Safety and Efficacy Study of Etanercept (Enbrel) on the Response Rate of HIV-infected Subjects
Condition: HIV Infection
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of conducting this already-FDA approved Phase I clinical trial is to evaluate the
      safety and efficacy of etanercept (Enbrel) on the response rate in HIV-infected subjects who
      have failed to respond to conventional antiretroviral (HAART) therapy and for whom no
      alternative therapy exists. The greatest challenge faced by HIV-treating clinicians today is
      the management of virologic failure and metabolic complications of anti-HIV treatment.
      Treatment failure can occur because of non-compliance, drug discontinuation, lack of drug
      potency, inadequate drug plasma concentration or drug resistance. Of these, drug resistance
      remains the single most important reason for virological failure and rapidly limits treatment
      options.
    

Detailed description: 
      I. Background and Rationale:

      The greatest challenge faced by HIV-treating clinicians today is the management of virologic
      failure and metabolic complications of anti-HIV treatment. Treatment failure can occur
      because of non-compliance, drug discontinuation, lack of drug potency, inadequate drug plasma
      concentration or drug resistance. Of these, drug resistance remains the single most important
      reason for virological failure and rapidly limits treatment options. Virus resistance to all
      three major antiretroviral drug classes is now being reported even in primary seroconverters.
      Although highly-active antiretroviral (ARV) therapy (HAART) has led to a sharp decline in
      AIDS-related morbidity and mortality, treatment failure is a common, significant problem and
      as many as 50% of patients have detectable plasma HIV RNA despite being on combination ARV
      therapy. Salvage therapy is the term commonly used to define the approach taken when previous
      anti-HIV treatments fail to achieve desired goals, which include: 1) undetectable viral load;
      2) CD4 cell levels below 200 cells/mm3; and, 3) the prevention of HIV disease progression. It
      is one of the most difficult situations to face as a patient, and one of the most problematic
      challenges for health-care providers. Although this state of treatment failure is sometimes
      euphemistically referred to as "management of treatment-experienced patients," many HIV
      positive patients, having already exhausted the benefits of at least a few drug combinations,
      think of their next regimen as salvage or "rescue" therapy. Some physicians argue that due to
      cross-resistance among different drugs within the same class, people with HIV infection have
      only one good shot at treating it, and that any treatment regimen beyond the first is
      therefore salvage therapy. Others see salvage therapy as literally the end of the line--when
      an individual's HIV has developed extensive resistance to all currently available treatments.
      But most providers consider salvage therapy to be somewhere in between these extremes. Data
      on salvage therapy mostly comes from anecdotal reports and retrospective cohort studies. With
      a paucity of clinical trial data, clinicians are often forced to prescribe unproven regimens
      based on what is anticipated about cross-resistance and drug interactions. It is important,
      therefore, that new agents and new approaches continue to be developed as an increasing
      number of patients in practice have exhausted all treatment options.

      The rationale of this study is based upon the existing literature which indicates that many
      of the manifestations and subsequent clinical deterioration of HIV-infected individuals are
      related to the immune dysfunction seen in HIV disease, many of which are caused by the
      overproduction of proinflammatory cytokines, most notable of which is the excessive
      production of TNF-α. It is further postulated that removal of this TNF-α by a commercially
      available TNF-α-binding medication [ENBREL (etanercept)] may provide therapeutic benefit for
      HIV-infected patients who have failed to respond to standard antiretroviral therapy.

      II. Goal and Objectives:

      The purpose of the project is to assess the safety profile and efficacy of a soluble p75
      tumor necrosis factor (TNF) receptor: Fc fusion protein (Enbrel; Amgen, (etanercept) Thousand
      Oaks, CA) [i.e. anti TNF-α] on the response rate of "salvage patients" who are in virologic
      failure and who have failed to respond to standard antiretroviral therapy.

      The protocol will evaluate:

        1. Changes in CD4 T-cell enumeration, viral load, and soluble immune activation markers in
           HIV-infected patients from baseline to week 24 following treatment with anti-TNF-α.

        2. Safety and tolerability of anti-TNF-α with respect to treatment-limiting symptoms and
           laboratory adverse events through week 24.
    

Intervention name(s): Etanercept (Enbrel)
Intervention type(s): Drug
Intervention MeSH terms: Etanercept
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV; Treatment Experienced; Complementary Therapies