Antiviral Activity of Peg-IFN-Alpha-2A in Chronic HIV-1 Infection
Condition: HIV Infections
MeSH terms: Infections; Communicable Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      The objective of the study is to compare two different doses of Peg-INF-α-2A (90 or 180
      ug/wk) for their ability to maintain viral control when initiated 5 weeks before ART
      (antiretroviral therapy) interruption in HIV positive, ART-suppressed subjects (viral load
      <50 copies/ml) as determined by observing the percentages of viral load measurements <400
      copies/ml between the two arms over a 24-week period, corresponding to the Pegasys
      monotherapy period (exclusive of dual ART/Pegasys 5-week period). Primary analysis will be an
      "intent to treat" analysis and will address the hypothesis that two different doses of
      Peg-INF-α-2A (90 and 180 ug/week) will be similarly effective at inhibiting viral
      replication.
    

Detailed description: 
      The high toxicity of current Anti-Retroviral Therapy (ART) regimens has driven a number of
      studies investigating therapeutic approaches aimed at reducing drug exposure while
      maintaining the beneficial effects of immune reconstitution. Preliminary observations in
      HCV/HIV co-infected individuals already support an antiviral effect by Pegylated
      Interferon-Alpha-2A (Peg-IFN-Alpha-2A:Pegasys®) on HIV-1 replication; however, the ability of
      Peg-IFN-Alpha-2A (as a single agent) to maintain long-term suppression of HIV-1 replication
      in patients who interrupt ART after having achieved immune reconstitution remains
      undetermined. The rationale for addressing two doses of Peg-IFN-Alpha-2A (180 and 90 ug/week)
      is based on the antiviral activity reported with both doses and the lower incidence of
      adverse events associated with doses lower than that approved for HCV therapy (90 versus
      180ug/week).

      The long-range goal of this proposal is to determine if Peg-IFN-Alpha-2A monotherapy can
      sustain HIV-1 suppression in the absence of ART in infected individuals. Our short-range goal
      is to determine the safety, viral suppressive potential and immune correlates of
      Peg-IFN-Alpha-2A administered upon the cessation of suppressive ART.

      Based on the current literature and our preliminary studies, we hypothesize that weekly doses
      of 90 or 180 ug/wk of Peg-IFN-Alpha-2A administered to pharmacologically-suppressed
      HIV-infected individuals in the course of antiretroviral therapy (ART) discontinuation will
      result in equivalent frequency of viral control, with the lower dose resulting in measurably
      lower rate and intensity of therapy-related adverse events (AE).

      We propose to compare two different doses of Peg-IFN-Alpha-2A (90 or 180 ug/wk) as a
      simplification step to ART, for their ability to maintain viral load suppression when
      initiated 5 weeks before ART interruption in HIV-infected, ART-suppressed patients (VL<50
      copies/ml). Briefly, control will be determined by the the percentages of viral load
      measurements <400 copies/ml between the two arms over a period of 24 weeks, corresponding to
      the Pegasys monotherapy period (exclusive of dual ART/Pegasys 5-week period). A threshold of
      400 is used based on the known potential for blipping on ART between 50 and 400 copies/ml
      with no clinical consequence to sustained suppression thereafter (JAMA 2005, 293:817-829).
      Primary analysis will be an "intent to treat" analysis and will address the hypothesis that
      two different doses of Peg-IFN-Alpha-2A (90 and 180 ug/week) will be similarly effective at
      inhibiting viral replication.

      The secondary objectives of the research are:

        1. To prospectively evaluate dose-dependent, treatment-associated toxicity, safety and
           tolerability of 29 weekly doses of Peg-IFN-Alpha-2A at 180 ug or 90 ug/week (in
           association with ART for the initial 5 weeks, followed by 24 weeks of Peg-IFN-Alpha-2A
           in the absence of ART).

        2. To determine innate immunity outcomes correlated to Peg-IFN-Alpha-2A dose and antiviral
           activity by monitoring Natural Killer (NK) and Dendritic cell (DC) subsets changes and
           the ability to maintain innate immune function (DC secretory responses, NK antiviral
           cytotoxic responses)

        3. To determine adaptive immunity outcomes correlated to Peg-IFN-Alpha-2A dose and
           antiviral activity by monitoring T-cell subsets changes and the ability to maintain
           cell-mediated proliferative and cytokine responses against recall antigens (anti-HIV-1
           gag p55).
    

Intervention name(s): Pegylated Interferon-alpha 2a, 180 mcg/week sc; Pegylated Interferon-alpha 2a, 90 mcg/week sc
Intervention type(s): Drug; Drug
Intervention description(s): Pegylated Interferon-alpha 2a, 90 mcg/week sc for 24 weeks, 5 weeks in combination with ART, then 7 weeks without ART to primary endpoint (VL < 400 c/ml at 12 weeks) and further 12 weeks without ART (24 weeks) to secondary endpoints; Pegylated Interferon-alpha 2a, 90 mcg/week sc for 24 weeks, 5 weeks in combination with ART, then 7 weeks without ART to primary endpoint (VL < 400 c/ml at 12 weeks) and further 12 weeks without ART (24 weeks) to secondary endpoints
Other intervention name(s): Pegasys; Pegasys
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV; HIV-1; Pegasys; Peg-IFN-Alpha-2A; Viral Suppression; ART cessation; Immune function; Innate Immunity; Toxicity; Immune-based therapy; Treatment interruption