Management of DAAs Failure

Management of DAAs Failure 

Prof. Gamal Esmat 

Prof. Hepatology &Ex. Vice President of Cairo University, Egypt 

Member of WHO Strategic Committee for Viral Hepatitis 

www.gamalesmat.com

3D-model of HCV comprising envelope, core proteins & single, 

positive RNA strand 

Envelope glycoprotein 1 (E1) 2 

Envelope glycoprotein 2 (E2) 1,2 

HCV RNA 1 

P21 Core protein 1,2 

55–56 nm 1 

HCV, Hepatitis C virus; RNA, Ribonucleic acid 

1. Krekulova L, et al. Folia Microbiol 2006;51:665-80; 2. Mauss S, et al. The Flying Publisher Short Guide to Hepatitis C. 2012 Edition. Available at: 

http://www.flyingpublisher.com (last accessed 12 October, 2012)

• HCV is an enveloped, positive-sense, single-stranded RNA virus that replicates using 

RNA polymerase that lacks general proof-reading ability. 

• This error-prone RNA polymerase is responsible for the genetic variability exhibited by 

HCV isolates.The spontaneous nucleotide substitution rate of HCV is high, with a 

frequency of 10 2 to 10 3 substitutions per nucleotide site per year 

• Accumulation of nucleotide substitution in the HCV genome results in alteration and 

evolution into distinct genotypes, subtypes

Sequence homology of whole genome and 

specific genes among HCV classifications

Antiviral Resistance 

• Each patient carries a preexisting 

heterogeneous population of 

viruses: 

Sensitive viral variants (wild-type) 

Resistant viral variants 

– Wild-type: dominant and drugsensitive 

– Resistant-associated variants 

/substitutes) minority population( 

• The selection of drug- resistant 

variants has been observed in 

patient who had treatment failure.

Mechanism of resistance 

• Most resistant variants are unfit and may be undetectable prior to therapy 

• Resistant variants are present before and can be selected during treatment 

Antiviral therapy eliminates sensitive variants 

Resistant variants expand 

Sensitive virus 

Resistant virus 

Antiviral therapy 

1. Pawlotsky JM. Clin Liver Dis. 2003;7:45-66. 2. Kuntzen T, et al. Hepatology. 2008;48:1769-1778. 

3. Bartels DJ, et al. J Infect Dis. 2008;198:800-807. Image reproduced and adapted with permission from Forum for Collaborative HIV Research. 

www.hivforum.org

All DAAs Can Select Resistant Variants 

Ala156 

Arg155 

Asp168 

Val36 

Thr54 

Pawlotsky JM. Ther Adv Gastroenterol 2009;2:205–219; Donaldson et al., Hepatology 2015;61(1):56-65; Lam et al., Antimicrob Agents 

Chemother 2012;56(6):3359-68.

Multiple factors can affect the emergence of 

resistance variants, particularly: 

1. The overall potency 

2. Barrier to resistance of the combination 

regimen

Barrier to Resistance 

Low-barrier drugs 

High-barrier drugs

HCV NS3/4A Protease Resistance 

D168 

R155 

Q80 

F43 

A156 

Lenz O, et al. Antimicrob Agents Chemother. 2010;54:1878-1887. Reproduced with permission from American Society for Microbiology. doi:10.1128/AAC.01452-09 Copyright © 2010, American Society for 

Microbiology. All Rights Reserved.

NS5B RAV(S) 

• Sofosbuvir has a high resistance barrier. 

• Although the S282T mutation has been selected in all genotypes during 

in vitro studies, the clinical significance of this RAV is unclear; it has 

been found in 1 of 1545 trial participants, who was not cured. 

• Yet successful re-treatment with sofosbuvir may be possible, even for 

people who were not cured by a sofosbuvir-containing regimen

Post-treatment RAV(S) persistence in patients who failed 

to achieve SVR

Protease inhibitor-Resistant Viruses are Progressively Replaced by WT- 

Sensitive Viruses after Rx Failures 

Lenz et al., J Hepatol 2015;62(5):1008-14.

Pts With NS5A RAVs (%) 

Durability of Treatment-Emergent NS5A RAVs After 

Virologic Failure 

• NS5A RAVs persisted in majority of pts for 96 wks 

100 

80 

98 100 98 100 

95 

86 

60 

40 

n/N = 

20 

0 

62/ 

63 

58/ 

58 

42/ 

43 

VF Baseline FU-12 FU-24 FU-48 FU-96 

45/ 

45 

Registry Study 

52/ 

55 

50/ 

58 

Dvory-Sobol H, et al. EASL 2015. Abstract O059.

SVR12 (%) 

24 Wks of LDV/SOF Retreatment After Failure of 8-12 Wks of 

LDV/SOF-Based Tx 

• GT1 HCV–infected pts with and without cirrhosis previously treated with 8 or 12 wks of LDV/SOF ± RBV 

100 

100 

80 

60 

71 68 

74 

80 

46 

60 

40 

n/N = 

20 

0 

29/ 

41 

Lawitz E, et al. EASL 2015. Abstract O005. 

15/ 

22 

14/ 

19 

All No Yes 

Cirrhosis 

24/ 

30 

5/ 

11 

8 Wks 12 Wks 

Previous Tx 

Duration 

11/ 

11 

No 

18/ 

30 

Yes 

BL NS5A RAVs

Guidelines of the National Treatment Program in Egypt 

• Patients who failed previous Sofosbuvir containing regimen 

• Treatment will be with Sofosbuvir + Daclatasvir + Ribavirin 

Or 

Sofosbuvir + ledipasvir +ribavirin 

• for 24 weeks. 

• The dose of ribavirin is 600 mg/day in cirrhotics, A trial should be done to 

reach a dose of 1000 mg/day based on the patient tolerability

DAA Treatment Failure 

•Relapse or Reinfection. 

•RAV (RAS) testing(if not available). 

•Sofo +Rib+ change from protease to NS5A 

inh. 

or vice versa. 

•24 weeks

Treatment recommendations for retreatment of HCV who failed to 

achieve SVR on prior antiviral therapy containing one or several 

DAAs 

‡ 

Patients who failed to achieve SVR with SOF + RBV or SOF + RBV + PegIFN-α 

LDV/SOF 

SOF/VEL 

OBV/PTV/ 

RTV ± DSV 

GZR/EBR SOF + DCV SOF + SMV 

GT1 or 

GT4 

12 weeks + RBV 

(F0-F2) or 


(F3-F4) 


(F0-F2) or 


(F3-F4) 

12 weeks + RBV (F0- 

F2) or 


F4) 

(For GT4 no DSV) 

12 weeks +RBV (F0-F2 with 

HCV RNA≤800,000 (5.9 log) 

IU/ml) or 24 weeks +RBV (F0- 

F2 with HCV RNA>800,000 

(5.9 log) IU/ml and F3-F4) 


(F0-F2) or 


(F3-F4) 

-12 weeks + RBV 

(F0-F2) or 


F4) 

GT2 or 

GT3 

- 


(F0-F2) or 


(F3-F4) 

- - 


(F0-F2) or 


(F3-F4) 

- 

GT5 or 

GT6 


(F0-F2) or 


(F3-F4) 


(F0-F2) or 


(F3-F4) 

- - 


(F0-F2) or 


(F3-F4) 

- 

•EASL Recommendations on Treatment of Hepatitis C 2016; Journal of Hepatology 2016 

http://dx.doi.org/10.1016/j.jhep.2016.09.001 (Accessed September 2016)

Treatment recommendations for retreatment of 

HCV who failed to achieve SVR on prior antiviral 

therapy containing one or several DAAs 

‡ 

‡ 

Patients who failed to achieve SVR with a PegIFN-α and telaprevir, or boceprevir, or simeprevir 

GT1 

LDV/SOF 

12 weeks + 

RBV 

SOF/VEL 

12 weeks + 

RBV 

OBV/PTV/ 

RTV + DSV 

OBV/PTV/ 

RTV 

- - - 


12 weeks 

+ RBV 

- 

Patients who failed to achieve SVR with a SOF + SMV 

LDV/SOF 

SOF/VEL 

OBV/PTV/ 

RTV + DSV 

OBV/PTV/ 

RTV 


GT1 

or 

GT4 

12 weeks + 

RBV (F0-F2) 

or 

24 weeks + 

RBV (F3-F4) 

12 weeks + 

RBV (F0-F2) 

or 

24 weeks + 

RBV (F3-F4) 

- - - 


(F0-F2) or 


(F3-F4) 

- 


http://dx.doi.org/10.1016/j.jhep.2016.09.001 (Accessed September 2016)

Treatment recommendations for retreatment of 

HCV who failed to achieve SVR on prior antiviral therapy 

containing one or several DAAs 

‡ 

SOF/VEL + 

RBV 

Patients who failed to achieve SVR with a NS5A-based regimen 

(LDV, VEL, OMV, EBR, DCV) 

SOF + OMV/PTV/RTV + 

DSV 

SOF + OMV/PTV/RTV 

+RBV 

SOF + 

GRZ/EBV 

+ RBV 

SOF + 

DCV + SMV 

+ RBV 

GT1a 24 weeks - 24 weeks 24 weeks 

GT1b 

F0–F2 12 weeks 


- F0–F2 12 weeks 


GT 3 24 weeks - - - - 

GT 4 



GT 5/6 24 weeks - - - - 


http://dx.doi.org/10.1016/j.jhep.2016.09.001 (Accessed September 2016) 

The regimens shown are not EMA approved regimens for retreatment of patients who failed to achieved SVR. The only 

regimen approved is SOF/VEL+RBV for 24 weeks in GT3 only.

A- Retreatment of patients with previous SOF/DAC failure 

1- Non cirrhotics and compensated cirrhotic patients: 

• Option I: SOF/Qurevo/RBV for 12 weeks. 

• Option II : SOF/SIM/DAC/RBV for 12 weeks 

• RBV ineligible: extend therapy for 24 weeks


1- Non cirrhotics and compensated cirrhotic patients: 

• Option I: SOF/Qurevo/RBV for 12 weeks. 

• Option II : SOF/SIM/DAC/RBV for 12 weeks 

• RBV ineligible: extend therapy for 24 weeks


2- Child’s B cirrhotic patients: 

SOF/DAC/RBV for 24 weeks 

Deferred treatment for Child C, Relapsers to Sofo+Dacla 

24weeks

Future Therapy of HCV 

With the help of God 

We will keep trying with Every New Day

Abstract ID: 849 

Author: Ng T. et al. 

Analysis of HCV Variants in the MAGELLAN-1 Part 1 Study: 

• Number of patients: n=50. 

AASLD 2016 

ABT-493 and ABT-530 Glecaprevir/Pibrentasvir(G/P) Combination Therapy of Genotype 1- 

Infected Patients 

who Had Failed Prior Direct Acting Antiviral-Containing Regimens 

• These DAA-experienced patient cohorts had broad representation of baseline variants at key 

resistance-associated positions, including those at NS3 V36, Q80, R155, and D168, as well as 

NS5A M28, Q30, L31, and Y93. 

• Results: All patients with baseline variants at position Y93 in NS5A that confer high level of 

resistance to currently approved NS5A inhibitors achieved SVR12 

• Conclusions: The combination of ABT-493 and ABT-530 demonstrated potent antiviral activity 

and a high barrier to resistance in non-cirrhotic HCV GT1-infected patients who had previously 

failed a DAA-containing regimen,

AASLD 2016 

Sofosbuvir/Velpatasvir/Voxilaprevir 

for 12 Weeks 

as a Salvage regimen in NS5A Inhibitor –Experienced 

Patients with Genotype 1-6 Infection : The Phase 3 

POLARIS-1 Study

Summary 

• Treatment-emergent RAV(S) seen in treatment failure and in all DAA classes and 

rarely with SOF 

• NS3 RAVs have low replication efficacy and disappear over 9-18 mos 

• If considering SMV + SOF: In treatment-naive and treatment-experienced pts 

with both genotype 1a HCV infection and compensated cirrhosis, ensure no 

Q80K 

• NS5A treatment-emergent RAVs persistent and a clinical challenge 

• If failure with any NS5A inhibitors , and treatment is urgent, test for NS3 and 

NS5A RAVs 

• Use SMV + SOF + RBV if NS5A but no NS3 RAVs 

• Use LDV/SOF orDacla + RBV if no NS5A RAVs 

• Treat in clinical trial if both NS5A and NS3 RAVs present

THANK YOU 

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www.gamalesmat.com 

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