A Study of Several Anti-HIV Drug Combinations in HIV-Infected Patients Who Have Used Indinavir

To compare the proportion of patients whose plasma HIV-1 RNA is below 500 copies/ml after 16 weeks of treatment. To assess the safety, toxicity, and tolerance of each treatment arm.

While indinavir is currently the most commonly prescribed protease inhibitor, the optimal therapy for a person on an indinavir-containing regimen who experiences a rebound in viral load or never experiences a decrease in viral load below 500 copies per milliliter is unknown. Current clinical practice for such patients typically involves empiric use of a combination of other protease inhibitors (saquinavir/nelfinavir or saquinavir/ritonavir) and at least 1 other antiretroviral agent to which the patient has had little or no prior exposure. This may involve the use of 1 or more reverse transcriptase inhibitors (RTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). This study attempts to formally evaluate some of these options in indinavir-experienced patients.

While indinavir is currently the most commonly prescribed protease inhibitor, the optimal therapy for a person on an indinavir-containing regimen who experiences a rebound in viral load or never experiences a decrease in viral load below 500 copies per milliliter is unknown. Current clinical practice for such patients typically involves empiric use of a combination of other protease inhibitors (saquinavir/nelfinavir or saquinavir/ritonavir) and at least 1 other antiretroviral agent to which the patient has had little or no prior exposure. This may involve the use of 1 or more reverse transcriptase inhibitors (RTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). This study attempts to formally evaluate some of these options in indinavir-experienced patients.

Patients are stratified by HIV RNA (2,000 - 20,000 copies/ml versus 20,000 - 200,000 copies/ml), and randomized to 1 of 6 treatment arms as follows:

Arm A: Saquinavir (SQV) plus ritonavir (RTV) plus delavirdine (DLV) plus adefovir dipivoxil placebo.

Arm B: SQV plus RTV plus DLV placebo plus adefovir dipivoxil. Arm C: SQV plus RTV plus DLV plus adefovir dipivoxil. Arm D: SQV plus nelfinavir (NFV) plus DLV plus adefovir dipivoxil placebo. Arm E: SQV plus NFV plus DLV placebo plus adefovir dipivoxil. Arm F: SQV plus NFV plus DLV plus adefovir dipivoxil. In addition to assigned study treatment patients receive an L-carnitine supplement.

Therapy is administered for 24 weeks. Patients who have an average HIV RNA value for Weeks 12 and 16 that is less than 5,000 copies or a least 1 log below their baseline value may continue their assigned study treatment for an additional 24 weeks. [AS PER AMENDMENT 3/30/98: Subjects with plasma HIV RNA greater than 5,000 copies/ml may elect to continue or discontinue study medications in the treatment extension and seek the best available treatment.] [AS PER AMENDMENT 06/11/98: The dose of adefovir dipivoxil is reduced at or after Week 16. Alternatively, patients may discontinue adefovir dipivoxil/placebo and substitute appropriate antiretroviral agent(s) or add appropriate antiretroviral agent(s) to their reduced-dose regimen. Also, at the discretion of the protocol chairperson, patients who have been on study for more than 16 weeks may substitute appropriate FDA-approved antiretroviral agent(s) for any study medication that must be discontinued because of toxicity. Addition of nonnucleoside reverse transcriptase inhibitors, protease inhibitors, or investigational agents is specifically excluded.]

• Drug: Ritonavir
• Drug: Nelfinavir mesylate
• Drug: Levocarnitine
• Drug: Adefovir dipivoxil
• Drug: Saquinavir
• Drug: Delavirdine mesylate

• Gulick RM, Hu XJ, Fiscus SA, Fletcher CV, Haubrich R, Cheng H, Acosta E, Lagakos SW, Swanstrom R, Freimuth W, Snyder S, Mills C, Fischl M, Pettinelli C, Katzenstein D. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis. 2000 Nov;182(5):1375-84. Epub 2000 Oct 9.
• Gulick RM, Hu XJ, Fiscus SA, Fletcher CV, Haubrich R, Cheng H, Acosta E, Lagakos SW, Swanstrom R, Freimuth W, Snyder S, Mills C, Fischl M, Pettinelli C, Katzenstein D. Durability of response to treatment among antiretroviral-experienced subjects: 48-week results from AIDS Clinical Trials Group Protocol 359. J Infect Dis. 2002 Sep 1;186(5):626-33.
• Fletcher CV, Jiang H, Brundage RC, Acosta EP, Haubrich R, Katzenstein D, Gulick RM. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group Study 359. J Infect Dis. 2004 Apr 1;189(7):1176-84. Epub 2004 Mar 16.
• Swanstrom R, Bosch RJ, Katzenstein D, Cheng H, Jiang H, Hellmann N, Haubrich R, Fiscus SA, Fletcher CV, Acosta EP, Gulick RM; AIDS Clinical Trials Group Protocol 359 Team. Weighted phenotypic susceptibility scores are predictive of the HIV-1 RNA response in protease inhibitor-experienced HIV-1-infected subjects. J Infect Dis. 2004 Sep 1;190(5):886-93. Epub 2004 Jul 23.
• Fletcher CV, Testa MA, Brundage RC, Chesney MA, Haubrich R, Acosta EP, Martinez A, Jiang H, Gulick RM. Four measures of antiretroviral medication adherence and virologic response in AIDS clinical trials group study 359. J Acquir Immune Defic Syndr. 2005 Nov 1;40(3):301-6.
• Haubrich RH, Jiang H, Swanstrom R, Bates M, Katzenstein D, Petch L, Fletcher CV, Fiscus SA, Gulick RM; AIDS Clinical Trials Group Protocol 359 Team. Non-nucleoside phenotypic hypersusceptibility cut-point determination from ACTG 359. HIV Clin Trials. 2007 Mar-Apr;8(2):63-7.
• Gulick RM, Hu XJ, Fiscus S, Fletcher CV, Haubrich R, Cheng H, Lagakos S, Acosta E, Swanstrom R, Mills C, Snyder S, Fischl M, Pettinelli C, Katzenstein D. Durability of salvage therapy with saquinavir SGC (SQV) in combination with ritonavir (RTV) or nelfinavir (NFV) plus delavirdine (DLV), adefovir dipivoxil (ADV), or both; ACTG 359: 48-week final results. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 338)
• Acosta EP, Gulick R, Katzenstein D, Haubrich R, Fischl M, Raasch R, Mills C, Pettinelli C, Remmel RP, Fletcher CV. Pharmacokinetic (PK) evaluation of saquinavir soft gel capsules (SQV)/ritonavir (RTV) or sqv/nelfinavir (NFV) in combination with delavirdine (DLV) and/or adefovir dipivoxil (ADV) - - ACTG 359. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:136 (abstract no 365)
• Gulick RM, et al. Salvage therapy with saquinavir sgc (SQV) in combination with ritonavir (RTV) or nelfinavir (NFV) and delavirdine (DLV), adefovir dipivoxil (ADV), or both-ACTG 359. Second International Workshop on Salvage Therapy for HIV Infection. 1999 May 19-21
• Fletcher CV, Testa MA, Haubrich R, Brundage R, Jiang H, Ickovics J, Martinez A, Snyder S, Gulick R. Relationships among Four Measures of Medication Adherence and Virologic Response in ACTG 359. 10th Conference on Retroviruses and Oppurtunistic Infections. Feb 2003. Abstract 577.

Inclusion Criteria

Concurrent Medication:

Required:

• Chemoprophylaxis for Pneumocystis carinii pneumonia for all patients who have a CD4 cell count of equal or less than 200 cells/mm3.

Allowed:

• Topical and oral antifungal agents except ketoconazole and itraconazole.
• Treatment, maintenance or chemoprophylaxis with approved agents for opportunistic infections.
• Antibiotics.
• 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 (not as a sole form of birth control), megestrol acetate, or testosterone.
• Alternative therapies, such as vitamins, acupuncture, and visualization techniques.
• [AS PER AMENDMENT 3/30/98: Calcium channel blockers may be used only with caution.]

Patients must have:

• HIV-1 infection documented by a licensed ELISA and confirmed by Western blot, HIV culture, HIV antigen, plasma HIV RNA, or a second antibody test other than ELISA.
• 2,000 to 200,000 HIV-1 RNA copies/ml as measured by any Roche-certified laboratory [AS

PER AMENDMENT 3/30/98:

• using the Roche Amplicor HIV-1 Monitor] within 30 days of study entry.
• Signed, informed consent from parent or legal guardian for patients less than 18 years of age.

Prior Medication: Required:

• More than 6 months cumulative indinavir therapy.
• Stable indinavir-containing antiretroviral regimen for at least 4 weeks [2 weeks AS PER AMENDMENT 3/30/98] prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

• Any active infection requiring acute treatment within 30 days [21 days AS PER AMENDMENT 3/30/98] prior to study entry.
• Unexplained temperature greater than 38.5 degrees for any 7 consecutive days within 30 days prior to study entry.
• Malignancy, including Kaposi's sarcoma, that requires systemic chemotherapy.

Concurrent Medication:

Excluded:

• Non-protocol-specified immunomodulatory and/or antiretroviral agents.
• Systemic cytotoxic chemotherapy.
• Ketoconazole, itraconazole, rifampin, rifabutin, alprazolam, amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, encainide, estazolam, flecainide, flurazepam, isotretinoin, meperidine, midazolam, piroxicam, propafenone, propoxyphene, quinidine, terfenadine, triazolam, zolpidem, phenytoin, phenobarbital, carbamazepine, and ergot alkaloids and [ AS PER AMENDMENT 3/30/98: dexamethasone, ergot derivatives, and pimozide].

Avoided:

• Herbal medications.

Prior Medication:

Excluded:

• At least 2 weeks or more total ritonavir and/or saquinavir (hard gelatin capsule).
• NNRTIs (nevirapine, delavirdine, DMP-266, etc.), saquinavir (soft gelatin capsule), nelfinavir, 141W94VX-478, and adefovir dipivoxil.
• Immunomodulator [systemic immunomodulator AS PER AMENDMENT 3/30/98] or investigational drug therapy within 30 days prior to entry.
• Active immunization within 30 days [21 days AS PER AMENDMENT 3/30/98] prior to entry.