Treatment Success and Failure in HIV-Infected Subjects Receiving Indinavir in Combination With Nucleoside Analogs: A Rollover Study for ACTG 320

Condition(s) targeted: HIV Infections

Intervention: Indinavir sulfate (Drug); Abacavir sulfate (Drug); Nelfinavir mesylate (Drug); Efavirenz (Drug); Levocarnitine (Drug); Adefovir dipivoxil (Drug); Lamivudine (Drug); Stavudine (Drug); Zidovudine (Drug); Didanosine (Drug)

Phase: Phase 2

Status: Completed

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

Official(s) and/or principal investigator(s):
Scott Hammer, Study Chair

Group A:

To compare the time to confirmed virologic failure (2 consecutive plasma HIV-RNA concentrations of 500 copies/ml or more) between the treatment arms: abacavir (ABC) or placebo in combination with zidovudine (ZDV), lamivudine (3TC), and indinavir (IDV). To evaluate the safety and tolerability of these treatment arms. [AS PER AMENDMENT 06/16/99: To compare the time to confirmed treatment failure, permanent discontinuation of treatment, or death between the treatment arms.] [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is applicable.]

Group B:

To compare the proportion of patients who achieve plasma HIV-1 RNA concentrations below 500 copies/ml, as assessed by the standard Roche Amplicor assay at Week 16, or to compare the absolute changes in plasma HIV-1 RNA concentrations at Week 16 across the treatment arms: ABC or approved nucleoside analogs and nelfinavir (NFV) or placebo in combination with efavirenz (EFV) and adefovir dipivoxil. To compare the safety and tolerability of these treatment arms.

Group C:

To monitor plasma HIV-1 RNA trajectory over time and determine the time to a confirmed plasma HIV-1 RNA concentration above 2,000 copies/ml on 2 consecutive determinations for patients treated with ZDV or stavudine (d4T) plus 3TC and IDV.

Group D:

To evaluate plasma HIV-1 RNA responses at Weeks 16 and 48. To evaluate the safety and tolerability of the treatment arms: ABC, EFV, adefovir dipivoxil, and NFV.

This study explores new treatment options for ACTG 320 enrollees (and, if needed, a limited number of non-ACTG 320 volunteers) who have been receiving ZDV (or d4T) plus 3TC and IDV and are currently exhibiting a range of virologic responses. By dividing the study into the corresponding, nonsequential cohorts (Groups A, B, C, D), different approaches to evaluating virologic success, i. e., undetectable plasma HIV-1 RNA levels, and virologic failure, i. e., plasma HIV-1 RNA levels of 500 copies/ml or more [AS PER AMENDMENT 12/27/01: 200 copies/ml or more], are explored while maintaining long-term follow-up of ACTG 320 patients. [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is applicable. This study will examine the question of whether intensification of therapy can prolong the virologic benefit in individuals whose plasma HIV-1 RNA concentrations have been below the limits of assay detection on ZDV (or d4T) plus 3TC plus IDV.]

Official title: A Phase II Study of the Prolongation of Virologic Success (ACTG 372A) and Options for Virologic Failure (ACTG B/C/D) in HIV-Infected Subjects Receiving Indinavir in Combination With Nucleoside Analogs: A Rollover Study for ACTG 320

Study design: Treatment, Double-Blind, Safety Study

Detailed description: This study explores new treatment options for ACTG 320 enrollees (and, if needed, a limited number of non-ACTG 320 volunteers) who have been receiving ZDV (or d4T) plus 3TC and IDV and are currently exhibiting a range of virologic responses. By dividing the study into the corresponding, nonsequential cohorts (Groups A, B, C, D), different approaches to evaluating virologic success, i. e., undetectable plasma HIV-1 RNA levels, and virologic failure, i. e., plasma HIV-1 RNA levels of 500 copies/ml or more [AS PER AMENDMENT 12/27/01: 200 copies/ml or more], are explored while maintaining long-term follow-up of ACTG 320 patients. [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is included. This study will examine the question of whether intensification of therapy can prolong the virologic benefit in individuals whose plasma HIV-1 RNA concentrations have been below the limits of assay detection on ZDV (or d4T) plus 3TC plus IDV.]

Rollover patients from ACTG 320 are given enrollment priority and permitted to enroll in all 4 study groups; non-ACTG patients are permitted to enroll in Groups A and B if accrual objectives are not met with ACTG 320 patients.

GROUP A:

Patients with screening plasma HIV-1 RNA concentrations below 500 copies/ml are randomized to 1 of 2 treatment arms and stratified according to their participation in ACTG 320 (original randomization to IDV versus open-label IDV). The 2 treatment arms are as follows:

ARM A1: IDV plus ZDV (or d4T) plus 3TC plus ABC. ARM A2: IDV plus ZDV (or d4T) plus 3TC plus ABC placebo. Patients who achieve a plasma HIV-1 RNA level of 500 copies/ml or more on 2 consecutive determinations may continue their assigned arm in a blinded fashion, or seek the best alternative therapy selected by the local investigator or primary care physician.

GROUP B:

Nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients with plasma HIV-1 RNA plasma concentrations of 500 copies/ml or more are randomized to 1 of 4 treatment arms and stratified by plasma HIV-1 RNA concentrations (above versus below 15,000 RNA copies/ml) and participation in ACTG 320 (original randomization to IDV versus open-label IDV). The treatment arms are as follows:

ARM B1: ABC plus EFV plus adefovir dipivoxil plus NFV. ARM B2: ABC plus EFV plus adefovir dipivoxil plus NFV placebo. ARM B3: 2 nucleoside reverse transcriptase inhibitors (NRTIs) (or 1 if 2 not tolerated) (chosen from ZDV, 3TC, d4T, or didanosine [ddI]) plus EFV plus adefovir dipivoxil plus NFV.

ARM B4: 2 NRTIs (or 1 if 2 not tolerated) (chosen from ZDV, 3TC, d4T, or ddI) plus EFV plus adefovir dipivoxil plus NFV placebo.

GROUP C:

NNRTI-naive patients with plasma HIV-1 RNA concentrations of 500-2,000 copies/ml at screening may elect to be randomized to a treatment arm in Group B or continue with their current ACTG 320 regimen as follows:

ARM C: ZDV (or d4T) plus 3TC plus IDV. Patients who elect this treatment are randomized in Group B if their plasma HIV-1 RNA concentrations are confirmed to be above 2,000 copies.

GROUP D:

NNRTI-experienced, ACTG 320 patients with screening plasma HIV-1 RNA concentrations of 500 copies/ml or more receive open-label treatment as follows:

ARM D: ABC plus EFV plus adefovir dipivoxil plus NFV. [AS PER AMENDMENT 06/29/98: Enrollment to Group B is closed to accrual. Group A patients with HIV-1 RNA of 200 copies/ml or more on 2 consecutive determinations may continue their assigned treatment or seek best alternative antiretroviral therapy, which may include access to ABC. Group B patients with plasma HIV-1 RNA of 500 copies/ml or more may continue their assigned treatment or seek best available antiretroviral therapy, which may include access to ABC, EFV, and adefovir dipivoxil with L-carnitine supplementation. Group C patients with HIV-1 RNA levels above 2,000 copies/ml and Group D patients with levels above 500 copies/ml may no longer be randomized to a treatment arm in Group B. Such patients may continue their assigned treatment or seek best available therapy, which may include access to therapy as per Group B patients.] [AS PER AMENDMENT 06/16/99: Study treatment for Groups B, C, and D has been completed. Group A patients with a confirmed plasma HIV-2 endpoint who remain on study may have access to ABC while on study.] [AS PER AMENDMENT 12/27/01: With Version 4. 0 of the protocol, many of the metabolic assessments and the cardiovascular risk assessment will be repeated, and a self-reported questionnaire of body shape changes will be added. In addition, an investigation of the effect of long-term IDV on pyuria/hematuria is added, as well as a study of HIV-1 RNA in peripheral blood mononuclear cells (PBMCs).]

Minimum age: 16 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria

Concurrent Medication:

Required:

- Chemoprophylaxis for Pneumocystis carinii pneumonia for all patients with a CD4 cell

count of 200 cells/mm3 or less.

Allowed:

- Treatment, maintenance, or chemoprophylaxis, including topical and/or oral antifungal

agents unless otherwise excluded by the protocol.

- All antibiotics as clinically indicated, unless otherwise excluded in the protocol.

- Systemic corticosteroid use for 21 days or less for acute problems as medically

indicated. Chronic corticosteroid use is not permitted, unless it is within physiologic replacement levels. Study team must be contacted in these instances.

- rEPO and G-CSF as medically indicated.

- Regularly prescribed medications such as [AS PER AMENDMENT 06/29/98: alternative,

FDA-approved antiretrovirals not supplied by the study] [AS PER AMENDMENT 12/27/01: or unapproved antiretrovirals available by expanded access (when permanently discontinued from randomized study treatment)], antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, megestrol acetate, testosterone, or any other medications not otherwise excluded by the protocol, as medically indicated.

- [AS PER AMENDMENT 12/27/01: Supplemental and] alternative therapies such as vitamins,

acupuncture, and visualization techniques.

Recommended as an alternative agent for chemoprophylaxis against Mycobacterium avium complex for patients randomized to EFV in Group B or D:

- clarithromycin or azithromycin.

Patients must have:

- HIV-1 infection as documented by any licensed ELISA test kit and confirmed by either a

Western Blot, HIV culture, HIV antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA at any time prior to study entry.

Non-ACTG patients:

- Documented CD4 cell count of 200 cells/mm3 or less at the time of initiation of ZDV

(or d4T) plus 3TC plus IDV.

- Signed, informed consent from a parent or legal guardian for patients under 18 years

of age.

Prior Medication:

Required:

Non-ACTG 320 patients:

- At least 3 months prior therapy with ZDV (or d4T) plus 3TC plus IDV and continued

receipt of ZDV (or d4T) plus 3TC plus IDV until enrollment. IDV and 3TC must have been initiated concurrently.

ACTG patients:

- Randomization to the ZDV (or d4T) plus 3TC plus IDV combination arm or receipt of

open-label prior to unblinding and maintenance of that treatment as participation in ACTG 320.

Group D:

- Prior NNRTI-exposure.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions and symptoms are excluded:

- Unexplained temperature above 38. 5 C for any 7 days or chronic diarrhea, defined as

more than 3 liquid stools per day persisting for 15 days, within 30 days prior to study treatment.

- AIDS-related malignancy, other than minimal Kaposi's sarcoma that requires systemic

chemotherapy. Minimal Kaposi's sarcoma is defined as 5 or fewer cutaneous lesions and no visceral disease or tumor-associated edema that does not require systemic therapy.

- Documented or suspected acute hepatitis within 30 days prior to study entry,

irrespective of laboratory values.

Concurrent Medication:

Excluded:

- All antiretroviral therapies other than study [AS PER AMENDMENT 06/16/99: provided]

medications, [AS PER AMENDMENT 06/16/99: unless approved by the protocol chairs] [AS PER AMENDMENT 12/27/01: while on original randomized treatment.]

- Rifabutin and rifampin.

- Investigational agents without specific approval from the protocol chair.

- Systemic cytotoxic chemotherapy.

- Oral ketoconazole and itraconazole. NOTE: Itraconazole may be permitted for Group B

and Group D patients if fluconazole is not an option.

- Terfenadine, astemizole, cisapride, triazolam, midazolam, amiodarone, quinine, ergot

derivatives, isotretinoin, [AS PER AMENDMENT 12/27/01: pimozide, St. John's Wort, and milk thistle.]

- [AS PER AMENDMENT 12/27/01: Concomitant use of lovastatin or simvastatin is not

recommended because of potential drug interactions. Pravastatin or atorvastatin may be used after consultation with the Study Team.]

To be avoided:

- Herbal medications.

Prior Medication:

Excluded:

- Any prior protease inhibitor therapy other than indinavir.

- Interferons, interleukins, or HIV vaccines within 30 days prior to study entry.

- Any experimental therapy within 30 days prior to study entry.

- Rifampin, rifabutin, ketoconazole, or itraconazole within 14 days of study entry.

Non-ACTG patients:

- Acute therapy for an infection or other medical illness within 14 days prior to study

therapy.

- NNRTI therapy prior to study entry (with the exception of Group D).

- Recombinant erythropoietin (rEPO), granulocyte colony-stimulating factor (G-CSF,

filgrastim), or granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) within 30 days prior to study entry.

Caution should be taken in the consumption of alcoholic beverages with study medications.

Univ of Puerto Rico, San Juan 009365067, Puerto Rico

Univ of Alabama at Birmingham, Birmingham, Alabama 35294, United States

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

Stanford Univ Med Ctr, Stanford, California 943055107, United States

Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States

Harbor UCLA Med Ctr, Torrance, California 90502, United States

San Mateo AIDS Program / Stanford Univ, Stanford, California 943055107, United States

Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium, San Jose, California 951282699, United States

Univ of Colorado Health Sciences Ctr, Denver, Colorado 80262, United States

Howard Univ, Washington, District of Columbia 20059, United States

Georgetown Univ Hosp, Washington, District of Columbia 20037, United States

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

Emory Univ, Atlanta, Georgia 30308, United States

Queens Med Ctr, Honolulu, Hawaii 96816, United States

Univ of Hawaii, Honolulu, Hawaii 96816, United States

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

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

Cook County Hosp, Chicago, Illinois 60612, United States

Louis A Weiss Memorial Hosp, Chicago, Illinois 60640, United States

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

Methodist Hosp of Indiana / Life Care Clinic, Indianapolis, Indiana 46202, United States

Division of Inf Diseases/ Indiana Univ Hosp, Indianapolis, Indiana 46202, United States

Univ of Iowa Hosp and Clinic, Iowa City, Iowa 52242, United States

Tulane Univ School of Medicine, New Orleans, Louisiana 70112, 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

Univ of Minnesota, Minneapolis, Minnesota 55455, United States

St Louis Regional Hosp / St Louis Regional Med Ctr, St Louis, Missouri 63112, United States

Univ of Nebraska Med Ctr, Omaha, Nebraska 681985130, United States

St Vincent's Hosp / Mem Sloan-Kettering Cancer Ctr, New York, New York 10021, United States

Univ of Rochester Medical Center, Rochester, New York 14642, United States

Bellevue Hosp / New York Univ Med Ctr, New York, New York 10016, United States

Mount Sinai Med Ctr, New York, New York 10029, United States

Cornell Univ Med Ctr, New York, New York 10021, United States

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

Beth Israel Med Ctr, New York, New York 10003, United States

Chelsea Ctr, New York, New York 10021, United States

Carolinas Med Ctr, Charlotte, North Carolina 28203, United States

Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States

Moses H Cone Memorial Hosp, Greensboro, North Carolina 27401, United States

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

Univ of Cincinnati, Cincinnati, Ohio 452670405, United States

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

MetroHealth Med Ctr, Cleveland, Ohio 441091998, United States

Univ of Kentucky Lexington, Cincinnati, Ohio 45267, United States

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

Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr, Knoxville, Tennessee 37920, United States

Vanderbilt Univ Med Ctr, Nashville, Tennessee 37203, United States

Univ Texas Health Science Ctr / Univ Texas Med School, Houston, Texas 77030, United States

Univ of Texas Galveston, Galveston, Texas 775550435, United States

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Related publications:

Henry K, Zackin R, Dube M, Hammer S, Currier J. ACTG 5056: metabolic status and cardiovascular disease risk for a cohort of HIV-1-infected persons durably suppressed on an indinavir-containing regimen (ACTG 372A). 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 656)

Hammer S, Squires K, Degruttola V, Fischl M, Bassett R, Demeter L, Hertogs K, Larder B. Randomized trial of abacavir (ABC) & nelfinavir (NFV) in combination with efavirenz (EFV) & adefovir dipivoxil (ADV) as salvage therapy in patients with virologic failure receiving indinavir (IDV). Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:159 (abstract no 490)

Hammer SM, Bassett R, Squires KE, Fischl MA, Demeter LM, Currier JS, Mellors JW, Morse GD, Eron JJ, Santana JL, DeGruttola V; ACTG 372B/D Study Team. A randomized trial of nelfinavir and abacavir in combination with efavirenz and adefovir dipivoxil in HIV-1-infected persons with virological failure receiving indinavir. Antivir Ther. 2003 Dec;8(6):507-18. No abstract available.

Last updated: August 4, 2006