 |
|
|
| |
Once-Daily vs.Twice-Daily Lopinavir/ritonavir in Antiretroviral-NaÔve Patients: 48-Week Results
|
| |
| |
Reported by Jules Levin
11th Conference on Retrovirus and Opportunistic Infections
February 8-11, 2004, San Francisco, CA
J Gathe*1, D Podzamczer2, M Johnson3, R Schwartz4,V Yeh5, N Travers6, K Luff6, M King6, R Tressler6, and S Brun6 1Therapeutic Concepts, P.A., Houston,TX, USA, 2Hospital de Bellvitge, Barcelona, Spain, 3Royal Free Hospital, London, UK, 4Private Practice, Fort Myers, FL, USA, 5AIDS Healthcare Foundation, Los Angeles, CA, USA, 6Abbott Laboratories, Abbott Park, IL USA
Summary: This study was conducted to explore Kaletra taken once daily (800/200, LPV/r) compared to Kaletra taken in its usual way as 400/100mg twice daily in 190 patients. Patients also received tenofovir once daily and FTC once daily. After 48 weeks the percent of patients with <50 copies/ml was similar (70% for the once daily regimen vs 64% for the twice daily regimen, p=0.35; intent-to-treat analysis, noncompleters=failures). Noninferiority of the LPV/r QD regimen compared to LPV/r BID-based regimen (ITT NC=F) was confirmed by the 95% confidence interval for the difference (QD minus BID) in response proportions (-7% to 20%). Gastrointestinal events were the most common adverse events, with a higher rate of diarrhea in the QD arm (16% vs 5%). Lipid elevations were the most common laboratory abnormality, although these did not result in significant changes to the 10-year coronary heart disease risk based on Framingham Heart Study calculations. The discontinuation rates were similar in both the once & twice daily arms with more patients discontinuing in the once daily arm due to adverse events, and more patients discontinuing in the twice daily arm for nonadherence (1% vs 4%). See more detailed results below.
Lopinavir (LPV) is an HIV protease inhibitor (PI) that is co-formulated with ritonavir (r), which functions as a pharmacokinetic enhancer (increases LPV blood leveld). LPV/r 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)-naïve and PI-experienced patients.
Kaletra is potent. In a phase 2 study of LPV/r in combination with stavudine (d4T) and lamivudine (3TC) in ARV-naïve patients (Study 720), 67% of patients maintained HIV RNA <400 copies/mL through 5 years. Kaletra side effects are gastrointestinal and can increase triglycerides.
A once-daily (QD) ARV regimen including LPV/r may offer an advantage with regard to convenience while maintaining antiviral potency in ARV-naïve patients. In a pilot study (Study 056), ARV-naïve, HIV-infected adults (N=38) received LPV/r 800/200 mg QD or 400/100 mg BID with d4T and 3TC given BID. LPV/r 800/200 mg QD produced similar Cmax and AUC but lower and more variable Ctrough compared to 400/100 mg BID. Still virologic response through 72 weeks was similar. The Inhibitory Quotient (IQ; Ctrough/IC50 for wild type HIV) achieved with once-daily LPV/r compares favorably to that of other QD PIs.
Based on these pilot results, Study 418 was initiated to further assess the pharmacokinetics, antiviral activity and safety of a once daily dosingregimen for LPV/r in ARV-naïve patients. In Study 418, patients received LPV/r with tenofovir DF (TDF) 300 mg and emtricitabine (FTC) 200 mgonce daily. Patients receiving LPV/r 800/200 mg QD demonstrated slightly higher lopinavir Cmax, similar AUC, and lower Ctrough compared to400/100 mg BID. The median IQ was 49 for QD and 94 for BID.This analysis presents the comparative safety and efficacy through 48 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-naïve, with HIV RNA >1,000 copies/mL and any CD4 count.
- 190 patients were randomized 3:2 to LPV/r 800/200 mg QD (n=115) or 400/100 mg BID (n=75).
- All patients also received tenofovir (TDF) 300 mg and FTC 200 mg once daily.
ANALYSIS
- 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, noncompleter=failure (ITT NC=F) method, inwhich missing values were considered failure unless the immediately preceding and following values were below 50 copies/mL. 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 responserates was assessed based on the binomial distribution.
- For each HIV RNA result above 500 copies/mL between Weeks 12-24, isolates were submitted for genotypic resistance testing, as werecorresponding baseline isolates for each patient. Resistance to lopinavir was defined as the emergence of any primary or active site mutation inprotease (positions 8, 30, 32, 46, 47, 48, 50, 82, 84, 90). Resistance to tenofovir and emtricitabine were defined by the presence of K65R andM184V/I mutations in reverse transcriptase, respectively.
- Cumulative incidence of adverse events through 48 weeks was summarized.
- Fasting laboratory determinations, including directly measured LDL and HDL cholesterol values, were obtained at baseline and Week 48.
- For patients remaining on study for 48 weeks, the impact of lipid changes and blood pressure on 10-year coronary heart disease (CHD) risk were calculated based on the results of the Framingham Heart Study, which also takes into consideration gender, age, history of diabetes mellitus (DM) and smoking status.
RESULTS
Baseline Characteristics
- Demographics and baseline disease characteristics were similar between treatment groups, with over 20% female and about 45% non-Caucasianpatients.
- The patient population was relatively advanced, as approximately 45% of patients had baseline CD4 count below 200 cells/mm3 and 38% hadbaseline HIV RNA above 100,000 copies/mL. Median viral load – 4.7 log (50,000 copies/ml). Median CD4 count- 220.
- The overall mean baseline viral load was approximately 65,000 copies/mL.
EFFICACY
- In the ITT (NC=F) analysis and the OD analysis, a similar proportion of patients achieved HIV RNA below 50 copies/mL through 48 weeks: 70% (QD) vs 64% <50 copies/ml, ITT analysis; 90% vs 85% <50 copies/ml, Observed Analysis
- Based on the ITT (NC=F) analysis, the 95% confidence interval for the difference (QD minus BID) in Week 48 response proportions was (-7%,20%), confirming the noninferiority of the QD regimen compared to the BID regimen through 48 weeks.
- Results of genotypic testing were available for 5 patients in each group with HIV RNA >500 copies/mL occurring at any time during Weeks 12-24. No patient demonstrated lopinavir or tenofovir resistance, and only 1 patient in each group demonstrated FTC resistance.
- CD4 cell count mean increases, +185, from baseline were comparable between treatment groups.
SAFETY
Patient Disposition
- Reasons for premature discontinuation prior to Week 48 are summarized below.
- A higher rate of discontinuations due to adverse events was observed in the QD group, 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 myositis died of multi-organ failure after 6 weeks on study, following a diagnosis of adenocarcinoma. The event was considered unrelated to study drugs.
DISPOSITION THROUGH WEEK 48
|
|
LPV/r QD
|
LPV/r BID
|
|
Patients discontinued
|
22 (19%)
|
19 (25%)
|
|
Adverse event
|
14 (12%)
|
4 (5%)
|
|
Death
|
0 (0%)
|
1 (1%)
|
|
Viral failure
|
0 (0%)
|
1 (1%)
|
|
Lost to follow-up
|
3 (3%)
|
6 (8%)
|
|
Withdrew consent
|
4 (3%)
|
4 (5%)
|
|
Nonadherence
|
1 (1%)
|
3 (4%)
|
Adverse Events/Laboratory Abnormalities
Moderate/severe, drug-related adverse events and grade 3/4 lab abnormalities occurring in >3% of patients in either treatment group are shown below.
Most Common Adverse Events & Grade 3/4 Lab Abnormalities
|
|
LPV/r OD
|
LPV/r BD
|
p-value
|
|
Diarrhea
|
16%
|
5%
|
0.04
|
|
Nausea
|
9%
|
8%
|
ns
|
|
Vomiting
|
3%
|
4%
|
ns
|
|
AST (>5xULN)
|
5%
|
3%
|
ns
|
|
ALT (>5xULN)
|
4%
|
3%
|
ns
|
|
Triglyc (>750mg/dL)
|
5%
|
4%
|
ns
|
|
Amylase (>2xULN
|
7%
|
5%
|
ns
|
Overall, 98% of patients demonstrated maximum creatinine ≤1.5 mg/dL. One subject in each group demonstrated creatinine >3.0 mg/dL (acute renal failure – ARF). One case of ARF occurred at Week 34 in a 75-year-old male patient with a baseline creatinine clearance of 40 mL/min who was started on full dose TDF. More recent dosing guidelines recommend that TDF be dosed every other day in this circumstance. Renal biopsy demonstrated non-specific changes with some renal tubules showing focal degenerative signs (cytoplasmic vacuolization). The second case of ARF occurred at Week 38 in a 54-year-old male patient, requiring temporary hemodialysis. Renal biopsy demonstrated tubulointerstitial nephritis. Both patients experienced improvement off study drug with creatinine levels returning to ≤1.7 mg/dL.
Mean Change From Baseline in Lipid Values
There was no difference between the once & twice daily regimens in lipid changes. Cholesterol was about 160 mg/dl at baseline for both QD & BID regimens and increased 27 mg/dl after 48 weeks. HDL cholesterol was 40 mg/dl in QD & BID arms and increased 3-6 for the QD & BID arms. LDL cholesterol was about 100 at baseline and increases about 13 for both arms. Triglycerides was 137 mg/dL at baseline and increased about 80 after 48 weeks on therapy. The increases for these lipid values were less than seen in study 863 where patients received Kaletra with d4T/3TC: baseline total cholesterol was 158 and increased by 53; TG was 168 mg/dl and increased by 125 after 48 weeks. One subject in each group in study 418 initiated lipid lowering agents during the study.
Overall, the mean 10-year CHD risk did not change significantly from baseline (4.6%) to Week 48 (5.0%) and analysis of risk rates by category likewise did not indicate increased CHD risk from baseline to Week 48.
|
|
| |
| |
|
| |
|
|
|
|
|
