Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy (ART)

Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy

The purpose of this study was to find out about the safety of sirolimus in individuals with HIV infection who were also being treated with ART. The investigators wanted to learn whether sirolimus decreases inflammation and immune activation in the body; whether sirolimus changes the level of HIV in the participants' blood; and how sirolimus interacts with ART in the blood. Sirolimus is approved by the Food and Drug Administration (FDA) to prevent organ rejection in patients aged 13 years and older receiving kidney transplants. Sirolimus had also been used for the prevention of complications after stem cell transplants and as a treatment for certain kinds of cancers in HIV-infected patients.

The study was conducted with an initial lead-in period of 12 weeks where participants remained on ART, without study intervention. Samples were collected to define the pre-intervention steady-state of HIV, inflammation and immune activation parameters.

At week 12, sirolimus therapy was initiated for the planned 20 weeks of treatment. In order to achieve therapeutic levels, sirolimus therapy was initiated with lead-in dose of 0.025 or 0.05 mg/kg/day, depending on the ART regimen. Doses for each participant were then adjusted, based on trough blood sirolimus concentrations, to achieve target concentrations between 5 and 10 ng/mL. There were frequent initial visits for sirolimus trough concentration monitoring and potential dose adjustments, at weeks 12.5, 13, 13.5, 14, 14.5, 15, 15.5 and 16. Then visits occurred at weeks 18, 20, 24, 28 and 32. After the week 32 visit, the planned end of study treatment, there was an additional 12 weeks of post-sirolimus follow-up, with a final visit at week 44.

Study visits included physical examinations, clinical assessments, safety monitoring, and blood and oral swab collection. Anal swabs were collected at week 12 and 32. Samples were stored for subsequent protocol testing for the study outcomes.

In the primary analysis, the significance level was 0.05 for all analyses.

Inclusion Criteria:

• HIV-1 infection
• On continuous ART for ≥24 months prior to study entry.
• CD4+ cell count ≥350 cells/mm^3
• Plasma HIV-1 RNA below the level of quantification for ≥24 months.
• White blood cell (WBC) ≥3000/mm^3
• Platelet count ≥125,000/mm^3
• Absolute neutrophil count (ANC) >1300/mm^3
• Aspartate aminotransferase (AST) <1.25 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) <1.25 x ULN
• Calculated creatinine clearance (CrCl) ≥60 mL/min
• Fasting or non-fasting triglyceride level ≤350 mg/dL
• Fasting or non-fasting LDL <160 mg/dL
• Urine protein to urine creatinine ratio ≤1 g/g from random urine collection

Exclusion Criteria:

• Serious illness requiring systemic treatment and/or hospitalization
• Documentation of any CDC Category C AIDS-indicator condition or oropharyngeal candidiasis (thrush)
• Intended modification of ART during the study.
• Latent tuberculosis (TB) infection
• TB disease within 48 weeks prior to study entry requiring treatment.
• History of active hepatitis B (HBV) infection.
• Hepatitis C virus (HCV) RNA-positive
• Previous myelodysplasia syndrome, lymphoproliferative disease, lung disease, malignancies, congestive heart failure, life-threatening fungal infection or herpes-zoster/varicella-zoster viral infection requiring treatment.
• Detectable Epstein-Barr virus (EBV) in blood
• Active infection other than HIV that required receipt of systemic antibiotic therapy by intravenous infusion
• History of major hypersensitivity reaction to macrolide drugs including angioedema, anaphylaxis, drug-induced dermatitis, or hypersensitivity vasculitis.
• Currently pregnant or breastfeeding, or planning to become pregnant prior to or during the study.
• Use of immunomodulators (eg, interleukins, interferons, and cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy.
• Active drug or alcohol use or dependence
• Vaccination within 14 days prior to study entry.
• On or planned to change to a PI-based ART or cobicistat-boosted regimen
• Anti-human papillomavirus (HPV) therapies