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Once Daily Kaletra plus Tenofovir & FTC: PK, resistance, antiviral activity
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JM Molina1, J Gathe2, PL Lim3, P Domingo4, V Yeh5, JR Delfraissy6, A Rubin7, K Luff7, R Tressler7, M King7, S Brun7
1Hopital Saint Louis, Paris France;
2Therapeutic Concepts, Houston, TX, USA; 3Tan Tock Seng Hospital, Singapore; 4Hospital De La Santa Creu, Barcelona, Spain;
5AIDS Healthcare Foundation, Los Angeles, CA, USA; 6Services de Medecine Interne et des Maladies Infectieuses, Le Kremlin Bicetre, France;
7Abbott Laboratories, Abbott Park, IL, USA
This study was reported at the VX Intl AIDS Conference (poster B5701), July 2004, Bangkok, Thailand.
The authors concluded:
This study compared Kaletra (800/200) once daily to Kaletra (400/100) twice daily in 190 treatment-naïve patients, all of whom also received once daily nukes tenfovir plus FTC. The stdy examined pharmacokinetics, antiviral activity, and resistance. This analysis focuses on resistance. Through 48 weeks in antiretroviral-naïve patients, a QD regimen of LPV/r plus TDF and FTC demonstrated noninferiority to the same regimen with LPV/r dosed BID (70% once daily vs 64% twice daily <50 copies/ml, ITT). For every available HIV RNA value above 500 copies/mL from Weeks 12-48, isolates were submitted for resistance testing. Consistent with previous trials of LPV/r-based regimens in antiretroviral-naïve patients, no patient in either group developed confirmed LPV resistance. Secondary protease mutations polymorphisms in 3 patients were not associated with phenotypic or clinical LPV resistance.No patient in either group demonstrated TDF resistance, and only 3 patients (2 QD, 1 BID) demonstrated FTC resistance.
Lopinavir (LPV) is an HIV protease inhibitor (PI) that is co-formulated with ritonavir (r), which functions as a pharmacokinetic enhancer. LPV/r is marketed as Kaletra. The approved adult dose of LPV/r is 400/100 mg twice daily (BID). Potent antiviral activity of LPV/r has been demonstrated in antiretroviral (ARV)-naïve and PI-experienced patients. In a phase 2 study of LPV/r in combination with stavudine (d4T) and lamivudine (3TC) in ARV-naïve patients (Study 720), by intent to treat analysis, 67% of patients maintained HIV RNA <400 copies/mL through 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-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 and lower and more variable Ctrough compared to 400/100 mg BID. However, virologic response through 72 weeks was similar. Further, 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 QD dosing regimen for LPV/r in ARV-naïve patients. In Study 418, patients received LPV/r (800 mg/200 mg QD or 400 mg/100 mg BID) with tenofovir DF (TDF) 300 mg and emtricitabine (FTC) 200 mg QD. Patients receiving LPV/r 800/200 mg QD demonstrated slightly higher lopinavir Cmax, similar AUC, and lower Ctrough compared to 400/100 mg BID. The median IQ was 49 for QD and 94 for BID. This analysis presents comprehensive resistance data obtained through 48 weeks.
Study 418 is the first trial of an entirely once-daily LPV/r-based regimen. It is a 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 TDF 300 mg and FTC 200 mg QD.
The authors stared that a comprehensive approach was employed to assess resistance development. For each HIV RNA result above 500 copies/mL between Weeks 12-48, isolates were submitted for genotypic resistance testing. Corresponding baseline isolates for each patient were also submitted for testing. Genotypic changes were assessed by population sequencing (GeneSeq, Virologic).
Resistance to LPV was defined as the emergence of any primary or active site mutation in protease (positions 8, 30, 32, 46, 47, 48, 50, 82, 84, 90) with corresponding phenotypic LPV resistance of at least 2.5-fold vs. wild-type.
TDF resistance was defined as the emergence of the K65R mutation or any thymidine analog mutation (TAM positions 41, 67, 70, 210, 215, 219 in reverse transcriptase). FTC resistance was defined by the emergence of the M184V/I mutation in reverse transcriptase.
RESULTS
Demographics and baseline characteristics were similar between treatment groups.
--Overall, 22% were female and 46% were non-white.
--The patient population was relatively advanced, as approximately 45% of patients had baseline CD4 count below 200 cells/mm3 and 38% had baseline HIV RNA above 100,000 copies/mL.
--Mean baseline HIV RNA and CD4 cell count were 4.8 log10 copies/mL and 260 CD4s, respectively.
By intent-to-treat (noncompleter=failure) analysis, 70% (QD) and 64% (BID) of patients demonstrated HIV RNA <50 copies/mL at Week 48, 95% CI for the difference (--7% to 20%).
CD4 cell count mean increases (+185 CD4s) from baseline were comparable between treatment groups.
22 patients (11 QD, 11 BID) had samples eligible for resistance testing (HIV RNA > 500 copies/mL at any time from Weeks 12-48).
Resistance testing results were available for a total of 27 samples from 15 patients (8 QD, 7 BID).
No patient demonstrated confirmed LPV or TDF resistance (0/8 in qd & 0/7 in bid regimens). 3 patients (2 QD, 1 BID) demonstrated FTC resistance.
3 patients (1 QD, 2 BID) demonstrated any substitution in protease, but none of the changes appeared to have an impact on phenotypic resistance, as phenotypic susceptibility to LPV and other PIs remained below baseline or wild-type levels (1.0 fold).
At Week 16, Patient A (QD) demonstrated I62V, L63P, and I93L mutations that were not present at baseline. However, the L63P and I93L mutations are common polymorphisms, and the I62V mutation has not been associated with PI resistance. No TDF or FTC resistance was observed. LPV phenotypic susceptibility remained below wild-type. Subsequently, Patient A achieved HIV RNA <50 copies/mL at Weeks 48-60 with no change in therapeutic regimen.
Patient B (BID) discontinued at Week 37 and had genotypic data available 1 week after the last dose of study drug. While some substitutions at position 33 have been associated with PI resistance (e.g., L33F), the L33L/S substitution observed in Patient B is uncommon and has not been associated with PI resistance. No TDF or FTC resistance was observed. LPV phenotypic susceptibility remained below wild type.
Patient C (BID) demonstrated mixtures at positions 46, 64, and 67 in protease during a temporary drug interruption at Week 40. The M46M/I mixture observed in Patient C is of unknown significance. When present with other mutations, the M46I mutation has been shown to increase resistance to various PIs, but the phenotypic resistance to LPV for this subject remained below wild type. No TDF or FTC resistance was observed. If any of these changes were a manifestation of PI resistance development, FTC resistance would also be expected. Resistance generally develops first to the most fragile component of a regimen. For example, in a recent study of subjects receiving nelfinavir, stavudine and lamivudine, all subjects demonstrating a primary PI mutation (D30N or L90M) also demonstrated the M184V/I mutation in reverse transcriptase.7 When study drugs were re-started, HIV RNA was re-suppressed below 50 copies/mL at Weeks 48 and 60.
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