Hepatitis, HIV and Malignancy

Transcription

1 11th International Workshop on Co-infection - HIV & Hepatitis London, June 11 th -12 th, 2015 Hepatitis, HIV and Malignancy Dr. David James PINATO MD MRCP (UK) MRes PhD NIHR Academic Clinical Lecturer in Medical Oncology Department of Surgery and Cancer Imperial College, Hammersmith Campus Du Cane Road, London W12 0HS National Centre for HIV Malignancies Chelsea & Westminster Hospital, 369 Fulham Road SW109NH

2 Conflicts of Interest No conflicts of interest to disclose.

3 Viruses and Cancer: old script new players transmissible cancer Rous Sarcoma Virus (RSV), enveloped retrovirus v-src c-src

4 Cancers in HIV disease Direct vs Indirect carcinogenesis AIDS Defining Cancers (ADCs) Cervical Carcinoma Kaposi s Sarcoma HHV8 NHL ADCs HAART HPV NADCs HBV HCV HPV Many Others Anal Cancer HL Hepatocellular Carcinoma Non-AIDS Defining Cancers (NADCs)

5 Overview of the Talk Pathogenesis of HCC. Viral hepatocarcinogenesis Contribution of HIV Hepatocellular Carcinoma Malignancy Epidemiology Relevance of HCC as a source of morbidity/mortality in people living with HIV. Risk modification How can we use our clinical knowledge to prevent HCC in HIV + Primary, Secondary, Tertiary prevention. Hepatitis HIV Management of HCC Does HIV influence tumor phenotype and treatment options?

6 Top 5 reasons to be interested in HCC. 1. Rising incidence in the Western World. 2. Highest mortality rates amongst solid tumors. 3. Well established risk factors (population at risk) 4. Highly multidisciplinary management 5. Leading cause of morbidity/mortality in co-infected patients.

7 Hepatocellular Carcinoma Most common form of primary liver cancer (90%) 5 th most common solid tumor 3 rd most fatal M/F ratio 2.4 Last and most adverse consequence of Chronic Liver Disease. Multiphasic carcinogenesis inflammation fibrosis carcinoma Chronic liver damage Hepatocyte regeneration Cirrhosis Genetic alterations Normal liver Chronic HCV liver disease Cirrhotic liver HCC HCC

8 HCC: a Complex Pathogenesis HBV 10-15%* HCV 60-70%* Alcohol Growth factor activation Chronic injury inflammation Metabolic disorders Cirrhosis Regeneration Environmental factors (AFB1) Genetic and/or epigenetic alterations * Europe Incidence HCC Moradpour D et al. Eur J Gastroenterol Hepatol 2005; 17: ; Llovet JM et al.lancet 2003; 362:

9 Hepatocellular Carcinoma: HCV induced carcinogenesis Genotoxicity Inflammation Limitless proliferative potential Immunity Avoidance of Apoptosis Jeong SW, Clin Mol Hepatol, 2012

10 Hepatocellular Carcinoma: HBV induced carcinogenesis

11 HCC: the magnitude of the problem Surveillance, Epidemiology, and End Results (SEER) registries. Annual age-adjusted incidence rates per 100,000 and trends, all hepatocellular carcinoma cases and by sex ( ) 4x Increase in incidence in 30 years Viral (HCV diffusion in the West) Non viral aetiology ( cryptogenetic cirrhosis) Alterkuse, J Clin Oncol. 2009

12 HCV: A mission far from being accomplished. Projected Number of Cases of HCC and Decompensated Cirrhosis due to HCV The Triumph of Caesar, A. Mantegna ( ) Hampton Court Palace + non viral aetiology of CLD NASH/NAFLD EtOH Despite the optimism from DAA, long term complications of HCV are on the rise Davis GL, et al. Gastroenterology 2010.

13 Cumulative probability of events The Natural History of Compensated Cirrhosis due to HCV 100 HCC in ESLD HCC was the first to develop complication and the major cause of death HCC Ascites Jaundice Gi haemorrhage Years PSE Patients still at risk Sangiovanni et al. Hepatology 2006; 43:

14 HCC in ESLD: a recognized challenge. Symptoms Percent of Patients None 23% Abdominal Pain 32% Ascites 8% Jaundice 8% Anorexia/weight loss 10% Malaise 6% Bleeding 4% Encephalopathy 2% Actively look for HCC in any case of decompensated liver disease Ideal scenario for screening in high risk populations How to define high risk What diagnostic methods should be used? Gastroenterology 2002

15 Surveillance for HCC Improves Mortality: A Randomized Controlled Trial A study of hepatitis B carriers in China 18,816 randomized to surveillance with AFP + US biannual vs. no surveillance Adherence to surveillance was 58% Endpoints: pick up rate of HCC, survival benefit. HCC related mortality was reduced by 37% in surveillance arm. Zhang BH, et al, J Cancer Res Clin Oncol 2004

16 Screening for HCC: EASL/EORTC Recommendations Surveillance for HCC should be performed with 6 monthly liver US AFP is not indicated Shortened recall for patients at higher risk of HCC (ie. suspicious unifocal nodules <1cm sign) 3 mo. No specific recommendations for HIV + EASL Practice Guidelines 2012

17 Linking staging, prognosis and treatment: the BCLC system Staging/Prognostic assessment is uniquely different in HCC. At least 7 staging systems proposed, variably encompassing predictors from: Staging (tumour size/n nodules) Liver function (Child Pugh Class/MELD) PLT/Alb Performance Status Tumour Markers: AFP, ALP, etc. BCLC Prognosis Treatment Allocation Llovet 1999

18

19 The contribution of HIV to Hepatocarcinogenesis Mechanistic Effects Tat

20 The contribution of HIV to Hepatocarcinogenesis Evidence from Epidemiological Studies McGinnis, JCO 2006 HIV + male veterans (n=14,018) HIV - controls (n=28,036) age-, race-, sex-, and location-matched Incidence rate ratios (IRR) HIV+/HIV- HIV not sufficient as causative factor (despite experimental evidence) Cirrhosis and Hepatocellular Carcinoma in HIV-Infected Veterans With and Without the Hepatitis C Virus: a Cohort Study, Giordano TP, Arch Intern Med Incidence rate ratios (IRR) HCV + -HIV + /HIV- Incresed incidence of Cirrhosis/HCC in HCV coinfected ++ post-haart Longer survival? Direct effect of HAART

21 Evolving Trends in the prevalence of Cirrhosis and HCC Ioannou, Hepatol, 2013 Veteran Affairs Healthcare DB patients/year receiving HIV care HCV co-infected 3.5% to 13.2% 3.7x HCV infection Adjusted OR % CI HBV infection Age Hispanic ethnicity Diabetes Alcohol abuse Prevalence ( ) Black ethnicity HCV eradication HCV co-infected 0.07% to 1.62% 23x Adjusted OR 95% CI HCV infection HBV infection Age Low CD4 count

22 The impact on mortality: a positive yet mixed message SHCS Swiss HIV Cohort Study deaths/9053 participants (5.1%) Median Age: 47 y 76% M Median HIV duration: 14 y 93% on ART = 9.5 years (median) CD4 + before death= 251 cells/mm 3 Co-infection 45% HCV 11% HBV Weber et al. Hiv Med 2013

23 Changing patterns of mortality in HIV + Mortality by cause 1. Non-AIDS defining cancers (n=85, 19.1%) including HCC (n=13, 2.8%) 2. AIDS (n=73, 16.4%) 3. Liver Diseases (n=67, 15%) non-malignant liver mortality + HCC = 1st Weber et al. Hiv Med 2013

24 The burden of HCC in HIV + patients mortality Rosenthal E., HIV Medicine 2015 Mortavic Study: multicenter, prospective, cross-sectional study. Prospectively recorded deaths, survey every 5 years centres (France), patients, 230 deaths, 30 liver-related. Liver related mortality (2010) Steady increase in LRM

25 Liver related mortality HCC leading and increasing cause of LRM in HIV + Despite cart (100% in 2010) HIV control HCV therapy Rosenthal E., HIV Medicine 2015

26 Modifying the Risks Adapted from Kim, Semin Oncol 2015 Antiviral treatment Screening for HCC (US) Antiviral treatment HCV testing EtOH BMI/diabetes (NAFLD) Infection HBV HCV HIV Paucity of data in risk-modifying strategies in HIV + HCC Most recommendations extrapolated from HCV/HBV monoinfection

27 Risk Modifying Strategies in HCV-related CLD

28 HCV eradication and risk of HCC Singal, CGH 2010 HCV infection is a modifiable risk factor for HCC 14 studies with SVR data (n = 3310) HCV+ with advanced fibrosis Rx: Ifn/Ifn+Rib

29 All HIV/HCV-coinfected patients diagnosed with HCC in 26 hospitals in Spain before 31 December 2012 HCC 167 HCV RNA 24wk post Rx SVR+ 13 SVR- 154 Median Time from SVR: 28 m (20-39) Median CD4 + : 438 ( ) 1 HBV, 1 EtoH, 11 no other risk factors Screened at physician discretion according to guidelines: Variability acknowledged but unlikely systematic bias Need for ongoing screening despite SVR? Timing/indication for HCV eradication (liver decompensation vs. primary HCC prevention)? Role / cost-effectivess of DAA Merchante, AIDS 2014

30 Risk Modifying Strategies in HBV carriers

31 Risk Evaluation of Viral Load Elevation & Associated Liver Disease/Cancer Study REVEAL: prospective, multicenter, observational cohort study : recruitment 7 Taiwanese townships; individuals aged years eligible (N = 89,293) HCV seropositive HCC follow-up: 41,779 PYs Cirrhosis follow-up: 40,038 PYs HCC-free individuals enrolled (N = 23,820) HBsAg(+) with adequate baseline HBV DNA sample (N = 3851) HCC analysis (n = 3653) Cirrhosis analysis (n = 3582) Insufficient serum for tests or HBsAg(-) HCV seropositive or diagnosed with cirrhosis or died within 6 months of entry Chen CJ, et al. JAMA. 2006;295: Iloeje UH, et al. Gastroenterology. 2006;130:

32 Cumulative Incidence of HCC at Year 13 Follow-up (%) REVEAL: High HBV DNA Associated With Increased HCC Incidence Relationship Between Baseline HBV DNA and HCC Incidence: All Participants (N = 3653) Chen CJ, et al. JAMA. 2006;295: < , ,999 HBV DNA at Baseline (copies/ml) ,000

33 Secondary Prevention of HCC in HBV infection Kim, Semin Oncol 2015 Prevention of HCC in CHB Patients Control of HBV risk modifier of HCC Resistance?post resistance Rescue therapy Residual risk beyond HBV-DNA suppression Positive metanalysis (Papatheodoridis GV 2010 J Hepatol)

34 Ct-HBX Recurrent HCC: it s the virus! Yin, JCO 2013 Large prospective Chinese study (N=1096) - Tertiary Prevention Non-randomised component (617) 215 Rx with NUC RCT (180): 90 NUC, 90 controls Rx: Lam 100 mg + Adefovir 10 mg or Entecavir 0.5 mg if resistance. STORM Adjuvant Sorafenib post radical resection Ct-HBX: product of HBV integration (truncated HBX) Enhances HCC cell invasion/metastasis Ct-HBX peritumoural expression = worse RFS in HBV + HCC treated with NUC (p<0.001).

35

36 The natural history of HIV + HCC Prognostic factors of survival of hepatocellular carcinoma in HIV/hepatitis C virus-coinfected patients. Mostly cross-sectional, case-control retrospective studies HIV/HCV coinfection Single-center experience Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIVinfected patients justify specific screening policies?. 2 Gelu-Simeon, AIDS

37 Diagnosis and Outcome of HIV + HCC Brau, J Hepatol 2007 Large retrospective, multi-centre case control study HIV + HCC (n=62), HIV - HCC (n=226), North America Features of HIV + HCC: Coinfection almost universal feature (HCV>HBV) Younger Age at diagnosis Median OS 7 months despite balanced staging Active HIV replication worse OS only in untreated HCC

38 OLT in HIV + Vibert E, Hepatology , 21 HIV+ patients and 65 HIV- patients with HCC listed for LT Single institution (Villejuif, FR) Drop-out: 5/21 (23%) vs 7/65 (10%) p=0.08 No impact on DFS / OS post OLT No difference in tumor biology

39

40 Advanced HCC. Cheng, A. L. et al. Lancet Oncol 2009 (Asia) Llovet, J. M. et al. NEJM 2007 (Europe/USA) Child A, PS 0-2 Discontinuation of Rx upon progression. OS Median Europe/USA (n=602) 10.7 vs 7.9 m Asia (n=226) 6.5 vs 4.2 m TTP Median 5.5 vs 2.8 m 74% 2.8 vs 1.4 m 74% Objective Responses < 3% (70% SD) < 3%

41 Sorafenib in HIV+ HCC Berretta M, Anticancer Drugs 2013 July 2007 and October 2010, 27 consecutive HIV + HCC

42 Conclusions HCC is a leading and increasing cause of morbidity and mortality in HIV +, especially in the context of co-infection. Prevention is key to optimize outcomes and reduce LRM. No specific recommendation for enhanced screening for HCC in HIV+. SVR/HBV-DNA are risk-stratifying biomarkers in coinfection. BCLC algorithm is key for prognosis/treatment allocation. HIV status should not be a barrier in curative & palliative interventions.

43 THANK YOU! Dr. David J Pinato david.pinato@imperial.ac.uk