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PHARMACOKINETICS |
From Abbott Laboratories, Abbott Park, Illinois (Dr Peng, Ms Causemaker, Ms Li, Dr DaSilva, Dr Brun); Hospital La Paz, HIV Unit, Madrid, Spain (Dr Lorenzo, Dr Arribas); Hospital 12 de Octubre, HIV Unit, Madrid, Spain (Dr Pulido, Dr Cepeda); and Abbott International, Madrid, Spain (Dr Cabanillas).
Address for reprints: Joanna Z. Peng, PhD, Abbott Laboratories, Clinical Pharmacology & Pharmacometrics (Department R4PK, Building AP13A-3), 100 Abbott Park Road, Abbott Park, IL 60064-6104.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Key Words: Lopinavir/ritonavir • hepatic impairment • HIV/HCV coinfection • pharmacokinetics
In the presence of an intact immune system, HCV slowly progresses over several decades, eventually leading to liver failure in a minority of patients. Progression of liver disease seems to be accelerated in immunocompromised patients, and a higher prevalence of liver failure has been observed in the presence of coinfection with HIV and HCV than when HCV infection is present alone.4 It is important to understand the potential clinical consequences of HAART therapy in these patients.
One component of HAART, lopinavir/ritonavir, is a peptidomimetic HIV protease inhibitor. Lopinavir is coadministered with ritonavir, which acts exclusively as a pharmacokinetic enhancer by blocking the cytochrome P450 3A (CYP3A)-mediated metabolism of lopinavir. Elevated and prolonged lopinavir serum levels support twice-daily dosing or once-daily dosing in antiretroviral-naïve patients.5
Because both lopinavir and ritonavir are primarily eliminated by hepatic CYP-mediated metabolism, hepatic disease may impair their elimination. In addition, ritonavir both inhibits and induces CYP3A (with the inhibitory effect predominant), and lopinavir induces its own metabolism.5 It is not clear whether enzyme induction or inhibition is likely to be affected in patients with hepatic impairment. Assessment of the steady-state pharmacokinetics of lopinavir/ritonavir in subjects with hepatic impairment as compared to subjects with normal hepatic function represents a topic of clinical relevance, as the potential change in lopinavir pharmacokinetics may affect antiviral activity and risk of adverse events. The current study evaluated multiple-dose pharmacokinetics of lopinavir/ritonavir in HIV/HCV-coinfected subjects with mild and moderate hepatic impairment, as assessed by Child-Pugh scoring.6
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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In addition, concomitant administration of prescribed or over-the-counter medications or herbal supplements known to affect lopinavir or ritonavir pharmacokinetics was prohibited, including nonnucleoside reverse transcriptase inhibitors such as delavirdine, efavirenz, and/or nevirapine.
Study Design
This was a phase 1, open-label, 2-center study. All subjects were taking lopinavir 400mg/ritonavir 100mg twice daily in combination with a stable regimen of other antiretroviral agents for at least 2 weeks prior to and during the study. The study consisted of a single period of 14 days. On day 7 and on 1 day between days 10 and 12, inclusive, a 5-mL trough (0 hour) pharmacokinetic blood sample was collected into heparinized collection tubes prior to morning dosing. On day 14, subjects were confined to the site and supervised for approximately 13 hours. After a standardized breakfast, the morning lopinavir/ritonavir dose was given with approximately 240 mL of water. The dose was given within 30 minutes from the beginning of the meal, and approximately 12 hours (±2 hours) after the previous dose. Pharmacokinetic blood samples (5 mL) were collected into heparinized collection tubes prior tomorning dosing (0 hour) and at 2,4,6,8,10,and 12 hours after dosing. In addition, on day 14, 5-mL samples were collected into heparinized collection tubes prior to morning dosing (0 hour) and 6 hours after dosing for the determination of lopinavir plasma protein binding. Subject safety was evaluated throughout the study through an analysis of adverse events, clinical laboratory test results, physical examinations, vital sign measurements, and electrocardiograms.
Study Drug and Treatment Compliance
Lopinavir/ritonavir (Kaletra; Abbott Laboratories) was supplied as soft gelatin capsules containing lopinavir 133.3 mg/ritonavir 33.3 mg. Medication event monitoring system (MEMS) caps were substituted for the standard cap on the lopinavir/ritonavir bottles and were used to collect the subjects' dosing history from day 1 through day 14.
Three adherence variables were collected using the MEMS caps: correct dosing, taking compliance, and timing compliance. Correct dosing (percentage) was defined as the number of days the pill bottle was opened as expected divided by the total number of monitored days, multiplied by 100. Taking compliance (percentage) was defined as the number of times the pill bottle was opened divided by the number of times the pill bottle was expected to be opened, multiplied by 100. Timing compliance (percentage) was defined as the percentage of times the subject opened the pill bottle within the correct dosing interval (between 9 and 15 hours of the previous dose).
Analytical Methods
Blood samples were processed within 2 hours of collection using a centrifuge to separate the plasma. Plasma samples were kept on ice and frozen (0°C) within 3 hours of collection. All plasma samples were received frozen at the central laboratory and were stored frozen at approximately -80°C until analyzed.
Plasma Concentration Measurement
Plasma concentrations of lopinavir and ritonavir were determined using a validated liquid chromatography tandem mass spectrometric method.7 Briefly, each 0.5-mL plasma sample was combined with 0.5 mL of 0.5 M sodium carbonate, 0.1 mL internal standard solution (A-86093.0), and 5 mL methyl-tert-butyl ether. Following vortex mixing and centrifugation, the organic layer was transferred to a clean tube and evaporated to dryness under nitrogen and low heat. Dried residues were reconstituted in mobile phase (60:40 [v:v] acetonitrile:50 mM ammonium formate at pH 3 with formic acid), vortexed, centrifuged, and transferred to autosampler vials. Samples were run on a Novapak C18 column (Waters Corporation, Milford, Mass). Calibration curves for lopinavir and ritonavir ranged from 5.0 to 10000.0 ng/mL and from 1.0 to 1000.0 ng/mL, respectively. All calibration curves had correlation coefficient (r) values greater than 0.997. Precision was assessed using the percentage relative standard deviation values of the quality control (QC) samples and were 
4.78 and 2.50% for lopinavir and ritonavir, respectively. Accuracy was assessed using percentage error of the QC samples and ranged from -6.2% to 4.4% for lopinavir and from -2.3% to 0.5% for ritonavir.
Protein Binding Determination
Lopinavir was uniformly labeled with tritium (3H) and stored in ethanol. Appropriate aliquots of radiolabeled lopinavir stock solution were added to the plasma to give an initial [3H]lopinavir concentration of 30 ng/mL. The spiked plasma aliquots were equilibrated before being loaded into the ultrafiltration system. Protein binding by ultrafiltration was determined with the Centrifree Micropartition system. Spiked plasma (1.0 mL) was placed in the sample reservoir of the device and centrifuged until enough ultrafiltrate was obtained. Duplicate aliquots of each ultrafiltrate and excluded (unfiltered) plasma were radioassayed directly in Insta-Gel scintillation cocktail and counted in a Tri-Carb Liquid Scintillation Analyzer (both manufactured by Packard Biosciences B.V. Chemical Operations, Ulgersmaweg, Groningen, the Netherlands). Correction for quenching was made by automatic external standardization.8
Statistical Analysis
For day 14, the lopinavir and ritonavir pharmacokinetic variables, including the maximum observed plasma concentration (Cmax), the time to Cmax (Tmax), concentration immediately prior to dosing (Ctrough), the minimum observed plasma concentration (Cmin, which can occur sometime after dosing due to slow absorption of lopinavir and ritonavir), and the area under the plasma concentration-time curve from 0 to 12 hours (AUC12), were determined using noncompartmental methods and were examined by an analysis of covariance (ANCOVA), with a classification by the 3 hepatic function groups: control, mild impairment, and moderate impairment. Covariates such as body weight and sex were included in the model if they reached a significant level of .1. Within the ANCOVA framework, each of the mild and moderate hepatic impairment groups was compared to the control group. Ninety percent confidence intervals were obtained for Cmax, Cmin, and AUC12 ratios for each of the central values of the 2 hepatic impairment groups relative to the control group central value. A repeated-measures analysis was performed on lopinavir and ritonavir Ctrough values on day 7, 1 day between days 10 and 12, and day 14. The repeated-measures model included effects for hepatic function group, day, and the interaction between hepatic function and day.
A repeated-measures analysis was performed on percentages of lopinavir unbound obtained immediately prior to dosing and 6 hours following dosing on day 14. Unbound lopinavir pharmacokinetic parameters were also examined by an analysis of repeated measures.
Because mild and moderate hepatic impairment displayed similar effects on lopinavir pharmacokinetics, additional analyses were performed on the total and unbound lopinavir pharmacokinetic parameters by combining the 2 hepatic impairment groups and comparing the combined group versus the controls. The combined hepatic impairment group was compared to the control group, and 90% confidence intervals were obtained for Cmax,Cmin, and AUC12 ratios for the central values of the hepatic impairment group relative to the control group central value.
With the exception of Tmax, pharmacokinetic parameters (AUC12, Cmax, Cmin, and Ctrough) were logarithmically transformed to provide approximately normal distribution.
All statistical tests were 2 tailed and were performed at a significance level of .05, unless otherwise indicated; a P value between .05 and .10 was considered marginally statistically significant. Computation for the statistical tests was performed with SAS version 6.12.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Total Lopinavir and Ritonavir Pharmacokinetics
Steady state was achieved for both lopinavir and ritonavir because the effect of day was not significant for the repeated-measures analysis on the trough concentrations (data not shown). The mean (SD) total lopinavir and ritonavir plasma concentration-time plots on day 14 following the administration of lopinavir 400 mg/ritonavir 100 mg twice daily are presented in Figure 1A and B. The total lopinavir plasma concentration-time plot with the mild and moderate hepatic impairment groups combined is presented in Figure 1C. The mean ± standard deviation pharmacokinetic parameters of total lopinavir and ritonavir on day 14 are provided in Table II.
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Mild or moderate hepatic impairment did not have a statistically significant effect on the Cmax or AUC12 of total lopinavir. Lopinavir Tmax for the mild hepatic impairment group was statistically significantly shorter than that for the control group (P = .0061). Compared to the control group, lopinavir Cmin was marginally statistically significantly higher (P = .065) for the mild hepatic impairment group and statistically significantly higher (P = .035) for the moderate hepatic impairment group. In comparison with the control group, lopinavir Ctrough was statistically significantly higher (P = .036) for the mild hepatic impairment group and marginally statistically significantly higher (P = .052) for the moderate hepatic impairment group.
After combining the mild and moderate hepatic impairment groups, lopinavir Cmin and Ctrough for the hepatic impairment group were statistically significantly higher than those for the control group (P = .015 and .013, respectively). Lopinavir Tmax for the hepatic impairment group was marginally statistically significantly shorter than that for the control group (P = .055). However, lopinavir Cmax and AUC12 for the hepatic impairment group were not statistically significantly different from those for the control group, likely due to the small number of subjects enrolled in the study and large intersubject variability.
Mild hepatic impairment did not have a statistically significant effect on total ritonavir Cmin or AUC12. Ritonavir Tmax for the mild hepatic impairment group was statistically significantly shorter than that for the control group (P = .0045). Both ritonavir Cmax and Ctrough for the mild hepatic impairment group were marginally statistically significantly higher than those for the control group (P = .066 and .073, respectively). For the moderate hepatic impairment group, ritonavir Cmax, Cmin, Ctrough, and AUC12 were all statistically significantly higher than those for the control group (P .0010).
Protein Binding of Lopinavir
The mean ± standard deviation percentage of lopinavir unbound on day 14 is shown in Table III. The results indicate that lopinavir was highly protein bound in the plasma of control subjects as well as in subjects with mild or moderate hepatic impairment. There was no statistically significant difference between the predose and 6-hour postdose percentage unbound within each group except for the mild hepatic impairment group (P = .011). Both the mild and moderate hepatic impairment groups showed a statistically significantly higher percentage of lopinavir unbound for the predose measurement versus the control group (P = .015 and .017, respectively). Similar results were observed for the 6-hour postdose measurement (P = .040 and .0007, respectively). When taking the average of the predose and 6-hour postdose measurements, the percentage of lopinavir unbound was similar between the mild (0.89% ± 0.21%) and moderate (0.94% ± 0.10%) hepatic impairment groups but statistically significantly higher than that in the control group (0.69% ± 0.06%, P < .01). The plasma albumin level on day 14 showed a negative correlation with the average percentage of lopinavir unbound (r =-0.624, Figure 2).
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Pharmacokinetic Parameters of Unbound Lopinavir
The average of the predose and 6-hour postdose percentages of lopinavir unbound was used to calculate the pharmacokinetic parameters of unbound lopinavir for each subject; the mean ± standard deviation values are presented in Table IV. For both mild and moderate hepatic impairment groups, all the lopinavir pharmacokinetic parameters tested (Cu,max, Cu,min, Cu,trough, and AUCu,12) were statistically significantly higher than those for the control group (P < .05).
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Relative Bioavailability of Lopinavir and Ritonavir
Based on the analyses of log-transformed AUC12,Cmax, and Cmin, the 90% confidence intervals and the corresponding point estimates of relative bioavailability of lopinavir and ritonavir, using the control group as the reference, were calculated and are presented in Table V. Mild and moderate hepatic impairment showed similar effects on total lopinavir pharmacokinetics. When data from the mild and moderate hepatic impairment groups were combined, hepatic impairment resulted in a 30% increase in total lopinavir AUC12, a 20% increase in Cmax, and a 79% increase in Cmin. When the differences in lopinavir protein binding were taken into account, hepatic impairment increased AUCu,12 by 68%, Cu,max by 56%, and Cu,min by 130%. Hepatic impairment had a greater effect on low-dose ritonavir pharmacokinetics in the moderate hepatic impairment group (181% increase in AUC12, 221% increase in Cmax, and 208% increase in Cmin compared to control) versus the mild hepatic impairment group (39% increase in AUC12, 61% increase in Cmax, and 52% increase in Cmin compared to control).
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Safety
The subjects entering this study were already receiving lopinavir/ritonavir as part of their stable antiretroviral regimen. During the period of study observation, the antiretroviral regimen, which included lopinavir/ritonavir, was generally well tolerated by subjects with normal hepatic function (control group) and by those with hepatic impairment. There were no deaths or serious adverse events reported during this study. No clinically significant physical examination result or vital sign was observed during the course of the study. Clinical laboratory results including AST, ALT, alkaline phosphatase, total bilirubin, indirect bilirubin, and direct bilirubin were plotted over time for all subjects, and there were no trends of concern during the study period. Furthermore, only 1 adverse event (mild diarrhea) was reported and was considered by the investigator to be unrelated to lopinavir/ritonavir administration. The event resolved while lopinavir/ritonavir therapy continued.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The percentage of lopinavir unbound was similar between the mild (0.89% ± 0.21%) and moderate (0.94% ± 0.10%) hepatic impairment groups but higher than that in the control group (0.69% ± 0.06%, P < .01), consistent with a decrease in albumin content in the plasma of patients with liver disease (Figure 2). Lopinavir also binds to 
-1-acid glycoprotein (AAG) in addition to albumin and has a higher affinity for AAG; however, AAG level was not measured in this study. After accounting for the differences in lopinavir protein binding, hepatic impairment increased AUCu,12 by 68%, Cu,max by 56%, and Cu,min by 130%.
Hepatic impairment had a greater effect on low-dose ritonavir pharmacokinetics in the moderate hepatic impairment group (181% increase in AUC12, 221% increase in Cmax, and 208% increase in Cmin compared to control) versus the mild hepatic impairment group (39% increase in AUC12, 61% increase in Cmax, and 52% increase in Cmin compared to control). It is likely that the moderate hepatically impaired subjects had higher ritonavir bioavailability compared to the mild hepatically impaired subjects. There was not much difference in the systemic clearance of ritonavir as suggested by the similarity in the peak-to-trough t1/2 between the 2 groups.
The higher concentrations of ritonavir, however, did not lead to higher lopinavir exposure in the moderate hepatic impairment group compared to that in the mild hepatic impairment group (Figure 3), suggesting that maximal inhibition of lopinavir metabolism by ritonavir might be reached in this population. Saturable inhibition of lopinavir metabolism by ritonavir was previously documented with lopinavir AUC12 after a lopinavir/ritonavir 400/200 mg twice-daily regimen being only 54% higher than that after 400/100 mg twice-daily administration, despite 2.5- to 4.5-fold increases in ritonavir exposure.15 Although ritonavir concentrations were increased by more than 2-fold, the average ritonavir AUC12 observed in the subjects with moderate hepatic impairment in this study was only 18% of that previously observed in HIV-1-infected patients after clinical doses of 600 mg twice-daily ritonavir.16
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It is noteworthy that 1 subject, a 35-year-old white woman with a body weight of 50 kg, had nearly double the exposure to both total lopinavir and ritonavir compared to the other 5 mild hepatically impaired subjects. This 1 subject led to particularly large intersubject variability for the mild hepatic impairment group. Without this subject, the 5 remaining mild hepatically impaired subjects had similar total lopinavir and ritonavir concentrations compared to the control group. No clear reason for this subject's high exposure to lopinavir/ritonavir could be identified. Despite the high exposure to lopinavir/ritonavir, this subject did not report any adverse events.
The higher total and unbound drug levels observed in this study did not lead to increased safety concerns in these subjects. Consistently, previous studies have shown that liver toxicity does not seem to be related to lopinavir plasma levels.18 However, one important caveat is that this study selected subjects who were already on stable lopinavir/ritonavir therapy. Therefore, it is uncertain whether subjects with hepatic impairment who start lopinavir/ritonavir treatment will tolerate the treatment as well as those enrolled in this study. Since a dose reduction would need to be balanced against the possible risk of inadequate HIV viral suppression,19,20 lopinavir/ritonavir dosage adjustment is not recommended in subjects with mild or moderate hepatic impairment. However, close monitoring of clinical status is warranted when lopinavir/ritonavir is administered to such subjects.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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1. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services; May 24, 2005. Available at: http://aidsinfo.nih.gov/guidelines/.
2. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34: 831-837.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Staples CT, Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999;29: 150-154.[Web of Science][Medline] [Order article via Infotrieve]
4. Koch J, Kim LS, Friedman S. Gastrointestinal manifestations of HIV. In: Peiperl L, Coffey S, Volberding P, eds. HIV In Site Knowledge Base [online textbook]. San Francisco: University of California, San Francisco; June 1998. Available at: http://hivinsite.ucsf.edu/InSite?page=kb-04-01-11#S10.1X.
5. Kaletra [package insert]. Abbott Park, Ill: Abbott Laboratories; April 20, 2005.
6. Figg WD, Dukes GE, Lesesne HR, et al. Comparison of quantitative methods to assess hepatic function: Pugh's classification, indocyanine green, antipyrine, and dextromethorphan. Pharmacotherapy. 1995;15: 693-700.[Web of Science][Medline] [Order article via Infotrieve]
7. Hsu A, Isaacson J, Brun S, et al. Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2003;47: 350-359.
8. Hsu A, Bertz R, Hickman D, et al. Assessment of plasma protein binding of lopinavir and ritonavir between in vitro and ex vivo experiments and between HIV-1-infectedpatients and HIV-negative healthy volunteers. Paper presented at: Eighth Conference on Retroviruses and Opportunistic Infections; February 2001; Chicago, Ill.
9. Micheli V, Meraviglia P, Regazzi M, et al. Lopinavir/r administration in HIV/HCV co-infected patients: pharmacokinetic considerations. Paper presented at: the Second Annual European HIV Drug Resistance Workshop; March 2004; Rome, Italy.
10. Canta F, Marrone R, Bonora S, et al. Pharmacokinetics and hepatotoxicity of lopinavir/ritonavir in non-cirrhotic HIV and hepatitis C virus (HCV) co-infected patients. J Antimicrob Chemother. 2005;55: 280-281.
11. Domínguez S. The HEPADOSE Study: differences of protease inhibitors and non-nucleoside analogue plasma concentrations between HIV/HCV and HIV patients [abstract CI34]. Presented at: First International Workshop on HIV and Hepatitis Co-infection; December 2004; Amsterdam, the Netherlands.
12. George J, Murray M, Byth K, Farrell GC. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology. 1995;21: 120-128.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Lown K, Kolars J, Turgeon K, Merion R, Wrighton SA, Watkins PB. The erythromycin breath test selectively measures P450IIIA in patients with severe liver disease. Clin Pharmacol Ther. 1992;51: 229-238.[Web of Science][Medline] [Order article via Infotrieve]
14. Guengerich FP, Turvey CG. Comparison of levels of several human microsomal cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J Pharmacol Exp Ther. 1991;256: 1189-1194.
15. Bertz R, Lam W, Brun S, et al. Multiple-dose pharmacokinetics (PK) of ABT-378/ritonavir (ABT-378/r) in HIV+ subjects. Paper presented at: 39th Interscience Conference of Antimicrobial Agents and Chemotherapy; September 1999; San Francisco, Calif.
16. Norvir [package insert]. Abbott Park, Ill: Abbott Laboratories; March 28, 2005.
17. Peng JZ, Bertz RJ, Hsu A, et al. Evaluation of single and multiple dose pharmacokinetics of ritonavir in subjects with mild or moderate hepatic insufficiency. Paper presented at: Fourth International Workshop on Clinical Pharmacology of HIV Therapy; March 2003; Cannes, France.
18. González-Requena D, Núñez M, Jiménez-Nacher I, GonzálezLahoz J, Soriano V. Liver toxicity of lopinavir-containing regimens in HIV-1-infected patients with or without hepatitis C coinfection. AIDS Res Hum Retroviruses. 2004;20: 696-698.
19. Gulick RM, Da Silva B, McMillan F, et al. Lopinavir/ritonavir (LPV/r)-based therapy in antiretroviral (ARV)-naïve, HIV-1-infected patients: 6-year follow-up of Study 720. Paper presented at: Seventh International Congress on Drug Therapy in HIV Infection; November 2004; Glasgow, UK.
20. 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.
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