Immune Reconstitution Syndrome in HIV-Infected Patients Taking Antiretroviral Therapy
Condition: Immune Reconstitution Inflammatory Syndrome
MeSH terms: Immune Reconstitution Inflammatory Syndrome; Syndrome
Study type: Observational

Summary: 
      This study will investigate what factors may lead to the development of immune reconstitution
      syndrome (IRIS) in HIV-infected patients and what the outcome is after IRIS. It will also
      seek to better define and describe the syndrome. IRIS is a condition that can occur in
      HIV-infected people following the start of antiretroviral therapy. The sudden improvement of
      immune function with this therapy can cause an unexpected worsening of diseases the patient
      already has, such as tuberculosis or fungal infections, and development of fever, enlarged
      lymph nodes or other complications, or even uncover a previously silent disease.

      HIV-infected people who are at least 18 years old, whose CD4+T cell count is 100 cells per
      microliter or less, and who have not previously been treated with combination antiretroviral
      therapy or have taken the drugs for less than 3 months and more than 6 months before
      screening for this study may be eligible to participate. Candindates must also live within
      the wider DC area so that acute problems after therapy initiation will be evaluated at NIH.
      Candidates are evaluated before starting therapy with a medical history and physical
      examination, blood and urine tests, electrocardiogram, chest x-ray and CT scan of the chest,
      tuberculin skin testing, apheresis, and possibly an intestinal (gut) and lymph node biopsy
      (surgical removal of a small piece of tissue for microscopic examination). For apheresis,
      blood is collected through a needle in an arm vein and spun in a machine that separates the
      blood components. The white blood cells and plasma are removed, and the red cells and
      platelets are returned through the same needle or through a needle in a vein in the other
      arm.

      Participants have a complete history and physical examination and additional blood tests,
      including genetic studies, upon entering the study. They start taking anti-HIV medications,
      prescribed according to the current standard of care, as well as medications to treat other
      infections, and treatment of IRIS, if needed. The study lasts about 4 years. Patients return
      to the clinic at 2, 4, 8 and 12 weeks after the entry visit, then every 12 weeks (about every
      3 months) until week 48 (the first year), and then every 16 weeks (about every 4 months)
      until the end of the study. At most visits, patients have a medical history, physical
      examination and blood and urine tests, including CD4+T cell count and HIV plasma viral load
      measurement. Apheresis is also done at weeks 24 and 48 and then once every 48 weeks.
      Intestinal and lymph node biopsies (optional) are also done at weeks 24 and 48. A syphilis
      test and PAP smear (for women) are done yearly. and plasma, cells and serum are stored at
      almost every visit for immunologic studies.
    

Detailed description: 
      A cohort observational study evaluating the predictors, incidence, clinical presentation and
      immunopathogenesis of Immune Reconstitution Syndrome (IRIS) in human immunodeficiency virus
      (HIV-1) infected patients with CD4 Count less than or equal to 100 cells/microL who are
      initiating antiretroviral therapy.

      Immune reconstitution syndrome (IRIS) is a clinical syndrome that has been described in HIV
      infected patients after initiation of highly active anti-retroviral therapy (HAART), and is
      characterized by paradoxical acute worsening of an underlying opportunistic infection or
      AIDS-defining illness. There is no widely accepted syndromic definition, the pathogenesis of
      the syndrome is unclear and there is no specific therapy. The syndrome is more common in
      patients with low CD4+ T cell counts (less than 50 cells/microL) and in those with certain
      underlying infections (e.g. mycobacterial or cryptococcal infection) and is typically
      observed when there is evidence of response to HAART and while patients are still at risk for
      other opportunistic infections (OIs) or AIDS defining illnesses (e.g. pneumocystis jirovecii
      pneumonia or cytomegalovirus [CMV] retinitis). The incidence of IRIS varies depending on the
      studied population and is very frequent in developing countries creating significant
      diagnostic and therapeutic challenges as well as utilization of limited health resources.

      DESIGN: International observational cohort study. Participants will be evaluated at baseline
      and followed according to the protocol follow up schedule after initiation of antiretroviral
      therapy for a total of two years. Acute symptoms that may be representing manifestations of
      IRIS will also be evaluated at additional acute care visits if necessary.

      DURATION: Enrollment is ongoing. Each volunteer will be followed for at least two years.
      Total duration of the study will be approximately 8 years (including the optional extension
      phase in US).

      SAMPLE SIZE: Approximately 600 patients will be enrolled, 200 in Kenya, 100 in Thailand and
      300 in US. (enrollment is US will continue until approximately the other sites are full).
      Based on the incidence of IRIS in patients with low CD4 counts (approximately 20-40 percent),
      we anticipate strong power (approximately 90 percent) to identify baseline factors predictive
      of IRIS.

      POPULATION: HIV-l-infected men and women, age greater than or equal to 18 years,
      antiretroviral therapy (ART)-naive with CD4+ T cell counts less than or equal to 100
      cells/mm(3). Participants will be recruited and followed at three sites: the broader
      Washington DC, Kericho, Kenya and Bangkok, Thailand areas.

      REGIMEN: Participants will be initiated on ART according to the clinical standard of care. If
      an OI or other AIDS defining illness is identified prior to or during screening or at any
      point during the study, they will also be treated according to standard of care.
    

Observational model: Cohort
Time perspective: Prospective
Keywords: Opportunistic Infections; Immune Restoration Disease; Mycobacterial Infections; HIV-1 Infection; HIV; ART Naive