Dose Reduction of Lopinavir in Children

Pharmacokinetics and Efficacy of Low- or Standard-dose of Lopinavir/Ritonavir (Kaletra®) in PI-naïve HIV-1 Infected Children

To study the pharmacokinetics of low-dose and standard dose, lopinavir/ritonavir in ARV PI naive HIV-1 infected Thai children.

To study clinical and immunological efficacy after 48 weeks of lopinavir/ritonavir in PI naïve HIV-1 infected Thai children

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Lopinavir/ritonavir standard dose According to WHO simplified dosing table; Drug: Lopinavir/ritonavir low dose ( 70% of WHO recommended dosing table)

Detailed Description

In 2002, the Thai Ministry of Public Health (MOPH) launched the National Access to Antiretroviral Program for People living with HIV/AIDS (NAPHA) with the aim of providing treatment to all Thai patients who needed antiretroviral treatment. By the end of 2005, 80,000 HIV-infected Thais were treated in the NAPHA program, including about 6,000 children. The antiretroviral treatment regimen consists of three antiretroviral drugs (ARV). The first-line regimen used in NAPHA are mainly generic drugs produced by Thai government pharmaceutical organization (GPO), including a fixed-drug combination of stavudine, lamivudine, and nevirapine (GPOvir);and a fixed-drug combination of zidovudine, lamivudine, and nevirapine (GPOvir-Z). Majority of patients respond very well with first-line regimen(1,2), however about 15% of patients have drug resistance to first-line regimen and require second-line regimen(3). The protease inhibitors (PIs) is used as a second-line regimen, however there are limitations in terms of cost and metabolic complications(4).

Lopinavir/ritonavir is the most widely use protease inhibitors in children because of its high efficacy and a syrup formulation that easy to use in small children. There is evidence supported that the recommended dose according to US-FDA or EU guidelines resulting in much higher plasma blood level in Thai children. Data from 19 Thai children demonstrated Cmin of 5.9 mg/L compare to 3.4 mg/L in US children when use the same dose (the minimum acceptable Cmin is 1.0 mg/L) (5,6). There is a study HIVNAT019, which demonstrated acceptable LPV plasma concentration and treatment outcome in Thai HIV-infected adult when use reduced dose of LPV/r 266mg/66 mg compare to standard dose of 400mg/100mg (7).

Therefore, the study of pharmacokinetic of low dose of LPV/r in Thai HIV-infected children is very important to assess the safety and efficacy of this strategy. This will lead to appropriate ARV dose in children to reduce long-term adverse events, and also reduce the ARV cost.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10330
    • HIV-NAT, Thai Red Cross AIDS Research Center, Bangkok

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age from 2- 18 years old
• Documented positive test for HIV-1 infection
• PI-naïve
• HIV RNA viral load > 1,000 copies
• Written informed consent

Exclusion Criteria:

• Active opportunistic infection
• Relevant history or current condition, illness that might interfere with drug absorption, distribution, metabolism or excretion.
• Use of concomitant medication that may interfere with the pharmacokinetics of lopinavir/ritonavir
• Pregnancy or lactating
• Inability to understand the nature and extent of the study and the procedures required.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Lopinavir/ritonavir standard dose + zidovudine and lamivudine	Drug: Lopinavir/ritonavir standard dose According to WHO simplified dosing table; BW 6-7.9 kg: 1.5 mL oral q 12 hr; BW 8.0-16.9 kg: 2.0 ml oral q 12 hr; BW 17.0-19.9 kg: 2.5 ml oral q 12 hr; BW 20.0 - 24.9 kg: 3.0 ml oral q 12 hr; BW 25.0 - 29.9 kg: 3.5 ml oral q 12 hr; BW 30.0-34.9 kg: 4.0 ml oral q 12 hr; BW > 35 kg: 5.0 ml oral q 12 hr Dose of Zidovudine (AZT) is 180-240 mg/m2 per dose every 12 hours Dose of Lamivudine (3TC) is 4 mg/kg every 12 hours Dose of Lopinavir/ritonavir (LPV/r)
Active Comparator: 2; Lopinavir/ritonavir low dose (70% of standard dose) + zidovudine and lamivudine	Drug: Lopinavir/ritonavir low dose ( 70% of WHO recommended dosing table); BW 6-7.9 kg: 1.0 mL oral q 12 hr; BW 8.0-16.9 kg: 1.5 ml oral q 12 hr; BW 17.0-19.9 kg: 1.8 ml oral q 12 hr; BW 20.0 - 24.9 kg: 2.0 ml oral q 12 hr; BW 25.0 - 29.9 kg: 2.5 ml oral q 12 hr; BW 30.0-34.9 kg: 3.0 ml oral q 12 hr; BW > 35 kg: 3.5 ml oral q 12 h Dose of Zidovudine (AZT) is 180-240 mg/m2 per dose every 12 hours Dose of Lamivudine (3TC) is 4 mg/kg every 12 hours Dose of Lopinavir/ritonavir (LPV/r)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
pharmacokinetics of standard vs low dose LPV/r	4 weeks after start ART

Secondary Outcome Measures

Outcome Measure	Time Frame
efficacy and safety of standard and low dose LPV/r	48 weeks

Collaborators and Investigators

• Sponsor: The HIV Netherlands Australia Thailand Research Collaboration
• Collaborators: Ministry of Education, Thailand
• Investigators: Principal Investigator: Kiat Ruxrungtham, MD, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Aids Research Centre - HIV-NAT

Publications and helpful links

General Publications

• Puthanakit T, van der Lugt J, Bunupuradah T, Ananworanich J, Gorowara M, Phasomsap C, Jupimai T, Boonrak P, Pancharoen C, Burger D, Ruxrungtham K. Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children. J Antimicrob Chemother. 2009 Nov;64(5):1080-6. doi: 10.1093/jac/dkp322. Epub 2009 Sep 2.

Helpful Links

• HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT)

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: April 21, 2009
• First Submitted That Met QC Criteria: April 22, 2009
• First Posted (Estimate): April 23, 2009

Study Record Updates

• Last Update Posted (Actual): July 17, 2020
• Last Update Submitted That Met QC Criteria: July 15, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: children; pharmacokinetic; Asia; therapeutic drug monitoring; Second line treatment; LPV; To study the pharmacokinetics of low-dose and standard dose, lopinavir/ritonavir in Protease inhibitor (PI)- naive HIV-1 infected Thai patients.; To study clinical and immunological efficacy after 48-weeks of lopinavir/ritonavir-based antiretroviral therapy in PI naive HIV-1 infected Thai patients.
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lopinavir
• Other Study ID Numbers: HIV-NAT045