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

Inclusion Criteria

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.