Survey Data Analysis
At week 8 and week 12, all subjects completed a self-administered questionnaire. The ease of dosing and overall satisfaction was assessed at week 8. Therapy preference (for subjects receiving LPV/r SGC until week 8), ease of dosing and overall satisfaction were assessed at Week 12. Subjects were asked to use a scale of 1 (very easy) to 5 (not easy), to describe how easy it had been to take the study medication (scale of 1 = excellent to 5 = poor), as prescribed. Subjects were also asked to rate their overall satisfaction with the study medication and to choose which formulation they preferred, SGC vs. tablet. For overall satisfaction, patients were asked to rate their experience as: excellent, very good, good, fair, or poor. For patient preference, subjects were asked to indicate Kaletra tablets, Kaletra soft gel capsules, or equal preference for Kaletra tablets and soft gel capsules. In those subjects who switched from SGC to tablet, subjects preferred the LPV/r tablet to the SGC (P < 0.001), with 80% (once daily) and 75% (twice daily) preferring the tablet and only 5% (once daily) and 3% (twice daily) preferring the SGC. Between weeks 8 and 12, the ease of use in both once-daily and twice-daily SGC groups improved significantly after switching to the tablet, (P = 0.001 and P = 0.002, respectively). In subjects switching from SGC to tablet, satisfaction significantly improved in the SGC once-daily group (P < 0.001) and showed a trend toward significant improvement in the SGC twice-daily group (P = 0.061).
A twice-daily regimen of combination therapy with LPV/r (400/100 mg) and 2 nucleoside reverse transcriptase inhibitors (NRTIs) is a potent, highly efficacious, well-tolerated, and durable regimen for the treatment of ARV-naive HIV-infected patients.2,14 This study is the largest study to date comparing once-daily and twice-daily dosing of LPV/r, and the first to utilize the tablet formulation, initially approved for use in the United States in 2005 and in Europe in 2006. The results of the present study indicate that, in ARV-naive patients treated more than 48 weeks, LPV/r taken once daily has ARV and immunological activity similar to that of twice-daily LPV/r, at the same total daily dose, each combined with once-daily NRTIs. Both regimens resulted in more than 75% of all randomized, dosed patients attaining a plasma HIV-1 RNA level of <50 copies per milliliter at 48 weeks. In addition, during the first 48 weeks of treatment, no clinically significant differences were identified in the safety or tolerability of once-daily vs. twice-daily dosing of LPV/r. Notably and in contrast to study M02-418 which evaluated the LPV/r SGC as initial therapy when dosed either once daily or twice daily, differences in rates of diarrhea were not observed when once-daily and twice-daily dosing of the LPV/r tablet were compared in this study.6,15,16 Therefore, the results from this study support the use of LPV/r-dosed once daily in combination therapy in ARV-naive subjects.
Prior studies using the LPV/r SGC formulation once daily have shown that although trough LPV concentrations during once-daily dosing are lower than those achieved with LPV/r-dosed twice daily, LPV plasma concentrations still remain significantly higher (median of 40-fold higher) than those needed for in vitro suppression of the wild-type HIV-1 virus across a dosing interval.17 Thus, the difference in LPV/r concentration when dosed once daily is not expected to impact virologic efficacy. Supportive of this concept are data from study M02-418 and from a smaller pilot study (M99-056); both demonstrated similar efficacy for LPV/r-dosed once daily and twice daily with 2 NRTIs in ARV-naive HIV-infected patients.6,17 Study M05-730 confirms these findings in a larger population by demonstrating similar efficacy for both once-daily LPV/r-dosed and twice-daily LPV/r-dosed subjects. Additional confirmation of the adequacy of drug concentrations was demonstrated by the findings that, in subgroups defined by baseline HIV-RNA and CD4+ T-cell count, numerically similar response rates were observed for the once-daily group compared with the twice-daily group. Of note, 2 previously reported smaller studies (AIDS Clinical Trial Group 5073 and ARTEMIS) have suggested that once-daily-dosed LPV/r may result in lower virologic response rates compared with twice-daily dosing in ARV-naive subjects.16,18 However, when data from studies M05-730, M02-418, M99-056, ACTG 5073, and ARTEMIS were analyzed in a meta-analysis, no difference in virologic response was detected when comparing LPV/r once daily and twice daily overall or stratified by baseline viral load (HIV-1 RNA >100,000 or <100,000 copies/mL).19
The results of genotype testing from this study show that patients with confirmed virologic rebound did not acquire resistance to PIs or to TDF. This finding is consistent with previous studies in ARV-naive subjects where there was a low rate of resistance development among treatment failures receiving LPV/r-based therapy.6,7 There was no evidence of increased risk of resistance in the once-daily group in this study, demonstrating that LPV/r retains a high genetic barrier to resistance even when dosed once daily.
Although administration of the tablet formulation provides slightly higher LPV exposure than the SGC, we did not observe a difference in the adverse event profile when comparing the SGC and tablet during the initial 8-week study treatment period, suggesting that the differences in drug exposure are not clinically significant. Interestingly, a preference questionnaire demonstrated that subjects overwhelmingly preferred the tablet formulation. Reasons for why subjects preferred tablet were not obtained in the survey, however, they may include the lack of refrigeration, no food effect, and possible tolerability effects not detected by the standardized adverse event assessment performed during a clinical trial. Data from this study are consistent with previous studies that demonstrated patient preference for the tablet formulation after switching from the SGC.14,20,21
Plasma concentrations for TG, LDL, and HDL cholesterol were similar for both the once-daily-dosed and twice-daily-dosed LPV/r groups throughout the study. TC:HDL and LDL:HDL ratios were similar in both groups and decreased slightly through 48 weeks compared with baseline. Although this may suggest limited impact on cardiovascular risk because these ratios only assess a portion of the potential contributing factors, consideration of additional factors will be useful in determining overall cardiovascular risk.22-24
Limitations of this study include the use of TDF and FTC, which were dosed once daily, whereas LPV/r was dosed either once daily or twice daily. Different dosing frequencies may adversely affect adherence and could have impacted study results. In addition, further surveillance of the reasons for patient preference of the tablet over the SGC would have been helpful but was not done in this study.
This large randomized trial strongly supports the conclusion that once-daily-dosed LPV/r is an effective, well-tolerated option for treatment of antiviral-naive patients. Response to therapy was comparable between the treatment groups within the overall study population and within subgroups defined by baseline viral load and CD4 T-cell count, confirming the potency of once-daily-dosed and twice-daily-dosed LPV/r. Consistent with this observation, the lack of LPV resistance mutations noted on virologic rebound in the once-daily treatment group suggests that the high barrier to resistance noted previously with twice-daily LPV/r is maintained when dosed once daily. Lastly, overall safety and tolerability was similar regardless of LPV/r-dosing frequency, further supporting the consideration of LPV/r as once-daily option treatment for ARV-naive patients.
The authors would like express gratitude and appreciation to the subjects who participated in this study and the study coordinators who helped make this study possible. We also thank the following study investigators for their significant contributions to this study: Mark Bloch, Norman Roth, Jennifer Hoy, Robert Colebunders, Michel Moutschen, Bernard Vandercam, Dirk Vogelaers, Eric Van Wijngaerden, Eric Florence, Michel Boissonnault, Joseph DeWet, Patrice Junod, Donald Kilby, Sharon Walmsley, Sylvie Trottier, Anita Rachlis, Shariq Haider, John Gill, Norbert Gilmore, Brian Conway, Paul MacPherson, Dalibor Sedlacek, Svatava Snopkova, Vincente Boix, Koldo Aguirrebengoa, Jose Lopez Aldeguer, Juan Ma Gonzalez-Lahoz, Jose M. Gatell, Pilar Miralles, Pere Domingo, Carmen Farinas, Maria Jesus Tellez, Esteban Ribera, Fernando Dronda, Juan Julian Gonzalez-Garcia, Bonaventura Clotet, Arturo Prieto, Jose Domingo Pedreira, Pompeyo Viciana, Dominique Salmon, Gilles Pialoux, Patrick Yeni, Christian Michelet, Jean-Michel Molina, Laurent Cotte, Jacques Reynes, Paul Allegre, Thierry May, Pierre-Marie Girard, Bruno Hoen, Jonathan Ainsworth, Philip Hay, Steve Taylor, George Scullard, Martin Fisher, Edmund Wilkins, Margaret Johnson, Gerd Fatkenheuer, Birger Kuhlmann, Schlomo Staszewski, Norbert Brockmeyer, Christiane Cordes, Jurgen Rockstroh, Dirk Schurmann, Lothar Schneider, Albrecht Stoehr, Thomas Buhk, Marios Lazanas, Paul Nikolaidis, Colm Bergin, John Lambert, Giampiero Carosi, Laveeza Bhatti, Larry Bush, Roberto Corales, Roger Trinh, Edwin DeJesus, Franco Felizarta, Eliot Godofsky, Stephan Green, Harold Katner, Alberto Mestre, Robert Myers, David Parenti, Frank Rhame, Barry Rodwick, Stefan Schneider, Sheetal Sharma, Donna Sweet, Jonathan Uy, Bienvenido Yangco, Philip Brachman, Stockton Roberts, David Parks, Moti Ramgopal, Louis Sloan, Thanes Vanig, Jorge E. Rodrigues, Roberto Ortiz, Charles Walworth, and Lewis McCurdy. The authors would also like to thank Hamani Henderson, PhD, of Abbott Laboratories for her contributions to the writing and development of this article.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; CD4+ T cell; HIV-1 RNA; lopinavir/ritonavir; virologic response