Viral Suppression After Analytic Treatment Interruption in Thai Patients Who Initiated Highly Active Antiretroviral Therapy During Acute HIV Infection
Condition: Acute HIV Infection; Antiretroviral Treatment Interruption
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Study type: Interventional

Summary: 
      This is a Phase 2, two-step, open-label study of the outcome of analytic treatment
      interruption (ATI) on patients who started antiretroviral therapy (ART) during Fiebig Stage I
      of acute HIV infection (AHI), defined as detectable HIV-RNA without detectable p24 antigen or
      HIV IgM. The primary endpoint will be rate of sustained viral suppression, defined as HIV-1
      RNA < 50 cps/ml at 24 weeks after treatment interruption. During ATI subjects will be
      monitored closely for safety and will have ART re-initiated if they meet predefined clinical,
      virological, or immunological criteria. In step I, there will be 8 subjects who undergo ATI.
      An interim analysis for safety will be conducted after 12 weeks. If none of the subjects
      maintain viral suppression at 12 weeks then no further subjects will be enrolled into the
      study. If at least 1 out of 8 subjects maintains viral suppression at 12 weeks then an
      additional 7 subjects will be enrolled in step 2.

      At ATI all antiretroviral drugs will be discontinued. Subjects will be monitored with
      clinical exam, immunological (CD4), and virological (HIV-RNA) testing at baseline and then on
      a fixed schedule for 24 weeks. ART will be re-initiated immediately if subjects meet any
      pre-defined clinical, immunological or virological safety endpoints during the monitoring
      period.
    

Detailed description: 
      This is a two step open label study of ATI in patients who initiated ART in the earliest
      detectable stage (Fiebig I) of HIV infection. In step I, eight subjects will discontinue ART
      for a period of up to 24 weeks. An interim assessment will be conducted after all eight

      subjects in step I complete follow-up for 12 weeks. If at least one out of eight subjects
      maintains viral suppression (HIV-1 RNA < 50 copies/ml) at 12 weeks, then the study will
      proceed to step 2, in which 7 additional subjects (maximum total sample size of 15) will
      undergo ATI. The primary endpoint is proportion of subjects who maintain viral suppression at
      24 weeks post ATI. Subjects will be monitored frequently for disease progression using
      clinical, immunological and virological criteria. ART will be re-initiated immediately for
      any subjects who meet pre-defined criteria for disease progression.

      Parent Study Cohort

      This is a sub-study of the protocol "Establish and characterize an acute HIV infection cohort
      in a high-risk population" (SEARCH 010, RV254, WRAIR 1494) implemented at the Thai Red Cross
      AIDS Research Center in Bangkok, Thailand. From April 2009 through February 2014 the cohort
      had enrolled 150 patients with acute infection and 145 (97%) are still in active follow-up.
      All patients in the cohort are offered ART at the time of enrollment through a separately
      funded protocol; all 145 subjects (100%) in active follow-up are currently on ART. The median
      age (range) of the cohort is 28 (18-57) years and 90% are men who have sex with men (MSM).

      The cohort currently has 50 volunteers who started ART during Fiebig Stage 1, of whom 24 have
      been on ART for > 24 months and have HIV-1 < 50 copies/ml. Another 13 volunteers have been on
      ART 6-24 months with undetectable HIV-1 RNA.

      During the period of co-enrollment in this substudy, no additional biological specimens will
      be collected as part of the RV254/SEARCH 010 protocol. Data and samples from this substudy
      will be shared with the parent protocol.

      Criteria to reinitiate ART after ATI

      The criteria to restart ART after ATI are designed to protect the subjects from any possible
      clinical, immunological, or virological adverse effects in the event that their VL rebounds
      while off ART. The viral load (VL) criterion of > 1,000 copies/ml was chosen because clinical
      symptoms of HIV infection or significant decline in CD4 count would not be expected at this
      low level of viremia. The Fiebig I patients in the SEARCH 010 cohort had a median (range)
      HIV-1 RNA of 4.8 (2.8-5.7) log10copies/ml, at a median (range) of 12 (4-40) days after
      exposure to HIV, prior to initiation ART and have therefore already been exposed to high
      levels of plasma virus during acute infection while maintaining low or no detectable HIV
      proviral reservoirs.

      In addition, the ANRS Visconti study found that patients who are virologic controllers
      (sustained VL < 50 copies/ml) after ATI may initially and transiently have VL above
      detection. Of 240 tests performed after treatment interruption in those who were subsequently
      virologic controllers or PTC, 2% had VL > 400 copies/ml and 18% had VL between 50 and 400
      copies/ml. Therefore, low-level viremia may not always be indicative of viral rebound and can
      potentially reverse.

      Specific criteria for re-initiation of ART after ATI are:

        1. HIV-1 RNA above 1,000 copies/ml on 2 consecutive determinations at least 3 days apart.
           OR

        2. HIV-1 RNA rise of ≥ 0.5 log10copies/ml per day provided that the last HIV-1 RNA is above
           1000 copies/ml OR

        3. A single HIV-1 RNA above 10,000 copies/ml OR

        4. CD4+ T-cell counts below 350 cells/mm3 on 2 consecutive determinations at least 2 weeks
           apart. OR

        5. CD4+ T-cell count decline of > 50% from baseline prior to ATI. OR

        6. Clinical progression to CDC Category B or C disease. OR

        7. Diagnosis of Acute Retroviral Syndrome. OR

        8. Pregnancy OR

        9. Subject requests re-initiation of ART.
    

Intervention name(s): Treatment interruption
Intervention type(s): Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment