JAC Advance Access originally published online on May 23, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):140-146; doi:10.1093/jac/dkl214
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C
1 Servicio de Medicina Interna, Hospital Universitario de Valme Sevilla, Spain 2 Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme Sevilla, Spain 3 Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar Cádiz, Spain 4 Servicio de Medicina Interna, Hospital Juan Ramón Jiménez Huelva, Spain 5 Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Virgen de la Victoria Málaga, Spain 6 Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen del Rocío Sevilla, Spain 7 Sección de Enfermedades Infecciosas, Hospital Punta de Europa Algeciras, Cádiz, Spain 8 Sección de Enfermedades Infecciosas, Hospital Universitario Reina Sofía Córdoba, Spain 9 Servicio de Medicina Interna, Hospital Universitario de Jerez Cádiz, Spain 10 F. Hoffman-La Roche San Diego, USA
*Correspondence address. Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Ctra de Cádiz s/n, 41014 Sevilla, Spain. Tel: +34-955015887; Fax: +34-955015747; E-mail: japineda{at}nacom.es
Received 11 December 2005; returned 14 February 2006; revised 2 April 2006; accepted 4 May 2006
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsDiscussionTransparency declarationsReferences |
|---|
Objectives: To determine the incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients with known stage of liver fibrosis.
Methods: All HIV/HCV-coinfected patients were monitored for a period of 12 months after starting nelfinavir-containing regimens and, with an available liver biopsy, were included in a retrospective study.
Results: A total of 82 patients were included in the study. Nine (10.9%) HIV/HCV-coinfected patients showed an episode of severe hepatotoxicity during the study period. Eight (9.8%) individuals showed grade 3 or 4 change in levels of serum alanine aminotransferase and one subject presented with an event of decompensated liver cirrhosis. Six (18.2%) of 33 patients with advanced liver fibrosis and three (6%) of 49 individuals without advanced liver fibrosis showed an episode of severe hepatotoxicity (P = 0.1). In the multivariate analysis, only nevirapine use during nelfinavir therapy [adjusted odds ratio (AOR) 8.9; 95% confidence interval (CI), 1.4–54.1; P = 0.01] was independently associated with risk of development of severe liver toxicity.
Conclusions: The incidence of severe hepatotoxicity of nelfinavir-containing regimens is low among HIV/HCV-coinfected patients with known stage of liver fibrosis. In addition, our findings show that concomitant nevirapine use is associated with an increased risk of severe hepatotoxicity in these subjects. Likewise, the proportion of severe liver toxicity tended to be higher in individuals with advanced liver fibrosis.
Keywords: protease inhibitors , nevirapine , liver fibrosis , liver toxicity
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionTransparency declarationsReferences |
|---|
All classes of antiretroviral drugs currently available have been reported to cause liver toxicity.1–6 The incidence of severe hepatotoxicity is greater in human immunodeficiency virus (HIV)-infected patients with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfections and in alcohol users.1,4,6–8 Likewise, advanced liver fibrosis stage has been associated with a higher risk of developing severe liver toxicity in patients coinfected with HIV and HCV receiving non-nucleoside reverse transcriptase inhibitors (NNRTIs).9 Liver toxicity may enhance the progression of HCV-related liver disease to cirrhosis,10,11 which is currently a leading cause of morbidity and mortality among HIV-infected patients.
The rate of liver toxicity associated with nelfinavir therapy has been reported to be lower than that found in patients receiving NNRTIs and other protease inhibitors (PIs).6,12,13 Nevertheless, there is little data reported regarding the incidence of severe liver toxicity secondary to nelfinavir outside of well-circumscribed trials. Moreover, it is not known how other factors, and specifically preexisting liver fibrosis and concomitant administration of other antiretroviral drugs, impact the risk for nelfinavir-related liver toxicity. As many as 60% of HIV-infected patients are coinfected with HCV in some areas, such as Spain.14 Most of these patients harbour liver fibrosis.15 Because of this, insight on the safety of nelfinavir in this setting is of the greatest interest.
For these reasons, we undertook the present study, whose objective was to assess the incidence of severe hepatotoxicity of nelfinavir-containing regimens and the risk factors of this liver toxicity among HIV-infected patients with chronic hepatitis C with an available liver biopsy.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionTransparency declarationsReferences |
|---|
Study population and follow-up
From January 1997 to February 2004, a cohort of 7393 HIV-infected patients on antiretroviral therapy was prospectively followed at eight university hospitals in southern Spain. Of these, 5027 (68%) also had HCV infection. A total of 166 (28%) of 592 HIV/HCV-coinfected patients who underwent a liver biopsy received nelfinavir-containing highly active antiretroviral therapy (HAART) at some time during the follow-up. Patients were seen at scheduled visits before starting therapy and every 3 months thereafter. For the present study, the date of starting nelfinavir was considered the baseline date.
Individuals with a liver biopsy and nelfinavir treatment (1500 mg per day) were included in a retrospective analysis if they fulfilled the following criteria: (i) at least 12 months of follow-up since the initiation of nelfinavir treatment, (ii) completed scheduled visits every 3 months after starting nelfinavir therapy during this follow-up and (iii) liver biopsy obtained within 24 months before or after starting nelfinavir therapy.
At each clinic visit during the follow-up, standard laboratory assessment was carried out. Standard laboratory testing included plasma HIV-RNA levels; CD4+ cell counts; and measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase and gamma-glutamyl transferase levels. Albumin concentration and the international normalized ratio (INR) were obtained at liver biopsy. Most liver biopsies were taken with the aim of establishing the prognosis and indicating therapy for chronic hepatitis C.
In the present study, the duration of HCV infection was estimated in injecting drug users who had shared needles. The year of infection was estimated as the first year of sharing needles.
Therapeutic strategies
HAART was offered to all HIV-infected individuals who received care in our clinics and who were candidates for treatment, according to the recommendations that were in force at the time. Nelfinavir was extensively available for prescription since 1997. Other non-antiretroviral drugs prescribed to each patient during the follow-up, such as statins, rifampicin, isoniazid, pyrazinamide and trimethoprim/sulfamethoxazole, were recorded.
Diagnosis of severe hepatotoxicity
A diagnosis of severe hepatotoxicity was made when patients presented with an episode of decompensated liver cirrhosis or a grade 3 or 4 change in either plasma ALT, AST or total bilirubin levels during a period of 12 months of follow-up after starting nelfinavir therapy. In patients with normal baseline ALT or AST values, grade 3 and grade 4 change in ALT or AST levels were defined, in accordance with Sulkowski et al.,4 as a 
5-fold and a 10-fold increase of plasma ALT or AST levels above the upper limit of normal (40 IU/mL), respectively. In individuals with elevated pre-treatment ALT or AST levels, a 3.5-fold increase in the baseline values was considered as grade 3 and a 5-fold increase in the baseline values as grade 4 in ALT or AST levels. Grade 3 and grade 4 changes in plasma total bilirubin levels were defined as a 3-fold and a 5-fold increase above the upper limit of normal (1.2 mg/dL), respectively. Other potential causes of liver disease, such as infectious diseases, alcoholic hepatitis and acute viral hepatitis, were excluded before making a diagnosis of liver toxicity.
Laboratory methods
Blood determinations. HIV antibodies were tested by enzyme immunoassay (EIA) (Genscreen HIV-1/2, Pasteur Diagnostics, Paris, France) and confirmed via western blot analysis (New LAV Blot I, Pasteur Diagnostics, Paris, France). Plasma HIV-RNA was measured using PCR (Amplicor HIV Monitor, Hoffman-La Roche, Basel, Switzerland) or NASBA (Nuclisens, Organon Teknika, Boxtel, The Netherlands), depending on the availability at each hospital. The limits of detection varied between 20 and 80 copies/mL, according to the time when the analysis was carried out and the procedure used. CD4+ cell counts were measured by a standard flow cytometry procedure. Serum HCV antibodies were detected by EIA (EIA, Ortho Diagnostic Systems, Raritan, NJ). HCV-RNA was determined by either qualitative PCR (Amplicor HCV or Cobas Amplicor HCV, Hoffmann-La Roche, Basel, Switzerland) or quantitative PCR (Amplicor HCV Monitor or Cobas Amplicor HCV Monitor, Hoffmann-La Roche, Basel, Switzerland). HCV genotype was determined by line-probe assay (INNOLiPA HCV, Innogenetics, Ghent, Belgium).
Histological evaluation. Liver biopsy specimens were fixed, paraffin-embedded, and stained with haematoxylin-eosin and Masson's trichrome stains. At each hospital, liver fibrosis was assessed by an experienced pathologist following the Knodell histological activity index modified by Scheuer.16 Thus, liver fibrosis was scored according to the following stages: F0, absent; F1, portal fibrosis without septa; F2, periportal or portal fibrosis with intact architecture; F3, architectural distortion without obvious cirrhosis; F4, definitive cirrhosis. All the patients gave their written informed consent for liver biopsy.
Statistical methods
Continuous variables are expressed as median (interquartile range) and categorical variables are expressed as the number of cases (percentage). Continuous variables were compared using the Mann–Whitney U-test. Frequencies were compared using the 
2 test or the Fisher's test if the expected frequency for any cell was five or lower. The density of incidence of severe hepatotoxicity was calculated as the number of cases per 100 person-years of follow-up. Changes in ALT, AST, total bilirubin, alkaline phosphatase and gamma-glutamyl transferase levels at each visit after beginning nelfinavir treatment were calculated using the Friedman test.
To assess the relationship between severe hepatotoxicity of nelfinavir-containing regimens and potential risk factors, we included the following variables in the statistical analysis: sex; age; alcohol intake; route of HCV infection; HCV genotype; CD4+ cell count and undetectable HIV viral load at baseline; liver fibrosis stage; ALT level at baseline; and use of trimethoprim-sulfamethoxazole, specific antiretroviral and tuberculostatic drugs during the follow-up. High alcohol intake was defined as the self-reported daily alcohol consumption >50 g for 12 months. Liver fibrosis was dichotomized into non-advanced (F0–F2) and advanced (F3–F4). The variables which showed a relationship with severe liver toxicity of nelfinavir-containing regimens with a P < 0.2 were entered in a forward stepwise logistic regression analysis. The adjusted odds ratio (AOR) and the corresponding 95% confidence intervals (CI) were also obtained.
The statistical analysis was performed using the SPSS statistical software package release 12.0 (SPSS Inc., Chicago, IL, USA).
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionTransparency declarationsReferences |
|---|
Characteristics of the study population
Eighty (49%) subjects who were treated with nelfinavir-containing regimens were excluded from the study due to a period more than 24 months between the liver biopsy and starting nelfinavir treatment. Likewise, 4 (2%) individuals were lost to follow-up during the study. Consequently, 82 (49%) patients fulfilled the inclusion criteria. The median age of the individuals studied was 35 (interquartile range, 32–38) years. No patient showed positive hepatitis B surface antigen. Other relevant baseline characteristics of the population and the different drugs that patients took during nelfinavir therapy are shown in Tables 1 and 2, respectively.
|
|
A total of 72 (88%) patients started nelfinavir therapy before undergoing liver biopsy. In these subjects, the median time from starting nelfinavir to liver biopsy was 15 (interquartile range, 10.5–19.1) months. Ten (12%) individuals started nelfinavir after liver biopsy. The median time from liver biopsy to beginning nelfinavir was 8 (interquartile range, 0.3–19.4) months. At the time of the liver biopsy, the median levels of albumin and INR were 4 mg/dL (interquartile range, 3.9–4.6) and 1.01 (interquartile range, 1–1.1), respectively. The distribution of fibrosis stage found at liver biopsy is displayed in Table 3.
|
Outcome
A total of nine (10.9%) HIV/HCV-coinfected patients showed an episode of severe hepatotoxicity during the study period. Eight (9.8%) individuals showed grade 3 or 4 change in levels of serum ALT. Of these, four patients also presented grade 3 or 4 change in levels of serum AST. One subject suffered from an event of decompensated liver cirrhosis with an episode of non-obstructive jaundice. There were no severe hyperbilirubinaemia cases during the follow-up. The density of incidence of severe liver toxicity was 11.4 cases per 100 person-years of follow-up (95% CI, 9.3–13.9). The median time from starting nelfinavir to the diagnosis of severe liver toxicity was 6 months (interquartile range, 3–6). Among the individuals developing severe hepatotoxicity, one received isoniazid therapy and four additional subjects received nevirapine therapy. The median time from starting nevirapine to the diagnosis of severe hepatotoxicity was 3.4 months (interquartile range, 2.8–5.5). Eight (12%) out of 66 patients with liver fibrosis (F1–F4) developed severe liver toxicity.
Among patients with grade 3 or 4 change in levels of serum ALT, two subjects improved these levels when nevirapine therapy was stopped and five individuals presented resolution of severe liver toxicity without antiviral therapy changes. Equally, in one individual severe hepatotoxicity disappeared after the discontinuation of isoniazid therapy.
During the follow-up, plasma total bilirubin levels decreased (Figure 1a), whereas there were no significant changes in the levels of ALT, AST, alkaline phosphatase and gamma-glutamyl transferase (Figure 1b).
|
Nine (11%) patients discontinued nelfinavir therapy during the study. Thus, five individuals stopped the therapy due to virological failure, three due to HAART simplification and only one due to elevation of plasma ALT levels. The median CD4+ cell count at baseline and at 12 months was 344 cells/mm3 (interquartile range, 212–563) and 495 cells/mm3 (interquartile range, 282–621), respectively. A total of 26 (32%) subjects at baseline and 58 (70%) individuals at 12 months showed undetectable viral load. One subject presented an AIDS-defining event during the follow-up. No patient died during the study period.
Risk factors for development of severe hepatotoxicity
Four (44%) patients with severe hepatotoxicity and five (7%) individuals without this adverse event received nevirapine during nelfinavir therapy (P = 0.007) (Table 4). Similarly, as shown in Figure 2, there was a higher proportion of severe liver toxicity among patients who were taking nevirapine treatment, compared with those who were not exposed to nevirapine. The use of other antiretroviral drugs was not associated with severe hepatotoxicity.
|
|
Six (18.2%) of 33 patients with advanced liver fibrosis and 3 (6%) of 49 individuals without advanced liver fibrosis showed an episode of severe liver toxicity (P = 0.1). Subjects with and without severe liver toxicity had median baseline CD4+ cell counts of 254 cells/mm3 (interquartile range, 103–409) and 360 cells/mm3 (interquartile range, 227–570) (P = 0.2), respectively. The relationship between the development of severe hepatotoxicity and other factors is shown in Table 4.
In the multivariate analysis, only nevirapine use during nelfinavir therapy was independently associated with the risk of development of severe hepatotoxicity (AOR 8.9; 95% CI, 1.4–54.1; P = 0.01).
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionTransparency declarationsReferences |
|---|
The results reported here show that the incidence of severe hepatotoxicity of regimens including nelfinavir is low among HIV-infected patients with chronic hepatitis C and known stage of liver fibrosis. In addition, concomitant nevirapine use is associated with an increased risk of severe liver toxicity in these subjects.
This is the first study, to our knowledge, in which the hepatotoxicity associated with nelfinavir has been assessed in HIV/HCV-coinfected patients with documented liver damage. The incidence of severe liver toxicity found in the population with fibrosis F1–F4 is 12%. This is a figure close to that found in other cohort studies in the entire population taking nelfinavir, including HCV-coinfected and HIV-monoinfected patients.6 The rate of liver toxicity found in patients with liver fibrosis in this study is lower than that reported previously in clinical trials and cohort studies in coinfected patients under other PIs, irrespective of the liver damage patients harbored.6,17
Severe liver toxicity related with nelfinavir could be under- or overestimated due to different study designs and methods of analysis.18 Heterogeneity in the frequency of aminotransferase measurements is a possible source of confusion. Nevertheless, in this study cohort liver function assessments were available every 3 months in all patients during the follow-up. This is the usual period of time between measurements in clinical trials. Other possible confounders are different definitions of asymptomatic severe hepatotoxicity. The most common definition, designed for clinical trials, has been proposed by the AIDS Clinical Trials Group (ACTG).19 However, a major problem with this definition is that subjects with high baseline ALT or ALT levels are more likely to achieve an increase above the normal limit than patients with lower levels at baseline. Thus, a modified version by Sulkowski et al.4 has been used in patients with baseline aminotransferase levels above the normal range. For these reasons, we have also applied this modified ACTG definition in our study. Finally, observational studies are more representative of real life than clinical trials, but they can be limited by the heterogeneity of the study population. This is not a concern in the present study. Thus, all the patients received nelfinavir-based regimens. In addition, all of them were infected by HCV, a major risk factor for hepatotoxicity, and liver toxicity could be adjusted by the degree of liver fibrosis.
Nevirapine is a well-characterized hepatotoxic agent. Thus, the incidence of severe hepatotoxicity ranges from 10% to 18% in individuals prescribed nevirapine.12,13,20–22 In addition, 
5% of subjects receiving this NNRTI develop symptomatic hepatic events.12 Likewise, a higher risk of nevirapine-associated hepatotoxicity has been reported in patients receiving PIs.20 In this sense, we found an association between severe liver toxicity and concomitant nevirapine use among subjects coinfected with HIV and HCV treated with nelfinavir-containing regimens. Thus, nearly half of the patients in our study who showed severe hepatotoxicity were receiving nevirapine therapy, in agreement with what has been previously reported.20 Nevirapine therapy was not associated with increased levels of nelfinavir.23,24 For this reason, a higher incidence of hepatotoxicity in regimens including nelfinavir and nevirapine could be related with additive liver toxicity of each antiretroviral more than to pharmacokinetic interactions.
The results of the present study suggest that the role of the drugs given concomitantly must be taken in consideration when assessing the liver toxicity associated with a specific antiretroviral agent. In this way, the results from other studies dealing with the same issue may not be totally translated into the clinical setting of our patients. Namely, in the study from the John Hopkins cohort,6 a lower incidence of severe hepatotoxicity was observed in individuals receiving lopinavir/ritonavir-based HAART than among subjects treated with nelfinavir-based HAART. However, the percentage of individuals with concurrent nevirapine was 2-fold higher in the subgroup of patients taking nelfinavir. In agreement with the results mentioned above, this may be a determinant factor for these results.
Advanced liver fibrosis stage has been associated with the risk of developing severe liver toxicity in patients coinfected with HIV and HCV receiving NNRTIs.9 However, the risk of hepatotoxicity for patients with fibrosis stage F1 or F2 and F3 or F4 was similar among individuals who were receiving non-NNRTIs. In the present study, the proportion of severe hepatotoxicity of nelfinavir-containing regimens tended to be higher in patients with advanced liver fibrosis, but the differences did not reach statistical significance. This was probably due to lack of statistical power, because of the low incidence of severe liver toxicity of regimens including nelfinavir.
On the other hand, the majority of our patients were selected before undergoing liver biopsy. Ideally, to assess the impact of liver fibrosis stage on the risk for liver toxicity of nelfinavir-based HAART, a liver biopsy should be performed before initiating this therapy. However, some data suggest that liver fibrosis would not have changed significantly during the 2 year period of time since the biopsy. In fact, in HIV-uninfected patients the liver fibrosis progression from stage to stage is not rapid.25 There are few data describing the rate of liver fibrosis progression in HIV-coinfected patients. In the population who underwent liver biopsy at our unit,10 the estimated median fibrosis progression rate was 0.143 (interquartile range, 0.059–0.25). This figure means that in only 25% of patients would the liver fibrosis progress one Scheuer stage every 4 years or less. In an unpublished study reported recently,26 the change in fibrosis stage was analysed in paired liver biopsies (median time between biopsies was 2.5 years) taken from coinfected patients. Biopsies were scored according to the Ishak criteria from F0 (no fibrosis) to F6 (cirrhosis). The authors reported an increase of the fibrosis degree 2 stages of 27%. This figure, which may approximately represent one Scheuer fibrosis stage, is within the limits of variability of liver biopsy results in chronic hepatitis C.27
In summary, based on the results of our study, nelfinavir-containing regimens show an appropriate hepatic safety in HIV-infected patients with chronic hepatitis C. In our opinion, it is recommendable to use the drugs with less hepatotoxicity, such as nelfinavir, in coinfected patients, since the risk of severe liver toxicity is low and PIs seems to exert a protective effect against the progression of liver fibrosis in HIV/HCV-coinfected patients.10,28,29 Likewise, when severe liver toxicity develops in individuals taking nelfinavir therapy, other causes, particularly concomitant hepatotoxic antiretroviral drugs, need to be assessed.
|
Transparency declarations |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionTransparency declarationsReferences |
|---|
J. A. M. has received a research grant from GlaxoSmithKline. J. M. has been an investigator in clinical trials supported by Roche, Bristol-Myers Squibb and Abbot Pharmaceuticals. He has received lecture fees from Roche and consulting fees from Boehringer Ingelheim. D. M. reports having participated as an investigator in a clinical trial supported by GlaxoSmithKline. She has received consulting fees from Roche, Abbot and Bristol-Myers Squibb. M. G. S. reports having participated as an investigator in clinical trials supported by Roche and GlaxoSmithKline. She has received lecture fees from Boehringer Ingelheim. J. T. C. has research grants from Roche, Pfizer and Bristol-Myers Squibb. He has been an investigator in clinical trials supported by Roche, Schering-Plough, Pfizer, Merck Sharp & Dohme, GlaxoSmithKline, Gilead and Bristol-Myers Squibb. He has received lecture fees from Roche, Schering-Plough, Pfizer, Merck Sharp & Dohme, GlaxoSmithKline, Gilead and Bristol-Myers Squibb. M. I. B. works as a consultant International Medical Manager for F. Hoffman-La Roche and Pfizer, Inc. A. A. Y. has received a research grant from Roche. J. A. P. reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbot, Gilead and Boehringer Ingelheim Pharmaceuticals. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbot and Boehringer Ingelheim Pharmaceuticals and has received lecture fees from GlaxoSmithKline, Roche, Abbot, Bristol-Myers Squibb, Boehringer Ingelheim and Schering-Plough Pharmaceuticals. The remaining authors have no conflicts of interest.
|
Acknowledgements |
|---|
This study has been partly supported by a research grant from Hoffmann-La Roche.
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionTransparency declarationsReferences |
|---|
1 den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. (2000) Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS 14:2895–902.[CrossRef][Web of Science][Medline]
2 Rodríguez-Rosado R, García-Samaniego J, Soriano V. (1998) Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS 12:1256.[CrossRef][Web of Science][Medline]
3 Gisolf EH, Dreezen C, Danner SA, et al. (2000) Risk factors for hepatotoxicity in HIV-1-infected patients receiving ritonavir and saquinavir with or without stavudine. Clin Infect Dis 31:1234–9.[CrossRef][Web of Science][Medline]
4
Sulkowski MS, Thomas DL, Chaisson RE, et al. (2000) Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 283:74–80.
5
Saves M, Raffi F, Clevenbergh P, et al. (2000) Hepatitis B or hepatitis C virus infection is a risk factor for severe hepatic cytolysis after initiation of a protease inhibitor-containing antiretroviral regimen in human immunodeficiency virus-infected patients. The APROCO Study Group. Antimicrob Agents Chemother 44:3451–5.
6 Sulkowski MS, Mehta SH, Chaisson RE, et al. (2004) Hepatotoxicity associated with protease inhibitor-based antiretroviral therapy regimens with or without concurrent ritonavir. AIDS 18:2277–84.[CrossRef][Web of Science][Medline]
7 Aceti A, Pasquazzi C, Zechini B, et al. (2002) Hepatotoxicity development during antiretroviral therapy containing protease inhibitors in patients with HIV: the role of hepatitis B and C virus infection. J Acquir Immune Defic Syndr 29:41–8.[Medline]
8 Lana R, Núñez M, Mendoza JL, et al. (2001) Rate and risk factors of liver toxicity in patients receiving antiretroviral therapy. Med Clin (Barc) 117:607–10.[Medline]
9 Aranzabal L, Casado JL, Moya J, et al. (2005) Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 40:588–93.[CrossRef][Web of Science][Medline]
10 Macías J, Castellano V, Merchante N, et al. (2004) Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS 18:767–74.[CrossRef][Web of Science][Medline]
11 Mehta SH, Thomas DL, Torbenson M, et al. (2005) The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection. Hepatology 41:123–31.[CrossRef][Web of Science]
12 Sanne I, Mommeja-Marin H, Hinkle J, et al. (2005) Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 191:825–9.[CrossRef][Web of Science][Medline]
13 Martín-Carbonero L, Núnez M, González-Lahoz J, et al. (2003) Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clin Trials 4:115–20.[CrossRef][Web of Science][Medline]
14 Macías J, Melguizo I, Fernández-Rivera FJ, et al. (2002) 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 21:775–81.[CrossRef][Web of Science][Medline]
15 Martínez-Sierra C, Arizcorreta A, Díaz F, et al. (2003) Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis 36:491–8.[CrossRef][Web of Science][Medline]
16 Scheuer PJ. (1991) Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 13:372–4.[CrossRef][Web of Science][Medline]
17 da Silva B, King M, Cernohous P, et al. Lopinavir/ritonavir (LPV/r) safety, tolerability and efficacy in hepatitis C and/or hepatitis B-infected patients: review of clinical trials. Program and Abstracts of the Fifteenth International AIDS Conference, Bangkok, Thailand, 2004(IAS International AIDS Society, Geneva, Switzerland) Abstract MoPeB3285, p. 54.
18 Sabin CA. (2004) Pitfalls of assessing hepatotoxicity in trials and observational cohorts. Clin Infect Dis 38:S56–64.[Medline]
19 AIDS Clinical Trials Group. (1996) Table of Grading Severity of Adult Adverse Experiences (US Division of AIDS, National Institute of Allergy and Infectious Diseases, Rockville, MD).
20 Sulkowski MS, Thomas DL, Mehta SH, et al. (2002) Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 35:182–9.[CrossRef][Web of Science][Medline]
21 Dieterich DT, Robinson PA, Love J, et al. (2004) Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 38:S80–9.[CrossRef][Medline]
22 Law WP, Dore GJ, Duncombe CJ, et al. (2003) Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996–2001. AIDS 17:2191–9.[CrossRef][Web of Science][Medline]
23 Skowron G, Leoung G, Hall DB, et al. (2004) Pharmacokinetic evaluation and short-term activity of stavudine, nevirapine, and nelfinavir therapy in HIV-1-infected adults. J Acquir Immune Defic Syndr 35:351–8.[Medline]
24 Merry C, Barry MG, Mulcahy F, et al. (1998) The pharmacokinetics of combination therapy with nelfinavir plus nevirapine. AIDS 12:1163–7.[CrossRef][Web of Science][Medline]
25 Poynard T, Ratziu V, Charlotte F, et al. (2001) Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol 34:730–9.[CrossRef][Web of Science][Medline]
26 Sulkowski M, Mehta S, Torbenson M, et al. Unexpected significant liver disease among HIV/HCV-co-infected persons with minimal fibrosis on initial liver biopsy. Program and Abstracts of the Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2005(National Institute of Allergy and Infectious Diseases and Centers for Disease Control and Prevention, USA) Abstract 121, p. 16.
27 Bedossa P, Dargere D, Paradis V. (2003) Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 38:1449–57.[Web of Science][Medline]
28 Benhamou Y, Di Martino V, Bochet M, et al. (2001) Factors affecting liver fibrosis in human immunodefiency virus- and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology 34:283–7.[CrossRef][Web of Science][Medline]
29 Marine-Barjoan E, Saint-Paul MC, Pradier C, et al. (2004) Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients. AIDS 18:2163–70.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Macias, F. Orihuela, A. Rivero, P. Viciana, M. Marquez, J. Portilla, M. J. Rios, L. Munoz, J. Pasquau, M. A. Castano, et al. Hepatic safety of tipranavir plus ritonavir (TPV/r)-based antiretroviral combinations: effect of hepatitis virus co-infection and pre-existing fibrosis J. Antimicrob. Chemother., January 1, 2009; 63(1): 178 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M K Baum, C Rafie, S Sales, S Lai, R Duan, D T Jayaweera, J B Page, and A Campa C-reactive protein: a poor marker of cardiovascular disease risk in HIV+ populations with a high prevalence of elevated serum transaminases Int J STD AIDS, June 1, 2008; 19(6): 410 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Pineda, J. Santos, A. Rivero, L. Abdel-Kader, R. Palacios, A. Camacho, F. Lozano, J. Macias, and on behalf of the Liverey Study Investigator Team Liver toxicity of antiretroviral combinations including atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses: impact of pre-existing liver fibrosis J. Antimicrob. Chemother., April 1, 2008; 61(4): 925 - 932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rivero, J. A. Mira, and J. A. Pineda Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors J. Antimicrob. Chemother., March 1, 2007; 59(3): 342 - 346. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||