Human immunodeficiency virus (HIV)-induced metabolic abnormalities and antiretroviral therapy (ART), genetic factors, most importantly the rs738409 C > G p.I148M variant in the patatin-like phospholipase domain containing 3 (PNPLA3)-gene, as well as hepatitis C virus (HCV) coinfection may all cause hepatic steatosis (HS). However, recent studies suggest a protective effect of HCV infection on HS. Thus, we evaluated HS prior and after HCV eradication in an HIV/HCV-coinfected cohort at the Medical University of Vienna between January 2014 and June 2017. Two hundred forty-seven patients underwent liver stiffness measurement and controlled attenuation parameter (CAP)-based steatosis assessment. A subcohort of 138 patients also had follow-up CAP measurement after HCV eradication by direct-acting antivirals (DAAs). A CAP value ≥248 dB/m defined HS and all CAP values were adapted to compensate for body mass index (BMI) and diabetes mellitus. Among all 247 HIV/HCV-coinfected patients, HS was prevalent in 31%, mean age was 43.3 years, 75% were male, the main ethnicity was Caucasian (96%), and mean BMI was 23.33 kg/m2. Independent risk factors for HS were BMI, years exposed to HIV, PNPLA3 G-alleles, and protease inhibitor (PI) intake. Notably, a significant increase in CAP (from 225 ± 52.9 to 235 ± 50.7 dB/m; p = 0.047) was observed after HCV eradication, whereas patients on PI-containing ART experienced a significant decrease in CAP. Overall, one-third of HIV/HCV-coinfected patients are affected by HS with PI-based ART and PNPLA3 impacting on HS prevalence. While HCV eradication by DAAs increased HS, as assessed by CAP, future studies should account for metabolic syndrome and evaluate whether changes in CAP-based steatosis assessments correspond to a clinically relevant outcome.
Get full access to this article
View all access options for this article.
References
1.
SmithC, SabinCA, LundgrenJD, et al.Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS, 2010; 24:1537–1548.
2.
AlterMJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol, 2006; 44(1 Suppl):S6–S9.
3.
MandorferM, SchwablP, SteinerS, ReibergerT, Peck-RadosavljevicM. Advances in the management of HIV/HCV coinfection. Hepatol Int, 2016; 10:424–435.
4.
MandorferM, PayerBA, SchwablP, et al.Revisiting liver disease progression in HIV/HCV-coinfected patients: The influence of vitamin D, insulin resistance, immune status, IL28B and PNPLA3. Liver Int, 2015; 35:876–885.
5.
ReibergerT, FerlitschA, SieghartW, et al.HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension. J Viral Hepat, 2010; 17:400–409.
6.
de ConinckZ, Hussain-AlkhateebL, BrattG, et al.Non-AIDS mortality is higher among successfully treated people living with HIV compared with matched HIV-negative control persons: A 15-year follow-up cohort study in Sweden. AIDS Patient Care STDS, 2018; 32:297–305.
7.
CasteraL, HezodeC, Roudot-ThoravalF, et al.Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut, 2003; 52:288–292.
8.
LeandroG, MangiaA, HuiJ, et al.Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data. Gastroenterology, 2006; 130:1636–1642.
9.
RomeoS, KozlitinaJ, XingC, et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet, 2008; 40:1461–1465.
10.
GaslightwalaI, BiniEJ. Impact of human immunodeficiency virus infection on the prevalence and severity of steatosis in patients with chronic hepatitis C virus infection. J Hepatol, 2006; 44:1026–1032.
11.
McGovernBH, DitelbergJS, TaylorLE, 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; 43:365–372.
12.
CarrA, CooperDA. Adverse effects of antiretroviral therapy. Lancet, 2000; 356:1423–1430.
13.
VachonML, FactorSH, BranchAD, et al.Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-alpha-2a and ribavirin in HIV/HCV co-infected patients. J Hepatol, 2011; 54:41–47.
14.
PembrokeT, DeschenesM, LeboucheB, et al.Hepatic steatosis progresses faster in HIV mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis. J Hepatol, 2017; 67:801–808.
15.
PriceJC, MaY, ScherzerR, et al.Human immunodeficiency virus-infected and uninfected adults with non-genotype 3 hepatitis C virus have less hepatic steatosis than adults with neither infection. Hepatology, 2017; 65:853–863.
16.
SassoM, Tengher-BarnaI, ZiolM, et al.Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan(®): Validation in chronic hepatitis C. J Viral Hepat, 2012; 19:244–253.
17.
KarlasT, PetroffD, SassoM, et al.Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol, 2017; 66:1022–1030.
18.
CasteraL, HezodeC, Roudot-ThoravalF, et al.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; 53:420–424.
19.
PattonHM, PatelK, BehlingC, et al.The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol, 2004; 40:484–490.
20.
MandorferM, SteinerS, SchwablP, et al.Response-guided boceprevir-based triple therapy in HIV/HCV-coinfected patients: The HIVCOBOC-RGT study. J Infect Dis, 2015; 211:729–735.
21.
MandorferM, SchwablP, SteinerS, et al.Interferon-free treatment with sofosbuvir/daclatasvir achieves sustained virologic response in 100% of HIV/hepatitis C virus-coinfected patients with advanced liver disease. AIDS, 2016; 30:1039–1047.
22.
RockstrohJK, LacombeK, VianiRM, et al.Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: The EXPEDITION-2 study. Clin Infect Dis, 2018; 67:1010–1017.
23.
ChromyD, SchwablP, BucsicsT, et al.Non-invasive liver fibrosis assessment and HCV treatment initiation within a systematic screening program in HIV/HCV coinfected patients. Wien Klin Wochenschr, 2018; 130:105–114.
24.
AdamsLM, BaldersonB, PackettBJ, 2nd. Meeting the challenge: Hepatitis C virus and HIV care experiences among HIV specialty providers. AIDS Patient Care STDS, 2018; 32:314–320.
25.
European Association for the Study of the Liver. ASL recommendations on treatment of hepatitis C 2018. J Hepatol, 2018; 69:461–511.
26.
CastéraL, VergniolJ, FoucherJ, et al.Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology, 2005; 128:343–350.
27.
MatthewsDR, HoskerJP, RudenskiAS, NaylorBA, TreacherDF, TurnerRC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1985; 28:412–419.
28.
SchwablP, BotaS, SalzlP, et al.New reliability criteria for transient elastography increase the number of accurate measurements for screening of cirrhosis and portal hypertension. Liver Int, 2015; 35:381–390.
29.
SassoM, BeaugrandM, de LedinghenV, et al.Controlled attenuation parameter (CAP): A novel VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: Preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol, 2010; 36:1825–1835.
30.
PriceJC, DodgeJL, MaY, et al.Controlled attenuation parameter and magnetic resonance spectroscopy-measured liver steatosis are discordant in obese HIV-infected adults. AIDS, 2017; 31:2119–2125.
31.
VuppalanchiR, SiddiquiMS, Van NattaML, et al.Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease. Hepatology, 2018; 67:134–144.
32.
BrauN. Treatment of chronic hepatitis C in human immunodeficiency virus/hepatitis C virus-coinfected patients in the era of pegylated interferon and ribavirin. Semin Liver Dis, 2005; 25:33–51.
33.
WylesD, SaagM, VianiRM, et al.TURQUOISE-I part 1b: ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for hepatitis C virus infection in HIV-1 coinfected patients on darunavir. J Infect Dis, 2017; 215:599–605.
34.
SteinerS, BucsicsT, SchwablP, et al.Progress in eradication of HCV in HIV positive patients with significant liver fibrosis in Vienna. Wien Klin Wochenschr, 2017; 129:517–526.
35.
MyersRP, FongA, ShaheenAA. Utilization rates, complications and costs of percutaneous liver biopsy: A population-based study including 4275 biopsies. Liver Int, 2008; 28:705–712.
36.
RatziuV, CharlotteF, HeurtierA, et al.Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology, 2005; 128:1898–1906.
37.
VernaEC. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in patients with HIV. Lancet Gastroenterol Hepatol, 2017; 2:211–223.
38.
ProvoostA, DrameM, CotteL, et al.Risk of diabetes in HIV-infected patients is associated with cirrhosis but not with chronic HCV coinfection in a French nationwide HIV cohort. Aliment Pharmacol Ther, 2018; 48:281–289.
39.
AlbertiKG, EckelRH, GrundySM, et al.Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 2009; 120:1640–1645.
40.
MaciasJ, GonzalezJ, TuralC, et al.Prevalence and factors associated with liver steatosis as measured by transient elastography with controlled attenuation parameter in HIV-infected patients. AIDS, 2014; 28:1279–1287.
41.
Vuille-LessardE, LeboucheB, LennoxL, et al.Nonalcoholic fatty liver disease diagnosed by transient elastography with controlled attenuation parameter in unselected HIV monoinfected patients. AIDS, 2016; 30:2635–2643.
42.
SchmittleinDC. Surprising inferences from unsurprising observations: Do conditional expectations really regress to the mean?. Am Stat, 1989; 43:176–183.
43.
LakeJE, McComseyGA, HulganTM, et al.A randomized trial of Raltegravir replacement for protease inhibitor or non-nucleoside reverse transcriptase inhibitor in HIV-infected women with lipohypertrophy. AIDS Patient Care STDS, 2012; 26:532–540.
44.
PalellaFJJr, FisherM, TebasP, et al.Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS, 2014; 28:335–344.
45.
BilalU, LauB, LazoM, et al.Interaction between alcohol consumption patterns, antiretroviral therapy type, and liver fibrosis in persons living with HIV. AIDS Patient Care STDS, 2016; 30:200–207.
46.
SchaeferEA, ChungRT. HCV and host lipids: An intimate connection. Semin Liver Dis, 2013; 33:358–368.
47.
MirandolaS, RealdonS, IqbalJ, et al.Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology, 2006; 130:1661–1669.
48.
PolgreenPM, FultzSL, JusticeAC, et al.Association of hypocholesterolaemia with hepatitis C virus infection in HIV-infected people. HIV Med, 2004; 5:144–150.
49.
TownsendK, MeissnerEG, SidharthanS, et al.Interferon-free treatment of hepatitis C virus in HIV/hepatitis C virus-coinfected subjects results in increased serum low-density lipoprotein concentration. AIDS Res Hum Retroviruses, 2016; 32:456–462.
50.
OgasawaraN, KobayashiM, AkutaN, et al.Serial changes in liver stiffness and controlled attenuation parameter following direct-acting antiviral therapy against hepatitis C virus genotype 1b. J Med Virol, 2017; 90:313–319.
51.
MohrR, BoeseckeC, DoldL, et al.Return-to-health effect of modern combined antiretroviral therapy potentially predisposes HIV patients to hepatic steatosis. Medicine (Baltimore), 2018; 97:e0462.
52.
ScheinerB, SchwablP, SteinerS, et al.Interferon-free regimens improve health-related quality of life and fatigue in HIV/HCV-coinfected patients with advanced liver disease: A retrospective study. Medicine (Baltimore), 2016; 95:e4061.
53.
YounossiZM, StepanovaM, SulkowskiM, NaggieS, HenryL, HuntS. Sofosbuvir and ledipasvir improve patient-reported outcomes in patients co-infected with hepatitis C and human immunodeficiency virus. J Viral Hepat, 2016; 23:857–865.
54.
AhnSB, JunDW, KangBK, KimM, ChangM, NamE. Optimal cutoff value for assessing changes in intrahepatic fat amount by using the controlled attenuation parameter in a longitudinal setting. Medicine (Baltimore), 2018; 97:e13636.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
