The Relapse Phenomenon in Mild COVID Treated With Nirmatrelvir/Ritonavir in an Immunocompetent Patient

A 44-year-old female patient first tested positive for SARS-CoV-2 via nasal swab in April 2022. The patient had received two vaccinations and two booster jabs (2 × Comirnaty/Spikevax); the last vaccination had been administered in October 2021. Vaccination success had been serologically verified by an anti-spike IgG assay following the booster jab (anti-receptor binding domain [RBD] IgG antibody—Abbott SARS-CoV-2 IgG-II Quant Kit, Abbott Alinity i platform). A value above the detection limit (> 11,360.0 BAU/mL) was documented. At 1 week prior to the positive SARS-CoV-2 PCR test, a repeat determination had still shown a high value of 7839.6 BAU/mL.

The Ct (cycle threshold) value, which inversely correlates with the viral load, was 24,0 at the time of initial detection (target: ORF region, cobas, SARS-CoV-2 test). By means of whole genome sequencing (Oxford Nanopore Technologies), Omicron variant BA.1.1 was detected in this sample. On the same day, the patient developed chills, muscle pain, and fever. In view of the risk of severe disease due to a congenital heart defect in this immunologically healthy patient, treatment with nirmatrelvir/ritonavir was initiated on the third day following symptom onset. Ritonavir-boosted nirmatrelvir was approved as an outpatient treatment option for COVID-19 “under specific conditions” in the European Union in January 2022. It can be used in adults not requiring supplemental oxygen and who are at greater risk of developing severe COVID (1). The treatment is administered orally over 5 days.

Thereupon, symptoms initially improved. Treatment was discontinued prior to administration of the final single dose due to pronounced gastrointestinal adverse drug reactions involving tenesmus and diarrhea.

On day 7 following initial detection, the Ct value was 35.3. Therefore, the patient was able to resume her everyday personal and work life as a healthcare professional (2). With the exception of fatigue, no further symptoms were observed during that time. An antigen test (Newgene SARS-CoV-2 antigen rapid test, Newgene Bioengineering) was negative on day 9 following initial detection. A repeat antibody test at that time showed a slight increase compared to the previous result (8519.7 BAU/mL). Simultaneously, interferon-gamma release assay (Quan-T-Cell SARS-CoV-2, Euroimmun Medizinische Labordiagnostika AG) detected a SARS-CoV-2-specific T-cell response of > 2394 mIU/mL.

However, on day 10 following initial detection, the patient tested positive on a rapid antigen test (SD Biosensor, Roche Diagnostics). Furthermore, a significantly higher viral load was detected in a nasopharyngeal swab (Ct value N2 gene 21.2, Xpert Xpress SARS-CoV-2, Cepheid) (Figure). In this sample, too, whole-genome sequencing detected variant BA.1.1, with no change in sequence from the previous result. Reinfection with the same variant was unlikely, given that there had been no contact with household members that were also infected. A relapse was also seen in terms of symptoms, with renewed onset of a sensation of cold, chills, rhinitis, headache, and diarrhea.

Figure

Time course of relapse phenomenon

These symptoms resolved spontaneously after a few days. On day 12 following symptom onset, an anti-spike IgG antibody test showed an increase to > 11,360.0 BAU/mL.

Conclusion

A few days following discontinuation of nirmatrelvir/ritonavir treatment, there was a rebound in respiratory viral load, and COVID-19-typical symptoms reappeared. Reinfection with another (sub-)variant was excluded by whole genome sequencing. It is possible that in this case, the pharmacologically induced reduction in viral load suppressed or delayed an adequate immune response that would permanently eliminate the virus. This may have been promoted by the premature discontinuation of treatment.

The rebound in viral load and renewed symptom onset in this individual case may have also led to renewed infectiosity (3), given that the criteria for ending isolation had already been met. This may have had an impact on public health. When prescribing nirmatrelvir/ritonavir, patients should be made aware of the possibility of this phenomenon, which has also been reported in other publications (3, 4).

In the case of a re-emergence of COVID-19-typical symptoms following the end of treatment, retesting should be initiated and a reduction in contacts recommended until results are obtained.

Sebastian Hoehl, Tuna Toptan, Holger F. Rabenau, Sandra Ciesek

Conflict of interest statement
The authors declare that no conflict of interests exists.

Manuscript received on 25 May 2022, revised version accepted on 30 June 2022.

Translated from the original German by Christine Rye.

Cite this as:
Hoehl S, Toptan T, Rabenau HF, Ciesek S: The relapse phenomenon in mild COVID treated with nirmatrelvir/ritonavir in an immunocompetent patient. Dtsch Arztebl Int 2022; 119: 619–20. DOI: 10.3238/arztebl.m2022.0267

References

1. European Medicines Agency: Paxlovid Annex i Summary of product characteristics. www.ema.europa.eu/en/documents/product-information/paxlovid-epar-product-information_en.pdf (last accessed on 10 May 2022).

2. RKI – Coronavirus SARS-CoV-2 – Empfehlungen zu Isolierung und Quarantäne bei SARS-CoV-2-Infektion und -Exposition, Stand 2.5.2022. www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Quarantaene/Absonderung.html#:~:text=Die%20Vorgaben%20des%20RKI%20f%C3%BCr,2022%20ist%20im%20Archiv%20abrufbar. (last accessed on 17 May 2022).

3. Carlin AF, Clark AE, Chaillon A, et al.: Virologic and immunologic characterization of COVID-19 recrudescence after Nirmatrelvir/Ritonavir treatment. Clin Infect Dis 2022; ciac496. doi: 10.1093/cid/ciac496. Online ahead of print

4. Charness M, Gupta K, Stack G, et al.: Rapid relapse of symptomatic omicron SARS-CoV-2 infection following early suppression with Nirmatrelvir/Ritonavir. www.doi.org/10.21203/rs.3.rs-1588371/v3