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Kaletra: 4 year follow-up
Reported by Jules Levin
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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%.
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