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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000919
• Other study ID #: ACTG 384
• Secondary ID: 11343AACTG A5005
• Status: Completed
• Phase: N/A
• First received: November 2, 1999
• Last updated: June 5, 2012
• Est. completion date: November 2002

Study information

• Verified date: June 2012
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 900
• Est. completion date: November 2002
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 13 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Pharmacokinetics Study, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Infection

Intervention

Drug:
• Indinavir sulfate

• Lamivudine/Zidovudine

• Ritonavir

• Hydroxyurea

• Abacavir sulfate

• Amprenavir

• Nelfinavir mesylate

• Efavirenz

• Lamivudine

• Stavudine

• Zidovudine

• Didanosine

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Umberto I	Ancona
Italy	Ospedale S Orsola	Bologna
Italy	Spedali Civili - Carosi	Brescia
Italy	Spedali Civili Cadeo	Brescia
Italy	Archispedale S Anna	Ferrara
Italy	Universita di Genova	Genova
Italy	Ospedale Luigi Cacco Moroni	Milano
Italy	Ospedale Luigi Sacco Cargnel	Milano
Italy	Azienda Ospedaliera di Parma	Parma
Italy	IRCCS Policlinico S Matteo Filice	Pavia
Italy	IRCCS Policlinico S Matteo Minoli	Pavia
Italy	Archispedale S Maria Nuova	Reggio Emilia
Italy	Universita di Roma - Delia	Roma
Italy	Azienda USL di Piacenza	Unknown
Italy	Francesco Leoncini	Unknown
Italy	Ospedale Civile Maggiore	Verona
Puerto Rico	Univ of Puerto Rico	San Juan
United States	Akron City Hospital	Akron	Ohio
United States	Emory Hemo Comp Evaluation Clinic / East TN Comp Hemo Ctr	Atlanta	Georgia
United States	Emory Univ	Atlanta	Georgia
United States	State of MD Div of Corrections / Johns Hopkins Univ Hosp	Baltimore	Maryland
United States	Univ of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess - West Campus	Boston	Massachusetts
United States	Boston Med Ctr	Boston	Massachusetts
United States	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts
United States	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York
United States	Univ of North Carolina	Chapel Hill	North Carolina
United States	Carolinas Med Ctr	Charlotte	North Carolina
United States	Cook County Hosp	Chicago	Illinois
United States	Northwestern Univ Med School	Chicago	Illinois
United States	Rush Presbyterian - Saint Luke's Med Ctr	Chicago	Illinois
United States	Univ of Cincinnati	Cincinnati	Ohio
United States	Univ of Kentucky Lexington	Cincinnati	Ohio
United States	Case Western Reserve Univ	Cleveland	Ohio
United States	MetroHealth Med Ctr	Cleveland	Ohio
United States	Ohio State Univ Hosp Clinic	Columbus	Ohio
United States	Univ of Colorado Health Sciences Ctr	Denver	Colorado
United States	Duke Univ Med Ctr	Durham	North Carolina
United States	Univ of Texas Galveston	Galveston	Texas
United States	Moses H Cone Memorial Hosp	Greensboro	North Carolina
United States	Milton S Hershey Med Ctr	Hershey	Pennsylvania
United States	Univ of Hawaii	Honolulu	Hawaii
United States	Division of Inf Diseases/ Indiana Univ Hosp	Indianapolis	Indiana
United States	Indiana Univ Hosp	Indianapolis	Indiana
United States	Methodist Hosp of Indiana / Life Care Clinic	Indianapolis	Indiana
United States	Univ of Iowa Hosp and Clinic	Iowa City	Iowa
United States	UCLA CARE Ctr	Los Angeles	California
United States	Univ of Southern California / LA County USC Med Ctr	Los Angeles	California
United States	Willow Clinic	Menlo Park	California
United States	Univ of Miami School of Medicine	Miami	Florida
United States	Univ of Minnesota	Minneapolis	Minnesota
United States	Charity Hosp / Tulane Univ Med School	New Orleans	Louisiana
United States	Tulane Med Ctr Hosp	New Orleans	Louisiana
United States	Tulane Univ School of Medicine	New Orleans	Louisiana
United States	Beth Israel Med Ctr	New York	New York
United States	Chelsea Ctr	New York	New York
United States	Columbia Presbyterian Med Ctr	New York	New York
United States	Cornell Univ Med Ctr	New York	New York
United States	Manhattan Veterans Administration / New York Univ Med Ctr	New York	New York
United States	Mem Sloan - Kettering Cancer Ctr	New York	New York
United States	Mount Sinai Med Ctr	New York	New York
United States	Univ of Nebraska Med Ctr	Omaha	Nebraska
United States	Philadelphia Veterans Administration Med Ctr	Philadelphia	Pennsylvania
United States	Univ of Pennsylvania at Philadelphia	Philadelphia	Pennsylvania
United States	Univ of Pittsburgh Med Ctr	Pittsburgh	Pennsylvania
United States	St Mary's Hosp (Univ of Rochester/Infectious Diseases)	Rochester	New York
United States	Univ of Rochester Medical Center	Rochester	New York
United States	Univ of California / San Diego Treatment Ctr	San Diego	California
United States	San Francisco AIDS Clinic / San Francisco Gen Hosp	San Francisco	California
United States	San Francisco Gen Hosp	San Francisco	California
United States	Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium	San Jose	California
United States	Marin County Specialty Clinic	San Rafael	California
United States	Univ of Washington	Seattle	Washington
United States	St Louis Regional Hosp / St Louis Regional Med Ctr	St Louis	Missouri
United States	San Mateo AIDS Program / Stanford Univ	Stanford	California
United States	Stanford Univ Med Ctr	Stanford	California
United States	Harbor UCLA Med Ctr	Torrance	California
United States	Georgetown Univ Hosp	Washington	District of Columbia
United States	Howard Univ	Washington	District of Columbia
United States	Julio Arroyo	West Columbia	South Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Italy,  Puerto Rico, 

References & Publications (11)

Dube MP, Zackin R, Tebas P, et al. Prospective study of regional body composition in antiretroviral-naive subjects randomized to receive zidovudine+lamivudine or didanosine+stavudine combined with nelfinavir, efavirenz, or both: A5005s, a substudy of ACTG 384. Antiviral Ther. 2002;7:L18. Abstract 27.

Gandhi RT, Spritzler J, Chan E, Asmuth DM, Rodriguez B, Merigan TC, Hirsch MS, Shafer RW, Robbins GK, Pollard RB; ACTG 384 Team. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1- — View Citation

Haas DW, Smeaton LM, Shafer RW, Robbins GK, Morse GD, Labbe L, Wilkinson GR, Clifford DB, D'Aquila RT, De Gruttola V, Pollard RB, Merigan TC, Hirsch MS, George AL Jr, Donahue JP, Kim RB. Pharmacogenetics of long-term responses to antiretroviral regimens c — View Citation

Hulgan T, Haas DW, Haines JL, Ritchie MD, Robbins GK, Shafer RW, Clifford DB, Kallianpur AR, Summar M, Canter JA. Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. AIDS. 2005 Sep — View Citation

Marc LG, Testa MA, Walker AM, Robbins GK, Shafer RW, Anderson NB, Berkman LF; ACTG Data Analysis Concept Sheet Study Team. Educational attainment and response to HAART during initial therapy for HIV-1 infection. J Psychosom Res. 2007 Aug;63(2):207-16. — View Citation

Reynolds NR, Testa MA, Marc LG, Chesney MA, Neidig JL, Smith SR, Vella S, Robbins GK; Protocol Teams of ACTG 384, ACTG 731 and A5031s. Factors influencing medication adherence beliefs and self-efficacy in persons naive to antiretroviral therapy: a multice — View Citation

Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dubé MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS; AIDS Clinical Trials Group 384 Team. Comp — View Citation

Shafer RW, Smeaton LM, Robbins GK, De Gruttola V, Snyder SW, D'Aquila RT, Johnson VA, Morse GD, Nokta MA, Martinez AI, Gripshover BM, Kaul P, Haubrich R, Swingle M, McCarty SD, Vella S, Hirsch MS, Merigan TC; AIDS Clinical Trials Group 384 Team. Compariso — View Citation

Smeaton LM, DeGruttola V, Robbins GK, Shafer RW. ACTG (AIDS Clinical Trials Group) 384: a strategy trial comparing consecutive treatments for HIV-1. Control Clin Trials. 2001 Apr;22(2):142-59. — View Citation

Smith PF, Robbins G, Shafer R, Wu H, Yu S, Hirsch M, Merigan T, Morse GD, ACTG 384 Study Team. Effect of Efavirenz on the Pharmacokinetics of Nelfinavir and M8 in Naïve, HIV-infected Patients Receiving Long-term HAART Therapy. 10th Conference on Retroviruses and Oppurtunistic Infections. Feb 2003. Abstract 148.

Smith PF, Robbins GK, Shafer RW, Wu H, Yu S, Hirsch MS, Merigan TC, Park JG, Forrest A, Fischl MA, Morse GD; ACTG 384-5006 Team. Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when admi — View Citation

* Note: There are 11 references in all — Click here to view all references

External Links

•   Click here for more information about abacavir sulfate
•   Click here for more information about amprenavir
•   Click here for more information about didanosine
•   Click here for more information about efavirenz
•   Click here for more information about indinavir sulfate
•   Click here for more information about lamivudine
•   Click here for more information about lamivudine/zidovudine
•   Click here for more information about nelfinavir
•   Click here for more information about ritonavir
•   Click here for more information about stavudine
•   Click here for more information about zidovudine