As a result of shared transmission routes, hepatitis C virus (HCV) infection is common in patients infected with human immunodeficiency virus (HIV) 123. In the USA and Western Europe, at least 30% of HIV-infected patients are also infected with HCV 1234. 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 5678910.

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 16111213. 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 1214151617181920212223. 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 2425262728. 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 1214151819202229303132. 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 1622 and influence by the viral genotype 1622. 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.

Hepatic steatosis has emerged as a major comorbidity in HIV-HCV coinfected patients 1335. 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 121415161718192021222336. 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 3738, in particular with those conducted in France 3940. 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 3839404142434445. It is well-known that HCV-infected Black people have a lower prevalence of HS than Caucasian 41454647, probably related to lower visceral adipose tissue 1622.

HS is a frequent histological finding in patients with chronic hepatitis C virus infection, particularly among those infected with genotype 3 strain 244849. 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 515253545556. 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 15171920. 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) 12151617182022383940424423, 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 2341. 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 1622. 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 575859. 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 1215161841. 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 233841426162. 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 1622. 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.

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.

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

The authors declare that they have no competing interests.

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.

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.

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