1. Treatment of Hepatitis C in patients with thalassaemia
Treatment of Hepatitis C in patients with thalassaemia. Where are we now?
Telaprevir and boceprevir harbingers of important treatment advance
Improved response rates observed :
naive and experienced patients
SVR > 70% have been reported
in genotype 1 infection
Efficacy in the treatment of genotype 2-6 has not been fully tested.

2. The natural history of fibrosis in chronic viral hepatitis
Courtesy Pierre Bedossa

3. Telaprevir ADVANCE: SVR in naïve patients
T12PR
T8PR PR
P<0.0001
P<0.0001 75 69
Percent of patients with HCV RNA Undetectable 44
Results
n/N =
271/363
250/364
158/361
SVR
Jacobson IM, et al. N Engl J Med 2011;364: ; 2.

4. Evidence for efficacy: boceprevir in treatment-naïve, genotype 1 patients (SPRINT-2)* *
PR48
137/363
BOC RGT
233/368
BOC44/PR48
242/366
n/N =
*p<0.001 for both boceprevir arms versus PR48
SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24.
If there was no such value, the follow-up Week 12 value was carried forward
Boceprevir EU SmPC

5. The first generation protease inhibitors. Where are we now?
Response rates in patients with cirrhosis improved but suboptimal
Naïve patients without severe fibrosis
respond better
Prior null response and cirrhosis less likely to respond to retreatment
Inherited IL28b haplotypes continue to influence response rates
Response rates lower in subtype 1a vs 1b.
Side effects testing for patients

6. REALIZE (telaprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV
Prior relapsers
Prior partial responders
Prior null responders
Pbo/PR48
Pooled T12/PR48
SVR (%)
Key Point
Regardless of fibrosis stage and across all prior response categories, telaprevir plus PR was associated with increased SVR rates versus PR alone.
Notes
Fibrosis stage is a predictor of SVR with telaprevir-based therapy. In general and apart from prior relapsers, telaprevir-treated patients with bridging fibrosis/cirrhosis had lower SVR rates than those without.
In prior relapsers treated with telaprevir, SVR rates were similar between patients with no, minimal or portal fibrosis and those with bridging fibrosis/cirrhosis.
SVR rates were lowest in null responders with cirrhosis.
Given the small numbers of patients in some of the subgroups on this slide, these data should be interpreted with a degree of caution.
References
Pol S, et al. Hepatology 2011;54(Suppl. S1):374A.
n/N=
12/38
145/167
2/15
53/62
1/15
48/57
3/17
36/47
0/5
10/18
1/5
11/32
1/18
24/59
0/9
16/38
1/10
7/50
No, minimal or portal fibrosis
Bridging fibrosis
Cirrhosis
No, minimal or portal fibrosis
Bridging fibrosis
Cirrhosis
No, minimal or portal fibrosis
Bridging fibrosis
Cirrhosis
Stage
SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used
Pol S, et al. Hepatology 2011;54(Suppl. S1):374A

7. Boceprevir (SPRINT-2): SVR rates by IL28B genotypeCC CT TT
SVR (%)
n/N=
50/64
63/77
44/55
33/116
67/103
82/115
10/37
23/42
26/44
PR48
BOC RGT
BOC44/ PR48
PR48
BOC RGT
BOC44/ PR48
PR48
BOC RGT
BOC44/ PR48
Samples were available for 653/1048 (62%) patients enrolled in SPRINT-2 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week If there was no such value, the follow-up Week 12 value was carried forward
Boceprevir EU SmPC

8. Telaprevir (ADVANCE): SVR rates by IL28B genotypeCC CT TT
SVR (%)
n/N=
35/55
38/45
45/50
20/80
43/76
48/68
6/26
19/32
16/22 PR
T8/PR
T12/PR PR
T8/PR
T12/PR PR
T8/PR
T12/PR
Samples were available for 454/1088 (42%) patients (Caucasian) enrolled in ADVANCE SVR: sustained virologic response, defined as undetectable HCV RNA 24 weeks after last planned dose
Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

9. Interim results: Royal Free Cohort
Undetectable VL at TW4
n (%)
Met stopping rule at TW4
Met stopping rule week TRW12 1a
21 (70)
4 (13)
9 (30)* 1b
16 (84)
rs860 Non CC
31 (76)
4 (10)
8 (20)
rs860 CC
8 (89 )
rs916 Non TT
19 (70)
4 (15)
6 (23)
rs917 TT
20 (87)
2 (9)
VL> 800,000
29 (73)
8 (21)
VL <800,000
12 (92)
1 (8)
triple therapy week 4, n (%)
At triple therapy week 4 and 12

10. The paradox of progress
Advances have brought higher rates of cure
but more complexity to treatment of hepatitis C- a paradox of progress
Do not make treatment more straightforward
Complex process of decision making is required to assess
Side effects?
Resistance in patients who fail treatment
the indications for treatment for naive and previously treated patients,
and for patients with mild disease versus patients with cirrhosis or advanced cirrhosis

11. Managing adverse events:
Rashes
varying grades of severity and duration have been reported in 55% telaprevir
Most drug related dermatitis moderate severity
Unpredictably progress
5 % of patients experienced severe rash
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) occurred in 0.4% and Stevens-Johnson syndrome in 0.1% in clinical trials.
Anaemia
Particular relevance in patients with thalassaemia

12. Boceprevir: similar SVR when RBV dose modification and EPO are used to manage anemia
178
249
178
251
Treatment-naive G1 patients (n=687) received BOC-based therapy. Overall, 500 patients developed anemia (Hb ≤10g/dL or were expected to reach that nadir before next visit) and were randomized to have anemia managed with either EPO (40,000 units/wk subcutaneously), or RBV dose reduction (by 200–400mg/day). Transfusion in patients with Hb ≤8.5 g/dL was allowed to prevent study discontinuation.
Poordad F, et al. EASL Abstract Poster presented on Thursday 19th April

13. Still stuck with IFN The requisite backbone of PEG IFN:
other problems associated with PEG IFN and RBV use
Including depression, psychiatric symptoms worsening of liver function and severe infections
render a large group intolerant of PEG IFN ineligible for treatment.

14. What threat does resistance pose?
HCV does not replicate via DNA intermediate
HCV genome does not integrate into the human genome
there is no stable genetic reservoir
Drug selection pressure discontinued
advantage is lost: RAV’s outgrown by more fit, wild-type virus
Theoretical possibility of restoration of drug susceptibility
Drug selection pressure discontinued
advantage is lost and resistant variants are again outgrown by more fit, wild-type virus
discontinuation of telaprevir or boceprevir: wild-type variants increase relatively rapidly and may completely replace resistant variants in the quasispecies
The result is the theoretical possibility of restoration of drug susceptibility

15. EXTEND (telaprevir): resistant variants no longer detected in 85% of patients by last visit
100
100 95 91 85 84 82 80 60
Percent of patients with no detectable variants 40
Population
Sequencing 20
Key Point
Among patients who did not achieve SVR with telaprevir-based treatment, resistant variants were replaced by wild-type virus in 85% of patients after a median of 29 months (range 7–49) after the end of therapy. Furthermore, clonal sequencing in representative samples indicated that HCV populations returned to the pre-treatment state during long-term follow-up.
Notes
One objective of the EXTEND follow-up study is to determine how HCV variants change over time in patients who did not achieve SVR with telaprevir-based treatment. This will help to answer the question of whether resistant variants persist.
In the EXTEND study, after a median follow-up time of 29 months from the end of telaprevir-based treatment, 85% of patients no longer had detectable resistant variants by population sequencing.
Specific single variants associated with decreased susceptibility to telaprevir (V36M, T54A, R155K and A156T) were no longer detectable in 84–100% of patients after 25 months’ follow-up.
Similarly, the double variant V36M+R155K was no longer detectable in 49 out of 60 patients (82%) after 29 months’ median follow-up.
References
Sherman KE, et al. Hepatology 2011;54 (Suppl. S1):485A.
n/N =
107/126
74/81
20/21
69/82
11/11
0/1
49/ patients
Overall 36 54
155
156
168
36+155
variants
Variants at HCV NS3 position
Median follow-up time from treatment-failure: 29 months (range 7–49)
Clonal sequencing performed in representative Phase 2 samples (n=20 patients) indicated that HCV populations returned to pre-treatment state*
Variant categories are not mutually exclusive *Zeuzem S, et al. Hepatology 2010;52(Suppl):227A
Sherman KE, et al. Hepatology 2011;54 (Suppl. S1):485A

16. Patients with RAVs no longer detected by population sequencing (%)
Boceprevir resistance analysis: detectability of most common RAVs* declines during follow-up
Patients with RAVs no longer detected by population sequencing (%)
*In non-SVR patients with detectable RAVs at treatment failure in SPRINT-2 and RESPOND-2. As of latest follow-up time point (range 6–14 months)
Barnard RJO, et al. Hepatology 2011;54 (Suppl. S1): Abstract 164

17. Treatment-naïve patients Treatment-experienced patients
Viral kinetics in patients who met the >1000 IU/mL HCV RNA Week 4 stopping rule with telaprevir
Treatment-naïve patients
Treatment-experienced patients
108
107
106
105
104
103
102 10
108
107
106
105
104
103
102 10
HCV RNA (IU/mL)
HCV RNA (IU/mL) 2 4 6 8 10 12 2 4 6 8 10 12
Weeks
Weeks
Adda N, et al. HepDART Abstract 45

18. ATOMIC study: GS7977 + IFN + RBV 12 weeks Interferon sparing: a new threshold
Background and aims: PSI-7977, a potent uridine nucleotide analog, has demonstrated >90% SVR in HCV GT1, GT2, or GT3, independent of predictors of poor responsiveness to interferon. ATOMIC was designed to assess a 12-week regimen of once-daily PSI mg + PEG/RBV. Methods: Treatment-naïve, non-cirrhotic patients with HCV GT1 and HCV RNA ≥50,000 IU/mL were randomized (1:2:3) into one of three treatment arms: A) PSI-7977+PEG/RBVx12wk, B) PSI PEG/RBVx24wk, or C) PSI-7977+PEG/RBVx12wk, with re-randomization at Week 12 to PSI-7977 or PSI-7977/RBV. 25 patients with HCV GT4/5/6 could be enrolled into Arm B. Results: 316 subjects with HCV GT1, 11 with GT4, and 5 with GT6 were enrolled: mean age 50 years, mean BMI 28, 65% male, 10% Black, 20% Hispanic. Mean baseline HCV RNA 6.4 log10 IU/mL and 18% subjects have IL28B genotype TT. At abstract submission, all subjects have received >8 weeks of PSI Rapid and consistent antiviral suppression was demonstrated, with 259/332 (78%) achieving HCV RNA < LOD (15 IU/mL) by Week 2 and 323/332 (97%) achieving RVR. The two non-RVR subjects had ~5 log10 IU/mL change from baseline. To date, there has been no viral breakthrough during weeks of PSI-7977 and no relapse following completion of treatment in 32 subjects who have reached follow-up. PSI-7977+PEG/RBV was well-tolerated, with 20 overall discontinuations [14/332 (4%) due to AEs]. Frequency and severity of AEs were consistent with the historical safety profile of PEG/RBV and included fatigue (54%), nausea (29%), headache (29%), chills (19%) and insomnia (19%). Six unrelated SAEs have been reported. Grade 3/4 lab abnormalities included 6% Gr3 Hgb (7-8.9g/dL) and 17% Gr3/Gr4 neutropenia (< 750/mm3). Arm C subjects who received PSI-7977/PEG/RBV x 12 wks and were then re-randomized to PSI-7977+/-RBV demonstrated almost immediate return to baseline values in Hgb and ANC, confirming the predominant effect of PEG in hematologic abnormalities. Conclusion: PSI mg QD with PEG/RBV resulted in 97% RVR in HCV GT1, GT4, or GT6. To date no viral breakthrough or relapse has been observed in subjects completing at least 10 weeks of PSI SVR for 12 and 24-week regimens of PSI-7977/PEG/RBV will be presented.
SVR12 not yet reported for the 24 week groups
Kowdley KV, et al. EASL 2012, Barcelona, #1

19. BMS-790052 + BMS-650032: AI447011 Quad versus DAA combination
In null-responders, BMS BMS appear to require PegIFN/RBV to prevent breakthrough and the occurrence of resistance
BMS BMS
BMS BMS PR
Quadruple regimen 7 6 5 4 3 2 1 7 6 5 4 3 2 1
Log10 HCV RNA
Log10 HCV RNA
LOQ 25 IU/mL
LOD <10 IU/mL
6/11 patients in group A experienced viral breakthrough; no patient experienced viral breakthrough in group B
Group A: drug-resistant variants in both the NS3 protease and NS5A *
LOQ
LOQ
LOD
LOD
Week
Week
initiation of PegIFN/RBV
(NS5a inhibitor and Protease inhibitor)
Lok A, et al NEJM 19

20. ASPIRE (TMC435): SVR24 by prior response and Metavir score
Relapsers
Partial responders
Null responders
Patients with SVR24 (%)
PR48
TMC mg* PR48
TMC mg* PR48
PR48
TMC mg* PR48
TMC mg* PR48
PR48
13 3 2
TMC mg* PR48
TMC mg* PR48 n=
*All TMC435 duration pooled
Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1

21. Will we have better, more tolerable interferons?
Lambda interferon
No haematological toxicity

22. Daclatasvir and GS-7977 across HCV genotypes 1–3
mITT*
G1a/b
G2/3
% <LLOQ
100
100
100 87 86 93
100
100
100
100
100
100 94
100 86 88
100 86
Background: Oral combinations of direct-acting antivirals, without peginterferon-alfa, are much needed therapeutic options for patients with chronic HCV infection. Ongoing study AI evaluates daclatasvir 60mg QD (DCV; BMS ), a first-in-class NS5A replication complex inhibitor, in combination with GS-7977 (PSI-7977) 400mg QD, a nucleotide analog NS5B inhibitor, with or without ribavirin, in treatment-naïve patients. Both DCV and GS-7977 have potent antiviral activity, broad genotypic coverage in vitro, and once-daily administration. Methods: In this parallel, open-label study, 44 noncirrhotic patients with HCV GT1 and 44 noncirrhotics with HCV GT2/3 were randomized (1:1:1) to: (i) GS-7977 for 7 days then DCV + GS-7977 for 23 weeks; or (ii) DCV + GS-7977 for 24 weeks; or (iii) DCV +GS ribavirin for 24 weeks. The primary endpoint is undetectable HCV RNA at 12 weeks post-treatment. Interim 12-week on-treatment results are reported. Results: GT1 patients were 73% GT1a and 27% GT1b; GT2/3 patients were 59% GT2 and 41% GT3. HCV RNA was < LLOQ at week 4 in 100% of patients (see table). Virologic breakthrough occurred in one GT3 patient who had Peg-IFN/RBV added for confirmed detectable HCV RNA < LLOQ after week 8. Inclusion of ribavirin did not increase on-treatment virologic response. The most frequent AEs (≥25% overall) were fatigue, headache, and nausea. Two patients discontinued therapy for non-drug related AEs (fibromyalgia, CVA). Grade 3-4 laboratory abnormalities included elevated cholesterol (n=1), elevated glucose (2), low hemoglobin (6), lymphopenia (1), and low phosphorus (2). Conclusions: Interim results of this phase 2 study show that the once-daily combination of DCV and GS-7977 was generally well tolerated and achieved high rates of early virologic suppression in treatment-naïve patients infected with HCV genotypes 1a, 1b, 2, or 3
% <LOD
*Bars <100% after 4 weeks reflect missing values
Sulkowski M, et al. EASL 2012, Barcelona, #1422

23. All oral regimens: a realistic dream?
Therapeutic landscape is undoubtedly forever changed for the better
High barrier to resistance and pan-genotypic effects.
Do not yet know whether RBV remains important, or the appropriate dose of RBV in these regimens
Null responders to PEG IFN and RBV are null responders to both agents?
Multiple DAAs without RBV?
Costs will escalate

24. DAA + IFN (IFN freer) or IFN free?
12 weeks

25. Next priorities for all oral
More data in patients with
Cirrhosis
Decompensated cirrhosis
Post transplant recurrent hepatitis C
HIV and HCV coinfected patients
Patients with haemoglobinopathies
Patients with renal impairment or
post renal transplant patients
Children
Surely the next group of patients requiring attention will be those resistance to first generation PI’s?

26. Overcoming null response
May be nullified in patients treated with potent regimens given for sufficient time to effect clearance of HCV from the liver and perhaps extrahepatic sites.
An inverse correlation between the influence of the innate response and potency of DAA agents.
Difficult to develop an experimental model

27. Who should be treated now and who should wait?
Whoever wants treatment
Whoever is fit for treatment
Fit for the regimen
No contraindications
Motivated to have treatment
Understands :
likelihood of response
Risks and benefits of treatment
Understands what is coming down the line
Agrees it is an opportune time
Reimbursed
Indicated
Introduce thinking and evidence