Study Of An Investigational Regimen Including FDA Approved HIV Drugs In HIV-Infected Pediatric Subjects

Plasma samples were assayed for APV concentrations using a validated assay. The GlaxoSmithKline (GSK) Department of Clinical Pharmacology Modeling and Simulation conducted pharmacokinetic (PK) analysis of the plasma APV concentration-time data using a model-independent approach. As a measure of total drug exposure, the area under the plasma-concentration-versus-time curve over the dosing interval at steady-state (AUC[0-τ]), where "τ" is the length of the dosing interval, was calculated by the linear up/log down trapezoidal method. hours, hr.

The maximum concentration at steady state (Cmax) was measured.

The plasma concentration at the end of the dosing interval at steady state (Cτ) was measured.

Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated using the formulation: APV Dose in mg/kg units divided by AUC(0-τ). For FPV, doses were expressed in APV molar equivalents (50 mg of FPV = 43.2 mg of APV). Normalizing CL/F for bodyweight allows for comparison of CL/F across populations.

Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose/AUC(0-τ). For FPV, doses were expressed in APV molar equivalents (50 mg of FPV = 43.2 mg of APV).

Participants who are <2 years old may have reduced protein binding; therefore, plasma unbound APV concentrations were measured to determine dosing recommendations at acceptable dosing volumes. Unbound or "free" APV is the fraction of drug that is not bound to protein. Cτ is the plasma concentration at the end of the dosing interval at steady state.

Participants who are <2 years old may have reduced protein binding; therefore, plasma unbound APV concentrations were measured to determine dosing recommendations at acceptable dosing volumes. APV %Cτ unbound is the percentage of the total APV Cτ that is unbound.

Blood samples of the participants were collected for the evaluation of ALT and AST. Clinical chemistry analyses were carried out using the observed analysis strategy.

Blood samples of all participants were generally collected under non-fasting conditions (given the age of participants) for the evaluation of cholesterol, serum glucose, HDL cholesterol, LDL cholesterol and triglyceride (TG). Clinical chemistry analyses were carried out using the observed analysis strategy.

Blood samples of all participants were collected for the evaluation of serum lipase. Clinical chemistry analyses were carried out using the observed analysis strategy. Change from Baseline in serum lipase was calculated as the value at the indicated time point minus the value at Baseline.

TE toxicities were presented for each laboratory parameter. A toxicity was considered TE if it was greater than the Baseline grade, and if it was observed on/after the date of the first dose of study drug (SD), and on/before the date of the last dose of SD. Per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs, Grade 3=severe; Grade 4=potentially life-threatening.

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE is considered TE if it has an onset date on or after the date of the first dose of study drug, and on or before the date of the final dose of study drug. As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs, Grade 3=severe; Grade 4=potentially life-threatening.

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Blood samples of participants were collected to measure plasma HIV-1 RNA concentrations.

Blood samples of participants were collected to measure plasma HIV-1 RNA copies. Baseline value was defined as the value observed at the day 1 visit or if this value is missing the last value observed before the start of investigational product. Change from baseline value was defined as post-dose value minus baseline value.

Blood samples of participants were collected for the measurement of the CD4+ cells.

A blood sample was drawn from participants failing to respond to therapy, and genotyping was performed to identify the mutations present in the baseline (pre-therapy) and the sample obtained at virologic failure (VF). For each participant, the HIV-1 mutations found at the time of failure were compared with any HIV-1 mutations detected in the blood sample at baseline. New International AIDS Society-USA defined resistance mutations that developed at the time of failure were tabulated by drug class- NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Participants are grouped by study arm (prior therapy experience), results displayed in this table are from participants who met virologic failure criteria from Week 48 through Week 684.

A blood sample was drawn from participant failing to respond to therapy, and the mutations present in the virus were identified. Phenotypic resistance was assessed for virologic failure population and evaluated for Protease Inhibitors (PIs), Nucleotide reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNTRIs) using Monogram PhenoSense Assay. Virologic failure was defined as having failed to achieve a plasma HIV-RNA of <400 copies/mL by Week 24 or having had a confirmed HIV-RNA rebound to ≥400 c/mL at any time after achieving a plasma HIV-RNA of <400 c/mL.

Blood samples of participants were collected to measure plasma HIV-1 RNA concentrations. Viral load, measured in RNA copies per milliliter of plasma, is an efficacy measure for antiretroviral drugs. In the Missing, Switch, or Discontinuation=Failure (MSD=F) analysis, participants who had missing data at or had discontinued the study prior to a certain time point or had changed their background antiretroviral regimen are classified as non-responders.

Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA copies.

Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA copies. Change from Baseline in plasma HIV-1 RNA was calculated as the value at the indicated time point minus the value at Baseline.

Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA copies. In the MSD=F analysis, participants who had missing data at or had discontinued the study prior to a certain time point or had changed their background antiretroviral regimen are classified as non-responders.

Blood samples of participants were collected for the measurement of the percentage of total lymphocytes that are CD4+ cells. Observed analysis was used for the summary of proportion endpoints using viral load data. CD4+ cells are white blood cells that are important in fighting infection. HIV infects CD4+ cells, replicates in them, and destroys them. A CD4+ cell count provides a measure of the status of the immune system and to what extent it is affected by HIV.

Blood samples of participants were collected for the measurement of the percentage of total lymphocytes that are CD4+ cells. Observed analysis was used for the summary of proportion endpoints using viral load data. Change from Baseline in percentage was calculated as the value at indicated time points minus the value at Baseline.

Blood samples of participants were collected to measure plasma HIV-1 RNA concentrations. PI-exp = PI-experienced. Virologic success was defined as plasma HIV-1 RNA <400 copies/mL. Virologic failure: (1) HIV-1 RNA >=400 copies/mL, (2) change of background antiretroviral treatment (ART), (3) discontinued study due to lack of efficacy, (4) discontinued study with last HIV-1 >=400 copies/mL. No virologic data at Week 48 window: (a) discontinued study due to an adverse event or death, (b) discontinued study due to other reasons (withdrew consent, loss to follow-up, moved, etc.).

Plasma samples were assayed for RTV concentrations using a validated assay. The GSK Department of Clinical Pharmacology Modeling and Simulation conducted PK analysis of the plasma RTV concentration-time data using a model-independent approach. As a measure of total drug exposure, the area under the plasma-concentration-versus-time curve over the dosing interval at steady-state (AUC[0-τ]), where τ is the length of the dosing interval, was calculated by the linear up/log down trapezoidal method.

The maximum concentration at steady state (Cmax) was measured.

The plasma concentration at the end of the dosing interval at steady state (Cτ) was measured.

Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose in mg/kg units divided by AUC(0-τ). Normalizing CL/F for bodyweight allows for comparison of CL/F across populations.

Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose in mg/kg units divided by AUC(0-τ).

A blood sample was drawn for par. failing to respond to therapy, and the mutations present in the virus were identified. For each par., the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New International AIDS Society-USA defined resistance mutations that developed at the time of failure were tabulated by drug class. VF, virologic failure; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Par. are grouped by study arm and prior therapy experience.

A blood sample was drawn for par. failing to respond to therapy, and changes in DS for HIV isolated from the par. for each drug used in the study were assessed. The changes in DS detected by phenotypic assay in virus from the sample collected at the time of failure was compared with DS in the virus from the blood sample at baseline. Par. are grouped by study arm and prior therapy experience. DS is the state of HIV being susceptible to the antiretroviral agent (the virus can be inhibited by the drug). Reduced DS (i.e., HIV is resistant to the antiretroviral agent) can lead to treatment failure.

A separate questionnaire was administered for FPV and RTV. Items 1-4 of the Adherence Questionnaire measured a participant's adherence with FPV or RTV during the last 3 days and the weekend prior to the indicated study visits. Perfect adherence was defined as not missing any doses of FPV or RTV since the last study visit.

P/G perceptions of FPV/RTV BID were assessed using a P/G Perception of Study Medication questionnaire administered during Weeks 2, 24, and 48/premature study discontinuation. Questions 1 to 4 ask directly about the P/G's assessment of 1=color, 2=texture/consistency, 3=odor, and 4=general satisfaction. Questions 5 to 10 ask about the P/G's perception of the child's assessment of the oral suspension. Data are reported as the number of participants with the indicated response by question, response category (1-3=dislike, 4=neutral, 5-7=like), and timing of visit.

Parent/guardian perceptions of FPV/RTV BID was assessed using a Parent/Guardian Perception of Study Medication questionnaire. Questions 1 to 4 ask directly about the parent/guardian's assessment of the color, texture/consistency, odor, and general satisfaction. Questions 5 to 10 ask about the parent/guardian's perception of the child's assessment of the oral suspension (Items: 5=reaction to new medicine [med.]; 6=taste; 7=acceptance; 8=swallowing; 9=willingness compared to other med.; 10=overall liking. Data for items 6/10 are reported in response categories: 1-3=dislike; 4=neutral; 5-7=like.

No formal analysis has been performed or is planned to correlate plasma APV PK with efficacy and safety outcomes.

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Blood samples were collected for the analysis of all clinical chemistry parameters. Laboratory toxicities were graded using the Division of AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events, where grade 1=mild, grade 2=moderate, grade 3=severe and grade 4=potentially life-threatening. Results for participants with Grade 1 to 4 clinical chemistry toxicities is presented.

Blood samples were collected for the analysis of all hematology parameters. Laboratory toxicities were graded using the DAIDS Table for grading the severity of adult and pediatric adverse events, where grade 1=mild, grade 2=moderate, grade 3=severe and grade 4=potentially life-threatening. Results for participants with Grade 1 to 4 hematology toxicities is presented.

Treatment limiting toxicities are defined as those that are related to investigational medicinal products and deemed to be unacceptable, leading to restriction of further dose escalation.

An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.