icon-folder.gif   Conference Reports for NATAP  
  43rd ICAAC Meeting
Chicago, Sept 13-17, 2003
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Kaletra (Lopinavir/ritonavir) in Antiretroviral-Naive HIV-Infected Patients: 5-Year Follow-Up
  Reported by Jules Levin
43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, September 2003. Poster #H-844
This report contains excerpts from the Abbott poster at the ICAAC meeting.
Brief Summary: The results of this study show durability and potency og Kaletra. Through 5 years of follow-up, antiretroviral-naïve patients receiving Kaletra (LPV/r-based therapy) exhibited sustained virologic response, with 67% of patients demonstrating HIV RNA <400 copies/mL and 64% demonstrating HIV RNA <50 copies/mL by intent-to-treat (NC=F) analysis. Through 252 weeks of follow-up, no protease inhibitor resistance mutations have been observed in subjects with sustained viral load rebound. Discontinuations due to LPV/r-related adverse events were 10/100, 10%.
Lopinavir (LPV) is an HIV protease inhibitor (PI) that is co-formulated with ritonavir, which functions as an inhibitor of cytochrome P450 3A. Even at low ritonavir doses, there is a substantial increase in LPV exposure. At a dosage of 400 mg of LPV/100 mg ritonavir twice daily (3 co-formulated tablets BID), ritonavir concentrations are below those required for antiviral activity.1 By contrast, the mean LPV C trough /IC 50 ratio (Inhibitory Quotient or IQ) for wild-type HIV is >70 when dosed at 400/100 mg twice a day, potentially providing a barrier to emergence of viral resistance and activity against resistant virus.
Lopinavir/ritonavir (LPV/r, marketed as Kaletra) has been studied in both antiretroviral-naïve and experienced HIV-infected patients. However, few long-term data are available on continued safety and efficacy. The M97-720 study is an ongoing phase II trial of LPV/r in combination with d4T and 3TC in antiretroviral-naïve patients. This was the first trial of LPV/r in HIV-infected patients and hence provides the longest duration of follow-up for patients treated with LPV/r. This poster presents data on antiviral activity, immunologic parameters, and safety through 252 weeks (5 years).
One hundred antiretroviral-naïve patients were randomized to receive one of three dosage levels of LPV/r (200/100 mg BID, 400/100 mg BID or 400/200 mg BID), together with d4T (40 mg BID) and 3TC (150 mg BID) given either after 3 weeks of monotherapy (Group I) or from study entry (Group II).
Enrollment into Group II began following an evaluation of preliminary efficacy and safety of LPV/r in Group I. After 48 weeks, all patients began conversion to open-label LPV/r 400/100 mg BID dosing.
Samples from patients with sustained HIV RNA rebound to >400 copies/mL while receiving LPV/r during the study were submitted for genotypic and phenotypic analyses. Genotype (GeneSeq) and phenotype (PhenoSense) analyses were performed by ViroLogic, Inc. Genotypic resistance to LPV was defined as the development of any primary or active site mutation in protease (amino acids 8, 30, 32, 46, 47, 48, 50, 82, 84, and 90) confirmed by phenotypic analyses (2.5 fold increase in IC 50 to LPV relative to wild type HIV). Resistance to 3TC was defined as the presence of an M184V and/or M184I mutation in reverse transcriptase.
Cumulative incidence through Week 252 for adverse events and grade 3/4 laboratory values was summarized, as was the prevalence at Week 252, defined as the presence of an ongoing adverse event or a grade 3/4 lab measurement obtained at the Week 252 visit. All laboratory measurements were obtained without regard to fasting.
Viral Load Suppression Below the Level of Detection
Based on the ITT NC=F analysis through Week 252, 67% of patients had HIV RNA <400 copies/mL (on-treatment analysis: 99%) and 64% of patients had HIV RNA <50 copies/mL (on-treatment analysis: 94%).
The only HIV RNA >400 copies/mL at year 5 occurred during a lengthy treatment interruption. Three patients with HIV RNA between 50 and 400 copies/mL (65, 100 and 274) maintained HIV RNA <400 copies/mL at the following visit (Week 264, ultrasensitive testing not conducted).
Duration of Virologic Response Analysis
Through Week 252, the proportion of patients maintaining virologic response was 81.4% by Kaplan-Meier analysis. Among the 17 patients with loss of virologic response, 9 remained on study through Week 252 without a change in regimen, and 8/9 patients had HIV RNA <50 copies/mL at Week 252.
Drug Resistance
Through Week 252, genotype was available on 11 patients with confirmed HIV RNA rebound to >400 copies/mL while receiving LPV/r, including all 8 who prematurely discontinued the study. Consistent with results obtained in previous studies of LPV/r in ARV-naïve patients, 0 of 11 patients demonstrated protease inhibitor resistance, and 3 of 11 demonstrated 3TC resistance.
CD4 Cell Count Response
Among subjects with values at both baseline and Week 252, the mean CD4 cell count increased from 281 cells/mm 3 at baseline to 791 cells/mm3 at Week 252, an increase of 510 cells/mm3. CD4 cell count response appeared to be consistent regardless of baseline CD4 cell count. Among patients with baseline CD4 cell count <50 cells/mm3, mean CD4 cell count increased from 24 cells/mm3 at baseline to 543 cells/mm3 at Week 204, an increase of 519 cells/mm3.
Other studies have observed an association between higher age and lower CD4 count increases, but no correlation was observed between age and CD4 count increase in this study through Week 252 (r=0.013, p=0.92).
Patient Dispositions Through Week 252
100 patients were enrolled and 32 discontinued, reasons for discontinuationprobably or possibly due to study drugs: AST/ALT increases- 2; diarrhea- 1; liver pain-, enlargement, fatty deposites- 1; arthralgia- 1; elevated cholesterol- 1; fat redistrin=bution-3; death-1 (death of unknown cause occurred in a patient 10 days following thoracic spinal surgery with peroperative myocardial infarction). Other reasons for discontinuation: adverse event unrelated to study drugs (lymphoma, hyperglycemia in diabetic patient, alcohol detox)- 3; lost to follow-up; non-compliance; personal reasons (mover, drug addiction, “virologic success”).
Most Common Adverse Events Through week 252 (occurring in >10% of patients)
  Most Common Grade 3/4 Lab Abnormalities Through Week 252 (occurring in >10% of patients)  
  Distribution of Lipid Values at week 252  
  23 patients with grade 2 or higher lipid values initiated lipid-lowering agents, and all but 2 subsequently demonstrated grade 0-1 lipid values.