Kaletra Report


Lopinavir/Ritonavir (Kaletra) studies reported at IAS Conference (July 2001): Updated 60-week data was presented on the M98-983 study comparing lopinavir/ritonavir (LPV/r) 400mg/100mg twice a day with Nelfinavir 750mg three times a day, both in combination with D4T and 3TC in 653 antiretroviral nave patients. At 60 weeks, in an intent-to-treat analysis where those who discontinued the study for any reason were considered as treatment failures, 74% achieved viral loads of <400 copies in the LPV/r arm vs. 61% in the nelfinavir arm (p<0.001). 63% and 51% were <50 copies respectively (p<0.001).


144-week data (about 3 years) was presented from the M97-720 study of D4T+3TC+LPV/r. The study enrolled 100 antiretroviral nave subjects. At the beginning, subjects received one of 3 doses of LPV/r (200/100mg BID, 400mg/100mg BID, or 400mg/200mg with D4T and 3TC either given after 3 weeks of monotherapy or from the entry of the study. After 48 weeks, all patients received the 400mg/100mg of LPV/r, the dose that is used now in practice. Median viral load was 4.9 log10 and median CD4 was 326 at baseline. In an intent-to treat analysis, 79% were <400 and 76% were <50 copies. Only 5 subjects discontinued due to drug-related adverse events. The yearly rate of viral load rebound after the first year was calculated to be a only 1.2% per year. This means that this combination should be able to control virus for 30 years in most patients. CD4 counts increased a mean of 384 cells from baseline in three years.


RESISTANCE. In this same study, all those subjects who had any viral loads above 400 were tested for resistance. NO resistance to the LPV/r has been seen in any of the people on the drug with detectable virus. This is quite impressive that at 3 years, over 300 patients have not developed protease resistance either by genotype or phenotype. Of 40 samples who were tested for resistance, only 7 had minor secondary protease mutations (L10I, M36I, L63P, and A71T) and no major mutations were seen. Only 38% had had resistance to 3TC (M184V). In contrast, in the nelfinavir arm, 31 of 84 samples (37%) had resistance to nelfinavir (either a D30N or L90M) and 81% had resistance to 3TC.


Ruane P, et al. Abstract 6
White C, et al. Abstract 217
Kempf D, et al. Abstract 129


Written for NATAP by Nancy Shulman, MD, Stanford University


Adverse Events and Lab Abnormalities


Diarrhea appears to be the main adverse event associated with Kaletra. 10% of patients report cholesterol and triglycerides increases above 300 or 750, respectively, in study 863. Most of the increases in triglycerides that are above 400 are reported to fall within the range of 400-750. A few percent of patients receiving Kaletra experience increases of 750-1200 or above 1200. The study reports ALT elevations in patients with hepatitis B or C is no more, and perhaps less, for patients receiving Kaletra than for those receiving nelfinavir.


Phase 3 Study M98-863 (Kaletra vs Viracept):


Subjects Enrolled 326 327
Discontinuation Wk 60 19% 24%
Study-drug related AE 4% 4%
Virologic failure 1% 9%
Noncompliance 3% 2%


Most Common Adverse Events
(the differences were not statistically significant) events of moderate or greater severity with a possible or probable relationship to study drug


Diarrhea 17% 18%
Nausea 7% 5%
Asthenia 4% 3%
Abdominal pain 4% 3%
Vomiting 3% 2%
Headache 3% 2%


Grade 3/4 Lab Abnormalities
(differences not statistically different, except for triglycerides where the difference was statistically significant) labs withdrawn without regard to fasting


ALT (5X ULN)* 5% 4%
AST (5X ULN)* 3% 4%
Glucose (>250 mg/dL) 2% 2%
Total cholesterol (>300 mg/dL) 10% 6%
Triglycerides (>750 mg/dL) 11% 2% (p<0.001)
* ULN is upper limit of normal


115 patients were Hep B surface antigen positve (n=39) or hepatitis C antibody positive (n=76) before starting the study. Patients were allowed to participate in the study if their liver function tests were <3X below ULN (upper limit of normal). Patients were allowed to remain on medications unless their liver function tests exceeded 10x ULN, provided they remained asymptomatic without concomitant Grade 3+ elevations in total bilirubin or alkaline phosphatase.


Percentage of Patients With Hep B or C with ALT Elevations


 Kaletra NFV
 N=50 N=65
ALT 12% 17%
AST 4% 12%


The study reported that the risk of grade 3/4 AST/ALT elevations was greater in patients with Hep B/C compared to to patients without Hep B/C. Risks of elevations were comparable between B+ and C+ patients.


Phase 2 Study M97-720


Most Common Adverse Events
Adverse events of at least moderate severity and probable, possible or unknown relationship to LPV/r. Authors said that the higher rates of adverse events in this study compared to phase 3 Kaletra vs Viracept study could be due to longer follow-up (144 weeks vs 60 weeks) or due to higher dose of LPV/r some patients received (400/200).


Diarrhea* 25%
Nausea 15%
Abdominal pain 8%
Abnormal stools** 8%
Asthenia 8%
Cholesterol >300 17%
Triglyc >750 16%
AST/ALT >5 ULN 10%


*>3 loose stools per day
**3 loose stools per day


Body Fat Composition Changes


Authors reported that study investigators (M98-863) were instructed to report all changes in body composition: stomach paunch, peripheral wasting, breast enlargement, multiple lipomas, dorsal fat pad, Cushingoid syndrome. Through 60 weeks the study reported an incidence of 7% in each arm for patients with a change in body fat composition. In the smaller 144 week phase 2 M97-720 study (n=100) 12% were reported to have body fat composition changes. Are these percentages low? Perhaps.


Bernstein B, et al, poster 525
White AC, et al, poster 217
Ruane P, et al, poster 6


Written by Jules Levin



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