What’s new in liver disease?

Eric F. Martin, MD

Transplant hepatology

Assistant professor of medicine

Financial Disclosures

• Medical advisory board – Gilead Sciences, Inc

What’s New in Liver Disease?

• Hepatitis A virus (HAV)

• Hepatitis B virus (HBV)

• Hepatitis C virus (HCV)

• Non-alcoholic fatty liver disease (NAFLD)

• Primary biliary cholangitis (PBC)

• Liver transplantation

• Hepatocellular carcinoma

HEPATITIS A VIRUS (HAV)

Hepatitis A Virus (HAV)

• More cases of HAV in Miami Dade County in 2017 than all of 2014, 2015, and 2016

- 2017: 111 cases

- 2014-2016: 104 cases

• Reported outbreaks in California, Michigan, Colorado, and Utah

- State of emergency issued for San Diego in 2017

- Largest person-to-person HAV outbreak in US since HAV vaccine became available 1995

https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/Immunization/Hepatitis-A-Outbreak.aspx

HAV – Clinical Course

• Usually self-limiting viral illness; fulminant hepatic failure <1%

• Full clinical and biochemical recovery within 2-3 months in 85% of patients with nearly 100% recovery by 6 months

• Relapsing hepatitis (~10%)

- Relapse of symptoms during 6 months after initial recovery

• Cholestatic hepatitis (<5%)

- Prolonged cholestasis characterized by protracted period of jaundice and pruritus lasting >3 months

• HAV does not become chronic

• HAV infection confers lifelong immunity and patients can not become reinfected

HAV Prophylaxis

• HAV vaccination

- Provides active immunity against HAV

- Series of 2 injections (0 and 6-12 months) or in combination with HBV (Twinrix) given

at 0, 1, and 6 months

• HAV immune globulin (IG)

- Provides passive immunity through transfer of antibodies

- Provides temporary immunity for both pre- and post-exposure

- Dose – updated July 2017 due to concerns for low HAV IgG potency

- 0.1 mL/kg IM anticipated risk of exposure up to 1 month

- 0.2 mL/kg IM anticipated risk of exposure up to 2 months

- Repeat dose of 0.2 mL/kg every 2 months if anticipated risk of exposure >2 months

HAV Post-Exposure Management

• Individuals with recent HAV exposure who have not received HAV vaccine should receive post-exposure prophylaxis with single dose of HAV vaccine or immune globulin as soon as possible (within 2 weeks)

(1) Healthy individuals 12 months – 40 years HAV VACCINE

• Vaccination is preferred over immune globulin

- Induces active immunity with greater durability of protection

- Easier to administer

- More readily available

(2) Individuals >40 years (particularly >75 years) IMMUNE GLOBULIN

• Immune globulin is preferred due to limited data regarding vaccine performance in this age group and more severe manifestations of hepatitis A in older patients

(3) Children <12 months, immunocompromised, individuals with chronic liver disease, and/or individuals allergic to HAV vaccine IMMUNE GLOBULIN

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5641a3.htm

HEPATITIS B VIRUS (HBV)

HEPLISAV-B

Hepatitis B Vaccine (Recombinant), Adjuvanted

• Heplisav-B is first new hepatitis B vaccine approved in U.S. in more than 25 years

• Approved by FDA November 2017

• Endorsed by CDC’s Advisory Committee on Immunization Practices (ACIP)

• Provides significantly higher and earlier protection against HBV compared to existing HBV vaccine using fewer doses with acceptable safety profile

• First and only two-dose HBV vaccine approved for adults

• Two doses (0.5 mL each) given IM 1 month apart

- Compared to 3 doses over 6 months for other currently available non-adjuvanted recombinant vaccines

• Two-dose schedule may improve compliance

• Appears more immunogenic than other non-adjuvanted vaccines

• Higher rates of protection may help move closer to goal of eliminating HBV as public health problem in the US

https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM584762.pdf

Available Hepatitis B Vaccines

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5641a3.htm

Hepatitis B Vaccine Manufacturer Approved Dosage Volume # of doses Schedule

Recombivax HB Merck 1983

- adults (>20 yrs) 10 µg 1 mL 3 0, 1, 12 months

- adults on HD 40 µg 1 mL 3 0, 1, 12 months

Engerix-B GlaxoSmithKline 1989

- adults (>20 yrs) 20 µg 1 mL 3 0, 1, 6 months

- adults on HD 40 µg 2 mL† 4 0, 1, 2, 6 months

Heplisav-B Dynavax 2017

- adults (>18 yrs) 0.5 mL 2 0 and 1 month

†May be given as single 2mL dose, or two 1mL doses

Heplisav-B – Seroprotection Studies

• Approval of Heplisav-B based on data from three Phase 3 non-inferiority trials involving close to 10,000 adults who received the vaccine

• Results from the largest study (n=6,665) showed that compared to Engerix-B, Heplisav-B demonstrated a statistically significantly higher seroprotection rates (95% vs. 81%)

• In subgroup analysis of participants with type 2 diabetes (n=961), Heplisav-B provided statistically significantly higher rate of protection compared to Engerix-B (90% vs. 65%)

SPR = seroprotection rate (% with anti-HBs >10 mIU/mL)

http://www.dynavax.com/files/8615/1214/6163/v.01_final-label-20nov17_clean.pdf

Heplisav-B – Safety Studies

• After rejecting it twice in the last 4 years due to safety concerns, FDA granted

conditional approval of Heplisav-B in November 2017

• Ongoing safety concerns regarding potentially increased risk of acute myocardial

infarction and immune-mediated disorders

• FDA approval hinges on a large phase 4 post marketing study comparing Heplisav-B

with currently licensed hepatitis B vaccine called Engerix-B (GlaxoSmithKline) for

the risk for acute myocardial infarctions (AMIs) and immune-mediated diseases

• Expected to be available first quarter of 2018

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5641a3.htm

Tenofovir Alafenamide (TAF) – VEMLIDY

• Tenofovir alafenamide (TAF) [VEMLIDLY] is an orally bioavailable prodrug of tenofovir (TFV), which is a nucleotide analog that inhibits reverse transcription of HBV and HIV

• Recently joined list of preferred HBV therapies (AASLD Guidelines 2018)

- Tenofovir alafenamide (TAF) [VEMLIDY]

- Tenofovir disoproxil fumarate (TDF) [VIREAD]

- Entecavir

- PEG-interferon (peg-IFN)

• Indications for treatment of HBV

(1) Acute HBV

- Protracted, severe course (Tbili >3 mg/dL), INR 1.5, hepatic encephalopathy, and/or ascites (acute liver failure)

(2) Chronic HBV (CHB)

- Immune-active CHB

- ALT >2x ULN or evidence of significant histological disease plus HBV DNA >2,000 IU/mL (HBeAg-) or >20,000 IU/mL (HBeAg+)

- Immune-tolerant CHB

- Adults >40 yrs with normal ALT and HBV DNA >1,000,000 IU/mL and liver biopsy showing significant necroinflammation and/or fibrosis

Journal of Hepatology 2018;68:672-681

Tenofovir Alafenamide (TAF) – Mechanism of Action

• TAF designed to have greater plasma stability than tenofovir disoproxil fumarate (TDF) [VIREAD]

- More efficient delivery of active metabolite (TFV) to hepatocytes than TDF, which must be dosed at relatively high

levels to achieve necessary therapeutic concentrations in hepatocytes

- Reduced systemic exposure, with 90% less tenofovir circulating in the plasma compared to TDF

• As a result, TAF improved renal and bone laboratory safety parameters compared to TDF

https://vemlidyhcp.com/

Powerful Viral Suppression Proven at Weeks 48 and 96

Journal of Hepatology 2018;68:672-681

Improved Rates of ALT Normalization

Journal of Hepatology 2018;68:672-681

50% 50%

32% 42%

Less Impact on Bone Mineral Density Compared to

Tenofovir Disoproxil Fumarate (VIREAD)

Journal of Hepatology 2018;68:672-681

Reduced Effect on Renal Safety Parameters vs

Tenofovir Disoproxil Fumarate (VIREAD)

Journal of Hepatology 2018;68:672-681

HEPATITIS C VIRUS (HCV)

Timeline of HCV Therapy

1975 1989 1998 2001 2003 2011 2014 2015 2016 2017

Description of non-A, non-B hepatitis

Identification of HCV

IFN-α and

ribavirin

Proof-of-concept studies for HCV protease inhibitors

Elbasvir and grazoprevir (ZEPATIER)

pegIFN-α and ribavirin

pegIFN-α and ribavirin

with 1st generation

protease inhibitor for

GT1

- Telaprevir (Incivek)

- Boceprevir (Victrelis)

Simeprevir + Sofosbuvir +/- RBV

Sofosbuvir/Ledipasvir

(HARVONI)

Sofosbuvir/Velpatasvir (EPCLUSA)

Daclatasvir (DAKLINZA)

Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (VIEKIRA)

Ombitasvir/Paritaprevir/Ritonavir (TECHNIVIE)

Glecaprevir/Pibrentasvir (MAVYRET)

Sofosbuvir/Velpatasvir/Voxilaprevir (VOSEVI)

New Hepatitis C Treatments

• Sofosbuvir/Velpatasvir (EPCLUSA) – June 2016

- First all-oral, pangenotypic regimen for treatment of adults with genotype 1-6 chronic

HCV

• Sofosbuvir/Velpatasvir/Voxilaprevir (VOSEVI) – July 2017

- First once-daily, single-tablet regimen approved for genotype 1-6 (pangenotypic) who

have been previously treated with sofosbuvir or other NS5A inhibitors

• Glecaprevir/Pibrentasvir (MAVYRET) – August 2017

- 1st 8 week treatment for all HCV genotypes (pangenotypic) without cirrhosis

Sofosbuvir/Velpatasvir (EPCLUSA)

• Sofosbuvir nucleotide analog NS5B polymerase inhibitor

• Velpatasvir HCV NS5A inhibitor

• 1 tablet (sofosbuvir 400 mg and velpatasvir 100 mg) taken daily with or without food

Patient Population Regimen and Duration

Treatment-naïve and treatment-experienceda, without cirrhosis and

with compensated cirrhosis (Child-Pugh A)

EPCLUSA 12 WEEKS

Treatment-naïve and treatment experienceda, with decompensated

cirrhosis (Child-Pugh B and C)

EPCLUSA + ribavirin 12 WEEKS

a. In clinical trials, regimens contained pegIFN-a/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir)

http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/epclusa/epclusa_pi.pdf

Sofosbuvir-Velpatasvir (EPCLUSA) in HCV Genotype 1-6

ASTRAL-1: SVR12 by Genotype

Feld JJ, et al. N Engl J Med. 2015;373:2599-607.

Sofosbuvir, Velpatasvir, Voxilaprevir (VOSEVI)

• Sofosbuvir nucleotide analog NS5B polymerase inhibitor

• Velpatasvir HCV NS5A inhibitor

• Voxilaprevir HCV NS3/4A protease inhibitor

• 1 tablet (sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg) taken daily with or without food

Genotype Patients Previously Treated with an HCV Regimen Containing: Duration

1, 2, 3, 4, 5, or 6 An NS5A inhibitora 12 weeks

1a or 3 Sofosbuvir without an NS5A inhibitorb 12 weeks

a. In clinical trials, regimens contained pegIFN-a/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir)

b. In clinical trials, prior treatment experience included sofosbuvir with or without any of the following: pegIFN-α/ribavirin, HCV NS3/4A protease inhibitor

(boceprevir, simeprevir, or telaprevir)

http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/vosevi/vosevi_pi.pdf

Sofosbuvir, Velpatasvir, Voxilaprevir (VOSEVI) in NS5A-

Experienced in GT 1-6

POLARIS-1: SVR12 Results by Genotype

Bourliere M, et al. N Engl J Med. 2017;376:2134-46

Glecaprevir/Pibrentasvir (MAVYRET)

• Glecaprevir HCV NS3/4A protease inhibitor

• Pibrentasvir HCV NS5A inhibitor

• 3 tablets (glecaprevir 300 mg and pibrentasvir 120mg) taken daily with food

http://www.rxabbvie.com/pdf/mavyret_pi.pdf

Recommended Duration for Treatment-Naïve Patients

HCV Genotype

Treatment Duration

No Cirrhosis Compensated Cirrhosis

(Child-Pugh A)

1, 2, 3, 4, 5, or 6 8 weeks 12 weeks

Glecaprevir/Pibrentasvir (MAVYRET)

Recommended Duration for Treatment-Experienced Patients

HCV Genotype Patients Previously Treated with Regimen Containing:

Treatment Duration

No Cirrhosis Compensated Cirrhosis

(Child-Pugh A)

1

NS5A inhibitor without prior treatment with an NS3/4A protease inhibitor1 16 weeks 12 weeks

NS3/4A protease inhibitor without prior treatment with an NS5A inhibitor2 12 weeks 12 weeks

1, 2, 4, 5, or 6 PRS3 8 weeks 12 weeks

3 PRS3 16 weeks 16 weeks

http://www.rxabbvie.com/pdf/mavyret_pi.pdf

1. In clinical trials, subjects were treated with prior regiments containing ledipasvir and sofosbuvir or daclatasvir with pegIFN-αand ribavirin

2. In clinical trials, subjects were treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegIFN-αand ribavirin

3. PRS = prior treatment experience with regimens containing interferon, pegIFN, ribavirin, and/or sofosbuvir, but no prior treatment experience with HCV NS3/4A PR or NS5A inhibitor

Sofosbuvir, Velpatasvir, Voxilaprevir (VOSEVI) in NS5A-

Experienced in GT 1-6

POLARIS-1: SVR12 Results by Genotype

Zeumem S, et al. N Engl J Med. 2017;376:2134-46

Regimen Trade Name Duration Cost

Glecaprevir/Pibrentasvir MAVYRET 8 weeks $26,400

12 weeks $39,600

16 weeks $52,800

Sofosbuvir/Velpatasvir/Voxilaprevir VOSEVI 12 weeks $74,760

Sofosbuvir/Velpatasvir EPCLUSA 12 weeks $74,760

Elbasvir/Grazoprevir ZEPATIER 12 weeks $54,600

16 weeks $72,800

Sofosbuvir + Daclatasvir SOVALDI + DAKLINZA 12 weeks $147,000

24 weeks $294,000

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir + Ribavirin VIEKIRA PAK 12 weeks $83,819

24 weeks $167,638

Ombitasvir/Paritaprevir/Ritonavir + Ribavirin TECHNIVIE 12 weeks $77,000

Ledipasvir/Sofosbuvir HARVONI 8 weeks $63,000

12 weeks $94,500

24 weeks $189,000

Sofosbuvir + Simeprevir SOVALDI + OLYSIO 12 weeks $150,000

HBV Reactivation with HCV Treatment

• True prevalence of HBV/HCV coinfection is unknown, although studies from US report 1.4% - 5.8% of HCV-infected patients are HBsAg(+)1-4

• HBV/HCV coinfection is associated with higher rates of hepatic decompensation, cirrhosis, and hepatocellular carcinoma (HCC)5

• In many coinfected patients, the HCV infection is dominant, suppressing HBV replication6

• Curing a patient of HCV infection can create favorable environment for increase in HBV replication

• Because HBsAg(+) patients were excluded from clinical trials of DAAs, HBV reactivation after HCV clearance was only reported after DAAs entered clinical use

1. Hepatology 2013;58:538-545 2. Hepatology 2010;51:759-766 3. BMJ Open 2016;6:e012016 4. PloS One 2013;8:e54815 5. Aliment Pharmacol The 2017;46:1054-1060 6. J Hepatol 2012;57:167-185

BLACK BOXED WARNING -- ISSUED OCTOBER 2016--

https://www.gilead.com/~/media/files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf

HBV Reactivation with HCV Treatment

• In October 2016 FDA released a black box warning about risk of HBV reactivation upon treatment with DAAs for HCV

• FDA boxed warning based on 29 reported cases of HBV reactivation in HBV/HCV coinfected patients on DAA therapy over 34 months from Nov 2013 to Oct 20161

- 2 pts died

- 1 required liver transplant

• FDA recommended screening all individuals scheduled to received DAAs for evidence of current or past HBV infection with follow-up HBV DNA for any positive serology

- HBsAg (Hepatitis B surface antigen)

- HBsAb (Hepatitis B surface antibody)

- HBcAb (Hepatitis B core antibody)

• Up until recently, risk of HBV reactivation among HBV/HCV coinfected patients undergoing DAA therapy was not characterized in large prospective study

Ann Intern Med 2017;166:792-798

HBV/HCV coinfected patients treated with sofosbuvir/ledipasvir

(Harvoni) x12 weeks N=111

HBV DNA during/after HCV treatment

Remained undetected N=6 (16%)

Became quantifiable N=31 (84%)

• None had increase in ALT >2x ULN up to 12 weeks posttreatment • 24/31 (77%) remained quantifiable 48 weeks after treatment • 2 had increase in ALT >2x ULN after 48 weeks, only 1 started on

entecavir

No change in HBV DNA N=35 (47%)

Increase in HBV DNA >1 log10 IU/mL N=39 (53%)

• 5/39 (13%) had increase in ALT >2x ULN up to 12 weeks posttreatment (“clinical HBV reactivation”)

• 14/39 (36%) had HBV DNA >log10 IU/mL also at posttreatment week 48, but none with ALT elevation 2x ULN

Liu CJ, et al. Gastroenterology 2018;1-9

Clinical HBV reactivation N=5 (4.5%)

• All had HBV DNA >20 IU/mL at baseline • 4/5 (80%) had ALT >2x ULN at baseline • 3 received HBV treatment; all asymptomatic

HBV DNA during/after HCV treatment

Baseline HBV DNA >20 IU/mL N=74 (67%)

Baseline HBV DNA <20 IU/mL N=37 (33%)

HBV DNA reactivation N=70 (63%)

Proposed Management of HBV/HCV Coinfection

• HBsAg(-)/HBcAb(+)

- Monitored with ALT alone until SVR12

- Test with HBsAg +/- HBV DNA only if ALT

increased or fails to normalize on therapy

• HBsAg(+) with undetectable HBV DNA at baseline

- Considered for preemptive anti-HBV therapy

or

- Monitored with ALT and HBV DNA until SVR12

• HBsAg(+) with detectable HBV DNA at baseline

- Preemptive anti-HBV treatment until SVR12

Gastroenterology 2018;e;1-4

NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Current Treatment of NAFLD/NASH

• Body weight loss via physical activity and diet is mainstay of treatment of NAFLD

- 7%-10% weight loss

- >60 minutes aerobic exercise per week

- Low carb (20g/day) and calorie restricted diet: Women 1200 kcal/day; Men 1500-1800 kcal/day

• Bariatric and endoscopic weight loss surgery can be effective in obese patients with NAFLD, with and without metabolic complications

• No currently approved pharmacotherapy

• Vitamin E and pioglitazone are available medications with most evidence of efficacy

• Treatment of NAFLD should be individualized to each patient’s comorbidities and unique situation

Clin Liver Dis. 2018;22:175-187

Registered phase II and III clinical trials for

NAFLD-NASH from 2006 - 2016

Clin Liver Dis 2018;22:189-199

Emerging Treatments for NAFLD/NASH

Drug Mechanism

Obeticholic acid FXR agonist

• Modulates lipid and glucose homeostasis and hepatic inflammation

Elafibranor PPAR-α and -δ agonist

• Improve insulin sensitivity, lipid handling, and inflammation

Liraglutide GLP-1 analogue

• ↑ insulin sensitivity

• ↓ glucagon secretion

• Suppresses hepatic de novo lipogenesis

• ↑ fatty acid oxidation

• Delays gastric emptying

Cenicriviroc C-C chemokine receptors 2 and 5 antagonist

• Inhibits macrophage recruitment and migration to the liver

Selonsertib Inhibitor of apoptosis signal-regulating kinase (ASK1)

• Improved hepatic fibrosis, inflammation, steatosis, and insulin sensitivity

Simtuzumab Monoclonal antibody to lysyl oxidase (LOX)-like 2

• Antifibrotic

FXR, Farnesoid X receptor; PPAR, peroxisome proliferator activated receptor; GLP-1, glucagon-like peptide-1 Clin Liver Dis 2018;22:189-199

PRIMARY BILIARY CHOLANGITIS (PBC)

Obeticholic Acid (OCALIVA)

• Farnesoid X receptor (FXR) agonist

• FXR regulates variety of target genes involved in

- Bile acid synthesis and transport

- Reduces inflammation and portal pressure (anti-inflammatory)

- Reverses fibrosis and stimulates repair (anti-fibrotic)

- Reduces steatosis (anti-steatotic)

- Improves insulin sensitivity and glucose uptake

- Regulates lipid metabolism

• Approved June 2016 for treatment of primary biliary cholangitis (PBC)

- in combination with ursodeoxycholic acid (ursodiol) in adults with inadequate response to ursodiol

- as monotherapy in adults unable to tolerate ursodiol

• Indication approval based on reduction in alkaline phosphatase

BLACK BOXED WARNING -- ISSUED SEPTEMBER 2017 --

https://ocaliva.com/pdf/ocaliva-us-package-insert.pdf

Obeticholic Acid - Recommended Dosage Regimen

Staging/Classification Non-cirrhotic or

Compensated Cirrhosis

(Child-Pugh Class A)

Child-Pugh Class B or C or Patients

with a Prior Decompensation Event†

Starting Dosage for first 3 months 5 mg once daily 5 mg once weekly

Dosage Titration after first 3 months‡

- For patients who have not

achieved adequate reduction in alk

phos and/or total bilirubin

- Tolerating Ocaliva

10 mg once daily 5 mg twice weekly

(at least 3 days apart)

Titrate to 10 mg twice weekly

(at least 3 days apart) based on

response and tolerability

Maximum Dosage 10 mg once daily 10 mg twice weekly

(at least 3 days apart) †Gastroesophageal variceal bleeding, new or worsening jaundice, spontaneous bacterial peritonitis, etc

‡Prior to dosage adjustment, re-calculate Child-Pugh classification

https://ocaliva.com/pdf/ocaliva-us-package-insert.pdf

HCV AND KIDNEY TRANSPLANT

HCV(+) Kidney Transplant Recipients

• Prevalence of chronic HCV infection in end-stage renal disease (ESRD) patients exceeds

that of the general population and correlates with duration of hemodialysis (HD)1,2

• HCV-infected patients receiving chronic HD have increased mortality compared to

uninfected population3

• Until recently, clinical trials excluded patients with reduced kidney function

• Treatment of HCV-infected ESRD patients limited by low efficacy and poor tolerability of

interferon-based regimens

• Treatment of kidney transplant recipients infected with HCV generally not recommended

due to increased risk of allograft dysfunction and rejection with use of interferon4

1. Carbone M, et al Transplantation 2013;95:779 2. Saxena V, et al. Am J Transplant 2016;16:1345 3. Fabrizi F, et al. J Viral Hepat 2013;19:601 4. Terrault NA, et al. Clin j Am Soc Nephrol 2007;2:563

HCV(+) Kidney Transplant Recipients

• Historically, many kidneys from anti-HCV-positive deceased donors were discarded as there were no safe and effective antiviral agents to use post-kidney transplant

• Ability to treat HCV-infected kidney transplant recipients with DAAs now permits this issue to be readdressed

• Transplantation of a kidney from an anti-HCV-positive deceased organ donor into HCV-infected recipient with early post-transplant DAA treatment is now a viable strategy

• Two potential strategies

(1) Increasing the size of the donor pool

(2) Significantly shortening the waitlist time for those patients accepting a kidney from an anti-HCV-positive donor

HCV(+) Kidney Transplant Recipients

• Retrospective study of the first 25 anti-HCV-positive recipients of kidney transplant treated with DAAs at Miami Transplant Institute (MTI) between May 2014 – April 2016

• Median waiting time to transplant was 427 days after initial listing

• Median waiting time to transplant was 58 days after patient agreeable to accepting an offer from HCV-positive donor

• Average wait-list time of ~4-7 years

• Treatment with DAA therapy started post-kidney transplant after median of 125 days

- Sofosbuvir/Ledipasvir (HARVONI) + Ribavirin; n=19

- Sofosbuvir/Ledipasvir (HARVONI); n=4

- Sofosbuvir + Simeprevir; n=1

- Sofosbuvir + Daclatasvir; n=1 Bhamidimarri KR, et al. Transplant International 2017;30:865-873

HCV(+) Kidney Transplant Recipients

• 24 patients completed the course of treatment and achieved SVR12

• 1 patient was non-compliant with DAA therapy and entered as treatment failure

• Overall SVR12 was 96% - intention to treat (ITT) analysis

• SVR12 was 100% in patients who completed treatment as per protocol analysis

• Pre-transplant genotype remained dominant genotype in all but 1 patient

(HCV GT 3 1a)

Bhamidimarri KR, et al. Transplant International 2017;30:865-873

Transplantation of HCV-Infected Kidneys into

Uninfected Recipients

• Waiting times for kidney transplants exceed 3-5 years in many parts of

the US1

• More than 500 high-quality kidneys from deceased donors with HCV

infection are discharged annually2,3

• DAAs have now created potential to substantially increased the number

of kidney transplants by making HCV-infected kidneys available to

HCV-negative candidates on the waiting list4,5

1. Reese PP, et al. J Am Soc Nephrol 2016;27:973-80. 2. Reese PP, et al. N Engl J Med 2015;373:303-5. 3. Goldbert DS, et al. Am J Transplant 2016. 4. Roth D, et al. Lancet 2015;386:1537-45. 5. Zeuzem S, et al. Ann Intern Med 2015;163:1-13.

Transplantation of HCV-Infected Kidneys into

Uninfected Recipients

• Open-lab, single-center, pilot study at the University of Pennsylvania -Transplanting Hepatitis C Kidneys into Negative Kidney Recipients [THINKER]

• To determine safety and efficacy of transplantation of kidneys from HCV GT 1-viremic donors into HCV-negative patients followed by treatment with elbasvir/grazoprevir (ZEPATIER)

N Engl Med 2017;376:24

Transplantation of HCV-Infected Kidneys into

Uninfected Recipients

• 10 patients received HCV-infected kidneys

• Donors limited to those with positive qualitative

HCV NAT and HCV GT 1

• Median time from eligibility on waiting list for

HCV-infected kidney to transplant was 58 days

• All recipients had detectable HCV RNA on post-

transplant day 3

• Elbasvir-grazoprevir (ZEPATIER) was initiated on

all patients and continued for 12 weeks

• SVR12 of 100%

N Engl Med 2017;376:24

SIMULTANEOUS LIVER-KIDNEY (SLK) TRANSPLANT

Simultaneous Liver-Kidney (SLK) Transplant

Implementation of

MELD

SLK Transplant Candidate Acute Kidney Injury (AKI) Chronic Kidney Disease (CKD) • GFR <60 mL/min for >90

consecutive days

Metabolic Diseases • Hyperoxaluria • Aytpical hemolytic uremic

syndrome (HRS) from mutation in Factor H or I

• Familial non-neuropathic systemic amyloidosis

• Methylmalonic aciduria

Simultaneous Liver-Kidney Transplant

(SLK)

On dialysis at least once every 7 days

for the last 6 weeks

GFR <25 mL/min at least once every 7 days

for the last 6 weeks

and/or On dialysis as ERSD patient

GFR <30 mL/min at time of listing for kidney transplant

and/or

Liver Transplant only “SAFETY NET”

HEPATOCELLULAR CARCINOMA (HCC)

Palliation of HCC

• Prior to 2007, no therapy was of benefit in

advanced HCC

• FDA approval sorafenib (NEXAVAR) in 2008 for

palliation of advanced-stage HCC

• Sorafenib shown to delay progression and

prolong overall median survival from 7.9 to 10.7

months in Child-Pugh A patients with advanced

HCC

• Up until recently, it was the only systemic

therapy for HCC

Llovet J, et al. N Engl J Med. 2008

Regorafenib (STIVARGA)

• Next generation multikinase inhibitor

• Approved by FDA in April 2017 as second-line treatment for patients

with HCC who have previously received sorafenib (NEXAVAR)

• Also approved for metastatic colon cancer and gastrointestinal stromal

tumors (GIST)

• Approval based on phase III RESOURCE trial

• Median overall survival (OS) was 10.6 months with regorafenib plus

best supportive care (n=379) compared to 7.8 months for placebo plus

best supportive care (n=194); 38% reduction in risk of death (HR 0.62;

95% CI 0.50-0.78; P<0.001)

• Adverse events similar to sorafenib

- hand-foot skin reaction

- fatigue

- diarrhea

Bruix J, et al. Lancet. 2017;389(10064):56-66

THANK YOU