A Study to Evaluate Various Combinations of Anti-HIV Medications to Treat Early HIV Infection

Study of Protease Inhibitor and/or Non-Nucleoside Reverse Transcriptase Inhibitor With Dual Nucleosides in Initial Therapy of HIV Infection

The purpose of this study is to compare the effectiveness of various combinations of anti-HIV drugs in HIV-positive men and women. Patients receive specific combinations of 3 or 4 of the following 6 drugs: didanosine (ddI), stavudine (d4T) efavirenz (EFV), nelfinavir (NFV), lamivudine (3TC), or zidovudine (ZDV).

Anti-HIV therapy is effective in preventing the spread of HIV in the body. However, patients often experience unpleasant side effects and have difficulties following the dosing schedule. This study looks for combinations of anti-HIV drugs ("cocktails") which will be the most effective with the fewest problems.

Highly active antiretroviral therapy, though effective in the suppression of HIV proliferation, is often complicated by difficulties with adherence and drug toxicity. Various combinations of highly active antiretroviral therapy exist; all have proved efficacious in related trials. The question addressed in this trial is which combination of antiretroviral "cocktails" provides the single greatest advantage in preventing the spread of HIV in the body. In effect, which therapy provides the greatest benefit with the fewest complications.

Step 1: Patients are randomized to 1 of 6 arms:

Arm A: didanosine (ddI), stavudine (d4T), efavirenz (EFV), and nelfinavir (NFV) placebo.

Arm B: ddI, d4T, EFV placebo, and NFV. Arm C: lamivudine (3TC)/zidovudine (ZDV), EFV, and NFV placebo. Arm D: 3TC/ZDV, EFV placebo, and NFV. Arm E: ddI, d4T, EFV, and NFV. Arm F: 3TC/ZDV, EFV, and NFV. Patients with virologic failure on 2 successive measurements or study-drug intolerance discontinue their randomized study therapy and proceed to Step 2. [AS PER AMENDMENT 7/5/00: Patients must switch regimens as soon as possible after confirmation of virologic failure to prevent development of drug resistance.]

Step 2:

Arm A: Patients receive treatment as in Arm D of Step 1. Arm B: Patients receive treatment as in Arm C of Step 1. Arm C: Patients receive treatment as in Arm B of Step 1. Arm D: Patients receive treatment as in Arm A of Step 1. Arms A, B, C, and D: Patients who fail Step 2 treatment proceed to Step 3. Arms E and F: Patients with virologic failure on Step 1 proceed immediately to Step 3.

Step 3 (salvage therapy):

Arm A, B, C, and D: Patients receive indinavir (IDV), amprenavir (APV), ddI, and hydroxyurea (HU).

[AS PER AMENDMENT 7/5/00: Patients now receive treatment on Regimen 1, 2, 3, 4, 5, or 6. Regimen 1 consists of IDV, ritonavir (RTV), ddI, and HU. Regimen 2 consists of APV, RTV, ddI, and HU. Regimen 3 consists of IDV, RTV, abacavir (ABC), and 3TC/ZDV. Regimen 4 consists of APV, RTV, ABC, and 3TC/ZDV. Regimen 5 consists of IDV, RTV, ABC, d4T, and 3TC. Regimen 6 consists of APV, RTV, ABC, d4T, and 3TC.] Arm E: Patients receive IDV, APV, and 3TC/ZDV. [AS PER AMENDMENT 7/5/00: Patients now receive treatment on Regimen 7 or 8. Regimen 7 consists of IDV, RTV, and 3TC/ZDV. Regimen 8 consists of APV, RTV, and 3TC/ZDV.] Arm F: Patients receive IDV, APV, ddI, and d4T. [AS PER AMENDMENT 7/5/00: Patients now receive treatment on Regimen 9 or 10. Regimen 9 consists of IDV, RTV, ddI, and d4T. Regimen 10 consists of APV, RTV, ddI, and d4T.] [AS PER AMENDMENT 7/5/00: Patients already enrolled in Step 3 before site registration to Version 4.0 of this protocol have the option of receiving 1 of the appropriate new Step 3 regimens as outlined above or staying on their originally assigned Step 3 therapy.] [AS PER AMENDMENT 3/21/01: If virologic failure on Step 1 or 2 is confirmed, then HIV-1 RNA genotype resistance testing (in real-time, if possible) is performed. Patients receive 1 of the Step 3 drug regimens based on the results of the resistance testing.] Patients may co-enroll in metabolic, pharmacologic, immunologic, or adherence substudies.

Inclusion Criteria

Concurrent Medication:

[Required: AS PER AMENDMENT 7/5/00:

• Chemoprophylaxis for Pneumocystis carinii pneumonia if CD4+ cell count is less than or equal to 200 cells/mm3.]

[Suggested as an alternative agent for chemoprophylaxis against Mycobacterium avium complex:

• Azithromycin.]

[Allowed: AS PER AMENDMENT 7/5/00:

• Topical and oral antifungal agents. Oral itraconazole may be administered concurrently with IDV if the dose of IDV is reduced to 600 mg every 8 hours.
• Treatment, maintenance, or chemoprophylaxis for opportunistic infections, as clinically indicated unless otherwise prohibited by the protocol.
• All antibiotics, as clinically indicated unless otherwise prohibited by the protocol.
• Systemic corticosteroid use for 21 days or less for acute problems, as medically indicated.
• Recombinant erythropoietin (rEPO, epoetin alfa, Epogen, epoetin beta, Marogen), granulocyte colony-stimulating factor (G-CSF, filgrastim, Neupogen), and granulocyte-macrophage colony-stimulating factor (GM-CSF, Regramostim).
• Regularly prescribed medications, such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, megestrol acetate (Megace), testosterone, or any other medications, as medically indicated unless otherwise prohibited by the protocol. NOTE: Due to the possibility that study medications may alter the effectiveness of oral contraceptives or depoprogesterone, these agents must not be used as the sole form of birth control, because the role of some study medications on the effectiveness of these methods has not yet been established.
• Alternative therapies, such as vitamins.
• Medications requiring low gastric pH if not administered at the same time as buffered ddI. Patients taking these agents should do so at least 2 hours before ddI.]
• Vaccinations, if administered at least 2 weeks prior to an HIV RNA viral load evaluation.

[Allowed with caution: AS PER AMENDMENT 7/5/00:

• Oral ketoconazole with IDV.

Medications that interact with PIs as substrates, inhibitors, or inducers, including, but not limited to:

• allopurinol, alprazolam, amitriptyline, atorvastatin, bupropion, carbamazepine, cerivastatin, chlorpheniramine, chlorpromazine, chlorzoxazone, cimetidine, clarithromycin, clofibrate, clorazepate, clozapine, codeine, dapsone, desipramine, diazepam, diltiazem, disopyramide, encainide, erythromycin, estazolam, estrogens and progesterones, fluoxetine, flurazepam, fluvastatin, glucocorticoids, hypericum perforatum (St. John's wort), imipramine, isoniazid, itraconazole, ketoconazole, labetalol, lamotrigine, lidocaine, lovastatin, mexiletine, morphine, naloxone, nefazodone, nifedipine, nortriptyline, opioids, oxazepam, pentazocine, phenobarbital, phenytoin, promethazine, propofol, propranolol and other beta blockers, sildenafil, simvastatin, temazepam, T3 (thyroid hormone), warfarin, valproic acid, and zolpidem.
• Drugs with high protein-binding properties, nephrotoxic drugs, and opiate agonists (e.g., methadone or buprenorphine).]

NOTE:

• Refer to package insert for potential drug interactions with IDV, RTV, NFV, or APV that may require therapeutic drug monitoring and/or adjustment of concomitant medications.]

[Allowed with extreme caution:

• AS PER AMENDMENT 7/5/00:

ddI, as clinically indicated in patients with known risk factors, including, but not limited to, alcohol abuse, morbid obesity, hypertriglyceridemia, cholelithiasis, endoscopic retrograde cholangiopancreatography, use of medications known to cause pancreatitis (e.g., pentamidine) and use of medications known or thought to increase exposure to ddI (e.g., HU, allopurinol).]

Concurrent Treatment:

[Allowed:

• AS PER AMENDMENT 7/5/00:

Acupuncture and visualization techniques.]

Patients must have:

• HIV infection, as documented by any licensed ELISA test kit and confirmed by either 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.
• Plasma HIV-1 RNA of 500 copies/ml or more, confirmed by the Roche Amplicor assay only and performed within 60 days [AS PER AMENDMENT 5/5/99:
• 70 days] of study entry by any certified laboratory.
• Inclusion laboratory parameters, documented within 14 days prior to study entry (see lab values).

[AS PER AMENDMENT 9/9/99:

• Co-enrollment on ACTG A5005s (Metabolism Substudy) is required for patients enrolling under Version 3.0 of ACTG 384.]

Risk Behavior:

[Allowed with caution:

• AS PER AMENDMENT 7/5/00:

Alcoholic beverages.]

Exclusion Criteria

Co-existing Condition:

Patients with the following condition are excluded:

AIDS-related malignancy other than minimal Kaposi's sarcoma.

Concurrent Medication:

[Excluded:

• AS PER AMENDMENT 7/5/00:
• Chronic systemic corticosteroids.
• For Steps 1 and 2, all antiretroviral therapies other than study medications. For step 3, contact the team to discuss potential addition or substitution with off-study antiretroviral medications.
• Investigational drugs without specific approval from the study chairs.
• Neurotoxic and pancreatotoxic drugs.
• Systemic cytotoxic chemotherapy.
• Amiodarone, astemizole, bepridil, cisapride, cholestyramine, ergot and ergot derivatives, flecainide, ganciclovir, interferon alfa, midazolam (unless used for sedation on ACTG 723), pimozide, propafenone, propoxyphene, quinidine, ribavirin, rifampin, sucralfate, terfenadine, and triazolam.
• Rifabutin for patients on RTV in Step 3 and for patients on Steps 1 and 2 because of the contradictory effects of EFV and NFV on plasma rifabutin levels. If a patient on Step 1 or 2 requires treatment with rifabutin after coming on the study, the team must be notified.
• Alpha tocopherol (vitamin E) supplementation since vitamin E is contained in the soft gelatin capsule formulation of APV.
• ddI concurrently with IV pentamidine.
• Herbal medications.]

Patients with the following prior conditions are excluded:

• Pancreatitis within 3 years of study entry.
• Current peripheral neuropathy grade 2 or greater or history of peripheral neuropathy grade 3 or greater.
• Documented or suspected acute hepatitis within 30 days prior to study entry.
• Unexplained temperature above 38.5 C for any 7 days or chronic diarrhea (defined as more than 3 liquid stools per day persisting for more than 15 days) within 30 days prior to study entry.
• Any previous hypersensitivity to study drugs or their components.

Prior Medication:

Excluded:

• Receipt within 30 days of erythropoietin, G-CSF, or GM-CSF.
• Treatment within 14 days of study entry with any of the following:
• amiodarone, astemizole, cisapride, ergot or ergot derivatives, ketoconazole, midazolam, propoxyphene, quinidine, rifampin, terfenidine, or triazolam.
• Prior antiretroviral therapy for 7 days or more, including protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs). [AS PER AMENDMENT 5/5/99:
• Systemic ketoconazole or itraconazole, intravenous pentamidine, and rifabutin are prohibited. Midazolam is allowed for sedation in patients participating on ACTG 723.]
• Any vaccination within 14 days prior to study entry.
• Any immunomodulator or investigational therapy within 30 days prior to study entry.

[AS PER AMENDMENT 5/5/99:

• 6. Rifabutin is discouraged.]

Prior Treatment:

Excluded:

• Acute therapy for an infection or other medical illness within 14 days prior to study entry.

[AS PER AMENDMENT 5/5/99:

• Acute therapy for a serious infection or other serious medical illness that is potentially life-threatening and requires systemic therapy and/or hospitalization within 14 days of study entry. Patients with Pneumocystis carinii pneumonia must have completed acute therapy at least 7 days prior to entry and be clinically stable. Patients with other serious infection or serious medical illness who must continue chronic therapy must have completed at least 14 days of therapy prior to entry and be clinically stable. Patients with all other infections or medical illnesses must have completed therapy, or at least 14 days of maintenance therapy, prior to entry and be clinically stable (restrictions do not apply to oral and vaginal candidiasis, mucocutaneous herpes simplex infection, and minor skin conditions).]

Risk Behavior:

Excluded:

• Possible current substance abuse that could prevent compliance with the study medication.