Michael W. Fried, M.D., FAASLD Professor of Medicine ... · Michael W. Fried, M.D., FAASLD...

Michael W. Fried, M.D., FAASLD Professor of Medicine

Director, UNC Liver Center University of North Carolina at Chapel Hill

Disclosures Michael W. Fried, M.D.

• Grants/Research Support – AbbVie, BMS, Gilead, Janssen, Merck, NIH

• Consultant:

– AbbVie, BMS, Gilead, Janssen, Merck

• Stock/Shareholder: TARGET PharmaSolutions • Speakers Bureau: None • Other Financial Support: NIH Grants • HCV-TARGET: Co-Principal Investigator

Current HCV Treatment Landscape Combines Multiple Classes of Direct-Acting Antiviral Agents

3’UTR 5’UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5B p7

Polymerase

Simeprevir Paritaprevir Grazoprevir

Daclatasvir Ledipasvir Ombitasvir Elbasvir

Sofosbuvir

Dasabuvir

NS5B NUC Inhibitors

NS3 Protease Inhibitors

NS5A Replication

Complex Inhibitors

Ribavirin NS5B

Non-NUC Inhibitors (NNI)

Protease

4A

• Combinations of different classes of DAAs: • Provide near-universal cure • Are generally safe and well-tolerated

Olysio + Sovaldi= Simeprevir + Sofosbuvir Harvoni= Ledipasvir + Sofosbuvir Viekira= Paritaprevir/r + Ombitasvir + Dasabuvir Daklinza + Sovaldi = Daclatasvir + Sofosbuvir Zepatier = Grazoprevir + Elbasvir

CP-A Cirrhosis Treated with LDV/SOF: Low Rate of SAEs

• Post-hoc pooled analysis of several studies of patients with CP-A cirrhosis (n= 513)

• SAEs – 6% of patients treated with LDV/SOF – 3% of patients treated with LDV/SOF + RBV

• Death: n=1 not considered related to HCV treatment

Reddy et al, 2015

Paritaprevir/r + Ombitasvir + Dasabuvir +/- RBV in CP-A Cirrhosis: Low rates of AE or Decompensation

Event OBV/PTV/r + DSV ± RBV

N=1066 AE leading to discontinuation of treatment, n (%) 23 (2.2) Any AE consistent with hepatic decompensation,* n (%) 13 (1.2) Ascites 7 (0.7) Esophageal varices hemorrhage 3 (0.3) Hepatic failure 1 (<0.1) Hepatorenal syndrome 1 (<0.1) Hypoalbuminemia 1 (<0.1) Hepatic encephalopathy 2 (0.2) Clinical Outcome of Adverse Event Events resolved, n (%) 9/13 (69.2) Event ongoing‡, n (%) 2/13(15.4) Death§, n (%) 1/13 (7.7) Information not available, n (%) 1/13 (7.7) * Adverse events consistent with hepatic decompensation from adjudication of hepatic disorders (Standardized MedDRA Query) (broad search) by primary

MedDRA system organ class and preferred term, events of jaundice (n=3) and increased bilirubinemia (n=1) also occurred in 3 subjects with hepatic decompensation events; † a total of 15 adverse events consistent with hepatic decompensation occurred in 13 patients; ‡ At least one event was ongoing at the end of the follow-up or data-cut date; § One patient died as a result of pneumonia leading to multiple organ failure.

F. Tatsch, AbbVie, Personal Communication

EBR/GZR EBR/GZR/RBV Drug-related AEs 111 (42%) 141 (73%) SAEs 8 (3.0%) 6 (3.1%) Deaths 1 (0.4%) 1 (0.5%) Discontinued due to AE 1 (0.4%) 4 (2.1%) Discontinued due to lab AE ALT Total bilirubin

1 (0.4%) 0 (0.0%)

0 (0.0%) 0 (0.0%)

Integrated Analysis of Elbasvir/Grzoprevir in Patients with Cirrhosis CP-A: Low Rates of SAE or Discontinuation

Jacobson et al, AASLD, 2015

Challenges in Evaluating DILI in Patients with Advanced Cirrhosis

• Difficult to measure new onset elevations of ALT and bilirubin against abnormal baseline

• Intercurrent acute on chronic liver disease – Sepsis/Spontaneous Bacterial Peritonitis – ETOH hepatitis – Choledocholithiasis – Portal vein thrombosis

• Spectrum of natural history of cirrhosis with progression of underlying liver disease – Compensated vs decompensated – “Falling off the cliff”

SOLAR-1 and -2: Impact of Treatment Duration in Decompensated Cirrhosis (LDV/SOF + RBV)

Error bars represent 90% CIs. Charlton et al, 2015; Manns et al, 2016

100

80

60

40

20

0

SVR

12 (%

)

CTP B CTP C CTP B CTP C

SOLAR-1 SOLAR-2

87 89 86 90 87 96 85 72

26/30

3 relapses 1 death

24/ 27

1 relapse 2 deaths

19/22

1 relapse 1 death 1 LTFU

18/ 20

1 relapse 1 death

26/30

3 relapses

22/23

1 relapse

17/20

1 relapse 2 deaths

13/18

1 relapse 3 deaths 1 w/d consent

LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks

n/N =

SAE= 30/108 (28%) D/C due to AE=5/108 (5%) Deaths=5/108 (5%)

SAE= 31/107 (29%) D/C due to AE=7/107 (7%) Deaths=5/107 (5%)

DCV/SOF/RBV (N=60) Deaths 0 SAEs 10 (17%) Grade 3 or 4 AEs 11 (18%) Discontinued due to AE All drugs discontinued Ribavirin discontinued

13 (19%) 1 ( 12

Treatment Emergent AE: ALT > 5 x ULN Total bilirubin > 2.5 x ULN

2 (3%)

9 (15%)

Daclatasvir/Sofosbuvir/Ribavirin in Patients with Advanced Cirrhosis

Poordad et al, 2016

CP-A= 20% CP-B= 53% CP-C= 27%

Paritaprevir/r + Ombitasvir + Dasabuvir +/- RBV: Safety Warning Issued 10/22/15

• FDA Adverse Event Reporting System (FAERS) – 26 worldwide cases attributed to HCV treatment as probable

or possible • Temporal association within 1-4 weeks • Not associated with elevation of ALT • 10 patients with hepatic failure-death or transplant • 16 patients with varying hepatic dysfunction

– Some cases occurred among CP-B and CP-C patients in whom this regimen is contraindicated

FDA website

• Detailed clinical data may be lacking to exclude other etiologies or naturally progressive liver disease

• Denominator unknown • Case reports of other DAA regimens associated with decompensation

and liver failure

Considerations from Prescribing Information for DAAs (Developed from Prescribing Information)

Regimen Contraindicated in Hepatic Impairment

Impact of Renal Impairment

ALT Warnings Other Warnings

Ledipasvir Sofosbuvir

No contraindication

No dosing information

None Symptomatic bradycardia*

Paritaprevir Ombitasvir Dasabuvir

Child-Pugh B or C Dose adjustment not needed (Caution with RBV)

Monitor ALT during first 4 weeks

Hepatic decompensation in CP-B or CP-C

Grazoprevir Elbasvir

Child-Pugh B or C Dose adjustment not needed (Caution with RBV)

Monitor ALT at week 8

Sofosbuvir/Daclatasvir

No contraindication

No dosing information

None Symptomatic bradycardia*

Sofosbuvir/Simeprevir

Child Pugh B or C No dosing information

Monitor during therapy

Symptomatic bradycardia*

* Associated with amiodarone use, beta blockers, underlying cardiac disease, advanced liver disease

Impact of Hepatic Impairment on Concentrations of DAAs for HCV

Agent Class Exposure change in CP-A

Exposure Change in CP-B

Exposure Change in CP-C

Sofosbuvir (Metabolite GS331007)

NUC No impact No impact

1.26 1.18

1.43 1.09

Ribavirin NUC No impact No impact No impact

Simeprevir PI No impact 2.4x 5.2x

Paritaprevir PI No impact 1.6x 9x

Grazoprevir PI 2x ~5x 12x

Ledipasvir NS5A Unchanged Unchanged Unchanged

Ombitasvir NS5A Modestly Lower Modestly Lower Modestly Lower

Daclatasvir NS5A Modestly Lower Modestly Lower Modestly Lower

Elbasvir NS5A Modestly Lower Modestly Lower Modestly Lower De Kanter et al, 2014 Hcvdruginfo.ca

HCV-TARGET: Evaluating HCV Therapies in Usual Clinical Practice

• Created to understand the impact of new HCV therapies utilized in usual clinical practice at academic and community centers • Improve information about populations underrepresented in

phase III trials • Evaluate regimens used in usual clinical practice (approved &

unapproved) • Evaluate adverse event management • Provide biospecimens for collaborative, translational studies

• Sponsors: AbbVie, BMS, Gilead, Janssen, Merck, Vertex, Genentech, Kadmon

• Over 9000 patients enrolled at 58 sites • Multiple publications and presentations at

national/international meetings

13

HCV-TARGET Collaboration

The HCV-TARGET observational cohort includes: • A collaboration platform with academic experts,

regulatory agencies, pharmaceutical sponsors, and patient advocacy

• Centralized abstraction of complete redacted EMR narratives/labs/phone calls/radiology to assess demographics, co-morbidities, conmeds, AEs, SAEs, outcomes

• Multilevel data monitoring to ensure completeness and accuracy (Able to query to patient level)

• Data analysis and dissemination via scientific presentations and publications

14

HCV-TARGET: An International Consortium at Academic and Community Practices

Non Cirrhotic N=3214

Cirrhotic N=2540 (44%)

Total* N=5754

Male N (%) 1850 (57.6%) 1672 (65.8%) 3522 (61.2%) Age, yr, median, range 58 (18-96) 60 (19-86) 59 (18-96) Race N (%) Caucasian 2199 (68.4%) 1948 (76.7%) 4147 (72.1%) Black 686 (21.3%) 319 (12.6%) 1005 (17.5%)

Treatment Status N (%) Naive 1929 (60.0%) 975 (38.4%) 2904 (50.5%)

PEG/RBV only Experienced

924 (28.7%) 1097 (43.2%) 2021 (35.1%)

DAA Experienced

235 (7.3%) 330 (13.0%) 565 (9.8%)

History of Decompensation N (%) 98 (3.0%) 1054 (41.5%) 1152 (20.0%)

Liver transplant N (%) 294 (9.1%) 334 (13.1%) 628 (10.9%)

HIV N (%) 106 (3.3%) 69 (2.7%) 175 (3.0%)

Albumin 4.2 (1.3-6.9) 3.7 (1.0-5.3) 4.0 (1.0-6.9)

Total bilirubin 0.6 (0.1-27.1) 1.0 (0.1-34.5) 0.7 (0.1-34.5)

Platelets 203.0 (6.0-748.0) 102.0 (3.0-567.0) 163.0 (3.0-748.0)

HCV-TARGET: Baseline Characteristics of Patients Treated with DAAs in HCV-TARGET 2.0/3.0

Decompensated cirrhosis was defined as presence of current or past ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatic hydrothorax, variceal hemorrhage, or concomitant medications with a specific indication for the before mentioned indications at the time of HCV treatment start

HCV-TARGET: Baseline Characteristics of Patients According to Treatment Regimen

SOF/RBV SOF/SMV +/-RBV

HVN +/-RBV VKR +/-RBV SOF/DAC +/-RBV

N=779 N=1209 N=2496 N=579 N=265 Male N (%) 479 (61.5%) 744 (61.5%) 1507 (60.4%) 334 (57.7%) 178 (67.2%) Age, yr, range 58 60 60 59 58 Race N (%) Caucasian 640 (82.2%) 900 (74.4%) 1649 (66.1%) 437 (75.5%) 225 (84.9%)

Black 44 (5.6%) 157 (13.0%) 625 (25.0%) 102 (17.6%) 3 (1.1%)

Treatment Status N (%) Naive 461 (59.2%) 499 (41.3%) 1259 (50.4%) 311 (53.7%) 141 (53.2%)

PEG/RBV only Experienced 260 (33.4%) 535 (44.3%) 789 (31.6%) 203 (35.1%) 93 (35.1%)

DAA Experienced 26 (3.3%) 136 (11.2%) 321 (12.9%) 25 (4.3%) 10 (3.8%) Albumin g/dl, median, 4.0 (1.8-5.4) 3.9 (1.2-5.3) 4.0 (1.0-6.9) 4.0 (3.2-4.7) 3.9 (2.3-5.1) T Bilirubin g/dl, median, 0.7 (0.1-14.7) 0.8 (0.1-21.9) 0.7 (0.1-34.5) 0.7 (0.2-4.4) 0.8 (0.1-16.1) Platelets, median, (x103) 155 (14-485) 134 (19-748) 166 (6-647) 187 (75-320) 142 (19-455) Cirrhosis N (%) 354 (45.4%) 707 (58.5%) 1030 (41.3%) 160 (27.6%) 138 (52.1%) Decompensated N (%) 186 (23.9%) 353 (29.2%) 465 (18.6%) 47 (8.1%) 73 (27.5%) Liver transplant N (%) 64 (8.2%) 183 (15.1%) 315 (12.6%) 13 (2.2%) 27 (10.2%)

Causes of Death for All Participants in HCV-TARGET 2.0 and 3.0

SOF PEG RBV SOF RBV SOF SMV SOF SMV

RBV SOF DCV SOF DCV RBV LDV/SOF LDV/SOF

RBV PrOD RBV Total

(N=2) (N=7) (N=6) (N=3) (N=1) (N=4) (N=12) (N=1) (N=1) (N=37) ACUTE RESPIRATORY FAILURE 0 0 0 0 0 0 1 0 0 1 BREAST CANCER METASTATIC 0 0 0 0 0 0 1 0 0 1 CARDIAC ARREST 0 2 0 1 0 0 0 0 0 3 COMPLETED SUICIDE 0 0 0 1 0 0 0 0 0 1 CORONARY ARTERY DISEASE 0 0 0 0 0 0 1 0 0 1 DEATH NOS 1 1 0 1 1 0 1 0 1 6 GENERAL PHYSICAL HEALTH DETERIORATION 0 0 0 0 0 1 0 0 0 1 HAEMORRHAGE 0 0 0 0 0 1 0 0 0 1 HEPATIC ENCEPHALOPATHY 0 1 0 0 0 0 0 0 0 1 HEPATIC FAILURE 0 0 2 0 0 0 0 0 0 2 INTRAVENTRICULAR HAEMORRHAGE 0 0 0 0 0 0 1 0 0 1 ISCHAEMIC STROKE 0 0 1 0 0 0 0 0 0 1 LEUKAEMIA RECURRENT 0 0 0 0 0 1 0 0 0 1 MULTI-ORGAN FAILURE 0 3 0 0 0 1 1 0 0 5 PNEUMONIA ASPIRATION 0 0 1 0 0 0 0 0 0 1 RENAL FAILURE ACUTE | HEPATIC FAILURE 0 0 1 0 0 0 0 0 0 1 ROAD TRAFFIC ACCIDENT 0 0 0 0 0 0 1 1 0 2 SEPSIS /SHOCK 1 0 1 0 0 0 2 0 0 4 SUBDURAL HAEMATOMA 0 0 0 0 0 0 1 0 0 1 SUDDEN DEATH 0 0 0 0 0 0 1 0 0 1 TOXICITY TO VARIOUS AGENTS 0 0 0 0 0 0 1 0 0 1

21/37 Potential liver-related deaths

Frequency of Δ Bilirubin > 3.0 mg/dl During or Within 30 Days of Treatment

Regimen No. of Events

N % of Treated

PEG + SOF + RBV 3 356 0.8%

SOF + RBV 25 699 3.6%

SOF + SMV 18 850 2.1%

SOF + SMV + RBV 15 240 6.2%

LDV + SOF 8 1763 0.5%

LDV + SOF + RBV 19 325 5.9%

PrOD 1 125 0.8%

PrOD + RBV 16 297 5.4%

DCV + SOF 1 76 1.3%

DCV + SOF + RBV 2 82 2.4%


N % of Treated

PEG + SOF + RBV 353 356 99.2%

SOF + RBV 674 699 96.4%

SOF + SMV 832 850 97.9%

SOF + SMV + RBV 225 240 93.8%

LDV + SOF 1755 1763 99.6%

LDV + SOF + RBV 306 325 94.2%

PrOD 124 125 99.2%

PrOD + RBV 281 297 94.6%

DCV + SOF 75 76 98.7%

DCV + SOF + RBV 80 82 97.6%

Outcomes of Patients with Δ Bilirubin > 3.0 mg/dl During or Within 30 Days of Treatment

Total Δ Bilirubin > 3.0 mg/dl (N=108)

Started treatment 108 (100.0%)

Discontinued Prematurely 24 (22.2%)

Due to AE 21 (19.4%)

For other reasons 3 (2.8%)

Completed treatment 82 (75.9%)

Ongoing 2 (1.9%)

Treatment outcome SVR 61/79 (77.2%)

Relapser 14/79 (17.7%)

Viral Breakthrough 1/79 (1.3%)

Non-Responder 3/79 (4.5%)

6 patients were lost to post-treatment follow-up; 13 patients remain in post treatment follow up

Causes of Death (n=8): Cardiac arrest (1, SOF/RBV); Death NOS (1 SOF/PEG/RBV, 1 SOF/LDV); Hemorrhage (1 SOF/DCV/RBV); Hepatic failure (3 SOF/SMV); Shock (1 SOF/SMV)

Adverse Events Leading to Discontinuation in Patients with Δ Bilirubin > 3.0 mg/dl (N=108)

SOF PEG RBV SOF RBV SOF

SMV SOF SMV

RBV SOF DCV SOF DCV RBV HVN RBV VKR VKR RBV Total

(N=2) (N=3) (N=6) (N=2) (N=1) (N=1) (N=1) (N=1) (N=4) (N=21) Ascites 0 0 0 0 0 0 0 0 1 1 Biliary tract disorder 0 0 0 0 1 0 0 0 0 1 Cardiac arrest 0 1 0 0 0 0 0 0 0 1 Cholecystitis 0 0 1 0 0 0 0 0 0 1 Haemolysis 0 1 0 0 0 0 0 0 0 1 Haemolytic anaemia 0 0 0 0 0 0 1 0 0 1 Hepatic encephalopathy 0 0 0 1 0 0 0 0 0 1 Hepatic failure 0 0 1 0 0 0 0 0 0 1 Hyperbilirubinaemia 0 0 1 0 0 0 0 0 2 3 Jaundice 0 0 0 0 0 0 0 1 0 1 Klebsiella bacteraemia 0 1 0 0 0 0 0 0 0 1 Multi-organ failure 0 0 0 0 0 1 0 0 0 1 Pneumonia 0 0 1 0 0 0 0 0 0 1 Renal failure 0 0 1 0 0 0 0 0 0 1 Renal failure acute 1 0 0 1 0 0 0 0 0 2 Syncope 1 0 0 0 0 0 0 0 0 1 Toxicity to agents 0 0 0 0 0 0 0 0 1 1 Incarcerated hernia, 0 0 1 0 0 0 0 0 0 1

Causes of Death: Cardiac arrest (1, SOF/RBV); Death NOS (1 SOF/PEG/RBV, 1 SOF/LDV); Hemorrhage (1 SOF/DCV/RBV); Hepatic failure (3 SOF/SMV); Shock (1 SOF/SMV)

10/21 had liver-related AEs leading to discontinuation

• Patients with increased bilirubin = 108

• Patients with concurrent 2-fold elevation of ALT = 17/108 (16%)

• 10/17 had liver transplants during treatment

– 8/10 previously decompensated

Concurrent Δ Bilirubin > 3.0 mg/dl and > 2-fold Increase of ALT During Therapy

• Liver transplant patients: 6 SVR; 2 relapse; 1 Non-responder; 2 outcome pending • Other (n=7): 1 SVR; 1 relapse; 2 deaths; 2 pending; 1 LTF

• Cirrhotic without prior decomp; completed LDV/SOFtreatment, BILI and ALT rise started 6 weeks on treatment, Decompensated after EOT, Death with unknown cause recorded.

• Cirrhotic with prior decomp on SOF/RBV discontinued due to cardiac arrest (and died) 6 weeks after starting treatment. Acute decompensation also noted.

• Baseline predictors of Bilirubin change of 3mg/dl or more: • Low Albumin at baseline • Higher TBIL at baseline • Cirrhosis • History of decompensating events

Odds Ratio, 95% CL, and p-value

Baseline Predictors for Δ Bilirubin > 3.0 mg/dl During Therapy

*Minimally adjusted for age and sex

Odds ratio estimates for TBIL increase by 3mg/dl or more using appropriate Propensity Score Inverse Probability Weighting • Specific regimen is not associated with the outcome of interest. • Use of RBV is associated with increased odds of bilirubin increase by 3mg/dl or more.


Association of Treatment Regimens with Δ Bilirubin > 3.0 mg/dl

IPW adjustment for baseline age, sex, baseline ALB, TBIL, PLT, cirrhosis status and History of decompensating events before treatment start

Logistic regression using Firth penalized maximum likelihood estimation was performed to determine predictors of total bilirubin increase >3 and decompensating events. Firth approach was preferred because TBIL>3 and decompensation was a very rare event in our data (2% or less).

Odds ratio estimates for TBIL increase by 3mg/dl or more using appropriate Propensity Score Inverse Probability Weighting Comparison of Regimens with and without Ribavirin • Confirms Ribavirin association with change in bilirubin by 3mg/dl or more


Association of Ribavirin with Δ Bilirubin > 3.0 mg/dl During Therapy


Regimens without RBV Regimens with RBV

Association of Ribavirin with Δ Bilirubin > 3.0 mg/dl During Therapy


• LDV and PrOD regimens not associated with outcome of interest • Among RBV-containing regimens, SOF/DCV/RBV was associated with lower

odds of developing outcome of interest, while PrOD/RBV showed a positive association

HCV-TARGET: Frequency of Hepatic Decompensation During or Within 30 Days of Treatment


N Treated

% of Treated

PEG + SOF + RBV 2 366 0.5%

SOF + RBV 5 592 0.8%

SOF + SMV 7 668 1.0%

SOF + SMV + RBV 5 188 2.7%

LDV + SOF 10 1752 0.6%

LDV + SOF + RBV 3 275 1.1%

PrOD 0 176 0%

PrOD + RBV 4 349 1.2%

DCV + SOF 0 115 0%

DCV + SOF + RBV 0 76 0%


N Treated

% of Treated

PEG + SOF + RBV 3 24 13%

SOF + RBV 52 186 28%

SOF + SMV 32 252 13%

SOF + SMV + RBV 24 101 24%

LDV + SOF 45 362 10%

LDV + SOF + RBV 10 103 10%

PrOD 0 6 0%

PrOD + RBV 7 41 17%

DCV + SOF 2 26 8%

DCV + SOF + RBV 5 47 11% Early term due to AE = 3 (Sepsis, AKI, Ascites); Deaths = 1 sepsis and 1 aspiration pneumonia

AEs Leading to Discontinuation in Previously Decompensated Patients with New Decompensating Events

12/29 liver-related AEs leading to discontinuation

Causes of Death in Previously Decompensated Patients with New Decompensating Events (N=180)


RBV LDV/SOF Total

(N=1) (N=5) (N=5) (N=2) (N=4) (N=17) ACUTE RESPIRATORY FAILURE 0 0 0 0 1 1 BREAST CANCER METASTATIC 0 0 0 0 1 1 CARDIAC ARREST 0 2 0 1 0 3 DEATH NOS 0 1 0 1 1 3 HEPATIC ENCEPHALOPATHY 0 1 0 0 0 1 HEPATIC FAILURE 0 0 2 0 0 2 ISCHAEMIC STROKE 0 0 1 0 0 1 MULTI-ORGAN FAILURE 0 1 0 0 0 1 RENAL FAILURE ACUTE | HEPATIC FAILURE 0 0 1 0 0 1

SEPSIS 1 0 0 0 0 1 SEPTIC SHOCK 0 0 0 0 1 1 SHOCK 0 0 1 0 0 1

• Deaths = 17/180 (9%) • 11/17 liver related mortality

Baseline predictors for new hepatic decompensation in patients with no history of decompensating events:

• Low Albumin at baseline • Cirrhosis


Patients with No History of Prior Decompensation

Minimally adjusted for age and sex

Odds ratio estimates for new hepatic decompensation in patients without history of prior decompensating events using appropriate Propensity Score Inverse Probability Weighting • Specific regimen not associated with the outcome of interest.





Odds ratio estimates for new hepatic decompensation in patients without history of prior decompensation using appropriate Propensity Score Inverse Probability Weighting comparing regimen with and without addition of RBV: • Specific regimen was not associated with the outcome of interest.

• There were no patients on VKR without RBV therefore result is uninterpretable • There were no patients on DCV containing regimens therefore result is unavailable





Odds ratio estimates for hepatic decompensation in patients without history of decompensating events using appropriate Propensity Score Inverse Probability Weighting performed separately for RBV free regimens and regimens with addition of RBV. • Specific regimen is not associated with the outcome of interest.

• There were no patients on VKR without RBV therefore result is uninterpretable




• Baseline predictors for new Hepatic decompensation in patients with history of prior decompensation:

• Low Albumin at baseline • Higher TBIL at baseline • Cirrhosis

Patients with History of Prior Decompensation

Minimally adjusted for age and sex




Odds ratio estimates for new hepatic decompensation in patients with history of prior decompensation using appropriate Propensity Score Inverse Probability Weighting • A few regimens show slight association with the outcome of interest, but may be due to

RBV effect. • Use of RBV is associated with increased odds of developing new decompensating events

Logistic regression using Firth penalized maximum likelihood estimation was performed to determine predictors of total bilirubin increase >3 and decompensating events. Firth approach was preferred because TBIL>3 and decompensation was a very rare event in our data (2% or l )

Odds ratio estimates for new hepatic decompensation in patients with history of prior decompensation using appropriate Propensity Score Inverse Probability Weighting comparing regimen with and without addition of RBV. • Use of RBV is associated with increased odds of developing new decompensating events

among patients treated with SOF/SMV regimen • There were no patients on VKR without RBV therefore result is uninterpretable




Odds ratio estimates for new hepatic decompensation in patients with history of decompensating events using appropriate Propensity Score Inverse Probability Weighting performed separately for RBV free regimens and regimens with addition of RBV. • Specific regimen is not associated with the outcome of interest.

• There were no patients on VKR without RBV therefore result is uninterpretable





Summary

• Overall, the event rate for hyperbilirubinemia and hepatic decompensation was low, even among advanced cirrhosis

• Features of advanced liver disease including cirrhosis, baseline elevation of bilirubin, decreased albumin, prior decompensation were associated with increased risk

• Among patients with a change in bilirubin, <20% had a concomitant increase in ALT, usually associated with a clinical event, although hepatotoxicity could not be excluded in a minority of these patients

• Despite changes in bilirubin and new hepatic decompensation, treatment regimens were infrequently discontinued and patients often achieved SVR

• In multivariable analyses of hepatic decompensation across multiple regimens, ribavirin was modestly associated with increased risk

• Specific DAA regimens were not associated with hepatic decompensation

Caveats and Take Home Messages • HCV-TARGET is continues to enroll and acquire new data so

this presentation is only a snapshot • Differentiating hepatotoxicity from natural course of disease in

an observational, non-randomized study is a complex undertaking for which multiple factors must be explored

• Clinicians should monitor closely all patients at risk for decompensating events (i.e. those with baseline evidence of advanced liver disease) so that appropriate investigation and interventions can be performed in a timely manner

• Next steps:

– Analyze data within eDISH protocol and other analysis tools to further explore associations of HCV therapy and clinical events

– Attempt to standardize the information provided for patients with advanced liver disease when a clinical event suspected/attributed to medication is voluntarily reported

Center Investigator Univ of Florida Nelson/Morelli UNC Fried Saint Louis University Di Bisceglie Scripps Pockros University of Colorado Everson University of Cincinnati Sherman University of Chicago Reau/Jensen Harvard Afdhal Indiana University Kwo Puerto Rico Rodriquez-Torres Duke Muir University of Massachusetts Szabo Virginia Commonwealth Sterling University of Miami Schiff Johns Hopkins Sulkowski Yale Lim AshevilleGastro Harlan Cornell Jacobson University of Pennsylvania Reddy UCSD Kuo Henry Ford Health System Gordon Emory University Spivey University of Michigan Lok Toronto Western Hospital Liver Center Feld Columbia Medical Center Brown Goethe University Hospital, Frankfurt Zeuzem RWTH University Hospital, Aachen Trautwein Sheba Medical Center, Israel Ben-Ari

Center Investigator Atlanta Med Center Pearlman The Methodist Hospital, Houston, Texas Galati

Mayo- Rochester Watt

Mayo- AZ Vargas Orlando Immunology Center Hinestrosa

Virginia Mason Bredfeldt

Wilmington Gastro Meyer

HRH Care Kerr

University of Minnesota Hassan

Minnesota Gasto Coleman Smith

Lake Shore Gastro- Chicago community O'Riordan

UCSF Terrault

Liver Institute of Virginia/Bon Secours Shiffman

Hannover Medical School Manns

Dartmouth Dickson

Baylor O’Leary

University of Nebraska Malliard

Mountainview Medical Center Ramani

Massachusetts General Chung

Liver Wellness Center Arkansas Williams/Frazier

Baptist Medical Center Elbeshbeshy

Northwestern Levitsky

Southwest Care Center Hawkins

Thomas Jefferson University Fenkel

Sponsors: Genentech, Kadmon, Janssen, Merck, Vertex, AbbVie, Bristol Myers Squibb, Gilead, GSK

HCV-TARGET is an investigator-initiated study jointly sponsored by University of Florida (PI: Nelson), and University of North Carolina at Chapel Hill (PI: Fried). Many thanks to the staff of the Clinical and Data Coordinating Centers and investigative sites:

Sponsors: Genentech, Kadmon, Janssen, Merck, Vertex, AbbVie, Bristol Myers Squibb, Gilead, GSK

AEs Leading to Discontinuation in Previously Decompensated Patients with New Decompensating Events


RBV SOF DCV LDV/SOF PrOD RBV Total

(N=1) (N=10) (N=7) (N=5) (N=1) (N=4) (N=1) (N=29) Acute respiratory failure 0 0 0 0 0 1 0 1 Anaemia 0 1 0 0 0 0 0 1 Breast cancer metastatic 0 0 0 0 0 1 0 1 Cardiac arrest 0 2 0 1 0 0 0 3 Chest pain 0 1 0 0 0 0 0 1 Cholecystitis 0 0 1 0 0 0 0 1 Death (NOS) 0 1 0 1 0 0 0 2 Dysphagia 0 0 0 0 0 1 0 1 Failure to thrive 0 1 0 0 0 0 0 1 Gastrointestinal haemorrhage 0 0 0 1 0 0 0 1 Haemolysis 0 1 0 0 0 0 0 1 Hepatic cirrhosis 0 0 0 0 0 0 1 1 Hepatic encephalopathy 0 1 0 1 0 0 0 2 Hepatic failure 0 0 1 0 0 0 0 1 Hepatocellular carcinoma 0 0 0 0 1 0 0 1 Influenza like illness 0 0 1 0 0 0 0 1 Ischaemic stroke 0 0 1 0 0 0 0 1 Klebsiella bacteraemia 0 1 0 0 0 0 0 1 Oesophageal varices haemorrhage 0 1 0 0 0 0 0 1 Pneumonia 0 0 1 0 0 0 0 1 Renal failure 0 0 1 0 0 0 0 1 Renal failure acute 0 0 0 1 0 0 0 1 Sepsis 1 0 0 0 0 0 0 1 Septic shock 0 0 0 0 0 1 0 1 Umbilical hernia, obstructive 0 0 1 0 0 0 0 1

Michael W. Fried, M.D., FAASLD Professor of Medicine ... · Michael W. Fried, M.D., FAASLD...

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