This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. -Goals and Methods (provide the page reference to the research design/statistical analysis section of the full protocol) - Goals: Pages 37-38 This is a 'proof of concept' study, designed to examine the feasibility of treating subjects who have failed PI-containing HAART therapy with high doses of LPV/r. The primary objectives of the study are to estimate pharmacokinetic parameters for LPV/r and SQV (see section 9), and to examine the safety of LPV/r and SQV at the doses specified in section 5 of this protocol. PACTG P1038 is a Phase I/II, open label study of high dose lopinavir/ritonavir (LPV/r) to assess the safety, tolerability, and pharmacokinetics of LPV/r with or without saquinavir (SQV) in HIV-infected children and adolescents who have at least six months of prior PI experience and are failing their current antiretroviral therapy (plasma HIV RNA > 5000 copies/mL). The study will seek to enroll 48 subjects = 2 years to < 18 years of age. Subjects will be stratified by concurrent NNRTI treatment, and subjects will be treated for 48 weeks from the start of the initial LPV/r dose. The primary objectives of the study are to estimate pharmacokinetic parameters for LPV/r and SQV (see section 9), and to examine the safety of LPV/r and SQV at the doses specified in section 5 of this protocol. A key secondary objective is to estimate the proportion of subjects who can achieve an IQ of 15 or greater on the doses of LPV/r specified in section 5, without experiencing unacceptable toxicity. Further secondary objectives are to assess the intermediate and long term virologic and immunologic outcomes, and to examine whether these vary as a function of concurrent NNRTI use and of success in achieving an IQ > 15. Each of these factors is intertwined with other effects which may affect treatment success: some subjects currently on an NNRTI will be treated at higher doses of LPV/r to compensate for the reduction of LPV/r concentrations when co-dosed with NNRTIs, and subjects failing to achieve IQ = 15 will have saquinavir added to their regimens, provided that they can swallow the saquinavir capsules (see schema). In the analyses described below, the extent to which achieving an IQ = 15 predicts long term virologic and immunologic success may be confounded by use of NNRTIs or saquinavir, which may successfully compensate for failure to achieve a LPV/r IQ = 15, thereby eliminating the potential virologic advantage of those who do meet this criteria. Co-variance analyses will be used in an attempt to control for these potentially confounding factors, but complete adjustment for confounding will not be possible This study will use a higher than standard dose of lopinavir. The rationale for this is that 'resistance' to most antivirals is a relative phenomenon, i.e. even in vitro 'resistant' strains of HIV-1 are rarely 100% resistant. If higher doses of the drug are used, viral replication can be suppressed even in 'resistant' clones. The net result will be the suppression of a greater number of virions. This strategy has been successfully employed in other infectious diseases (higher doses of fluconazole to treat candida, higher acyclovir doses for longer chronic suppression) and oncology (multi-drug resistant cancer cells can be eliminated with higher doses). In fact 'dose intensity' (i.e. the amount of drug given per unit time) is a fundamental principle in cancer chemotherapy (50, 51). Standard oncology textbooks warn 'ad hoc adjustment of dosing is a major reason for treatment failure in patients with drug-sensitive human tumors undergoing their first chemotherapy treatment' (50). The goal of therapy is long-lasting control of HIV replication to prevent or reverse HIV-related symptoms, or immune system suppression. Combination therapy with three or more antiretroviral medications is better than therapy with monotherapy or therapy with only 2 antiretrovirals (5-12), and triple-drug therapy is currently recommended for treatment of patients with HIV infection (13-18). Potent multi-drug therapy can decrease virus replication (4, 19, 20), reduce plasma virus load to below limits of quantitation on sensitive assays (BLQ), reverse symptoms of HIV infection (21-26), improve growth (27-31), and lead to improved immune system function, including increased CD4+ cell count, decreased CD8+ cell count, and improved response to vaccination (32-37). While potent regimens can initially reduce virus load to below assay quantitation limits in the majority of persons with HIV infection, 30% to 80% of treated subjects will have regimen failure and return of detectable plasma virus within one year (8, 9, 38, 39). Loss of control of HIV replication can be benign in some subjects, who will have sustained high or rising CD4+ cell counts, no risk of opportunistic infection, and no symptoms of HIV infection (40-43). However, in other subjects, return of plasma viremia may be associated with a decrease in CD4+ cell count, selection of drug-resistant virus, and return of symptoms of HIV or opportunistic infection (38). Progress report will be made available to the participating sites. The safety data from the first six subjects enrolled in P1038 will be reviewed when the sixth subject has been on treatment for 4 weeks. The following algorithm will be applied to determine whether an intensive review of safety data, with the potential for stopping accrual to the study or stopping study treatment for all subjects enrolled in the study, should be performed: 1) Fail, if 1 or more subjects have drug related life threatening toxicity 2) Fail, if 3 or more subjects have drug related, non-life-threatening Grade 3 or 4 toxicity If either of the criteria for safety failure is met, accrual to the study will be suspended, pending a thorough investigation of the safety data by a committee which will include: the Chair, Vice Chairs, Medical Officers, Statisticians, Clinical Trials Specialist from P1038, a representative from the Primary Therapy RAC, and Abbott and Roche representatives There are no publications to date that have resulted from this study.
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