High-titer convalescent plasma plus nirmatrelvir/ritonavir treatment for non-resolving COVID-19 in six immunocompromised patients

Abstract

Objectives: Immunocompromised patients have an increased risk of severe or prolonged COVID-19. Currently available drugs are registered to treat COVID-19 during the first 5 to 7 days after symptom onset. Data on the effectivity in immunocompromised patients with chronic non-resolving COVID-19 are urgently needed. Here, we report the outcome of patients treated with nirmatrelvir/ritonavir together with high-titer convalescent plasma (CP) in six immunocompromised patients with non-resolving COVID-19.

Methods: Immunocompromised patients with persisting COVID-19 (positive PCR with Ct values <30 for ≥20 days) received off-label therapy with nirmatrelvir/ritonavir. It was combined with CP containing BA.5 neutralizing titers of ≥1/640 whenever available. Follow-up was done by PCR and sequencing on nasopharyngeal swabs on a weekly basis until viral genome was undetectable consecutively.

Results: Five immunocompromised patients were treated with high-titer CP and 5 days of nirmatrelvir/ritonavir. One patient received nirmatrelvir/ritonavir monotherapy. Median duration of SARS-CoV-2 PCR positivity was 70 (range 20-231) days before nirmatrelvir/ritonavir treatment. In four patients receiving combination therapy, no viral genome of SARS-CoV-2 was detected on day 7 and 14 after treatment while the patient receiving nirmatrelvir/ritonavir monotherapy, the day 7 Ct value increased to 34 and viral genome was undetectable thereafter. Treatment was unsuccessful in one patient. In this patient, sequencing after nirmatrelvir/ritonavir treatment did not show protease gene mutations.

Conclusions: In immunocompromised patients with non-resolving COVID-19, the combination of nirmatrelvir/ritonavir and CP may be an effective treatment. Larger prospective studies are needed to confirm these preliminary results and should compare different treatment durations.

Figure 1.

Timeline on viral load and treatment in immunocompromised patients with persisting COVID-19. From left to right and from above to below, this represents patients 1 to 6 as described in Table 1 and Supplemental Data S1. Day 0 is the first positive SARS-CoV-2 test: if this test was not performed in the hospital (e.g. antigen test) than no Ct value was reported; however, these days also count as the time of follow-up. The grey dots represent the Ct values of the PCR test performed on a nasopharyngeal swab. The blue dot represents the timing of treatment with tixagevimab/cilgamab. The yellow dot represents the timing of treatment with CP. The green dot represents the timing of nirmatrelvir/ritonavir and CP combination therapy and the red dot represents treatment with nirmatrelvir/ritonavir monotherapy. The vertical black line represents the start of follow-up (day 0) and is also the Ct value scale that ranges from 15 to 45 (no lower Ct values were reported during follow-up). The horizontal black line represents the threshold for which patients had a Ct value above 32 and for which isolation may be halted. According to the local protocol, virological follow-up was halted if the Ct value exceeded 32; however, since viral rebound is reported after treatment with nirmatrelvir/ritonavir, we advise to perform follow-up until viral genome was undetectable twice.