OPtimisation of Antiviral Therapy in Immunocompromised COVID-19 Patients: a Randomized Factorial Controlled Strategy Trial

Inclusion Criteria: 1. Laboratory confirmed SARS-CoV-2 infection by RT-PCR or positive antigenic test (commercialized assay) 2. Asymptomatic or mild to moderate COVID-19 (WHO progression scale \<5. Patients receiving oxygen therapy for reasons other than a pulmonary COVID-19 are eligible). 3. ≥ 16 years of age (for patients recruited in Italy and in Norway, ≥ 18 years of age); 4. Immunocompromised as defined by ≥ 1 risk factors for severe COVID-19 as assessed by the FOPH list (criteria 5: diseases/treatments leading to immune suppression) or other immunosuppression criteria such as Severe immunosuppression (e.g., HIV infection with CD4 + T cell count \<350 / µl) Neutropenia (\<1000 neutrophils / µl) ≥1 week Lymphocytopenia (\<200 lymphocytes/µl) On dialysis treatment Hereditary immunodeficiencies Intake of drugs which suppress the immune system (e.g. glucocorticoids for a long time \[an equivalent dose of prednisone \>20 mg/day \> 3 months\], monoclonal antibodies, cytostatics, biological products, everolimus, mTOR inhibitors etc.) in the last 12 months Active cancer under cytostatics or targeted therapy known to be immunosuppressive (e.g., platinum salts, cyclophosphamide, anthracyclines, taxanes, 5-fluorouracil, gemcitabine, purine inhibitors, proteasome inhibitors) or associated with hematologic toxicity (neutropenia, lymphopenia), for example sunitinib, imatinib, regorafenib. Aggressive lymphomas (all types) Acute lymphatic leukemia Acute myeloid leukemia Acute promyelocytic leukemia T prolymphocytic leukemia Primary central nervous system lymphoma Stem cell transplantation Light chain amyloidosis Chronic lymphoid leukemia Multiple myeloma Sickle cell disease Bone marrow transplant Organ transplant Being on the waiting list for an organ transplant 5. Willing and able to comply with study requirements and restrictions as described in the informed consent form (ICF) 6. Enrolled in or a beneficiary of a Social Security program (State Medical Aid (AME) is not a Social Security program) or holders of health insurance (LAF for participants recruited in Norway). 7. Participant's or its legal representative's signature of the informed consent form Exclusion Criteria: 1. SARS-CoV-2 PCR ≥30 CT at screening 2. Hypersensitivity to study drugs (active substance(s) or excipients) 3. Body weight \< 40 kg 4. AST and/or ALT \> 5 times the upper limit 5. Cirrhosis Child-Pugh score C 6. Is taking or is anticipated to require any prohibited therapies\*. 7. Participation in another interventional clinical study with an investigational compound or device, including COVID-19 therapeutics, where the study intervention is performed in the 28 days preceding the inclusion and the 10 days after the inclusion. Investigators of the different clinical studies should agree on participant's inclusion. 8. Presence of any condition for which, in the opinion of the investigator, participation would not be in participant's best interest or that could prevent, limit, or confound the protocol-specified assessments 9. Having received antiviral treatments against SARS-CoV-2 in the 14 days before the inclusion with exception of those having received one or two doses of nirmatrevir/r in the 24h preceding the inclusion in the study. 10. Pregnant or breastfeeding female * Study SOPs based on recommendations from the Liverpool COVID-19 interactions, French Society for Pharmacology and Therapeutics (https://sfpt-fr.org/recommandations-et-publications) and French Speaking Transplantation Society will be provided to guide investigators.