Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo-controlled randomized trial in healthcare workers.

OBJECTIVES: To assess the effect of hydroxychloroquine (HCQ) and Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis on COVID-19 risk. METHODS: EPICOS is a double-blind, placebo-controlled randomized trial conducted in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to the following: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo, and TDF/FTC placebo plus HCQ placebo. Randomization was performed in groups of four. Primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19. We compared group-specific 14-week risks via differences and ratios with 95% CIs. RESULTS: Of 1002 individuals screened, 926 (92.4%) were eligible and there were 14 cases of symptomatic COVID-19: 220 were assigned to the TDF/FTC plus HCQ group (3 cases), 231 to the TDF/FTC placebo plus HCQ group (3 cases), 233 to the TDF/FTC plus HCQ placebo group (3 cases), and 223 to the double placebo group (5 cases). Compared with the double placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00-1.98) for TDF + HCQ, 0.34 (0.00-2.06) for TDF, and 0.49 (0.00-2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21-1.00) for TDF + HCQ, 0.81 (0.44-1.49) for TDF, and 0.73 (0.41-1.38) for HCQ. Adverse events were generally mild. DISCUSSION: The target sample size was not met. Our findings are compatible with both benefit and harm of pre-exposure prophylaxis with TDF/FTC and HCQ, alone or in combination, compared with placebo.

Tenofovir disoproxil fumarate/emtricitabine and severity of coronavirus disease 2019 in people with HIV infection.

BACKGROUND: Effective, safe, and affordable antivirals are needed for coronavirus disease 2019 (COVID-19). Several lines of research suggest that tenofovir may be effective against COVID-19, but no large-scale human studies with appropriate adjustment for comorbidities have been conducted. METHODS: We studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4+ cell count, HIV-RNA viral-load, comorbidities and the following outcomes: laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting. RESULTS: Of 51 558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% confidence interval) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals ≥50 years and 1.15 (0.59, 1.93) in younger individuals. DISCUSSION: Compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.

Systematic review and meta-analysis of randomized trials of hydroxychloroquine for the prevention of COVID-19.

BACKGROUND: Recruitment into randomized trials of hydroxychloroquine (HCQ) for prevention of COVID-19 has been adversely affected by a widespread conviction that HCQ is not effective for prevention. In the absence of an updated systematic review, we conducted a meta-analysis of randomized trials that study the effectiveness of HCQ to prevent COVID-19. METHODS: A search of PubMed, medRxiv, and clinicaltrials.gov combined with expert consultation found 11 completed randomized trials: 7 pre-exposure prophylaxis trials and 4 post-exposure prophylaxis trials. We obtained or calculated the risk ratio of COVID-19 diagnosis for assignment to HCQ versus no HCQ (either placebo or usual care) for each trial, and then pooled the risk ratio estimates. RESULTS: The pooled risk ratio estimate of the pre-exposure prophylaxis trials was 0.72 (95% CI: 0.58-0.90) when using either a fixed effect or a standard random effects approach, and 0.72 (95% CI: 0.55-0.95) when using a conservative modification of the Hartung-Knapp random effects approach. The corresponding estimates for the post-exposure prophylaxis trials were 0.91 (95% CI: 0.72-1.16) and 0.91 (95% CI: 0.62-1.35). All trials found a similar rate of serious adverse effects in the HCQ and no HCQ groups. DISCUSSION: A benefit of HCQ as prophylaxis for COVID-19 cannot be ruled out based on the available evidence from randomized trials. However, the "not statistically significant" findings from early prophylaxis trials were widely interpreted as definite evidence of lack of effectiveness of HCQ. This interpretation disrupted the timely completion of the remaining trials and thus the generation of precise estimates for pandemic management before the development of vaccines.

Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo-controlled randomized trial in healthcare workers.

OBJECTIVES: To assess the effect of hydroxychloroquine (HCQ) and Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis on COVID-19 risk. METHODS: EPICOS is a double-blind, placebo-controlled randomized trial conducted in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to the following: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo, and TDF/FTC placebo plus HCQ placebo. Randomization was performed in groups of four. Primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19. We compared group-specific 14-week risks via differences and ratios with 95% CIs. RESULTS: Of 1002 individuals screened, 926 (92.4%) were eligible and there were 14 cases of symptomatic COVID-19: 220 were assigned to the TDF/FTC plus HCQ group (3 cases), 231 to the TDF/FTC placebo plus HCQ group (3 cases), 233 to the TDF/FTC plus HCQ placebo group (3 cases), and 223 to the double placebo group (5 cases). Compared with the double placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00-1.98) for TDF + HCQ, 0.34 (0.00-2.06) for TDF, and 0.49 (0.00-2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21-1.00) for TDF + HCQ, 0.81 (0.44-1.49) for TDF, and 0.73 (0.41-1.38) for HCQ. Adverse events were generally mild. DISCUSSION: The target sample size was not met. Our findings are compatible with both benefit and harm of pre-exposure prophylaxis with TDF/FTC and HCQ, alone or in combination, compared with placebo.

Incidence and Severity of COVID-19 in HIV-Positive Persons Receiving Antiretroviral Therapy : A Cohort Study.

BACKGROUND: The incidence and severity of coronavirus disease 2019 (COVID-19) among HIV-positive persons receiving antiretroviral therapy (ART) have not been characterized in large populations. OBJECTIVE: To describe the incidence and severity of COVID-19 by nucleos(t)ide reverse transcriptase inhibitor (NRTI) use among HIV-positive persons receiving ART. DESIGN: Cohort study. SETTING: HIV clinics in 60 Spanish hospitals between 1 February and 15 April 2020. PARTICIPANTS: 77 590 HIV-positive persons receiving ART. MEASUREMENTS: Estimated risks (cumulative incidences) per 10 000 persons and 95% CIs for polymerase chain reaction-confirmed COVID-19 diagnosis, hospitalization, intensive care unit (ICU) admission, and death. Risk and 95% CIs for COVID-19 diagnosis and hospital admission by use of the NRTIs tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and others were estimated through Poisson regression models. RESULTS: Of 77 590 HIV-positive persons receiving ART, 236 were diagnosed with COVID-19, 151 were hospitalized, 15 were admitted to the ICU, and 20 died. The risks for COVID-19 diagnosis and hospitalization were greater in men and persons older than 70 years. The risk for COVID-19 hospitalization was 20.3 (95% CI, 15.2 to 26.7) among patients receiving TAF/FTC, 10.5 (CI, 5.6 to 17.9) among those receiving TDF/FTC, 23.4 (CI, 17.2 to 31.1) among those receiving ABC/3TC, and 20.0 (CI, 14.2 to 27.3) for those receiving other regimens. The corresponding risks for COVID-19 diagnosis were 39.1 (CI, 31.8 to 47.6), 16.9 (CI, 10.5 to 25.9), 28.3 (CI, 21.5 to 36.7), and 29.7 (CI, 22.6 to 38.4), respectively. No patient receiving TDF/FTC was admitted to the ICU or died. LIMITATION: Residual confounding by comorbid conditions cannot be completely excluded. CONCLUSION: HIV-positive patients receiving TDF/FTC have a lower risk for COVID-19 and related hospitalization than those receiving other therapies. These findings warrant further investigation in HIV preexposure prophylaxis studies and randomized trials in persons without HIV. PRIMARY FUNDING SOURCE: Instituto de Salud Carlos III and National Institutes of Health.