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BACKGROUND
Kaletra (formerly known as ABT-378/r, lopinavir/ritonavir) is a novel HIV protease inhibitor (PI) that has shown significant antiviral activity and tolerability in clinical trials to date.
Lopinavir is co-formulated with ritonavir, an inhibitor of cytochrome P450 3A. It is uniquely sensitive to pharmacokinetic enhancement by ritonavir, resulting in substantially increased lopinavir drug exposure, even at low ritonavir doses. At the dosage selected for phase III clinical trials in adults, 400 mg lopinavir/100 mg ritonavir BID capsules, ritonavir concentrations are below those required for antiviral activity.1
The efficacy and safety of Kaletra are currently being studied in HIV-infected adult patients, both antiretroviral-naïve and PI-experienced. Study M98-940 is a Phase I/II, open-label study of coformulated Kaletra (liquid) at two doses in combination with reverse transcriptase inhibitors in treatment-naïve and -experienced pediatric subjects.
Evaluate the safety, tolerability and antiviral activity of Kaletra (liquid formulation) in HIV-infected children.
Entry Criteria
• Age: between 3 months and 12 years
• Plasma HIV RNA >400 copies/mL
• No prior NNRTI therapy
Study Design and Analysis
• One hundred antiretroviral-naïve and -experienced pediatric subjects were randomized to receive one of two dosage levels of Kaletra (230/57.5 mg/m 2 Q12H or 300/75 mg/m 2 Q12H) selected to approximate the adult drug exposure at 400/100 mg BID.
• Subjects were defined as antiretroviral-naïve if they had received =3 months of prior antiretroviral therapy or =1 week of treatment with 3TC. Subjects were defined as antiretroviral-experienced if they received >3 months of prior antiretroviral therapy or >1 week of treatment with 3TC.
• In addition to Kaletra, naïve subjects received treatment with d4T and 3TC and experienced subjects received treatment with nevirapine and 1 or 2 NRTIs of the investigator’s choice.
• All subjects were switched to a dose of Kaletra 300/75 mg/m 2 following an analysis of safety/tolerability, efficacy and Week 3 pharmacokinetics.
RESULTS
Table 1. Baseline Characteristics
Treatment Experience and Pharmacokinetics
• Of the 56 experienced subjects enrolled, 32 were NRTI experienced and 24 were protease inhibitor and NRTI experienced.
• 88% of the PI experienced subjects had received ritonavir (standard dose) and 29% had received multiple PIs.
• There was no statistically significant effect of age on the pharmacokinetic parameters of lopinavir. From the analysis of covariance (ANCOVA) for age effect p=0.2 for AUC and p=0.7 for C trough .
Subject Disposition
• Of the 100 subjects enrolled in the study, two subjects had discontinued as of Week 60 (Table 2).
Safety
• There were few adverse events of at least moderate severity and of probable or possible relationship to study drug or grade 3/4 laboratory abnormalities at 60 weeks (Tables 3 and 4).
Viral Load Suppression to <400 Copies/mL at 60 Weeks
• The proportion of subjects with viral load less than 400 (less than 50) copies at Week 60 was 77% (68%) for naïve subjects and 70% (61%) for experienced subjects by the Intent-to-Treat method of analysis.
• In general, the proportion of subjects below 400 copies was higher in the naïve group than in the PI-experienced group beginning at Week 12 and beyond (Figure 3).
Incidence of Resistance in Naïve Subjects
• Plasma viral isolates from 10 treatment-naïve subjects with HIV RNA >400 copies/mL at Weeks 24 or 48 were examined for evidence of resistance (Table 6).
• Resistance to Kaletra was defined as any primary or active site mutation.
CD 4 Response
• Mean CD 4 cell count increase from baseline was 404 cells for naive subjects and 238 cells for experienced subjects by Week 60.
CONCLUSIONS
• The liquid formulation of Kaletra was well tolerated by HIV-infected children with only one discontinuation related to study drugs through 60 weeks.
• There were few adverse events of at least moderate severity and of probable or possible relationship to study drugs or grade 3/4 laboratory abnormalities at 60 weeks.
• Kaletra demonstrated excellent antiviral activity with 77% of treatment-naive subjects and 70% of treatment-experienced subjects <400 copies/mL HIV RNA at Week 60 by an Intent-to-Treat Analysis.
REFERENCE
1. Bertz R, Lam W, Brun S, et al. Multiple-dose pharmacokinetics (PK) of ABT-378/ritonavir (Kaletra) in HIV+ subjects. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 1999, (abstract 0327).
ACKNOWLEDGMENTS
The Hospital for Sick Children, Toronto, Canada Upton
Allen
Fundacion Huesped, Buenos Aires, Argentina Pedro Cahn
Princess Margaret Hospital, Nassau, Bahamas Perry Gomez
Hospital del Nino, Panama City, Panama Xavier Saez-Llorrens
Univ. of Texas Southwestern Medical Center, Dallas, U.S.A. Octavio Ramilo
St. Luke’s Roosevelt Hospital Center, New York City, U.S.A. Stephen Arpadi
Children’s Memorial Hospital, Chicago, U.S.A. Ellen Chadwick
University Hospital of Brooklyn, New York City, U.S.A. Edward Handelsman
Max Finland Laboratory of Infectious Disease, Boston, U.S.A. Stephen Pelton
Chris Hani Baragwanath Hospital, Johannesburg, South Africa Avyi Violari
Genotype and Phenotype testing was performed by ViroLogic,
© 2001 Medical Advocates
for Social Justice
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