Prior ACTG studies have shown that the 3-drug combination regimen (IDV/ZDV/3TC) resulted in improved clinical outcomes and therefore may prolong the effects of therapy. The enhanced effects seen with combination therapies are likely related to a greater suppression of RNA replication and alterations in resistance patterns. Due to the progressive success of combination regimens, it is possible that more potent regimens will further enhance viral suppression and provide more durable treatment responses. In light of the additive suppression of HIV replication determined by pharmacological, immunological, and virological results, nelfinavir (NFV) as an addition to IDV/ZDV/3TC will be evaluated. Based on the potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) to suppress viral replication and the effectiveness of 3-drug regimens containing NNRTIs, efavirenz (EFV) will also be evaluated as an addition to IDV/ZDV/3TC. Patients with HIV infection, CD4 cell count less than or equal to 200 cells/mm3 or plasma HIV RNA greater than or equal to 100,000 copies/ml, and limited (no prior 3TC, NNRTI, or protease inhibitor) or no prior antiretroviral treatment are randomized to 1 of 3 arms. Patients are stratified by CD4 cell count (less than or equal to 50 cells/mm3 vs greater than 50 cells/mm3), HIV-1 RNA copy number (less than or equal to 40,000 copies/ml vs greater than 40,000 copies/ml), and prior antiretroviral therapy (no therapy vs any therapy), and then randomly assigned to 1 of 3 treatment arms: Arm 1: 3TC plus ZDV plus IDV. Arm 2: 3TC plus ZDV plus IDV plus EFV. Arm 3: 3TC plus ZDV plus IDV plus NFV. Patients are followed for at least 72 weeks \[AS PER AMENDMENT 2/16/99: 96 weeks\] beyond the enrollment of the last patient. Patients who experience virologic relapse will have the option of continuing randomized study medications, switching to Step 2 treatment, switching to another ACTG study, or seeking best available therapy for the remaining weeks of the study. Step 2 treatment consists of abacavir or 2 NNRTIs plus efavirenz plus amprenavir or another protease inhibitor. \[AS PER AMENDMENT 4/3/00: Optimally, Step 2 treatment regimens should contain 3 or 4 drugs to which the virus is susceptible. If this is not possible, a drug to which the virus is partially susceptible is acceptable, but a drug to which the virus is resistant should not be included.\]
Inclusion Criteria Concurrent Medication: Allowed: * Chemoprophylaxis for Pneumocystis carinii pneumonia. * Topical and oral antifungal agents (except for oral ketoconazole and itraconazole). * All antibiotics as clinically indicated (unless otherwise excluded). * Treatment, maintenance, or chemoprophylaxis with approved agents for opportunistic infections as clinically indicated (unless otherwise excluded). * Systemic corticosteroids for 21 days or less for acute problems. * Recombinant erythropoietin (rEPO) and granulocyte colony-stimulating factor (G-CSF, filgrastim). * Regularly prescribed medications such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, megestrol acetate, testosterone. * Alternative therapies such as vitamins. Patients should report the use of these therapies. * \[AS PER AMENDMENT 2/16/99: Rifabutin can be administered at a reduced dose.\] * \[AS PER AMENDMENT 4/3/00: Systemic cytotoxic chemotherapy. Study team should be notified.\] * \[AS PER AMENDMENT 4/3/00: Expanded access and compassionate use drugs are allowed as part of Step 2 treatment only.\] Allowed with caution: * \[AS PER AMENDMENT 4/3/00: Viagra (sildenafil citrate) at a reduced dose unless otherwise approved by the protocol chair.\] * \[AS PER AMENDMENT 4/3/00: Lovastatin or simvastatin with PIs is not recommended. Caution should be exercised with the use of all other statins when used concomitantly with PIs.\] Concurrent Treatment: Allowed: * Alternative therapies such as acupuncture and visualization techniques. Patients should report use of these therapies. Patients must have: * Documented HIV-1 infection. * CD4 count less than or equal to 200 cells/mm3 or a plasma HIV RNA greater than or equal to 100,000 copies/ml \[AS PER AMENDMENT 2/16/99: * 80,000 copies/ml\] within 60 days prior to entry. * Other lab values performed within 14 days prior to entry. Prior Medication: Allowed: * Zidovudine (ZDV), didanosine (ddI), stavudine (d4T), or zalcitabine (ddC) therapy alone or in combination any time prior to study entry. Exclusion Criteria Concurrent Medication: Excluded: * All antiretroviral therapies other than study medications. \[AS PER AMENDMENT 4/3/00: Compassionate use and expanded access drugs are allowed as part of Step 2 treatment.\] * Investigational drugs without specific approval from the Study Chair. \[AS PER AMENDMENT 4/3/00: Compassionate use and expanded access drugs are allowed as part of Step 2 treatment.\] * Systemic cytotoxic chemotherapy. \[AS PER AMENDMENT 4/3/00: Systemic cytotoxic chemotherapy is allowed. Study team should be notified.\] * Alprazolam, amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, encainide, ergot alkaloids and derivatives of ergot alkaloids, estazolam, flecainide, flurazepam, itraconazole , ketoconazole, meperidine, midazolam, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, rifampin, terfenadine, triazolam, or zolpidem. \[AS PER AMENDMENT 2/16/99: Amiodarone, astemizole, cisapride, ergot alkaloids or drugs containing derivatives of ergot alkaloids, itraconazole, midazolam, triazolam, quinidine, rifampin, terfenadine.\] \[AS PER AMENDMENT 4/3/00: Amiodarone, astemizole, bepridil, cisapride, ergot alkaloids and derivatives of ergot alkaloids, Hypericum perforatum (St. John's wort), itraconazole, midazolam, quinidine, rifampin, terfenadine, triazolam.\] * Vitamin E supplements. \[AS PER AMENDMENT 4/3/00: Multivitamins containing vitamin E are allowed.\] Avoided: * Herbal medications. Patients should report use. Patients with the following prior conditions are excluded: * Acute therapy for an infection or other medical illnesses within 14 days prior to study entry. \[AS PER AMENDMENT 2/16/99: Acute therapy for a serious infection or other serious medical illnesses that are potentially life-threatening and require systemic therapy and/or hospitalization within 14 days of study entry.\] Prior Medication: Excluded within 30 days prior to entry: * More than 1 day experience with lamivudine (3TC), nonnucleoside reverse transcriptase inhibitor, or protease inhibitor. * Erythropoietin, G-CSF, or GM-CSF. * Interferons, interleukins, HIV vaccines, or any experimental therapy. Excluded within 14 days prior to entry: * Alprazolam (Xanax), amiodarone (Cordarone), astemizole (Hismanal), bepridil (Vascor), bupropion (Wellbutrin, Zyban), cisapride (Propulsid), clorazepate (Tranxene), clozapine (Clozaril), diazepam (Valium), encainide (Enkaid), ergot alkaloids or drugs containing derivatives of ergot alkaloids, estazolam (ProSom), flecainide (Tambocor), flurazepam (Dalmane), itraconazole (Sporanox), ketoconazole (Nizoral), meperidine (Demerol), midazolam (Versed), piroxicam (Feldene), propafenone (Rythmol), propoxyphene (Darvon, Darvocet), quinidine, rifabutin (Mycobutin), rifampin (Rifadin, Rifamate, Rifater, Rimactane), terfenadine (Seldane), triazolam (Halcion), or zolpidem (Ambien). \[AS PER AMENDMENT 2/16/99: Agents excluded within 14 days prior to entry are now as follows: * amiodarone, astemizole, cisapride, ergot alkaloids or drugs containing derivatives of ergot alkaloids, itraconazole, midazolam, quinidine, rifampin, terfenadine, and triazolam. Note: * Rifabutin can be administered at a reduced dose of 150 mg/day.\]