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  9th European AIDS Conference (EACS)
Warsaw, Poland
Oct 25-29, 2003
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5-Year Results of Lopinavir/ritonavir (LPV/r)-Based Therapy in Antiretroviral-Naïve HIV-Infected Patients
  9th European AIDS Conference, Warsaw, Poland, 26–29 October 2003 Abstract 7.3/16. C Hicks (University of North Carolina) and Abbott Labs
Summary. The 5 year data from this study demonstrate the potency and durability of Kaletra. 100 treatment-naïve patients received Kaletra (400/100) plus d4T/3TC. After 5 years 68 patients remain on study treatment. By 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%). 17 patients met loss of virologic response criteria. 9/17 were on study at week 252: 8 with VL <50 at week 252. The mean CD4 cell count increased from 281 cells at baseline to 791 cells at Week 252, an increase of 510 cells. Among patients with baseline CD4 cell count <50 cells, mean CD4 cell count increased from 24 cells/mm3 at baseline to 543 cells at Week 252, an increase of 519 cells. There was no correlation between age & CD4 response in this study. Adverse events and lab abnormalities reported below. Most common side effects were GI--diarrhea. 23-26% of patients experienced lipid abnormalities. Lipid lowering agents were used.
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.
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).
Entry Criteria
--Antiretroviral-naïve patients.
--Plasma HIV RNA >5,000 copies/mL with no CD4 cell count restriction.
Study Design and Analysis
--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.
--Proportion of patients HIV RNA below the limit of quantitation (LOQ) was measured using an on-treatment method (missing values and values obtained during treatment interruptions excluded) and an intent-to-treat, noncompleter=failure method (ITT NC=F, missing values considered failure unless the immediately preceding and following values were below the LOQ).
--Loss of virologic response was defined by two consecutive HIV RNA measurements above 400 copies/mL following any value below 400 copies/mL or failure to achieve HIV RNA below 400 copies/mL. Patients were considered virologic failures if they met loss of response criteria even if they achieved viral resuppression without a change in study medication.
--Immunologic response was assessed by the mean change in CD4 count from baseline to each study visit.
Virologic Evaluation
--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.
Effects of the use of lipid-lowering agents were assessed by comparing the last lipid value prior to lipid-lowering agent initiation to the minimum and final available lipid values through Week 252.
Antiviral Activity
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).
17 patients met loss of virologic response criteria. 9/17 were on study at week 252: 8 with VL <50 at week 252 (genotypic resistance for 3 patients: 0/3 with PI resistance, 1/3 with 3TC resistance); 1 with VL >400 during transient interruption. 8 discontinued prior to week 252: at rebound, 0/8 with PI resistance, 2/8 with 3TC 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 at baseline to 791 cells/mm 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 252, 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 Disposition
32 discontinuations prior to week 252
discontinuations probably or possibly due to study drugs ALT/AST increases 2 Diarrhea 1 Liver pain, enlargement, fatty deposits 1 Arthralgia 1 Elevated cholesterol 1 fat redistribution 3 Death 1
Other reasons for discontinuations
Adverse events unrelated to study drugs (lymphoma, hyperglycemiain diabetic patient, alcohol detox) 3 lost to followup 9 non-compliance 5 personal reasons (moved 3, drug addiction, “virologic success” 5
Most Common Adverse Events Week 252
  Table 1. ARV Attributes  
  Incidence Prevalence
  Thru wk 252 at wk 252
  N=100 n=68
Diarrhea 28% 0%
Nausea 16% 0%
Lipodystrophy 12% 15%
Abdominal pain 10% 0%
  Most Common Grade 3/4 Lab Abnormalities Thru wk 252  
  Incidence Prevalence
Cholesterol >300 mg/dl 23% 0%
Triglycerides >750 mg/dl 26% 0%
AST/ALT >%xULN 11% 0%
Through 5 years of follow-up, antiretroviral-naïve patients receiving 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. Corresponding on-treatment response rates were 99% and 94%, respectively.
Through 252 weeks of follow-up, no protease inhibitor resistance mutations have been observed in subjects with sustained viral load rebound.
LPV/r was generally well tolerated, as indicated by the low rate of study discontinuations due to LPV/r-related adverse events (10/100, 10%).
Lipid values generally declined with lipid-lowering agent use, as approximately 90% of patients treated with lipid-lowering agents subsequently demonstrated lipid values below grade 2 levels.