Efficacy of sotrovimab for persistent coronavirus disease-2019 in a severely immunocompromised person living with HIV

Abstract

Long-term persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication has been reported in immunocompromised patients, probably because of their inadequate adaptive immune response and noneffective viral clearance [1–3]. These persistent infections are usually characterized by intermittently detectable SARS-CoV-2 RNA, prolonged isolation of replicative virus by virus culture and a within-patient virus evolutionary trajectory marked by accumulation of an unusually high number of mutations [1,2,4,5]. At present, there is a lack of knowledge about the optimal treatment for persistent COVID-19 as immunosuppressed participants have been systematically excluded from clinical trials [5]. Repeated cycles of remdesivir [6], convalescent plasma [7] and neutralizing monoclonal antibody (REGN-COV2) therapy [8] has been used to treat immunocompromised patients with persistent COVID-19. Here, we describe treatment with Sotrovimab of a severely immunocompromised patient with persistent coronavirus disease 2019 (COVID-19). Our patient is a 30-year-old man who was diagnosed with HIV infection in 2015 with a nadir of CD4+ count 662 cells/μl and was treated with Abacavir/Lamivudine/Dolutegravir, subsequently switched to Lamivudine/Dolutegravir in January 2020. He has maintained undetectable HIV-1 viral load since 2015. On October 2020, he was also diagnosed with diffuse large B-cell lymphoma. He had received frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone) followed by salvage therapy with R-ICE (rituximab, ifosfamide, carboplatin and etoposide) and CAR-T-cell therapy in April 2021 because of refractory disease. He had never been vaccinated against COVID-19. On 27 May 2021 (day 1 of symptoms), the patient developed general malaise, and COVID -19 infection was diagnosed by a real-time PCR (RT-PCR) test in a nasopharyngeal swab sample. Sequencing of the nasopharyngeal sample revealed alpha variant, with an RT-PCR cycle threshold (Ct) values of 20 and 23. At that moment, he did not have dyspnea or fever and chest X-ray did not reveal pneumonia. On that date, antiretroviral treatment was modified to tenofovir disoproxil fumarate/emtricitabine, lopinavir and ritonavir, in an attempt to use drugs with possible, although unproven, efficacy for COVID-19 in the HIV population [9]. He maintained HIV virological control, although severe immunosuppression with CD4+ count 49 cells/μl (normal range 500–1500 cells/μl, 30–60%). On 1 July 2021 (day 36), the patient was admitted to the COVID-19 hospitalization ward because of bilateral pneumonia. Oxygen saturation was 96% at ambient air. Chest computed tomography revealed disseminated ground-glass opacities. On 8 July, he presented respiratory worsening, needing supplemental oxygen with nasal canula at 3 l/min. A RT-PCR for SARS-CoV-2 in blood was positive with a Ct value of 37. A RT-PCR test in a sample from nasopharyngeal swab remained positive and SARS-CoV-2 alpha variant was again detected. A RT-PCR test from bronchoalveolar lavage showed Ct values of 24 for the N gene and 22 for the ORF gene. Corticosteroids (prednisone 30 mg twice daily), remdesivir for 10 days and hyperimmune convalescent plasma were prescribed, with respiratory improvement in the following days and negativization of SARS-CoV-2 RT-PCR in plasma and blood. However, a sample from a nasopharyngeal swab remained SARS-CoV-2 positive with a Ct value of less than 30. Meanwhile, a PET-CT scan showed progression of lymphoma, and polatuzumab vedotin, rituximab and bendamustine were initiated. The patient improved clinically and could be discharged from the hospital. The patient maintained a low-grade fever and pulmonary infiltrates with persistently positive SARS-CoV-2 RT-PCR in nasopharyngeal samples, with low Ct values on days 54, 62 and 67. In addition, viral culture from a nasopharyngeal sample was positive at day 54, and SARS-CoV-2 IgG serology was positive (Table 1). Because of the persistent COVID-19 and the concomitant chemotherapy treatment on 18 August (day 83), we initiated the monoclonal antibody Sotrovimab through a compassionate use program. Two weeks after initiation of Sotrovimab, the patient became afebrile and clinically improved. On day 99, despite severe immunosuppression [CD4+ 97 cells/μl (6%)], nasopharyngeal swab RT-PCR was negative and subsequent nasopharyngeal swab RT-PCR remained negative on days 100, 114 and 131. Table 1 - Timeline of clinical presentation, diagnostic tests and treatments. Results Day of illness Date Sample Gene E Gene N Gene S Gene ORF Treatment 1 27 May 21 NP RT-PCR + 20.6 23.1 29 24 June 21 NP RT-PCR + 33.3 32.6 36 1 July 21 NP RT-PCR + 34.8 33 Prednisone 30 mg twice daily 37 2 July 21 SERUM - 39 4 July 21 NP RT-PCR + 31.3 30.1 30 Remdesivir (10 days course) and hyperimmune plasma 42 7 July 21 BAL RT-PCR + 24.1 22.6 47 12 July 21 NP RT-PCR + 35.5 36.7 50 15 July 21 Plasma RT-PCR - Blood RT-PCR + 37 52 17 July 21 NP RT-PCR + 28.6 28.7 28.8 54 19 July 21 NP RT-PCR + 25.7 25.2 Viral culture + 57 22 July 21 Plasma RT-PCR - Blood RT-PCR - 62 27 July 21 NP RT-PCR + 23.7 22.8 67 1 August 21 NP RT-PCR + 23.3 25.6 68 2 August 21 SERUM + 70 4 August 21 NP RT-PCR + 27.8 26.7 77 11 August 21 NP RT-PCR + 29.4 29.1 79 13 August 21 NP RT-PCR + 28.2 27.6 28.6 84 18 August 21 NP RT-PCR + 29.2 29.9 Sotrovimab 87 21 August 21 NP RT-PCR + 33.3 30.9 92 26 August 21 NP RT-PCR + 30 30.6 99 2 September 21 NP RT-PCR - BAL RT-PCR - 100 3 September 21 NP RT-PCR - 114 17 September 21 NP RT-PCR - 131 4 October 21 NP RT-PCR - BAL, bronchoalveolar lavage; NP, nasopharyngeal; RT-PCR, real-time PCR. To the best of our knowledge, this is the first case of persistent COVID-19 in a severely immunosuppressed patient treated with the monoclonal antibody Sotrovimab. Although follow-up is relatively short (48 days) since the initiation of Sotrovimab, we have not been able to detect SARS-CoV-2 by RT-PCR in nasopharyngeal swabs. Sotrovimab is an appealing monoclonal antibody for the treatment of persistent COVID-19 in immunosuppressed patients because of its efficacy regardless of the SARS-CoV-2 variant, its higher barrier to resistance as a result of targeting a pan-sarbecovirus epitope, and its long terminal half-life of approximately 49 days [10]. We believe that further studies of Sotrovimab for the treatment of persistent COVID-19 in immunosuppressed patients are warranted. Acknowledgements The authors thank the patient and his family. We would also like to thank the healthcare workers and laboratorians at Hospital Universitario La Paz. Funding: This study was carried out as part of our routine work. R.M. is supported by Instituto de Salud Carlos III (JR18/00039). Conflicts of interest There are no conflicts of interest.

Topics & Concepts