





































 Volume 2 No. S3: Second Quarter Editorial 
 https://doi.org/10.47488/dhrp.v2iS3.67 

 

DHR Proceedings ǀ http://dhrproceedings.org   2022, Vol. 2 No. S3 1-9 1 
 

 

EDITORIAL 

Paxlovid Rebound: Proposed Strategy to 

Prevent Reinfection Following Treatment of 

COVID-19 Positive Nonhospitalized Patients  
 

Sohail Rao, MD, MA, DPhil,1 and Manish Singh, MD, FACS, FASMBS2 

 
1Executive Vice President for Research & Leadership Development, DHR Health, 5501 S. McColl Road, Edinburg, Texas 78539, 

and Founding President & Chief Executive Officer, DHR Health Institute for Research & Development, 5323 S. McColl Road, 

Edinburg, Texas 78539.  

ORCID: https://orcid.org/0000-0001-5027-9992  

 
2DHR Health Bariatric and Metabolic Institute and Chief Executive Officer, DHR Health, 5501 S. McColl Road, Edinburg, Texas 

78539 and DHR Health Bariatric & Metabolic Institute, 5500 Raphael Drive, Edinburg, TX 79539 

ORCID: https://orcid.org/0000-0003-4146-3282 

 

Correspondence should be addressed to: Sohail Rao, MD, MA, DPhil., DHR Health Institute for Research & Development, 5323 

S. McColl Road, Edinburg, Texas 78539. E-mail: s.rao@dhr-rgv.com.  

 

 

Keywords: COVID-19; SARS-CoV-2; BA.5; BA.5; Omicron; Paxlovid; Malnupiravir; Bebtelovimab; EVUSHELDTM; 

Malnupiravir; Remdesivir; CDC: Centers for Disease Control and Prevention; FDA: U.S. Food and Drug Administration; WHO: 

World Health Organization 

 

 

 B.1.1.529, the new lineage of SARS-CoV-2 

variant was first detected in Botswana on November 

11, 2021, and in South Africa on November 14, 2021. 

This new variant had many mutations in portions of 

the genome that increased its infectivity and 

transmissibility; conferred resistance to certain 

therapeutics; and reduced neutralization by 

monoclonal antibodies (1,2). Given these 

observations, On November 26, 2021, WHO classified 

B.1.1.529 as a variant of concern and named it 

Omicron (3). On November 30, 2021, the U.S. SARS-

CoV-2 Interagency Group (SIG), which includes the 

Centers for Disease Control and Prevention (CDC), 

the National Institutes of Health, the Food and Drug 

Administration, the Biomedical Advanced Research  

 

and Development Authority, and the Departments of 

Defense, Agriculture, and Health and Human 

Services, classified the Omicron variant as a Variant 

of Concern. 

Since its first identification, a total of six 

Omicron variants have been identified (Table 1). 

Many of the earlier variants were responsive to 

available experimental treatment including 

monoclonal antibodies such as Sotrovimab (4). 

However, both BA.4 and BA.5 were found less 

responsive to some for the existing therapies. BA.4 

was first identified in the US in April 2022 but was 

soon replaced by BA.5 as the dominant variant that is 

currently responsible for majority of COVID-19 cases 

https://orcid.org/0000-0001-5027-9992
https://orcid.org/0000-0003-4146-3282
mailto:s.rao@dhr-rgv.com


Rao, et al   Paxlovid Rebound 
 https://doi.org/10.47488/dhrp.v2iS3.67 

 

DHR Proceedings ǀ http://dhrproceedings.org   2022, Vol. 2 No. S3 1-9 2 
 

(Figure 1). BA.5 is probably the most transmissible 

variant of Omicron and has certain characteristic that 

are unique to this mutant: 

• Infects those who have had previous natural 

infection from earlier variants of SARS-CoV2 

• Escapes immunity due to COVID-19 vaccination 

• Poor neutralization by previously existing 

experimental monoclonal antibodies 

Given these characteristics, FDA revised its 

recommendation for the treatment of hospitalized and 

nonhospitalized patients infected with the BA.4 and 

BA.5 variants of Omicron (Table 2). Paxlovid, an oral 

antiviral medication, was recommended as the 

preferred option for the treatment of nonhospitalized 

mild-to-moderate SARS-CoV-2 infection in 

individuals 12 and older at high risk of progression to 

severe disease (Figure 3 and 4). Additionally, 

Bebtelovimab, a monoclonal antibody for the 

treatment of acute COVID-19 in the outpatient setting, 

is equally effective but in extremely short supply and 

it is recommended that it should be reserved for 

individuals with a contraindication to preferred 

therapies. More importantly, availability of 

Bebtelovimab after the third week of August is 

uncertain and as of August 01, 2022, patients would be 

required to pay to get treated with this monoclonal 

antibody. It is noteworthy that under an IRB-approved 

protocol, we at the DHR Health Institute for Research 

& Development have treated to date over 400 high risk 

COVID-19 positive patients with Bebtelovimab with 

very satisfactory outcomes. 

 

While Paxlovid is the recommended drug of 

choice for treating mild-moderate nonhospitalized 

patients, it does have certain limitations (5). Despite 

its therapeutic effectiveness, Paxlovid is 

contraindicated in the following conditions which 

limits its utility (6): 

 

• Patients requiring hospitalization 

• For pre-exposure or post-exposure prophylaxis 

• For use beyond recommended 5 consecutive days 

• Patients with clinically significant 

hypersensitivity reactions (e.g., toxic epidermal 

necrolysis and Stevens-Johnson syndrome) 

• Patients on drugs requiring CYP3A for clearance 

• Patients on drugs that are potent induces of 

CYP3A 

 

Of equal concern is the recent observation of 

high incidence of re-infection following treatment 

with Paxlovid (8). In a recent study involving 13,600 

patients, it was reported that 7-day and 30-day 

COVID-19 rebound rates after Paxlovid treatment 

were 3.53% and 5.40% for SARS-CoV-2 infection, 

2.31% and 5.87% for COVID-19 symptoms, and 

0.44% and 0.77% for hospitalizations (8). While it 

requires further validation, there is however some 

recent evidence that the re-infection rate is probably as 

high as 20-40% in patients treated with Paxlovid (9). 

Rebound of SARS-CoV-2 infection in high profile 

cases following the recommended 5-day oral 

treatment with Paxlovid has further highlighted this  

concern (10 - 11). In one particular case, the patient 

resorted to taking a second course of Paxlovid after 

experiencing COVID-19 rebound which, at the present 

time is not recommended by the FDA (10).  

 

Rebound of COVID-19 symptoms 

following the use of Paxlovid treatment is likely due 

to insufficient drug exposure: not enough of the 

drug was getting to infected cells to stop all viral 

replication. This could be due to the drug being 



Rao, et al   Paxlovid Rebound 
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DHR Proceedings ǀ http://dhrproceedings.org   2022, Vol. 2 No. S3 1-9 3 
 

metabolized more quickly in some individuals or 

that the drug needs to be delivered over a longer 

treatment duration. It is therefore our 

recommendation that has also been voiced by others 

(12) that both Pfizer (the manufactures of Paxlovid) 

and FDA review the data and either increase the 

duration of treatment (from 5 days to 7-10 days) 

and/or allow the use of another 3–5-day course of 

Paxlovid for patients suffering from rebound. 

Alternatively combined use of Bebtelovimab and 

Paxlovid could be considered for contemporaneous 

reduction of both the circulating viral load and 

prevention of viral replication in infected cells.  

 

Funding:  

The project was funded by a Seed Grant from the  

DHR Health Institute for Research & Development  

and the DHR Health 

 

Conflict of Interest:  

The authors have reported no conflict of interest 

 

References: 

1. Chen J, Wei GW. Omicron BA.2 

(B.1.1.529.2): high potential to becoming the 

next dominating variant. Res Sq [Preprint]. 

2022 Feb 23:rs.3.rs-1362445. doi: 

10.21203/rs.3.rs-1362445/v1. Update in: J 

Phys Chem Lett. 2022 Apr 25:3840-3849. 

PMID: 35233567; PMCID: PMC8887081. 

2. Chen J, Wang R, Gilby NB, Wei GW. 

Omicron Variant (B.1.1.529): Infectivity, 

Vaccine Breakthrough, and Antibody 

Resistance. J Chem Inf Model. 2022 Jan 

24;62(2):412-422. doi: 

10.1021/acs.jcim.1c01451. Epub 2022 Jan 6. 

PMID: 34989238; PMCID: PMC8751645. 

3. Classification of Omicron (B.1.1.529): 

SARS-CoV-2 Variant of Concern. WHO. 

November 26, 2021. 

https://www.who.int/news/item/26-11-2021-

classification-of-omicron-(b.1.1.529)-sars-

cov-2-variant-of-concern  

4. Martin-Blondel G, Marcelin AG, Soulié C, 

et.al. Sotrovimab to prevent severe COVID-

19 in high-risk patients infected with 

Omicron BA.2. J Infect. 2022 Jul 5:S0163-

4453(22)00406-6. doi: 

10.1016/j.jinf.2022.06.033. Epub ahead of 

print. PMID: 35803386; PMCID: 

PMC9254651. 

5. Hammond, J., Leister-Tebbe, H.,  Gardner, 

A, et.al. Oral Nirmatrelvir for High-Risk, 

Nonhospitalized Adults with Covid-

19.Hammond, Ph.D.,  April 14, 2022 

N Engl J Med 2022; 386:1397-1408 

DOI: 10.1056/NEJMoa2118542 

6. Coronavirus (COVID-19) Update: FDA 

Authorizes First Oral Antiviral for Treatment 

of COVID-19. FDA. December 22, 2021. 

https://www.fda.gov/news-events/press-

announcements/coronavirus-covid-19-

update-fda-authorizes-first-oral-antiviral-

treatment-covid-19  

7. COVID-19 Rebound After Paxlovid 

Treatment. CDC. May 24, 2022, 

https://emergency.cdc.gov/han/2022/han004

67.asp  

8. Wang L., Berger NA., Davis PB., et.al. COVID-

19 rebound after Paxlovid and Molnupiravir 

during January-June 2022, medRxiv 2022. 

08.21.22276724; 

https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern
https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern
https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern
https://www.nejm.org/doi/full/10.1056/NEJMoa2118542
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
https://emergency.cdc.gov/han/2022/han00467.asp
https://emergency.cdc.gov/han/2022/han00467.asp


Rao, et al   Paxlovid Rebound 
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DHR Proceedings ǀ http://dhrproceedings.org   2022, Vol. 2 No. S3 1-9 4 
 

doi: https://doi.org/10.1101/2022.06.21.222

76724 

9. Farrell P. COVID reinfection rate with 

treatment Biden is taking is more than 40% - 

and not 2% as marketed: Paxlovid is thought 

to suppress immune response meaning body 

can’t fight off new infection. Daily Mail. July 

30, 2022. 

https://www.dailymail.co.uk/news/article-

11065467/COVID-reinfection-rate-treatment-

Biden-taking-40-not-2-marketed.html  

10. Lee BY. Dr. Fauci Takes 2nd Course of 

Paxlovid After Suffering Covid-19 Rebound. 

Forbes. June 30, 2022. 

https://www.forbes.com/sites/brucelee/2022/

06/30/dr-fauci-takes-2nd-course-of-

paxlovid-after-suffering-covid-19-

rebound/?sh=4964bf0315d6  

11. Judd D and Cole D. Biden still testing 

positive after rebound Covid-19 case but 

‘continues to feel well,’ White House says. 

CNN. July 31, 2022. 

https://www.cnn.com/2022/07/31/politics/jo

e-biden-covid-positive-day-two/index.html  

12. Mlynark N. COVID-19 Rebound after 

Taking Paxlovid Likely Due to Insufficient 

Drug Exposure. UCSD. June 21, 2022. 

https://health.ucsd.edu/news/releases/Pages/

2022-06-21-covid-19-rebound-after-taking-

paxlovid-likely-due-to-insufficient-drug-

exposure.aspx  

 

 

 

 

 

https://doi.org/10.1101/2022.06.21.22276724
https://doi.org/10.1101/2022.06.21.22276724
https://www.dailymail.co.uk/news/article-11065467/COVID-reinfection-rate-treatment-Biden-taking-40-not-2-marketed.html
https://www.dailymail.co.uk/news/article-11065467/COVID-reinfection-rate-treatment-Biden-taking-40-not-2-marketed.html
https://www.dailymail.co.uk/news/article-11065467/COVID-reinfection-rate-treatment-Biden-taking-40-not-2-marketed.html
https://www.forbes.com/sites/brucelee/2022/06/30/dr-fauci-takes-2nd-course-of-paxlovid-after-suffering-covid-19-rebound/?sh=4964bf0315d6
https://www.forbes.com/sites/brucelee/2022/06/30/dr-fauci-takes-2nd-course-of-paxlovid-after-suffering-covid-19-rebound/?sh=4964bf0315d6
https://www.forbes.com/sites/brucelee/2022/06/30/dr-fauci-takes-2nd-course-of-paxlovid-after-suffering-covid-19-rebound/?sh=4964bf0315d6
https://www.forbes.com/sites/brucelee/2022/06/30/dr-fauci-takes-2nd-course-of-paxlovid-after-suffering-covid-19-rebound/?sh=4964bf0315d6
https://www.cnn.com/2022/07/31/politics/joe-biden-covid-positive-day-two/index.html
https://www.cnn.com/2022/07/31/politics/joe-biden-covid-positive-day-two/index.html
https://health.ucsd.edu/news/releases/Pages/2022-06-21-covid-19-rebound-after-taking-paxlovid-likely-due-to-insufficient-drug-exposure.aspx
https://health.ucsd.edu/news/releases/Pages/2022-06-21-covid-19-rebound-after-taking-paxlovid-likely-due-to-insufficient-drug-exposure.aspx
https://health.ucsd.edu/news/releases/Pages/2022-06-21-covid-19-rebound-after-taking-paxlovid-likely-due-to-insufficient-drug-exposure.aspx
https://health.ucsd.edu/news/releases/Pages/2022-06-21-covid-19-rebound-after-taking-paxlovid-likely-due-to-insufficient-drug-exposure.aspx


Rao, et al   Paxlovid Rebound 
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DHR Proceedings ǀ http://dhrproceedings.org   2022, Vol. 2 No. S3 1-9 5 
 

 

TABLE 1: VARIOUS VARIANTS OF OMICRON SINCE ITS FIRST IDENTIFICATION 

IN NOVEMBER 11, 2022 AND THE FREQUENCY OF PATIENTS INFECTED IN THE 

UNITED STATES AS OF JULY 23, 2022 

 

 

OMICRON Lineage Percentage Of Patients Infected 

BA.1.1 0.0% 

BA.1.1.529 0.0% 

BA.2 0.3% 

BA.2.12.1 5.0% 

BA.4 12.9% 

BA.5 81.9% 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



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FIGURE 1: TIMELINE OF VARIOUS OMICRON LINEAGES CAUSING SARS-COV-2 

INFECTION IN THE UNITED STATES (Adopted From CDC Website): 

https://covid.cdc.gov/covid-data-tracker/#variant-proportions) 

 

 

  

https://covid.cdc.gov/covid-data-tracker/#variant-proportions


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DHR Proceedings ǀ http://dhrproceedings.org   2022, Vol. 2 No. S3 1-9 7 
 

TABLE 2: HOSPITALIZED AND OUTPATIENT TREATMENT OF PATIENTS 

INFECTED WITH THE BA.4 AND BA.5 VARIANTS OF OMICRON 

 

Experimental Drug 
Inpatient  

Vs. Outpatient 

Severity  

Of Disease 
Reference 

Bebtelovimab 

Monoclonal Antibody 

Outpatient Mild to 

Moderate 

https://www.fda.gov/media/156152/download 

Remdesivir (Velkury) Outpatient Mild to 

Moderate 

https://www.fda.gov/news-events/press-

announcements/fda-takes-actions-expand-use-

treatment-outpatients-mild-moderate-covid-19 

Remdesivir + 

Baricitinib (Olumiant) 

Inpatient Severe https://www.fda.gov/news-events/press-

announcements/coronavirus-covid-19-update-

fda-authorizes-drug-combination-treatment-

covid-19 

Ritonavir-boosted 

Nirmatrelvir 

(Paxlovid) 

Outpatient Mild-Moderate https://www.paxlovid.com/?source=bing&HB

X_PK=s_paxlovid&skwid=43700068281647

229&gclid=c926586053d315737f663a86b321

0308&gclsrc=3p.ds  

Malnupiravir 

(Lagevrio) 

Outpatient Mild-Moderate https://www.nejm.org/doi/full/10.1056/NEJM

oa2116044  

EVUSHELDTM 

(Tixagevimab and 

Cilgavimab) 

Outpatient Pre-Exposure 

Prophylaxis in 

High-Risk 

Patients 

https://www.evusheld.com/en/patient  

 

https://www.fda.gov/drugs/drug-safety-and-

availability/fda-authorizes-revisions-

evusheld-dosing  

 

  

https://www.fda.gov/media/156152/download
https://www.fda.gov/news-events/press-announcements/fda-takes-actions-expand-use-treatment-outpatients-mild-moderate-covid-19
https://www.fda.gov/news-events/press-announcements/fda-takes-actions-expand-use-treatment-outpatients-mild-moderate-covid-19
https://www.fda.gov/news-events/press-announcements/fda-takes-actions-expand-use-treatment-outpatients-mild-moderate-covid-19
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19
https://www.paxlovid.com/?source=bing&HBX_PK=s_paxlovid&skwid=43700068281647229&gclid=c926586053d315737f663a86b3210308&gclsrc=3p.ds
https://www.paxlovid.com/?source=bing&HBX_PK=s_paxlovid&skwid=43700068281647229&gclid=c926586053d315737f663a86b3210308&gclsrc=3p.ds
https://www.paxlovid.com/?source=bing&HBX_PK=s_paxlovid&skwid=43700068281647229&gclid=c926586053d315737f663a86b3210308&gclsrc=3p.ds
https://www.paxlovid.com/?source=bing&HBX_PK=s_paxlovid&skwid=43700068281647229&gclid=c926586053d315737f663a86b3210308&gclsrc=3p.ds
https://www.nejm.org/doi/full/10.1056/NEJMoa2116044
https://www.nejm.org/doi/full/10.1056/NEJMoa2116044
https://www.evusheld.com/en/patient
https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-revisions-evusheld-dosing
https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-revisions-evusheld-dosing
https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-revisions-evusheld-dosing


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FIGURE 2: COVID-19 OUTPATIENT THERAPEUTICS CLINICAL DECISION AID 

FOR AGES 12+ YEARS ADULT OR PEDIATRIC PATIENT (AGES 12 AND OLDER 

WEIGHING AT LEAST 40 KG) WITH MILD TO MODERATE COVID-19 AND AT 

HIGH RISK FOR PROGRESSION TO SEVERE DISEASE 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  



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FIGURE 3: COVID-19 OUTPATIENT THERAPEUTICS 18 JULY 2022 CLINICAL 

DECISION AID FOR AGES 28 DAYS TO LESS THAN 12 YEARS PEDIATRIC 

PATIENT (28 DAYS OF AGE TO LESS THAN 12 YEARS, WEIGHING AT LEAST 3 

KG TO LESS THAN 40 KG) WITH MILD TO MODERATE COVID-19 AND AT HIGH 

RISK FOR PROGRESSION TO SEVERE DISEASE 

 

 

 

 

 

 

 

 
 

 

 

 


