Special considerations before/ during/

after therapy

Dr Kosh Agarwal

Institute of Liver Studies

King’s College Hospital

London

13th Co-infection workshop

2017

Disclosures:

Pharma support:

AbbVie/Achillion/ Astellas/ BI/ BMS/ Gilead/ GSK/ Intercept/Janssen/ Merck/ Novartis/ Roche

Spectrum in audience

take the ‘Why not’ viewpoint

It all depends where you have come from….expectations so you will get a personalised view

Non-Nucs

NS5A-Inhibitors „…asvirs“

Sofosbuvir Ledipasvir

Sofosbuvir Daclatasvir

Sofosbuvir Simeprevir Protease- Inhibitors „…previrs“

Polymerase-Inhibitors „…buvirs“

Nucleos(t)ide

Sofosbuvir Velpatasvir

Grazoprevir Elbasvir

Paritaprevir/r Ombitasvir Dasabuvir

Asunaprevir Daclatasvir

Sofosbuvir + RBV

Wedemeyer, Der Internist 2014 & Lancet 2015

HCV Therapy: Direct Acting Antivirals

Glecaprevir Pibrentasvir

Voxilaprevir Sofosbuvir Velpatasvir

Grazoprevir Ruzasvir Uprifosbuvir

Simeprevir Odalasvir AL-355

From my friend Heiner W

4

95-100 %

SVR

(%

)

Phase 2/3 studies of DAAs against HCV = Real Life

With minimal side effects

>50 x NEJM, Lancet, JAMA, Ann Intern Med, Lancet ID

Van der Meer AJ, et al.

JAMA 2012

ALL CAUSE MORTALITY

HCV cure is associated with reduced mortality

SVR patients have a survival similar

to the general population

Van der Meer AJ, et al.

JAMA 2014

Similar Data: France: Nahon et al., Gastroenterology 2017; 152: 142-156

Italy: Bruno et al., J Hepatol 2016; 64: 1217-23;

Scotland: Innes et al., J Hepatol 2017; 66: 19-27

HCV Genotype

Stage of liver disease (F0-F4-decompensation)

HCV Viral Load

Kidney Function

Selection of DAAs

Ribavirin

yes / no

Duration

8, 12, 16, 24 weeks

DDI

Adherence

Comorbidities

Age >70, >75, >80

HBV Co-infection

ESRD

PWID

History of HCC

Real-World Data?

Ethnicity

Selecting the optimal HCV treatment: EASL guidelines

And do the associated bureaucracy associated with treatment ++++++

Its mostly easy unless its complicated…

My talk in 1 slide

Approaches to HCV

Comprehensive approach

CURE Population management

Primary prevention

Early Detection

Clinical management

Follow up

Rx

Awareness Surveillance Harm reduction

Screening Risk group Access/ Diagnostics

Standards of care Training Outcomes Pathways Package

R Benjoa Madrid 2016

You don’t know my life…

HCV from a provider & patient perspective

This is so easy – just take the tablets!

SN – 43yr old

• HIV dx 1995 • HCV Genotype 4

– Peg-interferon/ribavirin 2011- non responder

• Liver transplant HIV/HCV 2012 • Poor clinic attender [used to have sensible girlfriend] • Did relapse to alcohol/ IVDU post LT (perhaps a bit of a rascal) nil since

2012 • Hospital Admission Feb 2017 – Acute Kidney Injury • Cryoglobulinemia • Nephrotic range proteinuria • cirrhotic– fibroscan 13.2 – borderline but albumin preserved/ plt 110 • CNI sparing immunosuppression March 2017 • HD started April 2017 • Panic at local HIV/ renal (not C&W) • Still working…

What shall we treat him with?

• Poor adherence to all meds, HIV drug resistance, now on Truvada, Dolutegravir, darunavir/rit

• Options are: +/- ribavirin

• Elbasvir/grazoprevir

• Sofosbuvir/ledipasvir

• Sofosbuvir/velpatasvir

• Abbvie 3d

• What shall we do?

• My question: is he going to turn up…

Medications

• MMF 500mg BD ----- CNI free • Prednisolone 7.5mg od

• Dolutegravir 50mg BD • Darunavir 800mg od • Ritonavir 100mg od

• Doxazosin 2mg od • Biosprolol 2.5mg od

• Commenced Sofosbuvir / Ledipasvir / Ribavirin 200mg od on 27 April

• TW 0 HCV RNA 2.25 E5 IU/ml

• TW1 HCV RNA 147 IU/ml

• TW2 HCV RNA 15 IU/ml

• TW4 HCV RNA not detected

No plan B

GD – 48 yr old

• HCV Geno 3a – diagnosed 2005. Variable attendance • HBV, e antigen negative. Delta Ab negative • Fibroscan August 2015 LSM 48kPa • Ex- IVDU, mental health issues - anxiety • Difficult vascular access – bloods only available via neck

vein – only community BB nurse • Alcohol 6-20 units/ day. Heavy bouts of excess • External iliac and femoral vein thrombosis with severe post

thrombotic syndrome • Inflammatory Arthritis • 6 children, came to clinic with 3/12 baby and partner • GI bleed 2 weeks ago. Refused to stay. Hb 9, plts 46

Medications

• Clexane – switched to Apixaban July 2015 • Omeprazole 40mg • Mirtazepine 45mg • Tenofovir 245mg • Topiramate 50mg • Quetiapine 25mg BD • Tiotropium 18cg od • Seretide inhaler 125 BD • Tramadol 100mg QDS PRN • Tiamine 100mg TDS • Zopiclon 7.5mg od • Diazepam 2mg od • Buprenorphine 14mg od

Pretreatment bloods

• Bili 17

• AST 54

• eGFR >90

• Hb 131

• Plate 76

• INR 1.41

• AFP 12.6

• HCV RNA 50,078 IU/ml

• HBV DNA detected <20 IU/ml

• Apixaban switched to enoxaparin

• Omeprazole 20mg 4 hours post sof/vel

Treatment week 8

• Bili 16

• ALT 15

• eGFR >90

Turned up for our preceptorship….engaged

• HBV DNA detected <20IU/ml

• HCV RNA not detected

• ‘Stopped’ drinking alcohol

On –treatment monitoring Adherence Prescription Positive re-inforcement Needs to be simplified? Tele-clinics Functional Currently over-bureaucreatic

Management of HCV coinfected patients

EASL 2017 CPG HBV, J Hepatol 2017 epub

Recommendations:

1) Treatment of HCV with direct-acting antivirals (DAAs) may cause

reactivation of HBV. Patients fulfilling the standard criteria for HBV

treatment should receive NA treatment. (Evidence level II, grade of

recommendation 1)

2) HBsAg-positive patients undergoing DAA therapy should be considered

for concomitant NA prophylaxis until week 12 post DAA, and monitored

closely. (Evidence level II-2, grade of recommendation 2)

3) HBsAg-negative, anti-HBc positive patients undergoing DAA should be

monitored and tested for HBV reactivation in case of ALT elevation.

(Evidence level II, grade of recommendation 1)

HCC recurrence post-SVR with all-oral

DAAs? An FDA issue

‘DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC’

Conti F, et al. J Hepatol 2016;65:727–33

‘Our data show an unexpected high rate and pattern of tumor recurrence coinciding with HCV clearance’

Reig M, et al. J Hepatol 2016;65:719–26

‘we did not observe an increased risk of HCC recurrence after DAA treatment’

ANRS collaborative study group on hepatocellular carcinoma. J Hepatol 2016;65:734–40

EASL. J Hepatol 2016;doi: 10.1016/j.jhep.2016.09.001 [Epub ahead of print]

“Further data is required to evaluate the impact of highly effective IFN-free regimens on the short-, mid- and long-term risk of recurrent HCC following resection or ablation”

Relatively low HCV re-infection rates have been reported among PWID

Weir A, et al. Drug Alcohol Depend; 2016;165:53–60; Midgard H, et al. J Hepatol 2016;64:1020–6; Simmons B, et al. Clin Infect Dis 2016;62:683–94; Dore G, et al. AASLD 2016; Poster #871 CI: confidence interval

2.2 (95% CI 1.3–3.3)

4.9 (95% CI 2.3–8.9)

1.7 (95% CI 0.7–3.5)

1.7 (95% CI 0.8–3.1)

4.0 (95% CI 1.7–8.0)

HCV re-infection rates post-SVR among PWID

Strategies to prevent HCV re-infection are required for people with ongoing risk behaviour

Rescue options for patients who failed an NS5A-containing regimen

overall SVR • 12 weeks: 89% • 16 weeks: 92%

SOF/VEL/VOX for 12 weeks6

RZV/GZR/MK3682 for 16 or 24 weeks7

1. www.easl.eu 2. de Lédinghen V. JFHOD, March 23 2017 3. Poordad F. AASLD 2015 4. Gane EJ. ILC 2016, #PS024 5. Poordad F. EASL 2017, # PS-156 6. Bourliere M. AASLD 2016, #194 7. Wedemeyer H. EASL 2017, #159

GLE/PIB5 for 12 or 16 weeks

Note: Includes presentation of non-approved regimens

EBR/GZR + SOF/R

PrOD + SOF/R

PrO + SOF/R

SIM+DAC + SOF/R

SOF/VEL + R

GT1 + + +

GT4 + + +

GT2,3,5,6 +

EASL 2016 guidelines1

SVR 92-100% (30/31)2 93% (14/15)3 76-91% (26/31)4

Impact of DAAs on inactivation/delisting of

liver transplant candidates listed for

decompensated C cirrhosis

• 103 patients listed for transplant at 11 European centres

• 52 on SOF + RBV, 51 on LDV/SOF or DCV + SOF

• Median follow-up: 52 weeks

• Endpoint: inactivation and delisting for clinical improvement

Belli L, et al J Hepatol 2016: 65: 524-531

Remain active (n=67)

Inactivated (n=34)

Baseline to 24 weeks

Median (IQR) Median (IQR) P-value

MELD 0 (–2 to 2) –3.3 (–5 to –1) <0.0001

CTP 0 (–1 to 1) –2 (–4 to –1) <0.0001

albumin 0.1 (–0.1 to 0.4) +0.5 g/mL (0.25 to 0.85)

<0.0002

• 21/34 inactivated patients delisted (62%)

– 6 more in near future (total 79%)

– All MELD <15; MELD 3 in 19/21

– 0/21 HE, 5/21 ascites on diuretics

• Regression or improvement of ascites and HE in all inactivated patients

Clinical improvement during therapy Inactivation

Understanding/ logistics

Can they turn up – what model works

Baseline fibrosis

Genotype

DDI – Liverpool web site [Back]

HBV status

Intermittment monitoring

LFTs/ RNA

Adherence

Post SVR health: long term outcomes

Optimisation

Small % of failure -

Summary