13th European Meeting on HIV & Hepatitis Treatment...

Drug Resistance to Protease Inhibitors

Francesca Ceccherini-Silberstein

Università degli Studi di Roma “Tor Vergata” Dipartimento di Medicina Sperimentale e Chirurgia

Cattedra di Virologia

Session 6: Drug Resistance to HCV DAA's

Barcelona 4 June 2015

13th European Meeting on HIV & Hepatitis Treatment Strategies & Antiviral Drug Resistance, Barcelona 3-5 June 2015

F. Ceccherini-Silberstein has received funds for attending symposia, speaking, organizing educational activities, grantresearch support, consultancy and advisory board from AbbVie, Merck Sharp & Dohme, Gilead, Janssen Cilag, Roche Diagnostics, Bristol MyersSquibb, and ViiV.

Disclosures

New Approved DAAs

Simeprevir Sofosbuvir Daclatasvir

Nucleotide analogue 400 mg qd

All genotypes High barrier January 2014

Protease inhibitor 150 mg qd

Genotypes 1 and 4 Low barrier

May 2014

NS5A inhibitor 30 or 60 mg qd All genotypes Low barrier

September 2014

Harvoni

Nucleotide analogue + NS5A inhibitor

400 mg sofosbuvir + 90 mg of ledipasvir qd

HCV-1 and HCV-4 High barrier

September 2014

Paritaprevir/ ombitasvir/

ritonavir (Viekirax)

Dasabuvir (Exviera)

NS3 protease inhibitor + NS5A inhibitor + ritonavir

NS5B polymerase inhibitor

HCV-1 and HCV-4 +

250 mg bd Low barrier

75 mg / 12.5 mg / 50 mg qd

The importance of genotype….

Jackowiak P. Genetics and Evolution, 2014

A high degree of genetic variability among the endemic HCV strains have been acquired during long-term evolution

Strains that exhibit lower genetic distance and are widely spread likely have a shorter history and a higher transmission rate…

The 7 HCV genotypes vary in their geographical distribution and in their level of genetic diversity

Genotype 1 is by far the most frequent genotype in chronically infected patients worldwide as well as in Europe

Esteban JI et al J Hepatol 2008

3a

1b

1b

1b

2

1a

1a 3a

2

2 1b

1b

1b 1b

1b

1b

1b 1b

1a 3a

1a 3a

1a 3a

1a 3a

1a 3a

1a 3a

1a 3a

4 4

4

1a

2

4 3a

28,2

23,9

17,7

10,8

6,8 5,1

2,8 1,8 1,7 1,4

0%

5%

10%

15%

20%

25%

30%

3an=354

1an=300

not testedn=222

1bn=136

4n=85

othern=64

1n=35

3n=23

4c/4dn=21

2a/2cn=17

Proportion of HCV genotypes in HCV-RNA+ patients N= 1257

37.5% HCV-1 30% HCV-3 8.5 % HCV-4

Distribution of HCV genotypes (G) was: G1a, 439 (30%); G1b, 178 (12%); G2, 35 (2%); G3a, 339 (23%); G4, 147 (10%). 92% were currently receiving ART. M Shanyinde et al ICAR 2015

1,462 PLHIV-HCV patients

HCV genotype was the most important baseline predictor for response

to Peg-IFN + Ribavirin Combination Therapy

HCV genotypes 2 and 3

HCV genotype 1

HCV genotypes 4 and 6

SVR = 78-86 % HCV-2= 80-95% HCV-3 Low viremia = 75-80% HCV-3 High viremia = 60-70%

SVR = 42-52 %

SVR = 35-65 % HCV-1 Low viremia = 50% HCV-1 High viremia = 30-35%

0% 25% Amino acid variability:

47% amino acids of HCV PROTEASE NS3 are conserved

among all HCV-genotypes

55% amino acids of HCV POLYMERASE NS5B are conserved


0% 25% Amino acid variability:

46% amino acids of HCV NS5A are conserved


Cento et al., PLoS ONE 2012 Love et al., J Vir 2009 Di Maio et al., AAC 2014

Today only few DAAs are pangenotypic…….

What about today or tomorrow in the era of new DAAs?

Still genotype important predictor for response?

(Grazoprevir) Daclatasvir Sofosbusvir

Ceccherini-Silberstein et al., AIDS 2004

68% 45%

HIV-1 protease conservation

Gt1a

Gt1b

Gt2a

#1

Gt2a

#2

Gt2b

#1

Gt2b

#2

Gt2b

#3

Gt2b

#4

Gt2b

#5

Gt3a

#1

Gt3a

#2

G3a #

3

Gt3a

#4

Gt4a

#1

Gt4a

#2

Gt 5a

#3

Gt5a

#4

Gt 6a

MK-5172 boceprevir TMC-435 telaprevir

0

1000

2000

3000

4000

5000

6000

Comparative Activity of PIs Against HCV NS3 Genotype 1-6 Proteases from Patient Isolates from Genotypes 1-6 in Cell-Based SEAP assay

IC

50 (n

M)

NS3 Genotype Graham D et al. AASLD 2011 Poster # 370

Association between HCV genotype and prevalence of liver steatosis

Poordad F. et al., NEJM 2014

TURQUOISE-II, phase 3 trial, combination of coformulated paritaprevir–ombitasvir and dasabuvir + RBV for 12/24 weeks in previously untreated and previously treated adults with chronic HCV genotype 1 infection and compensated cirrhosis.

OMV/PTV/RTV + DSV + RBV treatment in cirrhotic GT1a patients requires 24 weeks instead of 12

Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C with compensated (Child-Pugh A) cirrhosis,

including treatment-naïve patients and patients who failed on a treatment based on PegIFN-a and ribavirin (RBV).

EASL HCV clinical guidelines 2015

Day 0 4w 5w 6w 7w 9w 11w 13w 15w 19w

1

2

3

4

5

6

HCV

- RN

A (lo

g IU

/ml)

Naive

HCV genotype: 1b Age: 55 Sex: M ID_476 Cirrhotic

Paritaprevir/ritonavir+Ombitasvir+ Dasabuvir+RBV

LLOQ (12 IU/ml)

GRT Day 0 NS3 Resistance mutations: None NS5A Resistance mutations: None NS5B Resistance Mutations: None

275.674 IU/ml

211 IU/ml

193 IU/ml

30 IU/ml

45 IU/ml

The importance of resistance….

Mutations occur frequently during the replication of HCV

M.D. Schneider, C. Sarrazin Antiviral Research 2014

Rong L et al., Sci Transl Med 2010

CONSEQUENCES OF HCV VARIABILITY AT PATIENT’S LEVEL: QUASISPECIES POPULATION

HCV resistant variants are naturally produced during the HCV life cycle

It has been predicted that every nucleoside of the 3.2 kb HBV genome or the 10 kb HIV and HCV genomes theoretically can be substituted every day within a given infected patient

Different distribution of TVR RAVs in TVR treated patients according to subtype

Kieffer, PLoS ONE 2012

Ogert RA et al., AASLD 2011 (poster n° 927)

Different emergency of resistance mutations in GT1a and GT1b

also in BOC-failing patients

Slow HCV-RNA decay and early resistance predict the risk of failure to TVR/BOC treatment

N=2 V36L (1.5%)

N=5 T54S (3.8%)

N=109 wild-type (83.8%)

N=1 V55A (0.8%) N=13 Q80K (10.0%)

N=1 T54S+R155K (2.1%) N=1 V36M

(2.1%) N=1 T54A (2.1%) N=1 T54S (2.1%)

N=40 wild-type (85.1%)

N=2 Q80K (4.3%) N=1 A156V (2.1%)

N=2 A156T (14.3%)

N=1 V36L+Q80K 5.6%)

N=1 R155T+A156V (5.6%)

N=1 V36M+R155K (5.6%)

N=10 wild-type (55.6%)

N=3 Q80K (16.7%)

Baseline RAVs in 21 patients (16.2%)

Baseline resistance test (N=130, TVR & BOC)

Resistance test 48h (N=47, TVR & BOC) 48h new RAVs in 4 patients (8.5%)

Resistance test 3-17 days (N=18, TVR & BOC)

3-17 days new RAVs in 4 patients (22.2%)

Characteristics Crude OR 95% C.I. P-value Adjusted OR 95% C.I. P-value Lower Upper Lower Upper HCV-RNA >100 IU/ml at week 2 12.667 3.308 48.504

Simeprevir

IAS list 2013 Bolded type under the amino acid position number represents the key mutations that are clearly associated with virologic failure and result in a resistant phenotype. ©IAS–USA 2013

Protease Inhibitor Resistance

HCV DRAG, Forum for Collaborative HIV Research, April 2014

paritaprevir/r

Beware of HCV-genotype for daclatasvir resistance ...

Nakamoto S., WJG 2014

Useful a HCV sequencing test before starting treatment?

Currently, all international guidelines list several new treatment options with similar

high efficacy for initial treatment and retreatment of prior non-responders.

The new DAAs may be used with or without ribavirin for 12 or 24 weeks, depending on

factors including HCV genotype, subtype (1a or 1b), presence of liver cirrhosis, and prior

treatment history…..

Jacobson I, et al. EASL 2013

SMV + P/R P/R

105/117 29/56 105/147 36/74

71

49

90

52

100

60

20

0

SVR1

2 (%

)

GT 1a GT 1b

80

40

Differences in SVR12 by Subgroup (95% CIs) GT 1a/other HCV - With baseline Q80K vs Pbo - Without baseline Q80K vs Pbo GT 1b HCV

28.2 (13.4-42.9) 4.7 (-14.6 to 24.1) 40.3 (25.8-54.8) 42.1 (26.5-57.6)

147 60 86

117

74 74 74 56

SMV (n) Pbo (n)

Favors Placebo Favors SMV -100 -50 0 50 100

Virologic failure during simeprevir treatment was more common in patients with genotype 1a with Q80K

No differences between 1b and 1a without Q80K

Overall prevalence of Q80K in G1 across different regions

Includes 15 patients with non-1a/b genotype.

Jacobson et al. Presented at AASLD 2013 Lenz et al. Presented at AASLD 2013

14%

30%

All G1 G1a

Overall

6%

19%

All G1 G1a

Europe

34%

48%

All G1 G1a

North America

3% 9%

All G1 G1a

South America

13.7% of patients (274/2007) all HCV G1 29.5% (269/911) of those with HCV GT1a and 0.5% (5/1096) of those with HCV GT1b

Italy our data : all G1 9%

0,05,0

10,015,020,025,0

HCV GT-1a (N=89)

HCV GT-1b

(N=136)

Patie

nts w

ith

Q80

K (%

) 20/89

1/136

Vicenti el al JAC 2012

Figure 1. Radial dendrograms of the 109 HCV NS3 sequences obtained together with reference sequences for subtypes 1a, 1b and 1c (outgroup).

Different clusters of HCV genotypes 1

Different frequency of natural resistance mutations in GT1a NS3 by clade

n=293

De Luca et al IWDR 2013

Overall prevalence of Q80K in QUEST-2 Simeprevir study was 10.2% (EASL 2013) Prevalence of Q80K in GT1a infected patients was 24.2%.

McCloskey RM et al., J Infect Dis 2014

McCloskey RM et al., J Infect Dis 2014

The majority (96%) of HCV infections carrying Q80K descended from a single lineage in which a Q80K substitution occurred around the 1940's in the United States, which implies that this polymorphism is likely highly transmissible

SMV + SOF (12 weeks) SVR12 rates according to Q80K presence at baseline in G1a non-cirrhotic patients

OPTIMIST-1

Kwo P, et al. EASL 2015. Poster LP14

0

20

40

60

80

100

G1a G1a with Q80K G1a without Q80K

SVR1

2 (%

)

Q80K did not impact SMV + SOF efficacy when administered for 12 weeks to G1a non-cirrhotic treatment-naïve and -experienced patients

112/116 68/70

97 (92.8,100)

96 (88.7,100)

97 (92.5,100)

44/46

Asselah T, EASL 2015 SYMPOSIUM

SMV + SOF (12 weeks) SVR12 rates according to Q80K presence at baseline in G1a cirrhotic patients:

OPTIMIST-2

Eligible patients were 18–70 years with chronic HCV G1 infection; HCV RNA >10 000 IU/mL at screening, platelets >50 000/mm3, albumin >3 g/dL and presence of cirrhosis determined by any of: FibroScan with kPa >12.5 within 6 months of screening; FibroTest score of >0.75 and AST to platelet ratio >2 at screening; liver biopsy documenting cirrhosis Treatment-experienced = IFN-intolerant, prior relapsers, prior nonresponders, other Brackets = 95% CI; AST = aspartate aminotransferase

Lawitz E, et al. EASL 2015. Poster LP04

0

20

40

60

80

100

G1a G1a with Q80K G1a without Q80K

SVR1

2 (%

)

60/72 25/34 35/38

83 (74.0,92.6) 74

(57.2,89.8)

92 (82.2,100)


93 96 91

0

20

40

60

80

100

Overall G1a with Q80K G1a without Q80K

SVR1

2 (%

) SMV + SOF (12 weeks) SVR12 rates according to Q80K

presence at baseline in G1a cirrhotic patients

Randomised, prospective, open-label trial that was investigator-initiated. Patients were assigned randomly to receive either SMV + SOF for 12 weeks or SOF + PR for 12 weeks. Randomisation was stratified according to previous PR treatment (non- or null responder). SVR12 rate in the SOF + PR arm was 75% CPT = Child-Pugh Turcotte score Pearlman B, et al. Gastroenterology 2015

Discrepant results were reported regarding the impact of Q80K in cirrhotic patients

54/58 22/23 32/35


82 cirrhotic CPT A pts with chronic HCV G1a

Natural RAVs were detected in 55/286 (19.2%) NS3 sequences and in 30/96 (31.3%) NS5A sequences from PI-naïve patients with an

available baseline resistance test DAA naïve pts were analysed for NS3 (1a=121, 1b=154, 3=6, 4=5) and NS5a (1a=42, 1b=42, 3=7, 4=5). Prevalence of NS3 RAVs was more frequent in GT-1a (28.3%) compared to genotype 1b (7.8%).

NS3 RAVs Genotype, n

NS5A RAVs Genotype, n

1a (N=121)

1b (N=154)

3a (N=6)

1a (N=42)

1b (N=42)

3a (N=7)

V36L 3 2 1 M28V 1 V55A/I 2/3 Q30H 1 T54S 3 3 Q30R 1

Q80L/R 5/1 6/0 L31M 1 4 Q80K 19 1 Q54H 17 S122A 1 Q54Y 1 R155K 1 Y93H 1 3 D168E 2 1

Sorbo MC et al., ICAR 2015

Comparative study of RAVs prevalence in NS3 and NS5A genes in different HCV sub-genotypes, in liver and plasma specimens in

patients with HCC / transplanted and not 13 HCC/LT pts infected by HCV GT1a [N=4], 1b [N=5], 3a [N=3], and 4d [N=1] underwent LT due to HCC, in 2014.

RAVs

Patient Genotype Compartment NS3-Protease NS5A

TT none Q54H

Pt.2 1b NT none Q54H, Y93H/P/Y/S

PL none Q54H

TT T54T/S Y93H/Y

Pt.22 1b NT none Y93H/Y

PL none none

TT S122A none

Pt.1 3a NT S122A none

PL S122A none

PL 49w S122A none Table 1. Prevalence of NS3 and NS5A RAVs found in different compartments of HCC/transplanted pts: tumorous tissue (TT), normal tissue (NT), plasma (PL), 49 week post-LT plasma (PL 49w).

RAVs were not present in any compartments of the other 10 remaining pts included in the current study (neither in NT/TT /PL for 5 pts nor in PL for additional 5 pts). Interestingly, the NS3 RAV S122A found in 1/13 HCC/LT (1, GT3) was detected in only 1 control-pt GT1b: in HCC pts 7.7% (1/13) vs 0.3% in controls (1/286), p= 0.08 Fisher test.

Sorbo MC et al., ICAR 2015

Sex: MALE Country of Origin: ITALY Age: 41 year Liver status: OLT in 2007, today decompensated cirrhosis (ascites) HCV genotype: 4d Outcome to previous pegIFN+RBV treatment: Null responder

Clinical case

New treatment strategies are available for GT-4

The main limitations of these clinical trials on HCV-G4 are their small sample size and the relatively mild stage of liver diseases …

Asselah T, J Hepatol 2015

Treatment selection in patients before and after OLT based on currently available evidence

Ferenci, Nat Rev 2015

The oral combination of daclatasvir + simeprevir was chosen for this patient.

Would you have tested this patient for Q80K presence?

Sarrazin C et al., Antivir Res 2015

Analyzing 77 GT-4 NS3-sequences from Los-Alamos DB, the Q80K prevalence is 6.5% (5/77).

Day 0 Day1 Day2 1w 2w 4w 6w 7w 2w

1

2

3

4

5

6

7

Null Responder to SOC

HCV genotype: 4d Age: 41 Sex: M ID_451 OLT in 2007

HC

V- R

NA

(log

IU/m

l)

Daclatasvir+Simeprevir Interruption

LLOQ (12 IU/ml)

GRT 2 weeks after therapy interruption NS3 Resistance Mutations: A156G, D168E NS5A Resistance Mutation: L28V, T58P

Generation of multiple-resistant viruses

IAS list 2013

Bolded type under the amino acid position number represents the key mutations that are clearly associated with virologic failure and result in a resistant phenotype. ©IAS–USA 2013

Day 0 Day1 Day2 1w 2w 4w 6w 7w 2w

1

2

3

4

5

6

7

Null Responder to SOC

HCV genotype: 4d Age: 41 Sex: M ID_451 OLT in 2007

HC

V- R

NA

(log

IU/m

l)

Daclatasvir+Simeprevir Interruption

GRT Day 0 NS3 Resistance Mutations: D168E NS5A Resistance Mutation: T58P

LLOQ (12 IU/ml)

GRT 2 weeks after therapy interruption NS53 Resistance Mutations: A156G, D168E NS5A Resistance Mutation: L28V, T58P

Useful a genotypic HCV resistance test after failure?

Treatment Failure

=

Failure to Cure HCV infection

=

There remains hepatocytes in the liver that are infected with wt and/or resistant HCV viruses

when treatment is stopped

In the era of DAA…..

Virological failures to all-oral, IFN-free, regimens are likely to involve multiple RAVs on

multiple drug targets

Krishnan P et al., EASL 2015

• Pooled prevalence of NS3 RAVs at failure: 76%

• Pooled prevalence of NS5A RAVs at failure: 68%

• Pooled prevalence of NS5B RAVs at failure: 55%

The rate of decline is specific to each drug resistant mutation and it is related to the replication capacity

Genotype 1b

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

Time after treatment failure (years) 0 0.5 1 1.5 2

T54A T54S All

Genotype 1a

% re

sist

ant v

iral v

aria

nts

dete

cted

2 Time after treatment failure (years)

0.5 1 1.5 0%

10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

V36M T54S R155K All

0 % V

aria

nt v

iral r

ésis

tant

dét

ecté

Sullivan et al., EASL 2011, Sullivan et al CID 2013

Dynamics of Resistant HCV Variants Post-Treatment (BOC)

Dynamics of Resistant HCV Variants Post-Treatment (TVR)

Barnard et al., Virology 2013

Long-term follow-up data on a cohort of 314 BOC-failing patients indicated that NS3 RAVs reverted to

wild-type in 73% of cases within 3 years post-therapy

From a different perspective, these data indicate that 27% of patients still presented dominant resistant (and presumably fit) variants after 3 years since boceprevir discontinuation.

Furthermore, the remaining 73% can still harbor minority residual resistant strains, since reversion was evaluated by population sequencing, able of detecting variants at a frequency >20%.

Howe, Antivir Res 2014

TVR + pegIFN+RBV pegIFN+RBV Interruption

Day 0 Day 2 2 w 4 w 8 w 12 w 16 w 18 w 6w 12w 20w 25w 34 w 45 w 72 w 100 w

1

2

3

4

5

6

7

HC

V- R

NA

(log

UI/m

l)

TVR INTERRUPTION

PegIFN+RBV INTERRUPTION

GRT Day 0 NS3-protease (bulk+UDPS): None

GRT Day 2 NS3-protease bulk: None By UDPS: V36A 2.5%,R155K 4.1% Mutational Load: V36A=183 IU/ml R155K=301 IU/ml

GRT 18 weeks NS3-protease (bulk+UDPS): V36M 100%, R155K 100%

GRT 100 weeks after therapy interruption NS3-protease bulk: None By UDPS R155K 3.7% Mutational Load: R155K:77966 IU/ml

GRT 72 weeks after therapy interruption NS3-protease bulk: None By UDPS V36M 1.3%, R155K 32.8% Mutational Load: V36M: 38329 IU/ml R155K: 942015 IU/ml

Null responder to SOC

HCV genotype: 1a Age: 44 IL-28: CT Sex: M ID_13

An HCV-1a infected patient who failed Telaprevir triple therapy with V36M+R155K still showed R155K at 100 weeks after therapy interruption

Follow-up after treatment Follow-up on treatment

LLOQ (12 IU/ml)

The low prevalence of minority RAVs does not always means low amount of circulating resistant virus

WT R155 (65.5%)

WT= wild-type

PT 13 PT 11

WT R155 (96.3%)

R155K (35.5%)

R155K (3.7%)

Mutational Load of R155K: 77,966 IU/ml


HCV-RNA : 1,671,926 IU/ml HCV-RNA: 2,090,903 IU/ml


WT R155 (96.0%)

R155K (4.0%)

HCV-RNA: 1,104,189 IU/ml

At 100 weeks of therapy interruption

At 62 weeks of therapy

interruption

PT 211

Three HCV-1a infected patients, all failing TVR-containing regimen with RAVs, still showed the R155K after 60-100 weeks of therapy interruption.

Di Maio VC, EASL 2015

First documentation of a transmission of an HCV DAA resistant variant from a DAA treated patient to his sexual HIV-infected partner

Patient A, a man chronically infected with HCV genotype 1a and co-infected with HIV- 1, treated with pegIFN/RBV plus telaprevir in July 2012 with HCV breakthrough. HCV NS3 protease sequences before treatment with telaprevir did not have any major substitution associated with NS3 PIs. Patient B, a man also HIV-1 infected and sexual partner of patient A, diagnosed of acute HCV co-infection in January 2011, with HCV genotype 1a. This patient refused therapy with pegIFN/RBV during the acute phase of HCV infection. In April 2012 he entered a clinical HCV trial and was treated for 24 weeks with pegIFN/RBV plus Daclatasvir, with undetectable HCV RNA at week 24 and 36 after the end of treatment. However, at week 48 after stopping therapy, presented elevated transaminase and detectable HCV RNA, suggesting a HCV re-infection. The patient denied any known risk for HCV infection except unprotected sexual intercourse with his partner (patient A). After 12 weeks, patient B tested negative for HCV infection.

108 and 28 individual NS3 protease clones from patient A and B early samples, respectively, were sequenced

Franco et al Gastroenterology May 2014

V36M substitution detected in 9/20 clones in patient A (20 weeks off therapy) and in all late sequences from patient B.

Risk of Late Relapse or Re-Infection with Hepatitis C After Sustained Virological Response:

Meta-Analysis of 66 Studies in 11,071 Patients

Low Risk 43 studies N = 9,419

Avg. FU = 4.1±2.1y

High Risk (IDUs/prisoners) 16 studies

N = 819 Avg. FU = 2.9±1.6y

HIV/HCV Co-Infected 7 studies N = 833

Avg. FU = 3.1±1.2 years

Five-Year Rate (95%CI) of Recurrence Post-SVR, by Risk Group

Hill A, et al. 22nd CROI; Seattle, WA; February 23-26, 2015. Abst. 654.

0

5

10

15

20

25

30

Low risk High risk HIV/HCV co-infected

5-yr

recu

rren

ce ra

te p

ost S

VR, %

1.1% (95%CI 0.9–1.4%)

13.2% (95%CI 9.9–17.2%)

21.7% (95%CI 18.3–25.5%)

When treating patients with chronic viral hepatitis C with direct antiviral agents we should always remember: The complexity: virus, host, clinical aspects, previous treatment outcome, DAA The virus is very variable: • At population level: different genotypes and subtypes,

different response to PegIFN/RBV and to new DAA! Different PI, NS5A and NS5B resistance development and prevalence (1a vs 1b subtype, genotypes).

• At patient level: quasispecies, minor variants, pre-existing resistance.

Conclusions

In GT-1a patients: test for Q80K in patients eligible for simeprevir treatment. What about NS5A natural resistance Y93H and other mutations? What about NS5B L159F polymorphism in GT-1b patients for sofosbuvir? Potential role for the duration of therapy?

Conclusions

HCV-RNA decay at early time points (i.e. 8? 24-48h? week 2) may help in predicting treatment outcome: HCV-RNA >100 IU/ml at week 2 may identify patients at risk of failure in clinical practice. Attention to early resistance development/selection!

The performance of a baseline sequencing of HCV can provide at the same time two important virological information for clinical management of patients with chronic HCV infection: 1) a correct genotype/subtype assignment based on sequence analysis (often incomplete, or even wrong, with old diagnostic methods). 2) detection of variants that are potential non responders to therapy (natural resistance or previous failure resistance).

Slide Number 1Slide Number 2New Approved DAAs Slide Number 4Slide Number 5Slide Number 6Genotype 1 is by far the most frequent genotype in �chronically infected patients worldwide as well as in EuropeSlide Number 8HCV genotype was the most important baseline predictor for response �to Peg-IFN + Ribavirin Combination Therapy�Slide Number 10Slide Number 11Slide Number 12Slide Number 13OMV/PTV/RTV + DSV + RBV treatment in cirrhotic GT1a patients requires 24 weeks instead of 12Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C with compensated (Child-Pugh A) cirrhosis,�including treatment-naïve patients and patients who failed on a treatment based on PegIFN-a and ribavirin (RBV).Slide Number 16Slide Number 17Slide Number 18Slide Number 19Different distribution of TVR RAVs �in TVR treated patients according to subtypeSlide Number 21Slow HCV-RNA decay and early resistance predict the risk of failure to TVR/BOC treatment�SimeprevirProtease Inhibitor ResistanceBeware of HCV-genotype for daclatasvir resistance ...Useful a HCV sequencing test before starting treatment?Currently, all international guidelines list several new treatment options with similar high efficacy for initial treatment and retreatment of prior non-responders.� The new DAAs may be used with or without ribavirin for 12 or 24 weeks, depending on factors including HCV genotype, subtype (1a or 1b), presence of liver cirrhosis, and prior treatment history…..Slide Number 28Overall prevalence of Q80K in G1 across different regionsSlide Number 30Slide Number 31Slide Number 32Slide Number 33SMV + SOF (12 weeks) SVR12 rates according to Q80K presence at baseline in G1a non-cirrhotic patients OPTIMIST-1SMV + SOF (12 weeks) SVR12 rates according to Q80K presence at baseline in G1a cirrhotic patients: OPTIMIST-2SMV + SOF (12 weeks) SVR12 rates according to Q80K presence at baseline in G1a cirrhotic patientsSlide Number 37Slide Number 38Slide Number 39Clinical case �New treatment strategies are available for GT-4�Treatment selection in patients before and after OLT based on currently available evidence Would you have tested this patient for Q80K presence?Slide Number 44Slide Number 45Slide Number 46Useful a genotypic HCV resistance test after failure?Treatment FailureVirological failures to all-oral, IFN-free, regimens are likely to involve multiple RAVs on multiple drug targetsSlide Number 50Long-term follow-up data on a cohort of 314 BOC-failing patients indicated that NS3 RAVs reverted to wild-type in 73% of cases within 3 years post-therapySlide Number 52Slide Number 53Slide Number 54Risk of Late Relapse or Re-Infection with Hepatitis C After Sustained Virological Response: �Meta-Analysis of 66 Studies in 11,071 Patients�Conclusions�Conclusions

13th European Meeting on HIV & Hepatitis Treatment...

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