV-2 infection prior to the date fully vaccinated (history of COVID-19). Additional vaccine dose was defined as any vaccine dose 28 days or more after the second primary mRNA dose or Ad26.COV2.S single dose. COVID-19 diagnoses prior to full vaccination included any infection prior to the date fully vaccinated.
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