Email updates

Keep up to date with the latest news and content from BMC Research Notes and BioMed Central.

Open Access Research article

Hepatic steatosis in HIV-HCV coinfected patients receiving antiretroviral therapy is associated with HCV-related factors but not antiretrovirals

Valrie Martinez12*, Thi Dieu Ngan TA3, Zahra Mokhtari4, Marguerite Guiguet5, Patrick Miailhes6, Marc-Antoine Valantin25, Frderic Charlotte7, Philippe Bertheau8, Jean-Michel Molina9, Christine Katlama25 and Eric Caumes25

Author Affiliations

1 Service de Mdecine Interne et Immunologie Clinique, Assistance Publique-Hpitaux de Paris, INSERM UMR_S 996, Universit Paris Sud, Hpital Antoine Bclre, 157, rue de la Porte de Trivaux, 92141, Clamart, France

2 Service des Maladies Infectieuses et Tropicales, Hpital Piti-Salptrire, Universit Pierre et Marie Curie, APHP, 45/83 Boulevard de lHpital, 75013, Paris, France

3 Departement of Infectious Disease, Hanoi Medical University, 01, Ton That Tung Street, Hanoi, Vietnam

4 Departement of Internal Medicine, Hospital National Iranian oil company, Hafez Avenue, Tehran, Iran

5 INSERM U943, UPMC Univ Paris 06, UMR S943, Paris, F-75013, France

6 Service de Maladies Infectieuses et Tropicales, 103 Grande-Rue de la Croix-Rousse, Hpital de la Croix-Rousse, Hospices Civils de Lyon, 69317 Lyon cedex 04, Paris, France

7 Service dAnatomopathologie, Hpital Piti-Salptrire, Universit Pierre et Marie Curie, APHP, 45/83 Boulevard de lHpital, 75013, Paris, France

8 Service dAnatomopathologie, Hpital Saint-Louis, Universit Denis Diderot, APHP, 1, avenue Claude Vellefaux, 75010, Paris, France

9 Service des Maladies Infectieuses et Tropicales, Hpital Saint-Louis, Universit Denis Diderot, APHP, 1, avenue Claude Vellefaux, 75010, Paris, France

For all author emails, please log on.

BMC Research Notes 2012, 5:180  doi:10.1186/1756-0500-5-180


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1756-0500/5/180


Received:24 October 2011
Accepted:10 April 2012
Published:9 July 2012

© 2012 Martinez et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

In HIV and hepatitis C virus (HCV) coinfected patients, the role of antiretroviral therapy (ART) on hepatic steatosis (HS) remains controversial.

Methods

HIV/HCV coinfected patients receiving ART and previously untreated for HCV who underwent a liver biopsy were included. Cumulative duration of exposure to each antiretroviral was recorded up to liver biopsy date. Logistic regression analyses evaluated factors associated with steatosis and its severity.

Results

184 patients were included: median age 41years, 84% male, 89% Caucasian, 61% with a past history of intravenous drug use. HCV genotypes were 1 (55%), 2 (6%), 3 (26%), and 4 (13%). Median HCV-RNA was 6.18 log10 IU/ml. HIV-RNA was undetectable (<400 copies/ml) in 67% of patients. Median CD4 count was 321/mm3. All patients had been exposed to nucleoside reverse transcriptase inhibitors (median cumulative exposure 56months); 126 received protease inhibitors (23months), and 79 non-nucleoside reverse transcriptase inhibitors (16months). HS was observed in 102 patients (55%): 41% grade 1; 5% grade 2, and 9% grade 3. In multivariate analysis, HCV genotype 3 and HCV viral load were moderately associated with mild steatosis but strongly with grade 2-3 steatosis. After adjustment for the period of biopsy, no association was detected between HS and exposure to any antiretroviral class or drug, or duration of ART globally or comparing genotype 3 to others.

Conclusions

Among our ART-treated HIV-HCV cohort predominantly infected with genotype 1, 55% of patients had HS which was associated with HCV-related factors, but not ART class or duration of exposure.

Keywords:
HIV; HCV; steatosis; antiretroviral drugs; genotype 3

Introduction

As a result of shared transmission routes, hepatitis C virus (HCV) infection is common in patients infected with human immunodeficiency virus (HIV) [1-3]. In the USA and Western Europe, at least 30% of HIV-infected patients are also infected with HCV [1-4]. The immunosuppression induced by HIV accelerates the natural history of HCV-related liver disease and the progression of chronic hepatitis C to cirrhosis and end-stage hepatic disease [5-10].

The introduction of highly active antiretroviral therapy has been associated with a dramatic decline in the morbidity and mortality related to specific HIV complications, whereas that related to liver disease has increased significantly in coinfected patients [1,6,11-13]. The relative increase in morbidity and mortality due to liver disease in the HIV population is a composite of accelerated liver disease progression in HCV patients and extended survival of these individuals due to the benefit of antiretroviral therapy (ART).

Hepatic steatosis (HS), defined by the accumulation of lipid droplets in hepatocytes, is present in 24-75% of HIV and HCV coinfected patients [12,14-23]. Some factors contributing to the development of HS in the general population, such as visceral obesity, alcohol consumption, hypertriglyceridemia, hypertension and diabetes mellitus remain hugely discrepant during coinfection [24-28]. In HIV and HCV coinfected patients, HS may occur as a result of the HIV infection or as a consequence of concomitant HCV infection, as well as metabolic factors such diabetes, obesity or antiretroviral drugs which could induce metabolic syndrome, lipodystrophy or lactic acidosis due to mitochondrial damage [12,14,15,18-20,22,29-32]. Nevertheless, the role of ART, particularly stavudine exposure, remains controversial. Moreover, in some studies, HS appears to be more common and severe in coinfected than in HCV-monoinfected patients [16,22] and influence by the viral genotype [16,22]. Borghi et al., showed previously that HIV related steatosis increase in genotype 3 patients and a putative role of ART in patients infected by HCV genotype other than 3 [23]. Other factors besides immunesuppression account for faster progression to ESLD in coinfected patients (i.e. HIV hepatocyte infection, drug liver toxicity).

To assess the prevalence and risk factors of HS, particularly characteristics associated with severity, we reviewed the epidemiological, clinical and biological data of HIV-HCV coinfected patients receiving ART, before HCV therapy and at the time of liver biopsy. Moreover, we compared the effect of ART according to the genotype.

Patients and Methods

Patients

For this study, HIV-HCV coinfected patients were retrospectively screened in histopathology databases of two hospitals. All HIV-infected patients with detectable HCV RNA load (qualitative or quantitative detection), receiving ART but naive of HCV-specific therapy and who underwent a liver biopsy between January 1995 and January 2008, were included. When repeated liver biopsies were performed, only data associated with the first one was studied.

Patients were excluded if they were positive for hepatitis B surface antigen, had a negative plasma HCV RNA load, or other chronic liver diseases, such as autoimmune hepatitis, hemochromatosis, Wilsons disease or alpha-1 antitrypsin deficiency. All patients have been tested for all of these parameters and the patients included were negative.

At the day of liver biopsy, the following variables were assessed: age, gender, ethnicity, alcohol (reported by physician in the medical report, but no data about the quantity consumed daily), intravenous drug abuse, duration of documented HIV and HCV infections, risk factors for viral transmission, CD4 cell count, HIV and HCV plasma levels, HCV genotype, fasting glycemia, total cholesterolemia and triglyceridemia, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyl transferase (GGT) and alkaline phosphatase. Measure of insulinemia, not performed in clinical practice, was not available in this retrospective study, nor measure of weight, body mass index and waist circumference which were not recorded in the medical report. Metabolic parameters were also recorded for each patient on a fasting state. For the purposes of this study, metabolic syndrome was defined as triglycerides

    >
1.7mmol/l and glycemia 5.6mmol/l as recommended by the International Diabetes Federation 2005 and diabetes as a fasting glycemia>7mmol/l and excluded waist circumference [33].

HCV RNA detection was performed using a signal amplification nucleic acid probe assay (bDNA 3.0, Bayer diagnostics, Tarrytown NY) and was expressed in KIU/ml. All biological data were assessed directly to the data system of the different laboratories of the 2 hospitals. All of the parameters collected were routinely performed in HIV-HCV patients who underwent a liver biopsy and were assessed on the day of biopsy or during the week before.

History of antiretroviral therapy was assessed in the medical report and from our database (Nadis software). The cumulative duration of exposure to each drug and class of drugs was recorded for each patient up to the date of liver biopsy. As patients could have received more than one ART regimen, and because of the large diversity of regimens available in France, it would be impossible to select specific drug combinations for analysis. Therefore, we hypothesized that a relationship between a combination of drugs and severity of HS would be evident by studying each component of the combination.

Histologic evaluation

Percutaneous or transjugular liver biopsy specimens were fixed in formalin and embedded in paraffin. Minimal size was 10mm and contained at least 6 portal spaces, excepted if cirrhosis. Sections 4m thick were stained with hematoxylin and eosin, with picrosirius stain for collagen and Perls stain for iron. All liver biopsy specimens were evaluated by two experienced pathologists, one in each hospital (F.C. or P.B.).

The grade of activity and the stage of fibrosis were evaluated according to the METAVIR scale [34]. Necroinflammatory activity was graded A0 (none), A1 (mild), A2 (moderate) or A3 (high). The degree of portal and septal fibrosis was assessed as F0 (none), F1 (portal fibrosis without septa), F2 (portal fibrosis with a few septa), F3 (portal fibrosis with numerous septa) or F4 (cirrhosis). HS was evaluated and graded as proposed by Brunt et al.[33]: grade 0, none; grade 1, steatosis involving <33% of hepatocytes; grade 2, 33-66% and grade 3, >66%. HS was defined as mild (grade 1) or severe (grade 2-3).

Statistical analysis

Median and interquartile ranges (IQRs) described continuous variables. Comparisons between patients found with and without steatosis were performed using Kruskal-Wallis or Wilcoxon tests for quantitative variables, and 2 test or Fishers exact test for qualitative variables. Logistic regression analyses were used to identify determinants of liver steatosis, and polytomous logistic regression analyses evaluated factors associated with the presence of mild or severe steatosis.

Exposure to ART was studied after adjustment for the period of biopsy (1995-1998, 1999-2001, 2002-2008). The periods were chosen at the time of the statistical analysis according to the introduction of drugs such as abacavir in 1999 and tenofovir in 2002 to show an impact of the use of more metabolic friendly drugs. Exposure to ART and cumulative exposure duration (per 1year increased) were evaluated globally for all patients and according to genotype: genotype 3 compared to others.

Variables with p<0.15 in univariate analyses were included in the final model. Analyses were processed with the use of SAS software (SAS Institute, Cary, North Carolina, USA).

Results

Study population

Between January 1995 and January 2008, 250 HIV-HCV coinfected patients who underwent a liver biopsy and fulfilled all inclusion criteria were evaluated. Sixty-six patients were not analyzed for the following reasons corresponding to exclusion criteria: hepatitis B coinfection (n=28), loss of medical records (n=8) or no ART at the time of biopsy (n=30). Therefore, 184 patients were included. Demographic and biological characteristics are summarized in Table1.

Table 1. Characteristics of HIV-HCV coinfected patients treated with antiretroviral therapy at the time of liver biopsy (parameters collected the day of the liver biopsy or during the week before)

No correlation was observed between the duration of HIV infection and CD4 cell count in this cohort of ART-treated patients. HIV plasma viral load was undetectable (<400 copies/ml) in 119 out of the 178 (67%) evaluable patients and median HIV viral load on average was 3.93 log10 copies/ml for the remaining 33% patients. The median HCV viral load was 6.18 log10 IU/ml (IQR 5.76-6.60) in the 148 (80%) patients with quantificative HCV values. The other patients (n=36) had only a positive HCV RNA without quantification.

All patients had been exposed to a nucleoside reverse transcriptase inhibitor (NRTI), including zidovudine (n=144), lamivudine (n=161), stavudine (n=114), zalcitabine (n=22), didanosine (n=105), tenofovir (n=24) and abacavir (n=24); 126 patients had received protease inhibitors (PI), including ritonavir as boosted-PI (n=59), indinavir (n=68), nelfinavir (n=47), saquinavir (n=16), lopinavir (n=17) and atazanavir (n=8); and 79 patients had received non-nucleoside reverse transcriptase inhibitors (NNRTI), including efavirenz (n=51) and nevirapine (n=44).

Histologic findings

Overall, 102 (55%) out of the 184 patients had HS. Steatosis was grade 1 in 76 (41%) patients, grade 2 in 10 (5%), and 3 in 16 (9%). Macrovesicular fatty changes were observed in 56 patients (55%), microvesicular in 10 (10%), and mixed form in 36 (35%). Fibrosis was present in 163 patients (89%) with METAVIR F1 score in 66 (36%), F2 in 53 (29%), F3 in 39 (21%) and F4 in 4 (2%). Necroinflammatory activity was detected in 164 out of the 184 (89%) patients with A1 in 109 (59%), A2 in 50 (27%) and A3 in 5 (3%).

Factors associated with hepatic steatosis

Comparison of parameters in patients with or without HS are presented in Table2. In univariate analysis, intravenous drug use (p=0.05) and HCV genotype 3 (p=0.005) were strongly linked with HS. The median HCV viral load was significantly higher in patients with HS compared with those without (p=0.003). HS was also associated with increased levels of ALT, AST and decreased levels of serum total cholesterol, but not with triglyceridemia nor available parameters of metabolic syndrome (only 7 patients have a glycemia >7mmol/l with mild steatosis for 6 patients and 1 had no steatosis) (Table2).

Table 2. Comparison of various parameters in patients with mild (<33% of hepatocytes affected) or severe (>33% of hepatocytes affected) steatosis and those without steatosis (univariate analysis)

Also, there was no association with CD4 cell count or an undetectable HIV viral load. Similar results were found in patients with mild versus severe steatosis.

HS was also associated with fibrosis (Figure1). Thus, the frequency of HS increased with the stages of fibrosis, with 76%, 54%, 32%, and 28% of patients without steatosis having fibrosis scores of F0, F1, F2, and F3F4, respectively (Cochran-Armitage trend test, p<0.0001). However, the severity of steatosis was not different among patients presenting fibrosis scoring F1, F2, or F3F4. No association was observed between HS and necroinflammatory activity.

thumbnailFigure 1. Distribution of steatosis according to fibrosis index in 184 HIV-HCV coinfected patients treated with antiretroviral therapy. Steatosis is defined as mild (<33% of hepatocytes affected) or severe (>33% of hepatocytes affected).

After adjustment for the period of biopsy, neither the type of ART nor the duration of exposure to a specific antiretroviral agent or class of antiretroviral was related to HS (Table3). The same results were observed in separate analyses among patients presenting genotype 3, or another genotype (Tables4 and 5).

Table 3. The effects on steatosis of exposure to specific antiretroviral medication in 184 HIV-HCV coinfected patients

Table 4. The effects on steatosis of exposure to specific antiretroviral medication in 184 HIV-HCV coinfected patients according to the genotype

Table 5. The effects on steatosis of cumulative exposure duration to specific antiretroviral medication in 184 HIV-HCV coinfected patients according to the genotype

In the multivariate analysis, only two independent factors remained associated with an increased risk of HS: HCV genotype 3 (odds ratio [OR], 2.6; 95% confidence intervals [CI], 1.1-6.3), and HCV RNA load (OR, 2.2 per 1 log higher; 95% CI, 1.2-3.8). Using a multivariate polytomous logistic regression model, HCV genotype 3 and HCV RNA load were moderately associated with mild steatosis and strongly associated with severe steatosis (Table6).

Table 6. Results from multivariate polytomous logistic regression analyses of factors associated with mild (<33% of hepatocytes affected ) and severe (>33% of hepatocytes affected) steatosis in 184 HIV-HCV coinfected patients treated with antiretroviral therapy

Discussion

Hepatic steatosis has emerged as a major comorbidity in HIV-HCV coinfected patients [13,35]. In this retrospective observational study of 184 HIV-HCV coinfected patients ART-treated but untreated for HCV at the time of liver biopsy, HS was present in about half patients (55%), which is similar to rates of 24-75% found in other studies of HIV-HCV coinfected and HCV monoinfected patients [12,14-23,36]. In multivariate analysis, HS and its severity were only significantly associated with HCV genotype 3 and HCV viral load. Neither the type of ART, nor their prolonged duration of exposure with a median of near five years were related to steatosis. Moreover, ART have no differential effect on occurrence of HS according to the genotype 3 compared to others.

We confirmed previously data of higher HS associated with genotype 3 [23]. Here, the rate of severe HS (14%) was higher in our study compared with 2-9% found in US studies in HIV-HCV coinfected individuals [12], but was similar with rates found in other studies [37,38], in particular with those conducted in France [39,40]. Several reasons may explain these discrepancies. Whereas most of our patients, and those included in the study of Bauerle et al. [37], were Caucasian and carrying HCV genotype 3, other studies have included a high proportion of Africo-American patients (47-94%) and patients infected with HCV genotype 1 [38-45]. It is well-known that HCV-infected Black people have a lower prevalence of HS than Caucasian [41,45-47], probably related to lower visceral adipose tissue [16,22].

HS is a frequent histological finding in patients with chronic hepatitis C virus infection, particularly among those infected with genotype 3 strain [24,48,49]. The prevalence of 26% of genotype 3 in our study was similar to the prevalence of 18% reported in the French HepaVIH cohort [50]. It has been postulated that genotype 1 is associated with metabolic steatosis rather than viral steatosis developed through a direct cytopathologic effect observed especially in genotype 3 infected patients [51-56]. When we examined the factors impacting the level of steatosis on ART patients, genotype 3, and high HCV viral load were two independent factors associated with HS in accordance with previous studies [15,17,19,20]. Both factors moderately increased the risk of mild steatosis, but were strongly associated with severe steatosis (grade 2 or 3).

Other factors such as greater age [18], higher body mass index (BMI) [12,15-18,20,22,38-40,42,44][23], hyperglycemia [12], lower cholesterolemia [17], and presence of lipodystrophy [17] have also been found to be independently associated with steatosis in coinfected patients. In our study, patients with metabolic syndrome were not more likely to present HS. However, only seven patients had diabetes, and this limited sample size could have prevent to study this risk factor. Moreover, as expected, exposure to PIs and stavudine, were associated with elevated triglycerides (p=0.08 and p<0.0001, respectively), but this metabolic abnormality was not a risk factors of HS in our ART-experienced population. According to the lack of data about HOMA scoring, weight and BMI, we probably missed the impact of metabolic steatosis in genotype other than 3 [23,41]. Other limitation of our retrospective study is lack of information about alcohol consumption. Nevertheless, as described by Machado et al., metabolic syndrome and alcohol were not associated to HS. BMI was considered an increasing risk factor but with small magnitude and diabetes as a possible risk factor with no data for HOMA scoring [16,22]. Moreover, the higher percentage of genotype 3 reflect the association between HS and HCV viral parameters.

Many antiretroviral drugs have been associated with hepatic damage [57-59]. It has been suggested that steatosis due to an accumulation of fatty acids in the hepatocytes could be a consequence of mitochondrial dysfunction, secondary to drugs or viruses inducing oxidative stress [60]. The effect of the drug class and drugs within classes on HS in HIV-HCV coinfected patients remain unclear. Previously, some studies reported no significant association between HS and ART as in our study [12,15,16,18,41]. When focusing on the use of stavudine, a medication closely linked with HS and lipodystrophy syndrome resulting from mitochondrial damage, Sulkowski et al.[45] found that stavudine exposure was a risk factor for steatosis like in the study of Borghi et al., whereas no such association was found for this drug as well as the D-drug group of antiretrovirals (didanosine, zalcitabine) in other studies [23,38,41,42,61,62]. Recently, in a meta-analysis of the risk factors associated with HS in HIV-HCV patients, Machado et al. failed to find any association with antiretrovirals of any class and HS as well as in our study [16,22]. Moreover, Woreta et al., showed in a study including a majority of Black patients (87%) with 94% genotype 1, the lack of association with antiretroviral drugs with a median cumulative drug exposure similar to ours [41]. Despite its relatively small sample size, our study had a statistical power of 80% to detect an increased risk of steatosis of 3 for the antiretroviral drugs used less frequently such as abacavir, tenofovir and lopinavir. We could hypothesize that discrepancies with other studies were linked to the differential prevalence of Caucasion subjects, of metabolic characteristics and frequency of genotype 1 and 3. Borghi et al. evocated a putative role of ART in the occurrence of HS in patients infected with genotypes other than 3 [23] but in our study, the impact of ART on HS was not different between genotype 3 and the others.

In conclusion, for our Caucasian cohort predominantly infected with genotype-HCV 1, hepatic steatosis in HIV-HCV coinfected patients receiving antiretroviral therapy is associated with HCV-related factors particularly in genotype 3 patients but not antiretrovirals. Nevertheless, as showed in our study, ART seems play a minor role in HS since the choose and use of more "metabolically friendly" antiretroviral drugs. Overall, we found only viral parameters, HCV genotype 3, and HCV RNA value, which were strongly associated with HS, particularly a severe steatosis. Among HIV-HCV co-infected patients receiving ART and who had never been treated for HCV, neither the type of drugs nor the duration of exposure was related to HS whatever the genotype.

Abbreviations

HIV = human immunodeficiency virus; HCV = hepatitis C virus; ART = antiretroviral therapy; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gammaglutamyl transferase; IQR = interquartile range; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; OR = odds ratio; CI = confidence intervals; IVDU = intravenous drug use; AOR = adjusted odds ratio; NE = not estimable.

Meeting presentation

13th Conference of Retroviruses and Opportunistic Infections, 58 February 2006, Denver, Colorado, USA. Poster number: p-169 and 16th Conference of Retroviruses and Opportunistic Infections, 811 February 2009, Montral, Canada. Poster number: p-853.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

VM conceived the study, collected data of patients, participated in its design and coordination and drafted the manuscript. TDNT and ZM collected the data and helped to draft the manuscript. MG made the statistical analysis and helped to draft the manuscript. PM and MAV helped to draft the manuscript. FC and PB made the histological analysis of liver biopsy. CK and EC participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.

Financial disclosure

The authors have no commercial links or other associations that might pose a conflict of interest (e.g. pharmaceutical stock ownership, consultancy, advisory board membership, relevant patents, or research funding) relevant to this study.

Statement naming sources of financial support (including grant numbers)

None

Acknowledgements

English language assistance for the preparation of this manuscript was provided by Andrea Bothwell of inScience Communications.

References

  1. Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, Arizcorreta A, Gonzalez A, Rockstroh J, Asensi V, et al.: Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study.

    Clin Infect Dis 2004, 38(1):128-133.

    Epub 2003 Dec 2008

    PubMed Abstract | Publisher Full Text OpenURL

  2. Mehta SH, Thomas DL, Torbenson M, Brinkley S, Mirel L, Chaisson RE, Moore RD, Sulkowski MS: The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection.

    Hepatology 2005, 41(1):123-131. PubMed Abstract | Publisher Full Text OpenURL

  3. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauerbruch T, Rockstroh JK, Spengler U: Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection.

    Lancet 2003, 362(9397):1708-1713. PubMed Abstract | Publisher Full Text OpenURL

  4. Lauer GM, Walker BD: Hepatitis C virus infection.

    N Engl J Med 2001, 345(1):41-52. PubMed Abstract | Publisher Full Text OpenURL

  5. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ: Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis.

    Clin Infect Dis 2001, 33(4):562-569. PubMed Abstract | Publisher Full Text OpenURL

  6. Macias J, Castellano V, Merchante N, Palacios RB, Mira JA, Saez C, Garcia-Garcia JA, Lozano F, Gomez-Mateos JM, Pineda JA: Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine.

    AIDS 2004, 18(5):767-774. PubMed Abstract | Publisher Full Text OpenURL

  7. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauerbruch T, Rockstroh JK, Spengler U: Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection.

    Lancet 2003, 362(9397):1708-1713. PubMed Abstract | Publisher Full Text OpenURL

  8. Mohsen AH, Easterbrook PJ, Taylor C, Portmann B, Kulasegaram R, Murad S, Wiselka M, Norris S: Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients.

    Gut 2003, 52(7):1035-1040. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  9. Soriano V, Martin-Carbonero L, Garcia-Samaniego J, Puoti M: Mortality due to chronic viral liver disease among patients infected with human immunodeficiency virus.

    Clin Infect Dis 2001, 33(10):1793-1795. PubMed Abstract | Publisher Full Text OpenURL

  10. Thein HH, Yi Q, Dore GJ, Krahn MD: Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis.

    AIDS 2008, 22(15):1979-1991. PubMed Abstract | Publisher Full Text OpenURL

  11. Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, Snydman DR: Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection.

    Clin Infect Dis 2001, 32(3):492-497. PubMed Abstract | Publisher Full Text OpenURL

  12. Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore RD, Thomas DL: Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus.

    AIDS 2005, 19(6):585-592. PubMed Abstract | Publisher Full Text OpenURL

  13. Pol S, Lebray P, Vallet-Pichard A: HIV infection and hepatic enzyme abnormalities: intricacies of the pathogenic mechanisms.

    Clin Infect Dis 2004, 38(Suppl 2):S65-S72. PubMed Abstract | Publisher Full Text OpenURL

  14. Sterling RK, Contos MJ, Smith PG, Stravitz RT, Luketic VA, Fuchs M, Shiffman ML, Sanyal AJ: Steatohepatitis: Risk factors and impact on disease severity in human immunodeficiency virus/hepatitis C virus coinfection.

    Hepatology 2008, 47(4):1118-1127. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  15. Bani-Sadr F, Carrat F, Bedossa P, Piroth L, Cacoub P, Perronne C, Degott C, Pol S: Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors.

    AIDS 2006, 20(4):525-531. PubMed Abstract | Publisher Full Text OpenURL

  16. Gaslightwala I, Bini EJ: Impact of human immunodeficiency virus infection on the prevalence and severity of steatosis in patients with chronic hepatitis C virus infection.

    J Hepatol 2006, 44(6):1026-1032. PubMed Abstract | Publisher Full Text OpenURL

  17. Marks KM, Petrovic LM, Talal AH, Murray MP, Gulick RM, Glesby MJ: Histological findings and clinical characteristics associated with hepatic steatosis in patients coinfected with HIV and hepatitis C virus.

    J Infect Dis 2005, 192(11):1943-1949.

    Epub 2005 Nov 1942

    PubMed Abstract | Publisher Full Text OpenURL

  18. Monto A, Dove LM, Bostrom A, Kakar S, Tien PC, Wright TL: Hepatic steatosis in HIV/hepatitis C coinfection: prevalence and significance compared with hepatitis C monoinfection.

    Hepatology 2005, 42(2):310-316. PubMed Abstract | Publisher Full Text OpenURL

  19. McGovern BH, Ditelberg JS, Taylor LE, Gandhi RT, Christopoulos KA, Chapman S, Schwartzapfel B, Rindler E, Fiorino AM, Zaman MT, et al.: Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients.

    Clin Infect Dis 2006, 43(3):365-372. PubMed Abstract | Publisher Full Text OpenURL

  20. Neau D, Winnock M, Castera L, Bail BL, Loko MA, Geraut L, Dupon M, Ragnaud JM, Lacoste D, Lafon ME, et al.: Prevalence of and factors associated with hepatic steatosis in patients coinfected with hepatitis C virus and HIV: Agence Nationale pour la Recherche contre le SIDA et les hepatites virales CO3 Aquitaine Cohort.

    J Acquir Immune Defic Syndr 2007, 45(2):168-173. PubMed Abstract | Publisher Full Text OpenURL

  21. Sanchez-Conde M, Berenguer J, Miralles P, Alvarez F, Carlos Lopez J, Cosin J, Pilar C, Ramirez M, Gutierrez I, Alvarez E: Liver biopsy findings for HIV-infected patients with chronic hepatitis C and persistently normal levels of alanine aminotransferase.

    Clin Infect Dis 2006, 43(5)):640-644. PubMed Abstract | Publisher Full Text OpenURL

  22. Castera L, Loko MA, Le Bail B, Coffie P, De Ledinghen V, Trimoulet P, Winnock M, Dabis F, Neau D: Hepatic steatosis in HIV-HCV coinfected patients in France: comparison with HCV monoinfected patients matched for body mass index and HCV genotype.

    Aliment Pharmacol Ther 2007, 26(1112):1489-1498. PubMed Abstract | Publisher Full Text OpenURL

  23. Borghi V, Puoti M, Mussini C, Bellelli S, Angeletti C, Sabbatini F, Prati F, Cossarizza A, Esposito R: HIV coinfection and antiretroviral therapy enhances liver steatosis in patients with hepatitis C, but only in those infected by HCV genotype other than 3.

    Antivir Ther 2008, 13(8):1057-1065. PubMed Abstract OpenURL

  24. Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL: Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol.

    Hepatology 2002, 36(3):729-736. PubMed Abstract | Publisher Full Text OpenURL

  25. Sanyal AJ: Review article: non-alcoholic fatty liver disease and hepatitis Crisk factors and clinical implications.

    Aliment Pharmacol Ther 2005, 22(Suppl 2):48-51. PubMed Abstract OpenURL

  26. Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE: Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis.

    Hepatology 1999, 29(4):1215-1219. PubMed Abstract | Publisher Full Text OpenURL

  27. Hu KQ, Kyulo NL, Esrailian E, Thompson K, Chase R, Hillebrand DJ, Runyon BA: Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States.

    J Hepatol 2004, 40(1):147-154. PubMed Abstract | Publisher Full Text OpenURL

  28. Sanyal AJ, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Stravitz RT, Mills AS: Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome.

    Am J Gastroenterol 2003, 98(9):2064-2071. PubMed Abstract | Publisher Full Text OpenURL

  29. Marks KM, Petrovic LM, Talal AH, Murray MP, Gulick RM, Glesby MJ: Histological findings and clinical characteristics associated with hepatic steatosis in patients coinfected with HIV and hepatitis C virus.

    J Infect Dis 2005, 192(11):1943-1949. PubMed Abstract | Publisher Full Text OpenURL

  30. Brinkman K: Editorial response: hyperlactatemia and hepatic steatosis as features of mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors.

    Clin Infect Dis 2000, 31(1):167-169. PubMed Abstract | Publisher Full Text OpenURL

  31. Balasubramanyam A, Sekhar RV, Jahoor F, Jones PH, Pownall HJ: Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: a model of 'systemic steatosis'.

    Curr Opin Lipidol 2004, 15(1):59-67. PubMed Abstract | Publisher Full Text OpenURL

  32. Ogedegbe AE, Thomas DL, Diehl AM: Hyperlactataemia syndromes associated with HIV therapy.

    Lancet Infect Dis 2003, 3(6):329-337. PubMed Abstract | Publisher Full Text OpenURL

  33. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.

    Am J Gastroenterol 1999, 94(9):2467-2474. PubMed Abstract | Publisher Full Text OpenURL

  34. The French METAVIR Cooperative Study Group: Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C.

    Hepatology 1994, 20(1 Pt 1):15-20. PubMed Abstract OpenURL

  35. Tien PC, Grunfeld C: The fatty liver in AIDS.

    Semin Gastrointest Dis 2002, 13(1):47-54. PubMed Abstract OpenURL

  36. Bauerle J, Miquel R, Laguno M, Mallolas J, Murillas J, Gatell JM, Walker UA: Hepatic steatosis with stavudine in HIV/hepatitis C virus co-infection.

    AIDS 2005, 19(13):1441-1442. PubMed Abstract | Publisher Full Text OpenURL

  37. Bauerle J, Miquel R, Laguno M, Mallolas J, Murillas J, Gatell JM, Walker UA: Hepatic steatosis with stavudine in HIV/hepatitis C virus co-infection.

    AIDS 2005, 19(13):1441-1442. PubMed Abstract | Publisher Full Text OpenURL

  38. Gaslightwala I, Bini EJ: Impact of human immunodeficiency virus infection on the prevalence and severity of steatosis in patients with chronic hepatitis C virus infection.

    J Hepatol 2006, 44(6):1026-1032. PubMed Abstract | Publisher Full Text OpenURL

  39. Bani-Sadr F, Carrat F, Bedossa P, Piroth L, Cacoub P, Perronne C, Degott C, Pol S: Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors.

    AIDS 2006, 20(4):525-531. PubMed Abstract | Publisher Full Text OpenURL

  40. Castera L, Loko MA, Le Bail B, Coffie P, De Ledinghen V, Trimoulet P, Winnock M, Dabis F, Neau D: Hepatic steatosis in HIV-HCV coinfected patients in France: comparison with HCV monoinfected patients matched for body mass index and HCV genotype.

    Aliment Pharmacol Ther 2007, 26(1112):1489-1498. PubMed Abstract | Publisher Full Text OpenURL

  41. Woreta TA, Sutcliffe CG, Mehta SH, Brown TT, Higgins Y, Thomas DL, Torbenson MS, Moore RD, Sulkowski MS: Incidence and risk factors for steatosis progression in adults coinfected with HIV and hepatitis C virus.

    Gastroenterology 2011, 140(3):809-817. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  42. Marks KM, Petrovic LM, Talal AH, Murray MP, Gulick RM, Glesby MJ: Histological findings and clinical characteristics associated with hepatic steatosis in patients coinfected with HIV and hepatitis C virus.

    J Infect Dis 2005, 192(11):1943-1949.

    Epub 2005 Nov 1942

    PubMed Abstract | Publisher Full Text OpenURL

  43. Monto A, Dove LM, Bostrom A, Kakar S, Tien PC, Wright TL: Hepatic steatosis in HIV/hepatitis C coinfection: prevalence and significance compared with hepatitis C monoinfection.

    Hepatology 2005, 42(2):310-316. PubMed Abstract | Publisher Full Text OpenURL

  44. Neau D, Winnock M, Castera L, Bail BL, Loko MA, Geraut L, Dupon M, Ragnaud JM, Lacoste D, Lafon ME, et al.: Prevalence of and factors associated with hepatic steatosis in patients coinfected with hepatitis C virus and HIV: Agence Nationale pour la Recherche contre le SIDA et les hepatites virales CO3 Aquitaine Cohort.

    J Acquir Immune Defic Syndr 2007, 45(2):168-173. PubMed Abstract | Publisher Full Text OpenURL

  45. Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore RD, Thomas DL: Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus.

    AIDS 2005, 19(6):585-592. PubMed Abstract | Publisher Full Text OpenURL

  46. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH: Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.

    Hepatology 2004, 40(6):1387-1395. PubMed Abstract | Publisher Full Text OpenURL

  47. Martin-Carbonero L, Soriano V: Interplay between hepatitis C, liver steatosis and antiretroviral therapy in HIV-infected patients.

    AIDS 2005, 19(6):621-623. PubMed Abstract | Publisher Full Text OpenURL

  48. Castera L, Hezode C, Roudot-Thoraval F, Lonjon I, Zafrani ES, Pawlotsky JM, Dhumeaux D: Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis.

    Gut 2004, 53(3):420-424. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  49. Kumar D, Farrell GC, Fung C, George J: Hepatitis C virus genotype 3 is cytopathic to hepatocytes: Reversal of hepatic steatosis after sustained therapeutic response.

    Hepatology 2002, 36(5):1266-1272. PubMed Abstract | Publisher Full Text OpenURL

  50. Loko MA, Salmon D, Carrieri P, Winnock M, Mora M, Merchadou L, Gillet S, Pambrun E, Delaune J, Valantin MA, et al.: The French national prospective cohort of patients co-infected with HIV and HCV (ANRS CO13 HEPAVIH): early findings, 20062010.

    BMC Infect Dis 2010, 10:303. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  51. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G: Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.

    Hepatology 2001, 33(6):1358-1364. PubMed Abstract | Publisher Full Text OpenURL

  52. Castera L, Chouteau P, Hezode C, Zafrani ES, Dhumeaux D, Pawlotsky JM: Hepatitis C virus-induced hepatocellular steatosis.

    Am J Gastroenterol 2005, 100(3):711-715. PubMed Abstract | Publisher Full Text OpenURL

  53. Clement S, Negro F: Hepatitis C virus: the viral way to fatty liver.

    J Hepatol 2007, 46(6):985-987. PubMed Abstract | Publisher Full Text OpenURL

  54. Hezode C, Roudot-Thoraval F, Zafrani ES, Dhumeaux D, Pawlotsky JM: Different mechanisms of steatosis in hepatitis C virus genotypes 1 and 3 infections.

    J Viral Hepat 2004, 11(5):455-458. PubMed Abstract | Publisher Full Text OpenURL

  55. Patton HM, Patel K, Behling C, Bylund D, Blatt LM, Vallee M, Heaton S, Conrad A, Pockros PJ, McHutchison JG: The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients.

    J Hepatol 2004, 40(3):484-490. PubMed Abstract | Publisher Full Text OpenURL

  56. Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Male PJ, Mentha G, Spahr L, Zarski JP, Borisch B, Hadengue A, et al.: Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3.

    J Hepatol 2000, 33(1):106-115. PubMed Abstract | Publisher Full Text OpenURL

  57. Fortgang IS, Belitsos PC, Chaisson RE, Moore RD: Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy.

    Am J Gastroenterol 1995, 90(9):1433-1436. PubMed Abstract OpenURL

  58. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD: Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir.

    AIDS 2004, 18(17):2277-2284. PubMed Abstract | Publisher Full Text OpenURL

  59. Y B: Systemic overview of HAART- associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. In: 13 th Conference on Retroviruses and Opportunistic Infections 2006. Denver, CO, US; 2006. OpenURL

  60. Day CP, James OF: Steatohepatitis: a tale of two "hits"?

    Gastroenterology 1998, 114(4):842-845. PubMed Abstract | Publisher Full Text OpenURL

  61. Bauerle J, Laguno M, Mauss S, Mallolas J, Murillas J, Miquel R, Schmutz G, Setzer B, Gatell JM, Walker UA: Mitochondrial DNA depletion in liver tissue of patients infected with hepatitis C virus: contributing effect of HIV infection?

    HIV Med 2005, 6(2):135-139. PubMed Abstract | Publisher Full Text OpenURL

  62. Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL: Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol.

    Hepatology 2002, 36(3):729-736. PubMed Abstract | Publisher Full Text OpenURL