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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000919

Collaborator

(none)

900

Enrollment

Locations

11.3

Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Indinavir sulfate Drug: Lamivudine/Zidovudine Drug: Ritonavir Drug: Hydroxyurea Drug: Abacavir sulfate Drug: Amprenavir Drug: Nelfinavir mesylate Drug: Efavirenz Drug: Lamivudine Drug: Stavudine Drug: Zidovudine Drug: Didanosine	N/A

Detailed Description

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.

Study Design

Study Type:

Interventional

Masking:

Double

Primary Purpose:

Treatment

Official Title:

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

Actual Study Completion Date :

Nov 1, 2002

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Univ of Southern California / LA County USC Med Ctr	Los Angeles	California	United States	900331079
3	UCLA CARE Ctr	Los Angeles	California	United States	90095
4	Willow Clinic	Menlo Park	California	United States	94025
5	Univ of California / San Diego Treatment Ctr	San Diego	California	United States	921036325
6	San Francisco AIDS Clinic / San Francisco Gen Hosp	San Francisco	California	United States	941102859
7	San Francisco Gen Hosp	San Francisco	California	United States	941102859
8	Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium	San Jose	California	United States	951282699
9	Marin County Specialty Clinic	San Rafael	California	United States	94903
10	San Mateo AIDS Program / Stanford Univ	Stanford	California	United States	943055107
11	Stanford Univ Med Ctr	Stanford	California	United States	943055107
12	Harbor UCLA Med Ctr	Torrance	California	United States	90502
13	Univ of Colorado Health Sciences Ctr	Denver	Colorado	United States	80262
14	Georgetown Univ Hosp	Washington	District of Columbia	United States	20037
15	Howard Univ	Washington	District of Columbia	United States	20059
16	Univ of Miami School of Medicine	Miami	Florida	United States	331361013
17	Emory Univ	Atlanta	Georgia	United States	30308
18	Emory Hemo Comp Evaluation Clinic / East TN Comp Hemo Ctr	Atlanta	Georgia	United States	303652225
19	Univ of Hawaii	Honolulu	Hawaii	United States	96816
20	Northwestern Univ Med School	Chicago	Illinois	United States	60611
21	Cook County Hosp	Chicago	Illinois	United States	60612
22	Rush Presbyterian - Saint Luke's Med Ctr	Chicago	Illinois	United States	60612
23	Indiana Univ Hosp	Indianapolis	Indiana	United States	462025250
24	Division of Inf Diseases/ Indiana Univ Hosp	Indianapolis	Indiana	United States	46202
25	Methodist Hosp of Indiana / Life Care Clinic	Indianapolis	Indiana	United States	46202
26	Univ of Iowa Hosp and Clinic	Iowa City	Iowa	United States	52242
27	Charity Hosp / Tulane Univ Med School	New Orleans	Louisiana	United States	70112
28	Tulane Med Ctr Hosp	New Orleans	Louisiana	United States	70112
29	Tulane Univ School of Medicine	New Orleans	Louisiana	United States	70112
30	State of MD Div of Corrections / Johns Hopkins Univ Hosp	Baltimore	Maryland	United States	212052196
31	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts	United States	02114
32	Boston Med Ctr	Boston	Massachusetts	United States	02118
33	Beth Israel Deaconess - West Campus	Boston	Massachusetts	United States	02215
34	Univ of Minnesota	Minneapolis	Minnesota	United States	55455
35	St Louis Regional Hosp / St Louis Regional Med Ctr	St Louis	Missouri	United States	63112
36	Univ of Nebraska Med Ctr	Omaha	Nebraska	United States	681985130
37	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York	United States	14215
38	Beth Israel Med Ctr	New York	New York	United States	10003
39	Manhattan Veterans Administration / New York Univ Med Ctr	New York	New York	United States	10016
40	Chelsea Ctr	New York	New York	United States	10021
41	Cornell Univ Med Ctr	New York	New York	United States	10021
42	Mem Sloan - Kettering Cancer Ctr	New York	New York	United States	10021
43	Mount Sinai Med Ctr	New York	New York	United States	10029
44	Columbia Presbyterian Med Ctr	New York	New York	United States	10032
45	St Mary's Hosp (Univ of Rochester/Infectious Diseases)	Rochester	New York	United States	14642
46	Univ of Rochester Medical Center	Rochester	New York	United States	14642
47	Univ of North Carolina	Chapel Hill	North Carolina	United States	275997215
48	Carolinas Med Ctr	Charlotte	North Carolina	United States	28203
49	Duke Univ Med Ctr	Durham	North Carolina	United States	27710
50	Moses H Cone Memorial Hosp	Greensboro	North Carolina	United States	27401
51	Akron City Hospital	Akron	Ohio	United States	44304
52	Univ of Cincinnati	Cincinnati	Ohio	United States	452670405
53	Univ of Kentucky Lexington	Cincinnati	Ohio	United States	45267
54	Case Western Reserve Univ	Cleveland	Ohio	United States	44106
55	MetroHealth Med Ctr	Cleveland	Ohio	United States	441091998
56	Ohio State Univ Hosp Clinic	Columbus	Ohio	United States	432101228
57	Milton S Hershey Med Ctr	Hershey	Pennsylvania	United States	170330850
58	Philadelphia Veterans Administration Med Ctr	Philadelphia	Pennsylvania	United States	19104
59	Univ of Pennsylvania at Philadelphia	Philadelphia	Pennsylvania	United States	19104
60	Univ of Pittsburgh Med Ctr	Pittsburgh	Pennsylvania	United States	15213
61	Julio Arroyo	West Columbia	South Carolina	United States	29169
62	Univ of Texas Galveston	Galveston	Texas	United States	775550435
63	Univ of Washington	Seattle	Washington	United States	98104
64	Azienda Ospedaliera Umberto I	Ancona		Italy
65	Ospedale S Orsola	Bologna		Italy
66	Spedali Civili - Carosi	Brescia		Italy
67	Spedali Civili Cadeo	Brescia		Italy
68	Archispedale S Anna	Ferrara		Italy
69	Universita di Genova	Genova		Italy
70	Ospedale Luigi Cacco Moroni	Milano		Italy
71	Ospedale Luigi Sacco Cargnel	Milano		Italy
72	Azienda Ospedaliera di Parma	Parma		Italy
73	IRCCS Policlinico S Matteo Filice	Pavia		Italy
74	IRCCS Policlinico S Matteo Minoli	Pavia		Italy
75	Archispedale S Maria Nuova	Reggio Emilia		Italy
76	Universita di Roma - Delia	Roma		Italy
77	Ospedale Civile Maggiore	Verona		Italy
78	Univ of Puerto Rico	San Juan		Puerto Rico	009365067
79	Azienda USL di Piacenza
80	Francesco Leoncini