a study of several anti-hiv drug combinations in hiv-infected patients who have used indinavir

Conditions: HIV Infections

Summary: 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. \[as per amendment 3/30/98: subjects with plasma hiv rna greater than 5,000 copies/ml may elect to continue or discontinue study medications in the treatment extension and seek the best available treatment.\] \[as per amendment 06/11/98: the dose of adefovir dipivoxil is reduced at or after week 16. alternatively, patients may discontinue adefovir dipivoxil/placebo and substitute appropriate antiretroviral agent(s) or add appropriate antiretroviral agent(s) to their reduced-dose regimen. also, at the discretion of the protocol chairperson, patients who have been on study for more than 16 weeks may substitute appropriate fda-approved antiretroviral agent(s) for any study medication that must be discontinued because of toxicity. addition of nonnucleoside reverse transcriptase inhibitors, protease inhibitors, or investigational agents is specifically excluded.\]

Eligibility criteria:
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.

Keywords: hiv-1 drug therapy, combination hiv protease inhibitors ritonavir indinavir rna, viral saquinavir delavirdine nelfinavir adenine anti-hiv agents viral load