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