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. There is an acute medical need for novel and potent antiretroviral therapy for HIV-infected patients who are experiencing resistance, suffer from toxicities on other possible regimens, or are failing their current antiretroviral regimen. These patients are often heavily pre-treated and have very limited or no remaining therapeutic options. The purpose of this pediatric study is to gain dosage, short and long term safety data, intensive and population PK data, drug interactions, and efficacy experience with raltegravir in HIV-1 infected children with which to guide potential usage in children ages two through adolescence. IMPAACT P1066 is a Phase I/II, multi-center, open-label, noncomparative study of approximately 120 to 140 HIV-1 infected children and adolescents ages =2 years to <19 years of age to evaluate the safety, tolerability, pharmacokinetic parameters and efficacy of raltegravir. The primary objectives are: In Stage I, to evaluate the short term safety and tolerability of raltegravir added to an initial stable background therapy which will then be optimized in children and adolescents in the age groups of =2 to <6, =6 to <12 and =12 to <19 years;In Stage I, to evaluate the steady state plasma concentration profiles and pharmacokinetic parameters of raltegravir added to stable background therapy* in children and adolescents in the age groups of =2 to <6, =6 to <12 and =12 to <19 years;and In chronic dosing, to evaluate the safety and tolerability of raltegravir at the selected dose in combination with optimized background therapy (OBT) in children and adolescents in the age groups =2 to <6, =6 to <12 and =12 to <19 years, as assessed by review of the accumulated safety data over 24 weeks. HYPOTHESIS: Dosage data, short and long term safety data, intensive and population PK data, drug interactions, and efficacy experience of Raltegravir 9MK-0518) will help guide potential usage in HIV infected children ages two through adolescence.
SPECIFIC AIMS :Primary-In Stage I, to evaluate the short term safety and tolerability of raltegravir added to an initial stable background therapy* which will then be optimized in children and adolescents in the age groups of =2 to <6, =6 to <12 and =12 to <19 years. In Stage I, to evaluate the steady state plasma concentration profiles and pharmacokinetic parameters of raltegravir added to stable background therapy* in children and adolescents in the age groups =2 to <6, =6 to <12 and =12 to <19 years. In chronic dosing, to evaluate the safety and tolerability of raltegravir at the selected dose in combination with optimized background therapy (OBT)in children and adolescents in the age groups =2 to <6, =6 to <12 and =12 to <19 years, as assessed by review of the accumulated safety data over 24 weeks. * Stable background therapy defined as unchanged therapeutic regimen for at least 12 weeks, or treatment experienced (not including therapy to interrupt maternal-infant transmission);but on no treatment for =4 weeks. See section 4.13. Secondary In chronic dosing, to evaluate the safety and tolerability of raltegravir at the selected dose in combination with optimized background therapy (OBT)in study subjects, as assessed by review of the accumulated safety data over 48 weeks. To evaluate the antiretroviral activity of raltegravir at study weeks 24 and 48 at the selected dose in combination with OBT in study subjects, as measured by the proportion of subjects achieving HIV RNA below 400 copies/mL, or maintaining a 1-log drop in HIV RNA from baseline. To evaluate the immunological activity of raltegravir at the selected dose in combination with OBT in study subjects, as measured by changes in CD4 cell count and changes in CD4 % over 24 and 48 weeks. To describe pediatric raltegravir exposure over time, using a population pharmacoknetic modeling approach BACKGROUND AND SIGNIFICANCE:Integrase is 1 of 3 HIV-1 enzymes required for viral replication. Integrase catalyzes the stepwise process which results in the integration of the HIV-1 DNA into the genome of the host cell. This ordered series of reactions includes the assembly of integrase in a stable complex with the viral DNA, the endonucleolytic processing of the viral DNA ends, and strand transfer or joining of the viral and cellular DNAs. Integration is required for stable maintenance of the viral genome as well as efficient viral gene expression. To date there are no approved drugs targeting this enzyme. Raltegravir is a potent and selective inhibitor of HIV-1 integrase catalyzed strand transfer (IC50=10 nM). Raltegravir exhibits >1000-fold selectivity over other phosphotranferases, including the structurally related enzyme HIV-1 RNase H and the human DNA polymerases, a, ?, and (IC50 values >50 ?M). The antiretroviral potency of raltegravir (IC95 of 33 ? 23 nM;50% human serum) measured in vitro is comparable to many clinically efficacious antiretroviral therapeutics. Inhibition of HIV-1 replication is shown to be a result of raltegravir interference with integration. Preclinical data, including in vitro inhibition assays and safety assessment, suggest that raltegravir has the promise to be a clinically safe and effective integrase inhibitor. In addition, raltegravir has been shown in Phase II and III clinical studies, to be generally well tolerated and has demonstrated potent efficacy in both treatment-na?ve and treatment-experienced patients with triple-class resistant virus.
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