To compare nelfinavir (NFV) with ritonavir (RTV) for delaying disease progression or death in HIV-infected patients with CD4+ cell counts less than 100 cells/mm3 [AS PER AMENDMENT 3/11/98: less than or equal to 200 cells/mm3]. To compare NFV with RTV for the development of adverse events and for rates of permanent discontinuation of study medication. [AS PER AMENDMENT 10/02/97: To compare by intention-to-treat analysis for disease progression, including death, the following two regimens: NFV plus background combination antiretroviral (AR) therapy followed by indinavir (IDV) or RTV in the event of significant intolerance; and RTV plus AR therapy followed by IDV, then NFV, in the event of significant intolerance.] [AS PER AMENDMENT 3/11/98: SUBSTUDY CPCRA 045: To determine the relative rates of emergence of HIV-1 resistance and to compare changes in plasma HIV RNA levels and CD4+ cell counts in a sample of patients with CD4+ cell counts <= 200/mm3 who are enrolled in protocol CPCRA 042.] AR therapy is rapidly becoming the standard of care for the treatment of HIV infection. AR therapy provides the best opportunity for maximizing viral suppression, reducing toxicity and delaying the emergence of resistant strains. The newest class of AR agents, the HIV protease inhibitors, exhibits the most potent anti-HIV effects described to date. This study will compare 2 protease inhibitors, NFV and RTV for efficacy and safety in a population with advanced HIV disease, who are taking various background nucleoside therapies.

Condition	Treatment or Intervention
HIV Infections	Drug: Indinavir sulfate  Drug: Ritonavir  Drug: Nelfinavir mesylate

Further Study Details: 

Expected Total Enrollment:  1300

AR therapy is rapidly becoming the standard of care for the treatment of HIV infection. AR therapy provides the best opportunity for maximizing viral suppression, reducing toxicity and delaying the emergence of resistant strains. The newest class of AR agents, the HIV protease inhibitors, exhibits the most potent anti-HIV effects described to date. This study will compare 2 protease inhibitors, NFV and RTV for efficacy and safety in a population with advanced HIV disease, who are taking various background nucleoside therapies.

Eligible patients will be randomized either to NFV plus background AR nucleoside therapy or to RTV plus background AR nucleoside therapy. Background AR therapy may also be no background therapy, although use of protease inhibitors as monotherapy is not recommended unless there is no alternative. Patients will be allowed to cross over to the alternate protease inhibitor if they reach a primary study endpoint. Data will be collected every 4 months. [AS PER AMENDMENT 10/2/97: Patients assigned to the NFV arm who develop a significant intolerance may switch to RTV or IDV; those assigned to the RTV arm who develop a significant intolerance are encouraged to switch to IDV (NFV allowed if IDV contraindicated). Switchover for intolerance is strongly discouraged during the first 4 weeks of follow-up. Patients initially assigned to NFV therapy who experience disease progression may switch to RTV; if RTV is not tolerated, patients may switch to IDV. Because of the cross-resistance between RTV and IDV, patients who progress on RTV should switch to NFV.] [AS PER AMENDMENT 12/15/98: Patients originally assigned to NFV who experience poor virologic control or disease progression should change to RTV or IDV or enroll in the PIP protocol (CPCRA 057). Conversely, patients originally assigned to RTV should change to NFV or enroll in the PIP protocol (such patients continue to be followed on this study). Because of cross-resistance between RTV and IDV, change from RTV to IDV is discouraged. Determination of poor virologic control or disease progression is at the discretion of the patient's clinician. Change in background antiretroviral therapy should occur at the same time that the protease inhibitor is changed for poor virologic control or progression; the choice of new background antiretroviral agents is at the discretion of the clinician.] Randomization is stratified by clinical site.] [AS PER AMENDMENT 3/11/98: SUBSTUDY CPCRA 045: At least 600 patients (>= 400 from CPCRA sites and >= 200 from CTN sites) will be enrolled in the substudy. These patients will have a plasma sample collected for HIV RNA and genotypic resistance within 30 days prior to randomization, at the 1-month visit, and at the q-4-month study visits thereafter until the end of the study. CD4+ cell counts will be done at the 1-month visit and at the q-4-month study visits until the end of the study. A subset of patients will also have immunophenotyping of CD4+ and CD8+ cell TCR V-beta clones carried out before and during treatment. Another subset of patients at selected sites will have viral cultures performed for phenotypic drug sensitivity testing. Initially, specimens for 50 randomly chosen patients in the group originally assigned RTV will be identified for resistance testing. Of this group, specimens for those who have received RTV/IDV for more than 1 month will be analyzed for genotypic resistance to obtain an estimate of the rate of resistance development and to estimate the risk of disease progression associated with resistance to RTV/ZDV. Based on these estimates, determination will be made of the total number of patients and specimens in both treatment groups in order to address the primary objective of comparing genotypic resistance in the two groups.]

Ages Eligible for Study:  13 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

Concurrent Medication:

• Background AR nucleoside therapy is required, although background AR therapy may also be no background therapy. However, the use of protease inhibitors is not recommended as monotherapy unless there is no other alternative. Therefore, patients who are not on AR treatment may be enrolled at the discretion of the clinician.

Allowed:

• Saquinavir.

Patients must have:

• Documented HIV infection.
• A CD4+ cell count <= 100/mm3 within 3 months prior to the study. [AS PER AMENDMENT 3/11/98: CD4+ cell count <= 200/mm3 any time prior to entry].
• Parental consent if patient is < 18 years old.

Prior Medication: Allowed:

• Saquinavir (SQV).

Exclusion Criteria

Co-existing Condition: Patients with the following symptoms or conditions are excluded:

• Stage 2 or greater AIDS dementia complex.
• [AS PER AMENDMENT 10/2/97: Any acute disease or condition that would, in the physician's judgement, contraindicate starting NFV or RTV.]
• Known hypersensitivity to RTV or any of its ingredients (for patients assigned to RTV therapy).

Concurrent Medication: Excluded:

• Concomitant use of protease inhibitors.
• Concomitant treatments that cannot be discontinued, and in the physician's judgement, should not be taken with NFV or RTV.

AS PER AMENDMENT 10/2/97:

• For patients randomized to NFV:
• Concomitant therapy with terfenadine, astemizole, cisapride, triazolam, midazolam, ergot derivatives, amiodarone, quinidine, or rifampin.

For patients randomized to IDV:

• Concomitant therapy with terfenadine, astemizole, cisapride, triazolam, midazolam, and rifampin.

Patients with any of the following prior symptoms are excluded: AS PER AMENDMENT 10/2/97:

• History of clinically significant hypersensitivity reaction to any component of NFV tablets (for patients assigned to NFV therapy).

Prior Medication: Excluded:

• Prior use of protease inhibitors except SQV.

[AS PER AMENDMENT 10/2/97:

• Prior use of IDV for more than 4 weeks or other protease inhibitors (except SQV) for any prior duration.]

California
      Community Consortium of San Francisco, San Francisco,  California,  94110,  United States
      Community Consortium / UCSF, San Francisco,  California,  94110,  United States
Colorado
      Denver CPCRA / Denver Public Hlth, Denver,  Colorado,  802044507,  United States
      Denver Community Program for Clinical Research on AIDS, Denver,  Colorado,  80204,  United States
      Denver CPCRA / Denver Pub Hlth / Rocky Mt Cancer Ctr Aurora, Denver,  Colorado,  802044507,  United States
District of Columbia
      Veterans Administration Med Ctr / Regional AIDS Program, Washington,  District of Columbia,  20422,  United States
      Washington Reg AIDS Prog / Dept of Infect Dis, Washington,  District of Columbia,  20422,  United States
      Timothy A Price, Washington,  District of Columbia,  204220001,  United States
      Infectious Disease Physicians / Northern Virginia, Washington,  District of Columbia,  204220001,  United States
Georgia
      AIDS Research Consortium of Atlanta, Atlanta,  Georgia,  30308,  United States
Illinois
      AIDS Research Alliance - Chicago, Chicago,  Illinois,  60657,  United States
Louisiana
      Louisiana Comm AIDS Rsch Prog / Tulane Univ Med, New Orleans,  Louisiana,  70112,  United States
      Louisiana Community AIDS Research Program, New Orleans,  Louisiana,  70112,  United States
Maryland
      Westat / NICHD, Rockville,  Maryland,  208503172,  United States
      Baltimore TRIALS, Baltimore,  Maryland,  21201,  United States
Michigan
      Henry Ford Hosp, Detroit,  Michigan,  48202,  United States
      Comprehensive AIDS Alliance of Detroit, Detroit,  Michigan,  48201,  United States
      Wayne State Univ / Univ Hlth Ctr, Detroit,  Michigan,  48201,  United States
New Jersey
      North Jersey Community Research Initiative, Newark,  New Jersey,  071032842,  United States
      Southern New Jersey AIDS Cln Trials / Dept of Med, Camden,  New Jersey,  08103,  United States
      New Jersey Community Research Initiative, Newark,  New Jersey,  07103,  United States
      Southern New Jersey AIDS Clinical Trials, Camden,  New Jersey,  08103,  United States
      Mercer Area Early Intervention Services, Camden,  New Jersey,  081031438,  United States
New Mexico
      Partners Research, Albuquerque,  New Mexico,  871315271,  United States
      Partners in Research - New Mexico, Albuquerque,  New Mexico,  87131,  United States
New York
      Harlem AIDS Treatment Group / Harlem Hosp Ctr, New York,  New York,  10037,  United States
      Harlem AIDS Treatment Group, New York,  New York,  10037,  United States
Oregon
      Portland Veterans Adm Med Ctr / Rsch & Education Grp, Portland,  Oregon,  972109951,  United States
      The Research and Education Group, Portland,  Oregon,  97210,  United States
Pennsylvania
      Philadelphia FIGHT, Philadelphia,  Pennsylvania,  19107,  United States
      Saint Joseph's Hosp, Philadelphia,  Pennsylvania,  19107,  United States
Virginia
      Richmond AIDS Consortium, Richmond,  Virginia,  23298,  United States
Canada, British Columbia
      Saint Paul's Hosp, Vancouver,  British Columbia,  Canada
Canada, Nova Scotia
      QEII Health Science Centre, Halifax,  Nova Scotia,  Canada
Canada, Ontario
      Wellesley Hosp, Toronto,  Ontario,  Canada
      Ottawa Gen Hosp, Ottawa,  Ontario,  Canada
      Toronto Gen Hosp, Toronto,  Ontario,  Canada
      Saint Joseph's Hosp, London,  Ontario,  Canada
      Sunnybrook Health Science Centre, Toronto,  Ontario,  Canada
Canada, Quebec
      Hotel - Dieu de Montreal, Montreal,  Quebec,  Canada
      Montreal Chest Institute, Montreal,  Quebec,  Canada
      Centre De Recherche En Infectiologie, Ste Foy,  Quebec,  Canada
      SMBD-Jewish Gen Hosp, Montreal,  Quebec,  Canada
Canada, Saskatchewan
      Royal Univ Hosp, Saskatoon,  Saskatchewan,  Canada

Study chairs or principal investigators

Perez G,  Study Chair
MacArthur R,  Study Chair

Study ID Numbers:  CPCRA 042
Record last reviewed:  August 2004
Last Updated:  October 13, 2004
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000859
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08