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1.
Med Res Rev ; 42(2): 647-653, 2022 03.
Article in English | MEDLINE | ID: covidwho-1718430

ABSTRACT

John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir.


Subject(s)
Antiviral Agents , Antiviral Agents/pharmacology , Humans , Tenofovir
3.
Trials ; 22(1): 831, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1529943

ABSTRACT

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Subject(s)
Anti-HIV Agents , Lamivudine , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , Atazanavir Sulfate , Healthy Volunteers , Humans , Oligopeptides , Pyridines , Ritonavir , Tenofovir , Uganda
4.
Am J Epidemiol ; 190(11): 2339-2349, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1493666

ABSTRACT

We assessed the teratogenicity of tenofovir, a human immunodeficiency virus (HIV) drug similar to remdesivir that is currently being evaluated for the treatment of coronavirus disease 2019 (COVID-19). Using US Medicaid Analytic eXtract (MAX) claims data (2000-2014), we identified a population-based pregnancy cohort of women with HIV who filled at least 1 prescription for antiretroviral therapies (ART) during the first trimester. Women on tenofovir disoproxil fumarate (TDF) were compared with women receiving ART without TDF. Major malformations were identified by International Classification of Diseases, Ninth Revision, codes using validated algorithms. Relative risks and 95% confidence intervals were estimated using propensity score stratification to control for potential confounders. We incorporated the results into prior knowledge by conducting a systematic literature review and a meta-analysis. Major congenital malformations were diagnosed in 37 out of 866 (4.27%) infants exposed to TDF and 38 out of 1,020 (3.73%) infants exposed to ART other than TDF; the adjusted relative risk was 1.21 (95% confidence interval: 0.77, 1.90). Estimates for specific malformations were imprecise. The pooled relative risk from the meta-analysis with 6 prior studies was 0.88 (95% confidence interval: 0.75, 1.03). Based on evidence accumulated in patients with HIV, first-trimester TDF use does not increase the risk of major congenital malformations overall in the newborn compared with other ART.


Subject(s)
Antiviral Agents/adverse effects , Pregnancy Complications, Infectious/drug therapy , Tenofovir/adverse effects , Adult , Anti-HIV Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , Cohort Studies , Female , HIV Infections/drug therapy , Humans , Pandemics , Pregnancy , Pregnancy Outcome , Pregnant Women , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/therapeutic use , SARS-CoV-2 , Tenofovir/therapeutic use
5.
PLoS One ; 16(10): e0258229, 2021.
Article in English | MEDLINE | ID: covidwho-1450734

ABSTRACT

BACKGROUND/AIMS: We measured the association between underlying chronic hepatitis B (CHB) and antiviral use with infection rates among patients who underwent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. METHODS: In total, 204,418 patients who were tested for SARS-CoV-2 between January and June 2020 were included. For each case patient (n = 7,723) with a positive SARS-CoV-2 test, random controls (n = 46,231) were selected from the target population who had been exposed to someone with coronavirus disease 2019 (COVID-19) but had a negative SARS-CoV-2 test result. We merged claim-based data from the Korean National Health Insurance Service database collected. Primary endpoints were SARS-CoV-2 infection and severe clinical outcomes of COVID-19. RESULTS: The proportion of underlying CHB was lower in COVID-19 positive patients (n = 267, 3.5%) than in COVID-19 negative controls (n = 2482, 5.4%). Underlying CHB was associated with a lower SARS-CoV-2 positivity rate, after adjusting for comorbidities (adjusted odds ratio [aOR] 0.65; 95% confidence interval [CI], 0.57-0.74). Among patients with confirmed COVID-19, underlying CHB tended to confer a 66% greater risk of severe clinical outcomes of COVID-19, although this value was statistically insignificant. Antiviral treatment including tenofovir and entecavir was associated with a reduced SARS-CoV-2 positivity rate (aOR 0.49; 95% CI, 0.37-0.66), while treatment was not associated with severe clinical outcomes of COVID-19. CONCLUSIONS: Underlying CHB and antiviral agents including tenofovir decreased susceptibility to SARS-CoV-2 infection. HBV coinfection did not increase the risk of disease severity or lead to a worse prognosis in COVID-19.


Subject(s)
COVID-19/pathology , Hepatitis B, Chronic/pathology , Adult , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/epidemiology , COVID-19/virology , Case-Control Studies , Cohort Studies , Databases, Factual , Female , Guanine/analogs & derivatives , Guanine/therapeutic use , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/epidemiology , Humans , Male , Middle Aged , Odds Ratio , Republic of Korea/epidemiology , Risk , Severity of Illness Index , Tenofovir/therapeutic use , Young Adult
7.
Clin Microbiol Infect ; 27(11): 1678-1684, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1284006

ABSTRACT

OBJECTIVES: We aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and factors associated with seropositivity and asymptomatic coronavirus disease 2019 (COVID-19) among people with HIV (PWH). METHODS: This was a cross-sectional study carried out within the cohort of the Spanish HIV Research Network. Participants were consecutive PWH with plasma collected from 1st April to 30th September 2020. We determined SARS-CoV-2 antibodies (Abs) in plasma. Illness severity (NIH criteria) was assessed by a review of medical records and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes mellitus, non-AIDS-related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, nucleoside/nucleotide reverse transcriptase inhibitor (N [t]RTI) backbone, type of third antiretroviral drug, and month of sample collection. RESULTS: Of 1076 PWH (88.0% males, median age 43 years, 97.7% on antiretroviral therapy, median CD4+ 688 cells/mm3, 91.4% undetectable HIV viral load), SARS-CoV-2 Abs were detected in 91 PWH, a seroprevalence of 8.5% (95%CI 6.9-10.3%). Forty-five infections (45.0%) were asymptomatic. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American countries versus Spain (adjusted odds ratio (aOR) 2.30, 95%CI 1.41-3.76, p 0.001), and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) versus tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR 0.49, 95%CI 0.26-0.94, p 0.031). CONCLUSIONS: Many SARS-CoV-2 infections among PWH were asymptomatic, and birth in Latin American countries increased the risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggests that TDF/FTC may prevent SARS-CoV-2 infection among PWH.


Subject(s)
Anti-HIV Agents , COVID-19 , HIV Infections , Adult , Anti-HIV Agents/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , Cross-Sectional Studies , Emtricitabine/therapeutic use , Female , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Male , Prevalence , Reverse Transcriptase Inhibitors/therapeutic use , Seroepidemiologic Studies , Spain/epidemiology , Tenofovir/therapeutic use
9.
J Med Virol ; 93(3): 1796-1804, 2021 03.
Article in English | MEDLINE | ID: covidwho-1206820

ABSTRACT

Little evidence on coronavirus disease 2019 (COVID-19) in people living with HIV (PLWH) is currently available. We reported clinical and viroimmunological data of all HIV-positive patients admitted to our center with COVID-19 from March 1 to May 12, 2020. Overall, five patients were included: all were virologically-suppressed on antiretroviral therapy and CD4+ count was greater than 350 cell/mm3 in all but two patients. Although all patients had evidence of pneumonia on admission, only one developed respiratory failure. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was never detected from nasopharyngeal swabs in two patients, whereas in the others, viral clearance occurred within a maximum of 43 days. Immunoglobulin G production was elicited in all patients and neutralizing antibodies in all but one patient. Specific-T-cell response developed in all patients but was stronger in those with the more severe presentations. Similarly, the highest level of proinflammatory cytokines was found in the only patient experiencing respiratory failure. Despite a mild presentation, patients with more pronounced immunosuppression showed high degrees of both cytokines production and immune activation. Our study did not find an increased risk and severity of COVID-19 in PLWH. Adaptative cellular immune response to SARS-CoV-2 appeared to correlate to disease severity. The mild clinical picture showed in advanced HIV patients, despite a significant T-cell activation and inflammatory profile, suggests a potential role of HIV-driven immunological dysregulation in avoiding immune-pathogenetic processes. However, other possible explanations, as a protective role of certain antiretroviral drugs, should be considered. Further larger studies are needed to better clarify the impact of HIV infection on COVID-19.


Subject(s)
Anti-Retroviral Agents/therapeutic use , COVID-19/drug therapy , HIV Infections/drug therapy , SARS-CoV-2/drug effects , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , CD4 Lymphocyte Count , Coinfection/virology , Cytokines/blood , Female , HIV Integrase Inhibitors/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Immunity, Humoral/immunology , Male , Middle Aged , Oxazines/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , RNA, Viral/analysis , Reverse Transcriptase Inhibitors/therapeutic use , Risk , Severity of Illness Index , Tenofovir/therapeutic use , Transgender Persons
10.
Am J Epidemiol ; 190(11): 2339-2349, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1180572

ABSTRACT

We assessed the teratogenicity of tenofovir, a human immunodeficiency virus (HIV) drug similar to remdesivir that is currently being evaluated for the treatment of coronavirus disease 2019 (COVID-19). Using US Medicaid Analytic eXtract (MAX) claims data (2000-2014), we identified a population-based pregnancy cohort of women with HIV who filled at least 1 prescription for antiretroviral therapies (ART) during the first trimester. Women on tenofovir disoproxil fumarate (TDF) were compared with women receiving ART without TDF. Major malformations were identified by International Classification of Diseases, Ninth Revision, codes using validated algorithms. Relative risks and 95% confidence intervals were estimated using propensity score stratification to control for potential confounders. We incorporated the results into prior knowledge by conducting a systematic literature review and a meta-analysis. Major congenital malformations were diagnosed in 37 out of 866 (4.27%) infants exposed to TDF and 38 out of 1,020 (3.73%) infants exposed to ART other than TDF; the adjusted relative risk was 1.21 (95% confidence interval: 0.77, 1.90). Estimates for specific malformations were imprecise. The pooled relative risk from the meta-analysis with 6 prior studies was 0.88 (95% confidence interval: 0.75, 1.03). Based on evidence accumulated in patients with HIV, first-trimester TDF use does not increase the risk of major congenital malformations overall in the newborn compared with other ART.


Subject(s)
Antiviral Agents/adverse effects , Pregnancy Complications, Infectious/drug therapy , Tenofovir/adverse effects , Adult , Anti-HIV Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , Cohort Studies , Female , HIV Infections/drug therapy , Humans , Pandemics , Pregnancy , Pregnancy Outcome , Pregnant Women , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/therapeutic use , SARS-CoV-2 , Tenofovir/therapeutic use
11.
Pan Afr Med J ; 38: 225, 2021.
Article in English | MEDLINE | ID: covidwho-1175756

ABSTRACT

Liver damage during COVID-19 disease has been described in numerous studies. Its mechanism is poorly understood. It is mainly reserved for severe forms and is manifested by abnormalities of the hepatic assessment and more particularly cytolysis. Particular attention must be paid to patients with chronic liver disease, both in terms of follow-up and treatment. We wanted to know the evolution of COVID-19 and its treatment, on the liver function of a 27-year-old patient followed for chronic non-cirrhotic hepatitis B at the Hassan II University Hospital in Fez. Our patient had stopped the antiviral B treatment and presented COVID-19 infection with minimal to moderate impairment. The initial evaluation showed cytolysis at 4 times upper limit of normal (ULN). Management consisted in the immediate resumption of Tenofovir in combination with hydroxychloroquine (HCQ) and azythromycin with good clinical and biological evolution.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/complications , Hepatitis B, Chronic/physiopathology , Adult , Azithromycin/administration & dosage , COVID-19/diagnosis , COVID-19/drug therapy , Hepatitis B, Chronic/drug therapy , Hospitals, University , Humans , Hydroxychloroquine/administration & dosage , Liver Function Tests , Male , Morocco , Tenofovir/administration & dosage
13.
AIDS ; 35(4): F1-F10, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-1135927

ABSTRACT

OBJECTIVE: To assess whether people living with HIV (PLWH) are at increased risk of coronavirus disease 2019 (COVID-19) mortality or adverse outcomes, and whether antiretroviral therapy (ART) influences this risk. DESIGN: Rapid review with meta-analysis and narrative synthesis. METHODS: We searched databases including Embase, Medline, medRxiv and Google Scholar up to 26 August 2020 for studies describing COVID-19 outcomes in PLWH and conducted a meta-analysis of higher quality studies. RESULTS: We identified 1908 studies and included 19 in the review. In a meta-analysis of five studies, PLWH had a higher risk of COVID-19 mortality [hazard ratio 1.95, 95% confidence interval (CI): 1.62-2.34] compared with people without HIV. Risk of death remained elevated for PLWH in a subgroup analysis of hospitalized cohorts (hazard ratio 1.60, 95% CI: 1.12-2.27) and studies of PLWH across all settings (hazard ratio 2.08, 95% CI: 1.69-2.56). Eight other studies assessed the association between HIV and COVID-19 outcomes, but provided inconclusive, lower quality evidence due to potential confounding and selection bias. There were insufficient data on the effect of CD4+ T-cell count and HIV viral load on COVID-19 outcomes. Eleven studies reported COVID-19 outcomes by ART-regimen. In the two largest studies, tenofovir disoproxil fumarate-based regimens were associated with a lower risk of adverse COVID-19 outcomes, although these analyses are susceptible to confounding by co-morbidities. CONCLUSION: Emerging evidence suggests a moderately increased risk of COVID-19 mortality among PLWH. Further investigation into the relationship between COVID-19 outcomes and CD4+ T-cell count, HIV viral load, ART and the use of tenofovir disoproxil fumarate is warranted.


Subject(s)
COVID-19/complications , HIV Infections , Tenofovir/therapeutic use , CD4 Lymphocyte Count , HIV Infections/complications , HIV Infections/drug therapy , Humans , Viral Load
15.
Eur J Pharmacol ; 890: 173720, 2021 Jan 05.
Article in English | MEDLINE | ID: covidwho-1071294

ABSTRACT

COVID-19 has intensified into a global pandemic with over a million deaths worldwide. Experimental research analyses have been implemented and executed with the sole rationale to counteract SARS-CoV-2, which has initiated potent therapeutic strategy development in coherence with computational biology validation focusing on the characterized viral drug targets signified by proteomic and genomic data. Spike glycoprotein is one of such potential drug target that promotes viral attachment to the host cellular membrane by binding to its receptor ACE-2 via its Receptor-Binding Domain (RBD). Multiple Sequence alignment and relative phylogenetic analysis revealed significant sequential disparities of SARS-CoV-2 as compared to previously encountered SARS-CoV and MERS-CoV strains. We implemented a drug re-purposing approach wherein the inhibitory efficacy of a cluster of thirty known drug candidates comprising of antivirals, antibiotics and phytochemicals (selection contingent on their present developmental status in underway clinical trials) was elucidated by subjecting them to molecular docking analyses against the spike protein RBD model (developed using homology modelling and validated using SAVES server 5.0) and the composite trimeric structures of spike glycoprotein of SARS-CoV-2. Our results indicated that Camostat, Favipiravir, Tenofovir, Raltegravir and Stavudine showed significant interactions with spike RBD of SARS-CoV-2. Proficient bioavailability coupled with no predicted in silico toxicity rendered them as prospective alternatives for designing and development of novel combinatorial therapy formulations for improving existing treatment regimes to combat COVID-19.


Subject(s)
Antiviral Agents/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Binding Sites , COVID-19/drug therapy , Drug Repositioning , Esters , Gabexate/analogs & derivatives , Gabexate/pharmacology , Guanidines , Molecular Docking Simulation , Phytochemicals/pharmacology , Protein Binding , Pyrazines/pharmacology , Raltegravir Potassium/pharmacology , Stavudine/pharmacology , Tenofovir/pharmacology
16.
Fundam Clin Pharmacol ; 35(2): 432-434, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-998909

ABSTRACT

Remdesivir was recently approved to treat COVID-19. While this antiviral agent delivers clinical benefits, several safety concerns in many cases have been raised. This study reports that remdesivir at nanomolar concentrations inhibits carboxylesterase-2 (CES2) through covalent modifications. CES2 is a major drug-metabolizing enzyme. The combination of high potency with irreversible inhibition concludes that cautions must be exercised when remdesivir is used along with drugs hydrolyzed by CES2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Carboxylesterase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/adverse effects , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Carboxylesterase/metabolism , Drug Interactions , Humans , Microsomes/metabolism , Pharmaceutical Preparations/metabolism , Tenofovir/metabolism
17.
J Med Chem ; 64(1): 782-796, 2021 01 14.
Article in English | MEDLINE | ID: covidwho-997766

ABSTRACT

Nucleotide analogues are used for treating viral infections such as HIV, hepatitis B, hepatitis C, influenza, and SARS-CoV-2. To become polymerase substrates, a nucleotide analogue must be phosphorylated by cellular kinases which is rate-limiting. The goal of this study is to develop dNTP/NTP analogues directly from nucleotides. Tenofovir (TFV) analogues were synthesized by conjugating with amino acids. We demonstrate that some conjugates act as dNTP analogues and HIV-1 reverse transcriptase (RT) catalytically incorporates the TFV part as the chain terminator. X-ray structures in complex with HIV-1 RT/dsDNA showed binding of the conjugates at the polymerase active site, however, in different modes in the presence of Mg2+ versus Mn2+ ions. The adaptability of the compounds is seemingly essential for catalytic incorporation of TFV by RT. 4d with a carboxyl sidechain demonstrated the highest incorporation. 4e showed weak incorporation and rather behaved as a dNTP-competitive inhibitor. This result advocates the feasibility of designing NTP/dNTP analogues by chemical substitutions to nucleotide analogues.


Subject(s)
Amino Acids/chemistry , Nucleotides/chemistry , Tenofovir/chemistry , Virus Diseases/drug therapy , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Catalytic Domain , Drug Design , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/metabolism , Humans , Magnesium/chemistry , Molecular Docking Simulation , Nucleotides/metabolism , Phosphorylation , SARS-CoV-2/isolation & purification , Substrate Specificity , Virus Diseases/virology
18.
Int J STD AIDS ; 32(1): 100-103, 2021 01.
Article in English | MEDLINE | ID: covidwho-858353

ABSTRACT

In the midst of the COVID-19 pandemic, health care providers have had to rapidly change how they deliver care to patients. We discuss how we are delivering a virtual HIV pre-exposure prophylaxis (PrEP) service during this time; challenges faced; challenges expected and goals for the coming months.


Subject(s)
Ambulatory Care , Anti-HIV Agents/administration & dosage , COVID-19/epidemiology , Emtricitabine/administration & dosage , HIV Infections/prevention & control , Pre-Exposure Prophylaxis , Tenofovir/administration & dosage , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/virology , Drug Therapy, Combination , Female , Humans , Ireland/epidemiology , Male , Middle Aged , Pandemics , SARS-CoV-2/isolation & purification
19.
HIV Med ; 21(8): 536-540, 2020 09.
Article in English | MEDLINE | ID: covidwho-707537

ABSTRACT

The unprecedented global scale of COVID-19 globally has triggered a race to discover interventions to reduce associated morbidity and mortality and rapid release of research findings prior to any degree of critical review. As with previous novel infection outbreaks, antiretrovirals are just one drug class that has been held up as a potential strategy for prophylaxis and treatment with scant evidence and risk of harm. Here we summarize the evidence for antiretrovirals to treat COVID-19 and, as a drug that has also been studied in HIV, hydroxychloroquine, and flag some of the pitfalls of using therapies that have not been evaluated robustly.


Subject(s)
Anti-Retroviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Research/standards , COVID-19 , Coronavirus Infections/prevention & control , Drug Combinations , Drug Repositioning/standards , Drug Repositioning/trends , Humans , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Research/trends , Ritonavir/therapeutic use , SARS-CoV-2 , Tenofovir/therapeutic use , Time Factors
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