icon-folder.gif   Conference Reports for NATAP  
  42nd ICAAC Meeting
San Diego, Sept 27-31, 2002
Back grey_arrow_rt.gif
Kaletra: 4 year follow-up
Reported by Jules Levin
  At this ICAAC meeting results were reported from following patients receiving Kaletra for 4 years in an ongoing phase II study of Kaletra (lopinavir 400 mg/ritonavir 100 mg) in combination with d4T and 3TC in treatment-naive patients. Abbott reported the viral load & CD4 responses, the discontinuation rate, cholesterol & triglyceride profile, resistance profile, and most common adverse events. Kaletra is a potent anti-HIV drug that is very successful in suppressing HIV and obtaining an undetectable viral load in patients with low or high viral load, and in patients who are treatment-naive and prior protease inhibitor resistance. CD4 increases are good. Resistance to Kaletra has yet to be seen in patients experiencing viral rebound. Gastrointestinal side effects are the associated with Kaletra in this study are are reviewed below, 28% of patients experienced diarrhea and 16% nausea at some point during the followup in this study. The cholesterol and triglyceride profiles are reviewed below, 17% of patients had cholesterol 240-300, and 26% had triglycerides 400-750.
For those of you not familiar with Kaletra and the concept of using ritonavir to boost the drug levels of other protease inhibitors here is a little background. Lopinavir (LPV) is an HIV protease inhibitor that is co-formulated in the same capsule with ritonavir, which functions as an inhibitor of cytochrome 450 3A. By inhibiting CYT 450 3A this results in increased blood levels of lopinavir and increases the antiviral effectiveness of lopinavir. Inhibiting the CYT 450 3A can also increase the drug blood levels of other drugs. 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 ritonavir antiviral activity. But, adding 100 mg of ritonavir increases the average LPV Ctrough (drug level 12 hours after taking Kaletra) inhibitory quotient by 70 times, helping to prevent drug resistance and increasing activity against resistant virus.
Ritonavir at low doses is also used to boost the drug blood levels of other protease inhibitors, particularly indinavir, saquinavir and amprenavir. The strategy of boosting PI blood levels with low dose ritonavir has become very popular and widely used as a way to increase antiviral efficacy and to improve success with therapy. Since drug blood levels are increased this increases antiviral effectiveness and provides a little buffer time-wise around when a patient takes doses. For example, indinavir is taken every 8 hours and you should take it on time but with a boost by 100 or 200 mg of ritonavir the combination is taken every 12 hours and more protection is provided if you miss a dose by 30-40 minutes.
In this phase II study (M97-720) 100 treatment-naive patients were randomized to receive one of three doses of LPV/r (200/100 mg bid, 400/100 mg bid, or 400/200 mg bid) together with d4T and 3TC given after 3 weeks of monotherapy (group 1) or from study entry (group 2). After 48 weeks all patients began switching to open-label LPV/r 400/100 mg bid, the dose used now. The average viral load and CD4 prior to starting this study were 4.8 log (about 75,000 copies/ml viral load) and 326 CD4s. After 204 weeks and using the more strict ITT NC=F analysis, (n=72) 71% of patients had <400 copies/ml viral load and 70% had <50 copies/ml viral load. Abbott reported that among the 15 patients with loss of viral response, 7 remained on study through week 204 without change in regimen, and all 7 patients had viral load <50 copies/ml; in other words they re-suppressed viral load perhaps due to adherence intervention.
Abbott reported these lipid elevations. The incidence of cholesterol through week 204 of >300 mg/dL cholesterol was 22%; the incidence of triglycerides >750 mg/dL was 22%; and the incidence of AST/ALT >5 times the upper limit of normal was 11%. At week 204, Abbott reported that among 70 patients observed in study, 81% had cholesterol <240 mg/dL, 17% 240-300, 1% 300-400, and 0% >400. 69% of patients had <400 mg/dL triglycerides, 26% had 400-750, 4% had 750-1000, and 1% had >1200.
Through week 24, genotype was available on 6 patients with sustained viral load rebound to >400 copies/ml while receiving LPV/r. Consistent with results seen in other studies of LPV/r in treatment-naive patients, there was no protease inhibitor resistance in the 6 patients, 3 of 6 showed 3TC resistance.
Average CD4 count increased to 721 from about 300. They reported that CD4 count increase appeared to be the same regardless of baseline CD4 count. Among patients with CD4 <50 the average increase was from 23 at baseline to 446 at week 24, an increase of 423 CD4s.
DISCONTINUATIONS 28 of 100 patients discontinued: possibly or probably related to study drugs: ALT/AST increases 2 patients; diarrhea 1; arthralgia 1; liver enlargement with pain & fatty deposites 1; elevated cholesterol 1; death 1. Other reasons for discontinuation: 9 lost to followup; 5 noncompliance; 5 personal reasons (left the USA, IVDU, mover out of state); 5 adverse events that were considered HIV related but not drug related: lymphoma, hyperglycemia in diabetic patient, alcohol detox).
MOST COMMON ADVERSE EVENTS Incidence through week 24. Diarrhea: 28%, nausea 16%, abdominal pain 10%, abnormal stool 8%, asthenia 8%, headache 8%, vomiting 6%.