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Kaletra QD Resistance Report: Lopinavir/ritonavir (LPV/r) with Tenofovir DF (TDF) and Emtricitabine (FTC) in Antiretroviral (ARV)-naïve Subjects
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Daniel E. Cohen, Martin S. King, Christian T. Naylor, Theresa M. Marsh, Barbara A. da Silva, Barry M. Bernstein
Abbott, Abbott Park, IL USA
12th European AIDS Conference · 11-14 November 2009 · Cologne, Germany
Corresponding author: Daniel Cohen, M.D., Abbott, 200 Abbott Park Rd., Abbott Park, IL 60064-6146 USA;
Tel: +1-847-938-1494; Fax: +1-847-938-3711; E-mail: daniel.cohen@abbott.com
AUTHOR SUMMARY
In this study, antiretroviral-naïve subjects treated with an LPV/r-based antiretroviral regimen demonstrated a low
frequency of resistance to FTC; no TDF-associated resistance mutations were detected in any subject
One subject (BID treatment group) with several protease inhibitor-associated mutations at baseline revealed additional protease and reverse transcriptase resistance mutations after 12 weeks of treatment; the subject's isolate retained sensitivity or partial sensitivity to saquinavir, atazanavir, indinavir, darunavir, and tipranavir
The pattern and frequency of treatment-emergent resistance mutations was similar to that seen at 48 weeks in Study
M05-730 and in previous studies of LPV/r treatment in naïve subjects through 360 weeks2, 5-7
The incidence of resistance to study drugs did not differ between QD- and BID-treated subjects
AUTHOR CONCLUSIONS
No LPV/r QD-treated subject developed evidence of lopinavir resistance over 96 weeks of treatment
In addition, QD LPV/r was associated with a low risk of FTC or TDF resistance
These findings are similar to those observed in antiretroviral-naïve subjects receiving BID LPV/r and confirm that QD LPV/r dosing maintains a resistance profile comparable to BID LPV/r dosing
BACKGROUND
Lopinavir/ritonavir (LPV/r) is a coformulation of the HIV-1 protease inhibitors lopinavir and low-dose ritonavir, which acts as a pharmacokinetic enhancer; LPV/r has been used extensively in both antiretroviral-naïve and antiretroviralexperienced patients, demonstrating durable response to therapy1-4
LPV/r was originally approved in 2000 for twice-daily (BID) dosing at 400/100 mg in both antiretroviral-naïve and treatment-experienced HIV-1-infected patients; LPV/r 800/200 mg administered once daily (QD) was approved for use in treatment-naïve patients in the US in 2005 and the EU in 2009
Previous findings have demonstrated that resistance develops infrequently in antiretroviral-naïve subjects treated with LPV/r 2, 5, 6 (Table 1)
Objective
To evaluate the emergence of resistance in antiretroviral-naïve subjects treated with QD and BID LPV/r through 96 weeks of treatment
Results
Subjects
Baseline demographics were similar between treatment groups7
-- However, mean baseline HIV-1 RNA was greater for subjects in the BID dosing group (QD: 4.93 log10 copies/mL; BID: 5.05 log10 copies/mL; P=0.020)
Through 96 weeks, the proportion of subjects discontinuing the study prematurely was similar for QD-treated subjects (N=77, 23.1%) and subjects in the BID group (N=77, 23.3%), with comparable rates of discontinuation due to adverse or HIV-related events and virologic failure9
Efficacy
QD and BID dosing of LPV/r resulted in similar efficacy through 96 weeks according to both intent-to-treat, noncompleters=failure analysis and on-treatment analysis (Figure 1)9
Similar efficacy in QD and BID treated subjects was also observed in subsets of subjects when stratified by baseline HIV-1 RNA level or CD4+ T-cell count9
Resistance
Genotypic resistance results were available for 51 (25 QD and 26 BID) subjects who met criteria for genotypic testing
The frequency of treatment-emergent resistance to study drugs was comparable for subjects taking LPV/r QD and BID (Table 2)
One BID-dosed subject ("Subject A") with several protease inhibitor-associated resistance mutations at baseline demonstrated additional resistance mutations after 12 weeks of treatment (Figure 2)
-- Fold change in lopinavir susceptibility (compared to wild type virus) correspondingly increased from 2.7-fold at screening to 72-fold at Week 12, although the subject's rebound isolate remained sensitive or partially sensitive to most other ritonavir-boosted protease inhibitors, including saquinavir, atazanavir, indinavir, darunavir, and tipranavir
Figure 2. Genotypic and phenotypic changes from wild type HIV-1 observed in isolates from subject A
Emergence of secondary protease mutations8 was also uncommon, with no obvious differences in the pattern of new substitutions between QD and BID subjects (Figure 3)
Figure 3. Number of subjects with treatment-emergent protease mutations*
*L10F/I/R/V, K20M/R, L24I, V32I, L33F, M36I, M46I/L, I47A/V, G48V, I50V, F53L, I54 (any change), A71T/V, G73S, V82A/F/S/T, I84V, L90M.
REFERENCES
1. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of infection. N Engl J Med. 2002;346:2039-2046.
2. Murphy R, da Silva BA, Hicks CB, et al. Seven-Year Effi cacy of a Lopinavir/ Ritonavir-Based Regimen in Antiretroviral-Naïve HIV-1-Infected Patients. HIV Clin Trials. 2008;9:1-10.
3. Bongiovanni M, Bini T, Capetti A, et al. Long-term antiretroviral effi cacy and
safety of lopinavir/ritonavir HAART-experienced subjects: 4 year follow-up study. AIDS. 2005;19:1934-1936.
4. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48
weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reversetranscriptase
inhibitors in human immunodefi ciency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis. 2002;185:599-607.
5. Kempf DJ, King MS, Bernstein B, et al. Incidence of resistance in a doubleblind
study comparing lopinavir/ritonavir plus stavudine and lamivudine to
nelfi navir plus stavudine and lamivudine. J Infect Dis. 2004;189:51-60.
6. Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based
once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses. 2007;23:1505-1514.
7. Gathe J, da Silva BA, Cohen DE, et al. A Once-Daily Lopinavir/Ritonavir-
Based Regimen Is Noninferior to Twice-Daily Dosing and Results in Similar
Safety and Tolerability in Antiretroviral-Naive Subjects Through 48 Weeks. J
Acquir Immune Defi c Syndr. 2009;50:474-481.
8. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance
mutations in HIV-1: 2007. Top HIV Med. 2007;15:119-125.
9. Gonzalez-Garcia J, Cohen DE, Johnson M, et al. Comparable safety and
efficacy with once-daily (QD) versus twice-daily (BID) dosing of lopinavir/
ritonavir (LPV/r) tablets with emtricitabine (FTC) + tenofovir DF (TDF) in
antiretroviral (ARV)-naïve, HIV-1-infected subjects: 96 week results of the
randomized trial M05-730. Paper presented at: 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 19-22
July, 2009; Cape Town, South Africa.
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