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HCV RNA monitoring in the era of new potent HCV therapies Johannes Vermehren, Frankfurt am Main, Germany

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Page 1: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

HCV RNA monitoring in the era of new potent HCV therapies

Johannes Vermehren, Frankfurt am Main, Germany

Page 2: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

HCV RNA monitoring in the era of IFN-based tx.

IFN-based treatments:

• low efficacy (40-50% in genotype 1) • long treatment durations (16-72 weeks) • multitude of side effects associated with both IFN + RBV

• many contraindications

• risk of hepatic decompensation in those with advanced disease

Advantages of HCV RNA monitoring:

• adherence

• response prediction

• efficacy – futility

Page 3: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

AU Neumann et al. Science 1998

Viral Kinetics Modeling

Free virion clearance rate (c)

Infected cell death rate (δ)

Page 4: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

RVR is the best predictor for SVR

MW Fried et al. J Hepatol 2011

Page 5: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Response guided treatment

Page 6: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Approved DAAs (as of April 2016)

Simeprevir

Ledipasvir

Sofosbuvir

Dasabuvir

Ombitasvir

Daclatasvir Sofosbuvir

Daclatasvir

Paritaprevir/r

Simeprevir Sofosbuvir

Ledipasvir Sofosbuvir Dasabuvir

Ombitasvir Paritaprevir/r

Grazoprevir Elbasvir

Velpatasvir

Page 7: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

99 97 94 91 94 93 96

0

20

40

60

80

100

LDV/SOF 12WLDV/SOF+RBV 12WLDV/SOF 8W LDV/SOF 8WLDV/SOF 12W LDV/SOF 8WLDV/SOF 12W

SVR

(%)

209 214

211 217

202 215

n N

Afdhal et al. NEJM 2014; Kowdley et al. NEJM 2014; Backus et al. AASLD 2015; Buggisch et al. EASL 2016

1070 1171

1718 1830

SVR rates in treatment-naive non-cirrhotic GT1 patients ION-1 und ION-3 Department of DHC-Register Veterans Affairs

632 677

1023 1066

Efficacy of current DAA regimens...in clinical trials

Page 8: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

99 97 94 91 94 93 96

0

20

40

60

80

100

LDV/SOF 12WLDV/SOF+RBV 12WLDV/SOF 8W LDV/SOF 8WLDV/SOF 12W LDV/SOF 8WLDV/SOF 12W

SVR

(%)

209 214

211 217

202 215

n N

Afdhal et al. NEJM 2014; Kowdley et al. NEJM 2014; Backus et al. AASLD 2015; Buggisch et al. EASL 2016

1070 1171

1718 1830

SVR rates in treatment-naive non-cirrhotic GT1 patients ION-1 und ION-3 Department of DHC-Registry Veterans Affairs

632 677

1023 1066

Efficacy of current DAA regimens...in real world

Page 9: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Efficacy of current DAA regimens...in clinical trials

Horizontal dashed line indicates the overall SVR12 rate in patients receiving the label-recommended regimen,97%. BMI, body mass index in kg/m2; PR, peginterferon/ribavirin

N Reau et al. EASL 2015

SVR by Baseline Host Characteristics 3D phase III trials

Page 10: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Efficacy of current DAA regimens...in real world

H Hinrichsen et al. EASL 2016

Page 11: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

EASL Guidelines

EASL Clinical Practice Guidelines 2015; J Hepatol 2015

Page 12: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

B Maasoumy, J Vermehren in prep.

Commercial Assays

Assay Manufacturer Extraction device Amplification device

IVD approval status

Limit of detection (LOD)

in IU/mL

Range of quantification

in IU/mL COBAS TaqMan HCV Test v2.0 For Use With The High Pure System (HPS/CTM)

Roche Molecular Diagnostics

High Pure System (manual) COBAS TaqMan CE (Europe)

FDA (USA)

8.8-9.3 (GT1; Europe)

20 (all GTs; USA)

25-3.91×108 (GT1; Europe)

25-3×108 (all GTs; USA)

COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 (CAP/CTM)

Roche Molecular Diagnostics COBAS AmpliPrep COBAS TaqMan CE (Europe)

FDA (USA) 15 15-1.0x108

RealTime HCV Abbott Molecular m2000SP m2000RT CE (Europe) FDA (USA) 12 12-1.0x108

Artus HCV QS-RGQ Assay Qiagen QIAsymphony SP/AS Rotor-Gene Q CE (Europe) 36.2 67.6-17.7x106

Versant HCV 1.0 kPCR assay Siemens Healthcare kPCR Sample Prep

kPCR Amplification and Detection (AD)

Module CE (Europe) 15 15-1.0x108

Page 13: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

6 Million Baseline Viral Load: ION-3

IM Jacobson et al. AASLD 2014

Page 14: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

6 Million Baseline Viral Load

FDA data, available online

Page 15: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

R Brown et al. EASL 2015

• Overall, screening and baseline HCV RNA measurements differed by>1M IU/mL in 55%, by >2M IU/mL in 35%, and by >3M IU/mL in 26% of patients

• Intrapatient variability in HCV RNA (IU/mL) increased with increasing screening HCV RNA; in patients with a screening HCV RNA above 2M IU/mL, 53% differed by >2M IU/mL

17% of patients had discordant baseline and screening HCV RNA

Baseline vs. Screening HCV RNA

Page 16: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

6 Million Baseline Viral Load: CAP vs. ART assay

J Vermehren, B Maasoumy et al. CID 2016

Page 17: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Abbott GmbH

6 Million Baseline Viral Load

HPS/CTM (IU/mL)

ART Calculation IU/mL

CAP/CTM Calculation

IU/mL

Treatment Duration

1.000.000 ~350.000 ~500.000 8 Wks.

2.000.000 ~700.000 ~900.000 8 Wks.

4.000.000 ~1.400.000 ~1.600.000 8 Wks.

6.000.000 ~2.000.000 ~2.300.000 8-12 Wks

8.000.000 ~2.800.000 ~2.900.000 8-12 Wks

Page 18: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

N Terrault et al. AASLD 2015

6 Million Baseline Viral Load: Real Life adherence

SVR

12 (%

)

242/254 127/131 119/123 LDV/SOF 8 Wochen

LDV/SOF 12 Wochen

215/215 127/131 187/192

97% 97%

323 patients qualified for 8 weeks but only 41% received 8 weeks

8 wks. LDV/SOF in the TARGET HCV Study (Real World Obervational Cohort)

Page 19: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

100 94 96 98 98 96

0

20

40

60

80

100

Week 1 Week 2 Weeks 4-6

SVR1

2 (%

)

CirrhosisNo Cirrhosis

On-treatment HCV RNA – predictive of SVR?

SVR by Time of First Undetectable HCV RNA (<15 IU/mL; n=2022 patients) Pooled Analysis from 6 clinical trials (3D regimen)

M Sulkowski et al. AASLD 2014

Page 20: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

On-treatment HCV RNA – predictive of SVR?

S Sidharthan et al. CID 2015

HCV RNA at EoT not predictive of Relapse: what is observed may be non-infectious HCV RNA

Page 21: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

B Maasoumy, J Vermehren et al. J Hepatol 2016

On-treatment HCV RNA: difficult-to-treat patients

Week 2 viral load during SOF/RBV therapy in HCV GT3 SVR vs. Relapse

Page 22: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

On-treatment HCV RNA: difficult-to-treat patients

Pts. with cirrhosis and detectable HCV RNA at wks. 1 and 2 had significantly higher SVR rates if treated for 24 vs. 12 weeks

TM Welzel et al. AASLD 2014

Page 23: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Potential for RGT in patients with cirrhosis

P Ferenci et al. J Hepatol 2015

Page 24: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Can Viral Kinetics be used for RGT?

L Rong et al. Plos Comput Med 2013

Phases of viral decline affected by the effectiveness of therapy in blocking intracellular viral production and assembly/secretion.

Free virion clearance rate (c)

Infected cell death rate (δ)

Blockage of intracellular secretion (εs)

Page 25: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

RGT with DAAs

GK Lau et al. AASLD 2015

Page 26: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Model predicts no patient hits cure boundary <10-4

GK Lau et al. AASLD 2015

Page 27: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

H Dahari et al. J Hepatol 2016

Projected duration according to model

n=23: 6 wks.; n=16: 8 wks.; n=7: 10 wks.

Page 28: HCV RNA monitoring in the era of new potent HCV · PDF fileHCV RNA monitoring in the era of new potent HCV therapies ... HCV RNA monitoring in the era of IFN-based tx. IFN-based treatments:

Conclusions

• There is no statistical evidence for 6 million cut-off

• Intra-patient and inter-assay variability may influence the decision on treatment duration

• DAA treatment leads to fast, triphasic HCV RNA decline • On-treatment HCV RNA not predictive of SVR in most patients treated with

highly potent DAA regimens

• VL monitoring not required in the majority of patients

• Cirrhotic patients have slower early HCV RNA kinetics

• Early on-treatment HCV RNA may be useful for further optimization of treatment duration in difficult-to-treat patient populations

• Ultra-fast cure is not predicted by current models

• Non-infectious HCV RNA enhanced by DAAs vs. restored immune control of virus


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