Case Discussion: Redefining Best Practices in HCV Management in the Transplant Setting This activity...

Case Discussion: Redefining Best Practices in HCV Management in the Transplant Setting

This activity is supported by an independent educational grant from Gilead Sciences

clinicaloptions.com/hepatitisTransforming HCV Management in the Pretransplant and Posttransplant Settings

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Faculty

Program Director

Norah Terrault, MD, MPH Professor of Medicine and SurgeryDepartment of MedicineDivision of GastroenterologyUniversity of California, San FranciscoSan Francisco, California

Additional Faculty

Jean C. Emond, MDThomas S. Zimmer Professor of Surgery Executive Director, Transplant InitiativeNewYork-Presbyterian HospitalColumbia University Medical CenterNew York, New York

Paul Y. Kwo, MDProfessor of MedicineMedical Director of TransplantationDivision of Medicine/Gastroenterology/ HepatologyIndiana University School of MedicineIndianapolis, Indiana


Case 1: 62-Yr-Old Female With Cirrhosis and HCC GT1a HCV, IL28B CT

Previous treatment

– Standard IFN for 1 yr followed by 5 yrs of maintenance IFN

– Most recently triple therapy with pegIFN/RBV + boceprevir in 2012: nonresponder

History of varices (on nadolol) but no prior bleeding

No ascites, hepatic encephalopathy, or infectious complications

3-mm HCC treated with TACE and RFA without residual HCC on latest CT

History of depression, on citalopram


Case 1: Laboratory Analysis and Transplantation Listing CBC

– WBC 3.4

– Hct 32.1, Hb 10.9

– Platelets 76, INR 1.4

Chemistries

– Albumin 3.1

– Total bilirubin 1.4

– AST 45, ALT 29

– Na 139

– Creatinine 0.95

Current HCV RNA 35,079,260 IU/mL

Listed for LT

– Blood type A

– MELD 22 with exception status, native MELD 11

At this transplant program, the average MELD for LT for blood group A is 31


Panel Discussion: Should Further Tests Be Ordered? Some experts would order additional testing if simeprevir

is being considered

– Resistance testing, given the failure on boceprevir and the potential for cross resistance

– Q80K, since SVR rates are reduced with simeprevir for patients having this polymorphism


Panel Discussion: What HCV Treatment Approach Would You Recommend? 2 potential approaches

– Viral suppression

– Try for SVR

Sofosbuvir + RBV for long-term suppression or sofosbuvir + simeprevir ± RBV for SVR were approaches favored by the panel

Child’s-Pugh classification should be considered when making choice to ensure medications are safe for the individual patient


Case 1: Follow-up

Treatment deferred until exception MELD = 29, then started on sofosbuvir 400 mg/day and RBV 800 mg/day

HCV RNA results

– Baseline: 35 million IU/mL

– Wk 1: 14,334 IU/mL

– Wk 2: 2274 IU/mL

– Wks 4, 6, and 8: < 43, DETECTED

Tolerating well except for mild anemia

– RBV reduced to 600 mg/day for Hct decline to 29 at Wk 4

– MELD upgraded to 31 (average MELD at LT in this region)


On-Treatment VR With SOF + RBV in Patients With CTP-A and CTP-B Cirrhosis

Afdhal N, et al. EASL 2014. Abstract O68.

HC

V R

NA

< L

LO

Q (

%)

100

80

60

40

20

0Wk 2 Wk 4 Wk 8 Wk 12

56

100 94

Wk 24

CTP ACTP B

44

75

100 100 10094 93

N = 25


Panel Discussion: What Would You Do Next? Some experts would consider adding an additional agent

to try to achieve SVR prior to transplantation

– Simeprevir or daclatasvir (compassionate use)

Timing of expected transplantation an important consideration


Days HCV RNA Negative Prior to LT and Rate of Recurrence

Median days TND (P < .001)No recurrence: 95.0Recurrence: 5.5

No recurrence (n = 30)

> 30 days TND

Recurrence (n = 10)

Curry MP, et al. ILTS 2014. Abstract O-137.

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480Days With HCV RNA Continuously TND Prior to Liver Transplant


DAA Primary Metabolic Pathway

Suitable in Patients With CirrhosisCTP-A CTP-B CTP-C

Suitable if Renal

Impairment

Sofosbuvir Renal Yes Yes Yes Not if CrCl < 30 mL/min

Simeprevir Hepatic Yes No No Not if CrCl < 15 mL/min

Asunaprevir Hepatic Yes No No Unknown

ABT-450/RTV Hepatic Yes No No Unknown

Ledipasvir Hepatic Yes Yes Yes Unknown

Ombitasvir Hepatic Yes No (as combo)

No (as combo)

Unknown

Daclatasvir Hepatic Yes Yes Yes Yes

Dasabuvir Hepatic Yes No No UnknownBifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clinical Pharm 2014. Abstract 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. Clinical Pharm 2013. Abstract PO20.

Studies on PK/PD in Patients With Renal and Hepatic Impairment


Panel Discussion: New Considerations With All-Oral Therapy in the Pretansplant Setting All-oral therapy offers safe, effective option for wait-list

patients

Best outcomes with sofosbuvir + RBV pre-LT achieved if HCV RNA is undetectable for > 4 wks prior to LT

– Approved for treatment up to 48 wks

Lack of data on safety in patients with advanced renal and liver disease may limit treatment options

– Sofosbuvir not recommended if CrCl < 30 mL/min

– Simeprevir not recommended if CTP B or C disease

– Daclatasvir (compassionate access) may be option if advanced liver or renal disease

Case 2


Case 2: 59-Yr-Old Male With GT3 HCV Who Received Liver Transplantation 59-yr-old male with cirrhosis due to HCV

Underwent transplantation with deceased donor (age 50 yrs, CDC high risk)

GT3A HCV, IL28B CT, treatment naive

Past history

– CAD, s/p LAD stent placement 2013

– Hypertension and dyslipidemia

Early posttransplantation course complicated by early mild rejection, managed with increase in tacrolimus dose


Case 2: Posttransplantation Course

At Month 3, increase in liver tests noted

Test Wk 10 Wk 12 Wk 13 Wk 14

AST 59 136 209 279

ALT 47 123 154 155

Total bilirubin 1.3 0.8 4.7 8.3

Alk phos 53 341 355 340

Creatinine 1.12 -- 2.39 2.01


Case 2: Additional Laboratories

HCV RNA 29 million IU/mL

Na 136, K 4.8, urea 28, Cr 2.01, WBC 1.9, Hb 9.6, platelets 141, INR 1.0, glucose 100, albumin 2.9, cryoglobulins negative

CMV DNA negative

HBcAb, IgM negative

HBsAg negative

HBcAb positive, HBV DNA negative

HAV Ab, IgM negative

HEV Ab negative


Case 2: Follow-up Liver Biopsy

Ultrasound results

– Heterogeneity of liver parenchyma, no biliary dilatation, hepatic and portal veins patent, spleen normal size, no fluid collections

Liver transplantation biopsy

– Chronic hepatitis consistent with recurrent hepatitis C with septal fibrosis and features suggestive of an aggressive/fibrocholestatic variant; no evidence of rejection


Panel Discussion: Management Approach for Severe Recurrence For a patient with genotype 3, options are limited

– Sofosbuvir plus ribavirin or sofosbuvir plus daclatasvir (compassionate use)

Additional options could be considered for genotype 1


Sofosbuvir + Ribavirin for Advanced Disease Post-LT: Compassionate Access N = 104, GT1-4

72 completed 24-48 wks of treatment

– 7 d/c due to AEs, 12 repeat LT, and 13 deaths

Median MELD: 15 (range:6-43)

– Included patients with FCH

Median mos from LT: 17 (range: 1-262)

Forns X, et al. EASL 2014. Abstract O62.

EOT SVR12

HC

V R

NA

< L

LO

Q (

%)

100

80

60

40

20

0

87

62

81/93 53/85

Patients were excluded from this analysis if received an LT (n = 8 at EOT; n = 12 at SVR12)

and/or no data were available (n = 3 at EOT; n = 7 at SVR12).


Clinical Case: Fibrosing Cholestatic Hepatitis

0 4 8/0 4 8 12 16 20 24/0 4 8

HC

V R

NA

(IU

/mL

)

Biliru

bin

Leve

l (mg

/dL

)

108

106

104

102

LOD

Wk

25

20

15

10

5

1

HCV RNA: 541,000,000 IU/mL

Fibrosing Cholestatic Hepatitis Diagnosed 2 Mos After LT

TE: 9.6 kPaLT TE: 17 kPa Ascites No Ascites

*Bilirubin normalized at Wk 9.

After LT SOF + RBV TreatmentPost-

treatmentFollow-up

HCV RNA Bilirubin level

*

Forns X, et al. AASLD 2013. Abstract 1084.


Panel: New Considerations With All-Oral Therapy for Severe Recurrence PegIFN is best avoided in the early post-LT period

SOF + RBV offers pangenotypic option for FCH and safety supported by compassionate access experience

Other oral combinations likely in future, but applicability will be depend on safety and PK/PD in moderate to severe hepatic impairment (typical of FCH)

GT3 recurrence has limited options for treatment

– SOF + RBV ± pegIFN

– Combination of SOF + NS5A inhibitors (LDV or DCV) can be considered in future

– Protease inhibitors not effective

Case 3


Case 3: 63-Yr-Old Male Transplanted 13 Yrs Ago With Cirrhosis on Recent Biopsy 63-yr-old male with transplanted HCV in 2001

Recent liver biopsy shows recurrent disease with stage 4 fibrosis (cirrhosis) and grade 2 necroinflammation

Previous post-LT treatment

– PegIFN/RBV (null response, stopped after 3 mos)

– PegIFN/RBV + telaprevir x 48 wks (response with relapse)

– No treatment in past yr

Returns to discuss treatment options in light of newly approved therapies

GT1b HCV, IL28B TT


Case 3: History and Laboratories

Past history

– Hypertension, controlled

– Diabetes, HbA1c 7.6

– Mild renal insufficiency, creatinine 1.6

– Depression, stable on citalopram

– No history of rejection

Immunosuppression: tacrolimus 1 mg BID with trough level 4.6

Laboratories

– WBC 4.3, Hb 11, platelets 74, INR 1.2

– AST 70, ALT 65, alk phos 104, total bilirubin 1.0, albumin 3.4

– Cr 1.6, Na 139, K 3.8

– HCV RNA 1.2 million IU/mL

– NS3A/4 GenoSure: negative for resistance mutations


New HCV Regimens Under Study in Posttransplantation Patients

1. Samuel D., et al. EASL 2014. Abstract P1232. 2. Forns X, et al. EASL 2014. Abstract O62. 3. Kwo PY, et al. EASL 2014. Abstract O114. 4. Pellicelli A, et al. Dig Liver Dis. 2014;46:923-927.


HCV DAAs and ImmunosuppressivesDrug–Drug Interactions Drug Class Drug DDI With CNIs

Yes No

Protease inhibitors

Boceprevir ✔

Telaprevir ✔

Simeprevir CsA ✔ Tac ✔

ABT-450/RTV ✔

Nucleoside Sofosbuvir ✔

Nonnucleoside Dasabuvir ✔

NS5A Ledipasvir ✔

Daclatasvir ✔

Ombitasvir ✔ (in combo) ✔

Tischer S, et al. J Hepatol. 2014;60:872-884.


Case 3: Initial Treatment and Results

Started on sofosbuvir 400 mg/day + simeprevir 150 mg/ day with planned treatment duration of 12 wks

HCV RNA on treatment

– Baseline: 1,357,200

– Wk 2: 3100

– Wk 4: < 25, DETECTED




COSMOS: Sofosbuvir + Simeprevir ± RBV in Patients With Cirrhosis

Lawitz E, et al. EASL 2014. Abstract 165.

Null responders

Treatment naive

Relapse in 3 pts in Cohort 1

and 1 pt in Cohort 2; all

with GT1a and Q80K

polymorphism at baseline

24 Wks 12 Wks Overall

SV

R12

(%

)

n/N =

100

80

60

40

20

0SMV/SOF

+ RBVSMV/SOF SMV/SOF

+ RBVSMV/SOF SMV/SOF

± RBV

9/9 3/3 4/4 5/5 4/5 6/6 4/4 2/3 21/22 16/17

100 100 100 100

80

100 100

67

96 94


Panel Discussion: New Considerations With All-Oral Therapy for Posttransplant IFN-free therapies offer advantages over previous

pegIFN/RBV/ PI therapy

– High efficacy and significantly improved tolerability

Anticipate more IFN-free and RBV-free options in near future (within 2014 in the US)

As choices increase, the factors that are likely to influence treatment choices are:

– DDIs

– Previous treatment experience (resistance)

– Availability/cost


Summary

Renal and hepatic clearance of DAAs

– Impact on management/treatment choice pretransplantation and posttransplantation

NS5A inhibitors and polymerase inhibitors do not have clinically significant DDIs with immunosuppression

– Simeprevir has DDI with cyclosporine, but not tacrolimus

IFN-free therapy add a much greater degree of safety and tolerability than previous therapies

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Case Discussion: Redefining Best Practices in HCV Management in the Transplant Setting This activity...

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