Antiretroviral Therapy in HIV and Hepatitis Coinfection: What Do We Need to Consider?

Transcription

1 Antiretroviral Therapy in HIV and Hepatitis Coinfection: What Do We Need to Consider? Saturday 22nd March 2014, Mumbai, India Jürgen K. Rockstroh Department of Internal Medicine I University Hospital Bonn, Germany

2 Conflict of interest I have received honoraria for speaking at educational events or consulting from: Abbott, Abbvie, Bionor, BMS, Boehringer, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Tibotec, Tobira and ViiV

3 Which questions need to be addressed?» Is HAART beneficial or harmful for further liver disease progression? When to start HAART in HCV co-infection?» Which antiretroviral drugs should we choose in coinfection?

4 If fibrosis progression and subsequent liver disease associated morbidity and mortality is linked to progressive immunodeficiency will HAART induced immunreconstitution delay further liver disease progression?

5 Cumulative Proportion (%) Cumulative Proportion of Patients With Cirrhosis by PI Exposure: MultivirC Group Retrospective cohort study 182 HIV/HCV-coinfected patients At liver biopsy PI-based HAART (n=63) Never treated with PI-based HAART (n=119) PI exposure versus no PI exposure Lower liver fibrosis stage (P=0.03) Cirrhosis rates (P=0.0006) 5-year: 2% versus 5% 15-year: 5% versus 18% 25-year: 9% versus 27% Benhamou Y, et al. Hepatology. 2001;34: Patients With Cirrhosis P= No PI Exposure PI Exposure Estimated HCV Infection Duration (y)

6 Cumulative Survival Cumulative Survival Impact of ART on Overall Liver Mortality in HIV/HCV-Coinfected Patients Bonn cohort ( ) 285 HIV/HCV coinfected patients Liver-related mortality rates per 100 person-years HAART: 0.45 ART: 0.69 No therapy: 1.70 Predictors for liver-related mortality No HAART Low CD4 cell count Increasing age Qurishi N, et al. Lancet. 2003:362: ,8 0,6 0,4 0,2 1 0,8 0,6 0,4 0,2 Overall Mortality HAART* ART *P<0.001 No therapy Days Liver-Related Mortality HAART* ART No therapy *P= Days

7 Estimated Time From HCV Infection to Cirrhosis (years) Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate 60 P=0.005 P=0.004 P= P=0.05 P= <400 (n=141) K (n=117) >100k (n=16) >350 (n=124) <350 (n=150) <400 (n=100) >400 (n=88) HIV RNA (copies/ml) CD4 (cells/mm 3 ) HIV RNA (copies/ml) + <500 CD4 cells/mm 3 Time to cirrhosis estimated using liver fibrosis progression rate based on Ishak Fibrosis units/year. Brau N, et al. J Hepatol. 2006;44:47-55

8 Effect of HAART on liver fibrosis progression: Sequential studies. Factors independently asociated with fibrosis progression Adjusted Odds Ratio (95% CI) 1.26 Year 1 st LBx (p=0.58) ART between LBx (p=0.8) Undetectable HIV-RNA (p=0.017) High necroinflamatory activity (p=0.008) Response to HCV Rx (p=0.018) Macías J, et al. Hepatology 2009; 50:

9 ART and SVR to HCV therapy are associated with slower liver fibrosis progression in HIV-HCV-coinfected patients: study from the ANRS CO 13 HEPAVIH cohort. Methods: HIV-HCV-coinfected adults enrolled in the ANRS CO 13 HEPAVIH cohort, for whom two results of LS, evaluated over 24 months, were available. Results: In multivariate linear and logistic analyses, excessive alcohol intake (β coefficient 6.8; P=0.0006) and high HCV viral load (OR 1.7, 95% CI 1.1, 2.5; P=0.01) were independently associated with an increase in LS, whereas time on ART>114.5 months (OR 0.5, 95% CI 0.3, 0.9; P=0.03) and achievement of sustained virological response (OR 0.1, 95% CI 0.01, 0.9; P=0.04) were independently associated with no increase in LS. Loko MA, et al; ANRS CO 13 HEPAVIH Study Group. Antivir Ther. 2012;17:

10 Activity Score HIV Suppression Is Associated with Less Hepatic Necroinflammatory Activity * * Viral Load Undetectable Viral Load Detectable Mehta SH et al. Hepatology 2005

11 % patients with detectable ELISpot response Median (IQR) log HCV-RNA (IU/mL) Rohrbach J, et al. CROI Abstract 105, Rohrbach J, et al. GUT 2010;59: HAART induces recovery of specific T-cell response to HCV core proteins 50 ART P=0.002 P= n=16 n=64 n=50 n=64 n=37 Median time (months) from ART starting 8 7,5 ART P for trend= ,5 6 5, n=20 n=51 n=51 n=66 n=35 Median time (months) from ART starting

12 Antiretroviral Therapy Reduces the Rate of Hepatic Decompensation Among HIV- and Hepatitis C Virus Coinfected Veterans Objective: To evaluate HIV/HCV-coinfected males from the Veterans Aging Cohort Study Virtual Cohort, who had not initiated ART at entry, for incident hepatic decompensation between 1996 and Results: Initiation of ART significantly reduced the rate of hepatic decompensation by 28% 41% on average. Anderson JP, et al. Clin Infect Dis Mar;58(5):

13 Standardized Cumulative Incidence of Hepatic Decompensation * * Based on competing risk regression analysis. ART-Treated HIV/HCV-Coinfected HCV-Monoinfected Log-rank p<0.001 HD risk was 83% higher in the coinfected group (ahr 1.83, 95% confidence interval [CI] 1.54 to 2.18) Lo Re V, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEAB0102.

14 Has the outcome of liver disease in HIV/HCV-coinfected patients become similar to that in HCV monoinfection? Metanalysis of 26 studies No HAART HAART (b) Deng L, et al. World J Gastroenterol 2009; 15:

15 EACS Guidelines: When to Start Initiation of ART ART is always recommended if CD4 count <350 cells/mm 3 Condition Current CD4 + lymphocyte count >500 HBV requiring anti-hbv treatment R R HBV not requiring anti-hbv treatment HCV for which anti-hcv treatment is being considered or given R C HCV for which anti-hcv treatment not feasible R C C = CONSIDER; D = DEFER; R = RECOMMENDED R C EACS treatment guidelines, Version 7.0, Nov Available at: Accessed November 2013

16 CD4 cell count (cells/μl) Median CD4 nadir according to year of ART start and different HIV transmission groups (n = 3094) MSM IDU HET HPC unknown Total Rockstroh J. Antivir Ther 2012; 17: Months prior to start of ART Median CD4 nadir 45 days prior to and 15 days after ART initiation (treatment was initiated 1996 and patients with treatment start after being in the cohort for 3 months were included) HET: heterosexuals; HPC: high prevalence countries; IDU: Injection Drug Users; MSM: men who have sex with men

17 Changes in death causes over time N= N=548 3,802 deaths in 49,734 HIV positive individuals followed for 304,695 person-years Death rate fell from 17.4 deaths per 1000 py in to 8.3 deaths in Weber R, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THAB03104.

18 Which questions need to be addressed?» Is HAART beneficial or harmful for further liver disease progression? When to start HAART in HCV co-infection?» Which antiretroviral drugs should we choose in coinfection?

19 Liver Toxicity due to HAART 14-20% of patients will develop elevated liver enzymes. 2-10% of patients will need to interrupt HAART due to severe liver injury. Risk factors: Viral hepatitis B or C First regimen Nevirapine Full dose ritonavir Female sex J Infect Dis 2002; 186:23-31

20 Mitochondrial Toxicity Fischer et al. 2003

21 didanosine

22 Liver disease of unknown etiology in HIV patients Clinical presentation Histology Etiology Treatment Reference Persistently elevated liver enzymes Steatosis & steatohepatitis Dislipidemia, hyperglycemia, obesity, d-drugs, AZT, alcohol Statins, metformin, diet, exercise, d-drug removal, alcohol abstinence Ingiliz et al. Hepatology 2009; 49: Kovari et al. CID 2010; 50: Portal hypertension* Nodular regenerative hyperplasia IL-2, ddi, prothrombotic conditions Anticoagulants, ddi or IL-2 removal Podevin et al. AIDS 2006; 20: Mallet et al. AIDS 2007; 21: Portal venular sclerosis ddi, pylephlebitis β-blockers, ddi removal, TIPS Maida et al. J AIDS 2006; 42: Schiano et al. Am J Gastroenterol 2007; 102: Maida et al. Antivir Ther 2008; 13: Kovari et al. CID 2009; 49: * Laboratory (pancytopenia), clinical (GI bleeding) or endoscopic (esophageal varices)

23 NEAT project Genetic markers involved in NCPH in HIV patients Mark Nelson. Chelsea & Westminster Hospital, London, UK Jürgen Rockstroh. University of Bonn, Bonn, Germany Vincent Soriano. Hospital Carlos III, Madrid, Spain

24 Cross-sectional studies assessing prevalence of abnormal/significant liver fibrosis in HIV Author (year) Number of subjects (all/ HIV monoinfected) Number of patients on HIV therapy Median CD4-count cells/µl (IQR) or mean ± SD HIV-RNA < limit of detection in an ultrasensitive assay Method for fibrosis determination Patients with abnormal/significant fibrosis (all) HIV-mono-infected patients with abnormal/significant fibrosis Anadol E et al.4 (2013) [4] (333/202) 88.6% 461 ( ) 79 % Fibroscan 18 % 11 % DallaPiazza M et al. (2010) [7] Han SH et al. 2013[5] Merchante N et al. (2010) [6] Stabinski L et al. (2011) [8] Tahiri M et al. (2013) [9] (0/432) 63% 340 ( ) 25 % Apri-Score n.a. 8,3 % (0/93) 100% 503 ± ,7 % Fibroscan n.a. 41,9% (0/258) 85% % Fibroscan n.a. 11,2% ( ) (500/n.a.) 60% 449 n.a. Fibroscan 17% n.a. ( ) (619) 92.1% 602 ± % FIB4 n.a. 15,5% Rockstroh J et al., Current Opinion in HIV and AIDS, 2014 in press

25 Effects of ART on the liver in HIV/HCVcoinfected patients: Conclusions The short- and mid-term effects of ART on the progression of HCV-related liver disease largely outweigh the potential risks for long-term toxicity. This supports an earlier starting of ART in patients with HIV/HCV-coinfection. However, surveillance of possible new side effects, as well as of changes in the natural history of hepatitis C infection in patients on HAART is required. Favorable liver tolerability and lack of drug-drug interactions make new drug classes such as integrase inhibitors appear as attractive components of ART in coinfected patients (particularly after OLTX and during HCV therapy) which need to be further explored

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