Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB

Study Overview
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Brief Summary
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The purpose of this study is to determine the lopinavir levels in blood of HIV and TB infected children (3-15kg) when given lopinavir/ritonavir in a 1:1 ratio with rifampicin containing TB regimen and its safety.

Detailed Description
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This is a multicentre, open label, non-randomized, prospective, noninferiority study to compare the pharmacokinetics of lopinavir administered with superboosting (LPV/r 1:1) and concurrent RIF treatment or with standard boosting (LPV/r 4:1) without concurrent RIF treatment, and to assess the safety, tolerance, and virological effect of superboosting in HIV-TB co-infected infants and children weighing >3 kg and ≤15 kg. LPV/r will be administered as the liquid 80/20 mg/mL formulation (4:1 standard boosting ratio). During anti-TB treatment, additional RTV liquid formulation will be provided to deliver a 1:1 superboosting ratio of LPV to RTV. Actual doses for antiretrovirals and anti-TB drugs will be based on the South African (SA) weight band dosing recommendations and provided as per the site standard of care.

Official Title
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A Pharmacokinetics Study Comparing Lopinavir Plasma Exposure When Given as Lopinavir/Ritonavir (1:1) in the Presence of Rifampicin and Lopinavir/Ritonavir (4:1) Without Rifampicin in HIV and TB Co-infected Children in South Africa.

Conditions
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Acquired Immunodeficiency Syndrome, Tuberculosis

Intervention / Treatment
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* Drug: lopinavir with ritonavir in 1:1 ratio
* Drug: Lopinavir/ritonavir 4:1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documentation of a confirmed diagnosis of HIV-1 infection following SA clinical guidelines Weight >3kg ≤15 kg at enrolment > 42 weeks gestational age On LPV/r-based therapy or about to start a LPV/r-based antiretroviral combination therapy with 2 NRTIs [ABC+3TC or AZT+3TC or d4T+3TC] Clinical diagnosis of TB requiring RIF-based therapy Parent or legal guardian able and willing to provide written informed consent and able to attend study visits. Exclusion Criteria: For neonates, less than 42 weeks gestation and 14 days old Concomitant/chronic treatment with potent enzyme-inducing/inhibiting drugs other than those in the study treatments . See Appendix E (minor inducers/inhibitors and drugs used as part of management of the condition are allowed eg. Steroids) Anticipation at the start that anti-TB treatment duration will be longer than 9 months Any other condition/finding that, in the investigator's opinion, would compromise the child's participation in this study eg. alanine transferase (ALT) more than 10 times upper limit of normal (ULN), or chronic renal, hepatic or gastrointestinal disease such as malabsorption. Children with known malignancies and contraindications to taking LPV/r Treatment with experimental drugs for any indication within 30 days prior to study entry; participation in another study may be approved by the study team.

Ages Eligible for Study
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Minimum Age: 2 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TB/HIV co-infection<br>Superboosting lopinavir with ritonavir in 1:1 ratio during TB/HIV co-infection and treatment of HIV with lopinavir/ritonavir 4:1 | Drug: lopinavir with ritonavir in 1:1 ratio<br>* During co-treatment of rifampicin containing tuberculosis treatment and lopinavir/ritonavir (4:1) based therapy, additional ritonavir is given to make lopinavir/ritonavir 1:1 ratio<br>* Other names: Ritonavir;Drug: Lopinavir/ritonavir 4:1<br>* This is the conventional dosing of LPV/r 4:1 for HIV when TB treatment has not been started or has been stopped<br>* Other names: Lopinavir/ritonavir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modelled C0/morning trough | Proportions of children treated with modelled lopinavir morning C0/morning trough <1mg/L at each of the intensive PK evaluations. | Predose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C0/morning trough | Proportions of children with observed lopinavir morning trough, C0/morning trough <1mg/L at each of the intensive PK evaluations | Predose | 
| ALT | Safety and tolerability of superboosting focusing on liver functions through clinical and biochemical monitoring. | baseline, PK1, PK2, PK3 | 
| ECG | Potential superboosting cardiac effect monitored by electrocardiogram at the beginning of anti-TB and HIV concomitant therapy | baseline, 2 weeks after LPV/r 1:1, PK1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human immunideficiency virus, Tuberculosis, superboosting, lopinavir/ritonavir 1:1, Pediatric TB/HIV co-infection