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Prevention and Prophylaxis of SARS-CoV-2 Infection

Last Updated: December 17, 2020

Summary Recommendations
Summary Recommendations
  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of any agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pre-exposure prophylaxis (PrEP), except in a clinical trial (AIII).
  • The Panel recommends against the use of any agents for SARS-CoV-2 post-exposure prophylaxis (PEP), except in a clinical trial (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies; III = Expert opinion

General Prevention Measures

Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to mainly occur through respiratory droplets transmitted from an infectious person to those within 6 feet of the person. Less commonly, airborne transmission of small droplets and particles of SARS-CoV-2 that are suspended in the air can result in transmission to those who are more than 6 feet from an infectious individual. Although rare, infection through this route of transmission can also occur in persons who pass through a room that was previously inhabited by an infectious person. SARS-CoV-2 infection via airborne transmission of small particles tends to occur after prolonged exposure (>30 minutes) to an infectious person who is in an enclosed space with poor ventilation.1 The risk of SARS-CoV-2 transmission can be reduced by covering coughs and sneezes and maintaining a distance of at least 6 feet from others. When consistent distancing is not possible, face coverings may further reduce the spread of infectious droplets from individuals with SARS-CoV-2 infection to others. Frequent handwashing is also effective in reducing the risk of infection.2 Health care providers should follow the Centers for Disease Control and Prevention (CDC) recommendations for infection control and appropriate use of personal protective equipment.3

Vaccines

Vaccines for SARS-CoV-2 are aggressively being pursued. Vaccine development is typically a lengthy process, often requiring multiple candidates before one proves to be safe and effective. To address the current pandemic, several platforms are being used to develop candidate vaccines for Phase 1 and 2 trials; those that show promise are rapidly moving into Phase 3 trials. Several standard platforms, such as inactivated vaccines, live-attenuated vaccines, and protein subunit vaccines, are being pursued. Some novel approaches are being investigated, including DNA-based and RNA-based strategies and replicating and nonreplicating vector strategies, with the hope of identifying a safe and effective SARS-CoV-2 vaccine that can be used in the near future.4,5 Phase 3 clinical trial data are available for two candidate vaccines. The Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for one of the vaccines and is discussing a possible EUA for the other vaccine.

Pre-Exposure Prophylaxis

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of any agents for SARS-CoV-2 pre-exposure prophylaxis (PrEP), except in a clinical trial (AIII).

Rationale

At present, there is no known agent that can be administered before exposure to SARS-CoV-2 (i.e., as PrEP) to prevent infection. Clinical trials are investigating several agents, including emtricitabine plus tenofovir alafenamide or tenofovir disoproxil fumarate, hydroxychloroquine, and supplements such as zinc, vitamin C, and vitamin D. Studies of monoclonal antibodies that target SARS-CoV-2 are in development. Please check ClinicalTrials.gov for the latest information.

Clinical Trial Data

Hydroxychloroquine

Randomized Controlled Trial of Hydroxychloroquine for SARS-CoV-2 Pre-Exposure Prophylaxis Among Health Care Workers

This randomized, double-blind, placebo-controlled trial was designed to determine whether hydroxychloroquine 600 mg per day reduced the frequency of SARS-CoV-2 infection over an 8-week period in hospital-based health care workers. The primary outcome was incidence of SARS-CoV-2 infection as determined by reverse transcriptase polymerase chain reaction (RT-PCR) assay of nasopharyngeal swabs collected at 4 and 8 weeks or the occurrence of COVID-19 symptoms.6

Study Population
  • Participants included health care workers of two Philadelphia hospitals who worked ≥20 hours per week in a hospital-based unit, had no known history of SARS-CoV-2 infection, and no COVID-19-like symptoms in the 2 weeks before enrollment. Enrollment focused on workers in the emergency department and in dedicated COVID-19 units.
  • The study excluded individuals with allergy to hydroxychloroquine, glucose-6-phosphate dehydrogenase deficiency, retinal diseases, or substantial cardiac disease.
Results
  • The study was based on an assumption of 10% infection rate for the planned inclusion of 100 participants per arm.
  • During April 9 to July 14, 2020, community infection rates declined. At the time of the second interim analysis (when 125 of 132 participants who provided consent were evaluable for the primary endpoint), the Data Safety Monitoring Board recommended early termination of the study for futility.
  • Four participants in each group developed SARS-CoV-2 infection (positivity rate of 6.3% vs. 6.6% in the hydroxychloroquine and placebo groups, respectively; P > 0.99). Across the groups, six individuals developed symptoms of COVID-19, but none required hospitalization.
  • Serologic testing for anti-spike protein immunoglobulin (Ig) M, IgG, and nucleocapsid protein IgG demonstrated more positive results among participants in the hydroxychloroquine group (4 participants [7.4%]) than in the placebo group (2 participants [3.7%]), although the difference was not statistically significant (P = 0.40).
  • Mild adverse events were more common among participants in the hydroxychloroquine group than in the placebo group (45% vs. 26%, respectively; P = 0.04). The greatest difference was the increased frequency of mild diarrhea in the hydroxychloroquine group.
  • The rates of treatment discontinuation were similar in the hydroxychloroquine group (19%) and in the placebo group (16%).
  • There were no cardiac events or significant difference in the median frequency of changes in QTc between the study arms (P = 0.98).
Limitations
  • The study was stopped early.
  • Due to the low SARS-CoV-2 infection rate among the participants, the study was underpowered to detect a prophylactic benefit of hydroxychloroquine.
  • The study population was mostly young, healthy, health care workers and, therefore, the applicability of the study findings to other populations is uncertain.
Interpretation
  • There was no clinical benefit of hydroxychloroquine 600 mg per day administered for 8 weeks as PrEP among health care workers exposed to patients with COVID-19.
  • Compared to placebo, hydroxychloroquine was associated with an increased risk of mostly mild adverse events.

Hydroxychloroquine as Pre-Exposure Prophylaxis for COVID-19 in Health Care Workers: a Randomized Trial (COVID PREP Study)

This was a randomized, double-blind, placebo-controlled clinical trial to evaluate whether hydroxychloroquine 400 mg given once- or twice-weekly for 12 weeks (compared to placebo) can prevent SARS-CoV-2 infection in health care workers at high-risk of exposure. The primary outcome was COVID-19-free survival time. Diagnosis of COVID-19 was defined as having confirmed SARS-CoV-2 infection or having cough, shortness of breath, or difficulty breathing or having two or more of the following symptoms: fever, chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorders. COVID-19-compatible illness was included as a primary outcome even if a SARS-CoV-2 PCR test was not performed or if it was performed and the result was negative.7

Study Population
  • The study participants had to be working in the emergency department, in the intensive care unit, on a dedicated COVID-19 hospital ward, or as a first responder; alternatively, they had to have a job description that included regularly performing aerosol-generating procedures.
  • Participants were recruited via social media platforms, informed consent was obtained remotely, and the study drug was delivered to the participants by couriers.
Results
  • The study was powered based upon an anticipated 10% event rate of new symptomatic infections. In order to have 80% power, the sample size was determined to be 1,050 participants per arm. However, it became apparent before the first interim analysis that the study would not meet the enrollment target. As a result, and without unblinding, enrollment was stopped. The investigators attributed the marked decline in enrollment to the negative reports related to the safety of hydroxychloroquine, including a warning from the FDA.
  • Among the 1,483 participants who were randomized, baseline characteristics were similar across the study arms.
  • The number of individuals who met the primary endpoint of confirmed or suspected SARS-CoV-2 infection was 39 (7.9%) in the placebo group and 29 (5.9%) in both the once- and twice-weekly hydroxychloroquine groups. Among the 97 participants, only 17 were confirmed to be SARS-CoV-2 PCR positive.
  • Compared to placebo, the hazard ratio for the primary endpoint was 0.72 (95% CI, 0.4–1.16; P = 0.18) for the once-weekly hydroxychloroquine arm and 0.74 (95% CI, 0.46–1.19; P = 0.22) for the twice-weekly hydroxychloroquine arm.
  • Across the groups, there were no significant differences for any of the secondary efficacy endpoints.
  • There were significantly more adverse events reported in the once- and twice-weekly hydroxychloroquine arms (31% vs. 36% of participants, respectively; P < 0.001 for both groups) than in the placebo group (21% of participants). The most common side effects were stomach upset and nausea.
  • Drug concentrations were measured in dried whole blood samples from a subset of 180 participants who received hydroxychloroquine. The median hydroxychloroquine concentrations for the twice- and once-weekly hydroxychloroquine groups were 200 ng/mL and 98 ng/mL, respectively, both substantially below the in vitro half-maximal effective concentration (EC50) of hydroxychloroquine. The investigators noted that simulations used to determine the hydroxychloroquine dose for the study predicted drug concentrations that should have been much higher than the observed levels.
Limitations
  • The study was prematurely halted due to poor enrollment; therefore, the study population was insufficient to detect differences in outcomes among the study arms.
  • The study only assessed the SARS-CoV-2 inhibitory activity of two doses of hydroxychloroquine, neither of which achieved concentrations that exceeded the in vitro EC50 of the drug.
  • Only 17.5% of the participants who met study endpoints had confirmed positive SARS-CoV-2 test results; the remainder had compatible symptoms without a confirmatory diagnosis.
Interpretation
  • Hydroxychloroquine 400 mg once- or twice-weekly as PrEP did not reduce documented SARS-CoV-2 infection or symptoms compatible with COVID-19 among health care workers at high risk of infection.
  • These findings may suggest that the hydroxychloroquine was not effective for SARS-CoV-2 PrEP or that the dose used for this indication was suboptimal.

Post-Exposure Prophylaxis

  • The Panel recommends against the use of any agents for SARS-CoV-2 post-exposure prophylaxis (PEP), except in a clinical trial (AIII).

Rationale

At present, there is no known agent that can be administered after exposure to SARS-CoV-2 infection (i.e., as PEP) to prevent infection. Potential options for SARS-CoV-2 PEP that are currently under investigation include chloroquine, hydroxychloroquine, lopinavir/ritonavir, nitazoxanide, vitamin super B-complex, and vitamin D. Other post-exposure preventive strategies that are in development include the use of SARS-CoV-2 monoclonal antibodies and convalescent plasma. Please check ClinicalTrials.gov for the latest information.

Clinical Trial Data

Hydroxychloroquine

Both chloroquine and hydroxychloroquine have in vitro activity against severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and SARS-CoV-2.8,9 A small cohort study without a control group has suggested that hydroxychloroquine might reduce the risk of SARS-CoV-2 transmission to close contacts.10

Randomized, Double-Blind, Controlled Trial of High-Risk or Moderate-Risk Occupational or Household Exposures

This randomized, double-blind, controlled trial included 821 participants who self-enrolled in the study using an internet-based survey. Participants were randomized to receive either hydroxychloroquine 800 mg given once, followed by hydroxychloroquine 600 mg given 6 to 8 hours later, and then hydroxychloroquine 600 mg given once daily for 4 additional days or placebo. Because enrollment was done online, study drugs were sent by overnight mail, resulting in more than 50% of participants initiating the first dose of their assigned treatment 3 to 4 days after exposure to SARS-CoV-2.11

Study Population
  • Participants had a high risk or moderate risk of occupational exposure (66% of participants) or household exposure (34% of participants) to SARS-CoV-2.
  • High-risk exposure was defined as being within 6 feet of an individual with confirmed SARS-CoV-2 infection for more than 10 minutes while not wearing a face mask or eye shield (87.6% of participants), and moderate-risk exposure was defined as the same distance and duration of exposure while wearing a face mask but no eye shield (12.4% of participants).
Results
  • A total of 107 participants developed the primary outcome of symptomatic illness, confirmed by a SARS-CoV-2 positive molecular test or, if testing was not available, by a compatible, COVID-19-related syndrome based on CDC criteria.
  • Due to limited access to molecular diagnostic testing, SARS-CoV-2 infection was confirmed in only 16 of the 107 participants (15%). There was no statistically significant difference in the incidence of the primary outcome (symptomatic illness) between the hydroxychloroquine group and the placebo group (11.8% vs. 14.3%, respectively; P = 0.35).
  • There were more adverse events in the hydroxychloroquine group; mostly nausea, loose stools, and abdominal discomfort; with no serious adverse reactions or cardiac arrhythmias.
Limitations
  • Initiation of therapy was delayed for at least 3 days after exposure to SARS-CoV-2 in most participants.
  • Only 15% of participants who reached the primary outcome had SARS-CoV-2 infection confirmed by molecular diagnostics.
  • The study population was young (with a median age of 40 years) and consisted of participants who had a relatively low risk of severe COVID-19.
Interpretation
  • There was no difference in observed symptomatic COVID-19 between participants who received hydroxychloroquine 600 mg once daily and those who received placebo.
  • Although hydroxychloroquine 600 mg per day was associated with an increase in the frequency of adverse events, they were mostly mild

Cluster-Randomized Trial of High-Risk Exposures in Spain

This open-label, cluster-randomized trial included 2,314 asymptomatic contacts of 672 COVID-19 cases in Spain.12 Participants who were epidemiologically linked to a PCR-positive COVID-19 case were defined as study clusters (called rings). All contacts in a ring were simultaneously cluster-randomized 1:1 to either usual care (the control arm) or hydroxychloroquine 800 mg once daily for 1 day followed by hydroxychloroquine 400 mg once daily for 6 days (the intervention arm). Participants were informed of their allocated study arm after being randomized to the intervention or control arm and signing a consent form. The primary outcome was onset of laboratory-confirmed COVID-19, defined as illness with at least one of the following symptoms: fever, cough, difficulty breathing, myalgia, headache, sore throat, new olfactory and taste disorders, or diarrhea; and a positive SARS-CoV-2 PCR test. A secondary outcome was onset of SARS-CoV-2 infection defined as either a SARS-CoV-2 PCR positive test or the presence of any of the symptoms compatible with COVID-19. Additional secondary outcomes were development of serological positivity at Day 14 and safety up to 28 days from treatment initiation.

Study Population
  • Study participants were health care or nursing home workers (60.3%), household contacts (27.1%), or nursing home residents (12.7%) who were documented to have spent >15 minutes within 2 meters of a PCR-positive COVID-19 case during the 7 days prior to enrollment.
  • The baseline characteristics of the participants were similar between the two study arms, including coexisting disease, number of days of exposure to SARS-CoV-2 before enrollment and randomization, and type of contact.
Results
  • A total of 138 study participants (6.0%) developed PCR-confirmed, symptomatic SARS-CoV-2 infection, with no statistical difference for this outcome between the control and intervention arms (6.2% vs. 5.7%, respectively; risk ratio 0.86; 95% CI, 0.52–1.42).
  • There was no statistical difference between the study arms in the incidence of either PCR-confirmed or symptomatically compatible COVID-19, which occurred in 18.2% of participants, 17.8% in the control arm and 18.7% in the intervention arm (risk ratio 1.03; 95% CI, 0.77–1.38).
  • There was no statistical difference between the arms in the rate of positivity for SARS-CoV-2 IgM and/or IgG (8.7% in the control arm and 14.3% in the intervention arm; risk ratio 1.57; 95% CI, 0.94–2.62).
  • There were more adverse events among the hydroxychloroquine-treated participants (56.1%) than among the controls (5.9%), although most of the adverse events were mild, including gastrointestinal events, nervous system disorders, myalgia, fatigue, or malaise. No serious adverse events were attributed to the study drug.
Limitations
  • The study lacked a placebo comparator, which could have had an impact on safety reporting.
  • Data regarding the extent of the exposure to the index cases was limited.
  • For >50% of the study participants, the time from exposure to the index case to randomization was ≥4 days.
Interpretation
  • The hydroxychloroquine regimen used for PEP in this study did not prevent SARS-CoV-2 infection in healthy individuals exposed to a PCR-positive case.
  1. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): scientific brief: SARS-CoV-2 and potential airborne transmission. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-sars-cov-2.html. Accessed October 22, 2020.
  2. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): how to protect yourself & others. Available at: https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed December 9, 2020.
  3. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): infection control guidance for healthcare professionals about coronavirus (COVID-19). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html. Accessed December 9, 2020.
  4. Lurie N, Saville M, Hatchett R, Halton J. Developing COVID-19 vaccines at pandemic speed. N Engl J Med. 2020;382(21):1969-1973. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32227757.
  5. World Health Organization. Draft landscape of COVID-19 candidate vaccines. 2020. Available at: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. Accessed December 9, 2020.
  6. Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33001138.
  7. Rajasingham R, Bangdiwala AS, Nicol MR, et al. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial. Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33068425.
  8. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;71(15):732-739. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32150618.
  9. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
  10. Lee SH, Son H, Peck KR. Can post-exposure prophylaxis for COVID-19 be considered as an outbreak response strategy in long-term care hospitals? Int J Antimicrob Agents. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32305587.
  11. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med. 2020;383(6):517-525. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492293.
  12. Mitjà O, Corbacho-Monné M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for prevention of COVID-19. N Engl J Med. 2020;Published online ahead of print. Available at: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2021801.