The overall purpose of the trial is to evaluate the efficacy and safety of possible combination antiviral therapy direct antiviral agents (remdesivir + nirmatrelvir/r) versus the reference monotherapy (nirmatrelvir/r alone) and to assess the efficacy and safety of increasing the nirmatrelvir/r course from 5- to 10 days in immunocompromised patients diagnosed with asymptomatic or mild to moderate Coronavirus Disease 2019 (COVID-19).

This is a randomized, controlled, factorial, superiority trial to evaluate the viral efficacy of direct antiviral agent nirmatrelvir/r + direct antiviral agent remdesivir versus nirmatrelvir/r alone and of 5 days versus 10 days of nirmatrelvir/r in immunocompromised patients diagnosed with asymptomatic or mild to moderate COVID-19. The primary objective is to assess whether (i) a combination antiviral therapy of two antiviral agents (nirmatrelvir/r + remdesivir and/or (ii) an increase in nirmatrelvir/ r duration from 5 to 10 days improves viral efficacy by decreasing the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 2) positivity rate by real time polymerase chain reaction (RT-PCR) (cycle threshold CT<32) in nasopharyngeal swabs at day 10 (D10). Patients will be eligible if they are immunocompromised, have confirmed asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19, regardless of symptoms onset, provided that they have no contra-indication to any of the study drugs. A total of 256 patients will be recruited in Switzerland and in France, Italy and Norway (through the parallel protocol ANRS0176s OPTICOV).

Participants not eligible for randomisation or who refuse to participate to the trial for any reason will be proposed to be included in an exploratory non comparative cohort (maximum 97 participants, active only in Switzerland).

Inclusion Criteria:

1. Laboratory confirmed SARS-CoV-2 infection by real time 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;

4. Immunocompromised as defined by ≥ 1 risk factors for severe COVID-19 as assessed by the Federal Office of Public Health (FOPH) list (criteria 5: diseases/treatments leading to immune suppression) or other immunosuppression criteria such as:

   • Severe immunosuppression (e.g., human immunodeficiency virus (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.

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 (Aspartate transaminase) and/or alanine transaminase (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

Individual Participant Data are described in the study protocol