Skip Navigation



JAC Advance Access published online on September 5, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn383
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
62/6/1356    most recent
dkn383v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Guaraldi, G.
Right arrow Articles by Esposito, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guaraldi, G.
Right arrow Articles by Esposito, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

A pilot study on the efficacy, pharmacokinetics and safety of atazanavir in patients with end-stage liver disease

Giovanni Guaraldi1,*, Stefania Cocchi1, Alice Motta1, Sara Ciaffi1, Mauro Codeluppi1, Stefano Bonora2, Fabrizio Di Benedetto3, Michele Masetti3, Marco Floridia4, Silvia Baroncelli4, Diego Pinetti5, Antonio D’Avolio2, Alfio Bertolini5 and Roberto Esposito1

1 Department of Internal Medicine and Medical Specialties, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy 2 Department of Infectious Diseases, University of Turin, Turin, Italy 3 Department of General Surgery, Liver and Multivisceral Transplant Centre, University of Modena and Reggio Emilia, Modena, Italy 4 Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy 5 Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Modena, Italy

* Correspondence address. Department of Internal Medicine and Medical Specialties, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy. Tel: +39-059-422-5318; Fax: +39-059-422-3710; E-mail: g.guaraldi{at}unimore.it

Received 9 April 2008; returned 16 June 2008; revised 13 August 2008; accepted 16 August 2008


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
Objectives: Antiretroviral combinations including atazanavir are currently not recommended in HIV-infected patients with end-stage liver disease (ESLD). The objective of our study was to evaluate efficacy, pharmacokinetics and safety of unboosted atazanavir in HIV-infected patients with ESLD screened for orthotopic liver transplantation (OLTx).

Patients and methods: Single-arm, 24 week pilot study. Atazanavir-naive patients undergoing highly active antiretroviral therapy were switched to atazanavir 400 mg/day plus two non-thymidine nucleoside reverse transcriptase inhibitors.

Results: Fifteen patients (10 males and 5 females) were included. In the study period, 2 patients were transplanted and 10 completed 24 weeks of atazanavir treatment. Median area under the concentration–time curve at week 4 was 19 211 ng·h/mL (IQR = 8959–27 500). At week 24, median atazanavir trough concentrations (Ctrough) per patient calculated across the study were above the minimum effective concentration (MEC = 100 ng/mL) in 8 of 10 subjects. Atazanavir Ctrough time-point values were always above the MEC in five patients. The other three subjects experienced only one determination below the MEC, with median atazanavir Ctrough levels across the study being above the MEC in two of them. At 8 of 11 time-points when atazanavir and proton pump inhibitors (PPIs) were co-administered and at 16 of 19 time-points in which patients had a concomitant tenofovir association, atazanavir Ctrough was above the MEC.

Conclusions: Unboosted atazanavir showed a favourable pharmacokinetic profile and was able to maintain or gain immuno-virological eligibility for OLTx in all patients. Limited biochemical toxicities (including unconjugated hyperbilirubinaemia) and allowance of concomitant administration of tenofovir and PPIs were observed.

Key Words: HIV , therapeutic drug monitoring , unboosted protease inhibitors , liver insufficiency , drug–drug interactions


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
Since 1996, the availability of highly active antiretroviral therapy (HAART) for HIV-infected patients has resulted in a remarkable decrease in HIV-related morbidity and mortality.1 This decline has been accompanied by a relative increase in morbidity and mortality associated with chronic hepatic impairment.2,3 End-stage liver disease (ESLD), which is largely the result of hepatitis C virus (HCV) infection, now accounts for up to 50% of deaths among persons with HIV infection.2

Hepatic disease can affect drug metabolism,4,5 and HIV/HCV co-infected patients are at an increased risk of drug toxicity, which has been attributed to both changes induced by chronic viral infections and the impairment of the pathways involved in liver metabolism of antiretroviral agents (ARVs).6 The cytochrome P450 (CYP450) family of enzymes is responsible for the metabolism of most antiretroviral drugs, particularly protease inhibitors (PIs) as well as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase inhibitors.

Metabolic efficacy of the CYP450 enzyme family progressively decreases along with worsening liver function,7 producing an increase in plasma concentration of ARVs6,8–13 and, ultimately, the potential for serious hepatic toxicities and interference with concomitant treatments.14–16 On the other hand, a beneficial long-term effect of HAART in ESLD has been supported in some studies,17 suggesting a reduction in liver-related mortality that outweighs the potential risks of drug hepatotoxicity.

Up to now, data on PI pharmacokinetics in patients suffering from chronic liver disease are lacking.6,8–13,18–21 Recommendations about PI use and dose adjustments in subjects with hepatic impairment have been issued,22 and antiretroviral combinations including atazanavir [Reyataz; Bristol–Myers Squibb (BMS), Princeton, NJ, USA] are currently not recommended in patients with HIV infection suffering from ESLD.23

A pilot study to evaluate efficacy, pharmacokinetics [trough concentration (Ctrough) levels, area under the concentration–time curve (AUC) and maximum concentration (Cmax) levels] and safety of unboosted atazanavir was conducted in patients with HIV infection suffering from ESLD. The secondary objective of the study was to analyse any significant drug–drug interaction between atazanavir and tenofovir, proton pump inhibitors (PPIs) and H2-receptor antagonists (anti-H2). Patients were recruited at the Transplant Centre of the University of Modena and Reggio Emilia among HIV-infected individuals evaluated for orthotopic liver transplantation (OLTx) in accordance with the Italian National Liver Transplant Programme.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Funding
 Transparency declarations
 References
 
Study design, patients and study treatment

Single centre, 24 week, open-label pilot study in HIV-infected individuals with ESLD receiving an atazanavir-based HAART regimen from September 2005 to September 2006.

Consecutive adult patients with HIV infection and ESLD, evaluated for OLTx according to the Italian National Liver Transplant Programme for HIV-infected patients, were screened at the Transplant Centre of the University of Modena and Reggio Emilia. ESLD was defined as a Child–Pugh score ≥B7, hepatic cirrhosis documented either by liver biopsy (Ishak stage 4 fibrosis) or clinical and ultrasonographic diagnostic criteria (liver surface nodularity, caudate lobe hypertrophy and changes in hepatic venous flow) and at least one episode of liver decompensation.24–26

Patients with potential benefits of OLTx and no previous treatment with atazanavir and with no atazanavir-related major resistance mutations were switched at study entry from an NNRTI or a pharmacologically enhanced (boosted) PI to atazanavir 400 mg once daily, maintaining their nucleoside reverse transcriptase inhibitor (NRTI) backbone if plasma HIV-RNA viral load (VL) was undetectable (<50 copies/mL) or optimizing the NRTIs according to plasma HIV genotypic resistance test.

In accordance with BMS Pharmaceuticals’ warning on significant drug–drug interactions,27 the protocol discouraged the use of PPIs and anti-H2, if not strictly necessary, and collected pharmacokinetic data when atazanavir was concomitantly administered with these drugs. Dropout criteria were: OLTx, death and atazanavir discontinuation. The study was authorized by the local Ethics Review Board and all subjects provided written informed consent prior to enrolment.

Data collection

Baseline data included demographics (ethnic origin, gender and age), HIV characteristics (transmission risk factors, duration of HIV infection, HIV CDC classification, nadir CD4+ cell count, class type and exposure to antiretroviral therapy, plasma HIV genotypic resistance assay antecedent or concomitant to switching and current HAART) and ESLD history (aetiology, known duration of cirrhosis, HCV genotype, baseline serum HCV-RNA VL, previous cirrhotic decompensation episodes and presence of histologically documented hepatocellular carcinoma). Follow-up data collected at weeks 0, 2, 8, 16 and 24 included: (i) anthropometric characteristics [weight, height and body mass index (BMI)]; (ii) HIV parameters (plasma HIV-RNA VL, CD4+ cell count, immuno-virological eligibility for OLTx and plasma HIV genotypic resistance assay when VL was detectable); (iii) ESLD indexes [Child–Pugh score, the model for ESLD (MELD) score and the aspartate aminotransferase-to-platelet ratio index (APRI) score]; (iv) liver and kidney biochemistry tests [total and unconjugated bilirubin (TBIL and UBIL, respectively), alanine aminotransferase (ALT), {gamma}-glutamyl transpeptidase (GGT), alkaline phosphatase (ALKP), international normalized ratio (INR), albumin (ALB) and glomerular filtration rate with the modification of diet in renal disease (MDRD) calculation]; (v) concomitant treatments (PPIs and anti-H2); (vi) relevant clinical events [death, liver decompensation and virological failure (defined as plasma HIV-RNA VL ≥1000 copies/mL and grade III–IV pharmacological toxicities)]; and (vii) adherence evaluation (assessed with unstructured questionnaire and pill-counts).

Sample collection for therapeutic drug monitoring (TDM)

Pharmacokinetic assays were centralized at the Pharmacology Clinic of the Antiretrovirals Laboratory, Infectious Diseases Department, University of Turin, Italy. Plasma atazanavir concentration was measured at the end of the dosing interval (trough level) at each time-point of follow-up. Moreover, at week 4, additional samples (immediately before and 1.5, 3, 5, 7 and 24 h after atazanavir intake, respectively) were obtained in order to evaluate Cmax levels and AUC. Plasma samples were separated, inactivated in a bath at 58°C for 35 min and then frozen at –20°C until analyses were performed. Plasma atazanavir concentrations were measured by a modified HPLC method with UV detection validated over the concentration range of 100–5000 ng/mL, using 0.5 mL of plasma.28 The efficacy of extraction of atazanavir from human plasma was evaluated as the percentage of recovery equal to 102% ± 5 SD. The intraday precision of the method used for dosing atazanavir was measured as relative standard deviation percentage (RSD%) that was 1% for a low quality control (QC) level, 10% for medium and 11% for high. The interday RSD% was 4% for low QC level, 10% for medium and 11% for high. The intraday accuracy rates ranged from 96% to 98% and the interday from 98% to 99%.

The sensitivity for atazanavir Ctrough level of our method was 40 ng/mL in the range of linearity. For statistical purposes, the Ctrough level below the limit of detection was fixed as half of the assay sensitivity (equal to 20 ng/mL). Pharmacokinetic analysis compared Ctrough levels of samples with the minimal effective concentration (MEC) value of unboosted atazanavir (suggested by BMS as being equal to 100 ng/mL) at any time-point. Drug interactions were evaluated analysing the proportion of patients with Ctrough levels above the MEC in the presence or absence of a concomitant administration of tenofovir, PPIs and anti-H2 agents.

Outcome measures

Efficacy outcomes for the study were the proportion of patients with plasma HIV-RNA VL below the limit of detection, CD4+ cell count changes from baseline and the proportion of patients immuno-virologically eligible for OLTx with regard to the Italian National Liver Transplant Programme for people with HIV on HAART (stable CD4+ cell count ≥200 cells/mm3 for at least 12 months and undetectable plasma HIV-RNA VL).29

For pharmacokinetic analyses, the main study outcome was AUC, Cmax and the proportion of patients with atazanavir Ctrough levels above the MEC.

Safety outcomes were: death; grade III–IV drug toxicities; changes in serum TBIL, UBIL, ALT, GGT, ALKP, INR and ALB; changes in Child–Pugh, APRI, MELD and MDRD scores; and capacity to tolerate HAART in the follow-up period.

Data concerning outcome variables from patients who did not complete 24 weeks were collected in the follow-up.

Statistical analysis

Biochemical values (TBIL, UBIL, ALT, GGT, ALKP, INR and ALB) and CD4+ cell count were expressed as medians and inter-quartile ranges (IQRs). The changes from baseline were analysed for statistical significance using the Wilcoxon test. Differences in atazanavir Ctrough values between patients with/without concomitant treatment with tenofovir, PPIs and anti-H2 agents at different study weeks were analysed using the Mann–Whitney U-test. In all the above analyses, a threshold of 0.05 was used for statistical significance. All the analyses were performed using the SPSS software.30


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Funding
 Transparency declarations
 References
 
Subjects

Fifteen consecutive patients were enrolled in the trial and 10 completed the study after a 24 week follow-up. A flow chart summarizing outcomes and dropouts of study participants is given in Figure 1.


Figure 1
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1. Flow chart of the study population with outcomes during the study.

 
All the 15 evaluable subjects (10 males and 5 females) were Caucasian adults with a median age of 44 years (IQR = 41–46). Median weights and heights were 70 kg (IQR = 52.5–80) and 171 cm (IQR = 164–179), respectively, with a median BMI of 23 (IQR = 20–25.5).

The route of transmission for HIV was intravenous drug use in 14 patients and heterosexual intercourse in the remaining patient. Twelve (80%) subjects had a baseline undetectable (<50 copies/mL) plasma HIV-RNA VL. In the remaining three viraemic subjects, plasma HIV genotypic resistance test did not show any major atazanavir mutation. Eleven patients (73%) had a baseline CD4+ cell count >200 cells/mm3 (median value = 298 cells/mm3; IQR = 197–322). The median nadir CD4+ cell count was 161 cells/mm3 (IQR = 70–200).

Table 1 summarizes HIV data and concomitant treatments at study entry. Baseline data on ESLD, liver and kidney function tests are given in Table 2.


View this table:
[in this window]
[in a new window]

  		Table 1. HIV infection history, baseline variables and concomitant treatments

 


View this table:
[in this window]
[in a new window]

  		Table 2. ESLD history and baseline liver and kidney biochemical tests

 
Efficacy measures

Twelve patients (80%) had undetectable plasma HIV-RNA VL at enrolment; among the 10 subjects who completed the study, 9 had undetectable HIV-RNA VL at week 24 (90%) and 1 had a detectable but low VL (117 copies/mL). Median CD4+ cell count was 298 cells/mm3 among enrolled patients at baseline and 340 cells/mm3 among the 10 subjects who completed the study, indicating a small, although not significant, cell count increase during follow-up (P = 0.386).

At entry, 9 of 15 patients (60%) were immunologically and virologically eligible for OLTx. Among the 10 subjects who completed the study, 9 (90%) were eligible for transplantation at week 24 and 1 remained ineligible. Among the patients who did not complete 24 weeks, two were transplanted (Case 1 at week 17, after having become eligible at week 8, and Case 5, eligible from enrolment, at week 18), two remained OLTx-ineligible and died during the follow-up and one eligible patient discontinued atazanavir because of gastrointestinal intolerance. Two subjects (Cases 6 and 9) admitted to a transient lack of adherence to the study drug.

Pharmacokinetic analysis

Individual and median values of atazanavir Ctrough at any time-point of the follow-up period for the entire group of patients are represented in Figure 2.


Figure 2
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2. Atazanavir Ctrough levels at each time-point represented as individual and median values.

 
Median atazanavir Ctrough values at different study weeks were 186 ng/mL at week 2 (IQR = 83.5–270.5), 197.5 ng/mL at week 8 (IQR = 109–448.5), 321 ng/mL at week 16 (IQR = 169–540) and 147.5 ng/mL at week 24 (IQR = 50–664). Table 3 shows patient AUC and Cmax at week 4 of the study, as well as median atazanavir Ctrough levels across the study. Four patients had atazanavir Ctrough levels below the MEC at week 24. Two of them, Cases 6 and 9, admitted episodes of intermittent non-adherence and had a transient HIV-RNA viraemic blip 1 month after the conclusion of the trial.


View this table:
[in this window]
[in a new window]

  		Table 3. AUCs and Cmax levels at week 4 and median atazanavir Ctrough levels across the study

 
The role of concomitant treatment with tenofovir, PPIs or anti-H2 agents was assessed by examining individual and median values for patients with and without such concomitant treatments at different study weeks.

Overall, in eight patients receiving concomitant tenofovir, median atazanavir Ctrough values were above the MEC at all study weeks (week 2: 228 ng/mL, IQR = 144–354.5; week 8: 450 ng/mL, IQR = 449–519; week 16: 540 ng/mL, IQR = 529–580.5; and week 24: 301 ng/mL, IQR = 87.25–794.5). Atazanavir Ctrough time-point values were always above the MEC in five patients. The other three subjects experienced only one determination below the MEC, but in these, median atazanavir Ctrough values across the study were above the MEC. Atazanavir Ctrough levels were above the MEC in 16 of the 19 total samples (84%) collected in the presence of a concomitant administration of atazanavir and tenofovir.

In the study period, six patients had concomitant PPI administration in at least one study visit. In this group, median atazanavir Ctrough values were above the MEC at week 2 (307 ng/mL), week 8 (120 ng/mL) and week 16 (254 ng/mL), but not at week 24 (50 ng/mL). Overall, atazanavir Ctrough levels were above the MEC in 8 of 11 samples (73%) collected in the presence of a concomitant administration of atazanavir and PPIs. Three patients always had atazanavir Ctrough values above the MEC at any time-point. In the remaining three patients, atazanavir Ctrough levels were below the MEC only once (one at week 2 and two at week 24, respectively), but none experienced a viro-immunological or clinical failure during the follow-up. In two of them, median atazanavir Ctrough values across the study were above the MEC.

Eight patients had concomitant anti-H2 administration in at least one study visit. In this group, median atazanavir Ctrough levels were at or above the MEC at all study weeks (week 2, 100 ng/mL; week 8, 288 ng/mL; week 16, 529 ng/mL; week 24, 184.5 ng/mL). Atazanavir Ctrough time-point values were always above the MEC in five patients, while the other three subjects experienced only one determination below the MEC, with median atazanavir Ctrough levels across the study above the MEC in two of them. Overall, in 17 of 20 samples (85%) collected in the presence of atazanavir and anti-H2 co-administration, atazanavir Ctrough values were above the MEC.

Safety assessment

Two patients died during the follow-up. The first death (Case 11) occurred at week 9 from intracerebral haemorrhage, and the second (Case 10) at week 10 from lactic acidosis. Two subjects reported grade III toxicities (diarrhoea), which in one case (13) was responsible for atazanavir discontinuation at week 2.

In patients completing the study, no significant changes in ALT, GGT, ALKP and ALB occurred between week 0 and week 24 (all P values >0.05). INR showed a small but statistically significant decrease from week 0 (median value: 1.42) to week 24 (median value: 1.28, P = 0.021). TBIL did not show any significant change from week 0 to week 24. Conversely, UBIL showed a small but statistically significant increase at week 24 compared with baseline value (from 1.15 to 1.32 mg/dL, P = 0.047).

Median Child–Pugh, APRI, MELD and MDRD scores were not significantly changed in the follow-up period (all P values >0.05, data not shown). Eight clinical episodes of decompensated liver cirrhosis occurred in the study period: ascites (n = 5), variceal haemorrhages (n = 2) and hepatic encephalopathy (one case).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Funding
 Transparency declarations
 References
 
Toxicity and resistance issues limit therapeutic choices in HIV-infected patients with advanced liver disease. Currently available data on the use of atazanavir in patients with liver disease include a clinical series of subjects with moderate/severe hepatic impairment, evaluated after they received a single dose of atazanavir 400 mg once daily.31 In a clinical comparative study of atazanavir versus nelfinavir,32 no differences in virological response were observed, over a period of 48 weeks, in patients co-infected with HBV or HCV compared with subjects with HIV infection alone. Bilirubin elevations were similar in the co-infected group. Pineda et al.33 reported a low incidence of severe liver toxicity in 99 patients (60 of whom had chronic liver disease) receiving antiretroviral combinations including atazanavir. To our knowledge, the present study is the first to assess the potential benefits of OLTx and atazanavir efficacy, pharmacokinetics and safety in patients with ESLD.

No virological failures were documented in our study. A high number of liver decompensation episodes occurred during the follow-up period, confirming the clinical predominance of liver disease over HIV infection in the events observed during the study. Even when such episodes occurred, HAART was never interrupted for longer than 1 week. We believe that this capacity to maintain HAART was responsible for a statistically not significant, but clinically appreciable, increase of the CD4+ cell count between weeks 0 and 24. This amelioration in immune function was sufficient to maintain eligibility for OLTx in all the patients and to add three more subjects to the transplantation programme. In our study, an atazanavir-based regimen was effective to gain or maintain viral suppression and to preserve CD4+ cell count in all patients.

Median atazanavir AUC, Ctrough and Cmax were similar to those detected in other clinical trials in HIV-infected patients using atazanavir 400 mg once daily.27,31,34 The median Ctrough value at all study weeks was well above the median wild-type 90% effective concentration of 14 ng/mL for atazanavir,35 and also above the MEC suggested by BMS (100 ng/mL). These data, in conjunction with the lack of appreciable liver toxicity or severe increase in serum bilirubin levels, make atazanavir a useful drug option in patients suffering from ESLD. Our results demonstrated large inter-patient variability [with a percentage coefficient of variation (CV%) of AUCs equal to 76%] in subjects with ESLD, confirming the statement that hepatopathic individuals are candidates for TDM.23 Nonetheless, no correlation was found between the degree of liver insufficiency and the patient-to-patient variation in atazanavir pharmacokinetics. Tenofovir was previously suggested to affect unboosted atazanavir exposure. With regard to atazanavir/tenofovir co-administration,27,31,36 our data suggest the possibility of achieving adequate levels even without adding ritonavir, as shown by median plasma atazanavir Ctrough levels above the MEC among the eight subjects undergoing tenofovir-based nucleoside backbone therapy. PPIs are well known to interfere with atazanavir pharmacokinetics, with reduced or inadequate atazanavir absorption in the presence of the non-acid environment produced by these drugs.27,37–39 Our data showed, within a context of great variability in atazanavir Ctrough levels, the presence of median values above the MEC in most patients in whom atazanavir was co-administered with PPIs.

During the study period, treatment with atazanavir did not worsen hepatic impairment or renal function. From baseline to week 24, UBIL increased significantly, but its absolute change was small in terms of clinical significance. Atazanavir is a known inhibitor of UGT1A1 and its use is associated with unconjugated hyperbilirubinaemia.27 This observation indirectly suggests that the glucuronidation of atazanavir is not affected by liver disease, including cirrhosis.

The major methodological limitation of this study was the absence of a control group and the small sample size. In this particular setting, randomized trials are complicated and it may be difficult to achieve a large case series. Sample size constraints did not allow us to define the independent role of multiple cofactors potentially affecting atazanavir Ctrough levels in multivariate analyses, or to build a nomogram for dose adjustments according to the severity of liver failure.

TDM in subjects with liver impairment may be particularly useful to manage inter-patient variability and drug interactions, in the perspective of an optimal individualization of the antiretroviral regimen.


   Funding
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
Transparency declarations
 References
 
No specific funding has been received.


   Transparency declarations
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
 Transparency declarations
References
 
None to declare.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
1 . Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med (1998) 338:853–60.[Abstract/Free Full Text]

2 . Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis (2001) 32:492–7.[CrossRef][Web of Science][Medline]

3 . Macias J, Melguizo I, Fernandez-Rivera FJ, et al. Mortality due to liver failure and impact on survival of hepatitis virus infections in HIV-infected patients receiving potent antiretroviral therapy. Eur J Clin Microbiol Infect Dis (2002) 21:775–81.[CrossRef][Web of Science][Medline]

4 . Howden CW, Birnie GG, Brodie MJ. Drug metabolism in liver disease. Pharmacol Ther (1989) 40:439–74.[CrossRef][Web of Science][Medline]

5 . Rodighiero V. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet (1999) 37:399–431.[CrossRef][Web of Science][Medline]

6 . Robertson SM, Scarsi KK, Postelnick MJ, et al. Elevated plasma concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors in patients coinfected with human immunodeficiency virus and hepatitis B or C: case series and literature review. Pharmacotherapy (2005) 25:1068–72.[CrossRef][Web of Science][Medline]

7 . Branch RA. Drugs in liver disease. Clin Pharmacol Ther (1998) 64:462–5.[CrossRef][Web of Science][Medline]

8 . Veronese L, Rautaureau J, Sadler BM, et al. Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function. Antimicrob Agents Chemother (2000) 44:821–6.[Abstract/Free Full Text]

9 . Regazzi M, Maserati R, Villani P, et al. Clinical pharmacokinetics of nelfinavir and its metabolite M8 in human immunodeficiency virus (HIV)-positive and HIV-hepatitis C virus-coinfected subjects. Antimicrob Agents Chemother (2005) 49:643–9.[Abstract/Free Full Text]

10 . Maserati R, Villani P, Seminari E, et al. High plasma levels of nelfinavir and efavirenz in two HIV-positive patients with hepatic disease. AIDS (London, England) (1999) 13:870–1.

11 . Spagnuolo V, Gentilini G, De Bona A, et al. Liver function parameters in HIV/HCV co-infected patients treated with amprenavir and ritonavir and correlation with plasma levels. New Microbiol (2007) 30:279–82.[Medline]

12 . Seminari E, De Bona A, Gentilini G, et al. Amprenavir and ritonavir plasma concentrations in HIV-infected patients treated with fosamprenavir/ritonavir with various degrees of liver impairment. J Antimicrob Chemother (2007) 60:831–6.[Abstract/Free Full Text]

13 . Peng JZ, Pulido F, Causemaker SJ, et al. Pharmacokinetics of lopinavir/ritonavir in HIV/hepatitis C virus-coinfected subjects with hepatic impairment. J Clin Pharmacol (2006) 46:265–74.[Abstract/Free Full Text]

14 . Alberti A, Clumeck N, Collins S, et al. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol (2005) 42:615–24.[CrossRef][Web of Science][Medline]

15 . Carosi G, Puoti M, Antonucci G, et al. Antiretroviral therapy in chronic liver disease: focus on HIV/HCV coinfection—statements of the First Italian Consensus Workshop. AIDS Rev (2005) 7:161–7.[Web of Science][Medline]

16 . Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clin Infect Dis (2004) 38(Suppl_2):S90–7.[CrossRef][Web of Science][Medline]

17 . Qurishi N, Kreuzberg C, Luchters G, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet (2003) 362:1708–13.[CrossRef][Web of Science][Medline]

18 . Malavaud B, Dinh B, Bonnet E, et al. Increased incidence of indinavir nephrolithiasis in patients with hepatitis B or C virus infection. Antivir Ther (2000) 5:3–5.[Web of Science][Medline]

19 . Burger D, Hugen P, Reiss P, et al. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS (London, England) (2003) 17:1157–65.

20 . Damle B, Hewlett D Jr, Hsyu PH, et al. Pharmacokinetics of nelfinavir in subjects with hepatic impairment. J Clin Pharmacol (2006) 46:1241–9.[Abstract/Free Full Text]

21 . Khaliq Y, Gallicano K, Seguin I, et al. Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus-infected patients with chronic liver disease. Br J Clin Pharmacol (2000) 50:108–15.[CrossRef][Web of Science][Medline]

22 . Wyles DL, Gerber JG. Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction. Clin Infect Dis (2005) 40:174–81.[CrossRef][Web of Science][Medline]

23 . The Panel on Clinical Practices for Treatment of HIV infection convened by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 29 January 2008. http://aidsinfo.nih.gov/Guidelines(22 July 2008, date last accessed).

24 . Aube C, Oberti F, Korali N, et al. Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol (1999) 30:472–8.[CrossRef][Web of Science][Medline]

25 . Colli A, Fraquelli M, Andreoletti M, et al. Severe liver fibrosis or cirrhosis: accuracy of US for detection—analysis of 300 cases. Radiology (2003) 227:89–94.[Abstract/Free Full Text]

26 . Di Lelio A, Cestari C, Lomazzi A, et al. Cirrhosis: diagnosis with sonographic study of the liver surface. Radiology (1989) 172:389–92.[Abstract/Free Full Text]

27 . Bristol Myers Squibb Company. December 2007. Reyataz (atazanavir sulfate) capsules: prescribing information. [Online.]. http://www.bms.com(22 July 2008, date last accessed).

28 . Wu EY, Wilkinson JM 2nd, Naret DG, et al. High-performance liquid chromatographic method for the determination of nelfinavir, a novel HIV-1 protease inhibitor, in human plasma. J Chromatogr B Biomed Sci Appl (1997) 695:373–80.[CrossRef][Medline]

29 . Grossi P, Tumietto F, Costigliola P, et al. Liver transplantation in HIV-infected individuals: results of the Italian national program. Transplantation (2006) 82(Suppl 3 WTC Abstracts):446. Abstract 1139.

30 . SPSS software. (2006) Chicago, USA: SPSS Inc. Version 13.0.1.

31 . Kaul S, Bassi K, Damle B, et al. Pharmacokinetic evaluation of the combination of atazanavir, enteric-coated didanosine, and tenofovir disoproxil fumarate for once-daily antiretroviral regimen. In: In: Program and Abstracts of the Forty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2003. Washington, DC, USA: American Society for Microbiology. Abstract A-1616, p. 36.

32 . Cahn P, Piliero P, Giordano M, et al. Atazanavir: antiretroviral efficacy in HIV-infected patients co-infected with hepatitis B and/or C viruses. In: In: Program and Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Washington, DC, USA: American Society for Microbiology. Abstract H-1730, p. 278.

33 . Pineda JA, Palacios R, Rivero A, et al. Low incidence of severe liver toxicity in patients receiving antiretroviral combinations including atazanavir. J Antimicrob Chemother (2006) 57:1016–7.[Free Full Text]

34 . Barrios A, Rendon AL, Gallego O, et al. Predictors of virological response to atazanavir in protease inhibitor-experienced patients. HIV Clin Trials (2004) 5:201–5.[CrossRef][Web of Science][Medline]

35 . Busti AJ, Hall RG, Margolis DM. Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy (2004) 24:1732–47.[CrossRef][Web of Science][Medline]

36 . Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother (2004) 48:2091–6.[Abstract/Free Full Text]

37 . Agarwala S, Thal G, Nettles R, et al. Further information on the administration of H2-receptor antagonists with atazanavir. J Acquir Immune Defic Syndr (2006) 42:516.[Web of Science][Medline]

38 . Tomilo DL, Smith PF, Ogundele AB, et al. Inhibition of atazanavir oral absorption by lansoprazole gastric acid suppression in healthy volunteers. Pharmacotherapy (2006) 26:341–6.[CrossRef][Web of Science][Medline]

39 . Khanlou H, Farthing C. Co-administration of atazanavir with proton-pump inhibitors and H2 blockers. J Acquir Immune Defic Syndr (1999) (2005) 39:503.[Web of Science][Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
62/6/1356    most recent
dkn383v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Guaraldi, G.
Right arrow Articles by Esposito, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guaraldi, G.
Right arrow Articles by Esposito, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?