Gathe, Joseph MD*; da Silva, Barbara A MD†; Cohen, Daniel E MD†; Loutfy, Mona R MD, FRCPC, MPH‡; Podzamczer, Daniel MD§; Rubio, Rafael MD‖; Gibbs, Sara†; Marsh, Theresa BS†; Naylor, Christian†; Fredrick, Linda MS†; Bernstein, Barry MD†
The introduction of potent antiretroviral therapy has had a major impact on clinical outcomes for HIV-1-infected patients.1,2 In addition to the potency of a given regimen, tolerability and patient adherence to the chosen regimen can influence treatment outcomes.3-5 Therefore, modifications in treatment regimens that improve tolerability and adherence without compromising potency are likely to enhance the success and durability of initial antiretroviral therapy.
Lopinavir (LPV) is an HIV protease inhibitor (PI) that is coformulated with ritonavir, which functions as a pharmacokinetic enhancer. Lopinavir/ritonavir (LPV/r) has demonstrated durable antiviral activity in both antiretroviral (ARV)-naive and PI-experienced patients.6-9 The soft gelatin capsule (SGC) formulation of LPV/r-dosed once daily has shown comparable efficacy to twice-daily regimens when administered with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) through 96 weeks as initial therapy.6
A newly developed tablet formulation of LPV/r reduces the pill burden of the standard 800/200 mg LPV/r total daily dose from 6 capsules to 4 tablets and, unlike the SGC, does not require refrigeration and may be taken with or without food.
Pharmacokinetic studies have demonstrated that tablet administration results in an approximately 18% and 24% increase in LPV area under the curve and maximum concentrations, respectively, and a 20% and 35% increase in ritonavir area under the curve and maximum concentrations, respectively, compared with the SGC.10 Based on analyses of previous trials utilizing higher than standard doses of LPV/r, the increase in LPV and ritonavir exposure was not anticipated to impact overall safety.11-12
Study M05-730 is a Phase 3, randomized, open-label, multicountry study designed to compare the efficacy and safety of combination therapy with LPV/r once daily vs. twice daily in ARV-naive subjects and is the first such study utilizing the tablet formulation. Study M05-730 also assessed the safety and tolerability of the LPV/r SGC compared with the tablet formulation over the first 8 weeks of the study. A duration of 8 weeks for comparison of the 2 formulations was chosen based on observations from previous clinical trials of LPV/r in ARV-naive subjects, in which the majority of the most common adverse events had onset within the first 8 weeks of therapy. This is an ongoing 96-week study with results of virologic efficacy and safety analyses for the primary 48-week end point presented here.
Six hundred sixty-four ARV-naive HIV-1-infected subjects were randomized 1:1:1:1 and receive open-label LPV/r SGC or tablet formulations at a dose of 800 mg LPV/200 mg ritonavir once daily (n = 333; SGC: n = 166, tablet: n = 167) or 400 mg LPV/100 mg ritonavir twice daily (n = 331; SGC: n = 165, tablet: n = 166). Subjects randomized to the SGC formulation were switched to the tablet at week 8 and maintained their randomized dosing frequency. The primary efficacy end point is at week 48, however, total study duration is 96 weeks. All subjects also received FTC 200 mg once daily and TDF 300 mg once daily (Fig. 1).
Subjects were eligible to participate in the study if they had received no prior antiretroviral therapy, were at least 18 years of age, had plasma HIV-1 RNA ≥1000 copies per milliliter at screening, and had not been treated for an active AIDS-defining opportunistic infection within 45 days of initiating study drug. Subjects were excluded from study participation if laboratory analyses showed any of the following abnormal results: presence of hepatitis B surface antigen, hemoglobin ≤8.0 g/dL, absolute neutrophil count ≤750 cells per milliliter, platelet count ≤50,000 cells per milliliter, alanine aminotransferase (AST) or aspartate aminotransferase (ALT) ≥3.0 times the reference laboratory's upper limit of normal, or a calculated creatinine clearance <50 mL/min. Subjects were evaluated every 2 weeks through week 16, every 8 weeks through week 48, then every 12 weeks through week 96. Procedures at these visits included symptom-directed physical examinations, vital sign measurements, clinical laboratory tests, and determinations of antiviral and immunologic activity. Institutional review boards at participating centers approved the study, and all subjects provided written informed consent before any study procedures.
Virologic Efficacy-Primary Efficacy End Point
The primary efficacy analysis was the proportion of subjects with HIV-1 RNA <50 copies per milliliter at week 48 using an intent-to-treat, noncompleter = failure approach in which subjects with missing values at week 48 were considered to have HIV-1 RNA ≥50 copies per milliliter, unless the immediately preceding and following values were <50 copies per milliliter. The proportion of subjects with HIV-1 RNA levels below 50 copies per milliliter was determined for once-daily and twice-daily dosing arms, along with the corresponding 95% confidence interval (CI) for the difference in proportions (once daily minus twice daily), based on the normal approximation to the binomial distribution. If the lower limit of the CI remained above −12%, the once-daily dosing group was considered to have noninferior efficacy compared with the twice-daily group. Post hoc, this analysis was also performed for the subset of subjects with baseline HIV-1 RNA level ≥100,000 copies per milliliter and baseline CD4 cell count <200 cells per cubic millimeter. Differences between once-daily and twice-daily dosing arms were assessed using Fisher exact test; these differences were also assessed within prespecified subgroups defined by baseline HIV-1 RNA level (<100,000 and ≥100,000 copies/mL) and baseline CD4 cell count (<50, 50 to <200 and ≥200 cells/mm3). As a post hoc analysis, the stratum adjusted (baseline HIV-1 RNA <100,000 vs. ≥100,000 copies/mL); CI for the difference between the once-daily and twice-daily arms in week-48 response rates was calculated using Cochran-Mantel-Haenszel methodology. A preplanned observed data analysis of the proportion of subjects with HIV-1 RNA <50 copies per milliliter at week 48 in which missing values were excluded was also performed. HIV-1 RNA was measured using the Roche Ultrasensitive Cobas Amplicor HIV Monitor Test, version 1.5 (Roche Diagnostic Systems, Indianapolis, IN) with a lower limit of quantitation of 50 copies per milliliter.
Immunologic Response Through Week 48
Mean change from baseline in CD4+ T-cell count at 48 weeks was compared between the once-daily and twice-daily arms using a 1-way analysis of variance.
Safety Analysis Through Week 48 and Comparing SGC to Tablet Through Week 8
All randomized subjects who took at least 1 dose of study drug were included in the safety analysis. The primary safety end point was the proportion of subjects reporting a treatment-emergent adverse event of diarrhea during the first 8 weeks of dosing. The difference in this proportion between tablet and SGC formulations was assessed using the Cochran-Mantel-Haenszel test stratified by dosing group (once daily vs. twice daily). Secondary safety analyses included the proportion of subjects reporting moderate or severe study drug-related treatment-emergent adverse events, and the proportion with Grades 3-4 laboratory abnormalities, through week 48, which were compared between the once-daily and twice-daily dosing arms using Fisher's exact test. Prevalence of diarrhea at weeks 8 and 48 was assessed, and mean changes from baseline for laboratory results through 48 weeks were compared between the once-daily and twice-daily arms using 1-way analysis of variance.
Resistance Data Through Week 48
Resistance testing was performed beginning at week 24 for subjects who met criteria for virologic rebound, defined as a plasma HIV-1 RNA measurement >50 copies per milliliter (immediately preceded by a measurement ≤50 copies/mL) confirmed with a second measurement >400 copies per milliliter within 4 weeks. HIV-1 genotyping was performed using the ViroSeq HIV-1 Genotyping System Version 2.6 (Applied Biosystems, Alameda, CA). The proportion of subjects who developed genotypic resistance to each drug in the study regimen was compared between the once-daily and twice-daily dosing arms using Fisher's exact test.
Resistance was defined by the International AIDS Society-USA 2007 panel of drug resistance mutations.13 Evidence of LPV resistance was also defined more conservatively as the presence of 1 or more of the following protease mutations: I47V or A, G48V, I50V, V82A, or F, or T, or S, I84V, L90M; or the presence of 3 or more of the following protease mutations: L10F or I or R or V, K20M or R, L24I, V32I, L33F, M36I, M46I or L, F53L, any change to I54, A71V or T, and G73S.
Survey Data Analysis
At week 8 and week 12, all subjects completed a self-administered questionnaire. Ease of dosing and overall satisfaction were assessed at weeks 8 and 12, and for each of the 4 treatment arms, a Mantel-Haenszel approach was used to test the null hypothesis that the distribution of responses were the same at weeks 8 and 12. Therapy preference for subjects receiving LPV/r SGC until week 8 was assessed at week 12, and a 1-sample t test was used to test the null hypothesis that the mean score was zero (ie, equal preference).
Sample Size Determination
The planned sample size of 600 subjects, with 300 subjects in each of the once-daily and twice-daily treatment groups, provided more than 90% power to determine noninferiority for the primary efficacy end point based on a noninferiority margin of 12% for the difference in response rates and a 70% virologic response rate in both the once-daily and twice-daily treatment groups.
Baseline Characteristics and Subject Disposition
A total of 664 subjects were enrolled at 130 sites between January and September 2006. Subjects were primarily male and white, and baseline characteristics were generally similar between once-daily and twice-daily treatment groups (Table 1), with the exception of higher mean baseline viral load in the twice-daily group (5.05 log10 copies/mL vs. 4.93 log10 copies/mL, P = 0.020).
Reasons for discontinuation through week 48 are summarized in Table 1. Forty-nine subjects (14.7%) in the once-daily group discontinued, whereas 55 subjects (16.6%) in the twice-daily group discontinued. Discontinuations due to adverse events were noted in 4.8% of subjects in the once-daily group and 3% of subjects in the twice-daily group.
Virologic Efficacy-Primary Efficacy End Point Through Week 48
In the primary efficacy analysis at week 48, 77% of subjects in the once-daily group and 76% of subjects in the twice-daily group achieved a viral load <50 copies per milliliter by intent-to-treat noncompleter = failure analysis (Fig. 2A). The difference in response rates (once daily minus twice daily) was 1% (95% CI −5% to 8%), which confirmed the noninferiority of the once-daily regimen to the twice-daily regimen, as the lower bound of the CI was above the prespecified margin of −12%. A sensitivity analysis adjusting for the baseline imbalance in HIV-1 RNA level was consistent with the primary analysis, with an estimated difference (95% CI) in response rates of 1% (−6% to 7%). In an observed data analysis, in which missing values were excluded from the analysis, the proportion of subjects responding in both groups was slightly higher and results were still similar between dosing groups (Fig. 2B). In subgroups defined by baseline HIV-1 RNA (<100,000 copies/mL or ≥100,000 copies/mL) or baseline CD4+ T-cell count (<50 cells/mm3, 50 to <200 cells/mm3, and ≥200 cells/mm3), numerically similar proportions of once-daily-treated and twice-daily-treated subjects achieved HIV-1 RNA <50 copies per milliliter at week 48 (Fig. 3A). The virologic response in patients with baseline HIV-1 RNA ≥100,000 copies per milliliter and CD4+ T-cell counts <200 cells per cubic millimeter was 74% and 73% for the once-daily and twice-daily groups, respectively (Fig. 3B).
Immunologic Response Through Week 48
Similar mean increases from baseline in CD4+ T-cell count at week 48 were observed in the once-daily and twice-daily treatment groups (186 and 198 cells/mm3, respectively; P = 0.318).
Resistance Data Through Week 48
Seventeen subjects met the protocol-defined criteria for resistance testing. One subject in the once-daily dosing group did not have resistance testing performed until after week 48 and was not included in the 48-week analysis; another subject in the once-daily dosing group had resistance testing performed despite not meeting protocol-defined criteria (repeat HIV-1 RNA measurement was not >400 copies/mL). Thus 17 subjects had resistance testing performed (10 once daily and 7 twice daily) through week 48. No PI-associated or TDF-associated resistance mutations were observed.
Three subjects (2 once daily and 1 twice daily) developed the M184V mutation in reverse transcriptase, conferring high-level resistance to lamivudine or FTC.
Adverse Events Through Week 8 Comparing SGC to Tablet
There were no statistically significant differences between the tablet and SGC formulations in any of the following: the number of subjects discontinuing due to gastrointestinal adverse events or other adverse events; the incidence of treatment-emergent adverse events of diarrhea of any severity and of moderate or greater severity and related to the study drug; the proportion of subjects with grade 3+ laboratory abnormalities; or the mean change from baseline for total cholesterol (TC) or triglycerides (TG) at any time point during the first 8 weeks of treatment.
Adverse Events and Laboratory Abnormalities Through Week 48
Rates of study drug-related diarrhea of moderate or greater severity were similar between groups during the first 48 weeks (once daily 17%, twice daily 15%, P = 0.671). The rates of other adverse events and grade 3+ laboratory abnormalities occurring in greater than 2% of subjects in either treatment group were also similar in once-daily-treated and twice-daily-treated subjects (Table 2). Mean increases occurred from baseline to week 48 in TC, TG, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol. The mean increase in TC was statistically significantly less in the once-daily group (P = 0.044), but all other increases were similar between groups. Of note, grade 2+ TG (>399 mg/dL) elevations occurred less often in the once-daily group (19% once daily vs. 28% twice daily, P = 0.008), however, the mean change from baseline was not statistically significantly different (P = 0.070) between once daily and twice daily. The TC:HDL and LDL:HDL ratios decreased slightly in both groups (Table 3).
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.
1. Panel on Clinical Practices for the Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services and Henry J. Kaiser Foundation, May 29, 2008. Available at: http://www.hivatis.org/guidelines/AA599.pdf
. Accessed June 2008.
2. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;96:827-843.
3. Nieuwkerk PT, Sprangers MA, Burger DM, et al. Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study. Arch Intern Med. 2001;161:1962-1968.
4. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21-30.
5. Portsmouth SD, Osorio J, McCormick K, et al. Better maintained adherence on switching from twice-daily to once-daily therapy for HIV: a 24-Week randomized trial of treatment simplification using stavudine prolonged-release capsules. HIV Med. 2005;6:185-190.
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. Murphy RL, da Silva BA, Hicks CB, et al. Seven-year efficacy of a lopinavir/ritonavir-based regimen in antiretroviral-naive HIV-1-infected patients. HIV Clin Trials. 2008;9:1-10.
8. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039-2046.
9. Pollard RB, Thompson M, Hicks C, et al. Phase 3 comparison of lopinavir/ritonavir vs. investigator-selected protease inhibitors in single PI-experienced, NNRTI-naive patients: 48-week results of study M98-888. Presented at: 7th International Congress on Drug Therapy in HIV Infection; November 14-17, 2004; Glasgow, United Kingdom.
10. Klein CE, Chiu YL, Awni W, et al. The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect. J Acquir Immune Defic Syndr. 2007;44:401-410.
11. Podzamczer D, King MS, Klein CE, et al. High-dose lopinavir/ritonavir in highly treatment-experienced HIV-1 patients: efficacy, safety, and predictors of response. HIV Clin Trials. 2007;8:193-204.
12. Murphy RL, Brun S, Hicks C, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS. 2001;15:F1-F9.
13. 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.
14. Hicks C, King MS, Gulick RM, et al. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study. AIDS. 2004;18:775-779.
15. Johnson MA, Gathe JC Jr, Podzamczer D, et al. A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen. J Acquir Immune Defic Syndr. 2006;43:153-160.
16. Mildvan D, Tierney C, Gross R, et al. Randomized comparison in treatment-naïve patients of once-daily vs. twice-daily lopinavir/ritonavir-based ART and comparison of once-daily self-administered vs. directly observed therapy. Presented at: 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007; Los Angeles, CA.
17. Eron JJ, Feinberg J, Kessler HA, et al. Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial. J Infect Dis. 2004;189:265-272.
18. Clumeck N, van Lunzen J, Chiliade P, et al. ARTEMIS: efficacy and safety of lopinavir (BID vs. QD) and darunavir (QD) in antiretroviral-naive patients. Presented at: 11th European AIDS Conference. October 24-27, 2007; Madrid, Spain.
19. King M, Fredrick L, da Silva BA. Once daily and twice daily lopinavir/ritonavir-based regimens provide similar virologic response through 48 weeks: results of meta-analysis. Presented at: 14th Annual Conference of the British HIV Association (BHIVA). April 23-25, 2008, Northern Ireland, United Kingdom.
20. Ofotokun I, Chuck SK, Rivas M, et al. Switching from lopinavir/ritonavir (lopinavir/ritonavir) soft gel capsule (SGC) to tablet formulation improves tolerability in indigent AIDS clinic. Presented at: 45th Annual Meeting of the Infectious Disease Society of America. October 4-7, 2007; San Diego, CA.
21. Schrader S, Chuck SK, Rahn LW, et al. Significant improvements in self-reported gastrointestinal tolerability, quality of life, patient satisfaction, and adherence with lopinavir/ritonavir tablet formulation compared with soft gel capsules. AIDS Res Ther. 2008;5:21.
22. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Risk stratification of coronary heart disease in Greece: final results from CARDIO2000 Epidemiological Study. Prev Med. 2002;35:548-556.
23. Lemieux I, Lamarche B, Couillard C, et al. Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study. Arch Intern Med. 2001;161:2685-2692.
24. Grover S, Dorais M, Coupal L. Improving the prediction of cardiovascular risk: interaction between LDL and HDL cholesterol. Epidemiology. 2003;14:315-320.
© 2009 Lippincott Williams & Wilkins, Inc.