HCV Treatment Peri-Transplant: Update Nothing to Disclose Eliana - - PowerPoint PPT Presentation

9/30/2016 1

HCV Treatment Peri-Transplant: Update

Eliana Agudelo, PA-C

Physician Assistant Viral Hepatitis Clinic, UCSF Medical Center

Stephanie Straley, PA-C

Physician Assistant Viral Hepatitis Clinic, UCSF Medical Center

Nothing to Disclose

HCV TREATMENT PERI-TRANSPLANT

Objectives

Review of the current HCV treatment options peri-transplant Review of current Direct Acting Antivirals (DAAs) Review of HCV treatment efficacy data in the post-transplant patient Review of HCV treatment special considerations in the post- transplant patient Review of HCV treatment efficacy data in the pre-transplant patient Review of HCV treatment special considerations in the pre- transplant patient

HCV TREATMENT PERI-TRANSPLANT

A Brief History of Hepatitis C Medications

1989 Hepatitis C virus identified 1997 Interferon (alfa -2a, -2b, -alfacon-1) 1998 Interferon + ribavirin 2001 Peginterferon alfa-2b (PegIntron) 2002 Peginterferon alfa-2a (Pegasys) 2002 Peginterferon + ribavirin 2011 Boceprevir (Victrelis, discontinued 2015) 2011 Telaprevir (Incivek, discontinued 2014) 2013 Simeprevir (Olysio) 2013 Sofosbuvir (Sovaldi) 2014 Sofosbuvir/ledipasvir (Harvoni) 2014 Ombitasvir/paritaprevir/ritonavir+dasabuvir (ViekiraPak) 2015 Daclatasvir (Daklinza) 2015 Ombitasvir/paritaprevir/ritonavir (Technivie) 2016 Grazoprevir/elbasvir (Zepatier) 2016 Sofosbuvir/velpatasvir (Epclusa)

HCV TREATMENT PERI-TRANSPLANT

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HCV TREATMENT PERI-TRANSPLANT

Evolution of Chronic Hepatitis C Treatment and SVR Rates That Are Achieved

1989 1991 1992 1997 1998 2001 2002

Discovery

• f Hep C

IFN-α2b IFN-α2a IFN-αcon

IFN-α2b +RBV PEG-IFN α2b+RBV

PEG-IFN α2a+RBV

NS3/4 Protease Inhibitors

2011 NS5B Polymerase Inhibitor 2013 2014 NS5A Inhibitors

SVR 16% 35% 44% 70% ≥90%

SVR: sustained virologic response = cure

HCV TREATMENT PERI-TRANSPLANT

5’ UTR region 3’ UTR region 9.6 kb RNA Polyprotein Polyprotein Processing

Core Envelope Glycoproteins Protease NS3-4A protease inhibitors

Serine Protease Helicase Serine Protease Cofactor RNA-dependent RNA polymerase

NS5B polymerase inhibitors

nucleoside analogs non- nucleoside analogs

NS3 4A NS3 NS4A C E1 E2 C E1 E2 NS4B NS4B p7 NS2 p7 NS2 NS5A NS5B NS5A NS5B Simeprevir Paritaprevir Grazoprevir Asunaprevir Sofosbuvir Dasabuvir Beclabuvir Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir

*Agents are investigational in the United States

Multi-targeted Approach for Treatment: Approved Protease, Polymerase and NS5A Inhibitors

Adapted from McGovern B, Abu Dayyeh B, and Chung

• RT. Hepatology. 2008; 48:1700-12

How to Keep the Names Straight

Look at the end of the drug’s name:

• PREvir = PRotEase inhibitor

‒ Simeprevir, paritaprevir, grazoprevir

• Asvir = NS5A inhibitor

‒ Ledipasvir, daclatasvir, ombitasvir, elbasvir, velpatasvir

• BUvir = NS5B nUcleotide/nUcleotide inhibitor

‒ Sofosbuvir, dasabuvir

HCV TREATMENT PERI-TRANSPLANT

Hepatitis C Treatment: Common Adverse Effects

Ribavirin Simeprevir Elbasvir/Graz

• previr

Sofosbuvir + Ledipasvir / Daclatasvir/ Velpatasvir Ombitasvir / Paritaprevir Ritonavir ±Dasabuvir Hemolysis

(hemolytic anemia) *

Elevated indirect bilirubin Rash Nausea Insomnia Irritability

Teratogenic

Fatigue Nausea Headache Rash Photosensitivity Elevated bilirubin Fatigue Headache Nausea Diarrhea Elevated ALT Elevated bilirubin Ledipasvir: Fatigue Headache Nausea Daclatasvir: Fatigue Headache Velpatasvir Fatigue Headache Nausea Asthenia Fatigue Nausea Pruritus Insomnia Asthenia Elevated ALT Elevated bilirubin

* Potentially dose limiting.

HCV TREATMENT PERI-TRANSPLANT

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HCV TREATMENT PERI-TRANSPLANT

Opportunities to Treat HCV: Post-Liver Transplant

Saxena V et al. Clin Liver Dis 2015 Biggins SW et al. Infect Dis Clin N Am 2006 HCV TREATMENT PERI-TRANSPLANT

Natural History of HCV Post-Liver Transplant

D Joshi et al. Nat Rev Gas Hep, 2014 HCV TREATMENT PERI-TRANSPLANT

Treatment Data Post-Transplant Summary

Study Regimen SVR12 Comment

HCV- TARGET

SOF +SMV ± RBV SOF/LDV ± RBV

88% 93 -100%

• More anemia w/ RBV w/o

SVR benefit in SIM/SOF group

• Decreased efficacy in

decomp SOLAR-1 SOF/LDV + RBV 93 – 100%

• Less efficacy with CTP B

and C ALLY-1 SOF + DAC + RBV 94%

• NS5A RAVs universal if fail
• No decomps

ANRS CULPIT SOF + DAC ± RBV 93 – 100%

• No benefit from RBV
• No decomps

CORAL-I 3D + RBV 98-100%

• F0-F2 (24 weeks)

TREATING POST-TRANSPLANT HAS HIGH EFFICACY! JUST REMEMBER CNI AND PI INTERACTIONS.

Drug-drug interactions with IS Therapeutic options

DAA Cyclosporine Tacrolimus

Healthy volunteers Adjustment Healthy volunteers Adjustment

Sofosbuvir

Not significant Not required No change Not required

Simeprevir

AUC ↑19% Not recommended AUC ↑17% Not required

Ledipasvir Velpatasvir Daclatasvir

No change Not required No change Not required

Paritaprevir Ombitasvir Dasabuvir

AUC ↑72% ↓20% ↓ a 0.5/wk

Elbasvir

• grazoprevir No change

Not required No change Not required

HCV TREATMENT PERI-TRANSPLANT

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Drug Interactions: DAAs and IS

NS5a inhibitors (--asvir) are known to inhibit P- glycoprotein and mTOR-inhibitors are substrates to P- glycoproteins

• Theoretically one would expect the plasma levels of mTOR-

inhibitor to increase, but by what magnitude there is no published data.

• Clinically, this has been observed.
• No clinical actionable dose adjustments/ recommendations

regarding co-administration of m-TOR inhibitors (e.g. sirolimus, everolimus) and available DAAs .

HCV TREATMENT PERI-TRANSPLANT

Risk of Immune Graft Dysfunction with HCV Treatment

The risk of developing acute and chronic rejection was a high with interferon (immune-modulator).

Treatment with DAA therapies have been clinically associated with immune graft dysfunction

• Transplant recipients treated with DAA regimens exhibit increased

metabolism of IS.

• It is postulated that the rapid hepatic recovery after viral clearance

leads to improved drug metabolism.

• This observation suggests that attention needs to be given to IS

management on treatment and maintenance of target levels be closely monitored to avoid rejection episodes as patients clear HCV.

HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT

Coadministration of Harvoni and Epclusa with acid- reducing agents

aEg, aluminum and magnesium hydroxide. bEg, famotidine. cEg, omeprazole.

Ledipasvir and velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease the concentration of ledipasvir and velpatasvir. It is recommended to separate antacid and HARVONI or EPCLUSA administration by 4 hours

Antacidsa

H2-receptor antagonists may be administered simultaneously with or 12 hours apart from HARVONI or EPCLUSA at a dose that does not exceed doses comparable to famotidine 40 mg twice daily

H2-receptor antagonistsb

Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions Coadministration of omeprazole or other proton-pump inhibitors is not recommended with EPCLUSA

• If it is considered medically necessary to coadminister,

EPCLUSA should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton-pump inhibitors has not been studied

Proton-pump inhibitorsc

HCV TREATMENT PERI-TRANSPLANT

pH-Based Interactions: Acid-Reducing Agents

Perpetrator Object AUC, % Cmax, % SOF/VEL (fasted) simultaneous with FAM 40mg SOF ↔ ↔ GS-331007 ↔ ↔ VEL ↔ ↔ SOF/VEL (fasted) 12 h after FAM 40mg SOF ↔ ↓23 GS-331007 ↔ ↔ VEL ↔ ↔ SOF/VEL (fasted) simultaneous with OME 20mg SOF ↓29 ↓34 GS-331007 ↔ ↔ VEL ↓37 ↓37 SOF/VEL (fasted) 12 h after OME 20mg SOF ↓44 ↓45 GS-331007 ↔ ↔ VEL ↓56 ↓57 SOF/VEL (fed) 2 h after OME 20mg SOF ↔ ↓16 GS-331007 ↔ ↔ VEL ↓37 ↓48 SOF/VEL (fed) 4 h before OME 20mg SOF ↔ ↓21 GS-331007 ↔ ↔ VEL ↓26 ↓33 SOF/VEL (fed) 4 h before OME 40mg SOF ↔ ↓30 GS-331007 ↔ ↔ VEL ↓53 ↓56

• Administration of SOF/VEL with FAM 40 mg simultaneously or staggered by 12 hours resulted in no clinically

relevant change in SOF/VEL PK

• SOF/VEL exposures are lower when co-administered with a PPI under fasting conditions

Mogalian, EASL, 2016, Presentation # FRI-168; Mogalian E, et al., ASCPT 201, PI050 FAM=famotidine; OME=omeprazole

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HCV TREATMENT PERI-TRANSPLANT

Preemptive HCV Therapy (“CRUSH”)

Phase 2, multicenter, open-label study in US (CRUSH-C) Key eligibility criteria: Chronic HCV GT 1 or 4 Receipt of organ from an anti-HCV negative donor No concurrent HIV or HBV No prior exposure to HCV NS5A inhibitors Creatinine clearance ≥30 mL/min at screening and transplant Patients that relapse are eligible to receive LDV/SOF for 12 weeks

Verna E, Am Transplant Congress, 2016

1 Week 4 Week 16 Day −1

SVR12 N=16 1 dose LDV/SOF

Liver Transplant

HCV TREATMENT PERI-TRANSPLANT

Preemptive Therapy: LDV-SOF for 4 Weeks Virologic Responses

1 2 3 4 5 6 7

• 1

1 3 5 7 14 21 28

HCV RNA (log10 IU/mL)

Days

<LLOQ

LDV/SOF

Pre-transplant

14/16 Overall

1 discontinued Week 1 1 relapse

*Patient with relapse was retreated with LDV/SOF for 12 weeks and achieved SVR12

All patients achieved HCV RNA < LLOQ by day 14 of treatment

Verna E, Am Transplant Congress, 2016 HCV TREATMENT PERI-TRANSPLANT

Preemptive Antiviral Therapy: Summary

Preliminary data of antiviral therapy in the immediate post-LT period suggests treatment is safe and well- tolerated

Selected patients studied to date Important to have adequate renal function

SOF plus NS5Ai may be preferred:

Avoidance of RBV Avoidance of PI (as liver function may be variable early post-LT)

Preemptive therapy with potent DAA combo may offer

• pportunity to significantly shorten therapy AND

prevent HCV disease recurrence

HCV TREATMENT PERI-TRANSPLANT

Opportunities to Treat HCV Pre-Liver Transplant

Saxena V et al. Clin Liver Dis 2015 Biggins SW et al. Infect Dis Clin N Am 2006

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Pre-Liver Transplant HCV Treatment Evaluation

Two Questions when evaluating each patient: 1. When should patient receive HCV treatment (3 options)? Try to cure before transplant Treat peri-transplant (“CRUSH” protocol) Treat post-transplant 2. If to be treated, what regimen(s) would be best? Assessment of patient:

• Does patient have a living donor? Can we time the transplant?
• Does patient have compensated or decompensated liver disease?
• Does the patient have HCC?
• Does patient have renal disease?

HCV TREATMENT PERI-TRANSPLANT

Pre-Liver Transplant HCV Treatment Evaluation

Two Questions when evaluating each patient: 1. When should patient receive HCV treatment (3 options)? Try to cure before transplant Treat peri-transplant (“CRUSH” protocol) Treat post-transplant 2. If to be treated, what regimen(s) would be best? Assessment of patient:

• Does patient have a living donor? Can we time the transplant?
• Does patient have compensated or decompensated liver disease?
• Does the patient have HCC?
• Does patient have renal disease?

HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT

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HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT

DAA Primary Metabolic Pathway Suitable in Patients With Cirrhosis CP-A CP-B CP-C Suitable if Renal Impairment Sofosbuvir Renal Yes Yes Yes

Not if CrCl < 30 mL/min

Daclatasvir Hepatic Yes Yes Yes

Yes*

Simeprevir Hepatic Yes No No

Not if CrCl < 15 mL/min

Paritaprevir/ri tonavir Hepatic Yes No No

Yes*

Ledipasvir or velpatasvir Hepatic Yes Yes Yes

Yes*

Ombitasvir Hepatic Yes No No

Yes*

Dasabuvir Hepatic Yes No No

Yes*

Ribavirin Renal Yes Yes Yes

Yes, adjusted

Drug Choices Limited in Patients With Hepatic +/- Renal Impairment

*Not studied in dialysis patients

Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clin Pharm 2014. P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German et al. AASLD 2013. Abstract 467. Kirby R, et al. 8th International Workshop on Clinical Pharmacology of Hepatitis Therapy PO20

Pre-Liver Transplant HCV Treatment Evaluation

Two Questions when evaluating each patient: 1. When should patient receive HCV treatment (3 options)? Try to cure before transplant Treat peri-transplant (“CRUSH” protocol) Treat post-transplant 2. If to be treated, what regimen(s) would be best? Assessment of patient:

• Does patient have a living donor? Can we time the transplant?
• Does patient have compensated or decompensated liver disease?
• Does the patient have HCC?
• Does patient have renal disease?

HCV TREATMENT PERI-TRANSPLANT

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HCV TREATMENT PERI-TRANSPLANT

HCV Infected Listed Patients

Saxena V et al. Clin Liver Dis 2015

Listed Has Living Donor

• Compensated w/HCC
• Decompensated

No Living Donor

• Compensated w/HCC

No Living Donor

• Decompensated

HCV TREATMENT PERI-TRANSPLANT

HCV Infected Listed Patients

Saxena V et al. Clin Liver Dis 2015

Listed Has Living Donor

• Compensated w/HCC
• Decompensated

1. Peri-transplant treatment (“CRUSH” protocol) OR

• 2. Treat Post-transplant

HCV TREATMENT PERI-TRANSPLANT

Peri-transplant (“CRUSH” protocol)

• High efficacy rates
• Shorter overall duration of

treatment = more cost- effective

• Only living donor transplant

has predictable transplant timetable

• Getting medications authorized

may be difficult

• Antacid therapy adjustments

required

• May be challenge in patients

with renal impairment

HCV TREATMENT PERI-TRANSPLANT

HCV Infected Listed Patients

Saxena V et al. Clin Liver Dis 2015

Listed No Living Donor

• Compensated w/HCC
• 1. Treat to cure prior to transplant

OR

• 2. Treat Post-transplant

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HCV TREATMENT PERI-TRANSPLANT

New Rules for HCC Prioritization

For any HCC exception application submitted on or after October 8, 2015:

• First 6 months, must be registered at their calculated MELD score
• At 6 months, get exception points to MELD score of 28
• HCC exception score will be capped at 34

In light of Share-35 policy, cap of 34 disadvantages HCC patients At our center, patients without live donor options are waiting 18 – 24 months with delist risk ranging up to 40% We are forced to think of ways to shorten time on the wait list

OPTN/UNOS Website, accessed 2016 Mehta N et al. Liver Transpl 2013 HCV TREATMENT PERI-TRANSPLANT

Treat to cure HCV Listed Patient with Compensated Cirrhosis (i.e. HCC) Before Transplant

• Treatment highly effective and

relatively easy

• Eliminates risk of HCV recurrence in

graft

• May reduce risk of cirrhosis

complications/death before transplant and reduce risk of decompensation with local HCC treatments

• HCV cure doesn’t prevent need for

transplant and may lengthen wait list time (due to removing HCV + donor as option)

• If not cured, viral resistance possible and

may impact future treatment success

HCV TREATMENT PERI-TRANSPLANT

HCV Infected Listed Patients

Saxena V et al. Clin Liver Dis 2015

Listed No Living Donor

• Decompensated
• 1. Treat to cure prior to transplant

OR

• 2. Treat Post-transplant

HCV TREATMENT PERI-TRANSPLANT

Treatment Data Decompensated ASTRAL-4: SOF/VEL ± RBV

Curry MP et al. NEJM 2015

• 267 treatment naive or experienced

G1–6 with Child B cirrhosis

• 65% treatment experienced
• MELD <15 = 95%
• Ascites 65–75%; encephalopathy

58–66%

Wk 0 Wk 12 Wk 24 Wk 36 SVR12 SOF/VEL n=90 SVR12 SOF/VEL n=90 SVR12 SOF/VEL + RBV n=87

Breakthrough, n

• 1

1

• 1

1

• Relapse, n

11 2 7 5 1 3 6 1 4

• LTFU, n

1

• 3

1

• 3
• Death, n

3 2 2 2 2

• 1
• 1
• 1

83 88 50 100 94 96 85 100 86 92 50 86 20 40 60 80 100 Overall G1 G3 G2, 4, and 6 SVR12 (%) SOF/VEL 12 wk SOF/VEL+RBV 12 wk SOF/VEL 24 wk 75/ 90 82/ 87 77/ 90 60/ 68 65/ 68 65/ 71 7/ 14 11/ 13 6/ 12

G2 4/4 G4 4/4 G2 4/4 G4 2/2 G2 3/4 G4 2/2 G6 1/1

Safety d/c due to AE 3%; death 3% (9) AE more frequent with RBV Fatigue (29%); nausea (23%); HA (22%); anemia (13%; 31% in RBV arm) RBV dose: Hb <10 = 23%; Hb <8.5 = 7% RBV decreased in 37% and d/c in 17% Bili <3 x ULN

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HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT

Change in CPT Class From Baseline to Follow-up Week 4

All Cirrhotic Subjects (CPT A, B, or C) Treated with SOF-LDV plus RBV

Baseline CPT A (5–6) n=73 B (7–9) n=100 C (10–12) n=54 Follow-up Week 4 CPT A (5–6) 67 (96) 31 (35) 2 (5) B (7–9) 3 (4) 57 (65) 20 (48) C (10–12) 20 (48) No assessment 3 12 12

Manns, M et al, EASL 2015 HCV TREATMENT PERI-TRANSPLANT

MELD Purgatory?

HCV TREATMENT PERI-TRANSPLANT

Treat HCV Listed Patient with Decompensated Cirrhosis

Saxena V et al. Clin Liver Dis 2015

• Treatment highly effective and

safety signals more related to natural history of disease than drug

• HCV cure stabilizes liver

disease, keeping them alive on the wait-list

• Possible improvement in liver

function/delisting in some patients

• HCV cure stabilizes / improves

MELD, but perhaps not to pre-liver disease quality of life (MELD Purgatory)

• HCV cure to delisting is infrequent
• No access to HCV+ donors
• If not cured, viral resistance possible

and may impact future treatment success

SUMMARY

Today, treating HCV before or after transplant is relatively safe and easy

• Caution with IS, antacids, anemia and renal disease; watch for rejection

SVR rates in post transplant and compensated cirrhotics is high but lower in decompensated (Child’s class B and C) patients. Treatment decisions for patients on the wait list is complicated and many factors must be taken into account Treatment of the pre/ post transplant patient is a actively evolving field.

• Recommendations may change as new data emerge and new DAAs

become available.

• Evaluation by and communication with the transplant center is key when

treating these patients.

HCV TREATMENT PERI-TRANSPLANT