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Once Daily Kaletra; 24 week study results
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Study 418: Efficacy and Safety of Once-daily Lopinavir/ritonavir vs. Twice-daily Lopinavir/ritonavir in Antiretroviral-naive Patients: 24-Week Results
9th European AIDS Conference, Warsaw, Poland, 26–29 October 2003 Oral #F1/3
D Podzamczer1, J Gathe2, M Johnson3, R Schwartz4, J Villacian5, T Marsh6, C Naylor6, M King6, R Tressler6, S Brun6. 1 Hospital de Bellvitge, Barcelona; 2 Therapeutic Concepts, Houston,TX; 3 Royal Free Hospital, London; 4 Private Practice, Ft. Myers, FL; 5 Tan Tock Seng Hospital, Singapore, 6 Abbott Laboratories, Abbott Park, IL
Summary. Preliminary viral responses at week 24 showed once daily and twice daily both had 57% <50 copies/ml (ITT M=F), and 69% were <50 by observed data analysis. Among moderate or severe adverse events at least possibly related to study drug, the most common events were gastrointestinal. Diarrhea occurred more frequently in the QD group (12% vs. 5%), though the difference was not statistically significant. Nausea (9% QD 8% BID), and vomiting (3% QD, 4% BID) were the only other events occurring in at least 3% of patients in either group. LDL cholesterol >160 mg/dL occurred in 4% (QD) and 8% (BID) at Week 24. In each arm, this represented a 2% increase over baseline. At baseline, 64% (QD) and 52% (BID) had HDL cholesterol <40 mg/dL, a level considered low enough to represent a risk factor for cardiovascular disease. At Week 24, only 38% (QD) and 34% (BID) still demonstrated HDL cholesterol <40 mg/dL. LDL cholesterol to HDL cholesterol ratio was unchanged between baseline and Week 24. At Week 24, 6% (QD) and 13% (BID) of patients demonstrated triglycerides >400 mg/dL, including 2% in each group with triglycerides above 750 mg/dL. Grade 3 (>5 x upper limit of normal) SGOT/AST and SGPT/ALT elevations occurred in <3% of patients in either treatment group.
Background
Lopinavir (LPV) is an HIV protease inhibitor (PI) that is co-formulated with ritonavir (r), which functions as a pharmacokinetic enhancer, and is marketed as Kaletra. The approved adult dose of LPV/r is 400/100 mg twice daily (BID). Antiviral activity of LPV/r has been demonstrated in antiretroviral (ARV)-naive and PI-experienced patients. In a phase 2 study of LPV/r in combination with stavudine (d4T) and lamivudine (3TC) in ARV-naive patients, 67% of patients maintained HIV RNA <400 copies/mL after 5 years.
A once-daily (QD) ARV regimen including LPV/r may offer an advantage with regard to convenience while maintaining antiviral potency in ARV-naive patients. In a pilot study (Study 056), ARV-naive, HIV-infected adults (N=38) received LPV/r 800/200 mg QD and 400/100 mg BID with d4T and 3TC given BID.
LPV/r 800/200 mg QD produced similar C max and AUC and lower and more variable C trough compared to 400/100 mg BID. However, virologic response through 72 weeks, was similar. Further, the IQ achieved with once-daily LPV/r 800/200 mg compares favorably to that of other once-daily PIs.
Based on these pilot results, Study 418 was initiated to further assess the pharmacokinetics, antiviral activity and safety of a once daily dosing regimen for LPV/r in ARV-naïve patients. In Study 418, in which LPV/r was dosed with tenofovir DF (TDF) 300 mg and emtricitabine (FTC) 200 mg once daily, patients receiving LPV/r 800/200 mg QD demonstrated slightly higher C max , similar AUC, and lower C trough compared to 400/100 mg BID. The median IQ was 49 for QD and 94 for BID. This analysis presents the comparative safety and efficacy of these regimens through 24 weeks.
Methods
Study 418 is the first trial of an entirely once-daily LPV/r-based regimen
--Randomized, open-label, multi-center, international study.
--Patients were ARV-naive, with HIV RNA >1,000 copies/mL and any CD4 count.
--190 patients randomized 3:2 to LPV/r 800/200 mg QD (n=115) or 400/100 mg BID (n=75).
--All patients also received tenofovir DF (TDF) 300 mg and emtricitabine (FTC) 200 mg once daily.
--HIV RNA levels were assessed using Roche Amplicor HIV-1 Monitor Ultrasensitive Quantitative PCR Assay, Version 1.5 (limit of quantitation, 50 copies/mL).
--The proportion of patients with HIV RNA below 50 copies/mL was assessed using an intent-to-treat, missing=failure (ITT M=F) method, in which missing values and those above 50 copies/mL were considered failure. An observed data (OD) method was also used, in which missing values were excluded from the analysis. The 95% confidence interval for the difference in response rates was assessed based on the binomial distribution.
--Cumulative incidence of adverse events through 24 weeks was summarized.
--Fasting laboratory determinations, including directly measured LDL- and HDL-cholesterol values, were obtained at baseline and Week 24.
RESULTS
75-81% were men. Age: 39 yrs. 51-56% Caucasian. 27-36% Black. HIV RNA 4-6-4.8 log. Average Cd4 count: 220. 44-47% of patients had <200 CD4 cell count.
Efficacy
In the ITT (M=F) analysis (57%) and the observed data analysis (68%-70%), a similar proportion of patients achieved HIV RNA below 50 copies/mL through 24 weeks.
Based on the ITT (M=F) analysis, the 95% confidence interval for the difference (QD minus BID) in Week 24 response rates was (–14%, 14%), providing relatively strong evidence of equivalent efficacy through 24 weeks.
As has been reported in other studies, some patients require longer than 24 weeks to achieve HIV RNA below 50 copies/mL.
At Week 32 in the observed data analysis, 84% (QD) and 80% (BID) of patients demonstrated HIV RNA <50 copies/mL, compared to 70% (QD) and 68% (BID) of patients at Week 24.
CD4 cell count increases were comparable between treatment groups (103-128).
Safety
Patient Disposition
Through 24 weeks, 16% of patients in each treatment group prematurely discontinued.
A higher rate of discontinuations due to adverse events was observed in the QD group (11% vs 3%), while higher rates of loss to follow-up and nonadherence were observed in the BID group.
Adverse events resulting in discontinuation were generally gastrointestinal in nature. One patient in the BID group on chronic prednisone therapy for myosistis died of multi-organ failure after 6 weeks on study, following a diagnosis of adenocarcinoma. The event was considered unrelated to study drugs.
Adverse Events/Laboratory Abnormalities
Among moderate or severe adverse events at least possibly related to study drug, the most common events were gastrointestinal.
Diarrhea occurred more frequently in the QD group (12% vs. 5%), though the difference was not statistically significant. Nausea (9% QD 8% BID), and vomiting (3% QD, 4% BID) were the only other events occurring in at least 3% of patients in either group.
LDL cholesterol >160 mg/dL occurred in 4% (QD) and 8% (BID) at Week 24. In each arm, this represented a 2% increase over baseline.
At baseline, 64% (QD) and 52% (BID) had HDL cholesterol <40 mg/dL, a level considered low enough to represent a risk factor for cardiovascular disease.
At Week 24, only 38% (QD) and 34% (BID) still demonstrated HDL cholesterol <40 mg/dL.
LDL cholesterol to HDL cholesterol ratio was unchanged between baseline and Week 24, going from 2.60 to 2.56 (p=0.76) in the QD group and 2.54 to 2.66 (p=0.38) in the BID group.
At Week 24, 7% (QD) and 19% (BID) of patients demonstrated total cholesterol >240 mg/dL, including 1% (BID) and 2% (QD) with total cholesterol >300 mg/dL.
At Week 24, 6% (QD) and 13% (BID) of patients demonstrated triglycerides >400 mg/dL, including 2% in each group with triglycerides above 750 mg/dL.
Grade 3 (>5 x upper limit of normal) SGOT/AST and SGPT/ALT elevations occurred in <3% of patients in either treatment group.
CONCLUSIONS
Through 24 weeks, regimens containing LPV/r dosed once or twice daily, each dosed with tenofovir DF and emtricitabine, once daily, resulted in similar virologic and immunologic responses, with 57% in each treatment group achieving HIV RNA <50 copies/mL by intent-to-treat, missing = failure analysis.
Patients continued to achieve HIV RNA <50 copies/mL after Week 24.
Gastrointestinal events were the most common adverse events, with a somewhat higher rate of diarrhea in the QD arm.
LDL cholesterol >160 mg/dL occurred in 4% (QD) and 8% (BID) at Week 24. In each arm, this represented a 2% increase over baseline.
Overall, the proportion of patients with HDL cholesterol below 40 mg/dL decreased from 59% at baseline to 37% at Week 24.
HDL cholesterol increases were similar between treatment arms, resulting in more than 25% of patients reducing their coronary heart disease risk factor by one risk factor.
LDL cholesterol to HDL cholesterol ratio was unchanged between baseline and Week 24 in each treatment group.
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