Post-exposure prophylaxis against SARS-CoV-2 in close contacts of confirmed COVID-19 cases (CORIPREV): study protocol for a cluster-randomized trial

Darrell H S Tan, Adrienne K Chan, Peter Jüni, George Tomlinson, Nick Daneman, Sharon Walmsley, Matthew Muller, Rob Fowler, Srinivas Murthy, Natasha Press, Curtis Cooper, Todd Lee, Tony Mazzulli, Allison McGeer, Darrell H S Tan, Adrienne K Chan, Peter Jüni, George Tomlinson, Nick Daneman, Sharon Walmsley, Matthew Muller, Rob Fowler, Srinivas Murthy, Natasha Press, Curtis Cooper, Todd Lee, Tony Mazzulli, Allison McGeer

Abstract

Background: Post-exposure prophylaxis (PEP) is a well-established strategy for the prevention of infectious diseases, in which recently exposed people take a short course of medication to prevent infection. The primary objective of the COVID-19 Ring-based Prevention Trial with lopinavir/ritonavir (CORIPREV-LR) is to evaluate the efficacy of a 14-day course of oral lopinavir/ritonavir as PEP against COVID-19 among individuals with a high-risk exposure to a confirmed case.

Methods: This is an open-label, multicenter, 1:1 cluster-randomized trial of LPV/r 800/200 mg twice daily for 14 days (intervention arm) versus no intervention (control arm), using an adaptive approach to sample size calculation. Participants will be individuals aged > 6 months with a high-risk exposure to a confirmed COVID-19 case within the past 7 days. A combination of remote and in-person study visits at days 1, 7, 14, 35, and 90 includes comprehensive epidemiological, clinical, microbiologic, and serologic sampling. The primary outcome is microbiologically confirmed COVID-19 infection within 14 days after exposure, defined as a positive respiratory tract specimen for SARS-CoV-2 by polymerase chain reaction. Secondary outcomes include safety, symptomatic COVID-19, seropositivity, hospitalization, respiratory failure requiring ventilator support, mortality, psychological impact, and health-related quality of life. Additional analyses will examine the impact of LPV/r on these outcomes in the subset of participants who test positive for SARS-CoV-2 at baseline. To detect a relative risk reduction of 40% with 80% power at α = 0.05, assuming the secondary attack rate in ring members (p0) = 15%, 5 contacts per case and intra-class correlation coefficient (ICC) = 0.05, we require 110 clusters per arm, or 220 clusters overall and approximately 1220 enrollees after accounting for 10% loss-to-follow-up. We will modify the sample size target after 60 clusters, based on preliminary estimates of p0, ICC, and cluster size and consider switching to an alternative drug after interim analyses and as new data emerges. The primary analysis will be a generalized linear mixed model with logit link to estimate the effect of LPV/r on the probability of infection. Participants who test positive at baseline will be excluded from the primary analysis but will be maintained for additional analyses to examine the impact of LPV/r on early treatment.

Discussion: Harnessing safe, existing drugs such as LPV/r as PEP could provide an important tool for control of the COVID-19 pandemic. Novel aspects of our design include the ring-based prevention approach, and the incorporation of remote strategies for conducting study visits and biospecimen collection.

Trial registration: This trial was registered at www.ClinicalTrials.gov ( NCT04321174 ) on March 25, 2020.

Keywords: COVID-19; Chemoprophylaxis; Cluster randomization; Lopinavir/ritonavir; Post-exposure prophylaxis; Protocol; Randomized controlled trial.

Conflict of interest statement

DHST has received investigator-initiated research grants to his institution from Gilead and Viiv Healthcare. DHST is a Site Principal Investigator for clinical trials sponsored by Glaxo Smith Kline. PJ serves as an unpaid member of the steering group or executive committee of trials funded by Abbott Vascular, Astra Zeneca, Biotronik, Biosensors, St. Jude Medical, Terumo, and The Medicines Company, has received research grants to the institution from Appili Therapeutics, Astra Zeneca, Biotronik, Biosensors International, Eli Lilly, The Medicines Company, and honoraria to the institution for participation in advisory boards and/or consulting from Amgen, Ava, and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. SLW serves on advisory boards, speaks at continuing medical education events and conducts clinical trials through her institution with Gilead, Merck, Viiv Healthcare, and Jansen.

References

    1. Riou J, Althaus CL. Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. Euro Surveill. 2020;25(4). 10.2807/1560-7917.ES.2020.25.4.2000058.
    1. Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA. 2020;323(14):1335. 10.1001/jama.2020.4344.
    1. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603–2615. doi: 10.1056/NEJMoa2034577.
    1. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403–416. doi: 10.1056/NEJMoa2035389.
    1. WHO R&D Blueprint COVID-19. Informal consultation on the role of therapeutics in COVID-19 prophylaxis and post-exposure prophylaxis. Geneva: World Health Organization (WHO); 2020. 31st March 2020.
    1. Wu CY, Jan JT, Ma SH, et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci U S A. 2004;101(27):10012–10017. doi: 10.1073/pnas.0403596101.
    1. de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875–4884. doi: 10.1128/AAC.03011-14.
    1. Park SY, Lee JS, Son JS, et al. Post-exposure prophylaxis for Middle East respiratory syndrome in healthcare workers. J Hosp Infect. 2019;101(1):42–46. doi: 10.1016/j.jhin.2018.09.005.
    1. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787–1799. doi: 10.1056/NEJMoa2001282.
    1. Dalerba P, Levin B, Thompson JL. A trial of lopinavir-ritonavir in Covid-19. N Engl J Med. 2020;382(21):e68. 10.1056/NEJMc2008043.
    1. Kunz KM. A trial of Lopinavir-ritonavir in Covid-19. N Engl J Med. 2020;382(21):e68. 10.1056/NEJMc2008043.
    1. Corrao S, Natoli G, Cacopardo B. A trial of lopinavir-ritonavir in Covid-19. N Engl J Med. 2020;382(21):e68. 10.1056/NEJMc2008043.
    1. Carmona-Bayonas A, Jimenez-Fonseca P, Castanon E. A trial of lopinavir-ritonavir in Covid-19. N Engl J Med. 2020;382(21):e68. 10.1056/NEJMc2008043.
    1. Havlichek D Jr. A trial of lopinavir-ritonavir in Covid-19. N Engl J Med. 2020;382(21):e68. 10.1056/NEJMc2008043.
    1. WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernández García C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, García PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portolés A, Rasmin MR, Raza A, Rees H, Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen KAO, Trelle S, Zaid H, Røttingen JA, Swaminathan S. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511. 10.1056/NEJMoa2023184.
    1. RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396(10259):1345–52. 10.1016/S0140-6736(20)32013-4. Epub ahead of print.
    1. Tan D, Walmsley S. Lopinavir plus ritonavir: a novel protease inhibitor combination for HIV infections. Expert Rev Anti-Infect Ther. 2007;5(1):13–28. doi: 10.1586/14787210.5.1.13.
    1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at . Accessed Feb 17, 2020. 2020.
    1. Ford N, Shubber Z, Calmy A, et al. Choice of antiretroviral drugs for postexposure prophylaxis for adults and adolescents: a systematic review. Clin Infect Dis. 2015;60(Suppl 3):S170–S176. doi: 10.1093/cid/civ092.
    1. Murphy RL, Brun S, Hicks C, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS. 2001;15(1):F1–F9. doi: 10.1097/00002030-200101050-00002.
    1. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346(26):2039–2046. doi: 10.1056/NEJMoa012354.
    1. Johnson MA, Gathe JC, Jr, Podzamczer D, et al. A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen. J Acquir Immune Defic Syndr. 2006;43(2):153–160. doi: 10.1097/01.qai.0000242449.67155.1a.
    1. Gathe J, da Silva BA, Cohen DE, et al. A once-daily lopinavir/ritonavir-based regimen is noninferior to twice-daily dosing and results in similar safety and tolerability in antiretroviral-naive subjects through 48 weeks. J Acquir Immune Defic Syndr. 2009;50(5):474–481. doi: 10.1097/QAI.0b013e31819c2937.
    1. Leal L, Leon A, Torres B, et al. A randomized clinical trial comparing ritonavir-boosted lopinavir versus maraviroc each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection. J Antimicrob Chemother. 2016;71(7):1982–1986. doi: 10.1093/jac/dkw048.
    1. Leal L, Leon A, Torres B, et al. A randomized clinical trial comparing ritonavir-boosted lopinavir versus raltegravir each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection. J Antimicrob Chemother. 2016;71(7):1987–1993. doi: 10.1093/jac/dkw049.
    1. Fatkenheuer G, Jessen H, Stoehr A, et al. PEPDar: a randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis. HIV Med. 2016;17(6):453–459. doi: 10.1111/hiv.12363.
    1. Corporation A. Product monograph: Kaletra® lopinavir/ritonavir film-coated tablets (100/25 mg, 200/50 mg) 2019.
    1. U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. [July 2017]. Available from: .
    1. Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ca Suffit!) Lancet. 2017;389(10068):505–518. doi: 10.1016/S0140-6736(16)32621-6.
    1. Henao-Restrepo AM, Longini IM, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet. 2015;386(9996):857–866. doi: 10.1016/S0140-6736(15)61117-5.
    1. The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola. BMJ. 2015;351:h3740. 10.1136/bmj.h3740.
    1. Riley S, Fraser C, Donnelly CA, et al. Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions. Science. 2003;300(5627):1961–1966. doi: 10.1126/science.1086478.
    1. Al-Tawfiq JA, Rodriguez-Morales AJ. Super-spreading events and contribution to transmission of MERS, SARS, and SARS-CoV-2 (COVID-19). J Hosp Infect. 2020;105(2):111–12. 10.1016/j.jhin.2020.04.002.
    1. Kretzschmar M, van den Hof S, Wallinga J, van Wijngaarden J. Ring vaccination and smallpox control. Emerg Infect Dis. 2004;10(5):832–841. doi: 10.3201/eid1005.030419.
    1. Public Health Agency of Canada. Public health management of cases and contacts associated with novel coronavirus disease 2019 (COVID-19). Available at: . Accessed March 18, 2020.
    1. Joint Centre for Bioethics, University of Toronto. Community Tools: Aid to Capacity Evaluation (ACE). Available at: Accessed February 1, 2021.
    1. Product Monograph. Kaletra lopinavir/ritonavir film-coated tablets (100/25 mg, 200/50 mg). Human immunodeficiency virus (HIV) protease inhibitor. St-Laurent: AbbVie Corporation; 2019.
    1. Backer JA, Klinkenberg D, Wallinga J. Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro Surveill. 2020;25(5). 10.2807/1560-7917.ES.2020.25.5.2000062.
    1. Assiri A, McGeer A, Perl TM, et al. Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013;369(5):407–416. doi: 10.1056/NEJMoa1306742.
    1. Jiang X, Rayner S, Luo MH. Does SARS-CoV-2 has a longer incubation period than SARS and MERS? J Med Virol. 2020;13(10):25708.
    1. Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retrovir. 2007;23(12):1505–1514. doi: 10.1089/aid.2007.0107.
    1. Duthaler U, Berger B, Erb S, et al. Using dried blood spots to facilitate therapeutic drug monitoring of antiretroviral drugs in resource-poor regions. J Antimicrob Chemother. 2018;73(10):2729–2737. doi: 10.1093/jac/dky254.
    1. Kromdijk W, Mulder JW, Smit PM, Ter Heine R, Beijnen JH, Huitema AD. Therapeutic drug monitoring of antiretroviral drugs at home using dried blood spots: a proof-of-concept study. Antivir Ther. 2013;18(6):821–825. doi: 10.3851/IMP2501.
    1. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693–704. 10.1056/NEJMoa2021436.
    1. Furukawa TA, Kessler RC, Slade T, Andrews G. The performance of the K6 and K10 screening scales for psychological distress in the Australian National Survey of Mental Health and Well-Being. Psychol Med. 2003;33(2):357–362. doi: 10.1017/s0033291702006700.
    1. Kessler RC, Andrews G, Colpe LJ, et al. Short screening scales to monitor population prevalences and trends in non-specific psychological distress. Psychol Med. 2002;32(6):959–976. doi: 10.1017/s0033291702006074.
    1. Horowitz M, Wilner N, Alvarez W. Impact of event scale: a measure of subjective stress. Psychosom Med. 1979;41(3):209–218. doi: 10.1097/00006842-197905000-00004.
    1. Maunder RG, Lancee WJ, Balderson KE, et al. Long-term psychological and occupational effects of providing hospital healthcare during SARS outbreak. Emerg Infect Dis. 2006;12(12):1924–1932. doi: 10.3201/eid1212.060584.
    1. Pang X, Zhu Z, Xu F, et al. Evaluation of control measures implemented in the severe acute respiratory syndrome outbreak in Beijing, 2003. JAMA. 2003;290(24):3215–3221. doi: 10.1001/jama.290.24.3215.
    1. Goh DL, Lee BW, Chia KS, et al. Secondary household transmission of SARS, Singapore. Emerg Infect Dis. 2004;10(2):232–234. doi: 10.3201/eid1002.030676.
    1. Personal communication with Dr. Allison McGeer on Feb 14, 2020.
    1. Muller MP, Richardson SE, McGeer A, et al. Early diagnosis of SARS: lessons from the Toronto SARS outbreak. Eur J Clin Microbiol Infect Dis. 2006;25(4):230–237. doi: 10.1007/s10096-006-0127-x.
    1. Thai PQ, Mai le Q, Welkers MR, et al. Pandemic H1N1 virus transmission and shedding dynamics in index case households of a prospective Vietnamese cohort. J Inf Secur. 2014;68(6):581–590. doi: 10.1016/j.jinf.2014.01.008.
    1. Petrie JG, Ohmit SE, Cowling BJ, et al. Influenza transmission in a cohort of households with children: 2010-2011. PLoS One. 2013;8(9):e75339. doi: 10.1371/journal.pone.0075339.
    1. Carcione D, Giele CM, Goggin LS, et al. Secondary attack rate of pandemic influenza A(H1N1) 2009 in Western Australian households, 29 May-7 August 2009. Euro Surveill. 2011;16:3.
    1. Cauchemez S, Donnelly CA, Reed C, et al. Household transmission of 2009 pandemic influenza a (H1N1) virus in the United States. N Engl J Med. 2009;361(27):2619–27. doi: 10.1056/NEJMoa0905498.
    1. Burke RM, Midgley CM, Dratch A, et al. Active monitoring of persons exposed to patients with confirmed COVID-19 - United States, January–February 2020. MMWR Morb Mortal Wkly Rep. 2020;69(9):245–246. doi: 10.15585/mmwr.mm6909e1.
    1. Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis. 2020;27(20):30287–30285.
    1. Jing QL, Liu MJ, Zhang ZB, Fang LQ, Yuan J, Zhang AR, Dean NE, Luo L, Ma MM, Longini I, Kenah E, Lu Y, Ma Y, Jalali N, Yang ZC, Yang Y. Household secondary attack rate of COVID-19 and associated determinants in Guangzhou, China: a retrospective cohort study. Lancet Infect Dis. 2020;20(10):1141–50. 10.1016/S1473-3099(20)30471-0.
    1. Li W, Zhang B, Lu J, Liu S, Chang Z, Peng C, Liu X, Zhang P, Ling Y, Tao K, Chen J. Characteristics of Household Transmission of COVID-19. Clin Infect Dis. 2020;71(8):1943–46. 10.1093/cid/ciaa450.
    1. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, McDonald EG, Rajasingham R, Lee TC, Hullsiek KH. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517–25. 10.1056/NEJMoa2016638.
    1. Donner A, Klar N. Pitfalls of and controversies in cluster randomization trials. Am J Public Health. 2004;94(3):416–422. doi: 10.2105/ajph.94.3.416.
    1. Brown CH, Ten Have TR, Jo B, et al. Adaptive designs for randomized trials in public health. Annu Rev Public Health. 2009;30:1–25. doi: 10.1146/annurev.publhealth.031308.100223.
    1. Larios OE, Coleman BL, Drews SJ, et al. Self-collected mid-turbinate swabs for the detection of respiratory viruses in adults with acute respiratory illnesses. PLoS One. 2011;6(6):e21335. doi: 10.1371/journal.pone.0021335.
    1. Granados A, Quach S, McGeer A, Gubbay JB, Kwong JC. Detecting and quantifying influenza virus with self- versus investigator-collected mid-turbinate nasal swabs. J Med Virol. 2017;89(7):1295–1299. doi: 10.1002/jmv.24753.
    1. WHO R&D Blueprint COVID-19. Informal consultation on the role of therapeutics in COVID-19 prophylaxis and post-exposure prophylaxis. Geneva, Switzerland. 10 April 2020.
    1. WHO R&D Blueprint COVID-19. Informal consultation on the role of therapeutics in COVID-19 prophylaxis and post-exposure prophylaxis. Geneva, Switzerland. 16 April 2020.
    1. Corman VM, Landt O, Kaiser M, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25(3). 10.2807/1560-7917.ES.2020.25.3.2000045.
    1. Ali M, Han S, Gunst CJ, Lim S, Luinstra K, Smieja M. Throat and nasal swabs for molecular detection of respiratory viruses in acute pharyngitis. Virol J. 2015;12:178. doi: 10.1186/s12985-015-0408-z.
    1. Van Wesenbeeck L, Meeuws H, D'Haese D, et al. Sampling variability between two mid-turbinate swabs of the same patient has implications for influenza viral load monitoring. Virol J. 2014;11:233. doi: 10.1186/s12985-014-0233-9.
    1. Matsuishi K, Kawazoe A, Imai H, et al. Psychological impact of the pandemic (H1N1) 2009 on general hospital workers in Kobe. Psychiatry Clin Neurosci. 2012;66(4):353–360. doi: 10.1111/j.440-819.2012.02336.x.
    1. Wang Y, Xu B, Zhao G, Cao R, He X, Fu S. Is quarantine related to immediate negative psychological consequences during the 2009 H1N1 epidemic? Gen Hosp Psychiatry. 2011;33(1):75–77. doi: 10.1016/j.genhosppsych.2010.11.001.
    1. Guidelines for the economic evaluation of health technologies: Canada. 4th ed. Ottawa: CADTH; 2017.
    1. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549–556. doi: 10.2307/2530245.
    1. Kim JH, Marks F, Clemens JD. Looking beyond COVID-19 vaccine phase 3 trials. Nat Med. 2021;27(2):205–211. 10.1038/s41591-021-01230-y.
    1. Attwell K, Lake J, Sneddon J, Gerrans P, Blyth C, Lee J. Converting the maybes: crucial for a successful COVID-19 vaccination strategy. PLoS One. 2021;16(1):e0245907. doi: 10.1371/journal.pone.0245907.
    1. Tegally H, Wilkinson E, Lessells RJ, Giandhari J, Pillay S, Msomi N, Mlisana K, Bhiman JN, von Gottberg A, Walaza S, Fonseca V, Allam M, Ismail A, Glass AJ, Engelbrecht S, Van Zyl G, Preiser W, Williamson C, Petruccione F, Sigal A, Gazy I, Hardie D, Hsiao NY, Martin D, York D, Goedhals D, San EJ, Giovanetti M, Lourenço J, Alcantara LCJ, de Oliveira T. Sixteen novel lineages of SARS-CoV-2 in South Africa. Nat Med. 2021. 10.1038/s41591-021-01255-3.
    1. Barnabas RV, Brown ER, Bershteyn A, Stankiewicz Karita HC, Johnston C, Thorpe LE, Kottkamp A, Neuzil KM, Laufer MK, Deming M, Paasche-Orlow MK, Kissinger PJ, Luk A, Paolino K, Landovitz RJ, Hoffman R, Schaafsma TT, Krows ML, Thomas KK, Morrison S, Haugen HS, Kidoguchi L, Wener M, Greninger AL, Huang ML, Jerome KR, Wald A, Celum C, Chu HY, Baeten JM. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial. Ann Intern Med. 2020;M20–6519. 10.7326/M20-6519. Epub ahead of print.
    1. Mitjà O, Corbacho-Monné M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19. N Engl J Med. 2021;384(5):417–427. doi: 10.1056/NEJMoa2021801.
    1. Smit M, Marinosci A, Nicoletti GJ, et al. Efficacy of pragmatic same-day ring prophylaxis for adult individuals exposed to SARS-CoV-2 in Switzerland (COPEP): protocol of an open-label cluster randomised trial. BMJ Open. 2020;10(11):e040110. doi: 10.1136/bmjopen-2020-040110.

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