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ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results

Murphy, Robert L.; Brun, Scotta; Hicks, Charlesb; Eron, Joseph J.c; Gulick, Royd; King, Martina; White, A. Clinton Jr.e; Benson, Constancef; Thompson, Melanieg; Kessler, Harold A.h; Hammer, Scotti; Bertz, Richarda; Hsu, Anna; Japour, Anthonya; Sun, Eugenea

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From the Department of Medicine, Northwestern University, Chicago, aAbbott Laboratories, Abbott Park, Illinois, bDuke University Medical Center, Durham, the cDepartment of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, the dDepartment of Medicine, Cornell University, New York, eThomas Street Clinic/Baylor College of Medicine, Houston, Texas, the fDepartment of Medicine, University of Colorado, Denver, Colorado, the gAIDS Research Consortium of Atlanta, Atlanta, Georgia, the hDepartments of Medicine and Immunology/Microbiology, Rush Medical College, Chicago, Illinois and the iDepartment of Medicine, Columbia University, New York, USA.

Received: 24 July 2000;

revised: 12 October 2000; accepted: 26 October 2000.

Sponsorship: Supported by Abbott Laboratories, Abbott Park, Illinois, USA.

Requests for reprints to: R. L. Murphy, Department of Medicine, Division of Infectious Diseases, Northwestern University, 676 North St. Clair Street, Suite 1920, Chicago, IL 60611, USA.

Note: James Thommes, Pacific Oaks Research, Los Angeles, California, Mary Albrecht, Department of Medicine, Harvard University, Boston, Massachusetts and Kathryn Real, Abbott Laboratories, Abbott Park, Illinois, USA also contributed to this work.

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Abstract

Objective: To evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals.

Design: Prospective, randomized, double-blind, multicenter.

Methods: Eligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68).

Results: Mean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 × 106/l and 310 × 106/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50–100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound.

Conclusions: ABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.

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Introduction

Antiretroviral therapy with HIV-1 protease inhibitors is associated with dramatic and often sustained declines in plasma HIV-1 RNA levels, as well as improvement in immunologic status [1–5]. This treatment effect has resulted in a significant reduction in the incidence of opportunistic diseases and improvement in survival [5–8]. Despite these outcomes, clinical trials evaluating antiretroviral regimens containing a protease inhibitor and two nucleoside analog reverse transcriptase inhibitors have shown that plasma HIV-1 RNA is suppressed to levels below 50 copies/ml for only approximately one-half of patients by intent-to-treat (ITT) analyses after 24 or more weeks of therapy [9,10]. Although the reasons for treatment failure are multiple, currently available protease inhibitors exhibit marginal pharmacokinetics with trough plasma concentrations falling close to or below the levels required to fully inhibit replication of wild-type HIV-1 in vitro[11]. There is currently an unmet need for antiretroviral agents and regimens that combine marked and sustained efficacy, sufficient tolerability and ease of use.

ABT-378 is a novel HIV-1 protease inhibitor that is approximately 10 times more potent than ritonavir in vitro[12]. ABT-378 is extremely sensitive to pharmacokinetic enhancement by low doses of ritonavir, an inhibitor of the cytochrome P450 3A isoenzyme. (In vitro Ki = 0.013 nM compared to Ki = 0.14 nM for indinavir) [13]. When ABT-378 was co-administered with low doses of ritonavir (ABT-378/r) in phase I trials, the resultant steady-state plasma trough concentrations of ABT-378 were 50–100-fold greater than the EC50 (effective concentration to inhibit 50%) for wild-type HIV, corrected for plasma protein binding [14,15]. At the doses administered with ABT-378, ritonavir is unlikely to contribute significantly to antiviral activity based on drug levels achieved in pharmacokinetic studies which are well below estimated in vivo inhibitory concentrations [16].

The objective of this dose-ranging study was to assess the antiviral activity and safety of ABT-378/r in combination with stavudine and lamivudine, in antiretroviral-naive HIV-infected individuals.

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Methods

Study design

This study was a prospective, randomized, double-blind, multicenter clinical trial. Two groups were enrolled sequentially. Three different dose combinations of ABT-378 and ritonavir were used to evaluate safety and efficacy across a range of ABT-378 plasma concentrations achieved through ritonavir pharmacokinetic enhancement. In Group I, patients were randomized to receive either 200 mg ABT-378 with 100 mg ritonavir (ABT-378/r 200/100 mg) or 400 mg ABT-378 with 100 mg ritonavir (ABT-378/r 400/100 mg) orally every 12 h. During the first 2 weeks of therapy all doses were either directly observed by study personnel or monitored by telephone call. At week 3, stavudine 40 mg orally and lamivudine 150 mg orally every 12 h were added. Once all patients were enrolled in group I and a preliminary safety analysis had been performed, enrollment in group II began. Patients in group II were randomized to receive ABT-378/r at either 400/100 mg or 400/200 mg orally every 12 h plus standard doses of stavudine and lamivudine.

Study visits occurred at least monthly for the first 24 weeks and quarterly thereafter. Plasma HIV-1 RNA measurements were performed at all visits using the Roche Amplicor HIV-1 Monitor [Roche, Branchburg, New Jersey, USA; limit of quantitation (LOQ), 400 copies/ml] and the investigational Abbott Laboratories LCx HIV RNA quantitative assay [Abbott Laboratories, Abbott Park, Illinois, USA; LOQ, 50 copies/ml). CD4 and CD8 cell counts, hematology and clinical chemistry evaluations were performed at each study visit. In a subset of 45 patients, plasma samples were collected for pharmacokinetic analyses of ABT-378 and ritonavir over a 12-h dosing interval following the morning dose at week 3 (group I), week 4 (group II), and week 24 (both groups).

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Inclusion/exclusion criteria

Eligibility requirements included: no prior antiretroviral therapy, age ≥ 18 years, baseline plasma HIV-1 RNA > 5000 copies/ml, no acute illness, Karnofsky score ≥ 70, no active substance abuse, and the ability to comply with study procedures. Exclusion criteria included hemoglobin < 8.5 g/dl, absolute neutrophil count < 1000 × 106 cells/l, platelet count < 50 000 × 106/l, alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 times the upper limit of normal, creatinine > 1.5 times the upper limit of normal, and fasting triglycerides > 400 mg/dl. Women were excluded if pregnant or lactating and had to agree to use barrier birth control methods. Patients co-infected with hepatitis B and/or C virus were excluded from group I. All patients agreed to and signed an Institutional Review Board-approved informed consent form.

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Statistical analysis

The sample sizes were calculated to provide power to detect uncommon adverse events. For example, the sample sizes in group I and group II provided 82% and 83% power respectively to detect at least one adverse event if the true underlying event rates were 10% and 5% respectively.

All patients who received at least one dose of study drug were included in the analyses. Baseline demographic and disease characteristics were compared using a one-way analysis of variance and Fisher's exact test. The primary efficacy variables were the proportion of patients with plasma HIV-1 RNA below the LOQ (400 copies/ml) at week 24 and the duration of virologic response through week 48. ITT and on-treatment methods were used to analyze the proportion of patients with plasma HIV-1 RNA below the LOQ. The ITT analysis [missing value = failure (M = F)] considered any patient with a missing value at a visit for any reason as a treatment failure. On-treatment analyses excluded missing values and those obtained during treatment interruption of at least 3 days. Fisher's exact test was used to test whether there was no difference between dose groups in the proportion of subjects with HIV RNA level below the LOQ at each visit. The Cox proportional hazards model was used to test for differences between dose groups in the time to loss of virologic response. Adverse events were summarized using COSTART V [17]. The relative risk of grade III/IV liver enzyme elevations based on baseline hepatitis serology was computed.

Pharmacokinetic parameters for ABT-378 and ritonavir [Cmax, pre-morning dose concentration (trough level or Ctrough), area under the plasma concentration time curve for a dosing interval (AUC12), and half-life over a 12-h dosing interval (t1/2)] were determined by non-compartmental methods. Repeated measures analyses using a mixed linear model with effects of regimen, week and their interaction were performed to examine if the pharmacokinetic parameters changed over time. All reported P-values are based on two-sided tests of significance.

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Results

Baseline characteristics

A total of 100 patients participated, 32 in group I and 68 in group II. The groups were well-balanced for sex, age, race, ethnicity, risk factor for HIV-1 infection, and time since HIV-1 diagnosis. The mean age was 35 years, 96% were male, 70% were Caucasian and 30% were African–American. The mean time since diagnosis of HIV-1 infection was 2.3 years.

There were no significant differences in the mean baseline plasma HIV-1 RNA levels or CD4 cell counts for patients enrolled into either of the treatment arms in groups I or II. Overall, the mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml in both groups. The mean baseline CD4 cell count was 398 × 106/l and 310 × 106/l for patients enrolled in groups I and II respectively (Table 1).

Table 1
Table 1
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Antiviral activity

A rapid decline in plasma HIV-1 RNA was observed across all treatment arms and was sustained through week 48 with a mean reduction from baseline of 2.23 log10 copies/ml. At week 3, the mean decrease from baseline in HIV-1 RNA was −1.85 log10 copies/ml for patients receiving ABT-378/r alone in group I. The slope of HIV-1 RNA decay from baseline to week 2 in patients who initiated ABT-378/r alone was similar to that in patients who initiated all three drugs simultaneously in group II (−1.73 log10 copies/ml versus −1.68 log10 copies/ml). The lack of a week 3 study visit for group II precluded direct comparison with group I at that time point. All patients, except one who discontinued therapy early in the study, had a decline in plasma HIV-1 RNA to < 400 copies/ml.

The median times to achieve < 400 copies/ml were 43 and 42 days for group I (200/100 mg and 400/100 mg) and 56 and 57 days for group II (400/100 mg and 400/200 mg), respectively. The corresponding values for median time to achieve < 50 copies/ml were 77 and 72 days for group I (200/100 mg and 400/100 mg) and 74 and 85 days for group II (400/100 mg and 400/200 mg) respectively. Patients with baseline plasma HIV-1 RNA > 100 000 copies/ml generally took longer to achieve a viral load < 400 copies/ml than patients with baseline values < 100 000 copies/ml (median time to < 400 copies/ml 12 weeks versus 4 weeks respectively). Response rates were not significantly different at week 20 and thereafter.

In the ITT M = F analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml. 79%) of patients in groups I and II, respectively. Overall at week 48, 85% of patients had HIV-1 RNA < 400 copies/ml by ITT analysis, and 92% by on-treatment analysis. Using the Abbott LCx viral load assay, 78% of patients overall had HIV-1 RNA < 50 copies/ml at week 48 (ITT). Plots of antiviral activity by dose level are presented in Fig. 1.

Fig. 1
Fig. 1
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Response rates varied minimally between dose assignments in groups I and II at time points through week 48. At week 48 only, fewer patients achieved HIV-1 RNA < 50 copies/ml in the 400/100 mg dose arm in group I than in the 200/100 mg dose arm [50% (8/16) versus 100% (16/16) by ITT analysis;P = 0.002]. This observed rate of antiviral activity in the 400/100 mg dose arm in group I was also lower than that observed with the same dose level in group II at week 48 [86% (30/35) with HIV-1 RNA < 50 copies/ml by ITT]. Of the eight patients in the 400/100 mg arm in group I with HIV-1 RNA > 50 copies/ml at week 48, six patients had values < 50 copies/ml at their subsequent evaluation. Results were not significantly different for the proportion of patients with HIV-1 RNA < 400 copies/ml [100% (16/16) of the patients in the 200/100 mg arm and 81% (13/16) of the patients in the 400/100 arm;P = 0.226]. A similar result was seen between dose arms in group II at week 48 only in the on-treatment analysis of patients with HIV-1 RNA < 400 copies/ml [100% (32/32) of the patients in the 400/100 mg arm and 80% (24/30) of the patients in the 400/200 mg arm;P = 0.01]. This difference was not significant in the analysis of proportion of patients with HIV-1 RNA < 50 copies/ml at week 48. No significant differences between the dosing arms was noted at other times or in a time-to-virologic failure analysis through week 48.

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Immunologic changes

Substantial increases in the mean CD4 cell count were observed in all treatment arms from week 4 onwards, with no significant differences between treatment arms (Fig. 2). At week 48, the mean CD4 cell count had increased from baseline values by 244 × 106 and 213 × 106 cells/l in group I and group II respectively.

Fig. 2
Fig. 2
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Pharmacokinetics

ABT-378 and ritonavir pharmacokinetic parameters (mean ± SD) for the three dosing regimens at weeks 3/4 and 24 are presented in Table 2. ABT-378 and ritonavir AUC, Cmax, and Ctrough did not differ significantly between week 3/4 and week 24 for any of the dosing groups (P > 0.05;Table 2). At week 3/4, mean steady state ABT-378 trough concentrations were 53–103-fold more than the protein binding-adjusted EC50 of ABT-378 (0.07 μg/ml) for wild-type HIV-1 (Fig. 3) [18]. For the 400/100 mg regimen, mean ritonavir concentrations were below the protein binding-adjusted EC50 against wild-type HIV-1 for ritonavir throughout the dosing interval.

Fig. 3
Fig. 3
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Table 2
Table 2
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Adverse events

No discontinuations due to study drug-related clinical or laboratory adverse events occurred during the first 48 weeks of the study. The overall adherence rate was 98% based on patient-reported dose interruptions. Early termination from the study occurred in seven patients because of loss to follow up (two), non-compliance (two), personal reasons (one), development of an HIV-related event (lymphoma; one), and patient relocation (one). ABT-378/r was well tolerated with the most common adverse events of at least moderate severity related to study drug being diarrhea, nausea, and abnormal stools (Table 3).

Table 3
Table 3
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While gastrointestinal adverse events occurred most frequently during the first 2 months of treatment, the prevalence of these events decreased over time with continued therapy. The incidence of adverse events was similar between treatment arms, with the exception of nausea and vomiting. In group II patients, moderate-to-severe nausea attributed to ABT-378/r occurred in 10 out of 33 (30%) patients receiving the 400/200 mg dose compared to three out of 35 (9%) receiving the 400/100 mg dose (P = 0.031). In addition, moderate-to-severe vomiting was more common in the 400/200 mg dose group (12%) than the 400/100 mg dose group (0%;P = 0.05).

The most common grade III/IV laboratory abnormalities reported cumulatively through 48 weeks included elevations of triglycerides, cholesterol, and AST/ALT (Table 3). At week 48, total cholesterol and triglyceride levels were significantly higher than at baseline, with mean increases of 49 mg/dl and 111 mg/dl respectively. Of note, blood samples for lipid testing were collected without respect to fasting. The majority of patients with grade III/IV triglyceride (8/11) or cholesterol (6/10) levels had elevated baseline levels (> 213 mg/dl and > 200 mg/dl respectively). Only two out of ten patients with grade III/IV total cholesterol levels and two of the 11 patients with grade III/IV triglyceride levels had grade III/IV values persisting at their final measurement, including one patient with grade III/IV values for both lipids at week 48. Sixty-eight percent (56/82) of patients with baseline cholesterol values < 200 mg/dl did not develop a cholesterol value > 240 mg/dl (grade II) during ABT-378/r therapy. Similarly, 73% (66/90) of patients with baseline triglycerides < 250 mg/dl did not develop a triglyceride value > 400 mg/dl (grade II) during ABT-378/r therapy. Eight patients developed a grade III/IV elevation in AST or ALT. Four out of the eleven patients with serologic evidence of hepatitis B surface antigen or hepatitis C virus antibodies at baseline experienced grade III/IV AST or ALT elevations while on study therapy. Hepatitis B surface antigen or hepatitis C virus antibody seropositivity at baseline was associated with an eightfold increased relative risk of developing a grade III/IV AST or ALT while on study medication (P < 0.05). The majority of grade III/IV AST/ALT elevations returned to baseline with continued dosing and no patient discontinued ABT-378/r as a consequence of such elevations. No patients developed clinical hepatitis attributed to ABT-378/r.

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Discussion

The results of this study demonstrate that ABT-378/r therapy is highly potent, durable and well tolerated when administered concomitantly with two nucleoside analog reverse transcriptase inhibitors in antiretroviral-naive HIV-1 infected individuals. The intrinsic antiviral activity of ABT-378/r was illustrated by the magnitude of the decline in plasma HIV-1 RNA in the first 3 weeks of dosing in group I, where ABT-378/r was given as a single agent. Thus, the initial decline in HIV-1 RNA in group I patients was similar to that observed in group II patients, in whom the combination regimen of ABT-378/r, stavudine and lamivudine was initiated simultaneously. The overall efficacy and durability of the ABT-378/r dosing regimens used in this study were demonstrated by the high proportion of patients who experienced a decrease in plasma HIV-1 RNA to < 400 copies/ml at any time (99%) and after 48 weeks (85% by ITT and 92% on-treatment). Although statistically significant differences were observed between dose assignments within groups I and II at the 48 week time point, these differences were not reflected at other time points nor in a time-to-virologic failure analysis through week 48. These observations are probably due to the relatively small numbers within the dosing arms rather than intrinsic differences in antiviral activity.

The results of this study compare very favorably to those obtained from other clinical trials in which treatment-naive patients have been randomized to protease inhibitor-based treatment regimens. In a recent meta-analysis of 18 clinical trials in antiretroviral-naive patients that included protease inhibitor-based therapies, the proportion of patients with plasma HIV-1 RNA values < 400 copies/ml or < 50 copies/ml by ITT analysis at 24 weeks was 63% and 49% respectively [9]. In reported ITT analyses of clinical trials evaluating protease inhibitor-based treatment regimens through 48 weeks, the proportion of patients with plasma HIV-1 RNA levels < 400–500 copies/ml or < 50 copies/ml is in the range 30–60% and 35–47% respectively [3,19–23]. As the patients in this phase II study of ABT-378/r had a high mean plasma HIV-1 RNA at baseline as well as a wide range of CD4 cell counts, these results should be applicable to a broad segment of the treatment-naive, HIV-1 infected population.

The high proportion of subjects achieving maximal viral suppression (< 50 copies/ml) in this study probably reflects several factors: the high in vitro potency of ABT-378, the favorable pharmacokinetic profile achieved when it is dosed with ritonavir, and a tolerability profile that probably facilitates medication adherence. The ABT-378/r regimens evaluated used ritonavir doses that result in low ritonavir exposures, generally below those required for antiviral activity.

The mean trough plasma concentrations of ABT-378 were 50–100-fold higher than the protein binding-corrected EC50 for wild-type HIV-1. These ratios of drug levels to inhibitory concentrations are substantially higher than those seen with currently available protease inhibitors administered at their approved doses and frequency, which range from one- to four-fold above the protein binding-corrected EC50 for wild-type virus at trough [11]. These ratios can be improved by the coadministration of ritonavir; for example, a regimen of indinavir 800 mg and ritonavir 100 mg dosed twice daily provides indinavir trough levels approximately 26-fold higher than the EC50 for wild-type HIV, corrected for protein binding. However, the optimal dosing, safety, and efficacy of these regimens has not been well studied [18,24]. As protease inhibitor levels have been demonstrated to correlate with the development of viral mutations and subsequent resistance and are predictive of clinical virologic response [25–27], the pharmacokinetic profile of ABT-378/r may translate into prolonged durability of response. Therefore, when selecting a dose level of ABT-378/r for further clinical development, an attempt was made to maximize trough levels while maintaining an acceptable tolerability profile.

The favorable tolerability profile of ABT-378/r is reflected by the fact that no patient discontinued ABT-378/r because of a study drug-related adverse event or laboratory abnormality through 48 weeks of treatment. Higher rates of nausea and vomiting were seen in the 400/200 mg dose arm compared to the 400/100 mg dose arm, which factored into the decision to select the 400/100 mg dose for further clinical development. Increases in either serum cholesterol and/or triglycerides to grade III/IV levels occurred in 16% of patients. Most grade III/IV lipid elevations did not persist at this level and had decreased by week 48 with continued dosing. This observation may have been secondary to multiple factors, including the use of lipid-lowering agents in two patients, diet, or fasting prior to obtaining subsequent measurement. While elevations in serum ALT and AST were observed in a minority of patients, no patient was required to discontinue study medications nor did any patient develop clinical hepatitis attributed to ABT-378/r. The majority of elevated transaminase values returned to baseline levels with continued dosing. Patients with chronic hepatitis B and/or hepatitis C were more likely to experience significant increases in hepatic transaminase levels.

In conclusion, ABT-378 is a potent HIV-1 protease inhibitor that is exquisitely sensitive to pharmacokinetic enhancement by low doses of ritonavir. This results in ABT-378 drug levels that are well in excess of required inhibitory concentrations for wild-type HIV throughout the entire dosing interval. The drug levels achieved with ABT-378/r should create a pharmacologic barrier to viral resistance, leading to an antiviral regimen that would be expected to maintain significant durability of response beyond 48 weeks of treatment. The 400/100 mg dose level of ABT-378/r has been selected for further clinical development because this combination allows for maximization of ABT-378 plasma levels while maintaining a favorable tolerability profile.

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Acknowledgements

The authors thank the following for their contributions to this study: C. Achenbach, A. Belschner, J. Bruce, S. Canmann, P. Couey, T. Enstrom, H. Fitch, General Clinical Research Center at Northwestern University; J. Giner, M. Glesby, K. Gu, L. Harmon, C. Marcus, S. Myers, E. Narkiewicz, PPD Development; B. Putnam, T. Sarracco-Gerace, B. Sepcie, N. Smith, R. Stryker.

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References

1. Gulick RM, Mellors JW, Havlir D. et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997, 337: 734 –739.

2. Gulick RM, Mellors JW, Havlir D. et al. Simultaneous vs. sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up. JAMA 1998, 280: 35 –41.

3. Murphy RL, Gulick RM, DeGruttola V. et al. Treatment with amprenavir alone or with zidovudine and lamivudine in adults with human immunodeficiency virus infection. J Infect Dis 1999, 179: 808 –816.

4. Mitsuyasu RT, Skolnik PR, Cohen SR. et al. Activity of the soft gelatin formulation of saquinavir in combination therapy in antiretroviral-naive patients. AIDS 1998, 12: F103 –F109.

5. Cameron DW, Heath-Chiozzi M, Danner S. et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 1998, 351: 543 –549.

6. Palella FJ, Delaney KM, Moorman AC. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998, 338: 853 –860.

7. Mouton Y, Alfandare S, Valette M. et al. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centers. AIDS 1997, 11: F101 –F105.

8. Hammer SM, Squires KE, Hughes MD. et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997, 337: 725 –733.

9. Bartlett J, Demasi R, Quinn J, Moxham C, Rousseau F. Meta-analysis of efficacy of triple combination therapy in antiretroviral-naive HIV-1-infected adults.Seventh Conference on Retroviruses and Opportunistic Infections. San Francisco, January–February 2000 [abstract 519].

10. Montaner JSG, Hogg R, Raboud J, Harrigan R, O'Shaughnessy M. Antiretroviral treatment in 1998. Lancet 1998, 352: 1919 –1922.

11. Condra JH, Petropoulos CJ, Ziermann R. et al. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J Infect Dis 2000, 182: 758 –765.

12. Sham HL, Kempf DJ, Molla A. et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 1998, 42: 3218 –3224.

13. Kumar GN, Dykstra J, Roberts EM. et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug-drug interaction. Drug Metab Dispos 1999, 27: 902 –908.

14. Lal R, Hsu A, Chen P, et al. Single dose pharmacokinetics of ABT-378 in combination with ritonavir. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, September–October 1997 [abstract I-194].

15. Lal R, Hsu A, Granneman GR, et al. Multiple dose safety, tolerability and pharmacokinetics of ABT-378 in combination with ritonavir.Fifth Conference on Retrovirus and Opportunistic Infections. Chicago, February 1998 [abstract 647].

16. Bertz R, Lam W, Brun S, et al. Multiple-dose pharmacokinetics (PK) of ABT-378/ritonavir (ABT-378/r) in HIV+ subjects.39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, September 1999 [abstract 0327].

17. Division of Drug and Biological Products Experience, Food and Drug Administration. Coding Symbols for Thesaurus of Adverse Reaction Terms. 5th Edn. Place of publication: FDA: Rockville; 1996.

18. Molla A, Vasavanonda S, Kumar G. et al. Human serum alternates the activity of 1996 protease inhibitors toward wild-type human immunodeficiency virus. Virology 1998, 250: 255 –262.

19. Squires KE. An open-label, randomized comparative study of stavudine (d4T) + lamivudine (3TC) + indinavir (IDV) versus zidovudine (ZDV) + 3TC + IDV in treatment of HIV-infected patients (START I). AIDS 2000, 14: 1591 –1600.

20. Eron JJ, Murphy RL, Peterson D. et al. A comparison of stavudine, didanosine, and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START I). AIDS 2000, 14: 1601 –1610.

21. Staszewski S, Morales-Ramirez J, Tashima KT. et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999, 341: 1865 –1873.

22. The AVANTI Study Group. AVANTI 2. :Randomized, double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudine versus zidovudine plus lamivudine plus indinavir in HIV-infected antiretroviral-naive patients. AIDS 2000, 14: 367 –374.

23. Medical Economics Company. Agenerase (amprenavir) capsules. In Physicians’ Desk Reference. 54th Edn. Montvale New Jersey: Medical Economics Company; 2000: 1140 –1145.

24. Mallolas J, Blanco JL, Sarasa M et al.A dose finding study of once-daily indinavir/ritonavir plus combivir in HIV infected patients.First International Workshop on Clinical Pharmacology of HIV Therapy. Noordwijk, March 2000 [abstract 2.14].

25. Molla A, Korneyeva M, Gao Q. et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nature Med 1996, 2: 760 –766.

26. Acosta EP, Havlir DV, Richman DD, et al. Pharmacodynamics (PD) of indinavir (IDV) in protease-naive HIV-infected patients receiving ZDV and 3TC.Seventh Conference on Retroviruses and Opportunistic Infections. San Francisco, January–February 2000 [abstract 455].

27. Durant J, Clevenbergh P, Halfon P. et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet 1999, 353: 2195 –2199.

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Antimicrobial Agents and Chemotherapy
Virological and pharmacological parameters predicting the response to lopinavir-ritonavir in heavily protease inhibitor-experienced patients
Marcelin, AG; Cohen-Codar, I; King, MS; Colson, P; Guillevic, E; Descamps, D; Lamotte, C; Schneider, V; Ritter, J; Segondy, M; Peigue-Lafeuille, H; Morand-Joubert, L; Schmuck, A; Ruffault, A; Palmer, P; Chaix, ML; Mackiewicz, V; Brodard, V; Izopet, J; Cottalorda, J; Kohli, E; Chauvin, JP; Kempf, DJ; Peytavin, G; Calvez, V
Antimicrobial Agents and Chemotherapy, 49(5): 1720-1726.
10.1128/AAC.49.5.1720-1726.2005
CrossRef
AIDS Research and Human Retroviruses
Immunological changes after highly active antiretroviral therapy with lopinavir-ritonavir in heavily pretreated HIV-Infected children
Resino, S; Galan, I; Perez, A; Ramos, JT; Bellon, JM; Fontelos, PM; De Jose, MI; Gutierrez, MDG; Cabrero, E; Munoz-Fernandez, MAM
AIDS Research and Human Retroviruses, 21(5): 398-406.

Antimicrobial Agents and Chemotherapy
Early Postpartum Pharmacokinetics of Lopinavir Initiated Intrapartum in Thai Women
Cressey, TR; Van Dyke, R; Jourdain, G; Puthanakit, T; Roongpisuthipong, A; Achalapong, J; Yuthavisuthi, P; Prommas, S; Chotivanich, N; Maupin, R; Smith, E; Shapiro, DE; Mirochnick, M
Antimicrobial Agents and Chemotherapy, 53(5): 2189-2191.
10.1128/AAC.01091-08
CrossRef
Jaids-Journal of Acquired Immune Deficiency Syndromes
Reviving protease inhibitors: New data and more options
Murphy, RL
Jaids-Journal of Acquired Immune Deficiency Syndromes, 33(): S43-+.

Janac-Journal of the Association of Nurses in AIDS Care
Cardiovascular considerations in patients treated with HIV protease inhibitors
Colagreco, JP
Janac-Journal of the Association of Nurses in AIDS Care, 15(1): 30-41.
10.1177/1055329003256922
CrossRef
Expert Review of Anti-Infective Therapy
Lopinavir plus ritonavir: a novel protease inhibitor combination for HIV infections
Tan, D; Walmsley, S
Expert Review of Anti-Infective Therapy, 5(1): 13-28.
10.1586/14787210.5.1.13
CrossRef
Journal of Antimicrobial Chemotherapy
Reporting of adverse events in randomized controlled trials of highly active antiretroviral therapy: systematic review
Chowers, MY; Gottesman, BS; Leibovici, L; Pielmeier, U; Andreassen, S; Paul, M
Journal of Antimicrobial Chemotherapy, 64(2): 239-250.
10.1093/jac/dkp191
CrossRef
Antiviral Therapy
The NIQ of lopinavir is predictive of a 48-week virological response in highly treatment-experienced HIV-1-infected subjects treated with a lop inavir/ritonavir-containing regimen
Castagna, A; Gianotti, N; Galli, L; Danise, A; Hasson, H; Boerr, E; Hoetelmans, R; Nauwelaers, D; Lazzarin, A
Antiviral Therapy, 9(4): 537-543.

Drugs
Lopinavir/ritonavir - A review of its use in the management of HIV infection
Cvetkovic, RS; Goa, KL
Drugs, 63(8): 769-802.

Antiviral Therapy
Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy
Boffito, M; Acosta, E; Burger, D; Fletcher, CV; Flexner, C; Garaffo, R; Gatti, G; Kurowski, M; Perno, CF; Peytavin, G; Regazzi, M; Back, D
Antiviral Therapy, 10(3): 375-392.

AIDS Patient Care and Stds
Failure of modified directly observed therapy combined with therapeutic drug monitoring to enhance antiretroviral adherence in a patient with major depression
Goicoechea, M; Best, B; Seefried, E; Wagner, G; Capparelli, E; Haubrich, R
AIDS Patient Care and Stds, 20(4): 233-237.

Hiv Medicine
Treatment outcomes amongst previously antiretroviral-naive HIV-infected patients starting lopinavir/ritonavir-containing antiretroviral regimens at the Royal Free Hospital
Smith, CJ; Phillips, AN; Youle, MS; Sabin, CA; Lampe, FC; Tsintas, R; Tyrer, M; Johnson, MA
Hiv Medicine, 8(1): 55-63.

Future Lipidology
Cellular mechanisms of lipodystrophy induction by HIV protease inhibitors
Zhou, HP; Pandak, WM; Hylemon, PB
Future Lipidology, 1(2): 163-172.
10.2217/17460875.1.2.163
CrossRef
AIDS Patient Care and Stds
Overcoming obstacles to the success of protease inhibitors in highly active antiretroviral therapy regimens
Moyle, G
AIDS Patient Care and Stds, 16(): 585-597.

Antiviral Therapy
Analysis of virological efficacy in trials of antiretroviral regimens: drawbacks of not including viral load measurements after premature discontinuation of therapy
Kirk, O; Pedersen, C; Law, M; Gulick, RM; Moyle, G; Montaner, J; Eron, JJ; Phillips, AN; Lundgren, JD
Antiviral Therapy, 7(4): 271-281.

Expert Opinion on Pharmacotherapy
Lopinavir/ritonavir in the treatment of human immunodeficiency virus infection
Kaplan, SS; Hicks, CB
Expert Opinion on Pharmacotherapy, 6(9): 1573-1585.
10.1517/14656566.6.9.1573
CrossRef
Bmc Infectious Diseases
Effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children: 3 years of follow-up. Long-term response to nelfinavir in children
Resino, S; Larru, B; Bellon, JM; Resino, R; de Jose, MI; Navarro, M; Leon, JA; Ramos, JT; Mellado, MJ; Munoz-Fernandez, MA
Bmc Infectious Diseases, 6(): -.
ARTN 107
CrossRef
Clinical Infectious Diseases
Methods for integration of pharmacokinetic and phenotypic information in the treatment of infection with human immunodeficiency virus
Acosta, EP; King, JR
Clinical Infectious Diseases, 36(3): 373-377.

Journal of Virology
Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected subjects failing lopinavir- and ritonavir-based therapy: Mutation patterns and baseline correlates
Mo, HM; King, MS; King, K; Molla, A; Brun, S; Kempf, DJ
Journal of Virology, 79(6): 3329-3338.
10.1128/JVI.79.6.3329-3338.2005
CrossRef
Expert Opinion on Pharmacotherapy
Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients
Gazzard, BG
Expert Opinion on Pharmacotherapy, 7(6): 793-802.
10.1517/14656566.7.6.793
CrossRef
Enfermedades Infecciosas Y Microbiologia Clinica
Lipid alterations and cardiovascular risk associated with antiretroviral therapy
Masia-Canuto, M; Bernal-Morell, E; Gutierrez-Rodero, F
Enfermedades Infecciosas Y Microbiologia Clinica, 24(): 637-648.

Jaids-Journal of Acquired Immune Deficiency Syndromes
Protease inhibitor-based regimens for HIV therapy - Safety and efficacy
Walmsley, S
Jaids-Journal of Acquired Immune Deficiency Syndromes, 45(): S5-S13.

Antimicrobial Agents and Chemotherapy
Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors
Robbins, BL; Capparelli, EV; Chadwick, EG; Yogev, R; Serchuck, L; Worrell, C; Smith, ME; Alvero, C; Fenton, T; Heckman, B; Pelton, SI; Aldrovandi, G; Borkowsky, W; Rodman, J; Havens, PL
Antimicrobial Agents and Chemotherapy, 52(9): 3276-3283.
10.1128/AAC.00224-08
CrossRef
Drug Metabolism and Disposition
Binding of Lopinavir to Human alpha(1)-Acid Glycoprotein and Serum Albumin
Gulati, A; Boudinot, FD; Gerk, PM
Drug Metabolism and Disposition, 37(8): 1572-1575.
10.1124/dmd.109.026708
CrossRef
Hiv Medicine
A prospective, controlled study assessing the effect of lopinavir on amprenavir concentrations boosted by ritonavir
Mauss, S; Scholten, S; Wolf, E; Berger, F; Schmutz, G; Jaeger, H; Kurowski, M; Rockstroh, JK
Hiv Medicine, 5(1): 15-17.

Antiviral Therapy
Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study
Currier, J; Lazzarin, A; Sloon, L; Clumeck, N; Slim, J; McCgrty, D; Steel, H; Kleim, JP; Bonny, T; Millard, J
Antiviral Therapy, 13(2): 297-306.

Annals of Internal Medicine
Guidelines for using antiretroviral agents among HIV-infected adults and adolescents - The panel on clinical practices for treatment of HIV
Dybul, M; Fauci, AS; Bartlett, JG; Kaplan, JE; Pau, AK
Annals of Internal Medicine, 137(5): 381-433.

Hiv Medicine
Impact of antiretroviral choice on hypercholesterolaemia events: the role of the nucleoside reverse transcriptase inhibitor backbone
Jones, R; Sawleshwarkar, S; Michailidis, C; Jackson, A; Mandalia, S; Stebbing, J; Bower, M; Nelson, M; Gazzard, BG; Moyle, GJ
Hiv Medicine, 6(6): 396-402.

Pharmacotherapy
Pharmacokinetics of an indinavir-ritonavir-fosamprenavir regimen in patients with human immunodeficiency virus
Ofotokun, I; Acosta, EP; Lennox, JL; Pan, Y; Easley, KA
Pharmacotherapy, 28(1): 74-81.

Journal of Infectious Diseases
Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients
Benson, CA; Deeks, SG; Brun, SC; Gulick, RM; Eron, JJ; Kessler, HA; Murphy, RL; Hicks, C; King, M; Wheeler, D; Feinberg, J; Stryker, R; Sax, PE; Riddler, S; Thompson, M; Real, K; Hsu, A; Kempf, D; Japour, AJ; Sun, E
Journal of Infectious Diseases, 185(5): 599-607.

Journal of Antimicrobial Chemotherapy
Safety and antiviral activity of lopinavir/ritonavir-based therapy in human immunodeficiency virus type 1 (HIV-1) infection
Kaplan, SS; Hicks, CB
Journal of Antimicrobial Chemotherapy, 56(2): 273-276.
10.1093/jac/dki209
CrossRef
Clinical Infectious Diseases
A review of low-dose ritonavir in protease inhibitor combination therapy
Cooper, CL; van Heeswijk, RPG; Gallicano, K; Cameron, DW
Clinical Infectious Diseases, 36(): 1585-1592.

Netherlands Journal of Medicine
Antiretroviral therapy adults infected in previously untreated with the human immunodeficiency virus type I: established and potential determinants of virological outcome
Lowe, SH; Prins, JM; Lange, JMA
Netherlands Journal of Medicine, 62(): 424-440.

Journal of Infection
Lopinavir/ritonavir combination and total/HDL cholesterol ratio
Valerio, L; Fontas, E; Pradier, C; Lavrut, T; Garraffo, R; Dunais, B; Cua, E; Dellamonica, P
Journal of Infection, 50(3): 229-235.
10.1016/j.jinf.2004.01.014
CrossRef
Antiviral Therapy
The plasma and intracellular steady-state pharmacokinetics of lopinavir/ritonavir in HIV-1-infected patients
Crommentuyn, KML; Mulder, JW; Mairuhu, ATA; van Gorp, ECM; Meenhorst, PL; Huitema, ADR; Beijnen, JH
Antiviral Therapy, 9(5): 779-785.

Current Computer-Aided Drug Design
Current development on HIV-1 protease inhibitors
Aruksakunwong, O; Promsri, S; Wittayanarakul, K; Nimmanpipug, P; Lee, VS; Wijitkosoom, A; Sompornpisut, P; Hannongbua, S
Current Computer-Aided Drug Design, 3(3): 201-213.

Future Virology
Lopinavir/ritonavir: towards simplifying therapy in HIV infection
Kaplan, SS; Hicks, CB
Future Virology, 1(3): 293-304.
10.2217/17460794.1.3.293
CrossRef
Journal of Antimicrobial Chemotherapy
Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children
Puthanakit, T; van der Lugt, J; Bunupuradah, T; Ananworanich, J; Gorowara, M; Phasomsap, C; Jupimai, T; Boonrak, P; Pancharoen, C; Burger, D; Ruxrungtham, K
Journal of Antimicrobial Chemotherapy, 64(5): 1080-1086.
10.1093/jac/dkp322
CrossRef
Journal of Virology
Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients
Kempf, DJ; Isaacson, JD; King, MS; Brun, SC; Xu, Y; Real, K; Bernstein, BM; Japour, AJ; Sun, E; Rode, RA
Journal of Virology, 75(): 7462-7469.

Journal of Immunological Methods
Quantification of plasma and intracellular levels of the HIV protease inhibitor ritonavir by competitive ELISA
Akeb, F; Ferrua, B; Creminon, C; Roptin, C; Grassi, J; Nevers, MC; Guedj, R; Garraffo, R; Duval, D
Journal of Immunological Methods, 263(): 1-9.
PII S0022-1759(02)00026-1
CrossRef
Medicinal Research Reviews
New anti-HIV agents and targets
De Clercq, E
Medicinal Research Reviews, 22(6): 531-565.

AIDS
Clinical use of lopinavir/ritonavir in a salvage therapy setting: pharmacokinetics and pharmacodynamics
Boffito, M; Arnaudo, I; Raiteri, R; Bonora, S; Sinicco, A; Di Garbo, A; Reynolds, HE; Hoggard, PG; Back, DJ; Di Perri, G
AIDS, 16(): 2081-2083.

Deutsche Medizinische Wochenschrift
Antiretroviral therapy of HIV infection. German-Austrian guidelines (July 2002)
Brockmeyer, NH
Deutsche Medizinische Wochenschrift, 128(): S7-S18.

Protein Science
Structural analysis of an HIV-1 protease I47A mutant resistant to the protease inhibitor lopinavir
Kagan, RM; Shenderovich, MD; Heseltine, PNR; Ramnarayan, K
Protein Science, 14(7): 1870-1878.
10.1110/ps.051347405
CrossRef
Bmc Infectious Diseases
Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study
Yilmaz, A; Fuchs, D; Hagberg, L; Nillroth, U; Stahle, L; Svensson, JO; Gisslen, M
Bmc Infectious Diseases, 6(): -.
ARTN 63
CrossRef
Drugs
Lopinavir/ritonavir - A review of its use in the management of HIV infection
Oldfield, V; Plosker, GL
Drugs, 66(9): 1275-1299.

Hiv Medicine
Antiviral activity and safety of aplaviroc, a CCR5 antagonist, in combination with lopinavir/ritonavir in HIV-infected, therapy-naive patients: results of the EPIC study (CCR100136)
Yeni, P; LaMarca, A; Berger, D; Cimoch, P; Lazzarin, A; Salvato, P; Smaill, FM; Teofilo, E; Madison, SJ; Nichols, WG; Adkison, KK; Bonny, T; Millard, J; McCarty, D
Hiv Medicine, 10(2): 116-124.
10.1111/j.1468-1293.2008.00660.x
CrossRef
Annual Reports in Medicinal Chemistry, Vol 36
Chapter 24. Pharmacokinetics and design of aspartyl protease inhibitors
Thompson, LA; Tebben, AJ
Annual Reports in Medicinal Chemistry, Vol 36, 36(): 247-256.

Expert Opinion on Pharmacotherapy
Initial antiretroviral therapy in chronically-infected HIV-positive adults
Temesgen, Z; Cainelli, F; Warnke, D; Koirala, J
Expert Opinion on Pharmacotherapy, 5(3): 595-612.

Antiviral Therapy
Plasma concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and below
Verweel, G; Burger, DM; Sheehan, NL; Bergshoeff, AS; Warris, A; van der Knaap, LC; Driessen, G; de Groot, R; Hartwig, NG
Antiviral Therapy, 12(4): 453-458.

Digestive Diseases and Sciences
An overview of HIV and chronic viral hepatitis co-infection
Cooper, CL
Digestive Diseases and Sciences, 53(4): 899-904.
10.1007/s10620-007-0134-5
CrossRef
Antimicrobial Agents and Chemotherapy
In vitro antiviral interaction of lopinavir with other protease inhibitors
Molla, A; Mo, HM; Vasavanonda, S; Han, LX; Lin, CT; Hsu, QA; Kempf, DJ
Antimicrobial Agents and Chemotherapy, 46(7): 2249-2253.
10.1128/AAC.46.7.2249-2253.2002
CrossRef
Journal of Antimicrobial Chemotherapy
Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients
Zeldin, RK; Petruschke, RA
Journal of Antimicrobial Chemotherapy, 53(1): 4-9.
10.1093/jac/dkh029
CrossRef
Current Topics in Medicinal Chemistry
Peptidomimetic inhibitors of HIV protease
Randolph, JT; DeGoey, DA
Current Topics in Medicinal Chemistry, 4(): 1079-1095.

Antimicrobial Agents and Chemotherapy
Estimation of serum-free 50-percent inhibitory concentrations for human immunodeficiency virus protease inhibitors lopinavir and ritonavir
Hickman, D; Vasavanonda, S; Nequist, G; Colletti, L; Kati, WM; Bertz, R; Hsu, A; Kempf, DJ
Antimicrobial Agents and Chemotherapy, 48(8): 2911-2917.
10.1128/AAC.48.8.2911-2917.2004
CrossRef
Jama-Journal of the American Medical Association
Antiretroviral treatment for adult HIV infection in 2002 - Updated recommendations of the international AIDS Society-USA panel
Yeni, PG; Hammer, SM; Carpenter, CCJ; Cooper, DA; Fischl, MA; Gatell, JM; Gazzard, BG; Hirsch, MS; Jacobsen, DM; Katzenstein, DA; Montaner, JSG; Richman, DD; Saag, MS; Schechter, M; Schooley, RT; Thompson, MA; Vella, S; Volberding, PA
Jama-Journal of the American Medical Association, 288(2): 222-235.

Jaids-Journal of Acquired Immune Deficiency Syndromes
Cardiovascular risk associated with HIV therapy
Currier, JS
Jaids-Journal of Acquired Immune Deficiency Syndromes, 31(): S16-S23.

Clinical Infectious Diseases
Scientific and ethical considerations in trial design for investigational agents for the treatment of human immunodeficiency virus infection
Feinberg, J; Japour, AJ
Clinical Infectious Diseases, 36(2): 201-206.

AIDS Research and Human Retroviruses
Prediction of virological response to lopinavir/ritonavir using the genotypic inhibitory quotient
de Requena, DG; Gallego, O; Valer, L; Jimenez-Nacher, I; Soriano, V
AIDS Research and Human Retroviruses, 20(3): 275-278.

Antiviral Therapy
Virological success of lopinavir/ritonavir salvage regimen is affected by an lopinavir/ritonavir-related increasing number of mutations
Bongiovanni, M; Bini, T; Adorni, F; Meraviglia, P; Capetti, A; Tordato, F; Cicconi, P; Chiesa, E; Cordier, L; Cargnel, A; Landonio, S; Rusconi, S; Monforte, AD
Antiviral Therapy, 8(3): 209-214.

Antiviral Therapy
A computer-based system to aid in the interpretation of plasma concentrations of antiretrovirals for therapeutic drug monitoring
Goicoechea, M; Vidal, A; Capparelli, E; Rigby, A; Kemper, C; Diamond, C; Witt, MD; Haubrich, R
Antiviral Therapy, 12(1): 55-62.

International Journal of Infectious Diseases
Chronic viral hepatitis may diminish the gains of HIV antiretroviral therapy in sub-Saharan Africa
Cooper, CL; Mills, E; Wabwire, BO; Ford, N; Olupot-Olupot, P
International Journal of Infectious Diseases, 13(3): 302-306.
10.1016/j.ijid.2008.06.042
CrossRef
Antiviral Therapy
Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy
Kempf, DJ; Isaacson, JD; King, MS; Brun, SC; Sylte, J; Richards, B; Bernstein, B; Rode, R; Sun, E
Antiviral Therapy, 7(3): 165-174.

Journal of Antimicrobial Chemotherapy
Positive virological outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children: a prospective cohort study
Resino, S; Bellon, JM; Ramos, JT; Gonzalez-Rivera, M; de Jose, MI; Gonzalez, MI; Gurbindo, D; Mellado, MJ; Cabrero, E; Munoz-Fernandez, MA
Journal of Antimicrobial Chemotherapy, 54(5): 921-931.
10.1093/jac/dkh431
CrossRef
Antimicrobial Agents and Chemotherapy
Plasma amprenavir pharmacokinetics and tolerability following administration of 1,400 milligrams of fosamprenavir once daily in combination with either 100 or 200 milligrams of ritonavir in healthy volunteers
Ruane, PJ; Luber, AD; Wire, MB; Lou, Y; Shelton, MJ; Lancaster, CT; Pappa, KA
Antimicrobial Agents and Chemotherapy, 51(2): 560-565.
10.1128/AAC.00560-06
CrossRef
Digestive Diseases and Sciences
Inflammation and repair in viral hepatitis C
Neuman, MG; Sha, K; Esguerra, R; Zakhari, S; Winkler, RE; Hilzenrat, N; Wyse, J; Cooper, CL; Seth, D; Gorrell, MD; Haber, PS; McCaughan, GW; Leo, MA; Lieber, CS; Voiculescu, M; Buzatu, E; Ionescu, C; Dudas, J; Saile, B; Ramadori, G
Digestive Diseases and Sciences, 53(6): 1468-1487.
10.1007/s10620-007-0047-3
CrossRef
Fundamental & Clinical Pharmacology
Benefit of therapeutic drug monitoring of protease inhibitors in HIV-infected patients depends on PI used in HAART regimen - ANRS 111 trial
Duval, X; Mentre, F; Rey, E; Auleley, S; Peytavin, G; Biour, M; Metro, A; Goujard, C; Taburet, AM; Lascoux, C; Panhard, X; Treluyer, JM; Salmon-Ceron, D
Fundamental & Clinical Pharmacology, 23(4): 491-500.
10.1111/j.1472-8206.2009.00693.x
CrossRef
International Journal of Std & AIDS
A review of the aetiology of dyslipidaemia and hyperlipidaemia in patients with HIV
Moyle, G
International Journal of Std & AIDS, 16(): 14-20.

New England Journal of Medicine
Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection
Walmsley, S; Bernstein, B; King, M; Arribas, J; Beall, G; Ruane, P; Johnson, M; Johnson, D; Lalonde, R; Japour, A; Brun, S; Sun, E
New England Journal of Medicine, 346(): 2039-2046.

Clinical Drug Investigation
A comparison of the therapeutic plan costs in the treatment of HIV-positive patients
Sabbatani, S
Clinical Drug Investigation, 23(7): 473-478.

Antiviral Research
Characterization of resistant HIV variants generated by in vitro passage with lopinavir/ritonavir
Mo, HM; Lu, LJ; Dekhtyar, T; Stewart, KD; Sun, E; Kempf, DJ; Molla, A
Antiviral Research, 59(3): 173-180.
10.1016/S0166-3542(03)00107-4
CrossRef
Antimicrobial Agents and Chemotherapy
Pharmacokinetic and safety evaluation of high-dose combinations of fosamprenavir and ritonavir
Shelton, MJ; Wire, MB; Lou, Y; Adamkiewicz, B; Min, SS
Antimicrobial Agents and Chemotherapy, 50(3): 928-934.
10.1128/AAC.50.3.928-934.2006
CrossRef
New England Journal of Medicine
Class-sparing regimens for initial treatment of HIV-1 infection
Riddler, SA; Haubrich, R; DiRienzo, AG; Peeples, L; Powderly, WG; Klingman, KL; Garren, KW; George, T; Rooney, JF; Brizz, B; Lalloo, UG; Murphy, RL; Swindells, S; Havlir, D; Mellors, JW
New England Journal of Medicine, 358(): 2095-2106.

Tropical Medicine & International Health
Dose reduction of antiretrovirals: a feasible and testable approach to expand HIV treatment in developing countries
Vento, S; Lanzafame, M; Lattuada, E; Cainelli, F; Restelli, U; Foglia, E
Tropical Medicine & International Health, 18(1): 40-44.
10.1111/tmi.12008
CrossRef
AIDS
Lopinavir/ritonavir absorption in a gastrectomized patient
Boffito, M; Lucchini, A; Maiello, A; Dal Conte, I; Hoggard, PG; Back, DJ; Di Perri, G
AIDS, 17(1): 136-137.

PDF (152)
AIDS
Randomized open-label trial of two simplified, class-sparing regimens following a first suppressive three or four-drug regimen
Fischl, MA; Collier, AC; Mukherjee, AL; Feinberg, JE; Demeter, LM; Tebas, P; Giuliano, M; Dehlinger, M; Garren, K; Brizz, B; Bassett, R; for the Adult AIDS Clinical Trials Group A5116 Study Team,
AIDS, 21(3): 325-333.
10.1097/QAD.0b013e328011ddfa
PDF (218) | CrossRef
AIDS
The longer the better? Four years of durable, initially boosted protease treatment
Katzenstein, D
AIDS, 18(5): 811-813.

PDF (59)
AIDS
Mild clinical toxicity and dose-dependent pharmacokinetics following acute lopinavir/ritonavir poisoning in a HIV-positive patient
Roberts, DM; Ray, JE; Buckley, NA
AIDS, 22(6): 792-793.
10.1097/QAD.0b013e3282f4a0dd
PDF (178) | CrossRef
AIDS
Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen
Ribera, E; Azuaje, C; Lopez, RM; Diaz, M; Feijoo, M; Pou, L; Crespo, M; Curran, A; Ocaña, I; Pahissa, A
AIDS, 20(8): 1131-1139.
10.1097/01.aids.0000226953.56976.ad
PDF (199) | CrossRef
AIDS
Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial
Haas, DW; Zala, C; Schrader, S; Piliero, P; Jaeger, H; Nunes, D; Thiry, A; Schnittman, S; Sension, M; for the Protocol AI424-009 Study Group,
AIDS, 17(9): 1339-1349.

PDF (138)
AIDS
Virological, intracellular and plasma pharmacological parameters predicting response to lopinavir/ritonavir (KALEPHAR Study)
Breilh, D; Pellegrin, I; Rouzés, A; Berthoin, K; Xuereb, F; Budzinski, H; Munck, M; Fleury, HJ; Saux, M; Pellegrin, J
AIDS, 18(9): 1305-1310.

PDF (106)
AIDS
Rational use of antiretroviral therapy in low-income and middle-income countries: optimizing regimen sequencing and switching
Elliott, JH; Lynen, L; Calmy, A; De Luca, A; Shafer, RW; Zolfo, M; Clotet, B; Huffam, S; Boucher, CA; Cooper, DA; Schapiro, JM
AIDS, 22(16): 2053-2067.
10.1097/QAD.0b013e328309520d
PDF (330) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Plasma Levels, Safety, and 60-Week Efficacy of a Once-Daily Double-Boosted Protease Inhibitor Regimen of Atazanavir, Saquinavir, and Ritonavir
Manosuthi, W; Sungkanuparph, S; Ruxrungtham, K; Prasithsirikul, W; Athichathanabadi, C; Tantisiriwat, W; Bowonwatanuwong, C; Chumpathat, N; Chaovavanich, A
JAIDS Journal of Acquired Immune Deficiency Syndromes, 47(1): 127-129.
10.1097/QAI.0b013e318157b0da
PDF (306) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
A 14-Day Dose-Response Study of the Efficacy, Safety, and Pharmacokinetics of the Nonpeptidic Protease Inhibitor Tipranavir in Treatment-Naive HIV-1–Infected Patients
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Keywords:

ABT-378; ABT-378/r; protease inhibitor; antiretroviral-naive; phase II clinical study

© 2001 Lippincott Williams & Wilkins, Inc.

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