Hepatic steatosis in patients with HIV-Hepatitis C Virus coinfection: is it associated with antiretroviral therapy and more advanced hepatic fibrosis?
© Verma et al; licensee BioMed Central Ltd. 2008
Received: 26 March 2008
Accepted: 15 July 2008
Published: 15 July 2008
Background and aims
Patients with HIV and hepatitis C virus (HCV) coinfection are at increased risk of developing hepatic steatosis. The aims of this study were to assess the prevalence of steatosis in a cohort with HIV-HCV coinfection, and to determine an association, if any, between steatosis, antiretroviral therapy (ART), and advanced hepatic fibrosis.
Patients and methods
HIV-HCV coinfected patients were retrospectively identified from the HIV clinic. ART was classified as none, nucleoside reverse transcriptase inhibitors (NRTIs) only, highly active antiretroviral therapy (HAART) only, and sequential therapy (initial NRTIs followed by HAART). Fibrosis stage and necroinflammation grade were assessed by the modified HAI (Ishak) scoring method. Steatosis was graded as 0–3.
Sixty patients were identified. The overall prevalence of hepatic steatosis was 58%. Those that received HAART only had a lower prevalence of steatosis (41%) compared to those on NRTIs only (70%) or sequential therapy (82%). Independent predictors of hepatic steatosis were absence of HAART only therapy, OR 2.9, p = 0.09, and presence of cirrhosis, OR 4.6, p = 0.044. Forty five percent of the patients had advanced fibrosis (fibrosis stage ≥ 3). NI grade (OR 1.9, p = 0.030), and steatosis grade (OR 3.6, p = 0.045), were independent predictors of advanced fibrosis.
Hepatic steatosis is associated with more advanced hepatic fibrosis in the HIV-HCV coinfected population. HAART only therapy (rather than NRTIs only or sequential therapy) appears to be associated with a lower prevalence of hepatic steatosis. This may be one of the mechanisms by which HAART could attenuate hepatic fibrosis in such a cohort.
Highly active antiretroviral therapy (HAART) has significantly improved survival in patients with human immunodeficiency virus (HIV) infection . Increasing attention is now being focused on co infection with other viruses like hepatitis C (HCV). Because of similar routes of transmission, approximately 25–30% of patients with HIV are also coinfected with HCV . Factors associated with more advanced hepatic fibrosis in HCV infection include HIV coinfection  and hepatic steatosis, (prevalence of 47%–79%) [4–6].
Patients with HIV are also at increased risk of developing hepatic steatosis due to multiple factors including antiretroviral therapy (ART), obesity, hyperglycemia, lipodystrophy, and coinfection with HCV [2, 7–11]. In HIV-HCV coinfection prevalence of hepatic steatosis varies between 40–72.1% [9–13]. In the coinfected population, the association between ART and steatosis, and whether steatosis is associated with advanced fibrosis remains controversial [9–11]. The aims of this study were therefore to assess whether in those with HIV-HCV coinfection
1. Use of ART is associated with hepatic steatosis
2. Hepatic steatosis is an independent predictor of advanced hepatic fibrosis
3. Hepatic steatosis is associated with fibrosis progression in serial liver biopsies
Patients and methods
The study period was from 1990–2005. Patients with HIV-HCV coinfection were identified from the Pathology and HIV database after which, their charts and computerised chemical pathology and histology databases reviewed. To be included in the study the patients had to be
1. HCV antibody and or HCV PCR (qualitative) positive
2. HIV antibody positive
3. Have had a liver biopsy.
The indications for a liver biopsy in most patients were abnormal liver tests. All the liver biopsies had been reviewed by RG who was blinded to the clinical information. The fibrosis stage (0–6) and necroinflammatory (NI) grade (0–18) were assessed by the modified HAI (Ishak) scoring system . Steatosis was graded, (depending on % of hepatocytes containing fat), into grade 0 (< 5%), grade 1 (<33%), grade 2 (33%–66%), and grade 3 (>66%).
HCV disease duration and fibrosis progression were calculated as before . Lipoatrophy was stated to be present if mentioned in the patient records. Diabetes mellitus (DM) was defined by presence of one or more of the following: fasting blood glucose > 7 mmol/l, being on anti diabetic medications, and/or a note in the patient record stating that there was a history of DM.
Anti-HCV antibody testing, HCV RNA and HIV RNA quantification and HCV genotyping were performed in the hospital virology laboratory using standard commercial kits (Abbott, Bayer, Roche).
Alcohol abuse was defined as either consumption of > 3 units of alcohol/day (approximately 40 gms/day), and/or a written note in patient records stating that there was a history of alcohol excess. Details of ART were also recorded to assess duration of therapy prior to the liver biopsy. ART was classified as .
2. NRTIs only
3. HAART only. Those whose HIV was diagnosed in or after 1996 and were therefore treated with HAART at onset. For the purpose of this study HAART was defined as use of any two nucleoside reverse transcriptase inhibitors (NRTIs) with any protease inhibitor (PI) or non nucleoside reverse transcriptase inhibitors (NNRTI)
4. Sequential therapy: Those whose HIV was diagnosed prior to 1996; hence were initially treated with NRTIs and then converted to HAART after 1996.
Ethnicity was classified (according to the HIV database) into White, Other European and Others.
The following patients were excluded
1. Presence of liver disease of another etiology, e.g. active hepatitis B infection, autoimmune liver disease, genetic hemochromatosis, and cholestatic liver disease
2. Medical records/clinical data not available
Data are presented as mean ± SD except the HIV and HCV viral load (VL) which are presented as median (range). Differences between continuous variables were compared using the Mann Whitney (U) Test and between categorical variables by the Chi Square and Fischer's Exact Test. Binary logistic regression analysis was performed to assess independent predictors of hepatic steatosis and fibrosis stage ≥ 3. The statistical software programme used was SPSS version 14 (Chicago, IL)
From 1990–2005 there were sixty-six patients with HIV who had been coded as having had a liver biopsy for HCV. Six were excluded, and therefore 60 patients were found suitable for the study. Of these sixty patients 52 (87%) had abnormal transaminases. All were HCV antibody positive, and all but one was HCV RNA (qualitative) positive. Eight patients had undergone more than one biopsy, of whom seven had had two and one three biopsies.
Data in whole cohort (n = 60) at the time of the most recent liver biopsy
Age at biopsy (yrs)
39.4 ± 8.2
72.3 ± 10.1
> 75 kg
Risk factors for HCV
HIV VL (copies/ml)
HCV VL (IU/ml)*
HCV genotype 1*
HCV disease duration (yrs)
16.4 ± 8.0
2.8 ± 1.7
Fibrosis progression rate/yr
0.21 ± 0.16
3.7 ± 1.7
Data in patients with and without hepatic steatosis
n = 35
n = 25
Age at biopsy (yrs)
39.0 ± 8.9
40.0 ± 7.2
Age at HIV diagnosis (yrs)
32.9 ± 8.9
34.0 ± 6.8
74.2 ± 9.2
69.7 ± 10.8
Weight > 75 kg
22.3 ± 18.8
21.7 ± 12.4
30.4 ± 27.3
29.5 ± 27.1
92.8 ± 37.2
Time from HIV diagnosis to HAART (mths)
47.4 + 38.7
40.4 + 50.9
CD4 count (/mm3)
HIV VL (copies/ml)
HCV VL (IU/ml)
Non 1 genotype
4.3 ± 1.2
4.1 ± 1.08
1.1 ± 0.5
1.1 ± 0.3
2.2 ± 2.0
1.5 ± 0.6
4.8 ± 2.2
3.8 ± 1.0
Fasting blood glucose
6.1 + 6.4
5.1 ± 0.9
131 + 149.8
104 ± 74.6
3.0 ± 1.9
2.5 ± 1.7
3.7 ± 1.9
3.7 + 1.7
There was no difference in durations of different forms of ART in those with and without steatosis (Table 2). The overall duration of ART was longer in those with sequential therapy (94.3 ± 35.5 mths), compared to NRTI only (22.9 ± 17.3 mths) and HAART only groups (29.9 ± 26.5 mths), p < 0.05. However presence of steatosis was not associated with duration of ART (50.6 ± 43.0 vs. 32.7 ± 30.6 mths). Duration of stavudine (32.8 ± 21.7 vs. 45.8 ± 25.4), and didanosine (24.6 ± 16.6 vs. 31.2 ± 29.7) were also no different in those with and without steatosis (p value = 1.0 and 0.80 respectively). All factors that were significantly associated with steatosis on univariate analysis (p ≤ 0.1) (HAART only therapy, sequential therapy, and presence of cirrhosis) were then entered into a stepwise logistic regression model. Independent predictors of hepatic steatosis were absence of HAART only therapy, OR 2.9 (95% CI 0.84–9.9), p = 0.09 and presence of cirrhosis, OR 4.6 (95% CI 1.0–20.4), p = 0.044. Because of the small sample size we could not analyze the association between diabetes mellitus (n = 3), genotype 3 (n = 6), lipoatrophy (n = 5) and hepatic steatosis.
Data in patients with fibrosis stage ≥ vs. < 3
Fibrosis stage ≥ 3
n = 27
Fibrosis stage < 3
n = 33
Age at biopsy (yrs)
40.6 ± 8.7
38.3 ± 7.8
Age exposed to HCV (yrs)
20.3 ± 11.0
24.4 ± 7.2
Age at HIV diagnosis (yrs)
33.6 ± 9.6
33.1 ± 6.7
HIV diagnosed in or after 1996
70.7 ± 10.0
73.5 ± 10.2
Weight ≥ 75 Kg
4.5 ± 1.3
4.0 ± 1.0
2.1 ± 1.8
1.8 ± 1.5
5.0 ± 2.2
3.8 ± 1.3
Platelet count (/mm3)
163 ± 65.5
228 ± 66.8
11.2 ± 8.4
29.3 ± 17.1
29.5 ± 26.5
30.4 ± 27.9
105 ± 23.3
77.5 ± 47.3
1.0 ± 0.9
0.5 ± 0.5
4.4 ± 1.9
3.1 ± 1.3
CD4 count (/mm3)
HIV VL (copies/ml)
Of the eight patients with more than one biopsy, the mean interval between the biopsies was 52 ± 17.9 months. Five had fibrosis progression ≥ one stage of whom 4 (80%) showed evidence of hepatic steatosis in the index biopsy.
This study has shown that 58% of HIV-HCV coinfected patients (of whom 72% were on ART) have evidence of hepatic steatosis on liver biopsy, and this is consistent with earlier data [9–11]. Those who had received an NRTI, either alone, or as part of sequential therapy were twice as likely to have steatosis (70%–82%) compared to those who had received HAART only therapy (41%). Independent predictors of hepatic steatosis were absence of HAART only therapy, and presence of cirrhosis. Neither PI or NRTI therapy was independently associated with steatosis. 45% of patients had advanced fibrosis and both grade of stetaosis and NI were independent predictors of advanced fibrosis. In the subgroup with > 1 biopsy, 80% of those with fibrosis progression had steatosis on the index biopsy.
The lowest prevalence of hepatic steatosis was observed in the HAART only group. Furthermore, the duration between HIV diagnosis and HAART initiation was longer for those with steatosis (47.4 vs. 40.4 months). This suggests that receiving HAART early, may in some way be protective against development of subsequent hepatic steatosis. Prior authors have also found a lower prevalence of hepatic steatosis with certain antiretroviral drugs (NNRTI) .
So how do we explain this negative association between HAART and hepatic steatosis? It may be partly related to the fact that NNRTIs (especially nevirapine) do not result in insulin resistance and may also be associated with elevations in high density lipoproteins (HDL) . Secondly, HAART has been known to attenuate hepatic NI in coinfected patients [16, 18] and there may in fact be an association between NI and hepatic steatosis. This could be because the HCV core protein leads to oxidative stress  and hepatic steatosis could result from the inflammation associated with this oxidative stress . One could therefore speculate that appropriately initiated HAART could attenuate hepatic NI (either directly or via immune restoration induced changes in inflammatory cytokines) [21, 22], which in turn may reduce hepatic steatosis.
Steatosis has been independently associated with advanced fibrosis in HCV monoinfected patients [6, 23] though this remains controversial in HIV-HCV subjects [9–11]. In this study, those with advanced hepatic fibrosis had a significantly higher grade of hepatic steatosis compared to those with less severe hepatic fibrosis, (consistent with Sulkowski et al's data). In fact in our study 80% of patients with fibrosis progression had hepatic steatosis in the index biopsy. Also, a recent study has observed higher prevalence of hepatic steatosis in HIV-HCV coinfected patients compared with HCV monoinfected subjects (72.1% vs. 52%) . Therefore one of the factors contributing to the accelerated fibrosis progression in HIV-HCV coinfected patients could be the increased prevalence of hepatic steatosis.
We however accept the limitations of this study, including its retrospective design, and the small sample size of the coinfected cohort. In addition liver biopsies were performed in only carefully selected patients. Though this clearly resulted in a selection bias, such a bias is true for most studies in this area, and in our opinion is unavoidable.
In conclusion despite a low prevalence of obesity and DM, 58% of HIV-HCV coinfected patients have evidence of hepatic steatosis histologically. Absence of HAART only therapy was independently associated with steatosis in this study. The presence of hepatic steatosis was also associated with more advanced hepatic fibrosis in the coinfected cohort. The comparatively lower prevalence of hepatic steatosis seen in those that receive HAART only (rather than NRTIs only or sequential therapy) may contribute to the attenuated hepatic fibrosis that has been observed with this therapy [17, 22].
- Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD: Declining morbidity among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998, 338 (13): 853-60. 10.1056/NEJM199803263381301.View ArticlePubMedGoogle Scholar
- Sherman KE, Rouster SD, Chung RT, Rajicic N: Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002, 34 (6): 831-7. 10.1086/339042.View ArticlePubMedGoogle Scholar
- 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: 562-9. 10.1086/321909.View ArticlePubMedGoogle Scholar
- 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. Hepatol. 1999, 29 (4): 1215-9. 10.1002/hep.510290401.View ArticleGoogle Scholar
- Verma S, Bonacini M, Govindarajan S, Kanel G, Lindsay K, Redeker A: Hispanic ethnicity is associated with an aggressive course of chronic hepatitis C infection: role of patient demographics, hepatic necroinflammation and steatosis. Am J Gastroenterol. 2006, 101: 1817-1823. 10.1111/j.1572-0241.2006.00682.x.View ArticlePubMedGoogle Scholar
- 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. Hepatol. 2001, 33 (6): 1358-64. 10.1053/jhep.2001.24432.View ArticleGoogle Scholar
- Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP: Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998, 12 (14): 1735-44. 10.1097/00002030-199814000-00004. ReviewView ArticlePubMedGoogle Scholar
- Mehta SH, Moore RD, Thomas DL, Chaisson RE, Sulkowski MS: The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. J Acquir Immune Defic Syndr. 2003, 33 (5): 577-84. 10.1097/00126334-200308150-00005.View ArticlePubMedGoogle Scholar
- 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): 585-9. 10.1097/01.aids.0000163935.99401.25.View ArticlePubMedGoogle Scholar
- 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. Hepatol. 2005, 42 (2): 310-6. 10.1002/hep.20805.View ArticleGoogle Scholar
- 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): 1943-9. 10.1086/497608.View ArticlePubMedGoogle Scholar
- Bani-Sadr F, Carrat F, Bedossa P, Piroth L, Cacoub P, Perronne C, Degott C, Pol and ANRS HC02-Ribavic Study team: Hepatic stetaosis in HIV-HCV coinfected patients: analysis of risk factors. AIDS. 2006, 20 (4): 525-31. 10.1097/01.aids.0000210606.63138.f5.View ArticlePubMedGoogle Scholar
- 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): 1026-32. 10.1016/j.jhep.2006.02.009.View ArticlePubMedGoogle Scholar
- Ishak K, Baptista A, Biachi L, Callea F, De Groote J, Gudat F, Denk H: Histological grading and staging of chronic hepatitis. J Hepatol. 1995, 22: 696-9. 10.1016/0168-8278(95)80226-6.View ArticlePubMedGoogle Scholar
- Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 349 (9055): 825-32. 10.1016/S0140-6736(96)07642-8. 1997 Mar 22Google Scholar
- Verma S, Wang CH, Govindarajan S, Kanel G, Squires K, Bonacini M: Do type and duration of antiretroviral therapy attenuate liver fibrosis in HIV-hepatitis C virus-coinfected patients?. Clin Infect Dis. 2006, 42 (2): 262-70. 10.1086/499055.View ArticlePubMedGoogle Scholar
- van Leth F, Phanuphak P, Stroes E, Gazzard B, Cahn P, Raffi F, Wood R, Bloch M, Katlama C, Kastelein JJ, Schechter M, Murphy RL, Horban A, Hall DB, Lange JM, Reiss P: Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med. 2004, e19-10.1371/journal.pmed.0010019. 1Google Scholar
- 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. Hepatol. 2005, 41 (1): 123-31. 10.1002/hep.20541.View ArticleGoogle Scholar
- Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA: Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterol. 2002, 122 (2): 366-75. 10.1053/gast.2002.30983.View ArticleGoogle Scholar
- Day CP, James OF: Steatohepatitis: a tale of two "hits"?. Gastroenterol. 1998, 114 (4): 842-5. 10.1016/S0016-5085(98)70599-2.View ArticleGoogle Scholar
- Verma S: HAART attenuates Liver Fibrosis in patients with HIV/HCV Coinfection: Fact or Fiction?. J Antimicrob Chemother. 2006, 58: 496-501. 10.1093/jac/dkl280.View ArticlePubMedGoogle Scholar
- Graham CS, Curry M, He Q, Afdhal N, Nunes D, Fleming C, Horsburgh R, Craven D, Sherman KE, Koziel MJ: Comparison of HCV-specific intrahepatic CD4+ T cells in HIV/HCV versus HCV. Hepatol. 2004, 40 (1): 125-32. 10.1002/hep.20258.View ArticleGoogle Scholar
- Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, Adinolfi LE, Asselah T, Jonsson JR, Smedile A, Terrault N, Pazienza V, Giordani MT, Giostra E, Sonzogni A, Ruggiero G, Marcellin P, Powell EE, George J, Negro F, HCV Meta-Analysis (on) Individual Patients' Data Study Group: Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterol. 2006, 130 (6): 1636-42. 10.1053/j.gastro.2006.03.014.View ArticleGoogle Scholar
- Brau N, Salvatore M, Rios-Bedoya CF, et al: For The Puerto Rico-New York Hepatitis Study Group. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006, 44 (1): 47-55. 10.1016/j.jhep.2005.07.006.View ArticlePubMedGoogle Scholar
- Puoti M, Bonacini M, Spinetti A, Putzolu V, Govindarajan S, Zaltron S, Favret M, Callea F, Gargiulo F, Donato F, Carosi G, HIV-HCV Coinfection Study Group: Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and immunodeficiency virus. Infect Dis. 2001, 183: 134-137. 10.1086/317644.View ArticleGoogle Scholar
- Benhamou Y, Di Martino V, Bochet M, Colombet G, Thibault V, Liou A, Katlama C, Poynard T, MultivirC Group: Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatol. 2001, 34 (2): 283-7. 10.1053/jhep.2001.26517.View ArticleGoogle Scholar
This article is published under license to 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.