A Study of Abacavir Plus Indinavir Sulfate Plus Efavirenz in HIV-Infected Patients

A Randomized, Phase II, Placebo Controlled Trial of Abacavir (ABC, 1592U89) in Combination With Open-Label Indinavir Sulfate (IDV) and Efavirenz (EFV, DMP-266) in HIV-Infected Subjects With Nucleoside Analog Experience: A Rollover Study for ACTG 320

To compare the virologic response between abacavir (ABC, 1592U89) regimens (drug vs. placebo) and between the 2 dosing regimens (BID vs. TID) with respect to the proportion of patients with plasma HIV RNA levels below the limit of detection [AS PER AMENDMENT 8/27/97: < 500 copies/ml at week 16]. To evaluate the safety and tolerance of the study arms. [AS PER AMENDMENT 3/10/99: During the extension period, compare the time to detectable viremia (2 consecutive plasma HIV RNA levels greater than or equal to 500 copies/ml) between ABC and placebo.] Therapeutically, there is a need to explore potent alternative therapy for patients who have received, or are currently receiving, a double nucleoside analog combination including lamivudine (3TC), a regimen that was proven to be clinically inferior to indinavir (IDV) when combined with zidovudine/3TC in study ACTG 320. In order to produce and maintain a maximal antiviral response, all patients in this study will receive 2 or 3 potent, new agents; ABC, a nucleoside analog, EFV, a non-nucleoside reverse transcriptase inhibitor (NNRTI), and IDV, a protease inhibitor. Virologically, the major question this protocol seeks to answer is how prior 3TC exposure in a dual nucleoside regimen influences the response to subsequent treatment. It is unclear whether it is best to add a protease inhibitor either 1) an NNRTI at 1 of 2 doses, or 2) an NNRTI at 1 of 2 doses plus a new nucleoside analog to achieve plasma HIV RNA levels that are below the limits of detection.

Therapeutically, there is a need to explore potent alternative therapy for patients who have received, or are currently receiving, a double nucleoside analog combination including lamivudine (3TC), a regimen that was proven to be clinically inferior to indinavir (IDV) when combined with zidovudine/3TC in study ACTG 320. In order to produce and maintain a maximal antiviral response, all patients in this study will receive 2 or 3 potent, new agents; ABC, a nucleoside analog, EFV, a non-nucleoside reverse transcriptase inhibitor (NNRTI), and IDV, a protease inhibitor. Virologically, the major question this protocol seeks to answer is how prior 3TC exposure in a dual nucleoside regimen influences the response to subsequent treatment. It is unclear whether it is best to add a protease inhibitor either 1) an NNRTI at 1 of 2 doses, or 2) an NNRTI at 1 of 2 doses plus a new nucleoside analog to achieve plasma HIV RNA levels that are below the limits of detection.

Prior to randomization, patients are stratified by CD4 cell count (cells/mm3): less than or equal to 50 versus greater than 50 and by ACTG 320 participation: enrolled versus not enrolled. Patients with greater than 50 CD4 cells/mm3 are randomized to 1 of 4 treatment arms (Arms I, II, III, or IV) and patients with less than or equal to 50 CD4 cells/mm3 are randomized to 1 of 2 treatment arms (Arms I and II). All patients will be followed for 48 weeks beyond the enrollment of the last patient. The regimens for the treatment arms are as follows: Arm I - indinavir (IDV) plus EFV plus ABC placebo bid, Arm II - IDV (higher dose) plus EFV (lower dose) plus ABC, Arm III - IDV plus EFV plus ABC placebo, and Arm IV - IDV (higher dose) plus EFV (lower dose) plus ABC. If 15 week data indicates this is a reasonable dosing regimen, the sample size in Arms III and IV will be expanded to include additional patients with a CD4 count greater than 50 cells/mm3 and allow for equal enrollment across all 4 treatment arms. Those patients who roll over from ACTG 320 will be assigned to receive open-label treatment on Arm II and evaluated independently of the 4 treatment arms listed above.

[AS PER AMENDMENT 8/27/97: Patients with 2 consecutive HIV RNA measurements at least 500 copies/ml at week 16 or anytime thereafter are given the option to receive open-label treatment with IDV plus EFV plus ABC, or to seek the best available therapy outside of the study. NOTE: Patients who choose the open-label combination may take other prescribed nucleoside analogs provided outside the study.] [AS PER AMENDMENT 12/17/97: It is strongly recommended that patients who reach a confirmed endpoint and elect to receive open-label therapy consider adding additional approved (and novel, if possible) antiretroviral agents to their open-label regimen.] [AS PER AMENDMENT 1/12/98: Patients who choose the open-label combination may receive other approved antiretrovirals obtained outside the study provided the ACTG 368 team approves the combination.] [AS PER AMENDMENT 8/7/98: Subjects will take study medications for a maximum of 96 weeks, depending on their time of study enrollment.] [AS PER AMENDMENT 3/10/99: A 24-week extension, which will end July 30, 1999, has been added to the study. The extension applies to subjects currently on blinded Step 1 treatment, on open-labeled Step 2, or on study but off treatment. Subjects are to be unblinded in their study treatment and followed for the remainder of the extension. Subjects continue on their current study drug schedule. Subjects on blinded IDV plus EFV who, upon unblinding (not failure) decide to add prescription ABC to their regimen, will be considered off study treatment and will be followed for the duration of the extension; those already registered on Step 2 will continue their Step 2 therapy. Any subject who does not wish to continue on the study extension will be unblinded to their original randomized regimen. Subjects who experience virologic failure during the extension should seek best available treatment following current recommendations to use as many approved, novel antiretroviral agents as possible. The new drug regimen may incorporate any or all of the study drugs.]

Inclusion Criteria

Concurrent Medication:

Allowed:

• Chemoprophylaxis for Pneumocystis carinii pneumonia is required for all patients who have a CD4 cell count <= 200 cells/mm3.
• Topical and/or oral antifungal agents are permitted except for oral ketoconazole.
• Treatment, maintenance or chemoprophylaxis with approved agents for opportunistic infections as clinically indicated, except for rifabutin.
• All antibiotics as clinically indicated.
• Systemic corticosteroid use for <= 21 days for acute problems is permitted as medically indicated; chronic systemic corticosteroid use is not permitted, unless it is within physiologic replacement levels.
• Recombinant erythropoietin and granulocyte colony-stimulating factor are permitted as medically indicated.
• Regularly prescribed medications such as antipyretics, analgesics, allergy medications (except for terfenadine (Seldane) and astemizole (Hismanal)), antidepressants, sleep medications, oral contraceptives, megestrol acetate, testosterone or any other medications are permitted as medically indicated.

NOTE:

• Due to the possibility that EFV or ABC may alter the effectiveness of oral contraceptives or depo-progesterone, oral contraceptives or depo-progesterone must not be used as the sole form of birth control. [AS PER AMENDMENT 8/7/98: adequate birth control is hormonal plus barrier method or two barrier methods].
• Alternative therapies such as vitamins, acupuncture, and visualization techniques will be permitted. Herbal medications should be avoided. Patients should report the use of these therapies; alternative therapies will be recorded. [AS PER AMENDMENT 8/7/98: Due to the likelihood of IDV increasing the concentrations of sildenafil (Viagra) when coadministered, it is suggested that subjects who use viagra take the lowest dose (25 mg, i.e., half the typical dose).]

Both NIAID ACTG 320 participants and non-ACTG 320 patients must have:

• Documented HIV-1 infection.
• Written informed consent from parent or legal guardian for those patients < 18 years old.

Non-ACTG 320 patients must have:

• Documented CD4 cell count <= 200 cells/mm3 at the time of initiation of ZDV (or d4T) plus 3TC therapy [AS PER AMENDMENT 12/17/97:
• Documented CD4 cell count <= 250 cells/mm3 within 3 months of initiation of ZDV (or d4T) plus 3TC therapy].

Prior Medication:

Required:

For ACTG 320 patients:

• Patients must have participated in ACTG 320 with original randomization to the double-nucleoside combination arm, and maintenance of that treatment (on-study/on-treatment in ACTG 320) until enrollment into ACTG 368.

For non-ACTG 320 patients:

• Greater than or equal to 3 months [2 months AS PER AMENDMENT 12/17/97] of therapy with ZDV (or d4T) + 3TC and receiving ZDV (or d4T) + 3TC at the time of entry.

Exclusion Criteria

Co-existing Condition:

Non-ACTG 320 patients with the following symptoms and conditions are excluded:

Malignancy that requires systemic therapy other than minimal Kaposi's sarcoma.

NOTE:

• Minimal Kaposi's sarcoma, defined as <= 5 cutaneous lesions and no visceral disease or tumor-associated edema, allowed, provided systemic therapy not required.

Non-ACTG 320 patients with the following prior conditions or symptoms are excluded:

• Unexplained temperature > 38.5 degrees C for 7 consecutive days.
• Chronic diarrhea defined as > 3 liquid stools per day persisting for 15 days, within 30 days prior to entry.
• Proven or suspected acute hepatitis within 30 days prior to entry, even if AST (SGOT) and ALT (SGPT) are <= 5 X ULN.

Concurrent Medication: Excluded:

• All antiretroviral therapies other then study medications.
• Rifabutin and rifampin.
• Investigational drugs without specific approval from the protocol chair.
• Systemic cytotoxic chemotherapy.
• Oral ketoconazole (Nizoral), terfenadine (Seldane), astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion), and midazolam (Versed).
• Caution should be taken in the consumption of alcoholic beverages with study medications.
• Itraconazole.

Prior Medication: Excluded: For ACTG 320 patients:

• Those who opted to receive open-label IDV while on ACTG 320, or if they switched to open label IDV during the study.

For non-ACTG 320 patients:

• Acute therapy for an infection or other medical illness within 14 days prior to entry.
• Prior protease inhibitor therapy.
• Prior NNRTI therapy (approved or experimental).
• Erythropoietin, G-CSF or GM-CSF within 30 days prior to entry.
• Interferons, interleukins or HIV vaccines within 30 days prior to entry.
• Any experimental therapy within 30 days prior to entry.
• Rifampin or rifabutin within 14 days prior to entry.