A Study of Three Drugs Plus Zidovudine in the Prevention of Infections in HIV-Infected Patients

Condition(s) targeted: Pneumonia, Pneumocystis Carinii; HIV Infections

Intervention: Pentamidine isethionate (Drug); Sulfamethoxazole-Trimethoprim (Drug); Dapsone (Drug); Zidovudine (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
S Bozzette, Study Chair
S Spector, Study Chair

To evaluate and compare 3 anti-pneumocystis regimens plus zidovudine (AZT) in persons with HIV infection and T4 cell count less than 200 cells/mm3. All persons completing at least 8 weeks of therapy on 081 will be offered the opportunity to participate in the nested study (ACTG 981) of systemic antifungal therapy (fluconazole) versus local therapy (Clotrimazole) for the prevention of serious fungal disease.

Persons with HIV disease who are receiving AZT are at risk for PCP, toxoplasmosis, bacterial pneumonia, and other serious infections. It is therefore important to find drugs that can be given along with AZT to control these infections. Aerosolized pentamidine (PEN) has been shown to be useful in preventing PCP and is expected to lower the 2-year risk of PCP. Both sulfamethoxazole/trimethoprim (SMX/TMP) and dapsone probably also provide effective preventive treatment against PCP, and both may be useful in preventing toxoplasmosis and extrapulmonary pneumocystosis.

Official title: A Randomized Trial of Three Anti-Pneumocystis Agents Plus Zidovudine for the Primary Prevention of Serious Infections in Patients With Advanced HIV Infection

Study design: Treatment, Open Label

Detailed description: Persons with HIV disease who are receiving AZT are at risk for PCP, toxoplasmosis, bacterial pneumonia, and other serious infections. It is therefore important to find drugs that can be given along with AZT to control these infections. Aerosolized pentamidine (PEN) has been shown to be useful in preventing PCP and is expected to lower the 2-year risk of PCP. Both sulfamethoxazole/trimethoprim (SMX/TMP) and dapsone probably also provide effective preventive treatment against PCP, and both may be useful in preventing toxoplasmosis and extrapulmonary pneumocystosis.

All patients receive AZT. In addition, they are placed in one of three groups to receive either SMX/TMP, dapsone, or PEN. Stratification criteria are:

Received first AZT equal to or less than 6 weeks prior to study entry. Received first AZT more than 6 weeks prior to study entry. Potential to participate in ACTG 981. ACTG center in which the patient is enrolled.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria

Concurrent Medication:

Allowed:

- Antifolate medication required to treat an intercurrent infection.

- Treatment of intercurrent infections or malignancies.

- Fluconazole.

- Itraconazole.

- Standard or investigational therapy for pneumocystosis (PCP) or toxoplasmosis.

- Only the forms of primary prophylaxis for PCP or toxoplasmosis assigned to the

participant under the protocol. Patients who develop intolerance to all forms of prophylaxis assigned in this protocol or who develop PCP or toxoplasmosis may receive alternate or investigation forms of prophylaxis with or without zidovudine but must continue to be followed under this protocol.

- Discouraged but allowed: AL-721.

- Chronic acyclovir.

- Ketoconazole.

- Amphotericin B.

- Corticosteroids at greater than physiologic replacement doses are strongly

discouraged.

- They should be used as briefly as possible and only for definite specific

indications.

Patient must conform to the following:

- Receiving or candidates for zidovudine therapy at least 500 mg/day under current

labeled indications with no history of pneumocystosis (PCP) or toxoplasmosis.

- Evidence of HIV infection documented by HIV antibody tests.

- T4 cell count less than 200 cells/mm3 at any time prior to study entry.

- Willing to sign informed consent.

- Willing to be followed by a participating ACTG center for duration of the study.

- Allowed: Concurrent enrollment in long-term follow-up studies in previously blinded

trials of AZT (ACTG 016 and 019).

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions are excluded:

- History of documented or presumed pneumocystosis (PCP) or toxoplasmosis.

- Active bacterial or mycobacterial infection.

- History of type I hypersensitivity, exfoliative rash, or rash with mucosal

involvement, severe bronchospasm, or other life-threatening reaction to any of the study drugs or to other sulfas, sulfones, or pentamidine.

- History of intolerance causing dose interruption while receiving zidovudine at equal

to or less than 600 mg/day or causing dose reduction to less than 500 mg/day within 4 weeks prior to entry.

- Advanced Kaposi's sarcoma or other malignancy not specifically allowed that has been

rapidly progressive during the month prior to enrollment or which may be expected to require chemotherapy within 90 days of study entry.

Concurrent Medication:

Excluded:

- Active primary treatment for an infection or malignancy.

- Other form of antifolate medication not specifically allowed.

- Other antiretroviral or biologic response modifier.

- Ganciclovir, if it causes intolerance to AZT equal to or more than 500 mg/day.

- Foscarnet.

Patients with the following are excluded:

- Symptoms and conditions defined in Exclusion Coexisting Conditions.

- Glucose 6-phosphate dehydrogenase deficiency (GPD).

- History of pneumocystosis (PCP) or toxoplasmosis.

- History of type I hypersensitivity, exfoliative rash, or rash with mucosal

involvement, severe bronchospasm, or other life-threatening reaction to any of the study drugs or to other sulfas, sulfones, or pentamidine.

- History of intolerance causing dose interruption while receiving zidovudine at equal

to or less than 500 mg/day with 4 weeks pior to study entry.

Prior Medication:

Excluded within 4 weeks of study entry:

- Any other form of pneumocystosis (PCP) chemoprophylaxis.

- Active substance abuse, including alcohol.

Univ of California / San Diego Treatment Ctr, San Diego, California 921036325, United States

Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr, Sylmar, California 91342, United States

Stanford at Kaiser / Kaiser Permanente Med Ctr, San Francisco, California 94115, United States

San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco, California 941102859, United States

Children's Hosp of Oakland, Oakland, California 946091809, United States

Stanford Private Practice, Redwood City, California, United States

Stanford Univ School of Medicine, Stanford, California 94305, United States

UCSD Treatment Ctr, San Diego, California 92103, United States

Los Angeles County - USC Med Ctr, Los Angeles, California 90033, United States

Northern California Pediatric AIDS Treatment Ctr / UCSF, San Francisco, California 94143, United States

George Washington Univ Med Ctr, Washington, District of Columbia 20037, United States

Whitman - Walker Clinic, Washington, District of Columbia 20009, United States

Univ of Miami School of Medicine, Miami, Florida 331361013, United States

Chicago Children's Memorial Hosp, Chicago, Illinois 606143394, United States

Cook County Hosp, Chicago, Illinois 60612, United States

Rush Presbyterian - Saint Luke's Med Ctr, Chicago, Illinois 60612, United States

Northwestern Univ Med School, Chicago, Illinois 60611, United States

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

Johns Hopkins Hosp, Baltimore, Maryland 21287, United States

Harvard (Massachusetts Gen Hosp), Boston, Massachusetts 02114, United States

Beth Israel Deaconess Med Ctr, Boston, Massachusetts 02215, United States

Beth Israel Deaconess - West Campus, Boston, Massachusetts 02215, United States

Boston Med Ctr, Boston, Massachusetts 02118, United States

Baystate Med Ctr of Springfield, Springfield, Massachusetts 01199, United States

Univ of Massachusetts Med Ctr, Worcester, Massachusetts 01655, United States

Univ of Minnesota, Minneapolis, Minnesota 55455, United States

SUNY / State Univ of New York, Syracuse, New York 13210, United States

SUNY - Stony Brook, Stony Brook, New York 117948153, United States

Jack Weiler Hosp / Bronx Municipal Hosp, Bronx, New York 10465, United States

Saint Luke's - Roosevelt Hosp Ctr, New York, New York 10025, United States

Montefiore Med Ctr / Bronx Municipal Hosp, Bronx, New York 10467, United States

SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York 14215, United States

Beth Israel Med Ctr / Peter Krueger Clinic, New York, New York 10003, United States

Duke Univ Med Ctr, Durham, North Carolina 27710, United States

Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States

Holmes Hosp / Univ of Cincinnati Med Ctr, Cincinnati, Ohio 452670405, United States

Univ Hosp of Cleveland / Case Western Reserve Univ, Cleveland, Ohio 44106, United States

Univ of Pittsburgh Med School, Pittsburgh, Pennsylvania, United States

Julio Arroyo, West Columbia, South Carolina 29169, United States

Univ of Washington, Seattle, Washington 98105, United States

Click here for more information about Zidovudine

Click here for more information about Pentamidine isethionate

Click here for more information about Sulfamethoxazole-Trimethoprim

Related publications:

Bozzette SA, Hays RD, Berry SH, Kanouse DE. A Perceived Health Index for use in persons with advanced HIV disease: derivation, reliability, and validity. Med Care. 1994 Jul;32(7):716-31.

Bozzette SA, Finkelstein DM, Spector SA, Frame P, Powderly WG, He W, Phillips L, Craven D, van der Horst C, Feinberg J. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med. 1995 Mar 16;332(11):693-9.

Glick ME. CTG studies yield results. AIDS Clinical Trials Group. NIAID AIDS Agenda. 1995 Spring;:8-9. No abstract available.

Justice AC, Rabeneck L, Hays RD, Wu AW, Bozzette SA. Sensitivity, specificity, reliability, and clinical validity of provider-reported symptoms: a comparison with self-reported symptoms. Outcomes Committee of the AIDS Clinical Trials Group. J Acquir Immune Defic Syndr. 1999 Jun 1;21(2):126-33.

Justice AC, Holmes W, Gifford AL, Rabeneck L, Zackin R, Sinclair G, Weissman S, Neidig J, Marcus C, Chesney M, Cohn SE, Wu AW. Development and validation of a self-completed HIV symptom index. J Clin Epidemiol. 2001 Dec;54 Suppl 1:S77-90.

Ioannidis JP, Dixon DO, McIntosh M, Albert JM, Bozzette SA, Schnittman SM. Relationship between event rates and treatment effects in clinical site differences within multicenter trials: an example from primary Pneumocystis carinii prophylaxis. Control Clin Trials. 1999 Jun;20(3):253-66.

DiRienzo AG, van Der Horst C, Finkelstein DM, Frame P, Bozzette SA, Tashima KT. Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced HIV infection. AIDS Res Hum Retroviruses. 2002 Jan 20;18(2):89-94.

Last updated: June 23, 2005