Efficacy and safety of antiviral therapies for the treatment of persistent COVID-19 in immunocompromised patients since the Omicron surge: a systematic review.

Background: Persistent COVID-19 (pCOVID-19) in immunocompromised patients is characterized by unspecific symptoms and pulmonary infiltrates due to ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication. Treatment options remain unclear, leading to different approaches, including combination therapy and extended durations. The purpose of this study was to assess the efficacy and safety of antiviral therapies for pCOVID-19 in immunocompromised patients since the Omicron surge.

Methods: We searched MEDLINE and Scopus from 1 January 2022 to 6 August 2024 for cohort studies and case series on nirmatrelvir/ritonavir, remdesivir, ensitrelvir and molnupiravir. Evidence certainty was rated using Grading of Recommendations Assessment, Development, and Evaluation for outcomes including viral clearance, recurrence/relapse, mortality, adverse events (AEs) and symptom resolution.

Results: Thirteen studies involving 127 cases were included. Evidence certainty was very low. In combination therapy with at least two direct antiviral agents, viral clearance was 79%, with a 16% recurrence rate. All-cause mortality was 9%, and mortality was 6% while SARS-CoV-2 positive. In 47 cases, AEs were reported in 11%. Symptom resolution ranged from 3 to 6 days in two studies. In combination therapy with one direct antiviral agent and passive immunization, viral clearance was 89%, with an 11% recurrence rate and no deaths. In four documented cases, no AEs were observed. In monotherapy, viral clearance was 100%, with a 15% recurrence rate. One death, unrelated to SARS-CoV-2, occurred. In 12 documented cases, no AEs were observed.

Conclusions: Based on very low certainty evidence, combining one direct antiviral with passive immunization resulted in high rates of viral clearance and few recurrences. AEs occurred in cases treated with at least two direct antivirals. Controlled studies are needed.