A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing 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 and children
by weight. This study will evaluate the pharmacokinetics, safety, and tolerance of LPV/r
dosed according to these guidelines. The following strata were used to guide accrual:

Number of Participants to be Enrolled by Weight Band:

3-4.9 kg: 11 liquid

5-6.9 kg: 11 liquid

7-9.9 kg: 17 liquid

10-16.9 kg: 11 liquid, 22 tablet

17-19.9 kg: 11 tablet

20-24.9 kg: 11 tablet

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 they can swallow
pills. Dosing will be calculated using the WHO schedule. At all study visits, 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 participant 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