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Influence of Liver Fibrosis Stage on Plasma Levels of Antiretroviral Drugs in HIV-Infected Patients with Chronic Hepatitis C

  1. Pablo Barreiro1,
  2. Sonia Rodríguez-Novoa2,
  3. Pablo Labarga1,
  4. Andrés Ruiz1,
  5. Inmaculada Jiménez-Nácher2,
  6. Luz Martín-Carbonero1,
  7. Juan Gonzalez-Lahoz1 and
  8. Vincent Soriano1
  1. 1 Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain
  2. 1 Pharmacokinetic Unit, Hospital Carlos III, Madrid, Spain
  1. Reprints or correspondence: Dr. Vincent Soriano, Dept. of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain (vsoriano{at}dragonet.es).
 
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Abstract

Background. Most antiretrovirals are metabolized in the liver, and lower dosing could be advisable in patients with severe liver insufficiency.

Methods. Plasma drug levels were measured in hepatitis C virus (HCV)/human immunodeficiency virus (HIV)—coinfected patients receiving nevirapine (NVP), efavirenz (EFV), lopinavir/ritonavir (LPV/r), or atazanavir (ATV) with or without ritonavir. Liver fibrosis was measured using elastometry.

Results. A total of 268 coinfected patients with compensated liver disease were analyzed. Mean plasma levels were 6.1 μg/mL for NVP (35 patients), 2.8 μg/mL for EFV (46 patients), 5.8 μg/mL for LPV (56 patients), 0.4 μg/mL for ATV (58 patients), and 0.7 μg/mL for ATV/r (73 patients). Overall, drug levels were higher in patients with cirrhosis than in those without cirrhosis for EFV (median, 3.4 vs. 1.9 μg/mL; P< .01) and NVP (median, 6.6 vs. 5.8 μg/mL; P = .33). EFV plasma levels above the toxic threshold (>4 μg/mL) were more frequent in patients with cirrhosis than in those without (31% vs. 3%; P < .001). The same trend was seen for NVP levels >8 μg/mL (50% vs. 27%; P = .27). By contrast, plasma levels of protease inhibitors (PIs) did not differ significantly between patients with and those without cirrhosis.

Conclusion. Liver clearance of nonnucleoside reverse-transcriptase inhibitors, particularly EFV, is impaired in patients with cirrhosis. No similar effect is seen for PIs. Assessment of liver fibrosis by noninvasive tools may identify HCV/HIV-coinfected patients who might benefit from therapeutic drug monitoring to avoid drug overexposure.

Highly active antiretroviral therapy (HAART) has dramatically improved the natural course of HIV infection. However, the long-term use of antiretroviral therapy has been associated with a broad range of adverse events. Because most antiretroviral drugs are metabolized by the liver and a substantial proportion of HIVinfected individuals have chronic hepatic disease (caused by alcohol abuse, viral hepatitis B or C, etc.), overexposure to antiretrovirals could be more common in HIV-infected persons with hepatic insufficiency. Almost all antiretrovirals may cause liver toxicity, although this is by far more frequent in patients with chronic viral hepatitis [1–3]. At present, it remains unclear to what extent this increased risk of hepatotoxicity in subjects with underlying chronic viral hepatitis who receive antiretrovirals could be due to higher drug levels caused by an impaired drug metabolism [4, 5].

Any compromise in liver function in patients with chronic viral hepatitis is mainly due to the loss of a substantial proportion of hepatocytes, which are replaced by fibrotic tissue, generally after a long process that ends in liver cirrhosis. As a consequence, the ability of the liver to clear drugs from blood via the 2 main enzymatic pathways (cytochrome P450 [CYP] and UDP—glucuronosyl transferase) might be significantly compromised. Other mechanisms for altered pharmacokinetics of antiretrovirals in patients with significant liver fibrosis may depend on lower protein-drug binding or vascular hepatic shunting [4].

For many years, liver biopsy has been the only way to determine the stage of hepatic fibrosis in chronic liver disease. However, several noninvasive tools have recently been developed and proved to show enough good correlation with liver histology [6]. Among these new methods, transient elastometry (FibroScan), an ultrasound-based imaging technique, seems to be particularly accurate for determining the stage of liver fibrosis in patients with chronic hepatitis C virus (HCV)/HIV coinfection [7]. The purpose of the present study was to assess whether HIV-infected patients with chronic hepatitis C have different antiretroviral plasma levels as consequence of different stages of liver fibrosis. Given that nucleos(t)ide analogues require further intracellular metabolism to become active within their target cells, our study focused on plasma levels of widely used nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

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Patients and Methods

We identified all consecutive HIV-infected patients seen at our institution between September 2004 and December 2005 who were receiving stable treatment (for >6 months) with nevirapine (NVP), efavirenz (EFV), lopinavir-ritonavir (LPV/r), or atazanavir (ATV), the latter either with (/r) or without ritonavir boosting. Only subjects receiving standard doses of antiretrovirals were selected: NVP, 200 mg/12 h or 400 mg/24 h; EFV, 600 mg/24 h; LPV/r, 400/100 mg/12 h; ATV, 400 mg/24 h; and ATV/r, 300/100 mg/24 h.

Only patients with chronic hepatitis C, defined by the presence of positive serum HCV RNA, were chosen for further drug pharmacokinetic and liver elastometry studies. Furthermore, only individuals with treatment adherence >95%, based on information obtained from pharmacy records and patient interviews, were chosen. Finally, only patients for whom a questionnaire showed that they had ingested the last pill dose ∼12 h (during diner) before blood was drawn (always on a fasting stomach before breakfast) were chosen.

Plasma levels of antiretrovirals were measured using a validated UV reverse-phase high-performance liquid chromatography method, as described elsewhere [8]. Assays were run after methyl tert-butylmethyl ether liquid-liquid extraction from 500 μL of plasma. Chromatographic separation was performed on a 5-μm C-18 column (150-4.6; Merck). All analyses were done using a 64% phosphate buffer and 36% acetonitrile mobile phase. Three UV wavelengths were used for the detection of each specific drug. Plasma levels of NVP and LPV were measured at 12 h after the twice-daily drug intake; therefore, values reflected the minimum concentration (Cmin). Plasma samples for ATV were extracted 12 h after the last once-daily dose; the Cmin was estimated using standard pharmacokinetic calculations based on linear regression by square minimums [9]. In the case of EFV, middose plasma levels were measured, because this is the standard parameter used to define the therapeutic range of the drug (1–4 μg/mL) [10]. The therapeutic range chosen for NVP was 3.4–8 μg/mL, as reported in a previous study [10].

Liver fibrosis was measured using transient elastometry (FibroScan), a noninvasive method that was recently proved to provide reliable estimations of hepatic fibrosis in HCV/HIVcoinfected patients [7]. The elasticity of the hepatic parenchyma is expressed in kiloPascals and interpreted according to the Metavir score as follows: F0–F1 if <7 kPa, F2 if 7.1–9.4 kPa, F3 if 9.5–12.5 kPa, and F4 if >12.5 kPa [11]. The lag between the determination of plasma drug levels and elastometry liver assessment was <3 months in all cases. Patients with a Child-Pugh score of C were excluded from the study, because dose adjustments of many antiretrovirals are advised in this subset of patients with end-stage liver disease.

All statistical analyses were performed using the SPSS software package (version 11.01; SPSS). Descriptive values were expressed as percentages, mean ± SD, or median (interquartile range [IQR]). Comparisons were made using the χ2 test for proportions and parametric or nonparametric tests for mean values, as required. Correlations were done by linear regression analysis; statistical significance was determined according to Spearman's test, because liver elasticity did not follow a normal distribution. Only results with P < .05 were considered to be significant, and all P values were 2-sided.

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Results

Patient characteristics. A total of 268 HCV/HIV-coinfected patients were included in the study. Overall, 77.4% were men, the mean ± SD age was 44 ± 6 years, and mean body mass index was 22.8 ± 3.1 kg/m2. Nearly two-thirds of patients (65.4%) were former injection drug users, 23.1% were homosexual men, and 11.5% had acquired HIV infection via heterosexual contact.

The mean ± SD CD4 cell count was 501 ± 281 cells/mL, and the mean HIV load was 2.02 ± 0.82 log RNA copies/mL. All patients were receiving HAART, and 78% had HIV RNA loads <50 copies/mL at the time when drug levels were analyzed. With respect to chronic liver disease, the mean ± SD alanine aminotransferase level was 52 ± 56 IU/L, and mean ± SD total bilirubin level was 1.45 ± 1.08 mg/dL. The mean ± SD plasma HCV load was 5.19 ± 2.1 log HCV RNA IU/mL, and the distribution of genotypes was as follows: 68% genotype 1, 1% genotype 2, 20% genotype 3, and 11% genotype 4. No patients were receiving interferon-based therapies at the time of evaluation.

Plasma samples from these individuals, coupled with corresponding elastometry liver examinations, were obtained for the determination of drug levels. The number of samples analyzed was 35 for NVP, 46 for EFV, 56 for LPV/r, 58 for ATV, and 73 for ATV/r.

Liver fibrosis and plasma drug levels. All 268 patients were evaluated using transient elastometry, which was performed by the same operator after plasma samples were drawn. The distribution of patients according to estimated Metavir scores was as follows: F0–F1 (5.34 ± 1.1 kPa), 104 (39%); F2 (8.2 ± 0.66 kPa), 43 (16%); F3 (10.9 ± 0.94 kPa), 29 (11%); and F4 (26.2 ± 15.11 kPa), 92 (34%). The clinical status of patients with cirrhosis (Metavir score of F4) according to the Child-Pugh score was A in 63% and B in 27%. No patients in this series had a Child-Pugh score of C. table 1 shows the main characteristics of the study population, adjusted by cirrhosis status.

Mean ± SD plasma drug levels were as follows: 6.1 ± 2.2 μg/mL for NVP, 2.8 ± 2.3 μg/mL for EFV, 5.8 ± 2.6 μg/mL for LPV, 0.4 ± 0.3 μg/mL for ATV, and 0.7 ± 0.9 μg/mL for ATV/r. There were no significant differences in plasma levels of PIs in patients with cirrhosis (F4), compared with those in patients without cirrhosis (F0–F3). The median (IQR) values obtained for each particular drug were as follows: LPV, 5.4 (4.3–6.7) vs. 6.1 (4.3–7.8) μg/mL (P = .83); ATV, 0.3 (0.1–0.6) vs. 0.3 (0.1–0.5) μg/mL (P = .36); and ATV/r, 0.5 (0.3–0.9) vs. 0.6 (0.3–0.8) μg/mL (P = .36) (figure 1). Moreover, when only patients with cirrhosis were considered, there were no significant differences in plasma levels of any of the examined PIs according to Child-Pugh score (table 1).

Figure 1.
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Figure 1.

Plasma levels of antiretrovirals in patients with chronic hepatitis C with and without liver cirrhosis. ATV/300, atazanavir (300 mg daily, with ritonavir boost); ATV/400, atazanavir (400 mg daily); EFV, efavirenz; LPV, lopinavir (with ritonavir boost); NVP, nevirapine.

Figure 2.
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Figure 2.

Correlation between liver fibrosis estimations (hepatic stiffness, in kiloPascals) and plasma drug levels. ATV, atazanavir; EFV, efavirenz; LPV, lopinavir (with ritonavir boost); NVP, nevirapine.

Figure 3.
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Figure 3.

Distribution of hepatitis C virus/HIV-coinfected patients according to plasma levels of efavirenz (EFV) and nevirapine (NVP), in the presence or absence of liver cirrhosis.

Table 1.
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Table 1.

Mean characteristics of the study population according to cirrhosis status.

Conversely, in the case of NNRTIs, median (IQR) plasma drug levels were higher in patients with than in those without cirrhosis. These values were 3.4 (5.0–5.3) vs. 1.9 (1.4–2.5) μg/mL, respectively, for EFV (P = .001) and 6.6 (4.5–7.9) vs. 5.8 (4.4–7.9) μg/mL, respectively, for NVP (P = .12). No significant differences in median plasma levels of NVP or EFV were found when we compared patients with cirrhosis who had a Child-Pugh score of A versus B (table 2).

Table 2.
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Table 2.

Plasma levels of antiretrovirals in hepatitis C virus (HCV)/HIV-coinfected patients with and without liver cirrhosis.

When we examined liver fibrosis estimations using FibroScan as a continuous variable in kiloPascals, a positive correlation was found for EFV and NVP plasma levels, although this reached statistical significance for only EFV (figure 2). By contrast, there was no correlation between different liver fibrosis estimations and PI plasma levels.

The proportion of patients receiving EFV with drug levels above the toxic threshold (>4 μg/mL) was higher in patients with cirrhosis than in those without cirrhosis (31% vs. 3%; P = .016) (figure 3). With respect to NVP, 50% of patients with cirrhosis who were receiving NVP had plasma drug levels above the toxic threshold (>8 μg/mL), whereas this occurred in only 27% of patients without cirrhosis (P = .27). The results regarding NVP should be interpreted cautiously, given that only 6 patients with cirrhosis received this drug in our study.

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Discussion

Advanced stages of chronic liver disease may affect the metabolism of some antiretroviral drugs. A progressive replacement of the liver parenchyma by fibrotic tissue is generally induced by the presence of chronic hepatitis C, which translates at a certain point into a reduction in the main metabolic pathways of the liver, such as the CYP and UDP—glucuronosyl transferase enzymatic systems [12–14]. In our study, HIV-infected patients with underlying chronic hepatitis C and compensated liver cirrhosis (Child-Pugh score of A or B) were more prone to have higher plasma levels of NNRTIs than HCV/HIV-coinfected individuals with milder stages of liver fibrosis. This was particularly true for EFV. By contrast, the influence of liver fibrosis stage on drug levels was not found for PIs, because no differences in plasma levels of LPV or ATV were observed when we compared patients with and without cirrhosis. Interestingly, a previous study in which the pharmacokinetics of NNRTIs and PIs were examined in a smaller group of HCV/HIV-coinfected patients from whom a liver-biopsy sample had been obtained had similar results [15]. In that report, plasma levels of NVP and EFV were higher in HIV-infected patients with chronic hepatitis C than in control subjects, and the proportion of coinfected patients with NVP or EFV plasma levels above the toxic threshold was higher in patients with cirrhosis than in those with milder liver fibrosis. As in our study, those authors did not find significant differences in plasma levels of PIs according to HCV status or stage of liver fibrosis. In a more recent study, which focused on the pharmacokinetics of NVP in HCV/HIV-coinfected patients, the extent of liver fibrosis was measured using Fibrotest. Again, it was found to be associated with NVP plasma levels [16]; patients with cirrhosis had higher NVP plasma levels than the rest of the subjects.

According to our results, it seems that the metabolism of EFV in the liver might be more sensitive to the impairment of liver function than the metabolism of NVP. Although there were significantly fewer patients with cirrhosis (7%) than those without (16%) who were exposed to NVP in our study (P < .03), which precludes us from drawing definitive conclusions, there are some arguments that may explain our findings. Liver clearance of EFV is mainly restricted to the CYP2B6 isoenzyme [17], whereas the metabolism of NVP may occur via both the CYP2B6 and CYP3A4 isoenzymes [18]. The fact that NVP may be cleared by 2 different enzymatic pathways and that one of them—namely CYP3A4—is the most abundant pathway in hepatocytes may explain why more profound liver damage could be required for significant increases in plasma levels of NVP, compared with EFZ. Of note, the activity of the CYP3A4 enzymatic system remains fairly well preserved in patients with mild to moderate liver impairment [19, 20]. The case for EFV could be different, given that its metabolism largely depends on a single and relatively scarce isoenzyme, CYP2B6.

The relationship between NNRTI plasma levels and the risk of liver toxicity has been the subject of debate. The risk for liver enzyme elevations in patients starting NVP was associated with trough levels of the drug at week 24 in one study [21]. Likewise, the HEPADOSE study found that HCV/HIV-coinfected patients with NVP or EFV levels above the therapeutic threshold were at a higher risk for grade 2 hepatocytolysis [15]. By contrast, Almond et al. [5] found no association between liver enzyme elevations and higher plasma levels of NVP. Similar results have been reported more recently by Dailly et al. [22]. Despite this controversy, the facts that liver toxicity with NNRTIs correlates with the extent of liver fibrosis [2], that a relationship exists between the stage of liver fibrosis and NNRTI plasma levels, and that there is a therapeutic threshold for both NVP and EFV warrant considering HCV/HIV-coinfected patients as an adequate target population for therapeutic drug monitoring.

In our study, plasma levels of PIs did not correlate with the extent of liver fibrosis. This observation was based on the measurement of plasma levels of LPV and ATV and comparisons made between patients with and without cirrhosis. A recent multiple-dose study found that the Cmin of LPV was higher in HIV-infected patients with chronic hepatitis than in control subjects [23]. However, in accordance with our findings, no significant differences in LPV plasma levels were seen in the group of patients with liver disease when patients with cirrhosis were compared with those with mild hepatic impairment.

There are several reasons to explain why the pharmacokinetics of LPV and ATV could be only minimally affected in patients with compensated liver cirrhosis. Both PIs are mainly metabolized in the liver by CYP3A4. As was already mentioned, the amount and activity of this isoenzyme is well preserved in most patients with mild to moderate liver impairment [19, 20]. On the other hand, although most PIs inhibit their own CYP450 metabolic pathway, NNRTIs induce it. Therefore, high liver metabolic activity is usually required to keep NNRTI plasma levels below toxic levels, which does not seem to be required to avoid PI overexposure. Moreover, the inducibility of microsomal isoenzymes is impaired in patients with liver cirrhosis [24], which could enhance the effect on NNRTIs, because their plasma levels are strongly dependent on the induction of CYP450. Interestingly, plasma levels of nelfinavir, which also induces liver enzymes, have been shown to be higher in patients with cirrhosis than in those without cirrhosis [25].

Although the imaging technique used in the present study to assess the staging of liver fibrosis has been validated with histological findings derived from liver-biopsy samples [7, 11], and although it intuitively makes sense that greater hepatic fibrosis would result in reduced liver metabolism, the information available correlating liver stiffness determined using FibroScan and markers of reduced hepatic function is rather scarce. To our knowledge, only one study [26] has reported that different estimations of liver fibrosis by use of FibroScan may predict distinct risks of clinical complications in patients with cirrhosis, such as ascites or gastrointestinal bleeding. Our data add a new piece of evidence in support of a correlation between the stage of liver fibrosis and impaired drug metabolism, because there was a positive linear correlation between estimates of liver fibrosis and NNRTI plasma levels.

Our study has several limitations. First, total drug measurements, rather than free drug levels in plasma, were examined; therefore, drug exposure was only assessed indirectly. Free drug levels are much more difficult to measure and are not feasible for routine clinical practice. Differences in albumin levels between patients with cirrhosis and without cirrhosis could have influenced our results. However, patients with very severe hepatic insufficiency and, therefore, the expected lower albumin levels, such as those with Child-Pugh scores of C, were not included in the study. A second limitation is that plasma levels of ritonavir were not measured; therefore, the potential impact of different degrees of liver fibrosis on plasma levels of ritonavir were not taken into account. Thus, its effect boosting LPV and ATV could differ somewhat in patients with more or less hepatic fibrosis, as was shown in a recent study [23].

In summary, the availability of new, noninvasive methods to assess the extent of liver fibrosis in HIV-infected patients with chronic hepatitis C may allow the identification of those at higher risk for antiretroviral overexposure. Measurement of plasma levels of NNRTIs might be warranted in patients with chronic hepatitis C if advanced liver fibrosis is found. By contrast, the pharmacokinetics of PIs seem to be less influenced by the impairment of liver function, so therapeutic drug monitoring of PIs could be less relevant.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: Fundación Investigación y Educación en SIDA; Red de Investigación en SIDA; European Surveillance Network for Vigilance against Viral Resistance; Instituto de Salud Carlos III; Fondo de Investigaciones Sanitarias; Agencia Lain Entralgo.

  • Received July 20, 2006.
  • Accepted October 20, 2006.
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References

  1. 1.↵
    1. Sulkowski M,
    2. Thomas D,
    3. Chaisson R,
    4. Moore R
    . Hepatotoxicity associated with antiretroviral therapy in adults infected with HIV and the role of hepatitis C or B virus infection. JAMA 2000;283:74-80.
    Abstract/FREE Full Text
  2. 2.↵
    1. Aranzabal L,
    2. Casado JL,
    3. Moya J,
    4. et al
    . Influence of liver fibrosis on highly active antiretroviral therapy—associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 2005;40:588-93.
    Abstract/FREE Full Text
  3. 3.↵
    1. Soriano V,
    2. Puoti M,
    3. Sulkowski M,
    4. et al
    . Care of patients with hepatitis C and HIV co-infection: updated recommendations from the HIVHCV International Panel. AIDS 2004;18:1-12.
    CrossRefMedline
  4. 4.↵
    1. Wyles DL,
    2. Gerber JG
    . Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction. Clin Infect Dis 2005;40:174-81. [erratum: Clin Infect Dis 2005; 40:913].
    Abstract/FREE Full Text
  5. 5.↵
    1. Almond L,
    2. Boffito M,
    3. Hoggard P,
    4. et al
    . The relationship between nevirapine plasma concentrations and abnormal liver function test. AIDS Res Hum Retroviruses 2004;20:716-22.
    CrossRefMedlineWeb of Science
  6. 6.↵
    1. Nunes D,
    2. Fleming C,
    3. Offner G,
    4. et al
    . HIV infection does not affect the performance of non-invasive markers of fibrosis for the diagnosis of hepatitis C virus-related liver disease. J Acquir Immune Defic Syndr 2005;40:538-44.
    CrossRefMedlineWeb of Science
  7. 7.↵
    1. de Ledinghen V,
    2. Douvin C,
    3. Kettaneh A,
    4. et al
    . Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2006;41:175-9.
    CrossRefMedlineWeb of Science
  8. 8.↵
    1. Tribut O,
    2. Arvieux C,
    3. Michelet C,
    4. Chapplain J,
    5. Allain H,
    6. Bentue-Ferrer D
    . Simultaneous quantitative assay of six HIV protease inhibitors, one metabolite, and two non-nucleoside reverse transcriptase inhibitors in human plasma by isocratic reversed-phase liquid chromatography. Ther Drug Monit 2002;24:554-62.
    CrossRefMedlineWeb of Science
  9. 9.↵
    1. Gibaldi M,
    2. Perrier D
    . Pharmacokinetics. 2nd ed. New York: Marcel Dekker; 1982.
  10. 10.↵
    1. Khoo S,
    2. Lloyd J,
    3. Dalton M,
    4. et al
    . Pharmacologic optimization of protease inhibitor and non-nucleoside reverse transcriptase inhibitors (POPIN)—a randomized controlled trial of therapeutic drug monitoring and adherence support. J Acquir Immune Defic Syndr 2006;41:461-7.
    CrossRefMedlineWeb of Science
  11. 11.↵
    1. Castera L,
    2. Vergniol J,
    3. Foucher J,
    4. et al
    . Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-50.
    CrossRefMedlineWeb of Science
  12. 12.↵
    1. Howden C,
    2. Birnie G,
    3. Brodie M
    . Drug metabolism in liver disease. Pharmacol Ther 1989;40:439-74.
    CrossRefMedlineWeb of Science
  13. 13.
    1. George J,
    2. Murray M,
    3. Byth K
    . Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 1995;21:120-8.
    CrossRefMedlineWeb of Science
  14. 14.↵
    1. Frye R,
    2. Zgheib N,
    3. Matzke G,
    4. et al
    . Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther 2006;80:235-45.
    CrossRefMedlineWeb of Science
  15. 15.↵
    1. Dominguez S,
    2. Peytavin G,
    3. Guiget M,
    4. et al
    . Program and abstracts of the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment (Rio de Janeiro). San Francisco: International AIDS Society; 2005. The HEPADOSE study: evaluation of protease inhibitors and non nucleoside analogue plasma concentrations in HIV/HCV and HIV-infected patients [abstract WePp0305]; p. 246.
  16. 16.↵
    1. Dominguez S,
    2. Benhamou Y,
    3. Katlama C,
    4. Peytavin G
    . Program and abstracts of the 2nd International Workshop on Clinical Pharmacology of HIV Therapy (Amsterdam). Utrecht: Virology Education Publications; 2006. Nevirapine plasma concentrations in HIV/HCV and HIV infected patients, a case control study: NEVADOSE [abstract 21]; p. 74.
  17. 17.↵
    1. Ward B,
    2. Gorski J,
    3. Jones D,
    4. et al
    . The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 2003;306:287-300.
    Abstract/FREE Full Text
  18. 18.↵
    1. Erickson D,
    2. Mather G,
    3. Trager W,
    4. Levy R,
    5. Keirns J
    . Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999;27:1488-95.
    Abstract/FREE Full Text
  19. 19.↵
    1. George J,
    2. Murray M,
    3. Byth K,
    4. Farrell G
    . Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 1995;21:120-8.
    CrossRefMedlineWeb of Science
  20. 20.↵
    1. Guengerich F,
    2. Turvey C
    . 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;256:1189-94.
    Abstract/FREE Full Text
  21. 21.↵
    1. Gonzalez de Requena D,
    2. Jiménez-Nácher I,
    3. Soriano V
    . Changes in nevirapine plasma concentrations over time and its relationship with liver enzyme elevations. AIDS Res Hum Retroviruses 2005;21:555-9.
    CrossRefMedlineWeb of Science
  22. 22.↵
    1. Dailly E,
    2. Billaud E,
    3. Reliquet V,
    4. et al
    . No relationship between high nevirapine plasma concentration and hepatotoxicity in HIV-1-infected patients naive of antiretroviral treatment or switched from protease inhibitors. Eur J Clin Pharmacol 2004;60:343-8.
    MedlineWeb of Science
  23. 23.↵
    1. Peng J,
    2. Pulido F,
    3. Causemaker S,
    4. 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
  24. 24.↵
    1. Herold C,
    2. Ganslmayer M,
    3. Ocker M,
    4. et al
    . Inducibility of microsomal liver function may differentiate cirrhotic patientswith maintained compared with severely compromised liver reserve. J Gastroenterol Hepatol 2003;18:445-9.
    CrossRefMedlineWeb of Science
  25. 25.↵
    1. Regazzi M,
    2. Maserati R,
    3. Villani P,
    4. et al
    . Clinical pharmacokinetics of nelfinavir and its metabolite M8 in HIV-positive and HIV-hepatitis C virus-coinfected subjects. Antimicrob Agents Chemother 2005;49:643-9.
    Abstract/FREE Full Text
  26. 26.↵
    1. Foucher J,
    2. Chanteloup E,
    3. Vergniol J,
    4. et al
    . Diagnosis of cirrhosis by transient elastography (Fibroscan): a prospective study. Gut 2006;55:403-8.
    Abstract/FREE Full Text
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  1. J Infect Dis. (2007) 195 (7): 973-979. doi: 10.1086/512086
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