To the Editor:
We read with interest a recent article reported by Wang Y et al. 1. The authors reported a case of COVID-19 rebound in a severe COVID-19 patient during long term (20 days) treatment of Paxlovid. Paxlovid is a recommended treatment for mild-moderate COVID-19 and risk factors for severe disease. With wide-spread use of Paxlovid, there have been case reports of individuals experiencing virologic rebound. Hence, meta-analysis of the efficiency and safety of Paxlovid in patients with COVID-19 is of great importance.
An extensive literature search was performed in PubMed, Web of Science, EMBASE, and Cochrane Library to find all for relevant studies published from December 1, 2021, to September 20, 2022. We screened the references of the retrieved studies and restricted the language of the search to English. Following keywords were used in the search: Paxlovid (nirmatrelvir/ritonavir) and COVID-19 (SARS-CoV-2, SARS2, SARS Coronavirus 2, Coronavirus Disease 2019, 2019-nCoV, 2019 Novel Coronavirus). The inclusion criteria were as follows: (1) the article reported the clinical results of Paxlovid, including the total number of participants and the specific number of deaths, hospitalization, rebound or adverse events; (2) English language. The exclusion criteria were as follows: (1) irrelevant to the research direction, (2) no relevant data, (3) case reports, (4) review papers, (5) repeated articles.
The analysis was conducted using the Review Manager statistical software, version 5.3. A binary controlled study was used to calculate the number of deaths, hospitalization, rebound or adverse events. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the effect in a whole random-effects meta-analysis model. The I 2 and P value was used to quantify the heterogeneity of the effects among the included studies.
A total of 13 studies involving 186,306 patients were identified in the final analysis, and the detail of the included studies are shown in Table 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. Three studies described the rebound of COVID-19 patients in Paxlovid group and control group. The overall OR of rebound among COVID-19 patients in the Paxlovid vs. control group was 0.99 (95% CI, 0.28–3.57; I 2 =59%), P = 0.99 (Fig. 1 A). Five studies described adverse events in Paxlovid group and control group. The overall OR of adverse events among COVID-19 patients in the Paxlovid vs. control group was 1.07 (95% CI, 0.49–2.34; I 2 =90%), P = 0.87 (Fig. 1B). There is no significant difference of rebound and adverse events in Paxlovid group and control group.
Fig. 2.
Subgroup analysis: impact of Paxlovid on mortality and hospitalization rates of COVID-19 patients.
Table 1.
Basic information of the included studies.
| Study | Events | Paxlovid Group |
Placebo group |
||
|---|---|---|---|---|---|
| Events (n) | Total (n) | Events (n) | Total (n) | ||
| Dryden-Peterson S, 20222 | Death | 0 | 6036 | 39 | 24,286 |
| Hospitalization | 40 | 6036 | 223 | 24,286 | |
| Ganatra S, 20223 | Death | 0 | 1130 | 10 | 1130 |
| Hospitalization | 10 | 1130 | 23 | 1130 | |
| Hammond J, 20224 | Death | 0 | 697 | 9 | 682 |
| Hospitalization | 5 | 697 | 44 | 682 | |
| Adverse events | 476 | 1109 | 525 | 1115 | |
| Hedvat J, 20225 | Death | 0 | 28 | 3 | 75 |
| Hospitalization | 3 | 28 | 23 | 75 | |
| Pfizer; 20216 | Death | 0 | 607 | 10 | 612 |
| Hospitalization | 6 | 607 | 41 | 612 | |
| Adverse events | 10 | 607 | 40 | 612 | |
| Saravolatz LD, 20227 | Death | 0 | 1039 | 12 | 1046 |
| Hospitalization | 8 | 1039 | 66 | 1046 | |
| Adverse events | 67 | 1039 | 22 | 1046 | |
| Wong CKH, 20228 | Death | 31 | 890 | 83 | 890 |
| Yip TCF, 20229 | Hospitalization | 172 | 4921 | 1931 | 83,154 |
| Dai EY, 202210 | Rebound | 3 | 11 | 1 | 25 |
| Wang L, 202211 | Rebound | 609 | 11,270 | 204 | 2374 |
| Li HY, 202212 | Rebound | 2 | 258 | 3 | 244 |
| Anderson AS, 202213 | Adverse events | 23 | 990 | 17 | 980 |
| Yan GF, 202214 | Adverse events | 2 | 5 | 7 | 30 |
Fig. 1.
Incidence of rebound (A) and adverse events (B) in Paxlovid group and control group.
In addition, we analyze the efficacy of Paxlovid on death and hospitalization for COVID-19 patients. Seven studies described the death of COVID-19 patients in the Paxlovid group and control group, and seven studies described the hospitalization of COVID-19 patients. Our study showed that the overall OR for death and hospitalization among COVID-19 patients in the Paxlovid vs. control group was 0.22 (95% CI, 0.11–0.45; I 2 =93%), P <0.0001. The result indicates that the Paxlovid treatment is effective for patients with COVID-19, reducing the mortality or hospitalization rate by 78% (Fig. 1). Subtype analysis shows that the OR of mortality for COVID-19 patients in the Paxlovid vs. control group was 0.12 (95% CI, 0.04–0.36; I 2 =42%), P = 0.0001, indicating an 88% reduction in mortality. The OR of hospitalization for COVID-19 patients in the Paxlovid vs. control group was 0.32 (95% CI, 0.13–0.75; I2 =95%), P = 0.009, a 68% reduction in hospitalization rate.
In conclusion, our research shows that Paxlovid for COVID-19 is effective and safe. COVID-19 rebound is not unique to Paxlovid. There is no significant difference of rebound in Paxlovid group and control group. There has been more attention to COVID-19 rebounds following Paxlovid treatment, which may be attributable to more people being treated with Paxlovid. However, the phenomenon of rebounds following Paxlovid treatment reinforces the importance of testing for individuals with recurrent symptoms after Paxlovid treatment.
Funding
This work was supported by Science and Technology Fund of Guizhou Health Commission (No.gzwkj2021-024), and the cultivate project 2021 for National Natural Science Foundation of China, Affiliated Hospital of Guizhou Medical University (No.gyfynsfc-2021-14).
Declaration of Competing Interest
All authors report that they have no potential conflicts of interest.
References
- 1.Wang Y., Chen X., Xiao W., Zhao D., Feng L. Rapid COVID-19 rebound in a severe COVID-19 patient during 20-day course of Paxlovid. J Infect. 2022 doi: 10.1016/j.jinf.2022.08.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Dryden-Peterson S., Kim A., Kim A.Y., Caniglia E.C., Lennes I., Patel R., Gainer L., Dutton L., Donahue E., Gandhi R.T., Baden L.R., Woolley A.E. Nirmatrelvir plus ritonavir for early COVID-19 and hospitalization in a large US health system. medRxiv. 2022 doi: 10.1101/2022.06.14.22276393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ganatra S., Dani S.S., Ahmad J., Kumar A., Shah J., Abraham G.M., McQuillen D.P., Wachter R.M., Sax P.E. Oral Nirmatrelvir and Ritonavir in Non-hospitalized Vaccinated Patients with Covid-19. Clin Infect Dis. 2022 doi: 10.1093/cid/ciac673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hammond J., Leister-Tebbe H., Gardner A., Abreu P., Bao W., Wisemandle W., Baniecki M., Hendrick V.M., Damle B., Simon-Campos A., Pypstra R., Rusnak J.M., E.-H. Investigators Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397–1408. doi: 10.1056/NEJMoa2118542. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hedvat J., Lange N.W., Salerno D.M., DeFilippis E.M., Kovac D., Corbo H., Chen J.K., Choe J.Y., Lee J.H., Anamisis A., Jennings D.L., Codispodo G., Shertel T., Brown R.S., Jr., Pereira M.R. COVID-19 therapeutics and outcomes among solid organ transplant recipients during the Omicron BA.1 era. Am J Transplant. 2022 doi: 10.1111/ajt.17140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Mahase E. Covid-19: pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. 2021;375:n2713. doi: 10.1136/bmj.n2713. [DOI] [PubMed] [Google Scholar]
- 7.Saravolatz L.D., Depcinski S., Sharma M. Molnupiravir and Nirmatrelvir-Ritonavir: oral COVID Antiviral Drugs. Clin Infect Dis. 2022 doi: 10.1093/cid/ciac180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wong C.K.H., Au I.C.H., Lau K.T.K., Lau E.H.Y., Cowling B.J., Leung G.M. Real-world effectiveness of early molnupiravir or nirmatrelvir-ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study. Lancet Infect Dis. 2022 doi: 10.1016/S1473-3099(22)00507-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Yip T.C.F., Lui G.C.Y., Lai M.S.M., Wong V.W.S., Tse Y.K., Ma B.H.M., Hui E., Leung M.K., Chan H.L.Y., Hui D.S.C., Wong G.L.H. Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients. Clin Infect Dis. 2022 doi: 10.1093/cid/ciac687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Dai E.Y., Lee K.A., Nathanson A.B., Leonelli A.T., Petros B.A., Brock-Fisher T., Dobbins S.T., MacInnis B.L., Capone A., Littlehale N., Boucau J., Marino C., Barczak A.K., Sabeti P.C., Springer M., Stephenson K.E. Viral Kinetics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron Infection in mRNA-Vaccinated Individuals Treated and Not Treated with Nirmatrelvir-Ritonavir. medRxiv. 2022 doi: 10.1101/2022.08.04.22278378. [DOI] [Google Scholar]
- 11.Wang L., Berger N.A., Davis P.B., Kaelber D.C., Volkow N.D., Xu R. COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022. medRxiv. 2022 doi: 10.1101/2022.06.21.22276724. [DOI] [Google Scholar]
- 12.Li H., Gao M., You H., Zhang P., Pan Y., Li N., Qin L., Wang H., Li D., Li Y., Qiao H., Gu L., Xu S., Guo W., Wang N., Liu C., Gao P., Niu J., Cao J., Zheng Y. Association of nirmatrelvir/ritonavir treatment on upper respiratory SARS-CoV-2 RT-PCR negative conversion rates among high-risk patients with COVID-19. Clin Infect Dis. 2022 doi: 10.1093/cid/ciac600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Anderson A.S., Caubel P., Rusnak J.M., E.-H.T. Investigators Nirmatrelvir-Ritonavir and Viral Load Rebound in Covid-19. N Engl J Med. 2022 doi: 10.1056/NEJMc2205944. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Yan G., Zhou J., Zhu H., Chen Y., Lu Y., Zhang T., Yu H., Wang L., Xu H., Wang Z., Zhou W. The feasibility, safety, and efficacy of Paxlovid treatment in SARS-CoV-2-infected children aged 6-14 years: a cohort study. Ann Transl Med. 2022;10(11):619. doi: 10.21037/atm-22-2791. [DOI] [PMC free article] [PubMed] [Google Scholar]