Impact of a Short-Term Analytical Treatment Interruption and Re-Initiation of Antiretroviral Therapy on Immunologic and Virologic Parameters in HIV-Infected Individuals
Condition: HIV
Study type: Observational

Summary: 
      Background:

      The immune system helps the body fight off disease. Most people infected with HIV cannot
      control the infection and need daily medicine. Combination antiretroviral therapy (cART) are
      drugs taken to prevent HIV infection from damaging the immune system. Researchers want to
      study why some people develop resistance to the drugs or have permanent side effects.

      Objective:

      To study the impact of a short-term treatment stop on HIV that persists even while taking
      cART.

      Eligibility:

      Adults 18-65 years old with HIV who are being treated with cART

      Design:

        -  Participants will first be screened with a physical exam and medical history. They may
           have a chest x-ray. They will have heart, blood, and urine tests.

        -  At the baseline visit, participants will repeat the screening tests except the x-ray.
           They will get counseling about HIV and risk behavior.

        -  Participants will have leukapheresis. Blood will be removed through a needle in one arm.
           A machine will separate white blood cells from the rest of the blood. The remainder of
           the blood will be returned to the body by a different needle.

        -  Participants will stop their current treatment on day 0. They will visit the clinic each
           week until they meet the criteria to restart cART. These visits will have the same
           procedures as the baseline visit.

        -  Before restarting cART, most participants will have leukapheresis.

        -  After restart, participants will be seen weekly for 4 weeks and then monthly for about
           11 months. Participants will have blood drawn, physical exam, and medical history. They
           will have leukapheresis 2 more times over 1 year.
    

Detailed description: 
      While antiretroviral therapy (ART) has improved the clinical outcome for HIV-infected
      individuals, persistence of viral reservoirs in the peripheral blood and lymphoid tissues
      remains a hurdle to the eradication of virus. The vast majority of HIV-infected individuals
      treated with ART experience plasma viral rebound within weeks of cessation of therapy.
      Considering that current research regarding treatment has been heavily focused on developing
      strategies aimed at achieving sustained virologic remission in the absence of ART, it is of
      crucial importance to investigate the impact of short-term treatment interruption and
      re-initiation of ART on transcriptional, immunologic, and virologic parameters in
      HIV-infected individuals. Currently, much of our knowledge regarding the mechanism of viral
      rebound is based on investigations using structured treatment interruptions in supervised
      clinical settings dating back to 1999. Subsequent studies, performed primarily in chronically
      infected patients to minimize treatment exposure and toxicity, revealed poor outcomes in
      terms of viral rebound, clinical events and mortality 3-11 leading to the abandonment of this
      genre of investigation. However, various aspects have been identified as potential
      contributors to the observed negative outcomes including outmoded ART regimens, infrequent
      post-interruption monitoring, and repeated cycles of prolonged analytical treatment
      interruption (ATI). While long-term ATI was found to be associated with a decrease in CD4+ T
      cells, persistent plasma viremia, and an increased risk of opportunistic infections, it is
      unclear whether short term ATI elicits similar immunologic and virologic consequences in
      those receiving modern and efficacious ART. Furthermore, the mechanism, kinetics, degree, as
      well as immunologic and virologic predictors, of plasma viral rebound in patients receiving
      contemporary antiretroviral drug regimens after cessation of ART have not been explicitly
      investigated. Nor has the impact of persistent HIV reservoir size been fully correlated to
      the dynamics of plasma viral rebound in patients receiving modern drug regimens. As we
      develop clinical trials aimed at therapeutic and curative interventions, an integral
      component in design will require an ATI phase. Characterizing the corollaries of brief
      treatment cessation and re-initiation of ART on the dynamics of immunologic parameters and
      HIV reservoirs will provide valuable information for the design of future trials essential to
      our interpretation of the results as well as to ensuring the safest environment for the
      patients. We propose to examine the effect of ATI on plasma viral rebound, changes in
      immunologic parameters and the dynamics of viral reservoirs in HIV-infected individuals
      receiving state-of-the-art antiretroviral drug regimens following discontinuation and
      reinitiation of therapy.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        HIV patients which will be recruited from natural history and training protocols currently
        enrolling in clinic and the community
      
Keywords: Rebound; Reinitiation; ART; Reservoirs; Immune Exhaustion