The trial will test if two repurposed HIV antivirals can reduce symptom burden in adult participants with Long Covid compared to placebo. Viral infection and viral reactivation have been documented in Long Covid.

Participants will be randomly allocated to receive antivirals, Truvada (tenofovir disoproxil/emtricitabine, TDF/FTC, Group 1) or Selzentry (Group 2), or a placebo (pill) (Group 3), taken daily for 90 days.

Inclusion Criteria:

• Provision of signed and dated informed consent form

• Stated willingness to comply with all study procedures and availability for the duration of the study

• Any gender, aged 18+

• Diagnosed with:

  • Long Covid
  • Documented clinical history of confirmed or suspected acute SARS-CoV-2 infection a minimum of 6 months prior to contact with the study team
  • Formal diagnosis of Long Covid from a physician and a history of 6 months of Long COVID symptoms

• At least a six-month history of one of the following symptoms following SARS-CoV-2 infection:

  • headache, memory loss, insomnia, mood disturbance, chest pain, palpitations, shortness of breath, cough, muscle pains, joint pains, or GI upset] AND at least moderate fatigue (measured by Fatigue Severity Score) AND at least moderate post-exertional malaise (PEM) (measured by DePaul PEM screener)

• Participants who are willing and able to comply with all data collection, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.

• Baseline EQ-VAS ≤70; EQ-VAS before the index infection ≥80 (this information is collected before randomization as part of the baseline survey).

Exclusion Criteria:

• Pre-existing conditions including, but not limited to:

  • Autoimmune conditions such as Chronic EBV, Multiple Sclerosis, Hashimoto's Disease, etc. which would impact the immunological profiling analysis.
  • A pre-2020 diagnosis of another Post-Acute Infectious Syndrome such as Chronic Lyme disease, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, etc.
  • Documented history of vaccine injury
  • Or any other chronic condition that has the potential to impact on immunological profiling, at the discretion of the research physician

• HIV+ status

• Current use of either Truvada or Selzentry

• Taking a medication, within 6 weeks, with known interactions with Truvada or Selzentry including but not limited to: Acyclovir, valacyclovir, adefovir, cabozantinib, carbamazepine, cidofovir, cladribine, cobicistat, diclofenac, multiple NSAIDs or chronic high dose NSAIDs, fosphenytoin or phenytoin, ganciclovir, valganciclovir, oxcarbazepine, phenobarbital, primidone, rifabutin, rifampin, rifapentine, sofosbuvir, tipranavir, or other drugs that significantly affect renal function

• Current treatment with drugs known to affect EBV replication, including but not limited to: Acyclovir, valacyclovir, ganciclovir, valganciclovir, famciclovir, teriflunomide, interferon

• Known allergic reactions to components of Truvada or Selzentry

• Febrile illness within the last 3 months of planned baseline evaluation

• Treatment with another investigational drug or other investigational intervention within 6 months of planned baseline evaluation

• Immunosuppressed individuals (transplant on antiviral prophylaxis and/or patients taking immunosuppressive medications such as steroids, etc.)

• Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic or active hepatitis B or C infection, primary biliary cirrhosis, Child-Pugh Class B or C, or acute liver failure

• Receiving dialysis or have known renal impairment

• Any comorbidity requiring hospitalization and/or surgery within 7 days prior to study entry, or that is considered life threatening within days prior to study entry, as determined by the study team

• Other medical or psychiatric conditions, in the treating investigator's judgment, that makes the participant inappropriate for the study

• Unknown HIV status (subjects must have completed HIV antigen/antibody and viral load testing completed at the screening visit)

• Active or latent hepatitis B (subjects must have completed HBV serologies - HbsAg, anti-HBs, and anti-HBc - testing completed at the screening visit)

• Current symptoms of severe, progressive, or uncontrolled renal, hematologic, gastrointestinal, pulmonary, cardiac, or neurologic disease, or other medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study

• Creatinine clearance (CrCl) <75mL/min, as calculated by the Cockcroft-Gault equation

• Any history of bone fractures not explained by trauma

• Confirmed Grade 2 or greater hypophosphatemia

• Any Grade 2 or greater toxicity on screening tests and assessments