key: cord-1017496-h5uu4obe authors: Ayerdi, Oskar; Puerta, Teresa; Clavo, Petunia; Vera, Mar; Ballesteros, Juan; Fuentes, Manuel Enrique; Estrada, Vicente; Rodríguez, Carmen; Del Romero, Jorge title: Preventive efficacy of tenofovir/emtricitabine against SARS-CoV-2 among PREP users date: 2020-09-25 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofaa455 sha: 5190dd0cc45c91ca3ec966e973e3b22b46b340f4 doc_id: 1017496 cord_uid: h5uu4obe BACKGROUND: The preventive effect which tenofovir/emtricitabine could have against SARS-CoV-2 in HIV-negative people is unknown. The objective of this study was to analyse the seroprevalence and clinical manifestations of COVID-19 among users of PrEP, TDF/FTC or TAF/FTC, and to compare it to that of a control group. METHODS: Observational descriptive study of the seroprevalence of antibodies for SARS-CoV-2 among men who have sex with men and transgender women without use of PrEP(Group1;n=250) and PrEP users with TDF/FTC(n=409) or TAF/FTC(n=91) (Group2;n=500), conducted from 11-May-2020 to 27-Jun-2020. All were provided with a structured questionnaire which collected information on the variables to be analysed and testing for IgG antibodies to SARS-CoV-2 (CMIA) was then carried out. RESULTS: The seroprevalence of SARS-CoV-2 was 9·2%(95% CI: 5·9-13·5) in the group without PrEP and 15.0%(95% CI: 12·0-18·4) in the group with PrEP(p=0·026). Among users of TDF/FTC it was 14.7%(95% CI: 11·4-18·5) and in users of TAF/FTC it was 16·5%(95% CI: 9·5-25·7)(p=0·661). In those positive for SARS-CoV-2 receiving PrEP, 57·4% manifested symptoms compared to 78·3% in the control group (p=0·070). In users of TDF/FTC the figure was 53·3% and TAF/FTC 73·3%(p=0·100). The duration of symptoms was 11·5 days in the control group, 9·0 in PrEP users(p=0·116), 7·0 in users of TDF/FTC and 13·0 in users of TAF/FTC(p = 0·100). CONCLUSION: Users of PrEP, TDF/FTC or TAF/FTC presented a higher seroprevalence to SARS-CoV-2 than the control group. No statistically significant differences were found in relation to clinical manifestations. PrEP users should use the same prevention measures as those indicated for the general population. M a n u s c r i p t The most common symptoms of COVID-19, caused by the SARS-CoV-2 virus, include fever, cough, dyspnea, anosmia and ageusia among others, although there may be more serious manifestations, mainly in elderly patients and those with underlying comorbidities 1, 2 . Since the appearance of this infection in China in 2019, there have been multiple articles in relation to the clinical manifestations, diagnosis, treatment and prevention published 3, 4 . The triphosphates of tenofovir and emtricitabine, act as chain terminators for the reaction catalysed by SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). This fact has been demonstrated by means of molecular analysis, based on the premise that the active site of the SARS-CoV-2 RdRp is highly conserved among the different RNA viruses and shares structural characteristics with them. It presents low specificity when it comes to recognising nucleotide analogues as substrates, although these have different modifications, which means that many nucleotide and nucleoside analogues can inhibit the reaction catalysed by RdRp and have a potential use as antivirals against SARS-CoV-2 [5] [6] [7] . Other studies describe the immunomodulatory effects of tenofovir, which could also be beneficial against infection 8, 9 . These findings provide a molecular basis to evaluate the possible potential of these drugs in the prevention of COVID-19 infection. The FDA approved the use of disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis (PrEP) for HIV in 2012, 1 tablet daily of 300 mg of TDF and 200 mg of FTC 10 . The European Medicines Agency (EMA) approved it as PrEP in 2016 11 . In 2019, the FDA approved tenofovir alafenamide (TAF)/FTC as PrEP 12 . In November 2019, the Spanish Ministry of Health included the funding of PrEP as an additional measure of prevention against HIV within the National Health System, aimed at men who have sex with men (MSM) and transgender women (TGW) at risk of acquiring HIV 13 . 14 . Until now, the preventive effect which tenofovir/emtricitabine could have against COVID-19 in HIV-negative people is yet to be determined. Knowing this impact could be a finding of great importance in the face of a M a n u s c r i p t pandemic caused by an emerging virus. The objective of this study was to analyse the seroprevalence of the SARS-CoV-2 infection among users of PrEP, TDF/FTC or TAF/FTC, in a reference Center in Madrid and to compare it to that of a control group. In addition, there is a lack of knowledge regarding the possibility of a slower development of the disease in those users of tenofovir/emtricitabine infected with SARS-CoV-2, thus the clinical manifestations were also studied. This was an observational descriptive study of the seroprevalence of antibodies for SARS-CoV-2 in MSM and TGW without the use of PrEP (Group 1) and PrEP users with TDF/FTC or TAF/FTC (Group 2). The study period was seven weeks, from May 11, 2020 to June 27, 2020. For group 2, the PrEP users, the inclusion criteria were: being MSM or TGW, over the age of 18, having received PrEP before March 1, 2020 and having signed the informed consent. For group 1, the control group, the same inclusion criteria were used except that they received neither PrEP nor antiretroviral treatment (ART). The study was carried out at a reference HIV/STI clinic for PrEP in Madrid, Spain, where more than 600 PrEP users were followed up before confinement due to the COVID-19 pandemic (March 14, 2020). Upon the continuation of PrEP reviews in May 2020, all PrEP users who met the inclusion criteria were consecutively invited to participate in the study (Group 2; n=500). Patients who came to the Center with a suspicion of STIs/HIV and met the inclusion criteria for the control group were invited to participate (Group 1; n = 250). Given the lack of bibliography regarding the effect of PrEP on the acquisition of SARS-CoV-2, and based on a number of 500 accessible PrEP users, it was estimated that for a ratio of 2:1, a power of 80% and a significance level of 5%, a difference of 5·18% in seroprevalence could be detected, starting at an expected value in the control group of 11.3 % 15 . All participants who signed the informed consent were provided with a structured questionnaire that collected information on the variables to be analysed and the serological test for SARS-CoV-2 was carried out. The diagnostic assay used in our study was the SARS-CoV-2 ARCHITECT (Abbott). This assay is a chemiluminescent A c c e p t e d M a n u s c r i p t microparticle immunoassay (CMIA) used for the qualitative detection of IgG antibodies to SARS-CoV-2 in human serum. The assay is designed to detect IgG antibodies to the nucleocapsid protein of SARS-CoV-2 in serum and plasma, and has been used as epidemiological marker of previous infection. The specificity and sensitivity values of the test are 99·90% and 100·00% respectively 16 . Variables: The main outcome variable was the serological result of the presence of IgG antibodies to SARS-CoV-2. The independent variables were: sex (male or TGW), age, comorbidities associated with risk factors for COVID-19 (Chronic obstructive pulmonary disease (COPD), severe asthma, arterial hypertension (ATH), diabetes mellitus (DM), obesity, severe cardiopathy, smoker, immunosuppression, severe obesity, chronic kidney disease (CKD) on dialysis, liver disease), concomitant treatment associated with COVID-19 (systemic corticosteroids, hydroxychloroquine, methotrexate, finasteride) 17, 18 , use and start date of PrEP, drugs for PrEP (TDF/FTC or TAF/FTC), daily regimen (self-report adherence <85% or ≥85% ), exposure to coronavirus (community exposure: assigned to the exposure of any citizen of the Community of Madrid during the study period, cohabitant exposure: living with a person with a confirmed diagnosis of COVID-19, occupational exposure: work activity associated with contact with people with a high suspicion of infection), clinical manifestations associated with COVID-19 (asymptomatic, symptomatic), symptoms (fever, cough, dyspnea, myalgia, anosmia, ageusia, loss of appetite, diarrhea, severe asthenia, headaches, skin lesions), duration of symptoms (≤7 days,> 7 and a half days), hospital admission and assistance in intensive care unit (ICU), and specific treatment for COVID-19. Statistical analysis: The qualitative variables are expressed as their frequency distribution, the quantitative variables as the mean and standard deviation or, if they did not follow a normal distribution, as median and interquartile range. A comparison was made between the PrEP users and the control group as well as between the two PrEP alternatives, TDF/FTC vs TAF/FTC. The comparison of qualitative variables was analysed with the chi-square test (or Fisher's exact test where appropriate) and the quantitative variables using the Student's Ttest for independent samples or the non-parametric Mann-Whitney U test. The seroprevalence data are A c c e p t e d M a n u s c r i p t presented with a confidence interval of 95%. A significance value of 5% was accepted for all variables. The statistical analysis was done using STATA.15·0. Patient Consent Statement: The patient's written consent was obtained. All data derived from structured questionnaire were fully anonymized prior to access. The study protocol was approved by local ethical committees, IRB of Hospital Clínico San Carlos, approval Number: 20/368-E_COVID. A total of 750 MSM and TGW were analysed: 250 without PrEP (Group 1) and 500 with PrEP (Group 2). Of the PrEP users, 409 received TDF/FTC and 91 TAF/FTC, with an average time in preventive treatment of 3 months up to the date of the serological test for SARS-CoV-2. Among PrEP users, 99·9% were MSM, with no difference between the two groups, and 90·6% were between 20 and 49 years of age. The average age of the group without PrEP was 35·2 years and of the group with PrEP 37·2 years (p=0.003). In regards to the type of exposure to SARS-CoV-2, occupational activity and cohabiting with confirmed cases were studied, and there were no differences between groups 1 and 2. However, among the PrEP users, it was 34·2% in those who received TDF/FTC and 5·5% in TAF/FTC (p<0·001). In group 2, 23·5% presented some comorbidities considered as risk factors for SARS-CoV-2, with no significant differences compared to the control group. In the PrEP group, 9·0% received other drugs potentially associated with the treatment or prevention of COVID-19 and 4·4% in the control group (p=0·024). There were no significant differences between TDF/FTC and TAF/FTC users. A total of 63·3% had a PrEP adherence greater than 85% and there were no differences between the two combinations (Table 1 ). In the population studied, the seroprevalence of SARS-CoV-2, found via an analysis of the presence of IgG antibodies (CMIA), was 9·2% (95% CI: 5·9-13·5) in the group without PrEP and 15·0% (95% CI: 12·0-18·4) in the group with PrEP (p=0·026). Among users of TDF/FTC, it was 14·7% (95% CI: 11·4-18·5) and in users of TAF/FTC 16·5% (95% CI: 9·5-25·7), with no statistically significant differences (p=0·661) (Table 2) (Figure 1) . A c c e p t e d M a n u s c r i p t Common symptoms of Covid-19 manifested in 33·6% of PrEP users and 26·8% of people without PrEP (p=0·058), there were no significant differences between TDF/FTC and TAF/FTC. The most mentioned symptoms were fever (17·6%) and cough (14·9%). The manifestations occured for a median 7 days, with no differences related to the use of PrEP. A total of 2·7% received some pharmacological treatment related to COVID-19, with no significant differences between either group (Table 2) . Of people with a positive serological result for SARS-CoV-2 who received PrEP, 57·4% manifested symptoms whereas this figure was 78·3% among people in the control group (p=0·070). The duration of symptoms in PrEP users was shorter, a median of 9·0 days compared to 11·5 days for the other group, with no significant differences. Symptoms associated with COVID-19 were presented by 53·3% of users of TDF/FTC versus 73·3% of TAF/FTC (p=0·100). The duration of symptoms among people receiving TAF/FTC was longer (a median of 13·0 days) than in those taking TDF/FTC (7·0 days), without being statistically significant (Table 3 ). There were five patients who were hospitalised, all with a positive serological result: one without PrEP, three in treatment with TDF/FTC and one with TAF/FTC, who also required care in ICU. In Spain, the ENE-COVID study found a seroprevalence for SARS-CoV-2, through immunoassay tests, of 4·6% in the general population and more than 10·0% in Madrid 19 . These results concur with the 13·1% found in the total of patients analysed in our study, most of them being residents in Madrid. In our work, the seroprevalence of SARS-CoV-2, analysed through the presence of IgG antibodies, was higher in PrEP users than that found in those who did not take the drug (15·0% vs. 9·2%; p=0·026). There were some variables that differentiated the two groups: people who did not take PrEP were younger (median age: 35·2 vs. 21, 22 . For these reasons, the community exposure to SARS-CoV-2 among PrEP users was able to be higher than that of the control group, which would explain the higher seroprevalence. Among the PrEP users analysed in this study, the prevalence of SARS-CoV-2 in users of TDF/FTC was lower than that found in those of TAF/FTC, without statistically significant differences (14·7% vs. 16·5%; p=0·661). 23 . However, another study which analysed a cohort of HIV-positive patients with COVID-19, described that the incidence of cases for SARS-CoV-2 was comparable to that found in the general population and that there were no differences between those patients taking TDF/FTC or TAF/FTC versus other ARTs. The use of these drugs was also not associated with differences in the severity of the clinical manifestations [24] [25] [26] . Data published in the Annals of Internal Medicine describe that people receiving TDF/FTC had milder symptoms and a lower risk of hospitalization, 10·5 (95% CI, 5·6-17·9) among those receiving TDF/FTC versus 20·3 (95% CI, 15·2-26·7) in those who were taking TAF/FTC 23 . In our study, PrEP users had fewer symptoms and for a shorter duration than the control group, as did those receiving TDF/FTC when compared to TAF/FTC, although no statistically significant differences could be found. The preventive efficacy of tenofovir/emtricitabine was studied in MSM and TGW and the age range was 18 to 71 years 27 . Thus, these results could not be extrapolated to children, the elderly or women, in spite of the fact that no significant differences were found in the seroprevalence of COVID-19 according to sex in Spain 15 . In our study, a single diagnostic technique was used to measure the seroprevalence of COVID-19 and this was an A c c e p t e d M a n u s c r i p t immunoassay for the presence of IgG antibodies against SARS-CoV-2, which was considered the most appropriate test bearing in mind the high variability among the different antibody detection tests 28, 29 . It is the first study of the seroprevalence and evaluation of clinical manifestations of COVID-19 in PrEP users with TDF/FTC and TAF/FTC, in which a control group of similar characteristics is also compared, in one of the countries with the highest prevalences of the SARS-CoV-2 virus in Europe 30 . In conclusion, users of PrEP, TDF/FTC or TAF/FTC presented a higher seroprevalence to SARS-CoV-2 than the control group and no statistically significant differences were found in relation to clinical manifestations. In the absence of further studies, PrEP users should use the same prevention measures as those indicated for the general population. A c c e p t e d M a n u s c r i p t The authors declare that they have no conflicts of interest. Data were obtained through a structured epidemiological questionnaire completed systematically filled during the clinical practice, without funding for it. All data derived from medical histories were fully anonymized prior to access. The local ethics committee waived the requirement of informed consent for this research. The study protocol was approved by the IRB of Hospital Clínico San Carlos, approval Number: 20/368-E_COVID. JR, CR, TP, PC, MV, JB and OA conceived an designed the study. All the menbers of the Sandoval Study Group were responible for the patien inclusión, data collection, clinical follow up and help to write the manuscript. 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