Clinical trial NCT00001084: A Study of Three Treatment Combinations Using Zidovudine Plus Lamivudine Plus Indinavir in HIV-Infected Patients
Official title: A Prospective Randomized Double-Blind Trial of Three Maintenance Regimens for HIV-Infected Subjects Receiving Induction Therapy With Zidovudine, Lamivudine and Indinavir
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Prospective Studies
Drug Therapy, Combination
Zidovudine
HIV Protease Inhibitors
Lamivudine
Indinavir
RNA, Viral
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Viral Load
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To compare the proportion of patients who sustain suppression of plasma HIV RNA to undetectable levels \[AS PER AMENDMENT 09/19/97: below 200 copies/mL by Roche UltraSensitive assay\] among the 3 regimens during the maintenance phase.

The objective of antiretroviral therapy is to reduce HIV replication, preserve immunologic function and delay the development of HIV-related complications. In patients administered potent antiretroviral regimens, HIV RNA levels are reduced below 500 copies/ml of plasma and below the level of detection of commercially available assays. This protocol attempts to learn if a less intensive regimen can successfully sustain viral suppression after induction with a triple-drug regimen. The study also addresses whether HIV can be eradicated in patients following prolonged treatment with induction and maintenance regimens.

Detailed description: The objective of antiretroviral therapy is to reduce HIV replication, preserve immunologic function and delay the development of HIV-related complications. In patients administered potent antiretroviral regimens, HIV RNA levels are reduced below 500 copies/ml of plasma and below the level of detection of commercially available assays. This protocol attempts to learn if a less intensive regimen can successfully sustain viral suppression after induction with a triple-drug regimen. The study also addresses whether HIV can be eradicated in patients following prolonged treatment with induction and maintenance regimens.

All patients will receive open label induction therapy with zidovudine (ZDV), lamivudine (3TC) and indinavir (IDV) for 6 months. Following the 6 month induction phase, patients with undetectable plasma HIV RNA at weeks 16, 20 and 24 will enter the maintenance phase \[blinded maintenance phase AS PER AMENDMENT 09/19/97\] and be randomized to one of three maintenance regimens, i.e., either continued ZDV/3TC/IDV (control), or ZDV/3TC/IDV placebo or ZDV placebo/3TC placebo/IDV. Prior to randomization, patients are stratified according to entry HIV RNA level (greater than or equal to 30,000 or less than 30,000 copies/ml) and by prior ZDV therapy (at least 7 days or less than 7 days). After 12 months \[AS PER AMENDMENT 09/19/97: 18 months\] of maintenance therapy, treatment will be withdrawn at 6-month intervals in randomly-selected patients who have achieved undetectable HIV RNA. AS PER 09/19/97 AMENDMENT: After 18 months of blinded maintenance therapy, treatment is unblinded for patients whose HIV RNA levels remain detectable. Such patients receive optimal therapy, either continuing the protocol regimen or initiating alternative therapy.

AS PER AMENDMENT 2/27/98: An interim review conducted in January, 1998 demonstrated that the strategy of less intensive antiviral therapy after 6 months of IDV/3TC/ZDV induction therapy is less effective than continuation of triple drug therapy except for ZDV-naive patients assigned to ZDV/3TC. Therefore, the maintenance phase of this study has been discontinued.

Patients currently on blinded maintenance are unblinded immediately and have the option of reinitiating open-label triple therapy with IDV/3TC/ZDV or discontinuing study treatment. Patients currently on induction may register for continued open-label triple therapy or may discontinue study treatment. This amendment allows treatment extension so that subjects may receive open-label triple therapy until May 31, 1998. At that time, a rollover protocol or another modification with a longer period of drug supply may become available. Patients who choose to go off treatment are followed until May 31, 1998.

AS PER AMENDMENT 04/23/98: This study will now provide treatment with open-label ZDV/3TC/IDV until August 1, 1998. A rollover protocol or another 343 protocol modification with a longer period of drug supply may become available, but this cannot be guaranteed.

AS PER AMENDMENT 06/19/98: This study will now provide treatment with open-label ZDV/3TC/IDV until either November 1, 1998 or until 3 months after the rollover study (A5025) is available to the study sites (whichever comes first).

Eligibility criteria: Inclusion Criteria

Patients must have:

* Documented HIV infection.
* A CD4 cell count \>= 200 cells/mm3 within 90 days prior to study entry.
* Plasma HIV RNA \>= 1000 copies/ml within 90 days prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with any of the following conditions or symptoms are excluded:

* A malignancy that requires systemic chemotherapy.

Concurrent Medication:

Excluded:

* Oral ketoconazole (Nizoral), terfenadine (Seldane), astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion) or midazolam (Versed).
* All antiretroviral therapies other than study medications.
* Rifabutin and rifampin.
* Investigational drugs and vaccines.
* Systemic cytotoxic chemotherapy.
* Interferon, interleukins, GM-CSF and HIV vaccines.

Patients with any of the following prior conditions are excluded:

* Unexplained temperature \> 38.5 degrees C for any 7 days within 30 days prior to study entry.
* Chronic diarrhea as defined as \> 3 liquid stools per day persisting for 15 days within 30 days prior to study entry.
* Proven or suspected acute hepatitis within 30 days prior to study entry, even if AST and ALT are \<= 5.0 X ULN (upper limit of normal).
* A history of \>= Grade 2 bilateral peripheral neuropathy within 60 days prior to study entry.
* A history of intolerance to 300 mg/day of ZDV defined as any toxicity requiring a dose reduction or termination of ZDV.

Prior Medication:

Excluded:

* Acute therapy for an infection or other medical illness within 14 days prior to study entry.
* Any prior therapy with 3TC or experimental drug 1592.
* More than 2 weeks of lifetime exposure to protease inhibitor therapy; any exposure within 14 days prior to study entry.
* Interferons, interleukins, GM-CSF or HIV vaccines within 30 days prior to study entry.
* Any experimental therapy (drugs or vaccines) within 30 days prior to study entry.
* Rifampin or rifabutin within 14 days prior to study entry.
* Systemic cytotoxic chemotherapy within 30 days prior to study entry.
* Oral ketoconazole (Nizoral), terfenadine (Seldane), astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion) or midazolam (Versed).

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Univ of Southern California / LA County USC Med Ctr
state: California
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: San Francisco
country: United States
facility: San Francisco Gen Hosp
state: California
city: San Francisco
country: United States
facility: Stanford at Kaiser / Kaiser Permanente Med Ctr
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium
state: California
city: Stanford
country: United States
facility: San Mateo AIDS Program / Stanford Univ
state: California
city: Stanford
country: United States
facility: Stanford Univ Med Ctr
state: California
city: Torrance
country: United States
facility: Harbor UCLA Med Ctr
state: California
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory Univ
state: Georgia
city: Honolulu
country: United States
facility: Queens Med Ctr
state: Hawaii
city: Honolulu
country: United States
facility: Univ of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Univ Med School
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Division of Inf Diseases/ Indiana Univ Hosp
state: Indiana
city: Iowa City
country: United States
facility: Univ of Iowa Hosp and Clinic
state: Iowa
city: New Orleans
country: United States
facility: Tulane Med Ctr Hosp
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Univ School of Medicine
state: Louisiana
city: Baltimore
country: United States
facility: State of MD Div of Corrections / Johns Hopkins Univ Hosp
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hosp
state: Maryland
city: Boston
country: United States
facility: Harvard (Massachusetts Gen Hosp)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Med Clinic
state: Minnesota
city: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: Saint Paul
country: United States
facility: St Paul Ramsey Med Ctr
state: Minnesota
city: Saint Louis
country: United States
facility: St Louis Regional Hosp / St Louis Regional Med Ctr
state: Missouri
city: Omaha
country: United States
facility: Univ of Nebraska Med Ctr
state: Nebraska
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Saint Clare's Hosp and Health Ctr
state: New York
city: New York
country: United States
facility: Mem Sloan - Kettering Cancer Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Med Ctr
state: North Carolina
city: Greensboro
country: United States
facility: Moses H Cone Memorial Hosp
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Med Ctr
state: Ohio
city: Columbus
country: United States
facility: Ohio State Univ Hosp Clinic
state: Ohio
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Galveston
country: United States
facility: Univ of Texas Galveston
state: Texas
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
Study officials:
name: Havlir D
role: STUDY_CHAIR
name: Richman D
role: STUDY_CHAIR
References:
citation: Havlir DV, Marschner IC, Hirsch MS, Collier AC, Tebas P, Bassett RL, Ioannidis JP, Holohan MK, Leavitt R, Boone G, Richman DD. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. N Engl J Med. 1998 Oct 29;339(18):1261-8. doi: 10.1056/NEJM199810293391801.
citation: Bowersox J. ACTG 343: three drugs better than two for maintaining HIV suppression. NIAID AIDS Agenda. 1998 Mar:1-2, 10-1.
citation: Maenza JR. ACTG 343: (why) we can't relax our grip on viral suppression. Hopkins HIV Rep. 1998 May;10(3):10.
citation: O'Brien TR, McDermott DH, Ioannidis JP, Carrington M, Murphy PM, Havlir DV, Richman DD. Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy. AIDS. 2000 May 5;14(7):821-6. doi: 10.1097/00002030-200005050-00008.
citation: Zhou XJ, Havlir DV, Richman DD, Acosta EP, Hirsch M, Collier AC, Tebas P, Sommadossi JP; AIDS Clinical Trials Study 343 Investigators. Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients. AIDS. 2000 Dec 22;14(18):2869-76. doi: 10.1097/00002030-200012220-00008.
citation: Havlir DV, Bassett R, Levitan D, Gilbert P, Tebas P, Collier AC, Hirsch MS, Ignacio C, Condra J, Gunthard HF, Richman DD, Wong JK. Prevalence and predictive value of intermittent viremia with combination hiv therapy. JAMA. 2001 Jul 11;286(2):171-9. doi: 10.1001/jama.286.2.171.
citation: Seth A, Markee J, Ap S, Sevin A, Hoering A, Hirsch M, Collier A, Letvin N, McElrath MJ. Alterations in T cell phenotype and antigen-specific cytotoxicity in patients receiving three anti-retroviral agents (ACTG protocol 343). Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:132 (abstract no 340)
citation: Havlir DV, Hirsch M, Collier A, Marschner I, Bassett R, Tebas P, Ioannidis J, Richman DD. Randomized trial of indinavir (IDV) vs. zidovudine (ZDV)/lamivudine (3TC) vs IDV/ZDV/3TC maintenance therapy after induction IDV/ZDV/3TC therapy. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:225 (abstract no LB16)
citation: Gunthard HF, Havlir DV, Fiscus S, Zhang ZQ, Eron J, Mellors J, Gulick R, Frost SD, Brown AJ, Schleif W, Valentine F, Jonas L, Meibohm A, Ignacio CC, Isaacs R, Gamagami R, Emini E, Haase A, Richman DD, Wong JK. Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J Infect Dis. 2001 May 1;183(9):1318-27. doi: 10.1086/319864. Epub 2001 Apr 10.
citation: Gulick RM, Mellors J, Havlir D, Eron J, Gonzalez C, McMahon D, Richman D, Valentine F, Rooney J, Jonas L, Meibohm A, Emini E, Chodakewitz J. Potent and sustained antiretroviral activity of indinavir (IDV), zidovudine (ZDV) and lamivudine (3TC). Int Conf AIDS. 1996 Jul 7-12;11(Program Supplement):19 (abstract no ThB931)