10 Need to Know Ques2ons

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1 Cirrhosis/ESLD management 1 Need to Know Ques2ons Marion Peters MD UCSF December Once a pa2ent with HCV is imaged to look for cirrhosis and none is found, how omen should I repeat imaging in the future? 2. For HCC screening, in my HIV- HBV pa2ent and HIV- HCV cirrho2cs- does it maser if I use US or CT? 3. For HCC screening, How omen should I send an AFP, if ever? 4. Who should get an EGD? If no varices are found on the EGD, does it need to be repeated in the future? 5. Who needs propranolol? And once I start, how should I 2trate up? Cirrhosis/ESLD management 1. Once a pa2ent with HCV is imaged to look for cirrhosis and none is found, how omen should I repeat imaging in the future? 2. For HCC screening, in my HIV- HBV pa2ent and HIV- HCV cirrho2cs- does it maser if I use US or CT? 3. For HCC screening, How omen should I send an AFP, if ever? 4. Who should get an EGD? If no varices are found on the EGD, does it need to be repeated in the future? 5. Who needs propranolol? And once I start, how should I 2trate up? How to diagnose cirrhosis Ultrasound of CT poor at diagnosis of early cirrhosis: sensi2vity %; specificity % Portal hypertension Low platelets, splenomegaly, spider nevi Imaging with evidence of nodularity or PHTN Assess fibrosis Liver biopsy Serum tests: AI, FIB- 4, fibrosure Elastography 1

2 All HCC CASES REFERRED SINCE 1/2 (n=15) LIVER TRANSPLANTATION DATA (n=168) NAFLD? HCV HBV ALD OTHERS HCV HBV ALD OTHERS From El-Serag H. N Engl J Med 211;365: (with permission) Data from Marrero JA et.al: Hepatology 22;36: Data from UCSF and Columbia-NY: Yao et.al. Am J Transpl (In press) High Risk HCV HBV Hemochromatosis A1AT Deficiency NAFLD Alcoholic Liver Disease Risk further stratified Age (disease duration) Liver Disease Severity Gender (Male) Low risk Autoimmune hepatitis Wilson s disease Cholestatic Disease PBC PSC Incidence of HCC (%) Cumulative Probabilities of HCC in Patients with Cirrhosis Predictive Index: PT Activity 75% Age 55 Platelets < 75K HCV Ab (+) High Risk All Patients Low Risk Numbers at risk Time-Months Valazquez et.al. Hepatology 23;37:

3 Cirrhosis/ESLD management Once a pa2ent with HCV is imaged to look for cirrhosis and none is found, how omen should I repeat imaging in the future? For HCC screening, in my HIV- HBV pa2ent and HIV- HCV cirrho2cs- does it maser if I use US or CT? For HCC screening, How omen should I send an AFP, if ever? Who should get an EGD? If no varices are found on the EGD, does it need to be repeated in the future? Who needs propranolol? And once I start, how should I 2trate up? Ultrasound of the liver and alpha-fetoprotein every 6 months HCC screening was found to reduce mortality by 37% in a RCT of 18,816 HBV persons in Shanghai CT or MRI showing typical HCC characteristics * * Arterial phase hypervascularity and delayed phase washout HCC supplied by hepatic artery, rest PV Requires intravenous contrast and multi-phase imaging Quality of imaging and interpretation of findings Arterial Phase Enhancement Portal Venous phase washout 3

4 Cirrhosis/ESLD management Once a pa2ent with HCV is imaged to look for cirrhosis and none is found, how omen should I repeat imaging in the future? For HCC screening, in my HIV- HBV pa2ent and HIV- HCV cirrho2cs- does it maser if I use US or CT? For HCC screening, How omen should I send an AFP, if ever? Who should get an EGD? If no varices are found on the EGD, does it need to be repeated in the future? Who needs propranolol? And once I start, how should I 2trate up? Alpha-fetoprotein (AFP) - Not always reliable (normal < 8.5 ng/ml) - 2-% with liver cancer have normal AFP - 3-% without liver cancer with viral hepatitis have abnormal AFP - The higher the AFP the more likely the diagnosis of liver cancer: > ng/ml strongly suspicious for HCC (low sensitivity) - No longer recommended by AASLD but in EASL APASL guidelines Cirrhosis/ESLD management Des-gamma-carboxy prothrombin (DCP) (PIVKA-II) Marrero JA et.al. Hepatology 23;37:1114 Glypican-3 Capurro M, et.al. Gastroenterology 23;125:89 GGT-II (Hepatoma-specific band) Cui R, et.al. Br. J Cancer 23;88:1878 AFP-L3 (Lens culinaris agglutinin-reactive AFP) Yamashita F, et.al. Gastroenterology 1996;111:996 IGF-I (Insulin-like growth factor) Mazziotti G, et.al. Cancer 22;95: Once a pa2ent with HCV is imaged to look for cirrhosis and none is found, how omen should I repeat imaging in the future? 2. For HCC screening, in my HIV- HBV pa2ent and HIV- HCV cirrho2cs- does it maser if I use US or CT? 3. For HCC screening, How omen should I send an AFP, if ever? 4. Who should get an EGD? If no varices are found on the EGD, does it need to be repeated in the future? 5. Who needs propranolol? And once I start, how should I 2trate up? 4

5 Risk of Bleeding from Esophageal Varices Cirrhosis Prevalence 35%-8% 25%-% 5%-7% Survive 7% Rebleed Risk of Bleeding 3%-5% Die Variceal Surveillance All cirrhotics require Esophagogastroduodenoscopy No varices Repeat endoscopy in 3 years (well compensated); in 1 year if decompensated No beta-blocker prophylaxis Garcia-Tsao G, et al. Hepatology. 27;46: Small varices (< 5 mm), Child B/C Nonselective Beta-blocker prophylaxis Medium or large varices Child Class A, no red wales: beta blockers Child class B/C, red wales: beta blockers or band ligation Cirrhosis/ESLD management 1. Once a pa2ent with HCV is imaged to look for cirrhosis and none is found, how omen should I repeat imaging in the future? 2. For HCC screening, in my HIV- HBV pa2ent and HIV- HCV cirrho2cs- does it maser if I use US or CT? 3. For HCC screening, How omen should I send an AFP, if ever? 4. Who should get an EGD? If no varices are found on the EGD, does it need to be repeated in the future? 5. Who needs propranolol? And once I start, how should I 2trate up? Variceal Surveillance All cirrhotics require Esophagogastroduodenoscopy No varices Repeat endoscopy in 3 years (well compensated); in 1 year if decompensated No beta-blocker prophylaxis Small varices (< 5 mm), Child B/C Nonselective Beta-blocker prophylaxis Medium or large varices Child Class A, no red wales: beta blockers Child class B/C, red wales: beta blockers or band ligation Garcia-Tsao G, et al. Hepatology. 27;46:

6 Nonselec2ve beta blocker for varices Start propranolol at 1 mg bid or 2d Nadolol 1-2 mg per day Titrate up to decrease heart rate to 6 Alert pa2ent to orthosta2c symptoms Most pa2ents are controlled at 1-2 mg 2d Some pa2ents require as lisle as 5 mg bid Treatment ques2ons 1. My pa2ent with HCV and HIV is star2ng ART now and wants to get HCV treatment in the next few years. What are the best ART combina2ons to take to minimize drug/drug interac2ons? 2. Can I use any of the new DAA s in my genotype 2/3 HCV pa2ents? 3. Can I use response guided therapy (shortening therapy to 24 weeks based on early virologic response) in my HIV/HCV coinfected pa2ents receiving triple therapy with PEG/RBV/HCV protease inhibitor? 4. My pa2ent took IFN+ RBV in the past for HCV but did not get an and wants to be retreated with IFN/RBV/Telaprevir. Could the previous unsuccessful treatment have led to drug resistance to ribavirin and/or IFN? 5. Is prior hepa2c decompensa2on a contraindica2on to IFN- free treatment? Treatment ques2ons 1. My pa2ent with HCV and HIV is star2ng ART now and wants to get HCV treatment in the next few years. What are the best ART combina2ons to take to minimize drug/drug interac2ons? 2. Can I use any of the new DAA s in my genotype 2/3 HCV pa2ents? 3. Can I use response guided therapy (shortening therapy to 24 weeks based on early virologic response) in my HIV/HCV coinfected pa2ents receiving triple therapy with PEG/RBV/HCV protease inhibitor? 4. My pa2ent took IFN+ RBV in the past for HCV but did not get an and wants to be retreated with IFN/RBV/Telaprevir. Could the previous unsuccessful treatment have led to drug resistance to ribavirin and/or IFN? 5. Is prior hepa2c decompensa2on a contraindica2on to IFN- free treatment? HCV HIV and ART Drug drug interac2ons will differ depending upon which ART, which direct ac2ng an2viral (DAA) and what other drugs are being taken for co- morbidi2es Some newer DAA have fewer or different DDI than current HCV PI s 6

7 Contraindicated Drugs With Telaprevir & Boceprevir Common denominator is interaction with CYP3A4 interactions may occur via inhibition OR induction HIV protease inhibitors Alfuzosin, Rifampin Ergot derivatives Cisapride St. John s wort Lovastatin, simvastatin, atorvastatin (telaprevir) Sildenafil or tadalafil Oral midazolam, triazolam Consult package inserts for other established and potential Drosperinone drug-drug interactions (boceprevir) HIV HCVg1 and NS3 Peg/Riba Therapy Pa2ents not on ART: Use either boceprevir or telaprevir Pa2ents receiving RAL + 2- NRTI: Use either boceprevir or telaprevir Pa2ents receiving ATV/r + 2- NRTI: Use telaprevir at standard dose. Pa2ents receiving EFV + 2- NRTI: Use telaprevir at increased dose of 1125 mg every 7 9 hours Other ART: research studies E.g. A5294 for PI with BOC PegIFN RBV (LPV, ATV, DRV) Treatment ques2ons 1. My pa2ent with HCV and HIV is star2ng ART now and wants to get HCV treatment in the next few years. What are the best ART combina2ons to take to minimize drug/drug interac2ons? 2. Can I use any of the new DAA s in my genotype 2/3 HCV pa2ents? 3. Can I use response guided therapy (shortening therapy to 24 weeks based on early virologic response) in my HIV/HCV coinfected pa2ents receiving triple therapy with PEG/RBV/HCV protease inhibitor? 4. My pa2ent took IFN+ RBV in the past for HCV but did not get an and wants to be retreated with IFN/RBV/Telaprevir. Could the previous unsuccessful treatment have led to drug resistance to ribavirin and/or IFN? 5. Is prior hepa2c decompensa2on a contraindica2on to IFN- free treatment? 7

8 BOC or TPV with PegIFN RBV for genotype 2/3? NO Only genotype 1 MK-5172 Monotherapy in Genotype 1 or 3 Patients MK-5172: NS3/4a protease inhibitor with broad genotypic activity Genotype 1 (n = 48): MK mg QD for 7 days Genotype 3 (n = 3): MK mg QD for 7 days Mean Maximum Log 1 Change in HCV RNA Placebo 5 mg 1 mg 2 mg mg 6 mg 8 mg 8 5 N = 5 N/A Petry AS, et al. AASLD 211. Abstract Genotype 1 Genotype 3 ELECTRON: PSI-7977 ± RBV ± PegIFN in Genotype 2/3 Treatment-Naive Patients 12 weeks Polymerase Inhibitor and RBV in HCV moninfected Nucleotide analogue PSI-7977 mg QD + RBV for 12 wks PegIFN included for, 4, 8, or 12 wks All patients in all arms had undetectable HCV RNA by Wk 4 1% 12 in all RBVcontaining arms 24 in 1% of patients with evaluable data (n = 2) PSI-7977 monotherapy (RBV free) arm added; 6% 4 Gane EJ, et al. AASLD 211. Abstract 34. Patients (%) Outcomes n/n = 1/1 9/9 1/1 11/11 PSI-7977/ PSI-7977/ PSI-7977/ PSI-7977/ RBV RBV RBV RBV + Wks + 4 Wks + 8 Wks + 12 Wks PegIFN PegIFN PegIFN PegIFN (IFN Free) 8

9 Treatment ques2ons 1. My pa2ent with HCV and HIV is star2ng ART now and wants to get HCV treatment in the next few years. What are the best ART combina2ons to take to minimize drug/drug interac2ons? 2. Can I use any of the new DAA s in my genotype 2/3 HCV pa2ents? 3. Can I use response guided therapy (shortening therapy to 24 weeks based on early virologic response) in my HIV/HCV coinfected pa2ents receiving triple therapy with PEG/RBV/HCV protease inhibitor? 4. My pa2ent took IFN+ RBV in the past for HCV but did not get an and wants to be retreated with IFN/RBV/Telaprevir. Could the previous unsuccessful treatment have led to drug resistance to ribavirin and/or IFN? 5. Is prior hepa2c decompensa2on a contraindica2on to IFN- free treatment? EVR: Par2al versus Complete RGT= response guided therapy TPV: ADVANCE: Treatment Naïve G1 Randomized, Double-Blind, Placebo-Controlled for Telaprevir 72 weeks HCV RNA (log copies/ml) Viral RNA ( ) RVR ervr: ud at weeks 4 and 12 cevr pevr 2 log drop but HCV RNA (+) ETR Wks of Therapy 72 T12 T8 48 (control) TVR + TVR + Pbo + Pbo + ervr + ervr + Weeks ervr = HCV RNA undetectable at week 4 and week 12 (Taqman v2.) (T) TVR = telaprevir 75 mg q8h; Pbo = Placebo; (P) Peg- IFN = pegylated interferon alfa- 2a ( kd) 18 µg/wk; (R) RBV = ribavirin 1, or 1,2 mg/da Jacobson IM, et al. N Engl J Med 211;364:

10 Percent of patients with HCV RNA undetectable TVR Naïve ADVANCE: RVR and ervr Rates n/n = / /364 34/ /363 27/364 29/361 Week 4 (RVR) T12 T8 Patients eligible to receive 24 weeks of total treatment Weeks 4 and 12 (ervr) Jacobson IM, et al. N Engl J Med 211;364: Pa2ents With (%) Rates: ILLUMINATE 72 Δ 4.5% (2- sided 95% CI = - 2.1% to +11.1%) n/n= 388/5 149/162 1/16 76/118 23/1 ITT ervr+ ervr+ ervr- Other T1224 T1248 T1248 Sherman KE, et al. N Engl J Med 211;365: Control 48 P/R n = 363 BOC RGT n = 368 BOC/ 48 n = 366 SINT- 2: Boceprevir in G1 Naïve CHC Week 4 Week 28 Week 48 Week 72 lead- in lead- in lead- in + Placebo + Boceprevir + Boceprevir Follow- up TW 8-24 HCV RNA Undetectable Follow- up TW 8-24 HCV RNA Detectable + Placebo Follow- up Follow- up Peginterferon (P) administered subcutaneously at 1.5 µg/kg once weekly, plus ribavirin (R) using weight-based dosing of 6-1 mg/day in a divided daily dose Boceprevir dose of 8 mg thrice daily Poordad F et al. NEJM 211;364: % Patients 1 SINT-2: and Relapse Rates (ITT) p <.1 p < / /23 48 P/R BOC RGT BOC/48 Non- Black Pa2ents Poordad F, et al NEJM 211; Relapse Rate % Patients p =.4 p = * / /25 48 P/R BOC RGT BOC/ 48 Black Pa2ents *(mitt in 47% vs 53%)

11 Similari2es/ Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts Parameter TVR [1] BOC [2] lead-in? No Yes: 4 wks PegIFN alfa formulation 2a 2b PI dosing requirements Duration of PI triple therapy Qualification for shortened therapy (response guided) Qualified for shortened therapy, % TID; administer with fatty meal 8-12 wks followed by 12- wks Undetectable HCV RNA Wk 4 and 12 of triple therapy TID with food not low fat wks after 4 wks lead-in Undetectable HCV RNA w8 and w24 of triple therapy 58 (24 wks) 44 (28 wks), % Relapse, % 9 9 Adverse events more frequent in PI arms Rash, anemia, pruritus, nausea Anemia, dysgeusia 1. Jacobson IM, et al. AASLD 21. Abstract Poordad F, et al. AASLD 21. Abstract LB- 4. Clinical care op2ons slide Zeuzem Telaprevir in HIV/HCV co-infected patients: 12 data Part A: no ART T/ TVR + 1:1 48 (control) Pbo + Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) T/ TVR + 2:1 48 (control) Pbo + Weeks Week 6 72 Dieterich D, et al. 19th CROI; Seattle, WA; March 5-8, 212. Abst. 46 Study 11: Rates 12 Weeks Post-Treatment (12) Patients with Undetectable HCV RNA (%) n/n = 5/7 11/16 12/15 28/38 T/ 33 HCV moninfected 5 5 No ART EFV/TDF/FTC ATV/r/TDF/FTC Total 45 2/6 4/8 4/8 1/22 *Patient was defined as 12 if HCV RNA was < LLOQ in the visit window Dieterich D, et al. 19th CROI; Seattle, WA; March 5-8, 212. Abst. 46 Boceprevir: Study Design Arm 1 Arm 2 Weeks PEG2b +RBV 4 wk PEG2b +RBV 4 wk Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV 2:1 randomization (experimental: control) Boceprevir dose 8 mg TID Placebo + PEG2b + RBV 44 wk Boceprevir + PEG2b + RBV 44 wk Futility Rules 4-week lead-in with PEG2b/RBV for all patients PEG-2b 1.5 µg/kg QW; RBV 6-1 mg/day divided BID Futility rules: Week 12 <1, Week 24 <LLD -24 wk -24 wk Sulkowski 11

12 Virologic Response Over Time % HCV RNA Undetectable B/ /34 3/64 5/34 27/64 8/34 38/64 11/34 47/ % increase over /34 42/64 9/34 37/ EOT 12 Treatment Week Three patients undetectable at FW4 have not yet reached FW12 and were not included in 12 analysis. BOC Virologic Response Over Time % HCV RNA Undetectable /34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 1/34 42/64 9/34 37/ EOT 12 Treatment Week B/ HCV moninfected Three patients undetectable at FW4 have not yet reached FW12 and were not included in 12 analysis. 66 Treatment ques2ons 1. My pa2ent with HCV and HIV is star2ng ART now and wants to get HCV treatment in the next few years. What are the best ART combina2ons to take to minimize drug/drug interac2ons? 2. Can I use any of the new DAA s in my genotype 2/3 HCV pa2ents? 3. Can I use response guided therapy (shortening therapy to 24 weeks based on early virologic response) in my HIV/HCV coinfected pa2ents receiving triple therapy with PEG/RBV/HCV protease inhibitor? 4. My pa2ent took IFN+ RBV in the past for HCV but did not get an and wants to be retreated with IFN/RBV/Telaprevir. Could the previous unsuccessful treatment have led to drug resistance to ribavirin and/or IFN? 5. Is prior hepa2c decompensa2on a contraindica2on to IFN- free treatment? Interferon resistance No Ribavirin resistance NO 12

13 DAA resistance Rapid resistance selec2on with PIs- cross R Risk/benefit if used in prior null responders Return to wild type 6-12 months Not archived High barrier compounds: Nucleosides/2des Retreatment amer PI failure- second gen Treatment ques2ons 1. My pa2ent with HCV and HIV is star2ng ART now and wants to get HCV treatment in the next few years. What are the best ART combina2ons to take to minimize drug/drug interac2ons? 2. Can I use any of the new DAA s in my genotype 2/3 HCV pa2ents? 3. Can I use response guided therapy (shortening therapy to 24 weeks based on early virologic response) in my HIV/HCV coinfected pa2ents receiving triple therapy with PEG/RBV/HCV protease inhibitor? 4. My pa2ent took IFN+ RBV in the past for HCV but did not get an and wants to be retreated with IFN/RBV/Telaprevir. Could the previous unsuccessful treatment have led to drug resistance to ribavirin and/or IFN? 5. Is prior hepa2c decompensa2on a contraindica2on to IFN- free treatment? Great Ques2on Liver decompensa2on amer interferon based therapy related to clearance of virally infected hepa2c cells Phase 2 It is not clear whether DAAs can lead to death of virally infected hepatocytes However they can induce an endogenous IFN response Studies in cirrho2cs and ESLD underway Cau2on un2l further data Need a plan before Rx ini2a2on if pa2ent decompensates Percent of patients Survival Time from First Liver Decompensa2on to Death in HCV Year survival HIV+ HIV- 44 Death during study 366/137 HCV 1/18 HIV/HCV Risk factors for death: HIV Baseline CTP MELD >13 Age Pineda, Hepatology 25 13

14 HCV and HIV coinfected 212 Select who to treat Moderate to severe fibrosis F3-4 Assess fibrosis Liver biopsy Serum tests AI FIB- 4 Elastography Control HIV Encourage Adherence Avoid alcohol If cirrho2c needs HCC surveillance EGD More drugs on the horizon 14