Herpesviruses Reactivation In Hiv-Infected Women Initiating ART (HERA)
Condition: Herpes Virus-Related Illnesses
Study type: Observational

Summary: 
      Background:

      Herpes virus can cause sores on the body. It can cause flu-like symptoms like fever and
      muscle aches, and even a type of cancer. Many people with HIV also have infections with
      herpes virus. When these people start taking HIV medicines, their herpes virus symptoms can
      suddenly start or become worse. Researchers want to find out more about how often this
      happens and why.

      Objective:

      To study the effects of HIV treatment in women who may have herpes virus infections.

      Eligibility:

      Women age 18 years and older who have been diagnosed with HIV infection.

      Design:

      Participants will be screened with a physical exam, medical history, and blood and urine
      tests.

      Participants will have about 8 study visits. Each will take about 1-2 hours.

      Participants will return to the clinic 1-2 weeks after the screening visit to receive their
      antiretroviral (ART) medicine. They will get instructions for taking it.

      Participants will have 6 more study visits over 1 year.

      During study visits, participants will have blood and urine tests, vaginal fluid collected,
      and an oral swab. They may have an external genital exam. They will get their next supply of
      ART medicine.

      Some participants may have a chest x-ray.

      Participants may have leukapheresis. Blood will be removed through a needle in an arm. It
      will be run through a machine that separates out the white blood cells. The rest of the blood
      will be returned through a needle in the other arm.

      The total time participants will be in the study is about 1 year.
    

Detailed description: 
      Initiation of antiretroviral therapy (ART) can lead to a short-term increase of herpes
      virus-related illnesses including genital herpes flares, higher likelihood of varicella
      zoster virus (VZV), cytomegalovirus (CMV) uveitis or other end-organ disease, and herpes
      simplex virus (HSV) associated encephalitis. Herpesvirus reactivation upon ART initiation may
      be related to immune restoration disease of immune reconstitution inflammatory syndrome
      (IRIS), but the etiology is unclear. We hypothesize that ART initiation can induce
      herpesvirus reactivation causing increased cellular, systemic, and localized immune
      activation and that alterations of interferon (IFN) pathways during initial HIV viral
      suppression are involved in this reactivation.

      To investigate these mechanisms, we propose to document the incidence of clinical herpetic
      disease and viral shedding in vaginal and oral secretions from HIV-positive women initiating
      ART and to assess the associations between viral shedding or clinical disease and cellular,
      mucosal, and systemic immune activation. We will determine the role of IFN pathway in
      herpesvirus reactivation following initiation of ART. We will also evaluate the potential
      impact of herpesvirus reactivation on HIV cellular reservoirs by comparing residual HIV
      plasma viral replication and cell-associated virus prior to and 52 weeks after ART
      initiation.

      We propose to enroll up to 200 HIV-infected women initiating ART at the NIH Clinical Center
      (n=30 to 40) and between the Villa Maria Hospital, Rakai Health Sciences Program (RHSP) site
      in Kalisizo, Uganda and Kalisizo Hospital ARV clinic (n=160 to 170). Women will be recruited
      regardless of CD4+ T-cell count, presence of opportunistic infections and co-infection
      status. Pregnant women will be excluded. During 8 study visits to occur over a 12-month
      period, participants will receive standard-of-care treatment for HIV and opportunistic
      infections. Blood, vaginal fluid and oral swabs collected at study visits will be tested for
      viral levels of HIV and various herpesviruses. Vaginal samples will also be used to study
      differences in vaginal microbiota between women with and without herpetic disease prior and
      after ART. Plasma samples will be tested for antibody levels (IgG) specific for different
      herpesviruses to examine changes in anti-herpetic humoral responses. ART adherence will be
      monitored in plasma using high-resolution mass spectrometry.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Approximately 200 women initiating ART as part of standard HIV care will be recruited at
        four sites, the NIH Clinical Center (approximately 30-40), the RHSP/ICER , the Villa Maria
        Hospital and the Kalisizo sites in Uganda (approximately 160-170). Women will be recruited
        regardless of CD4+ T-cell count, presence of opportunistic infections and co-infection
        status. Participants taking antibiotics for co-infections and prophylaxis will be able to
        participate in the study and antibiotic use will be captured in study data. Participants
        may co-enroll in other non-interventional studies. Pregnant women will be excluded.
      
Keywords: HSV; Uganda; Sample; Natural History