Managing DAA treatment failure and Drug Resistance in Clinical Practice

Vicente Soriano Infectious Diseases Unit

La Paz University Hospital Madrid, Spain

The HCV cure equation

SVR Viral

replication suppression

Time length

Immune response

trigger = + X

DAA

Activity

time

40%

95%

HCV

Hepatocyte

RNA

Pro Cytosol

Pol

CD4+

T-lymphocyte

HIV

RNA

RT

Nucleus

Integration

Provirus Pro

Differences in the replication life cycle of HIV and HCV

Classification of recommended DAA (2016)

NS3 protease inhibitors

NS5A inhibitors

Nucleos(t)ide polymerase inhibitors

Non-nucleoside polymerase inhibitors

Simeprevir Asunaprevir Paritaprevir Grazoprevir

Ledipasvir Daclatasvir Ombitasvir Elbasvir Velpatasvir

Sofosbuvir Beclabuvir Dasabuvir

Squares record co-formulations or co-packaged medications. Velpatasvir will soon replace ledipasvir.

Real-World Experience with LDV-SOF in G1 Treatment Naïve,

Non-Cirrhotics with HCV-RNA <6 million IU/mL

N=131 N=192 N=254 N=456

42% 60% 50% 8-wks eligible but received 12 wks

N=1014 N=808

Curry M, Abstract 1108 Backus L, Abstract 93 Terrault, Abstract 94

DAA real world experience

TRIO (n=1685)

Spain (n=363)

Male 58% 75%

Advanced liver fibrosis 30% (cirrhosis) 48%

Elevated ALT ? 83%

Baseline HCV-RNA > 6 log 21% (>6 million) 59%

HCV genotype 4 0 (67% G1a ) 15%

HIV coinfection 7% 31%

Ribavirin added 5% 38%

Prior interferon failure ? 49%

SOF+LDV 88% 80%

SVR 96% 97%*

Afdhal et al. AASLD 2015 Arias et al. AVT (in press) *Analysis per protocol (no ITT)

Sustained virological response (n=352)

Treatment failure (n=11)

p

Male gender, n (%) 255 (73.1) 9 (81.8) 0.7

Elevated ALT, n (%) 311 (81.2) 10 (90.9) 0.8

IL28B-CC, n (%) 97 (27.1) 2 (18.2) 0.9

Advanced liver fibrosis, n (%) 146 (42.8) 10 (90.9) 0.003

Baseline HCV-RNA >6 log IU/mL, n (%) 225 (62.4) 6 (54.5) 0.7

Prior interferon exposure, n (%) 164 (47.2) 6 (54.5) 0.7

HIV coinfection, n (%) 91 (27.2) 7 (63.6) 0.04

HCV genotype 4, n (%) 46 (13.1) 4 (36.4) 0.05

Ribavirin added, n (%) 120 (34) 5 (45.4) 0.4

Main characteristics of the study population according to treatment outcome.

Arias et al. AVT (in press) *Analysis per protocol (no ITT)

Main baseline characteristics of chronic hepatitis C patients that experienced DAA treatment failure.

1 2 3 4 5 6 7 8 9 10 11

Age (years) 52 55 78 54 50 50 57 49 49 45 52

Gender male male male male male male male

female male

male female

ALT (IU/L) 39 87 53 64 45 30 73 70 55 69 83

Serum HCV-RNA (log IU/mL)

6.5 5.8 6.3 6.5 5.8 6.9 5.8 6.7 4.8 7.1 4.6

HCV genotype 1a 4 1b 1a 4 1a 1b 4 3 4 1b

Liver fibrosis stage (Metavir)

F4 F4 F4 F1 F4 F3 F4 F4 F4 F3 F3

IL28B polymorphisms CC CT CT CT CT CT CC CT CT TT CT

Prior interferon exposure

no no no no yes yes yes no yes yes yes

HIV coinfection yes yes no yes yes no yes yes no no yes

DAA regimen SOF/LDV/R

BV

SOF/LDV/RBV

SOF/LDV/RBV

SOF/LDV

SOF/LDV/RBV

SOF/LDV

SOF/SMV

SOF/SMV

SOF/RBV

SOF/LDV

SOF/LDV

Arias et al. AVT (in press)

Predictors of DAA treatment failure in the study population. Multivariate analysis.

Male gender (73%)

HIV coinfection (27%)

Advanced liver fibrosis (F3-F4) (43%)

Serum HCV-RNA >106 IU/mL (63%)

Interferon experience (47%)

HCV genotype 4 (13%)

treatment failure sustained virological response

Ribavirin added (34%)

p=0.04

p=0.01

1.7

2.1

odds ratio

Arias et al. AVT (In press)

Predictors of DAA failure

Baseline On-treatment

• Cirrhosis • Genotype 3 • RAVs • Prior interferon failure • Elevated serum HCV-RNA • IFNL4 unfavorable • AA ethnicity

• Drug adherence • Side effects • Drug interactions

Anecdotal SAEs with DAA

• Bradyarrithmias (and syncope) • Pulmonary arterial hypertension • Lung toxicity • Hepatotoxicity • Photosensitivity • Hyperbilirrubinemia • Hypoglycemia in diabetics on insulin • Hepatitis B reactivation

Fontaine et al. NEJM 2015; 373: 1886-8. Ahmad et al. Hepatology 2015; 62: 409-16. Dyson et al. J Hepatol 2016; 64: 234-8. Soriano et al. Hepatology (in press) Stine et al. Dig Dis Sci 2015; 60: 1031-5.

Shibata et al. Hepatology (in press) Marchan et al. J Hepatol (in press) Helmers et al. Mayo Clin Proc 2015; 90: 1294-7. Renard et al. Chest 2016; 149: e69-73. Soriano et al. Antivir Ther (in press)

Rapid HCV drop

HBV reactivation during DAA for hep C

Collins et al. Clin Infect Dis 2016 Ende et al. J Med Case Rep 2015 Takayama et al. Hepatol Res 2016 *De Monte J Clin Virol 2016

*

Difficult-to-cure HCV populations

• End-stage renal disease • Decompensated cirrhosis • Prior DAA failures • Potential drug interactions:

– HIV, psychiatric, elder, etc

• Difficult drug adherence: – homeless, illegal immigrants, jail, active IDU,

psychiatric

• Insufficient data: – Alcoholics, NASH-obese-diabetics, HBsAg+

Considerations for HCV re-treatment

• Virologic challenges: – Presence of RAVs (prior DAA failure)

– Exclude HCV genotype shift (misinterpretation)

– Exclude HCV re-infection (risk behaviors)

• Strategic management: – Adding ribavirin

– Extent the length of therapy

• Maximize drug benefit: – Avoid drug interactions (co-morbidities)

– Prevent and manage side effects

– Ensure drug adherence

How urgent is it ? Any chance to wait for better DAA?

Principles guiding selection of HCV regimens for re-treatment of prior DAA failures

NS3 protease inhibitors

Telaprevir Boceprevir Simeprevir

NS5A inhibitors

Ledipasvir Daclatasvir

NS3 protease inhibitors plus NS5A inhibitors

Paritaprevir + Ombitasvir Grazoprevir + Elbasvir

Prior DAA failure Re-treatment options

NS5A inhibitors

Ledipasvir Daclatasvir

NS3 protease inhibitors

Simeprevir

PegIFN+RBV o

Sofosbuvir + Sofosbuvir +

+ Sofosbuvir Sofosbuvir +

+ Sofosbuvir ?

HCV Drug Resistance (RAVs)

• Prevalence vary by geno/subtype and geographic region.

• Baseline RAVs may reduce SVR in some patients: – NS3 – Q80K – reduced SVR in G1a cirrhotics

– NS5A – reduced SVR in cirrhotics with prior IFN failure

• Extending the length of DAA therapy may overcome the harmful impact of baseline RAVs

• Not all RAVs are equal, “some are more equal than others” – NS3 protease – D168X

– NS5A – Y93H

– NS5B – S282T

GT 1 NS5A RAV Prevalence by Region

Using a 15% cut-off, the prevalence of NS5A RAVs was 14% in North America, 15% in Europe, 20% in Asia Pacific, and 17% in Oceania

21

Europe 25% (235/933)

USA

Canada

Puerto Rico

Belgium

Switzerland

Czech Republic

Germany

Spain

France

United Kingdom

Italy

Netherlands

Poland

China

India

Japan

Korea

Russia

Taiwan

Australia

New Zealand

Asia Pacific 26% (154/597)

Oceania 27% (115/427)

North America 25% (870/3440)

* Based on 1% cut-off

Zeuzem S, AASLD 2015. Abstract 91

LDV-SOF in Patients with and without Baseline NS5A RAVs

22

SVR

12

(%

)

Naïve & VL<6M Naive Experienced

Zeuzem S, AASLD 2015. Abstract 91

No cirrhosis

23

26/27 65/68

12 weeks 24 weeks

SVR

12 (

%)

10/10 8/9 27/27 19/19

Treatment Naive Treatment Experience

12 weeks 24 weeks

LDV-SOF in Patients with and without Baseline NS5A RAVs

With cirrhosis

Zeuzem S, AASLD 2015. Abstract 91

7/7

Estimated clearance time for RAVs selected upon treatment failure

days months years

10%

RAVs (%)

Benitez et al. Exp Op Pharmacother (in press)

Drug Resistance Tests

• Commercially available methods not available in most countries.

• Population sequencing (Sanger) of the NS3 protease, NS5A domain I and NS5B by homemade methods. Sensitivity for RAVs: 20%

• Potential interest of NGS, but thresholds for

clinical significance should be set up at 10%.

HCV resistance testing

• At baseline – Q80K in G1a if simeprevir to be used • At failure – RAVs selected to most agents on board but sofosbuvir • At re-treatment – persistence of RAVs mostly for NS5A inhibitors and NS5B non-nuc inhibitors and less frequently for NS3 protease inhibitors

Prospects for HCV resistance testing

Interesting academically to learn mechanisms of failure and potential cross-resistance. Avoid short lengths and close monitoring in cirrhotics However, the pace of development of better treatments and broader options would overcome the need to require individual resistance information for most re-treatments. Reminds what has happened in HIV.

Summary

• Failure to current DAA combinations occurs in 5-15% of chronic hepatitis C patients outside clinical trials.

• Most failures to oral DAA combinations are relapses instead of viral breakthroughs on therapy.

• Failures occur more frequently in treatment-experienced patients, those with advanced cirrhosis and infection with HCV genotypes 3 or 1a.

• In non-cirrhotics patients, DAA failure is rare and generally seen only when therapy is given for less than 12 weeks.

• Virologic breakthrough during DAA therapy generally reflects poor drug adherence.

• DAA failure is frequently associated with emergence of RAVs but to sofosbuvir.

• HCV drug resistance testing should be recommended for choosing the most convenient salvage DAA regimen as re-treatment for prior DAA failures.