Dose Reduction of Lopinavir in 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

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.

• 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)

• 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)

• Active Comparator: 1
  Lopinavir/ritonavir standard dose + zidovudine and lamivudine
  Intervention: Drug: Lopinavir/ritonavir standard dose According to WHO simplified dosing table
• Active Comparator: 2
  Lopinavir/ritonavir low dose (70% of standard dose) + zidovudine and lamivudine
  Intervention: Drug: Lopinavir/ritonavir low dose ( 70% of WHO recommended dosing table)

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.