Incidence of liver cirrhosis in HIV-infected patients with chronic hepatitis B or C in the era of highly active antiretroviral therapy

Abstract

Background

Longitudinal assessment of liver fibrosis with transient elastometry (TE) in patients with chronic viral hepatitis is becoming routine clinical practice in many clinics, as this procedure is non-invasive, easy to perform and relatively inexpensive, allowing early detection of cirrhosis. Herein, we examine the incidence of cirrhosis, using TE assessment, in HIV-infected individuals with chronic hepatitis B or C receiving highly active anti-retroviral therapy (HAART).

Methods

A longitudinal study was performed on a cohort of HIV-infected patients with chronic hepatitis B or C who were followed since 2004 at Hospital Carlos III (Madrid, Spain) with periodic TE assessments. The primary outcome was the development of cirrhosis, defined as liver stiffness >12.5 KPa.

Results

A total of 508 HIV-infected patients were examined, of whom 54 developed liver cirrhosis during a mean ±sd follow-up of 2.6 ±1.0 years (overall incidence was 41.13 cases per 1,000 person-years). The risk of developing cirrhosis was significantly higher in 297 HCV-RNA-positive patients (either untreated or non- responders to hepatitis C therapy) compared with 55 patients who had cleared HCV with therapy (odds ratio 3.73, 95% confidence interval 1.06–13.17; P=0.04). By contrast, the risk of developing cirrhosis was low and similar in 24 HIV–HBV-coinfected patients under long-term suppressive HBV therapy (mainly tenofovir disoproxil fumarate), 132 HIV-infected patients without chronic liver disease and those who had cleared HCV with therapy.

Conclusions

Development of liver cirrhosis in HIV- infected individuals in the HAART era is mainly associated with active HCV coinfection. The risk of developing cirrhosis is negligible in patients who cleared HCV with therapy, as well as in HIV–HBV-coinfected patients on long-term suppressive tenofovir disoproxil fumarate therapy.

References

The Data Collection on Adverse Events of Anti-HIV Drugs Study Group.

Liver-related deaths in persons infected with the HIV: the D:A:D study.

Arch Intern Med 2006; 166: 1632–1641.

Sulkowski

M.S.

, Mehta

S.H.

, Torbenson

M.S.

Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults.

AIDS 2007; 21: 2209–2216.

Bruno

, Sacchi

, Puoti

Natural history of compensated viral cirrhosis in a cohort of patients with HIV infection.

J Acquir Immune Defic Syndr 2007; 46: 297–303.

Castellares

, Barreiro

, Martin-Carbonero

Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome.

J Viral Hepat 2008; 15: 165–172.

Macias

, Berenguer

, Japon

Fast fibrosis progression between repeated liver biopsies in patients coinfected with HIV/hepatitis C virus.

Hepatology 2009; 50: 1056–1063.

Colin

J.F.

, Cazals-Hatem

, Loriot

M.A.

Influence of HIV infection on chronic hepatitis B in homosexual men.

Hepatology 1999; 29: 1306–1310.

Thein

H.H.

, Yi

, Dore

G.J.

, Krahn

M.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.

AIDS 2008; 22: 1979–1991.

de Lédinghen

, Barreiro

, Foucher

Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy.

J Viral Hepat 2008; 15: 427–433.

Macias

, Castellano

, Merchante

Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine.

AIDS 2004; 18: 767–774.

10.

Sulkowski

M.S.

Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors.

Clin Infect Dis 2004; 38 Suppl 2: S90–S97.

11.

Blanco

, Barreiro

, Ryan

Risk factors for advanced liver fibrosis in HIV-infected individuals: role of antiretroviral drugs and insulin resistance.

J Viral Hepat 2010. doi 10.1111/j.1365-2893.2009.01261.x.

12.

Balagopal

, Philp

, Astemborski

HIV-related microbial translocation and progression of hepatitis C.

Gastroenterology 2008; 135: 226–233.

13.

Sulkowski

M.S.

, Thomas

D.L.

, Chaisson

R.E.

, Moore

R.D.

Hepatotoxicity associated with antiretroviral therapy in adults infected with HIV and the role of hepatitis C or B virus infection.

JAMA 2000; 283: 74–80.

14.

Maida

, Garcia-Gasco

, Sotgiu

Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome.

Antivir Ther 2008; 13: 103–107.

15.

Kovari

, Ledergerber

, Peter

Association of non-cirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case-control study.

Clin Infect Dis 2009; 49: 626–635.

16.

Lanternier

, Roulot

, Bentata

Risks factors of liver fibrosis in a cohort of intravenous drug users coinfected with HIV and HCV in the HAART era: the role of mixed steatosis.

Gastroenterol Clin Biol 2007; 31: 822–827.

17.

Qurishi

, Kreuzberg

, Luchters

Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection.

Lancet 2003; 362: 1708–1713.

18.

Brau

, Salvatore

, Rios-Bedoya

Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy.

J Hepatol 2006; 44: 47–55.

19.

Pascual-Pareja

J.F.

, Caminoa

, Larrauri

HAART is associated with lower hepatic necroinflammatory activity in HIV-hepatitis C virus-coinfected patients with CD4 cell count of more than 350 cells/[mu]l at the time of liver biopsy.

AIDS 2009; 23: 971–975.

20.

Maida

, Soriano

, Castellares

Liver fibrosis in HIV-infected patients with chronic hepatitis B extensively exposed to antiretroviral therapy with anti-HBV activity.

HIV Clin Trials 2006; 7: 246–250.

21.

Mallet

V.O.

, Dhalluin-Venier

, Verkarre

Reversibility of cirrhosis in HIV/HBV coinfection.

Antivir Ther 2007; 12: 279–283.

22.

Miailhes

, Trabaud

, Pradat

Impact of highly active antiretroviral therapy (HAART) on the natural history of hepatitis B virus (HBV) and HIV coinfection: relationship between prolonged efficacy of HAART and HBV surface and early antigen seroconversion.

Clin Infect Dis 2007; 45: 624–632.

23.

Soriano

, Maida

, Núñez

Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies.

Antivir Ther 2004; 9: 987–992.

24.

Berenguer

, Alvarez-Pellicer

, Martín

Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with HIV and hepatitis C virus.

Hepatology 2009; 50: 407–413.

25.

Barreiro

, Labarga

, Martín-Carbonero

Sustained virological response following HCV therapy is associated with non-progression of liver fibrosis in HCV/HIV-coinfected patients.

Antivir Ther 2006; 11: 869–877.

26.

Rodriguez-Torres

, Rodriguez-Orengo

, Rios-Bedoya

Effect of hepatitis C virus treatment in fibrosis progression rate and time to cirrhosis in patients co-infected with HIV: a paired liver biopsy study.

J Hepatol 2007; 46: 613–619.

27.

Bani-Sadr

, Lapidus

, Bedossa

Progression of fibrosis in HIV and hepatitis C virus-coinfected patients treated with interferon plus ribavirin-based therapy: analysis of risk factors.

Clin Infect Dis 2008; 46: 768–774.

28.

Halfon

, Carrat

, Bedossa

Effect of antiviral treatment on serum markers of liver fibrosis in HIV-hepatitis C virus-coinfected patients: the Fibrovic 2 Study - ANRS HC02.

Antivir Ther 2009; 14: 211–219.

29.

Ogawa

, Furusyo

, Toyoda

, Takeoka

, Maeda

, Hayashi

The longitudinal quantitative assessment by transient elastography of chronic hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin.

Antiviral Res 2009; 83: 127–134.

30.

Soriano

, Martín-Carbonero

, García-Samaniego

Treatment of chronic hepatitis C virus infection: we must target the virus or liver fibrosis?

AIDS 2003; 17: 751–753.

31.

Castera

, Vergniol

, Foucher

Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.

Gastroenterology 2005; 128: 343–350.

32.

de Lédinghen

, Douvin

, Kettaneh

Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients.

J Acquir Immune Defic Syndr 2006; 41: 175–179.

33.

Kirk

G.D.

, Astemborski

, Mehta

S.H.

Assessment of liver fibrosis by transient elastography in persons with hepatitis C virus infection or HIV-hepatitis C virus coinfection.

Clin Infect Dis 2009; 48: 963–972.

34.

Sandrin

, Fourquet

, Hasquenoph

J.M.

Transient elastography: a new non-invasive method for assessment of hepatic fibrosis.

Ultrasound Med Biol 2003; 29: 1705–1713.

35.

Deeks

S.G.

, Phillips

A.N.

HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity.

BMJ 2009; 338: a3172.

36.

Iloeje

U.H.

, Yang

H.I.

, Su

, Jen

C.L.

, You

S.L.

, Chen

C.J.

Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.

Gastroenterology 2006; 130: 678–686.

37.

Jiménez-Nácher

, García

, Barreiro

Trends in the prescription of antiretroviral drugs and impact on plasma HIV-RNA measurements.

J Antimicrob Chemother 2008; 62: 816–822.

38.

Marcellin

, Heathcote

E.J.

, Buti

Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.

N Engl J Med 2008; 359: 2442–2455.

39.

Lee

, Nunez

Longer duration of HBV-active antiretroviral therapy is linked to favorable virological outcome in HIV-HBV co-infected patients.

HIV Clin Trials 2009; 10: 153–159.

40.

Mehta

S.H.

, Genberg

B.L.

, Astemborski

Limited uptake of hepatitis C treatment among injection drug users.

J Community Health 2008; 33: 126–133.

41.

Grebely

, Raffa

, Lai

Low uptake of treatment for hepatitis C virus infection in a large community-based study of inner city residents.

J Viral Hepat 2009; 16: 352–358.

42.

Torriani

F.J.

, Rodriguez-Torres

, Rockstroh

J.K.

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.

N Engl J Med 2004; 351: 438–450.

43.

Carrat

, Bani-Sadr

, Pol

Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients.

JAMA 2004; 292: 2839–2848.

44.

Nunez

, Miralles

, Berdun

M.A.

Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial.

AIDS Res Hum Retroviruses 2007; 23: 972–982.

45.

Soriano

, Peters

, Zeuzem

New therapies for hepatitis C virus infection.

Clin Infect Dis 2009; 48: 313–320.

46.

, Fellay

, Thompson

Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.

Nature 2009; 461: 399–401.

47.

Suppiah

, Moldovan

, Ahlenstiel

IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.

Nat Genet 2009; 41: 1100–1104.

48.

Tanaka

, Nishida

, Sugiyama

Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.

Nat Genet 2009; 41: 1105–1109.

49.

Rallon

N.I.

, Naggie

, Benito

J.M.

Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.

AIDS 2010; 24: F23–F29.

50.

Sterling

R.K.

, Contos

M.J.

, Smith

P.G.

Steatohepatitis: risk factors and impact on disease severity in HIV/hepatitis C virus coinfection.

Hepatology 2008; 47: 1118–1127.

51.

Schiavini

, Angeli

, Mainini

Risk factors for fibrosis progression in HIV/HCV coinfected patients from a retrospective analysis of liver biopsies in 1985–2002.

HIV Med 2006; 7: 331–337.