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Analysis of Severe Illness After Postvaccination COVID-19 Breakthrough Among Adults With and Without HIV in the US

Key Points Question In 2021, among fully vaccinated people with breakthrough COVID-19 illness, was the risk of severe illness higher for people with HIV (PWH) compared with people without HIV (PWoH)? Findings In this cohort study of 3649 patients with breakthrough COVID-19, there was no overall difference in risk of severe disease between PWH and PWoH. PWH with CD4 cell count less than 350 cells/μL had a 59% increased risk of severe breakthrough illness compared with PWoH. Meaning Although vaccinations effectively reduce the risk of severe COVID-19 illness in both PWH and PWoH, these findings suggest that PWH with moderate or severe immune suppression (CD4 cell count <350 cells/μL) could be at higher risk of severe breakthrough infection compared with PWoH, and PWH with moderate immune suppression should be considered for additional vaccine dosages and other risk-reduction measures.

Current US Centers for Disease Control and Prevention (CDC) guidelines recommend risk reduction behaviors (ie, mask wearing), an additional COVID-19 primary series vaccine dose, and a second booster dose for PWH with "advanced or untreated HIV infection." 21,22 PWH with partially recovered CD4 cell counts (>200 cells/μL) and moderate immune suppression are not currently recommended for an additional or second booster dose. Our objective was to determine whether HIV infection was associated with increased severe COVID-19 illness among fully vaccinated adults with a breakthrough SARS-CoV-2 infection and to identify the factors associated with severe COVID-19 breakthrough illness among PWH, including level of immune suppression and HIV viral replication.

Statistical Analysis
Study entry was the date of observed breakthrough COVID-19. Individuals were followed to the first date of severe breakthrough COVID-19 illness (outcome) or date of death, disenrollment from the health system, 28 days after breakthrough COVID-19, or December 31, 2021.
Severe COVID-19 breakthrough illness monthly incidence rates (IRs) per 100 person-years and 95% CIs were calculated by HIV status. Severe COVID-19 breakthrough cumulative incidence was estimated from the date of breakthrough through day 28; estimates were stratified by HIV status, and among PWH, CD4 cell count, and viral suppression. Using the same timescale, cumulative incidence was estimated by HIV status for each vaccine type and for those who received an additional vaccine dose (Ն28 days after primary series completion and before breakthrough COVID-19).
Log-rank tests were calculated to test for differences in cumulative incidence, and risk differences were estimated with SE and Wald 95% CI.
A discrete time-to-event analysis using a complimentary log-log model estimated the unadjusted and adjusted hazard ratios (aHRs) with 95% CI for severe COVID- 19

IRs and Cumulative Incidence of Severe COVID-19 Breakthrough Illness
The   (Figure 2A). PWH with lower CD4 cell counts (<350 cells/μL) at full vaccination had a higher risk of severe COVID-19 breakthrough illness compared with PWH with CD4 cell counts greater than or equal to 350 cells/μL and PWoH ( Figure 2B and eFigure 4 in the Supplement). Risk did not differ by HIV viral load ( Figure 2C).

Limitations
This study has limitations. Our findings may not be generalizable to all PWH, as our study population had a greater proportion of men (88.9%) than found in the US population of PWH, and those with higher barriers to accessing health care (who may be at greater risk for COVID-19) were less likely to be included in our study population. Health care utilization may also differ by HIV status, which could impact inclusion with recognized breakthrough and decisions for hospitalization (outcome). Other outcome data, including mechanical ventilation and death (particularly if death occurred out of hospital) may be underascertained. All discharge diagnoses were reviewed by clinicians to increase specificity in our classification of COVID-19 hospitalization, but discharge coding can be influenced by many factors including reimbursement practices. Our findings may not be generalizable to all SARS-CoV-2 variants; however, our study was conducted while Alpha, Delta, and Omicron variants were circulating. In addition, on the basis of the timing of additional primary series doses and booster recommendations in 2021, the majority of additional doses received were timed more similarly to a booster dose than an additional dose in the primary vaccination series.

Conclusions
Severe COVID-19 breakthrough illness was rare in our population of PWH and PWoH, with no overall differences in risk between the 2 groups; however, PWH with both moderate and severe immune suppression had an increased risk of severe COVID-19 breakthrough illness compared with PWoH. In addition to PWH with severe immune suppression, PWH with moderate immune suppression may benefit from being included in the CDC's recommendations for those with advanced and untreated HIV. Clinicians should continue to promote risk-reduction measures among PWH. The potentially increased risk of severe COVID-19 breakthrough illness in PWH with moderate and severe immune suppression merits ongoing surveillance to inform vaccine recommendations as the pandemic persists, immunity to primary vaccine series and booster doses wane, and new variants emerge.