District of Columbia
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
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.
- Age between 18 and 60 years.
- Confirmed diagnosis of HIV-1 infection, as documented by any licensed ELISA test kit,
and confirmed by Western blot at any time prior to study entry, HIV-1 culture, HIV-1
antigen, plasma HIV-1 RNA.
- Prior antiretroviral therapy, defined as: Receipt of at least two separate protease
inhibitor (PI)-containing regimens (minimum 12 weeks) which was changed because of
virological failure (per subject or physician history) or detectable plasma HIV-1 RNA
AND A minimum of 1 year total prior antiretroviral experience.
- A CD4 count of > 200.
- Signed a written informed consent prior to initiation of any study related
- All subjects should continue taking the same antiretroviral regimen between the
screening and entry visits.
- History or suspicion of active tuberculosis or a prior history of being treated for
- Documented history of sepsis.
- Known hypersensitivity to ENBREL or any of its components.
- Patients on concomitant immunosuppressive therapy, e.g., steroids, cyclosporine, etc.
- Any condition which may interfere with the trial, including the patient's mental
ability to follow protocol instructions.
- Patients with heart failure or a history of congestive heart failure.
- Renal insufficiency (creatinine >2.5 mg/dL)
- Women of child bearing potential who are not willing to avoid pregnancy for the
duration of the study and 3 months thereafter.
- Inability or unwillingness to take appropriate prophylaxis for opportunistic
infections (i.e., PCP toxoplasmosis, etc.)