Effectiveness of Zidovudine vs. Zidovudine Plus Alpha Interferon vs. Interferon for Treatment of HIV

Initial Study: THREE ARM (INTERVENTIONAL) STUDY

This randomized, controlled phase III protocol, initiated in 1988, was the first study to
examine intervention with antiretroviral therapy and alpha interferon in patients with HIV
infection. It evaluated the relative efficacy of zidovudine (AZT) vs. AZT + alpha interferon
(IFN) vs. IFN in increasing time to first opportunistic infection, reducing HIV viremia, and
lessening immune system deterioration in HIV-infected persons.

For the AZT alone arm, AZT dosing consisted ofthe standard regimen of 200 mg q4h. Persons on
the AZT + IFN combination arm received AZT 100 mg q4h with IFN beginning at 1 million units
qd, escalating up to 2.5 million units at 2 weeks, then in increments of 2.5 million units
every 2 weeks. Patients on the IFN-alone arm began therapy at 5 million units qd and
escalated in 2.5 million unit increments every 2 weeks, unless escalations were precluded by
toxicity. Patients who had evidence of HIV infection and a CD4 countgreater than or equal to
500 were randomized to one of the three treatment groups. Patients were treated with their
assigned medication until intolerable toxicity, opportunistic infection, or progressive
Kaposi's sarcoma developed, or CD4 count declined to less than 200/mm(3).

Our statistically significant findings during this pre-HAART era study showed that
interferon-alpha decreased HIV RNA viral load levels, both alone and in combination with AZT.

Long-Term Follow-up: EXTENSION PHASE (NATURAL HISTORY STUDY)

Once the intervention phase was completed, this protocol entered a long-term follow-up phase
and evolved into a longitudinal natural history study. As of 2013 this work earned the
distinction of following a cohort for 25 years or more. It continues to serve as an important
source of data regarding the long-term outcomes of patients receiving anti-HIV treatment, and
to provide information on the long-term consequences of therapy. In addition, stored blood
and cells enable the study of cutting edge research questions, such as those related to
immune activation, with new state-of-the-art laboratory assays.

- INCLUSION CRITERIA:

Over 18 years of age.

T4 lymphocyte count greater than or equal to 500/mm3.

Infection with HIV as documented by positive ELISA and Western blot and positive HIV
culture or positive p24 antigen or positive polymerase chain reaction.

Absence of current opportunistic infection (defined for purposes of this study as:
candidiasis, cryptosporidiosis, mycobacterial infection, persistent herpes simplex
infection, isosporiasis, cytomegalovirus infection, toxoplasmosis, pneumocystosis,
salmonellosis, and cryptococcosis). Routine clinical methods and observations were
performed to exclude such patients.

Afebrile (Temperature less the 38 degrees Centigrade orally) without antipyretics for at
least 72 hours prior to enrollment.

Performance status 0, 1, or 2.

Relatively stable clinical condition, with no deterioration of performance status in the
month prior to enrollment.

Ability to give informed consent and willing to comply with all procedures and visits
scheduled.

Suitability of I.V. access for the scheduled blood tests.

Normal renal function as defined by BUN less than or equal to 30 and creatinine less than
or equal to 1.5.

Normal hepatic function with transaminases and alkaline phosphatase less than 5 times the
upper limit of normal range.

Hemoglobin greater than or equal to 10 gm/dl, total granulocyte count greater than or equal
to 1250/mm(3), platelet count greater than or equal to 125,000/mm(3).

No previous therapy for KS within the month prior to enrollment, and no prior exposure to
investigational agents. Prior exposure to AZT did not disqualify a patient; however
patients were stratified on this basis.

EXCLUSION CRITERIA:

Patients with malignancy other than Kaposi's sarcoma were specifically excluded from this
study.

Pregnant women, nursing mothers, or women of childbearing potential who were not employing
effective means of contraception or abstinence.

Patients actively using illicit drugs.

Patients receiving systemically and potentially myelosuppressive drugs (such as TMP/SMX,
pyrimethamine-sulfa or DHPG), nephrotoxic agents (such as amphotericin B or
aminoglycosides), or cytotoxic or experimental chemotherapy.

Patients with a history of significant depressive disorder.

Patients with a history of an AIDS-defining opportunistic infection.

Subsequent Exclusion Criteria (Post Enrollment)

After enrollment, a patient was excluded from further participation in the study for any of
the following reasons:

Serious infection not cleared by antibiotic therapy. The occurrence of a life-threatening
infection, whether or not considered to be opportunistic, will prompt a discontinuation of
therapy during the infection and for 2 weeks following its successful resolution. Therapy
was re-initiated unless (1) in the investigator's judgment re-treatment with either or both
of the study medications would be contraindicated for other reasons or (2) therapy had been
held for more than 6 weeks.

Decrease in percent CD4 to less than 20 percent or in absolute CD4 count to less than
200/mm(3) on 3 consecutive blood tests.

Systemic allergic reaction to either study medication, characterized by angioedema,
bronchial constriction, or anaphylaxis.

It was the principal investigator's judgment that the patient was too ill to continue in
the trial.

Toxicity necessitating withdrawal.

Patient non-compliance: A patient not taking medication as directed or not keeping
appointments was not allowed to continue on this study.

Rapid or life-threatening progression of KS such that the principal investigator believed
other therapies would be in the patient's best interest.

Voluntary withdrawal: A patient could remove himself from study at any time. The patient
was allowed to withdraw without prejudice.

Termination of the study by the principal investigator, sponsor, or the FDA.