TreatmentStrategiesforChronicHCVinCKDG4andG5

IncludingDialysisPatientsChiu-ChingHuangTheKidneyInstituteandDivisionofNephrologyChinaMedicalUniversityandHospitalsTaichung,Taiwan

KDIGO

Outlines

• HistoricalprogressofHCVtreatmentsoverpast25years

• OverviewforcurrentHCVtreatmentsinCKDstage1-3B

• CurrentHCVtreatmentinCKDstage4-5(includingHDandPD)

•  Guidelines

KDIGO

Outlines

• HistoricalprogressofHCVtreatmentsoverpast25years

• OverviewforcurrentHCVtreatmentsinCKDstage1-3B

• CurrentHCVtreatmentinCKDstage4-5(includingHDandPD)

•  Guidelines

KDIGO

Evolution of Chronic Hepatitis C Treatment

Modified from: S. Baid-Agrawal et al. American Journal of Transplantation (2014)14: 2206–2220

95

75

55

42

34

SVR (%)

KDIGO

The Evolution of HCV DAA Therapy

Curability of HCV

without IFN

Frequent curability of

diverse populations without IFN

Simeprevir or Sofosbuvir

with IFN (GT1)

2015 2011 2012 2013 2014

Telaprevir and

Boceprevir (GT1)

Daclatasvir +

Asunaprevir (Japan)

Daclatasvir + Sofosbuvir

(Europe)

Ledipasvir/ Sofosbuvir (GT1)

Harvoni

Ombitasvir/ Paritaprevir/RTV (GT4)

+ Dasabuvir (GT1) Viekirax

Simeprevir + Sofosbuvir (GT1)

First approved IFN-free RxSofosbuvir

(sovaldi)+ RBV (GT2,3)

Daclatasvir + Sofosbuvir

(GT3) (2016: GT1)

Interferon Era 2016

Grazoprevir/ Elbasvir (GT1,4) Zepatier

1991-

Sofosbuvir/ Velpatasvir

(all genotypes) Epclusa

References in slidenotes.

2017

Sofosbuvir/Velpatasvir/ Voxilaprevir

(DAA failures, all genotypes)

Vosevi

Glecaprevir/ Pibrentasvir

(all genotypes) Maviret

?

Lok A, et al. N Engl J Med. 2012;366;216-224.

Poole RM. Drugs. 2014;74:1559-1571. Cortez KJ, et al. Ther Adv Chronic Dis. 2015;6:4-14 Webster DP, et al. Lancet. 2015;385:1124-1135. Pol S, et al. Hepat Med. 2016;8:21-26.

KDIGO

MetabolismofDirectActingAnti-viralAgents(DAAs)• Sofosbuvir-based Renal excretion • Non-Sofosbuvi-based Hepatic metabolism Biliary excretion KDIGO

OverviewoftheMetabolismofDAAs

DrugSaf.2016Jul;39(7):589-611 **Bothelbasvirandgrazoprevirarehepaticallymetabolizedand<1%isrenallyextracted;soareglecaprevirandpibrentasvir

KDIGO

Kim SM et al. The Korean Journal of Internal Medicine. 2018; 33: 607-678

Pan-genotypic regimen

Non-Sofosbuvir based

Sofosbuvir based

KDIGO

UTR = untranslated region; IRES = internal ribosome entry site. Moradpour and Penin. Curr Top Microbiol Immunol. 2013;369:113; Parfieniuk et al. World J Gastroenterol. 2007;13:5673.

HCV DAA class Nomination Drugs of class

NS3/4A protease inhibitor (PI) PREVIRAsunaprevir, Paritaprevir, Grazoprevir, Glecaprevir

NS5A inhibitor ASVIRDaclatasvir, Ombitasvir, Elbasvir, Ledipasvir, Pibrentasvir, Velpatasvir

NS5B polymerase inhibitor BUVIR Sofosbuvir, Dasabuvir

McCauley JA, et al. Curr Opin Pharmacol 2016;30:84-92 Eltahla AA, et al. Viruses 2015;7:5206-24 Gitto S, et al. J Viral Hepat 2017;24:180-6

BMSDualASU/DAC

PrOD Zepatier(EBR/GZR)

Harvoni(LED/SOF)

MaviretGLE/PIB

ClassesofHCVDirectActingAntiviralAgents

KDIGO

*Triple combination therapy efficacious but not useful due to the efficacy of double combination regimens; †TN patients without cirrhosis or with compensated (Child–Pugh A) cirrhosis; ‡TN and TE patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with HCV RNA ≤800,000 IU/mL (5.9 Log10 IU/mL); §TN and TE patients without cirrhosis; ǁTN and TE patients with compensated (Child–Pugh A) cirrhosis; ¶TN patients without cirrhosis or with compensated (Child–Pugh A) cirrhosis with HCV RNA ≤800,000 IU/mL (5.9 Log10 IU/mL) EASL CPG HCV. J Hepatol 2018;69:461–511.

Genotype Pangenotypic regimens

Genotype-specific regimens

(Epclusa) SOF/VEL

(Marviret) GLE/PIB

SOF/VEL/ VOX SOF/LDV GZR/EBR

OBV/PTV/r + DSV

1a Yes Yes No* Yes† Yes‡ No

1b Yes Yes No* Yes Yes Yes

2 Yes Yes No* No No No

3 Yes§ Yes Yesǁ No No No

4 Yes Yes No* Yes† Yes¶ No

5 Yes Yes No* Yes† No No

6 Yes Yes No* Yes† No No

KDIGO

TreatmentRecommendationsforTNorTEPatientswithCHCwithCompensated(Child–PughA)Cirrhosis

EASL CPG HCV. J Hepatol 2018;69:461–511.

GT SOF/VEL GLE/PIB SOF/VEL/VOX SOF/LDV GZR/EBR OBV/PTV/r + DSV

1a

TN 12 weeks 12 weeks No 12 weeks 12 weeks (HCV RNA ≤800,00 IU/mL) No

TE 12 weeks 12 weeks No No 12 weeks (HCV RNA ≤800,00 IU/mL) No

1b TN 12 weeks 12 weeks No 12 weeks 12 weeks 12 weeks

TE 12 weeks 12 weeks No 12 weeks 12 weeks 12 weeks

2 TN 12 weeks 12 weeks No No No No

TE 12 weeks 12 weeks No No No No

4 TN 12 weeks 12 weeks No 12 weeks 12 weeks (HCV RNA

≤800,00 IU/mL) No

TE 12 weeks 12 weeks No No No No

5 TN 12 weeks 12 weeks No 12 weeks No No

TE 12 weeks 12 weeks No No No No

6 TN 12 weeks 12 weeks No 12 weeks No No

TE 12 weeks 12 weeks No No No No

KDIGO

Outlines

• HistoricalprogressofHCVtreatmentsoverpast25years

• OverviewforcurrentHCVtreatmentsinCKDstage1-3B

• CurrentHCVtreatmentinCKDstage4-5(includingHDandPD)

•  Guidelines

KDIGO

AASLD and IDSA

AASLD and IDSA; last updated May 24, 2018 www.hcvguidelines.org

KDIGO

Outlines

• HistoricalprogressofHCVtreatmentsoverpast25years

• OverviewforcurrentHCVtreatmentsinCKDstage1-3B

• CurrentHCVtreatmentinCKDstage4-5(includingHDandPD)

•  Guidelines

KDIGO

OlderRegimen:InterferonsKDIGO

Summary for IFN Use in CKD

•  Mild renal impairment: no dose adjustment needed •  Moderate renal impairment: - Standard doses for pegIFN alfa-2a. - Peg IFN alfa-2b : 25% dose reduction - Ribavirin doses: 400 mg QOD if tolerated •  Severe renal impairment, including ESRD - Peg-IFN alfa-2a : 135 mcg per week - Peg-IFN alfa-2b : 50% dose reduction - Ribavirin dose : 200 mg/day or TIW if tolerated ( Starting at 200 mg TIW and titrating up to 200mg/day ) - May consider holding Ribavirin if Hb drop > 2 g/dL

16

Peg-IFN Use for Chronic Hepatitis C

KDIGO

Peg IFN α-2a ± Low Dose Ribavirin for Treatment of Chronic HD Patients with HCV-genotype 1 and 2 : HELPER-1 & 2 Trial

•  HELPER-1 & 2 trial: Hemodialysis Low Dose Peginterferon and Ribavirin for HCV-1 and HACV-2 Patients

•  Design: randomized, multicenter, open-label trial, 2-arm parallel, active control trial (n = 205 for HLEPER-1 and n = 172 for HELPER-2) in 8 academic centers in Taiwan

Dialysis HCV patients

Peg-IFN α-2a 135 µg/week + Ribavirin 200 mg/qd

Peg-IFN α-2a 135 µg/week

SVR24

SVR24

041224or48Weeks

•  Genotype 1: 48

weeks

•  Genotype 2: 24

weeks

LiuCH,etal.AnnInternMed2013;159:729-38

51 64

36 33

0 20 40 60 80

100

RVR SVR24

Peg-IFN + low-dose RBV Peg-IFN

HELPER-1

53/103 37/102 66/103 34/102

p < 0.001

p = 0.035

64 74

63 44

0 20 40 60 80

100

RVR SVR24

Peg-IFN + low-dose RBV Peg-IFN

HELPER-2

55/86 54/86 64/86 38/86

p < 0.001p = 0.99

Liu CH et al ,Gut 2015;64:303-11 17

KDIGO

Hemoglobin Levels (HELPER-1) Significant group differences for hemoglobin levels at week 8 of treatment (P < 0.001) and at week 4 post-treatment follow-up (P < 0.001). Tx: treatment, FU: follow-up.

Combination Therapy Cause Lower Hb Levels Than Monotherapy HELPER-1 & 2

18

Hemoglobin Levels (HELPER-2) Significant group differences for mean haemoglobin levels from week 8 of treatment (P <0.001) until week 4 post-treatment follow-up (P=0.006). Tx: treatment; FU: follow-up

Liu et al ,Gut 2015;64:303-11

KDIGO

DirectActingAnti-viralAgentsDAACombinationforCKDG4-5KDIGO

UTR = untranslated region; IRES = internal ribosome entry site. Moradpour and Penin. Curr Top Microbiol Immunol. 2013;369:113; Parfieniuk et al. World J Gastroenterol. 2007;13:5673.

HCV DAA class Nomination Drugs of class

NS3/4A protease inhibitor (PI) PREVIRAsunaprevir, Paritaprevir, Grazoprevir, Glecaprevir

NS5A inhibitor ASVIRDaclatasvir, Ombitasvir, Elbasvir, Ledipasvir, Pibrentasvir, Velpatasvir

NS5B polymerase inhibitor BUVIR Sofosbuvir, Dasabuvir

McCauley JA, et al. Curr Opin Pharmacol 2016;30:84-92 Eltahla AA, et al. Viruses 2015;7:5206-24 Gitto S, et al. J Viral Hepat 2017;24:180-6

BMSDualASU/DAC

PrOD Zepatier(EBR/GZR)

Harvoni(LED/SOF)

MaviretGLE/PIB

ClassesofHCVDirectActingAntiviralAgents

KDIGO

Daclatasvir/Asunaprevir for HCV-1b Patients Four Studies with HD Patients (6M)

•  Patients (n = 402): receiving DCV/ASV between September 2014 and September 2015; 258 patients with SVR12 analyzed

82.3 81 90

100

0

20

40

60

80

100

eGFR ≥ 60 eGFR < 60 eGFR < 30 eFGR < 10

Comparison of SVR12 (%) by eGFR

133/175 51/63 9/10 6/6

•  Design: DCV/ASV 24 weeks for HCV-1b patients on hemodialysis (n = 28), with propensity score-matched 56 patients without renal dysfunction

100 94.6

0 25 50 75

100

HD No renal impairment

DCV/ASV for 24 weeks

•  Design: DCV/ASV 24 weeks for HCV-1 patients on hemodialysis (n = 21)

28/28 53/56

95.2

0 25 50 75

100

HD

DCV/ASV for 24 weeks

20/21

Kondo C, et al. APASL 25th Annual Meeting, Tokyo, Japan, 2016 Suda G, et al. J Gastroenterol 2016;51:733-40

Toyoda H, et al. J Gastroenterol 2016;51:741-7 Kawakami Y, et al. J Viral Hepat 2016;23:850-6

SV

R12

(%)

SV

R12

(%)

100 96.2

0 25 50 75

100

HD No renal impairment

DCV/ASV for 24 weeks

•  Design: DCV/ASV 24 weeks for HCV-1b patients on hemodialysis (n = 18), with 54 patients without renal dysfunction, excluding baseline NS5A RAVs

SV

R12

(%)

18/18 52/54

21

N=258 SVR 12

Dual

From Liu CH

KDIGO

Paritaprevir/Ritonavir/Ombitasvir+DasabuvirforHCV-1PatientswithSevereRenalImpairmentorESRDRUBY-I(3D)

PatientCharacteristics 3D ± RBV (N=20) Age, years, median (range) 60(49-69)

Male, n (%) 17(85)

Black race, n (%) 14(70)

Hispanic or Latino ethnicity, n(%) 3(15)

BMI, median, kg/m2 (range) 30.5(20.3-37.1)

GT1a; n (%) 13(65)

IL28B non-CC, n (%) 14(70)

Hemoglobin, g/dL, median (range) 12.0(9.5-16.6)

History of DM, n (%) 11(55)

HCV RNA, log10 (IU/mL), median (range) 6.6(5.5-7.6)

Fibrosis stage*, n(%) F0-F1 10(50)

F2 6(30)

F3 4(20)

CKD stage, n (%) 4 (eGFR 15-30 mL/min/1.73m2) 7(35)

5 (eGFR <15 mL/min/1.73m2 or requiring dialysis) 13(65)

On dialysis, n (%) 13(65)

eGFR, mL/min/1.73m2, median (range) 10.9(5.4-29.9)

Creatinine, mg/dL, median (range) 6.2(2.2-10.8)

* Biopsy: 5 patients; Fibroscan: 10 patients; Fibrotest: 5 patients.

95 100 90 90 95

0 20 40 60 80

100

RVR EOTR SVR4 SVR12 mITT SVR12

19/20 20/20 18/20 18/20 18/19

2 patients failed to achieve SVR12 •  1 GT1a patients died 14 days after the EOT due to LV

systolic dysfunction, which was not attributed to DAA or RBV

•  1 GT1a patients relapsed at PTW4 ⁻  49 y/o, black male, on dialysis [F3 fibrosis, IL28B CT,

BMI: 37 kg/m2] ⁻  Compliance: < 92% for OBV/PTV/r, DSV ⁻  RAVs: no [at baseline], NS3 (D168V) and NS5A

(Q30R) [at relapse]

Pockros PJ, et al. Gastroenterology 2016;150:1590-8 22

Single Arm, Multicenter Study, N= 20 (GT1a N=13 GT1b N=7)

3D

From Liu CH

KDIGO

Paritaprevir/Ritonavir/Ombitasvir+DasabuvirforHCV-1PatientswithSevereRenalImpairmentorEnd-StageRenalDisease:RUBY-I(3D)

EventGT1a (N = 13) OBV/PTV/r/DSV RBV

GT1b (N = 7) OBV/PTV/r/

DSV

Any AE 13 (100) 6 (86)

Any AE related to DAAs 8 (62) 2 (29)

SAE 3 (23) 1 (14)

AE leading to Tx DC 0 0

AE leading to RBV reduction 9 (69) NA

Death 1 (8) 0

AEs ≥15%ofpatientsAnemia 9 (69) 0

Fatigue 5 (38) 2 (29)

Diarrhea 4 (31) 1 (14)

Nausea 5 (38) 0

Headache 3 (23) 0

Peripheral edema 1 (8) 2 (29)

EventGT1a (N = 13) OBV/PTV/r/DSV RBV

GT1b (N = 7) OBV/PTV/r/

DSV

Hemoglobin

Grade 2 (8-10 g/dL) 7 (54) 2 (29)

Grade 3 (6.5-8 g/dL) 1 (8) 0

Total bilirubin

Grade 2 (1.5-3X ULN) 2 (15) 0

Grade 3 (3-10X ULN) 0 0

ALT

Grade 3 (5-20X ULN) 0 0

AST

Grade 3 (5-20X ULN) 0 0

•  AE were primarily mild or moderate •  9 SAE reported in 4 patients [1 with fatal outcome]: cardiac chest

pain (Pt 1); diskitis and respiratory failure (Pt 2); partial small intestinal obstruction, pleural effusion, dysphagia, LV systolic dysfunction, cardiac arrest (Pt 3); loss of consciousness (Pt 4)

•  4 patients required EPO for anemia; none received blood transfusion

Pockros PJ, et al. Gastroenterology 2016;150:1590-8 23

3D

From Liu CH

KDIGO

Pockros et alGastroenterology 2016;150:1590–1598

3D

KDIGO

Grazoprevir/ElbasvirinTreatment-NaïveandTreated-ExperiencedPatientswithHCV-1InfectionandCKDC-SURFER(RCT)

•  Aim: to evaluate grazoprevir (GZR) + elbasvir (EBR) in HCV-infected patient with Ccr < 30 mL/min, including patients on hemodialysis [< 1% of GZR and EBR is renally excreted]

Roth D, et al. Lancet 2015;386:1537-45

GZR 100 mg / EBR 50 mg

Placebo GZR 100 mg / EBR 50 mg

041216202428Weeks

GZR 100 mg / EBR 50 mg (PK)

n = 111

n = 113

n = 11

SVR12

SVR12

SVR12

Design: randomized, parallel-group, placebo-controlled trial; stratified by DM and hemodialysis Inclusion: HCV GT1, treatment-naïve or experienced, CKD stage 4/5 (± hemodialysis dependence)

•  CKD stage 4: eGFR 15-29 mL/min/1.73 m2 •  CKD stage 5: eGFR < 15 mL/min/ 1.73 m2

•  Target 20% non-hemodialysis patients •  Compensated cirrhosis allowed HD dependent: 75% 25

Zepatier

From Liu CH

N=224

KDIGO

Grazoprevir/ElbasvirinPatientswithHCV-1InfectionandChronicKidneyDisease:RCT,C-SURFER(12w)

Roth D, et al. Lancet 2015;386:1537-45

99 94

0 25 50 75

100

Modified full analysis set

Full analysis set

SVR12 (%)

115/116 115/122

1 relapse 1 relapse 6 Dc Tx unrelated to Tx

66 90 100 100 99

0 20 40 60 80

100

TW2 TW4 TW12 (EOT)

FW4 FW12 (SVR12)

HCV RNA < LLOQ (%)

81/122 109/121 119/119 118/118 115/116

Relapse: GT1b; BL NS5A RAV (L31M); at failure NS3 RAV (V170I), NS5A RAV (L31M, Y93H)

Character n/N SVR12 (%) [95% CI]

All patients 115/116 99.1 [95.3, 100]

Cirrhosis

Yes 6/6 100 [54.1, 100]

No 109/110 99.1 [95.0, 100]

HCV genotype

1a 61/61 100 [94.1, 100]

1b 54/55 98.2 [90.3, 100]

Race

White 58/59 98.3 [90.9, 100]

African American 51/51 100 [93.0, 100]

Asian 5/5 100 [47.8, 100]

Previous treatment

Naïve 96/96 100 [96.2, 100]

Experienced 19/20 95.0 [75.1, 100]

CKD stage

4 22/22 100 [84.6, 100]

5 93/94 98.9 [94.2, 100]

Hemodialysis

Yes 86/87 98.9 [93.8, 100]

No 29/29 100 [88.1, 100]

26

Zepatier

From Liu CH

N=224

KDIGO

Grazoprevir/Elbasvir in Patients with HCV-1 Infection and CKD Low Rate of Adverse Events

Roth D, et al. Lancet 2015;386:1537-45

GZR/EBR (n = 111)

Placebo (n = 113)

Difference (%) [95% CI]

AEs, n (%) 84 (75.7) 95 (84.1) -8.3 [-18.9, 2.2]

Headache 19 (19.1) 19 (16.8) 0.3 [-9.6, 10.4]

Nausea 17 (15.3) 18 (15.9) -0.6 [-10.3, 9.1]

Fatigue 11 (9.9) 17 (15.0) -5.1 [-14.1, 3.7]

Insomnia 7 (6.3) 12 (10.6) -4.3 [-12.2, 3.2]

Dizziness 6 (5.4) 18 (15.9) -10.5 [-19.1, -2.6]

Diarrhea 6 (5.4) 15 (13.3) -7.8 [-16.1, -0.2]

Serious AEs, n (%) 16 (4.4) 19 (16.8) -1.5 [-11.2, 8.1]

Dc due to AE, n (%) 0 (0) 5 (4.4) -4.4 [-10.0, 1.0]

Deaths, n (%) 1 (0.9) 3 (2.7) -1.8 [-6.7, 2.5]

•  AE reported in 10% of patients in either treatment group •  1 SAE in GZR/EBR group was considered drug-related (elevated

lipase level) •  1 patient in GZR/EBR group died of cardiac arrest and 3 patients in

placebo group died of aortic aneurysm, pneumonia and unknown cause

GZR/EBR (n =

111) Placebo (n = 113)

Difference (%) [95% CI]

ALT, n (%)

1.1-2.5X baseline 2 (1.8) 36 (31.9) -30.1 [-39.4, -21.5]

> 2.5-5X baseline 1 (0.9) 6 (5.3) -4.4 [-10.3, 0.2]

> 5X baseline 0 (0) 1 (0.9) -1.1 [-6.3, 3.2]

AST, n (%)

1.1-2.5X baseline 4 (3.6) 38 (33.6) -30.0 [-39.6, -21.0]

> 2.5-5X baseline 0 (0) 4 (3.5) -4.6 [-11.3, -0.2]

Total bilirubin, n (%)

> 2.5-5X baseline 1 (0.9) 3 (2.7) -1.8 [-6.7, 2.5]

> 5X baseline 0 (0) 0 (0) 0.0 [-3.3, 3.4]

ALP, n (%)

1.1-2.5X baseline 42 (37.8) 36 (31.9) 6.0 [-6.6, 18.3]

> 2.5-5X baseline 0 (0) 0 (0) 0.0 [-3.3, 3.4]

•  Bilirubin level elevations were isolated and not associated with increased AST//ALT 27

Zepatier

From Liu CH

KDIGO

DirectActingAnti-viralAgentsPan-genotypicDAAforCKDG4-5KDIGO

Characteristic G/P N = 104

Male, n (%) 79 (76) Black, n (%) 26 (25) Age, median years (range) 57 (28 ̶ 83) BMI, median kg/m2 (range) 26 (18 ̶ 45) IL28B non-CC, n (%) 80 (77) HCV RNA, median log10 IU/mL (range) 5.9 (3.4 ̶ 7.5)

PPI use, n (%) 43 (41) HCVgenotype 1a/1b/other 23 (22)/29 (28)/2 (2) 2 17(16)3 11(11)4/5/6 20(19)/1(1)/1(1)Priortreatmenthistory Naïve 60(58)IFN/Peg-IFN±RBV 42(40)SOF+RBV±Peg-IFN 2(2)Compensatedcirrhosis Yes 20(19)No 84(81)CKDstage Stage4 13(12)Stage5 91(88)Hemodialysis 85(82)

Pan-genotypicGlecaprevir/Pibrentasvir(G/P)forHCVGT1-6PatientswithCKD:EXPEDITION-48w(GT1),12w(non-GT1)

•  EXPEDITION-4: phase 3, multicenter, open-label study for treatment-naïve or -experienced (SOF/PR also included) patients with chronic HCV GT1-6 infection with/without cirrhosis (Child-Pugh A) and CKD stage 4 or 5

Gane E, et al. AASLD 67th Annual Meeting, Boston, MA, 2016

GLE/PIB SVR12

0 12 Week

98 100

0 20 40 60 80

100

ITT mITT

SVR12 (%)

102/104 102/102

mITT: ITT population excluding 2 non-virologic failure (1 discontinuation, 1 LTFU)

Event, n (%) G/P (N = 121) Any AE 74 (71)

AEs leading to study drug discontinuation 4 (4)

Serious AEs 25 (24) Serious AEs related to DAA 0 Death 1 (1) AEs occurring in ≥ 10% total patients

Pruritus 21 (20)

Fatigue 15 (14)

Nausea 12 (12) Hemoglobin Grade ≥ 3 (6.5-8.0 g/dL) 5 (5)

AST Grade ≥ 2 (3-20X ULN) 0

ALT Grade ≥ 2 (3-20X ULN) 0

Total bilirubin Grade ≥ 3 (3-10X ULN) 1 (1)

29

Maviret N=104

KDIGO

Edward Gane et al. N Engl J Med 2017;377:1448-55

KDIGO

Edward Gane et al. N Engl J Med 2017;377:1448-55

KDIGO

Li et al. Liver International. 2017;37:974–981.

Screen 606 publications N=264 patients, 11 study

KDIGO

Li et al. Liver International. 2017;37:974–981.

KDIGO

Li et al. Liver International. 2017;37:974–981.

SVR12 Rate: •  Overall 93.2% •  Sofosbuvir-based 89.4% •  Non- Sofosbuvir-based 94.7%

KDIGO

Li et al. Liver International. 2017;37:974–981.

Nausea,vomiting,diarrhea19.3%Anemia22.6%Fatigue18.1%Headache14.4%

KDIGO

Comparison of DAA Efficacy in TaiwanKDIGO

N=19549

NHRI 2018 Report: SVR 12 after DAA Treatment

KDIGO

Drug-drug Interactions of DAAKDIGO

ZepatierHarvoni

DDIsbetweenHCVDAAsandCVDrugs

EASLRecommendationsonTreatmentofHepatitisC2018.EuropeanAssociationfortheStudyoftheLiver.JHepatol.2018;April9.

MaviretNo clinically significant interaction expected

Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring

These drugs should not be coadministered

KDIGO

DDIs for Oral contraceptives, Acid reducing agents and Lipid lowering agents

Lipitor

Crestor

Atorvastatin: The dose should not exceed a daily dose of 20 mg when co-administered The dose of Rosuvastatin should not exceed a daily dose of 10 mg

KDIGO

GuidelinesKDIGO

AASLD and IDSA; last updated May 24, 2018 www.hcvguidelines.org

EBR/GZR

GLE/PIB

AASLD and IDSA

Maviret

Zepatier

KDIGO

EASLGuidelinesforuseofDAAinCKDG4-5Patients

Elbasvir / Grazoprev

ir

ProD (3D)

Glecaprevir / Pibrentasvir

Sofosbuvir based

All genotype

8 or 12 weeks **

1a*, 4 12 weeks

1b 12 weeks 12 weeks *HCV RNA level ≤800,000 IU/ml

**Sofosbuvir should be used with caution in patients with an eGFR <30 ml/min/1.73 m2 or with end-stage renal disease, only if an alternative treatment is not available, because no dose recommendation can currently be found

Journal of Hepatology 2018

KDIGO

APASL recommendation for the treatment regimens of patients with HCV and severe impaired renal function

Treatment regimens for patients with HCV infection and severe renal impairment: APASL recommendation compared with those of EASL or AASLD-IDSA KDIGO

KDIGO guidelines 2018 Chapter 2: Treatment of HCV infection in patients with CKD

www.kisupplements.org

KDIGO

• 2.1: We recommend that all CKD patients infected with HCV be evaluated for antiviral therapy (1A).

2.1.1: We recommend an interferon-free regimen (1A). 2.1.2: We recommend that the choice of specific regimen be based on HCV genotype (and subtype), viral load, prior treatment history, drug–drug interactions, glomerular filtration rate (GFR), stage of hepatic fibrosis, kidney and liver transplant candidacy, and comorbidities (1A). 2.1.3: Treat kidney transplant candidates in collaboration with the transplant center to optimize timing of therapy

KDIGO

• 2.2: We recommend that patients with GFR > 30 ml/min per 1.73 m2 (CKD G1–G3b) be treated with any licensed direct acting antiviral (DAA)-based regimen (1A)

•  2.3: Patients with GFR < 30 ml/min per 1.73 m2 (CKD G4–G5D) should be treated with a ribavirin-free DAA-based regimen as outlined in Figure 1

KDIGO

KDIGO, Kidney International Supplements (2018) 8, 91–165

KDIGO

• 2.5: All treatment candidates should undergo testing for HBV infection prior to therapy (Not Graded)

• 2.5.1: If hepatitis B surface antigen [HBsAg] is present, the patient should undergo assessment for HBV therapy (Not Graded)

• 2.5.2: If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, monitor for HBV reactivation with serial HBV DNA and liver function tests during DAA therapy (Not Graded).

KDIGO

Conclusions

• Currentnon-sofosbuvirbasedDAAcombinationswithoutribavirinareeffectiveandwell-toleratedforHCVinfectedpatientswithCKDstage4-5,includinghemodialysis

KDIGO

51

Thank You for Your Attentions

KDIGO

KDIGO guidelines 2018 Chapter 2: Treatment of HCV infection in patients with CKD

www.kisupplements.org

KDIGO

FOURMAJORCLINICALSTUDIESINHCVINFECTEDCKDG4ANDG5(INCLUDINGDIALYSIS)PATIENTS

C-SURFER GT1 SVR 99% GZR/EBRN=116

ASU/DAC SVR 81-88%

N=73

RUBY GT1 SVR 90%

3DN=20

EXPEDITION-4 GT1-6 SVR 98%

GLE/PIBN=104

KDIGO

F. Fabrizi et al. Journal of Viral Hepatitis, 2014, 21, 681–689

KDIGO

Anti-HCV prevalence in dialysis patients ranges between 0.7 – 18.1% in Asia-Pacific countries1

KDIGO

First-generation IFN-free

First-generation pan-genotypic

IFN-free

Next-generation pan-genotypic

IFN-free

GLE/PIB (Maviret)

Sofosbuvir/Velpatasvir/

Voxilaprevir(Vosevi)

2014 2016 2017

Evolution and Optimization of HCV Therapy

8 wks for all DAA-naive non-cirrhotic patients

Pan-genotypic

Once daily, RBV-free

Minimal diagnostic tests/ on-treatment monitoring

GT1 & GT4 12~24 wks +/- RBV

Efficacy against common NS3 or NS5A mutations

High Efficacy

Cured more than >6,800 patients in Taiwan

SVR12: 99.2% (2017/8 updated)

High efficacy, irrespective of baseline patient and viral factors

Sofosbuvir/ Velpatasvir (Epclusa) Viekira / Exviera (3D)

KDIGO

FOURMAJORCLINICALSTUDIESINHCVINFECTEDCKDG4ANDG5(INCLUDINGDIALYSIS)PATIENTS

C-SURFER GT1 SVR 99% GZR/EBRN=116

ASU/DA SVR 81-88%

N=73

RUBY GT1 SVR 90%

3DN=20

EXPEDITION-4 GT1-6 SVR 98%

GLE/PIBN=104

KDIGO

DirectActingAntiviralAgents(DAAs)forCKDpatients

Stage of CKD DCV ASV SOF SOF/LDVPTV/r/

OBV+DSVEBR/GZR GLE/PIB

Stage 1 GFR > 90 ml/min

O O O O O O

Stage 2 (mild) GFR 60–89 ml/min

O O O O O O

Stage 3 (moderate) GFR 30–59 ml/min

O O O O O O

Stage 4 (severe) GFR 15–29 ml/min

O ONot

priorityNot

priorityO O

Stage 5 (renal failure) GFR<15 ml/min or dialysis O O

Not priority

Not priority

O O

O: No dosage adjustment. N: No dose recommendation can be given.

Kwo PY, Badshah MB. Curr Opin Organ Transplant 2015;20:235-41

Dosage and administration

DCV/ASV No dosage adjustment mentioned in the prescription information.

SOF/LDV

Mild or moderate renal impairment: no dosage adjustment No dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. Severe renal impairment or ESRD: no dosage recommendation The safety and efficacy of HARVONI have not been established in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD.

PRV/r/OBV + DBV

Mild, moderate or severe renal impairment: no dosage adjustment No dosage adjustment of VIEKIRA PAK is required in patients with mild, moderate or severe renal impairment. ESRD: no dosage adjustment No dosage adjustment of VIEKIRA PAK is required in patients with ESRD.

EBR/GZR or GLV/PIB

Mild, moderate or severe renal impairment: no dosage adjustment No dosage adjustment of ZEPATIER/ Maviret is required in patients with mild, moderate or severe renal impairment. ESRD: no dosage adjustment No dosage adjustment of ZEPATIER is required in patients with ESRD.

58From Liu CH

KDIGO

•  NS3/4A protease-inhibitor not be used : Child-Pugh B/C cirrhosis •  Sofosbuvir: should be used with caution for eGFR < 30 mL/min/1.73m2 if no alternative

treatment option available

EASL.JHepatol2018;69:461-511

Contraindications to HCV Therapy

KDIGO

Li et al. Liver International. 2017;37:974–981.

KDIGO

RenalFunctionOutcomeAfterDAAKDIGO

SOF-basedDAATreatmentisAssociatedwitheGFRDeclineinCKDG3b-5Patients

Saxena et al. Liver Int. 2016; 36: 807–816

eGFR< 40 N=73

KDIGO

MEDIAN eGFR* DURING TREATMENT AND FOLLOW-UP IN PATIENTS WITH CKD STAGE 3 AT BASELINE

*eGFR assessed using the Modification of Diet in Renal Disease equation EOT, end-of-treatment; FW12, follow-up week 12 CKD 3 defined as baseline eGFR <60 to ≥30 mL/min/1.73m2

eGFR

(mL/

min

/1.7

3m2 )

Baseline EOT FW1220

40

60

80

1. Reddy KR, et.al. HEPATOLOGY 2016;64(S1);443A Abstract 889

Median eGFR remained stable in patients with HCV infection and CKD 3, after receiving EBR/GZR for 8-18 weeks1

Zepatier

eGFR 30-60 N=32

KDIGO

SOF-based DAA treatment is associated with eGFR decline among CHC patients, especially among those with CKD risk factors. Renal function should be monitored under and after SOF-based DAA treatment.

eGFR>60 (CKD stage G1-3), N=814 Mallet, V., et al. "Estimated glomerular filtration rate variations and direct acting antivirals treatment for chronic hepatitis C: a retrospective longitudinal study." Journal of Hepatology 68 (2018): S22.

KDIGO