Prevention and Treatment Continuum for Youth at HIV Risk, Acutely Infected and With Established HIV Infection

Study Overview
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Brief Summary
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This is a strategic prospective cohort study which will measure the effects of early intensive antiretroviral therapy (ART) on the establishment and persistence of HIV-1 reservoirs and HIV-1-specific immunity in acutely /recently HIV infected youth aged 12 to 24 years as compared to newly diagnosed youth with established infection > 6 months. Participants with newly diagnosed acute /recent HIV-1 infection will be offered enrollment into the study with immediate initiation of ART which is the current standard of care.

Detailed Description
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Adolescents who are displaced and living in shelters or in the streets constitute an extremely vulnerable population for acquisition of HIV infection worldwide. In the U.S., homeless youth, particularly African American Gay, Bisexual, and Transgendered Youth (GBTY), are very susceptible to substance abuse, juvenile justice contact, and acquisition of HIV and other sexually transmitted infections (STI). The displaced adolescent population is not generally amenable to routine clinic follow-up in hospital settings and potentially more easily identified through mobile outreach efforts. HIV prevalence in this group can be as high as 5.3%. While HIV incidence is unknown, high rates of concurrent exposures to other STIs, substance abuse, and survival sex suggest acute infection is likely high. Pediatric studies of HIV perinatally infected infants treated very early with potent antiretroviral therapy as well as studies of adult cohorts treated during acute infection, have shown that very early treatment of HIV is associated with control and decrease in viral reservoir burden, which is likely predictive of long term HIV control. Although early treatment has not yet been demonstrated to induce a functional cure, it has been associated with an extended period of complete viral quiescence, also known as HIV drug free remission. No studies of this kind have enrolled significant numbers of adolescents. Some studies suggest HIV reservoirs from adolescents who were recently HIV infected may be more pliable and responsive to early combined antiretroviral treatment (cART) than that of adults. Prolonged control of HIV through cART initiated following established HIV infection does not appear to impact viral reservoir size. HIV remission is not attainable in this scenario following treatment interruption, even after many years of undetectable plasma virus levels while on cART. We hypothesize that very early antiretroviral treatment of adolescents with acute HIV infection will be associated with decreased viral reservoir size, and viral reservoir size will be significantly different between adolescents with acute, recent or established HIV infection. To evaluate our hypothesis, we propose to capitalize on a current community-based strategy to initiate very prompt antiretroviral treatment many times the very day of diagnosis of HIV infection. Patients with newly diagnosed HIV infection will be offered antiretroviral treatment immediately or within a very short time by our collaborating clinical sites, and through the present study will be monitored periodically for assessment of virus load and HIV reservoir assays.

Official Title
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A Comprehensive Community-Based Strategy to Optimize the HIV Prevention and Treatment Continuum for Youth at HIV Risk, Acutely Infected and With Established HIV Infection

Conditions
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Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: Antiretrovirals


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants age 12 to 24 years. A positive HIV diagnostic assay following a negative HIV diagnostic assay obtained in the previous study visit (if subjects are enrolled in the high risk cohort study- Project 3) or within the last six months if not followed in Study 3. A positive HIV test at baseline for subjects who are included as part of the recently diagnosed arm. HIV diagnostic assays include POC rapid tests including 4th generation rapid assays, GeneXpert HIV qualitative assays, HIV antibody assays, and HIV RNA or DNA PCR assays. Ability and willingness to provide written informed consent. Willingness to initiate ART Willingness of treating clinician to follow DHHS guidelines for antiretroviral naïve adolescents and adults Exclusion Criteria: Prior ART use. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Any acute, chronic, or recent and clinically significant medical condition that, in the opinion of the site investigator, would interfere with adherence to study requirements or jeopardize the safety or rights of the participant. Chronic or recurrent use of medications that modify host immune response, e.g., oral or parenteral steroids, cancer chemotherapy. Clinical treatment with an ARV regimen less effective than those recommended by DHHS HIV clinical guidelines. Enrollment on a experimental ARV regimen

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 24 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cases<br>36 youth with new diagnosis of acute/recent HIV as defined by laboratory assays Fiebig1-V with standard care of antiretrovirals (ARV) regimen provided by the clinician | Drug: Antiretrovirals<br>* The antiretroviral (ARV) regimen provided by the clinician must follow DHHS guidelines for antiretroviral naïve adolescents and adults<br>* Other names: Stribild;|
| Controls<br>36 youth with newly diagnosed HIV but established HIV infection (Fiebig VI) with standard care of antiretrovirals (ARV) regimen provided by the clinician | Drug: Antiretrovirals<br>* The antiretroviral (ARV) regimen provided by the clinician must follow DHHS guidelines for antiretroviral naïve adolescents and adults<br>* Other names: Stribild;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of cell-associated HIV-1 DNA | To compare the amount of cell-associated HIV-1 DNA (CAHD) in 5 million blood-derived CD4+ T-cells and total PBMC (assayed by quantitative ddPCR [qPCR]) at 12 months in participants who initiated ART in Fiebig I/II versus Fiebig III/IV versus Fiebig V and those with newly diagnosed but established/chronic HIV infection with sustained suppression of plasma HIV-1 RNA. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate HIV-1-specific CD4+ and CD8+ T-cells | To evaluate HIV-1-specific CD4+ and CD8+ T-cells by flow cytometry prior to ART initiation and while HIV-1 RNA is suppressed on ART at 12 and24 months. | 12 and 24 months | 
| Assess the amount of unspliced HIV-1 RNA | To assess the amount of unspliced HIV-1 RNA in 5 million blood-derived CD4+ T- cells prior to ART initiation and while HIV-1 RNA is suppressed on ART at 12, and 24 months | 12 and 24 months | 
| Assess cell-associated HIV-1 RNA to DNA ratio | To assess cell-associated HIV-1 RNA to DNA ratio in participants with quantifiable HIV-1 DNA prior to ART initiation and while HIV-1 RNA is suppressed on ART at 12, and 24 months | 12 and 24 months | 
| Assess the decay of HIV proviral DNA | To assess the decay of HIV proviral DNA by ddPCR over the observational period up to 24 months in youth with acute vs established infection. | 24 months | 
| Assess the time to undetectable HIV RNA | To assess the time to undetectable HIV RNA among the acute and established youth and the subsequent HIV DNA decay and HIV immune parameters over the observational period up to 24 months | 24 months | 
| Evaluate demographic and behavioral factors associated with sustained adherence to ART | To evaluate demographic and behavioral factors associated with sustained adherence to ART or contrarily, risk of HIV transmissibility in recently infected youth. | 24 months |