No association between use of tenofovir disoproxil fumarate, etravirine, or integrase-strand transfer inhibitors and acquisition or severe outcomes of SARS-CoV-2 infection in people with HIV in the Netherlands

In two Dutch observational cohorts of people with HIV, the use of TDF, ETR, or INSTIs was not independently associated with either the risk of incident SARS-CoV-2 infection or severe COVID-19 outcomes, as was suggested by previous observational and molecular docking studies. Our findings do not support a strategy of modifying antiretroviral therapy to include these agents to protect against SARS-CoV-2 infection and severe COVID-19 outcomes.

In two Dutch observational cohorts of people with HIV, the use of TDF, ETR, or INSTIs was not independently associated with either the risk of incident SARS-CoV-2 infection or severe COVID-19 outcomes, as was suggested by previous observational and molecular docking studies. Our findings do not support a strategy of modifying antiretroviral therapy to include these agents to protect against SARS-CoV-2 infection and severe COVID-19 outcomes.
Since the start of the COVID-19 pandemic, several studies have tried to determine factors associated with acquisition of and clinical outcome of SARS-CoV-2 infection in people with HIV (PWH). Recent observational studies have suggested a protective effect of tenofovir disoproxil fumarate (TDF) against acquisition of SARS-CoV-2 [1,2] and severe COVID-19 outcomes [1,3,4], whereas other studies found no benefit of TDF or tenofovir alafenamide (TAF) in PWH [5,6] or adults without HIV [7,8].
Etravirine (ETR) and the integrase-strand transfer inhibitors (INSTIs) -specifically raltegravir (RAL) and dolutegravir (DTG) -were proposed as potential inhibitors of two major SARS-CoV-2 proteins in a molecular docking [9] and molecular dynamics simulation study [10]. One recent study showed that in-vitro docking by SARS-CoV-2 to the ACE2 receptor is inhibited by DTG and ETR [11]. Thus far, no studies in PWH have reported epidemiological evidence for a protective effect of the use of INSTIs or ETR against acquiring SARS-CoV-2 infection and severe COVID-19 outcomes.
We investigated the association between the abovementioned antiretrovirals and incident SARS-CoV-2 infection and COVID-19-associated hospitalization and/ or death in two Dutch observational cohorts of PWH.
First, we used data from the COVID-19 substudy of the AGE h IV cohort collected from September 2020 until April 2021 [12]. PWH and participants without HIV were assessed every 6 months for incident SARS-CoV-2 infection. Incident SARS-CoV-2 infection was defined as positive combined IgA/IgM/IgG SARS-CoV-2 nucleocapsid (N) antibody assay or a self-reported positive PCR test in participants without detectable N-antibodies. We previously reported that younger age and sub-Saharan African origin, but not HIV-status, were independently associated with higher risk of incident SARS-CoV-2 infection. However, we did not investigate the association with specific antiretrovirals in PWH.
Second, we used data from the Dutch national observational HIV cohort (ATHENA), containing data of more than 95% of PWH in care in one of the 24 HIV-treatment centers in the Netherlands [13]. Within this cohort, we recently reported that the risk of severe COVID-19 outcomes was increased in individuals with uncontrolled HIV replication, low CD4 þ cell count and prior AIDS, independently of general risk factors such as age, comorbidity burden, and non-Western origin (F.W.N. M. Wit, P. Reiss, B. Rijnders, M. van der Valk, in preparation), but potential associations with specific antiretrovirals were not extensively analyzed.
Extending our earlier analyses, we now assessed whether use of TDF, ETR, and INSTIs were associated with the risk of incident SARS-CoV-2 infection in the AGE h IV COVID-19 substudy and the risk of COVID-19associated hospitalization and/or death in the ATHENA cohort. Associations between the aforementioned antiretrovirals and outcomes were assessed using multivariable logistic regression, both unadjusted and adjusted for age, sex at birth, ethnic origin, total comorbidity count (cardiovascular disease; non-AIDS-defining cancer; chronic kidney disease; diabetes mellitus; hypertension; and/or obesity (BMI !30 kg/m 2 ), prior AIDS, current CD4 þ cell count (categorized <200, 200-499, !500 cells/ml), and current HIV-1 viral load (categorized 200 or >200 copies/ml).
In the current analysis, 239 PWH using antiretroviral therapy ( African origin compared with those without incident SARS-CoV-2 infection (data not shown). ART regimen did not differ significantly between both groups.
Use of TDF, ETR, or INSTIs was not significantly associated with risk of incident SARS-CoV-2 infection, or severe COVID-19 (Table 1) in both unadjusted and adjusted analyses. Moreover, no associations between use of other antiretrovirals and incident SARS-CoV-2 infection or severe COVID-19 were observed.
Our analyses in two cohorts of PWH support previous findings that TDF does not protect against SARS-CoV-2 infection or severe COVID-19 outcomes [5,6]. Similar to our analyses, these studies adjusted their outcome for baseline participant characteristics, such as country of origin, socioeconomic status, current CD4 þ cell count and CD4/CD8 ratio, years on ART, presence of diabetes, chronic kidney disease, and metabolic disease [5]. Importantly, studies suggesting a protective effect of TDF in PWH did not adjust for these participant characteristics [2][3][4]. It is likely that the presence of risk factors such as higher age and comorbidities influence the choice of ART regimen, which may confound the association between ART use and COVID-19 outcomes, thereby explaining the difference in study findings.
With regard to INSTIs, two clinical studies likewise found no protective effect of INSTIs against acquisition of SARS-CoV-2 infection in PWH [2,6].
In conclusion, in two Dutch observational cohorts of PWH, the use of TDF, ETR, or INSTIs was not independently associated with a reduced risk of incident SARS-CoV-2 infection or severe COVID-19 outcomes. Our findings do not support a strategy of modifying ART to include these antiretrovirals to protect against SARS-CoV-2 infection and severe COVID-19.