Immediate Initiation of Antiretroviral Therapy During Hyperacute HIV Infection

Study Overview
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Brief Summary
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The purpose of this study is to identify and provide immediate antiretroviral therapy to a cohort of HIV-infected individuals with very early HIV infection (estimated date of infection within the last 90 days). The primary aim of the study is to evaluate whether initiation of dolutegravir plus emtricitabine/tenofovir during acute/early HIV infection leads to protection of CD4+ T cells and other immune cells in the peripheral blood and lymphoid tissue from infection.

Detailed Description
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Although ART decreases HIV-associated mortality, it does not appear to completely restore immune health, for reasons that remain unclear. In addition, while HIV prevention approaches have led to significant successes in decreasing the incidence of new HIV infection over the past few years, the epidemic continues to grow both locally and globally. While complete eradication may not currently be feasible, a functional cure in which patients are able to indefinitely maintain undetectable viral loads in the absence of therapy may be an attainable immediate goal. Studying patients with early HIV infection and immediate ART will provide a unique opportunity to investigate the pathophysiology of the earliest stages of HIV infection and may help identify the virologic/immunologic predictors of a functional cure.

Official Title
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Immediate Initiation of Antiretroviral Therapy During Acute HIV Infection

Conditions
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HIV

Intervention / Treatment
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* Drug: Dolutegravir
* Drug: Emtricitabine/Tenofovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent Male or female, age ≥18 years Acute HIV infection with a negative or indeterminate HIV-1 antibody test and plasma HIV-1 RNA > 40 cp/ml, OR clinical history consistent with new HIV infection in the last 90 days. Antiretroviral therapy untreated or recently initiated (within 7 days) Participant must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments. All participants must agree not to participate in a conception process (eg, active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).. When participating in sexual activity that could lead to pregnancy, female participants must agree to use a double barrier method of contraception for at least two weeks after discontinuation of study drug. Exclusion Criteria: Known severe kidney disease (CrCl < 60 ml/min via Cockcroft-Gault method) Known severe hepatic impairment (Child-Pugh Class C) Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Participants with anticipated need for Hepatitis C virus (HCV) therapy during study Concurrent treatment with dofetilide, oxcarbazepine, phenytoin, phenobarbital, carbamazepine, St. John's wort, or metformin Serious illness requiring systemic treatment and/or hospitalization in the preceding 90 days prior to study enrollment Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drugs in the preceding 90 days prior to study enrollment (e.g. IL-2, interferon-alpha, methotrexate, cancer chemotherapy) Concurrent treatment with investigational drugs, or exposure to any investigational drugs in the preceding 90 days prior to study enrollment Active drug or alcohol use or dependence that, in the opinion of the Principal Investigator, would interfere with adherence to study requirements Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation Pregnant or breastfeeding women. For participants who agree to colorectal biopsy Known blood coagulation disorder Platelets < 50,000/mm^3 PTT > 2x upper limit of normal INR > 1.3 Use of aspirin, NSAIDs, Plavix, Coumadin, or other blood thinners that cannot be stopped for clinical reasons for 5 days before and after each colorectal biopsy Inflammatory colitis (e.g., Crohn's disease and/or ulcerative colitis) and/or any contraindications to sigmoidoscopy or colorectal biopsy such as peritonitis, active diverticulitis, or recent bowel surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dolutegravir+Emtricitabine/Tenofovir<br>Dolutegravir 50 mg PO daily plus Emtricitabine 200 mg/Tenofovir alafenamide 25 mg | Drug: Dolutegravir<br>* Dolutegravir 50 mg PO daily<br>* Other names: Tivicay;Drug: Emtricitabine/Tenofovir<br>* Emtricitabine 200 mg/Tenofovir alafenamide 25 mg PO daily<br>* Other names: Truvada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of immediate Dolutegravir plus Emtricitabine/Tenofovir administered to acutely infected HIV patients. | The number of grade 2 or higher severity adverse events (AEs) or drug-related laboratory abnormalities that exceed a frequency of 5% over a 6 month study period. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HIV reservoir size (cell-associated total DNA) in peripheral blood | The change in HIV reservoir size (as measured by cell-associated total DNA levels in peripheral blood mononuclear cells) over a 6 month study period. | 5 years | 
| Change in HIV reservoir size (cell-associated integrated DNA) in peripheral blood | The change in HIV reservoir size (as measured by cell-associated integrated DNA levels in peripheral blood mononuclear cells) over a 6 month study period. | 5 years | 
| Change in HIV reservoir size (cell-associated unspliced RNA) in peripheral blood | The change in HIV reservoir size (as measured by cell-associated unspliced RNA levels in peripheral blood mononuclear cells) over a 6 month study period. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immediate antiretroviral therapy, hyperacute infection