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Introduction: People living with HIV (PLWH) and/or who inject drugs may experience lower vaccine effectiveness (VE) against SARS‐CoV‐2 infection. Methods: A validated algorithm was applied to population‐based, linked administrative datasets in the British Columbia COVID‐19 Cohort (BCC19C) to ascertain HIV status and create a population of PLWH and matched HIV‐negative individuals. The study population was limited to individuals who received an RT‐PCR laboratory test for SARS‐CoV‐2 between 15 December 2020 and 21 November 2021 in BC, Canada. Any history of injection drug use (IDU) was ascertained using a validated administrative algorithm. We used a test‐negative study design (modified case−control analysis) and multivariable logistic regression to estimate adjusted VE by HIV status and history of IDU. Results: Our analysis included 2700 PLWH and a matched population of 375,043 HIV‐negative individuals, among whom there were 351 and 103,049 SARS‐CoV‐2 cases, respectively. The proportion of people with IDU history was much higher among PLWH compared to HIV‐negative individuals (40.7% vs. 4.3%). Overall VE during the first 6 months after second dose was lower among PLWH with IDU history (65.8%, 95% CI = 43.5–79.3) than PLWH with no IDU history (80.3%, 95% CI = 62.7–89.6), and VE was particularly low at 4–6 months (42.4%, 95% CI = −17.8 to 71.8 with IDU history vs. 64.0%; 95% CI = 15.7–84.7 without), although confidence intervals were wide. In contrast, overall VE was 88.6% (95% CI = 88.2–89.0) in the matched HIV‐negative population with no history of IDU and remained relatively high at 4–6 months after second dose (84.6%, 95% CI = 83.8–85.4). Despite different patterns of vaccine protection by HIV status and IDU history, peak estimates were similar (≥88%) across all populations. Conclusions: PLWH with a history of IDU may experience lower VE against COVID‐19 infection, although findings were limited by a small sample size. The lower VE at 4–6 months may have implications for booster dose prioritization for PLWH and people who inject drugs. The immunocompromising effect of HIV, substance use and/or co‐occurring comorbidities may partly explain these findings. [ABSTRACT FROM AUTHOR]

• We estimated the vaccine effectiveness (VE) against SARS-CoV-2 infection in people living with HIV (PLWH). • The VE estimates in PLWH were compared with a matched HIV-negative comparator. • Two doses of COVID-19 vaccines were effective against SARS-CoV-2 infection among PLWH. • However, the VE in PLWH appeared to peak later, and the degree of waning was quicker. We estimated the effectiveness of COVID-19 vaccines against laboratory-confirmed SARS-CoV-2 infection among people living with HIV (PLWH) and compared the estimates with a matched HIV-negative cohort. We used the British Columbia COVID-19 Cohort, a population-based data platform, which integrates COVID-19 data on SARS-CoV-2 tests, laboratory-confirmed cases, and immunizations with provincial health services data. The vaccine effectiveness (VE) was estimated with a test-negative design using the multivariable logistic regression. The adjusted VE against SARS-CoV-2 infection was 71.1% (39.7, 86.1%) 7-59 days after two doses, rising to 89.3% (72.2, 95.9%) between 60 and 89 days. VE was preserved 4-6 months after the receipt of two doses, after which noticeable waning was observed (51.3% [4.8, 75.0%]). In the matched HIV-negative cohort (n = 375,043), VE peaked at 91.4% (90.9, 91.8%) 7-59 days after two doses and was sustained for up to 4 months, after which evidence of waning was observed, dropping to 84.2% (83.4, 85.0%) between 4 and 6 months. The receipt of two COVID-19 vaccine doses was effective against SARS-CoV-2 infection among PLWH pre-Omicron. VE estimates appeared to peak later in PLWH than in the matched HIV-negative cohort and the degree of waning was relatively quicker in PLWH; however, peak estimates were comparable in both populations. [ABSTRACT FROM AUTHOR]