Transcript 510-1x

Hepatitis C Virus in Solid Organ Transplantation: Have the Rules Changed?
Impact of Antiviral Therapy on
Extra-Hepatic Manifestations of
Chronic HCV Infection
Associate Professor Simone Strasser
AW Morrow Gastroenterology and Liver Centre
Australian National Liver Transplant Unit
Royal Prince Alfred Hospital
University of Sydney
Sydney, AUSTRALIA
Disclosures
• Advisory boards, speakers fee, travel support:
– Gilead Sciences, AbbVie, Bristol Myers Squibb,
MSD, Norgine, Bayer Health Care, Astellas,
Novartis
Impact of HCV on transplant recipients
Post transplant HCV
Liver disease
progression
Extrahepatic
manifestations
Extrahepatic disorders have a major impact on
patients with HCV
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Fatigue
Cognitive dysfunction
Depression
Arthritis
Skin disorders
Cardiovascular disease
and stroke
Type 2 diabetes/IR
Cryoglobulinaemia
Glomerulonephritis
Sjogrens syndrome
Others
Increased morbidity and
mortality
Reduced quality of life
Direct medical care costs
Poor work performance
High absenteeism
Inability to work
Prevalence of EHM of HCV
Many EHMs are over-represented in transplant recipients
Prevalence in
HCV
OR or [RR]
Compared to
non-HCV
No of studies (sample
size of HCV population)
11.50
21 studies (n=4145)
Mixed cryoglobulinemia
Any MC
Symptomatic MC
30.1%
4.9%
CRD (including ESRD)
10.1%
[1.23]
14 studies (n=336,227)
Diabetes mellitus*
15%
1.58
31 studies (n=61,843)
Lymphoma
NA
[1.60]
16 studies (n=207284)
Lichen Planus
1.9%
2.27
18 studies (n=40,063)
Sjogrens Syndrome
11.9%
2.29
11 studies (n=38,789)
Porphyria Cutanea Tarda
0.5%
8.53
7 studies (n=970,315)
Rheumatoid-like arthritis
1.0%
2.39
4 studies (n=10,970)
Depression
24.5%
2.30
12 studies (n=139,039)
Younossi Z et al. Gastroenterology. 2016 Jun;150(7):1599-608.
HCV associated extrahepatic manifestations
specific to transplant patients
• New Onset Diabetes after Transplant (10-65%)
• Transplant glomerulopathy in kidney
transplant recipients
• Coronary artery vasculopathy in heart
transplant recipients
• Allograft rejection
Transplantation 2015;99: 2458–2466
Am J Cardiol 2016;118:132e 137
What are the outcomes of HCV eradication
(SVR) on extrahepatic manifestations?
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Fatigue and HRQOL
Cognitive function
Stroke
Cardiovascular disease
Insulin resistance/Diabetes
Cryoglobulinaemia
Lymphoma
Mortality
Negro F et al. Gastroenterology. 2015 Nov;149(6):1345-60
Studies of
impact of SVR
with
PegIFN + RBV
in non-Tx pts
Limited data
after Tx,
particularly
kidney, heart,
lung Tx
recipients
Limited data
with DAAs
Potential benefits of SVR
in transplant recipients
• Improved symptoms
and QOL
• Reduced morbidity
• Improved survival
from hepatic and
extrahepatic
manifestations
Fatigue and Quality of Life
• Many people with HCV report no symptoms
• Others have severe, debilitating fatigue that impacts
on quality of life
Higher scores indicate better HRQOL. Abbreviations: BP, bodily pain; GH, general health; MH, mental health;
PF, physical functioning; pts., patients; RE, role emotional; RP, role physical; SF, social functioning; VT, vitality.
Bonkovsky HL et al.
J Hepatol. 2007
IFN-based treatment and HRQOL
• Severe side-effects of IFN-based treatments associated with
significant on-treatment impairment of HRQOL in almost all patients
• SVR with IFN-based treatments led to improved HRQOL
• However, limited use of IFN in non-liver transplant recipients
Abbreviations: BP, bodily pain; GH, general health; MH, mental health; PF, physical functioning; pts., patients;
RE, role emotional; RP, role physical; SF, social functioning; VT, vitality.
Bonkovsky HL et al.
J Hepatol. 2007
Impact of IFN-free DAA treatments on HRQOL
• Many recent clinical trials have incorporated patient
reported outcomes
• Ribavirin, when used, is associated with mild
impairment in HRQOL during treatment phase
• Ribavirin-free protocols associated with
improvements in HRQOL during treatment and
follow-up
• Patients report feeling better on treatment, and
after – many didn’t realise they were symptomatic
previously!
Minimal impact of sofosbuvir and ribavirin on health related
quality of life in Chronic Hepatitis C (CH-C)
SOF + RBV
SOF + RBV
SOF + RBV
SOF +
pegIFN +
RBV
PCS, physical component summary; MCS, mental component summary.
Younossi ZM et al. J Hepatol 2014:60;741–747
Sofosbuvir-Velpatasvir for 12 weeks: ASTRAL-1
Quality of life improves on treatment and to 24 weeks post-Rx
SOF 400 mg and VEL 100 mg for patients with
GT 1, 2, 4, 5, and 6 vs placebo for 12 wks
PCS,physical
component
summary (SF-36);
MCS, mental
component
summary (SF-36); FS,
fatigue scales (FACITF); FACIT-F, total
FACIT-F score; AE,
activity/
energy score (CLDQHCV); CLDQ-HCV,
total CLDQ-HCV
score; WI, work
productivity
impairment
(WPAI:SHP); AI,
activity impairment
(WPAI:SHP).
Younossi ZM et al. J Hepatol 2016:65;33–39
Cognitive Function
Divided attention (optical)
Vigilance
Computer-aided TAP (Test Battery of
Attentional Performance)
Kraus M et al. HEPATOLOGY 2013;58:497-504
Working memory
Altered cerebral metabolism in HCV patients with normal liver function
Control
With DAA treatment (LDV/SOF), increase in basal
ganglia NAA/Cr ratio at week 4 that became
significant at SVR (p=0.0134) ; correlated with
HCV patient
changes in HRQOL on SF36 and CLDQ- HCV
Alsop D, Younossi Z, Stepanova M and Afdhal NH. AASLD 2014
More marked in patients with moderate
rather than mild fatigue
Weissenborn K et al. J Hepatol 41 (2004) 845–851
HCV-associated arthropathy
• IFN-based treatments can worsen or precipitate inflammatory
arthritis
• Examples include:
– IFN – associated SLE with arthritis/arthralgia and serositis can present 2
weeks to 7 years after IFN-alfa therapy
– IFN-alfa-induced RA or polyarthritis - a few weeks to 10 months after IFN
alfa therapy
• Benefits of IFN-based treatment on arthropathy unclear
• No direct data of improvement in HCV-associated arthropathy
from the DAA era, but induction or worsening not reported
Best Practice & Research Clinical Rheumatology 29 (2015) 319e342
Successful Treatment of Hepatitis C Virus-associated
Oral Lichen Planus by Interferon-free Therapy with
Direct-acting Antivirals
N=7
No worsening of
symptoms was
observed during
DAAs.
Lesions
disappeared
(n=4) or
improved (n=3)
after SVR
Nagao Y et al. Clin Transl Gastroenterol. 2016 Jul 7;7(7):e179
Treatment of chronic hepatitis with boceprevir
leads to remission of porphyria cutanea tarda
PCT refractory to low-dose chloroquine and venesection
Antiviral treatment
During and after antiviral treatment, skin
fragility improved and cutaneous lesions
disappeared.
Urinary porphyrins decreased
to low normal values.
Aguilera P et al. Br J Dermatol. 2014 Dec;171(6):1595-6.
Atherosclerosis appears to be associated
with HCV infection
Forest plot of final eligible studies with risk of unambiguous coronary atherosclerosis related outcome.
Increasing data supporting an increased risk of carotid disease, stroke and CVD-related mortality
Strong association with smoking in the HCV population
Olubamwo OO et al. Public Health (2016) in press
Petta S et al. Gastroenterology 2016;150:145–155
Taiwan National Health Insurance Program
Treated (n=208)
Un-treated (n=2875)
Interferon-based therapy and stroke-free survival
rate in patients with CHC
Treatment
associated with
61% decreased risk
of stroke in
patients with HCV
after adjusting for
known prognostic
factors*
*age, sex, hyperlipidaemia, DM, IHD, HT,
alcohol-related illness, COPD, aspirin use,
clopidogrel
use, warfarin use, dipyridamole use,
ticlopidine use, statin use,
ACE inhibitors use and influenza vaccination
Aliment Pharmacol Ther 2013;38:415-23
Antiviral treatment associated with reduction in platelet
microparticles, particularly in smokers with HCV
n=28 treated with PegIFN and RBV
All patients
PMP - platelet-derived membrane vesicles involved in
cardiovascular diseases and atherosclerosis
Smokers vs Nonsmokers
Kanellopoulou et al. Ann Gastroenterol. 2016 Apr-Jun;29(2):201-7
Type 2 diabetes/Insulin Resistance and HCV
• 15% of pts with HCV have diabetes (OR 1.58)
• Prevalence of diabetes increases in
cirrhosis and with age
• In HCV, diabetes associated with older age,
male gender, non-white, obesity, lower SES,
family history of DM
Mehta SH et al. Ann Intern Med. 2000;133:592-9
HCV negative
HCV positive
• Diabetes associated with higher mortality
and increased incidence of liver, diabetes
and CV-related events, including in noncirrhotic patients
• Diabetes had negative impact on IFN-based
antiviral treatment; but not DAAs
• Mechanism unclear but includes hepatic
and peripheral insulin resistance
Younossi Z et al. Gastroenterology. 2016 ;150(7):1599-608
Mehta SH et al. Ann Intern Med. 2000;133:592-9
Stepanova M et al. J Viral Hep 2012:19;341-5
Hayashi T et al. Infect Agent Cancer. 2016 Feb 24;11:9
Patients who achieve SVR are less likely
to develop Type 2 diabetes
Retrospective study
Cumulative development rate of T2DM in patients with SVR or without SVR after IFN therapy.
Age ≥ 50
Cirrhosis
Pre Diabetes
Conclusion: SVR causes a two-thirds reduction of T2DM development in HCVpositive patients treated with antiviral drugs.
Sustained Virological Response Reduces Incidence of Onset of Type 2 Diabetes in
Chronic Hepatitis C. Arase Y et al. HEPATOLOGY 2009;49:739-744
SVR is associated with improved insulin resistance
n=48
Hepatic
expression of
Insulin receptor
substrate 1 and 2
increased with
HCV clearance
n=12
n=29
Reduction in
hepatic insulin
resistance
Kawaguchi T et al. Am J Gastroenterol 2007;102:570–576
Reduced peripheral insulin resistance after SVR
Milner et al. J Viral Hep, 2014, 21, 325–332
Does SVR improve diabetes?
• Any impact on IR or diabetes probably depends on the genetic,
demographic, clinical, histological and lifestyle characteristics of
the patients
• Case reports and retrospective series of significant improvement
in glycaemic control and insulin sensitivity with DAAs in absence
of change in BMI
• Reduced rates of complications in diabetics treated for HCV
• Must continue to manage metabolic risk factors, with diet, weight
loss, physical activity.
• We need large prospective trials, in the DAA era
Vanni E et al. Digestive and Liver Disease 48 (2016) 105–111
Hsu Y-C et al. Hepatology 2014;59:1293-1302; Pashun RA et al. DDW
2016; Morales A et al. AASLD 2015;BenitezGutierrez et al. AASLD 2015
Are there other benefits of HCV treatment
in patients with HCV and diabetes?
HR 0.16 (0.07-0.33%)
Taiwan National Health Insurance Research Database
Treated (PegIFN plus RBV) n=1411
Untreated controls n=1411
Uninfected (Diabetic patients without HCV) n=5644
HR 0.64 (0.39-1.06)
HR 0.53 (0.30-0.93)
Cumulative incidence of ESRD
Cumulative incidence of acute coronary event
*HR compares treated with untreated
Cumulative incidence of ischemic stroke
Hsu Y-C et al. Hepatology 2014;59:1293-1302
• 43 year old man
• Renal Tx for GN (no HCV, no diabetes)
• 6 years post-Tx developed NODAT, found to be HCV positive
(Gt 1); HbA1c 11.9%
• Diabetes required insulin then oral sitagliptin-metformin
• Treated with 12 weeks LDV-SOF
• SVR associated with normal LFTs and euglycaemia off all
diabetes medications
Indian Journal of Nephrology. 2016: 26(3):216-9
Mixed Cryoglobulinaemia
• Up to 91% of patients with MC have active HCV
infection
• Circulating cryoglobulins are found in 40-60% of
HCV-infected patients; however, only 5% to 10%
develop clinical consequences
Manifestations in patients with symptomatic
cryoglobulinaemia (5-10%)
Cutaneous vasculitis
Renal involvement (MPGN)
18% - 33%
27%
Neuropathy
11%–30%
Sicca syndrome
10%–25%
Arthralgias
35%–54%
Fatigue
50%
Negro F et al. Gastroenterology 2015;149:1345–1360
MC, mixed cryoglobulinemia;
MCS, mixed cryoglobulinemia syndrome.
(PegIFN/RBV)
424 pts enrolled
HCV
(n = 158)
MC-HCV (n = 132)
MCS-HCV (n = 121)
FU 35 - 124 months
(mean 92.5 months)
SVR Rates
HCV
MC-HCV
MCS-HCV
61.4%
45.5%
52%
p=0.014
Multiple AEs on treatment
which was poorly tolerated
Gragnani et al. Hepatology 2015;61:1145-1153
Retrospective series
12 patients with MCS treated with
SOFOSBUVIR-based regimen
Glomerulonephritis
Purpura
Arthralgia
Peripheral neuropathy
Raynaud’s phenomenon
Sicca
Renal arteritis/infarct
Cryoglobulin levels decreased in all except one pt
with virologic relapse
Median cryocrit dropped from 1.5% to 0.5%
Complete disappearance in 4/9 cases measured
7 (58%)
6 (50%)
6 (50%)
4 (33%)
2 (17%)
1 (8%)
1 (8%)
relapser
SVR 83%
Change in cryoglobulin levels over time
Sise et al. Hepatology 2016;63:408-417
Retrospective series
+ Ritux
6/7 patients with
GN who achieved
SVR12 had
improvement in
serum creatinine
and a reduction in
proteinuria.
Serum creatinine and proteinuria trends in HCV-MCS with renal involvement
Sise et al. Hepatology 2016;63:408-417
Sofosbuvir plus ribavirin for hepatitis C virus associated
cryoglobulinaemia vasculitis:VASCUVALDIC study
24 consecutive patients with MCS treated with SOF/RBV
Purpura and peripheral neuropathy
Arthralgia
Glomerulonephritis
Skin ulcers
(67%)
(58%)
(21%)
(12%)
SVR12 in 74%
Complete clinical
response in 87%
Saadoun D, et al. Ann Rheum Dis 2015;0:1–6.
Sofosbuvir plus ribavirin for hepatitis C virus associated
cryoglobulinaemia vasculitis:VASCUVALDIC study
HCV RNA
Cryoglobulin levels
Proteinuria
Creatinine levels
Treatment was well tolerated
C4 levels
GFR
Saadoun D, et al. Ann Rheum Dis 2015;0:1–6.
Complete recovery of kidney allograft function after
recurrence of HCV related MPGN:
A case of successful antiviral treatment of HCV in a kidney
allograft recipient requiring hemodialysis.
• A 63 year old woman received a kidney transplant in
2012 after 2 years of maintenance HD due to HCVassociated MPGN (GT1b)
• Recurrence of MPGN 3 years post Tx: rapid
deterioration of renal function, new onset proteinuria
>2g/d and need for HD, vasculitic skin rash
• DAA treatment (SIM/DCV) led to viral clearance and
complete clinical and histologic remission
Schrezenmeier E et al. 53rd ERA-EDTA
Congress Vienna Austria 2016
HCV-associated lymphoma in
transplant recipients
• HCV associated
with late onset
PTLD
• Usually EBVnegative
• Worse prognosis
than HCVnegative PTLD
n=126
n=9
Kinch A et al. Acta Oncol. 2014 May;53(5):669-79
HCV associated lymphoma
Non-transplant patients
•
B cell NHL
•
Marginal
zone
lymphomas
or
• Diffuse
large B-cell
lymphomas
•
DAAs may
be curative
alone in
MZL
Carrier P et al. Liver Int. 2015; 35: 2222–2227
Conclusions
• Chronic HCV is as associated with a significant burden of
extrahepatic manifestations in transplant recipients
• Clearance of hepatitis C may be associated with reversal of
many extrahepatic manifestations
• New treatments for HCV offer an opportunity to treat both
pre-and post transplant patients, and remove the risks
associated with post-transplant HCV
• Treatment is indicated, and should be available,
to everyone with hepatitis C, including in the
transplant setting