Hepatocellular Carcinoma in HIV-infected Patients A Growing Complication of Coinfection with HCV or HBV Mon, 31 May 2010

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1 Bronx VA Medical Center Mount Sinai School of Medicine Hepatocellular Carcinoma in HIV-infected Patients A Growing Complication of Coinfection with HCV or HBV Mon, 31 May 2010 Norbert Bräu, MD, MBA Associate Professor of Medicine, Mount Sinai School of Medicine, New York NY Director, Viral Hepatitis Program Bronx VA Medical Center, Bronx NY

2 Effect of HAART on Survival

3 Rising rate of liver-related deaths and of HCC France: Mortalité 2000 & N ~64,000 78,000 Deaths 964 (1.5%) 1,042 (1.3%) Liver deaths: 13.4% 15.4% HCC deaths: 15% 25% p=0.03 Salmon-Ceron D, J Hepatol, April May 2 June 2010 Tel Aviv, Israel

4 HCC in HIV - Literature HCC in HIV 2001 n= 7 García-Samaniego J et al. (Madrid), Am J Gastro 2004 n=41 Puoti M et al. (Italy), AIDS 2007 n=63 North American Liver Cancer in HIV Study Group Bräu N et al., J Hepatol

5 Italian HCC in HIV study Median survival: HIV-pos. HIV-neg. (Brescia) HIV-neg. (CLIP) 5.9 mo 17.7 mo 18.0 mo Puoti M et al., AIDS, Nov-2004

6 Italian HCC in HIV study Puoti M et al., AIDS, Nov-2004

7 Italian HCC in HIV study Puoti M et al., AIDS, Nov-2004

8 North American Liver Cancer in HIV Study Group * * ** * * * * * * * * * * * 12 sites (US, Canada) HIV-pos. HCC (n=63) 4 sites HIV-pos. + HIV neg. HCC (n=226)

9 N American HCC in HIV Study: Patient Characteristics HIV-positive n=63 HIV-negative n=226 Age, mean (years) <0.001 Male sex 98% 99% 0.39 Date of HCC Diagnosis, median Etiology of HCC (%) Viral Hepatitis HCV HBV Non-viral Alcohol Iron Overload Unknown Feb-2003 Nov-2000 < % 3% 72% 25% 2% 0% 2% 71% 29% 67% 4% 17% 2% 10% P <0.001 History of Alcohol Abuse 46% 70% HIV parameters CD4+ cells (per mm 3 ), median CD4+ cells <200 per mm % HIV RNA (copies/ml ml), median HIV RNA <400 copies/ml % Bräu N, J Hepatol, Oct 2007

10 N American HCC in HIV Study: Patient Characteristics HIV-positive n=63 HIV- negative n=226 P Initial Presentation Liver Mass on Imaging (Screening) Elevated AFP (Screening) Symptoms Abdominal Pain, Weight Loss, Abdominal Distension 32% 18% 51% 51% 11% 38% Portal Vein Thrombosis 16% 20% 0.43 Extrahepatic Metastases Skeletal, Lungs, Inferior Vena Cava, Heart, Adrenal, Gall Bladder, Lymph Nodes, Multiple Sites 13% 8% 0.25 AFP level * Median (ng/ml( ng/ml), Normal (<( ULN), n (%) n= % n= % Bräu N, J Hepatol, Oct 2007

11 N American HCC in HIV Study: Tumor Staging HIV-positive n=63 HIV-negative n=226 P Barcelona Clinic Liver Cancer (BCLC) Stage, % A B C D Advanced BCLC Stage (C+D) n=62 26% 24% 39% 11% 50% n=214 21% 21% 40% 18% 58% 0.47 UNOS TNM Stage, % = Advanced UNOS-TNM Stage n=48 2% 25% 17% 57% n=169 1% 28% 17% 54% 0.98 Bräu N, J Hepatol, Oct 2007

12 N American HCC in HIV Study: Survival All Patients Cumulative Survival p=0.44 HIV-neg HIV-pos Months At risk HIV[-] At risk HIV[+] median survival: 7.5 mo median survival: 6.9 mo

13 N American HCC in HIV Study: Survival HCV Patients Survival Functions Cumulative Survival HCV-monoinfected HIV/HCV-coinfected p= Months At risk HCV At risk HIV/HCV Bräu N, J Hepatol, Oct 2007

14 N American HCC in HIV Study: Survival HBV Patients Survival Functions Cumulative Survival HBV-monoinfected HIV/HBV-coinfected p= Months At risk HBV At risk HIV/HBV Bräu N, J Hepatol, Oct 2007

15 N America: Cox Proportional Hazard Model of Survival Factor Univariate P Hazard Ratio 95% Confidence Interval Multi- variable P Hazard Ratio 95% Confidence Interval Initial Presentation with Symptoms < < Any HCC Therapy Proven Effective < < Diagnosis on or after 01-Jan Jan BCLC stages C&D vs. A&B < < Portal Vein Thrombosis NS AST/ALT >2.00 < AFP >400 ng/ml < < Platelets >100,000 /mm HIV-positive NS (0.19)* ALT level elevated (>ULN) History of alcohol abuse Black Race Age at HCC Diagnosis >60 yrs Bräu N, J Hepatol, Oct 2007

16 N American vs. Italian HCC in HIV Study: Discussion Why discrepancy between survival data? Same median survival HIV-pos. (I 5.9 mo; US/CAN 6.9 mo) Different survival HIV-neg. (I 17.9 mo; US/CAN 7.5 mo) Possibly higher rate of HCC screening in Italy in HCV-monoinfected patients

17 HCC in HIV HCC in HIV Pooling of Data 2001 n= 7 García-Samaniego J et al. (Madrid), Am J Gastro 2004 n=41 Puoti M et al. (Italy), AIDS 2007 n=63 North American Liver Cancer in HIV Study Group Bräu N et al., J Hepatol Liver Cancer in HIV Study Group As of 23-May-2010: N=163, 13 countries, 6 continents presented : CROI, San Francisco, Feb-2010; EASL, Wien, Apr-2010 accepted HIV /Hepatitis Coinfection Workshop, Tel Aviv, May-2010, EASL HCC Symposium, Dubrovnik, Jun-2010; Intl AIDS Conference, Wien, Jul-2010 New cases welcome from any clinician:

18 Liver Cancer in HIV Study Group N=163

19 HCC in HIV Increasing Frequency of Cases Data of Liver Cancer in HIV Study Group 23 May 2010 N=163

20 HCC Screening -- AASLD 2005 Guidelines Whom to screen: How to screen: Sonogram every 6 12 mo Bruix J & Sherman M, Hepatol, Nov 2005

21 HCC Screening: Impact on Tumor Presentation HIV/HCV coinfection HCC Tumor Characteristics HCC screened n=39 HCC unscreened n=31 P Hepatic lesions Solitary tumors Multiple tumors Diffusely infiltrative tumors 28 (51%) 25 (46%) 2 (3.6%) 19 (45%) 21 (50%) 2 (4.8%) 0.85 Median size largest lesion (cm), range 3.2 (1.5 10) 4.7 (2.1 16) Eligibility for liver transplantation Meets Milan criteria Meets Expanded Milan Criteria ( up-to-7, Mazzaferro V et al., Lancet Oncology, Jan-09) 17/32 (53%) 25/28 (89%) 10/26 (39%) 11/17 (65%) Portal vein thrombosis Extrahepatic metastases 4 (10.3%) 3 (7.7%) 5 (16.1) 8 (25.8%) AFP level, median (ng/ml), interquartile range 222 (23 1,126) 2,818 (310 33,030) Núñez M, CROI 2010, San Francisco

22 HCC Screening: Impact on Staging and Therapy HIV/HCV coinfection HCC Staging BCLC Stage, n (%) A B C } Advanced, D } Incurable BCLC Stages C and D Screened n=39 18 (46%) 9 (23%) 9 (23%) 3 (8%) 12 (31%) Unscreened n=31 3 (10%) 3 (10%) 19 (61%) 6 (19%) 25 (80%) P <0.001 CLIP Score, Mean ±SD 1.99 (±1.1) 2.45 (±1.4) Potentially Curative Therapy Radiofrequency Ablation Ethanol Injections Surgical Resection Liver Transplantation Effective, Non-Curative Therapy Transarterial Chemoembolization Sorafenib HCC Therapy Screened n=39 15 (39%) (28%) 11 0 Unscreened n=31 6 (19%) (23%) 5 2 P No Therapy 13 (33%) 18 (58%) Any Potentially Curative Therapy Any Effective Therapy 15 (39%) 26 (67%) 6 (19%) 13 (42%) Núñez M, CROI 2010, San Francisco

23 HCC Screening: Impact on Survival HIV/HCV coinfection Cumulative Survival HCC Screen No HCC Screen p=0.021 Median Survival (adjusted for lead time bias) HCC screen 12.8 months No HCC screen 3.7 months Months At Risk HCC Screen No HCC Screen 31 0 Núñez M, CROI 2010, San Francisco

24 HIV Viral Load & Natural History of HCC Hypothesis: HIV viremia negatively influences course of HCC In HIV/HCV: More rapid progression of hepatic fibrosis with HIV RNA 400+ Copies/ml Bräu N, J Hepatol, Jan 2006

25 Fibrosis Progression Rate by HIV Viral Load in chronic hepatitis C IshFU / yr p= p= p=0.044 p= p=0.29 p=0.053 p= n = HIVnegative HIVpositive HIVnegative HIV RNA <400 HIV RNA 400+ HIV RNA <400 HIV RNA 400 to 99K HIV RNA 100K+ Bräu N, J Hepatol, Jan 2006

26 HIV Viremia: Influence on Survival Patient Characteristics HIV RNA <400 c/ml n=54 (55%) HIV RNA 400+ c/ml n=45 (45%) P Age (yrs), Mean ± SD 50.6 (±7.8) 51.4 (±8.1) 0.62 Male Sex 50 (93%) 40 (89%) 0.73 Race/Ethnicity Black White Latino Asian 18 (33%) 27 (50%) 8 (9.3%) 1 (1.9%) 25 (56%) 13 (29%) 7 (15.6%) Time of HCC Diagnosis, Median Aug-2004 Apr Etiology of HCC Chronic Hepatitis C Chronic Hepatitis B Non-Viral (Alcohol, NASH) 37 (69%) 16 (30%) 1 (1.9%) 34 (76%) 10 (22%) 1 (2.2%) 0.71 Liver Function, Mean ± SD Child-Turcotte-Pugh Score Stage A Stage B Stage C (56%) 21 (39%) 3 (5.6%) (42%) 20 (44%) 6 (13.3%) Initial Presentation at Screening Without Symptoms 35 (65%) 20 (44%) HIV parameter, Mean ± SD CD4+ Cells (per mm3) 349 (±191) 294 (±291) 0.19 Kikuchi L, EASL 2010, Wien

27 HIV Viremia: Influence on Survival At Risk HCC Screen No HCC Screen Kikuchi L, EASL 2010, Wien

28 HIV Viremia: Influence on Survival At Risk HCC Screen No HCC Screen Kikuchi L, EASL 2010, Wien

29 HIV Viremia: Influence on Survival HCC Therapy none Kikuchi L, EASL 2010, Wien

30 HIV Viremia: Influence on Survival HCC Therapy none effective, non-curative Kikuchi L, EASL 2010, Wien

31 HIV Viremia: Influence on Survival HCC Therapy none effective, non-curative potentially curative Kikuchi L, EASL 2010, Wien

32 HIV Entry And Replication in Stellate Cells Promote Cellular Activation And Fibrogenesis Ana C. Tuyama*, Feng Hong*, Alison D. Schecter, Arevik Mosoian, Benjamin K. Chen, Ping Chen, Isabel Fiel, Mary E. Klotman, Meena Bansal AASLD 2007, late-breaker oral

33 HCC in HIV: Continental Comparison North & South America & Europe Emma Page (Imperial College, London) 6 th International Workshop on HIV & Hepatitis Coinfection, Tel Aviv 31 May 2010, 17h30

34 Summary: HCC in HIV HIV-positive patients: liver disease increasing as cause of death

35 Summary: HCC in HIV HIV-positive patients: liver disease increasing as cause of death Within liver-related deaths: increase of HCC

36 Summary: HCC in HIV HIV-positive patients: liver disease increasing as cause of death Within liver-related deaths: increase of HCC Survival HIV[+] vs. HIV[-] cases of HCC: contradictory results Italy shorter survival (6 vs. 18 months) North America similar survival (7 vs. 8 months)

37 Summary: HCC in HIV HIV-positive patients: liver disease increasing as cause of death Within liver-related deaths: increase of HCC Survival HIV[+] vs. HIV[-] cases of HCC: contradictory results Italy shorter survival (6 vs. 18 months) North America similar survival (7 vs. 8 months) Screening in HCC with HIV/HCV-Coinfection smaller tumors, earlier BCLC stages, more frequent HCC therapy, better survival (4 vs. 13 months)

38 Summary: HCC in HIV HIV-positive patients: liver disease increasing as cause of death Within liver-related deaths: increase of HCC Survival HIV[+] vs. HIV[-] cases of HCC: contradictory results Italy shorter survival (6 vs. 18 months) North America similar survival (7 vs. 8 months) Screening in HCC with HIV/HCV-Coinfection smaller tumors, earlier BCLC stages, more frequent HCC therapy, better survival (4 vs. 13 months) Undetectable HIV RNA: better survival (but only without HCC therapy)

39 Summary: HCC in HIV HIV-positive patients: liver disease increasing as cause of death Within liver-related deaths: increase of HCC Survival HIV[+] vs. HIV[-] cases of HCC: contradictory results Italy shorter survival (6 vs. 18 months) North America similar survival (7 vs. 8 months) Screening in HCC with HIV/HCV-Coinfection smaller tumors, earlier BCLC stages, more frequent HCC therapy, better survival (4 vs. 13 months) Undetectable HIV RNA: better survival (but only without HCC therapy) Please give us your cases of HCC in HIV:

40 Thank you for your kind attention