We investigated changes in biomarkers of liver disease in HIV–HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals.
Methods
Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV–HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV–HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment.
Results
Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P <0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes.
Conclusions
Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.
References
1.
SulkowskiM.S., ThomasD.L.Hepatitis C in the HIV-infected person. Ann Intern Med2003; 138: 197–207.
2.
RauchA., RickenbachM., WeberR.Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study. Clin Infect Dis2005; 41: 395–402.
3.
ThomasD.L.The challenge of hepatitis C in the HIV-infected person. Annu Rev Med2008; 59: 473–485.
4.
BenhamouY., BochetM., Di MartinoV.Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology1999; 30: 1054–1058.
5.
Martinez-SierraC., ArizcorretaA., DiazF.Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis2003; 36: 491–498.
6.
QurishiN., KreuzbergC., LuchtersG.Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet2003; 362: 1708–1713.
7.
HammerS.M., EronJ.J.Jr., ReissP.Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society–USA panel. JAMA2008; 300: 555–570.
8.
RockstrohJ.K., BhaganiS., BenhamouY.European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med2008; 9: 82–88.
9.
RohrbachJ., RobinsonN., HarcourtG.Cellular immune responses to HCV core increase and HCV RNA levels decrease during successful antiretroviral therapy. Gut2010; 59: 1252–1258.
10.
RosenbergW.M., VoelkerM., ThielR.Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology2004; 127: 1704–1713.
11.
AfdhalN.H., NunesD.Evaluation of liver fibrosis: a concise review. Am J Gastroenterol2004; 99: 1160–1174.
12.
MummadiR.R., PetersenJ.R., XiaoS.Y., SnyderN.Role of simple biomarkers in predicting fibrosis progression in HCV infection. World J Gastroenterol2010; 16: 5710–5715.
NunesD., FlemingC., OffnerG.Noninvasive markers of liver fibrosis are highly predictive of liver-related death in a cohort of HCV-infected individuals with and without HIV infection. Am J Gastroenterol2010; 105: 1346–1353.
15.
BantelH., LugeringA., HeidemannJ.Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury. Hepatology2004; 40: 1078–1087.
16.
CalabreseF., PontissoP., PettenazzoE.Liver cell apoptosis in chronic hepatitis C correlates with histological but not biochemical activity or serum HCV-RNA levels. Hepatology2000; 31: 1153–1159.
17.
KronenbergerB., WagnerM., HerrmannE.Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis C. J Viral Hepat2005; 12: 307–314.
18.
LedergerberB., EggerM., OpravilM.Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet1999; 353: 863–868.
19.
Schoeni-AffolterF., LedergerberB., RickenbachM.Cohort profile: the Swiss HIV Cohort study. Int J Epidemiol2010; 39: 1179–1189.
20.
PatelK., GordonS.C., JacobsonI.Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients. J Hepatol2004; 41: 935–942.
21.
WaiC.T., GreensonJ.K., FontanaR.J.A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology2003; 38: 518–526.
22.
Vallet-PichardA., MalletV., NalpasB.FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology2007; 46: 32–36.
23.
CuzickJ.A Wilcoxon-type test for trend. Stat Med1985; 4: 87–90.
24.
WilliamsR.L.A note on robust variance estimation for cluster-correlated data. Biometrics2000; 56: 645–646.
25.
The SMART Study Group.Hyaluronic acid levels predict increased risk of non-AIDS death in hepatitis-coinfected persons interrupting antiretroviral therapy in the SMART Study. Antivir Ther2011; 16: 667–675.
26.
PetersL., RockstrohJ.K.Biomarkers of fibrosis and impaired liver function in chronic hepatitis C: how well do they predict clinical outcomes?Curr Opin HIV AIDS; 5: 517–523.
27.
PoynardT., Imbert-BismutF., RatziuV.Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal validation in a randomized trial. J Viral Hepat2002; 9: 128–133.
28.
Al-MohriH., MurphyT., LuY., LalondeR.G., KleinM.B.Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and hepatitis C coinfection using a noninvasive marker. J Acquir Immune Defic Syndr2007; 44: 463–469.
29.
MugaR., SanvisensA., FusterD.Unhealthy alcohol use, HIV infection and risk of liver fibrosis in drug users with hepatitis C. PLoS ONE2012; 7: e46810.
30.
WieckowskaA., ZeinN.N., YerianL.M., LopezA.R., McCulloughA.J., FeldsteinA.E.In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology2006; 44: 27–33.
31.
NalpasB., VassaultA., Le GuillouA.Serum activity of mitochondrial aspartate aminotransferase: a sensitive marker of alcoholism with or without alcoholic hepatitis. Hepatology1984; 4: 893–896.
32.
SanvisensA., FusterD., SerraI.Estimated liver fibrosis and its impact on all-cause mortality of HCV-monoinfected and HCV/HIV-coinfected drug users. Curr HIV Res2011; 9: 256–262.
33.
CacoubP., CarratF., BedossaP.Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: the fibrovic study–ANRS HC02. J Hepatol2008; 48: 765–773.
34.
SulkowskiM.S., MehtaS.H., TorbensonM.S.Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS2007; 21: 2209–2216.
35.
MacíasJ., BerenguerJ., JaponM.A.Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology2009; 50: 1056–1063.
36.
TheinH.H., YiQ., DoreG.J., KrahnM.D.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. AIDS2008; 22: 1979–1991.
37.
SouzaA.R., TovoC.V., MattosA.A., ChavesS.There is no difference in hepatic fibrosis rates of patients infected with hepatitis C virus and those co-infected with HIV. Braz J Med Biol Res2008; 41: 223–228.
PetersL., MocroftA., SorianoV.Hyaluronic acid as a prognostic marker of hepatic coma and liver-related death in HIV/viral hepatitis coinfected patients.16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, QC, Canada. Abstract 821.
40.
FiererD.S., UrielA.J., CarrieroD.C.Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study. J Infect Dis2008; 198: 683–686.
41.
VogelM., PageE., BoeseckeC.Liver fibrosis progression after acute hepatitis C virus infection in HIV-positive individuals. Clin Infect Dis2012; 54: 556–559.
42.
VillanoS.A., VlahovD., NelsonK.E., LylesC.M., CohnS., ThomasD.L.Incidence and risk factors for hepatitis C among injection drug users in Baltimore, Maryland. J Clin Microbiol1997; 35: 3274–3277.
43.
BräuN., SalvatoreM., Rios-BedoyaC.F.Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol2006; 44: 47–55.
44.
Sánchez-CondeM., Montes-RamirezM.L., MirallesP.Comparison of transient elastography and liver biopsy for the assessment of liver fibrosis in HIV/hepatitis C virus-coinfected patients and correlation with noninvasive serum markers. J Viral Hepat2010; 17: 280–286.
45.
ZinkernagelA.S., von WylV., LedergerberB.Eligibility for and outcome of hepatitis C treatment of HIV-coinfected individuals in clinical practice: the Swiss HIV cohort study. Antivir Ther2006; 11: 131–142.
