TABLE 2. Summary of seven SARS-CoV-2 rebound studies among persons who did and did not receive antiviral treatment with nirmatrelvir/ritonavir or molnupiravir — February 1, 2020–November 29, 2023*.
| Study author, year | Study type | Definition of rebound | Sample size | Treatment | Rebound prevalence, % (no./No.) |
p-value | Study conclusions and key limitations | |
|---|---|---|---|---|---|---|---|---|
| With treatment | Without treatment | |||||||
| Anderson et al., 2022† |
RCT |
0.5-log increase in viral load on day 10 or day 14 if only one value was available or on days 10 and 14 if both values were available |
2,216 |
N/R |
2.3 (23/990) |
1.7 (17/980) |
0.34 |
Similar incidence of viral load rebound in N/R and placebo groups |
| Viral load rebound not retrospectively associated with low nirmatrelvir exposure; recurrence of moderate to severe symptoms, or development of nirmatrelvir resistance | ||||||||
| Limitations: only unvaccinated persons included in study, conducted during pre-Omicron period, viral load determined by PCR, does not translate directly to the presence of infectious virus, and is not perfectly correlated with current or new clinical symptoms | ||||||||
| Edelstein et al., 2023§ |
PC |
Def 1: a positive SARS-CoV-2 viral culture result after a previous negative test result |
127 |
N/R |
21 (15/72) |
2 (1/55) |
0.001 |
Viral rebound associated with N/R use |
| Def 2: combination of a nadir viral load below 4.0 log10 copies/mL followed by an increase in viral load that was ≥1.0 log10 copies/mL above the nadir, and two consecutive viral load results of 4.0 log10 copies/mL or higher |
Limitations: not RCT; significant differences between those taking N/R and untreated persons (e.g., number of COVID-19 vaccinations, older, and immunosuppression) |
|||||||
| Pandit et al., 2023¶ |
PC |
Positive rapid antigen test result after a negative antigen test result and symptom rebound |
N/R = 127; control = 43 |
N/R |
14 (18/127) |
9 (4/43) |
0.41 |
Rebound after clearance of test result positivity or symptom resolution is higher than previously reported |
| Limitations: not RCT | ||||||||
| Smith-Jeffcoat et al., 2023** |
Prospective/propensity score matching |
Symptom rebound was defined as an increase of at least two symptoms any time after treatment completion or proxy. Viral load rebound was defined as an increase of ≥1 log10 IU/mL (increasing to or above 5.0 log10 IU/mL) any time after treatment |
1,234 |
N/R |
Symptom rebound: 32 (41/130) |
Symptom rebound: 20 (47/241) |
0.009 |
Patients completing N/R treatment experienced fewer symptoms and lower viral load but rebound occurred more often compared with untreated persons; providers should prescribe N/R, when indicated, and communicate rebound risk to patients |
| Viral load rebound: 27 (26/130) |
Viral load rebound: 7 (12/241) |
<0.001 |
Limitations: not RCT; daily symptoms and viral load were only available for 10 days after enrollment; unmeasured differences between N/R-treated and untreated participants |
|||||
| Tadmor et al., 2023†† |
RC (EMR) |
Positive PCR test result after negative test result |
331 |
N/R |
9.0 (8/89) |
3.6 (8/219) |
0.05 |
Higher incidence of rebound in patients with CLL treated for SARS-CoV-2 with N/R or molnupiravir compared with nontreated CLL patients or nonleukemia high-risk patients |
| molnupiravir |
8.7 (2/23) |
0.24 |
Limitations: not RCT |
|||||
| Wong et al., 2023§§ |
RC |
Reduction in Ct value (≥3) on quantitative RT-PCR test between 2 consecutive measurements, with decrease sustained in an immediately subsequent Ct measurement (for those patients with ≥3 Ct measurements) |
4,592 |
N/R |
6.6; 95% CI = 4.1–10.5 (6/242) |
4.5; 95% CI = 3.9–5.2 (170/3,787) |
0.13 |
Viral rebound rates were similar between patients with and without antiviral treatment |
| molnupiravir |
4.8; 95% CI = 3.3–6.9 (27/563) |
0.75 |
Viral burden rebound not associated with adverse clinical outcomes |
|||||
| Limitations: not RCT | ||||||||
| Wong et al., 2022¶¶ | RC | Def 1: Ct >40, decreased to ≤40 |
12,629 | N/R |
Def 1: N/R: 1.0 |
Def 1: 0.6 |
Def 1: 0.56 |
Low incidences of viral rebound in molnupiravir users, N/R users, and antiviral nonusers among patients with COVID-19 |
| Def 2: Ct >36, decreased to ≤36 |
Def 2: N/R: 4.6 |
Def 2: 4.4 |
Def 2: 0.95 |
Viral rebound is not associated with higher mortality in antiviral users |
||||
| Def 1: Ct>40, decreased to ≤40 |
molnupiravir | Def 1: molnupiravir: 0.8 |
Def 1: 0.6 |
Def 1: 0.56 |
||||
| Def 2: Ct >36, decreased to ≤36 | Def 2: molnupiravir: 4.6 | Def 2: 4.4 | Def 2: 0.95 | Limitations: not RCT | ||||
Abbreviations: CLL = chronic lymphocytic leukemia; Ct = cycle threshold; Def = definition; EMR = electronic medical records; N/R = nirmatrelvir/ritonavir; PC = prospective cohort; RC = retrospective cohort; RCT = randomized controlled trial; RT-PCR = real-time polymerase chain reaction.
* From PubMed, JSTOR, and Google Scholar databases, 303 publications published during February 1, 2020–November 29, 2023, were identified; nine duplicate citations were removed. Among the 294 abstracts reviewed, 229 irrelevant abstracts were removed (i.e., not COVID-19–related or examined another aspect of COVID-19). Among the 65 relevant publications determined to be eligible for detailed review, 42 publications were removed because they did not meet inclusion criteria (i.e., preprints, editorials, case reports, or studies of ancillary medications). Overall, 23 publications were included in the review including these seven publications that compared rates of rebound among persons with and without use of COVID-19 antivirals.
† https://doi.org/10.1056/NEJMc2205944
§ https://doi.org/10.7326/M23-1756
¶ https://doi.org/10.1093/cid/ciad102
** https://doi.org/10.1093/cid/ciad696
†† https://doi.org/10.1080/10428194.2023.2183732