Hepatitis C Current Therapy Christoph Jochum Clinic for - - PowerPoint PPT Presentation

Hepatitis C – Current Therapy

Christoph Jochum Clinic for Gastroenterology & Hepatology University Hospital Essen Germany

Use of Predictors to Decide to Treat or Wait: Current issues

• At least 24 wks for genotype 1 HCV
• Suboptimal results for non-RVR patients after

48 wks of treatment Long treatment duration

• Several IFN-related adverse effects
• New PIs: anemia, rash, etc

Challenging safety profile

• History of null response
• IL28B: TT
• Liver cirrhosis

Low efficacy in certain patients

Adapted from CCO

Severity of Disease Increases Need for HCV Therapy but Also Impairs Response

• May not need immediate

treatment

• BUT
• Easier to treat
• High likelihood of response

Advanced disease/ cirrhosis Mild disease

• Greater need for treatment
• BUT
• Response may be impaired
• Perhaps more effective options in future,

but efficacy of some investigational agents may be unclear due to trial eligibility criteria

Adapted from CCO

Survival in Patients With HCV and Cirrhosis

Fattovich G, et al. Gastroenterology. 1997;112:463-472.

Compensated After first major complication Survival Probability 100 Patients (%) 80 60 40 20 120 12 24 36 48 60 72 84 96 108 Mos 384 65 Pts at Risk, n 376 39 342 21 288 11 236 7 165 4 126 4 79 3 52 3 39 2 25 1

Adapted from CCO

Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis

Bruno S, et al. Hepatology. 2007;45:579-587.

No SVR SVR 100 Patients With Liver Complications (%) 80 60 40 20 168 24 48 72 96 120 144 Mos 759 124 702 119 634 116 527 108 345 70 207 41 34 12 Pts at Risk, n

Source CCO

Prognostic Factors in Current Therapy

• Black
• Cirrhosis
• Genotype 1

(1a worse than 1b)

• IFN nonresponsive
• IL28B TT

Favorable prognostic factors Less favorable prognostic factors

• White
• No fibrosis
• Genotype 2/3
• IFN responsive (eg,

RVR/EVR or response to lead-in)

• Previous relapser
• IL28B CC

Source CCO

For Genotype 2 - 6, PegIFN/RBV is still Standard of Care

• Effective therapy with higher cure rates in Genotype 2 and 3

than genotype 1

• 24-48 wks of therapy is recommended[1,2]
• Some patients (with RVR and low baseline HCV RNA) may be treated

for 16 wks if therapy poorly tolerated, although relapse rates may be higher[2]

• Future regimens may offer further improvements, such as
• Shorter durations
• All-oral therapy
• Fewer adverse events
• 1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. EASL. J Hepatol. 2011;55:245-264.

Source CCO

N-CORE: 24 vs 48 Wks of PegIFN alfa-2a + RBV in GT2/3 Patients Without RVR

Multicenter, international, randomized, open-label phase IIIb trial

Adapted from CCO; Cheinquer H, et al. AASLD 2012. Abstract 156.

Tx-naive patients with chronic GT2/3 HCV infection who initiated pegIFN/RBV therapy and did not achieve RVR but did achieve EVR (N = 235)*

Continue PegIFN/RBV (n = 93)

Stop therapy; 48-wk follow-up (n = 95) Stop therapy; 24-wk follow-up Wk 24 Wk 48 Wk 72 *47 patients dropped out and did not reach randomization at Wk 24.

N-CORE: SVR24 Rates Comparable With 24 or 48 Wks of PegIFN alfa-2a/RBV

• Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm

Adapted from CCO Cheinquer H, et al. AASLD 2012. Abstract 156. Reproduced with permission.

Odds Ratio 0.68 0.63 0.44 95% CI 0.38-1.21 0.35-1.16 0.22-0.89 P Value .1934 .1461 .0231 49/ 95 57/ 93 49/ 95 51/ 81 49/ 90 46/ 63 SVR24 (%) 52 ITT (n = 188) 20 40 60 80 100 Per Protocol (n = 176) Study Completer (n = 153) 24-wk pegIFN/RBV 48-wk pegIFN/RBV 61 52 63 54 73 n/N =

Milestones in Therapy of Genotype 1 HCV

Adapted from CCO

IFN 6 mos PegIFN/ RBV 12 mos IFN 12 mos IFN/RBV 12 mos PegIFN 12 mos 2001 1998 2011 Standard interferon Ribavirin Peginterferon 1991 Direct-acting antivirals PegIFN/ RBV/ DAA IFN/RBV 6 mos 6 16 34 42 39 55 70+ 20 40 60 80 100

Two Protease Inhibitors Approved for GT1 HCV Infection Combined With PR

Protease Inhibitor Recommendations Administration Boceprevir 800 mg TID (every 7-9 hrs)[1,2]

• Naive to previous therapy
• Previous treatment failure
• Compensated cirrhosis
• Response-guided therapy
• Take with food
• All patients initiate therapy

with 4-wk pegIFN/RBV lead- in phase

• After completion of lead-in

phase, boceprevir should be added to continued pegIFN/RBV for 24-44 wks Telaprevir 750 mg TID (every 7-9 hrs)[2,3]

• Naive to previous therapy
• Previous treatment failure
• Compensated cirrhosis
• Response-guided therapy
• Take with food (not low fat)
• All patients initiate therapy

with 12-wk period of triple therapy with telaprevir plus pegIFN/RBV

• Followed by 12-36 wks of

pegIFN/RBV

• 1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
• 3. Telaprevir [US package insert]. October 2012.

Source CCO

OPTIMIZE: Telaprevir BID vs Telaprevir q8h in Tx- Naive Pts With GT1 HCV Infection

Randomized, multicenter, open-label phase III noninferiority trial

Buti M, et al. AASLD 2012. Abstract LB-8. Treatment- naive patients with chronic GT1 HCV infection (N = 740) Telaprevir 750 mg q8h + PegIFN/RBV (n = 371) Telaprevir 1125 mg BID + PegIFN/RBV (n = 369) PegIFN/RBV

Stratified by fibrosis status (F0-F2 vs F3-F4), IL28B GT (CC, CT, TT)

Wk 12 Wk 24 Wk 48 PegIFN/RBV PegIFN/RBV

RVR No RVR

Follow-up PegIFN/RBV

RVR No RVR

Follow-up

Source CCO

• SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups
• Similar safety and tolerability profile in both treatment arms

OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection

Buti M, et al. AASLD 2012. Abstract LB-8.

TVR q8h/PR TVR BID/PR SVR12 (%) 20 40 60 80 100 CC CT TT

n/ N =

87 92 68 68 65 66

92/ 106 97/ 105 141/ 208 139/ 206 37/ 57 38/ 58

F0-2 F3/4 78 81 59 58

209/ 268 213/ 264 61/ 103 61/ 105

IL28B GT Liver Disease Status

Source CCO

SVR Rates With BOC or TVR + PR According to Treatment History

20 40 60 80 100 SVR (%)

Naive

63-75

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364: 2405-2416. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364: 2417-2428. Bronowicki JP, et al. EASL 2012. Abstract 11.

Relapsers

69-83

Partial Responders

40-59

Null Responders

29-40

> > >

Source CCO

RGT Paradigm With BOC + PegIFN/RBV in Tx- Naive Noncirrhotic Patients

Boceprevir [package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

BOC + PegIFN + RBV 48 28 12 4 PegIFN + RBV 8 36 24 Early response; stop at Wk 28; f/u 24 wks

HCV RNA

Undetectable Undetectable < 100 IU/mL 48 28 12 4 PegIFN + RBV PegIFN + RBV 8 36 BOC + PegIFN + RBV 24

HCV RNA

Detectable Undetectable Slow response; extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks < 100 IU/mL

Source CCO

RGT Paradigm With TVR + PegIFN/RBV in Treatment-Naive Noncirrhotic Patients

Telaprevir [package insert]. October 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

TVR + PegIFN + RBV 48 24 12 4 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV TVR + PegIFN + RBV 48 24 12 4 PegIFN + RBV

HCV RNA

Undetectable Undetectable Detectable (≤ 1000 IU/mL) Undetectable or detectable (≤ 1000 IU/mL) No eRVR; extend pegIFN + RBV to Wk 48; f/u 24 wks

HCV RNA

Source CCO

Boceprevir + PegIFN/RBV in Cirrhotics and Treatment-Experienced Patients

BOC + PegIFN + RBV 48 28 12 4 PegIFN + RBV 8 36 24 Early response; stop at Wk 36; f/u 24 wks Slow response; PegIFN + RBV F/u 24 wks

Boceprevir [package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

BOC + PegIFN + RBV 48 28 12 4 PegIFN + RBV 8 36 24 F/u 24 wks

• Previous relapsers or partial responders are eligible for shortened therapy if

HCV RNA undetectable at Wks 8 and 24

• Previous null responders or current cirrhotics receive fixed-duration therapy

Source CCO

Telaprevir + PegIFN/RBV in Cirrhotics and Treatment-Experienced Patients

Telaprevir [package insert]. October 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

F/u 24 wks TVR + PegIFN + RBV 48 24 12 4 PegIFN + RBV No eRVR; PegIFN + RBV TVR + PegIFN + RBV 48 24 12 4 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u 24 wks

• Previous relapsers are eligible for shortened therapy if HCV RNA negative at

Wks 4 and 12

• Previous partial responders, null responders, and current cirrhotics receive

fixed-duration therapy

Source CCO

Adverse Events With HCV Therapy

• Treatment-naive, GT1 protease inhibitor phase III trials
• IFN adverse events are a dominant feature

Adverse Event, % Boceprevir RGT (N = 368) Placebo (N = 363) ADVANCE T12PR (N = 363) Placebo (N = 361) Fatigue 53 60 57 57 Headache 46 42 41 39 Nausea 48 42 43 31 Diarrhea 22 22 28 22 Pyrexia 33 33 26 24 Chills 36 28 13 15 Insomnia 32 33 32 31

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Source CCO

Telaprevir : Side effects

• Significant more Rash, Anemia, and “anorectal events” in Telaprevir arms vs

cnontrol arms

Adverse event % PR48 (n = 493) TVR + PR RGT/48* (n = 1797) Rash 34 56 Anemia† 17 36 Anorectal events 7 29

*pooled data.

†Anemia was treated with RBV-dose reduction; Erythropoietin alfa was not allowed.

Telaprevir [package insert]. May 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

• Most patients showed a mild or moderate rash

– Severe Rash in 4%; discontinuation due to rash in 6%

– Appears early, generally during the first four weeks, can appear at every time point – < 1% SJS or DRESS (11 cases of DRESS and 3 cases of SJS)

Source CCO

Boceprevir: Side effects

• Significant more anemia, neutropenia and dysgeusia in

Boceprevir arms vs. control arms

Adverse event % PR48 (n = 467) BOC + PR RGT/48 (n = 1225) Anemia* 30 50 Neutropenia 19 25 Dysgeusia 16 35

*Anemia was treated with RBV-dose reduction and/or with Erythropoietin alfa (43% of BOC + PR and 24% of PR).

Boceprevir [package insert]. May 2011. Source CCO

• TVR
• Substrate of CYP3A
• Inhibitor of CYP3A
• Substrate and inhibitor of P-

gp

Both BOC and TVR Have Potential for Many Drug– Drug Interactions

• BOC

– Strong inhibitor of CYP3A4/5 – Partly metabolized by CYP3A4/5 – Potential inhibitor of and substrate for P-gp

• Most drug–drug interactions can be overcome by careful

survey of the patient’s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy)

Source CCO

Medicines That Are Contraindicated With BOC and TVR

• 1. Boceprevir [package insert]. July 2012. 2. Telaprevir [package insert]. October 2012.

Drug Class* Contraindicated With BOC[1] Contraindicated With TVR[2] Alpha 1-adrenoreceptor antagonist Alfuzosin Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin N/A Antimycobacterials Rifampin Rifampin Antiretrovirals EFV, all RTV-boosted PIs DRV/RTV, FPV/RTV, LPV/RTV Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents Cisapride Cisapride Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum HMG CoA reductase inhibitors Lovastatin, simvastatin Lovastatin, simvastatin Oral contraceptives Drospirenone N/A Neuroleptic Pimozide Pimozide PDE5 inhibitor Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN Sedatives/hypnotics Triazolam; orally administered midazolam Orally administered midazolam, triazolam

*Studies of drug–drug interactions incomplete.

Source CCO

SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC

• 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
• 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.

BOC + pegIFN-α2b/RBV RGT BOC + pegIFN-α2b/RBV 48 wks

93/ 133 89/ 134 100 50 1b 1a Genotype[1] 70 66 ≤ 800,000 > 800,000 HCV RNA (IU/mL)[1] 85 76 F0-2 F3/F4 Fibrosis[1] 67 67 SVR (%) 75 25 41/ 54 45/ 53 213/ 319 211/ 313 n/ N = 63 59 63 61 41 52 118/ 187 106/ 179 14/ 34 22/ 42 192/ 314 197/ 313 44/ 55 82/ 115 26/ 44 CC CT TT 80 71 59 IL28B[2]

Source CCO

1b 1a Genotype[1] < 800,000 ≥ 800,000 HCV RNA (IU/mL)[1] F0-2 F3/F4 Fibrosis[1]

ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR

• Data from TVR12 + pegIFN-α2a/RBV arm only
• 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

CC CT TT IL28B*[2] 152/ 213 118/ 149 100 50 79 71 78 74 62 78 SVR (%) 75 25 207/ 281 64/ 82 45/ 73 226/ 290 n/ N = 45/ 50 48/ 68 16/ 22 90 71 73

*IL28B testing was in whites only.

Source CCO

SVR by Response at Wk 4 in Lead-in Arms of Treatment-Experienced Trials

• 1. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 2. Foster G, et al. EASL 2011. Abstract 6.

≥ 1 log decline < 1 log decline 20 40 60 80 100 33 REALIZE (TVR)[2] 82 158

*Pooled data from RGT and fixed dose arms.

20 40 60 80 100 SVR (%) 33 RESPOND-2* (BOC)[1] 76 SVR (%)

Outcomes in Clinical Practice: CUPIC Study of the French Early Access Program

Outcome, % Telaprevir (N = 292) Boceprevir (N = 205) Serious adverse event 45 33 Premature discontinuation 23 26 Hepatic decompensation 2 3 Death* 3 1 Infection (grade 3 or 4) 7 2

• Why are the results different from phase III trials?

– Higher risk in cirrhotic patients? – Study population healthier in phase III trials? – Is the population truly compensated cirrhosis?

*Causes of death: septicemia, septic shock, pneumopathy (2), endocarditis, esophageal varices bleeding.

Hezode C, et al. AASLD 2012. Abstract 51. Source CCO

CUPIC: Efficacy of TVR in Cirrhotics

• ~ 80% of patients treated with TVR-based therapy had

undetectable HCV RNA at end of 16 wks of triple therapy

Hezode C, et al. AASLD 2012. Abstract 51.

20 40 80 100 Undetectable HCV RNA (%) 60

145/ 276

53 Wk 4 Wk 8 Wk 12 Wk 16

145/ 285 224/ 265 224/ 282 219/ 254 219/ 281 177/ 205 177/ 251

51 85 79 86 78 86 71 Per protocol ITT

n/N =

Source CCO

CUPIC: Efficacy of Boceprevir in Cirrhotics

• ~ 60% of patients treated with BOC-based therapy had

undetectable HCV RNA at Wk 16 of ongoing therapy

2/ 155

1 Wk 4 Wk 8 Wk 12 Wk 16

2/ 155 55/ 149 55/ 150 88/ 144 88/ 151 89/ 126 89/ 146

1 37 37 61 58 71 61 Undetectable HCV RNA (%)

n/N =

Per protocol ITT 20 40 80 100 60

Hezode C, et al. AASLD 2012. Abstract 51. Source CCO

Futility Rules for Boceprevir or Telaprevir + PegIFN/RBV

• All therapy should be discontinued in patients with the

following:

• 1. Boceprevir [package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
• 3. Telaprevir [package insert]. October 2012.

*Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of ~ 10-15 IU/mL.

Boceprevir[1,2] Time Point Criteria* Action Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue all therapy Telaprevir[2,3] Time Point Criteria* Action Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue pegIFN/RBV

Source CCO

Viral Kinetics in Patients Who Met > 1000 IU/mL HCV RNA Wk 4 Stopping Rule With TVR

Treatment-Naive Patients Treatment-Experienced Patients

108 107 106 105 104 103 102 4 6 8 12 10 2 Wks HCV RNA (IU/mL) 4 6 8 12 10 2 Wks HCV RNA (IU/mL) 108 107 106 105 104 103 102

Jacobson IM, et al. EASL 2012. Abstract 55.

10 10

Source CCO

Resistance Rates Differ According to Lead-in Response (SPRINT-2)

• ≥ 1 log HCV RNA decrease
• SVR in 82% of nonblack boceprevir recipients
• Boceprevir resistance in 4% to 6% of patients
• < 1 log HCV RNA decrease
• SVR in 29% to 39% of nonblack boceprevir recipients
• Boceprevir resistance in 40% to 52% of patients

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Source CCO

Study 110: Telaprevir + PegIFN/RBV in GT1 HCV Tx- Naive HCV/HIV Coinfection

• Multicenter, randomized, double-blind, placebo-controlled phase II trial

Placebo + PegIFN/RBV Placebo + PegIFN/RBV PegIFN/RBV (n = 16) Part B: Stable ART HCV/HIV-coinfected patients on stable ART,* CD4+ cell count ≥ 300 cells/mm3, HIV-1 RNA ≤ 50 copies/mL (N = 47) Follow-up Part A: No Current ART HCV/HIV-coinfected patients, CD4+ cell count ≥ 500 cells/mm3, HIV-1 RNA ≤ 100,000 copies/mL (N = 13) Follow-up PegIFN/RBV (n = 6) PegIFN/RBV (n = 7) TVR† 750 mg q8h + PegIFN/RBV PegIFN/RBV (n = 31) Wk 12 Wk 48 WK 72 (SVR24) Wk 60 (SVR12) TVR† 750 mg q8h + PegIFN/RBV

Sulkowski MS, et al. AASLD 2012. Abstract 54.

*Either EFV/TDF/FTC or ATV/RTV + TDF + (FTC or 3TC).

†TVR dose increased to 1125 mg q8h with EFV.

Source CCO

Study 110: SVR24 With TVR + PegIFN/RBV in HCV GT1/HIV-Coinfected Patients

• Higher SVR24 rate with TVR-based

therapy

• No significant drug–drug

interactions with TVR and ART

• TVR plasma levels similar in

patients with or without ART

• EFV and ATV/RTV plasma

levels similar in patients with

• r without TVR
• No HIV breakthroughs in patients

using ART during HCV treatment

• Safety and tolerability similar to

treatment in patients with HCV monoinfection

Sulkowski MS, et al. AASLD 2012. Abstract 54..

Telaprevir + PR Placebo + PR 74 71 69 80 45 33 50 50 20 40 60 80 100

28/ 38 10/ 22 5/ 7 2/ 6 11/ 16 4/ 8 12/ 15 4/ 8

SVR24 (%)

n/N =

Source CCO

Limitations of Current Regimens and Prospects for Future Regimens

Current

• Must be eligible for pegIFN/ RBV
• Large pill burden, TID dosing of PIs

(at present); parenteral IFN

• Challenging adverse events
• High likelihood of resistance with

treatment failure

• Current PIs only effective for

genotype 1

• Possibility of resistance with poor

adherence

Future

• Perhaps IFN free
• Lower pill burden, less than TID

dosing; perhaps all oral

• May be better tolerated
• May not generate resistance
• Pangenotypic or at least more
• Higher barrier to resistance with

some classes

However: There is no trial available for Non-Responder of tripple therapy! Patients with cirrhosis, non response to DAA‘s, Genotype 1a and probably 3 will be difficult to treat.

Source CCO

Thank you for your attention!