COVID rebound common, does not differ after VV116 vs nirmatrelvir–ritonavir treatment

Many patients with mild-to-moderate COVID-19 experience a resurgence of the virus as well as symptoms after a standard 5-day course of treatment with either VV116 or nirmatrelvir–ritonavir, as shown in a study from China.

In a cohort of 345 nonhospitalized patients (mean age 53.2 years, 50.7 percent men, 92.8 percent vaccinated) infected with the Omicron variant, viral load rebound rates were 20.0 percent in the VV116 arm and 21.7 percent in the nirmatrelvir–ritonavir arm, with no significant difference (p=0.70). [JAMA Netw Open 2024;7:e241765]

Likewise, symptom rebound rates were high and similar between the VV116 and nirmatrelvir–ritonavir arms (25.6 percent vs 24.5 percent; p=0.82).

A half-log increase in viral RNA copy numbers per mL at any point after treatment and a more than 2-point increase in symptom score from day 6 were considered a viral load and symptom rebound, respectively. The investigators noted a lack of consensus definition of COVID-19 rebound across studies. Nevertheless, comparable rebound rates were obtained between the VV116 and nirmatrelvir–ritonavir arms regardless of how rebound was defined in the current study, they added.

For example, the rates of viral rebound as defined by a half-log increase from the nadir viral load after treatment completion were 22.4 percent and 23.3 percent (p=0.84). Meanwhile, the rates of symptom rebound were 8.1 percent and 8.6 percent (p=0.88) when defined by an increase of more than 7 points (approximately 10 percent of the maximum score of 69) and 47.3 percent and 45.0 percent (p=0.67) when defined by an increase of more than 2 points in symptom score in the preceding time points after treatment completion.

“Therefore, using alternative definitions for COVID-19 rebound did not change the conclusions,” the investigators said. They also highlighted that none of the patients had disease progression due to rebound, despite the high rebound rates.

Genetic analysis of the virus in 24 rebound cases showed that the lineage of variant genomes was identical at baseline and at rebound in each case. Additionally, there was no known drug resistance mutations found in the NSP5 gene in the nirmatrelvir–ritonavir arm or in the NSP12 gene in the VV116 arm.

“This study adds important evidence of COVID-19 rebound after antiviral treatment in mostly vaccinated patients with COVID-19 who were infected with Omicron variants,” according to the investigators.

Study details

Of the patients included in the study, 165 received VV116 tablets and 180 received 300-mg nirmatrelvir plus 100-mg ritonavir tablets. VV116 was administered at 600 mg every 12 hours on day 1 and at 300 mg every 12 hours on days 2 through 5, while nirmatrelvir–ritonavir was administered every 12 hours for 5 days. All patients were followed up every other day until day 28 and every week until day 60.

The median time to viral load rebound since treatment completion was 8 days in the VV116 arm and 10 days in the nirmatrelvir-ritonavir arm (p=0.47). Viral load rebound rates were consistently similar between the two treatment arms within 14, 21, or 28 days after treatment completion.

In a post hoc analysis, patients 60 years of age or older had 164-percent greater odds of having viral load rebound than those who were younger than 40 years (odds ratio, 2.64, 95 percent confidence interval, 1.21–5.75).

As for safety, two patients in the VV116 arm and six in the nirmatrelvir–ritonavir arm discontinued treatment due to adverse effects including nausea, vomiting, diarrhoea, and discomfort in the stomach. Four and six patients in the respective groups were hospitalized for serious adverse events, none of which were deemed related to the study treatment. One patient in the VV116 arm died during the study period. This patient was admitted due to severe COVID-19 shortly after recruitment and before starting treatment.

The takeaway from this study is that rebound is not unique to nirmatrelvir–ritonavir and may be associated with a persistent viral infection in the patients treated with either nirmatrelvir–ritonavir or VV116, the researchers pointed out. “This finding was proved by viral full-genome sequencing showing the same lineage in sample pairs at baseline and at rebound.

“Therefore … viral load rebound could occur in patients with inadequate viral clearance. An insufficient drug exposure or insufficient duration of drug treatment is likely to result in incomplete viral clearance and, therefore, contribute to COVID-19 rebound, especially in participants with potentially reduced innate immune responses such as older patients, which was demonstrated in the post hoc analysis of the current trial,” they added. [medRxiv 2022;doi:10.1101/2022.06.21.22276724]