Safety and Effectiveness of World Health Organization Dosing Guidelines of Lopinavir/Ritonavir for Children

• Safety, as determined by non-occurrence of any recurring Grade 3 or non-life-threatening Grade 4 toxicity, or a single life-threatening Grade 4 toxicity [ Time Frame: Measured at study completion ] [ Designated as safety issue: Yes ]
• Area under the curve (AUC), as determined by a non-compartmental analysis of 12-hour pharmacokinetic sampling for lopinavir/ritonavir [ Time Frame: Measured after 4 weeks of treatment ] [ Designated as safety issue: No ]
• Maximum and minimum concentrations and half-life of lopinavir/ritonavir [ Time Frame: Measured at study completion ] [ Designated as safety issue: No ]
• Proportion of participants with an AUC of less than 10% of adults [ Time Frame: Measured after 4 weeks of treatment ] [ Designated as safety issue: No ]
• Number and percent of participants experiencing adverse events of Grade 3 or greater [ Time Frame: Measured at study completion ] [ Designated as safety issue: Yes ]
• Adherence, defined as proportion of doses taken [ Time Frame: Measured at study completion ] [ Designated as safety issue: Yes ]

Treatment of children and infants with HIV requires modification of medication dosing according to a child's specific weight. For lopinavir/ritonavir (LPV/r), a second line treatment option that is increasingly necessary due to infant drug resistance, this dosing is often complicated and impractical in busy clinical settings. To address this, the World Health Organization (WHO) has released a simplified dosing table based on infant weight bands. This study will evaluate the absorption, safety, and tolerance of LPV/r in infants when dosed according to the new WHO guidelines.

Because of previous exposure to nevirapine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs), either by direct treatment or through their mothers in pregnancy, infants must often receive an alternate antiretroviral regimen that includes LPV/r. Dosing of LPV/r is currently based on a child's specific weight, and calculations of proper dosages are often too complicated to be practical in busy clinics, particularly those in limited resource settings. In order to simplify medication delivery and reduce prescribing errors, the WHO has released a dosing schedule for LPV/r based on groupings of infants by weight. This study will evaluate the pharmacokinetics, safety, and tolerance of LPV/r dosed according to these guidelines.

Participation in this study will last 6 months. Infant participants and their caretakers will need to attend study visits at entry and Weeks 2, 4, 12, and 24. At entry, participants will be given LPV/r either in liquid or tablet form, depending on whether the infant can swallow pills. Dosing will be calculated using the WHO schedule. At all study visits, infant participants will undergo a physical exam and caretakers will be asked about how well the child is taking the study medications. In addition, at Weeks 4, 12, and 24, blood samples will be taken from the infant to determine health and levels of the medication in the body. The visit on Week 4 will also require pharmacokinetic testing, which means the child will need to be monitored at the hospital for 12 hours and complete six additional blood drawls. All other study visits will last 1 to 2 hours.

Inclusion Criteria:

• Weight equal to or greater than 3 kg, but less than 25 kg, at the time of enrollment
• Confirmed diagnosis of HIV-1 infection
• Lopinavir/ritonavir (LPV/r)-treatment naïve and LPV/r-treatment eligible as defined by country-specific guidelines or the WHO pediatric treatment guidelines and confirmed by investigator
• Willingness to take two nucleoside reverse transcriptase inhibitos (NRTIs), in accordance with appropriate national or international treatment guidelines
• Demonstrated ability and willingness to swallow tablets for children larger than 10 kg. This can be assessed before inclusion (for example, a test trial with similar size solid tablet such as tic-tac).
• Participants in the weight band between 10 and 16.9 kg that are unable to swallow tablets will receive liquid formulation
• Parent or legal guardian able and willing to provide written informed consent

Exclusion Criteria:

• Planned concurrent use of non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, or an entry inhibitor
• Planned concurrent protease inhibitor (PI) use, other than LPV/r
• Prior treatment with LPV/r. Prior treatment with other PIs is allowed.
• Results of certain laboratory tests indicating adverse events of Grade 3 or greater
• Results of a lipase test indicating adverse event of Grade 2 or greater or clinical evidence of pancreatitis within 30 days prior to study entry
• Tuberculosis co-treatment with rifampicin-containing regimen
• Treatment with any enzyme-inducing antiepileptic drugs, such as henobarbital, phenytoin or carbamazepine
• Clinical condition requiring the use of a prohibited medication (see protocol for more details)
• Clinically unstable child requiring acute treatment for a serious opportunistic infection
• Chemotherapy for active malignancy
• Any clinically significant diseases (other than HIV-1 infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise participation in this study
• Treatment with experimental drugs for any indication within 30 days prior to study entry
• Known history of cardiac conduction abnormality and/or underlying structural heart disease, including congenital long QT