Integrase is 1 of 3 HIV (Human Immunodeficiency Virus)-1 enzymes required for viral replication. Raltegravir is a drug that prevents integrase from working properly. This drug has been tested for safety and efficacy in adults, but this is the first study to examine raltegravir in children and adolescents. The purpose of this study was to determine the appropriate dose for raltegravir across the pediatric age range from 4 weeks to 18 years of age, by acquiring short and long term safety data, intensive and population pharmacokinetic (PK) data, and efficacy experience with raltegravir in HIV-infected children and adolescents.

Integrase is one of three enzymes necessary for HIV replication. Integrase allows for the integration of HIV DNA (deoxyribonucleic acid) into the human genome. Raltegravir is a strong and selective inhibitor of HIV integrase. In adults, raltegravir has shown significant antiretroviral activity in clinical trials and is well tolerated. The purpose of this study was to determine the appropriate dose for raltegravir across the pediatric age range from 4 weeks (30 days) to 18 years of age, by acquiring short and long term safety data, intensive and population PK data, and efficacy experience with raltegravir in treatment-experienced, HIV-infected children and adolescents.

The study consisted of two sequential Stages: I and II. The dose finding period of Stage I was intended to examine the pharmacokinetics and short term tolerability and safety of raltegravir in a limited number of participants to permit dose selection for further study in Stage II. The dose finding algorithm required a preliminary assessment of data from the first 4 patients of each cohort (termed a "mini-cohort"). Failure to meet PK targets required dose adjustments, contingent upon the mini-cohort's dose having met safety criteria, followed by reassessment of safety and PK data from the new mini-cohort dose. When a mini-cohort dose had passed both safety and PK criteria, further accrual to and an assessment of results from the full cohort could occur. Again, failure to meet PK targets required dose adjustments contingent upon the full cohort's dose having met safety criteria with subsequent PK and safety evaluation of data from a new cohort taking the new dose.

Chronic dosing, which includes Stage I extension (the period after Stage I dose finding) and Stage II (additional participants enrolled), was intended to provide longer term safety and antiviral activity data in a larger sample of participants. Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all patients received only the final selected doses for their respective cohorts. This group is denoted as the Final Dose Population, and results from this group are considered primary, since they reflect only the age-specific doses proposed for commercial use. The group with all participants exposed to raltegravir (at any dose) is denoted as the All Treated Population.

Stage I lasted for a minimum of 48 weeks, Stage II was for 48 weeks, and a long-term follow-up period lasted for 5 years from initial exposure (i.e., 48 weeks of treatment plus 4 years of follow-up). Participants were stratified by age and assigned to one of six cohorts. Participants in Cohort I were between the ages of 12 and 18 years and received poloxamer film coated raltegravir tablets. Participants in Cohort IIA were between the ages of 6 and 11 years, weighed at least 25 kg, and received poloxamer film coated raltegravir tablets. Participants in Cohort IIB were between the ages of 6 and 11 years and received chewable raltegravir tablets. Participants in Cohort III were between the ages of 2 and 5 years and received chewable raltegravir tablets. Participants in Cohort IV were between the ages of 6 months (defined as 180 days) and 23 months and received oral granules for suspension. Participants in Cohort V were between the ages of 4 weeks (defined as 30 days) and 5 months and received oral granules for suspension.

Enrollment for Stage I of this study began with Cohort I and progressed to the other cohorts once preliminary dosage had been determined and safety data were reviewed. When this information had been determined for Cohort I, Cohorts IIA and IIB began enrollment. Once safety and dose data for these cohorts were reviewed, enrollment into Cohort III began. Once safety and dose data for Cohort III were reviewed, enrollment into Cohort IV began and once safety and dose data for Cohort IV were reviewed, enrollment into Cohort V began.

During Stage II of this study, participants took raltegravir at the dosage determined as safe and reaching PK targets based on the the Stage I data. The purpose of Stage II was to determine long-term safety of raltegravir once a safe dose meeting PK targets has been determined.

Participants whose Stage I dose was different from the dose determined for Stage II and who had not had individual dose adjustments because of extreme PK values had their raltegravir dose changed to the selected Stage II dose once it was determined. If individualizing the dose for participants in this manner resulted in a dose increase, these participants had an additional safety visit 4 weeks after the dose modification, and then continued on study visits with no further changes in the visit schedule.

There were at least 9 study visits for participants in this study, occurring during the 48-week raltegravir treatment period. For participants who completed 48 weeks of study and appeared to have benefited from receiving study drug, raltegravir was provided until five years after initial raltegravir exposure. For participants who opted to continue on study-provided raltegravir, extended provision of drug was implemented as part of a protocol extension involving visits every 4 months for five years after initial raltegravir exposure. Participants who did not continue on study-provided raltegravir were followed with annual visits for five years after initial raltegravir exposure (i.e. 48 weeks of raltegravir treatment plus 4 years follow-up). At each visit, a physical exam, blood collection, and determination of treatment adherence occurred. At some visits, urine collection and Tanner staging occurred. Selected cohorts underwent a taste evaluation at 1 of 2 visits. Participants aged 2 to less than 6 years of age were asked to participate in an additional PK substudy in which blood was collected two times over a 12-hour visit (or, if more convenient, this assessment may have been completed in 2 separate visits) in order to collect additional Cmin PK data. Participants were re-registered into the same cohort if a dose change was recommended.

Current pediatric Food and Drug Administration approval and dosing recommendations are based upon evaluations in 122 Final Dose participants aged ≥4 weeks to 18 years enrolled in this study.

The results present safety and efficacy results of the complete 5 year follow up data (primary and key secondary endpoints) of the participants from IMPAACT P1066, the Final Dose Population. By the date on which most of the data were frozen, 24 July 2017, all participants enrolled had Week 24 data (i.e., had either completed the Week 24 visit, or, for those who discontinued before Week 24, had the potential to have experienced the Week 24 visit), had also completed (or had the potential to have experienced) the Week 48 visit, and had either completed 240 weeks of study and were subsequently taken off study, or had prematurely discontinued study and were no longer in follow up.

Inclusion Criteria for All Participants:

• Documentation of HIV-1 infection, defined as positive results from two samples collected at different time points. More information on this criterion can be found in the protocol.
• For participants in Cohorts I, IIA, IIB, and III: On unchanged therapeutic regimen for at least 12 weeks, or treatment experienced (not including therapy to interrupt maternal-to-child-transmission (MTCT)) but on no treatment for 4 or more weeks prior to study entry. More information on this criterion can be found in the protocol.
• Participants in Cohorts IV must have received therapy to either interrupt MTCT and/or to treat HIV infection and participants in Cohort V must have received therapy to interrupt MTCT but have not received other anti-HIV therapies.
• HIV RNA (ribonucleic acid) of 1,000 copies/mL or greater at screening
• Demonstrated ability or willingness to take assigned raltegravir preparation
• Parent or legal guardian or participant able and willing to provide signed informed consent when applicable
• Female participants who are sexually active and potentially able to become pregnant must use two methods of birth control while on study and for 3 months after stopping study drug. More information on this criterion can be found in the protocol. Male participants must not participate in sperm donation programs. Male participants engaging in sexual activity that could lead to pregnancy must use a condom.
• Willing to be re-registered within same cohort if a dose change is recommended

Exclusion Criteria for All Participants:

• Known Grade 3 or higher of any of the following laboratory tests within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lipase, serum creatinine
• Clinical evidence of pancreatitis
• Treatment for active tuberculosis (TB) infection or disease.
• History of lactic acidosis in 3 months prior to study entry. More information on this criterion can be found in the protocol.
• Diagnosis of new Centers for Disease Control Stage C criteria or opportunistic or bacterial infection diagnosed within 30 days prior to study screening and not considered clinically stable
• Prior treatment with another experimental HIV integrase inhibitor
• Immunosuppressive therapy within 30 days prior to beginning raltegravir study treatment. Participants taking short courses of corticosteroids are not excluded.
• Current or anticipated use of any disallowed medications, listed in the protocol.
• Any history of malignancy
• Participants who are unlikely to adhere to the study procedures or keep appointments
• Participants who are planning to relocate during study
• Any clinically significant diseases (other than HIV) or findings during the screening medical history or physical examination that, in the opinion of the investigator, would compromise the outcome of the study
• Current or past participation in an investigational study with a compound or device that is not commercially available within 30 days of signing informed consent
• Participants who are pregnant or breastfeeding. Infants who are receiving breastmilk are allowed to enroll.
• For participants in Cohorts IV and V, participant's caregiver is unable to access clean water supply (as defined by local standards) to re-suspend raltegravir oral granules

Exclusion Criteria for Stage I Participants:

• Stage I mini cohort (initial 4 participants) only: current or anticipated use of antiretroviral regimen that includes atazanavir, tenofovir, or tipranavir during Stage I. Any other commercially available antiretroviral drugs are acceptable.
• Stage I participants enrolling after initial 4 participants: use of atazanavir, tenofovir, or tipranavir prior to the intensive PK testing. More information on this criterion can be found in the protocol.

Exclusion Criteria for Stage II Participants Taking Atazanavir as Part of Their Background Regimen:

• Total bilirubin of Grade 4 or higher within 30 days of study entry
• Total bilirubin value lower than Grade 4 but direct bilirubin or concurrent transaminase greater than 1.5 times the upper limit of normal and participant is symptomatic, within 30 days prior to study entry