HCV, hepatitis C virus; ITT, intent to treat; TVR, telaprevir. For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/8.aspx
BOC, boceprevir; HCV, hepatitis C virus; ITT, intent to treat. For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/8.aspx
SVR, sustained virologic response.
HCV, hepatitis C virus.
BOC, boceprevir; HCV, hepatitis C virus; p egIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response.
HCV, hepatitis C virus; p egIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.
DAA, direct-acting antiviral; ESA, erythropoiesis-stimulating agents; Hb, hemoglobin; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin.
BOC, boceprevir; CI, confidence interval; DR, dose reduction; EPO, erythropoietin; HCV, hepatitis C virus; p egIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response. For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/1419.aspx
Key Point Cross-resistance does not occur between Peg-IFN/RBV and different classes of DAAs, and therefore combining multiple agents may provide an opportunity for elimination of DAA-resistant HCV variants. Notes Variants resistant to DAAs have shown to be susceptible to Peg-IFN/RBV, and combination therapy suppressed the emergence of variants in clinical trials. 1–9 Cross-resistance relates to mutations that confer resistance to more than one drug. Multiple DAAs are in development and can be classified according to which HCV moiety they bind to, and how/where they bind to it. Some examples include: NS3 protease inhibitors: macrocyclic (danoprevir, vaniprevir, TMC435, BI201335, and BMS-650032) or linear (telaprevir, boceprevir, ACH-1625 and GS 9256). NS5B polymerase inhibitors: Nucleoside (active site) inhibitors (RG7128, IDX184, INX-189 and PSI-7977) or non-nucleoside (allosteric) inhibitors. Non-nucleoside inhibitors: palm (ABT-333, ABT-072, GS 9190, ANA598 and IDX-375), thumb (VCH-759, VCH-916, VX-222, BI 207127 and filibuvir) or finger. NS5A inhibitors (BMS-790052, GS 5885 and PPI-461). Importantly, cross-resistance does not occur between DAA classes that have different mechanisms of action. Future HCV treatment regimens may include combinations of multiple classes of DAAs. References 1. Hézode C, et al. N Engl J Med 2009;360:1839–50. 2. Kwo P, et al. J Hepatol 2009;50(Suppl. 1):S4. 3. McHutchison JG, et al. N Engl J Med 2009;360:1827–38. 4. Sarrazin C, et al. J Hepatol 2009;50(Suppl. 1):S350. 5. Sarrazin C, et al. Gastroenterology 2007;132:1767–77. 6. Forestier N, et al. J Hepatol 2009;50(Suppl. 1):S35. 7. Manns MP, et al. Hepatology 2008;48(Suppl.):1133A. 8. Kieffer TL, et al. Hepatology 2007;46:631–9. 9. Forestier N, et al. Hepatology 2007;46:640–8.
GT, genotype; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; SVR, sustained virologic response; Tx, treatment. For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/2.aspx
EOT, end of treatment; GT, genotype; HCV, hepatitis C virus; NA, not available; pegIFN, peginterferon; PR, peginterferon/ribavirin; QD, once daily; RBV, ribavirin; SVR, sustained virologic response.
Inibitori delle proteasi di I generazione: sono una reale innovazione? - Gastrolearning®
18 Dicembre 2012Inibitori delle proteasi di HCV di I generazione: sono una reale innovazione? Antonio Craxì Gastroenterologia & Epatologia, Di.Bi.M.I.S. Università di Palermo firstname.lastname@example.org
Epidemiology of Hepatitis C in Europe Time trends incidence • 9 million chronic carriers • 27,000 to 29,000 newly diagnosed cases per year • 86,000 deaths per year • Most affected age group: 25- 44 year, followed by 15-24 year • Clustered to sub-populationsVan de Laar, Hepatitis Summit Conference, Brussels 2010
Map of estimated anti-HCV seroprevalence by GBD region, 2005Hanafiah et al, Hepatology in press
Treatment of Hepatitis C: Evidence for Effectiveness in SVR Patients 1. Durable HCV-RNA eradication achievable 2. Histological reversal of cirrhosis documented 3. Reduced rates of decompensation and HCC 4. Reduced rates of liver-related mortality
Accessibility to Peg-IFN antiviral therapy in different European countries 4 16 HCV prevalence HCV prevalence rate (%) Treatment levels 14 Patients treated per 100 3 12 prevalent cases 10 2 8 6 1 4 2 0 0 Belgium France Germany Italy Spain UK There are substantial differences between European countries in terms of HCV prevalence and access to antiviral therapyPeg-IFN/RBV: peginterferon plus ribavirin Deuffic-Burban S, et al. Gastroenterology 2012;[ePub ahead of print]
Effect of treatment strategy* according to fibrosisstage on HCV-related cirrhosis and deaths† Cumulative HCV-related cirrhosis and deaths (95% CI) Treatment scenario Cirrhosis Deaths With treatment 330,700 282,300 (baseline scenario) (313,200–342,000) (268,600–294,200) Never treating patients 359,300 295,000 with F0/F1 (339,900–372,200) (280,700–307,700) Not treating F0/F1 332,200 282,700 until F2 is reached (314,600–343,600) (269,000–294,600) Not treating F0/F1 342,400 285,900 until F3 is reached (324,100–354,300) (272,100–298,000) • In comparison to the baseline scenario, delaying treatment in patients with F0/F1 is associated with an increase in HCV-related cirrhosis and deaths, regardless of the scenario • Delaying treatment until F2 is reached appears to be efficient in terms of mortality but will necessitate efficient diagnostic testing of fibrosis to detect progression from F0/F1 to F2*With Peg-IFN + RBV; †All genotypes Deuffic-Burban S, et al. Gastroenterology 2012 [Epub ahead of print]
Milestones in Therapy of Genotype 1 HCV Direct-acting antivirals 100 2011 Peginterferon 80 Ribavirin 2001 Standard 70+ interferon 1998 60 SVR (%) 55 1991 42 39 40 34 20 16 6 0 IFN IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/ RBV RBV/ 6 mos 12 mos 6 mos 12 mos 12 mos 12 mos DAAAdapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.
Naive patients Increased SVR compared to Peg-IFN/RBV Boceprevir Telaprevir SVR increases from 38% to SVR increases from 44% to 63/66% 72/75% ( + 25-28%) (+ 28-31%) Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.
Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV Boceprevir Telaprevir Relapsers Relapsers SVR increases from 29% to 75% SVR increases from 24% to 83/88% Partial-Responders Partial-responders SVR increases from 7% to 52% SVR increases from 15% to 54-59% Null-responders SVR increases from 5% to 29/33%Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3
Chance for Cure in HCV 1. The Impact of Triple Therapy A Systematic Review Patients Dual Triple ∆ Pts # SVR Pts # SVRPreviously untreated 1545 39% 1634 <2-fold 68.5%Relapsers/Partial 539 26% 719 73% 3-foldResp.Nonresponders 255 7.5% 386 44% 6-foldJurchis AR et al. EASL 2012, Poster 1123 (S442)
Number of Patients Ever Treated With PEG IFNs per 100 Prevalent HCV Cases until End of 2005 Patients ever treated with Peg-IFNs per 100 prevalent casesLettmeier B et al, J Hepatol 2008;49:528-536
Treatment of HCV genotype 1 in Italy: the current situation∀ ∼ 7000 patients HCV Gt 1 patients treated each year (2008- 2011) with a 10% yearly trend to decrease (2010-2011): – Spontaneous change due to disease epidemiology – Warehousing effect (triple therapy IFN-free)∀ ∼ ¼ of Gt 1 patients treated yearly (2008-2010) were re- treatments. This figure has decreased markedly in 2011 (warehousing for triple therapy)• Yearly expenditure (2011) for P/R: 165,000,000 Euros• Aging population of naives (mean age at tx 48 years) with 25- 30% of F3/F4 fibrosis• At least 20,000 patients with previous P/R failures (usually unclassified) with a mean age > 55 years and at least 40% of F3/F4 fibrosis
HCV-AIFA Italian study: RVR and SRV to P/R in genotype 1 patients according to baseline factors Variables N. of patients RVR SVR No favorable factors 21/179 (11.7%) 1/19 (5.2%) 3/21 (14.3%) 1 favorable factor 82/179 (45.8%) 17/80 (21.2%) 25/82 (30.5%)MALES 2 favorable factors 62/179 (34.6%) 25/58 (43.1%) 37/62 (59.6%) 3 favorable factors 14/179 (7.8%) 9/14 (64.3%) 12/14 (85.7%)Favorable factors: HCV-RNA < 400,000 UI/mlC/C genotype of rs12979860 SNPNo visceral obesity (VOB) Variables N. of patients RVR SVR No favorable factors 58/152 (38.1%) 8/57 (14.1%) 16/58 (27.6%) 1 favorable factor 75/152 (49.4%) 20/70 (28.6%) 26/75 (48.0%)FEMALES 2 favorable factors 19/152 (12.5%) 12/17 (70.1%) 16/19 (84.2%)Favorable factors: Age < 50 yearsC/C genotype of rs12979860 SNP
The balance of triple therapy with boceprevir and telaprevir Advantages Disadvantages Not sufficiently tested in difficult First-generation protease inhibitors patients (cirrhosis) increase SVR rates in naive and Modest potency with development treatment-experienced patients1,2 of resistance2,3 and may reduce liver-related morbidity and mortality in the long- Genotype 1 restricted term1,2 Complex regimens, with risk of Potential for shorter poor adherence2 treatment duration1,2 Increased adverse reactions and toxicity burden2 Increased risk of DDIs2 Costs 1. Ghany MG, et al. Hepatology 2011; 54: 1433–44 2. Ferenci P & Reddy KR. Antivir Ther 2011; 16: 1187–1201 3. Pawlotsky J-M. Hepatology 2011; 53: 1742–51
Addition of BOC or TVR to PegIFN/RBV Improves SVR in Genotype 1 Patients BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV patients who are previously untreated or who have failed previous therapy 100 69-83 PegIFN + RBV 80 BOC/TVR + pegIFN* + RBV 63-75 40-59SVR (%) 60 38-44 29-40 40 24-29 20 7-15 5 0 Treatment Relapsers[3,4] Partial Null Naive[1,2] Responders[3,4] Responders[4,5] *BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.5. Bronowicki JP, et al. EASL 2012. Abstract 11.
RGT Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients Indicated for all noncirrhotic treatment-naive patients HCV RNA Undetectable < 100 IU/mL Undetectable PegIFN/ BOC + PegIFN/RBV Early response stop at Wk 28; f/u 24 wks RBV 0 4 8 12 24 28 36 48 HCV RNA Detectable < 100 IU/mL Undetectable Slow response extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks PegIFN/ BOC + PegIFN/RBV PegIFN/RBV RBV 0 4 8 12 24 28 36 48Boceprevir [US package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444.Boceprevir [EU package insert]. July 2012.
Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients Indicated for noncirrhotic previous relapsers or partial responders* [1,2] HCV RNA Undetectable < 100 IU/mL Undetectable PegIFN/ BOC + PegIFN/RBV Early response stop RBV at Wk 36; f/u 24 wks 0 4 8 12 24 28 36 48 HCV RNA Detectable < 100 IU/mL Undetectable Slow response PR to Wk 48; f/u 24 wks PegIFN/ BOC + PegIFN/RBV PegIFN/RBV RBV 0 4 8 12 24 28 36 48 *RGT for this group indicated in US only; European prescribing information indicates that noncirrhotic previous relapsers or partial responders should receive 4 wks of pegIFN/RBV followed by 32 wks of BOC + pegIFN/RBV and then 12 wks of pegIFN/RBV, regardless of early response. 1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Boceprevir [EU package insert]. July 2012.
RGT With TVR + PegIFN/RBV in Tx-Naive Patients and Previous Relapsers Indicated for all noncirrhotic treatment-naive pts and previous relapsers*[1,3] HCV RNA Undetectable Undetectable Undetectable TVR + PegIFN/RBV PegIFN/RBV eRVR stop at Wk 24, f/u 24 wks 0 4 12 24 48 HCV RNA Detectable Undetectable or(≤ 1000 IU/mL) Undetectable detectable (≤ 1000 IU/mL) No eRVR extend pegIFN/ RBV to Wk 48; f/u 24 wks TVR + PegIFN/RBV PegIFN/RBV 0 4 12 24 48 *AASLD guidelines say RGT “may be considered” for previous partial responders but package inserts recommend  48 wks of therapy.[1,3]1. Telaprevir [US package insert]. October 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [EU package insert]. March 2012.
Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive and Tx-Exp’d Pts All therapy should be discontinued in patients with the following: 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 *Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL.1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [US package insert]. October 2012.
Use of HCV RNA Assays in ManagingPatients Receiving BOC or TVR A quantitative assay with an LLOQ of ≤ 25 IU/mL and an LLOD of approximately 10-15 IU/mL must be used HCV RNA undetectable* (“target not detected”) required to qualify for RGT – Detectable but < LLOQ is not equivalent to undetectable – Carefully read HCV RNA assay report to ensure HCV RNA was undetected or “target not detected” before truncating therapy*An assay with a LLOD of approximately 10-15 IU/mL must be used.
BOC Plus PegIFN alfa-2b/RBV: Adverse Events Higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs control Adverse Event, % PR48 BOC + PR RGT/48* (n = 467) (n = 1225) Anemia* 30 50 Neutropenia 19 25 Dysgeusia 16 35 *Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR).Boceprevir [US package insert]. July 2012.
TVR Plus PegIFN alfa-2a/RBV: Adverse Events Higher rates of rash, anemia, and anorectal signs and symptoms in TVR arms vs control Adverse Event, % PR48 TVR + PR RGT/48* (n = 493) (n = 1797) Rash 34 56 Anemia‡ 17 36 Anorectal events 7 29 *Pooled results from TVR arms. † Anemia was managed with RBV dose modification; epoetin alfa was not permitted. In most subjects, rash was mild to moderate – Severe rash in 4%; discontinuation due to rash in 6% of subjectsTelaprevir [US package insert]. October 2012.
Multivariate analysis: baseline predictors of severe complications*Predictors OR 95%CI p-valueProthrombin Time 1.03 1.01-1.06 0.038(per unit decrease)Age 1.05 1.01-1.11 0.025(per year increase)Platelet count 3.19 1.32-7.73 0.0098≤100,000/ mm3Albumin level 4.95 2.04-12.01 0.0004<35 g/L * Death, severe infection and hepatic decompensation, n=32
Multivariate analysis: predictors of anemia <8g/dL or blood transfusion *Predictors OR 95%CI p-valueAge 1.06 1.026-1.09 0.0003(per year increase)Gender 2.32 1.10-4.35 0.023(Female)No lead-in phase 2.33 1.22-4.35 0.01Hemoglobin level 5.85 2.83-12.08 <0.0001≤12 g/dL for female≤13 g/dL for male * n=71
Rationale for Prompt Treatment of HCV HCV is a progressive disease, associated with persistence of viral replication and ongoing necroinflammation and fibrosis Remission (SVR) is associated with loss of active viral replication and improvement in hepatic fibrosis Important questions – Does that equate to a need to treat all patients? – Can we avoid losing time for patients destined to progress? – How do we avoid unnecessary or detrimental treatment when there are improved treatments pending?
Indications for Treatment of ChronicHCV Infection All patients, regardless of the degree of fibrosis, are potential candidates for treatment IFN-based therapy is current standard of care Patients with mild disease may not require immediate treatment For those who require treatment – Patients should be fit for the regimen – Patients should have the ability to adhere to treatment goals and monitoring There is a complex ongoing debate regarding opportune timing for treatment given the therapeutic landscape
Who Should Be Treated Now?Pts Who Want Tx Pts Who Are Pts Who AreWant to be cured of Eligible for Tx Motivated anddisease Eligible for pegIFN/ RBV Understand . . .Personal or social Fit for regimen Likelihood of responsereasons No contraindications Risks/benefits ofPlans for pregnancy treatment Disease stageSocial support Risk of resistanceEligible for Possibility of shortenedreimbursement now therapy What is “coming down the line” for their genotype
Severity of Disease Increases Need forHCV Therapy but Also Impairs Response May not need immediate treatment Greater need for treatment BUT BUT Easier to treat Response may be impaired High likelihood of Perhaps more effective options in response future, but efficacy of some investigational agents may be unclear due to trial eligibility criteria Mild disease Advanced disease/ cirrhosis
What Are the Chances of Being Cured WithCurrent Therapy? Black Cirrhosis Genotype 1 White No fibrosis (1a worse than 1b) IFN nonresponsive Genotype 2/3 IFN responsive (eg, IL28B TT RVR/EVR or response to lead-in) Previous relapser IL28B CC Less favorable Favorable prognostic factors prognostic factors
Limitations of Current Regimens andProspects for Future RegimensCurrent FutureMust be eligible for pegIFN/ RBV Perhaps IFN freeLarge pill burden, TID dosing of Lower pill burden, less than TIDPIs (at present); parenteral IFN dosing; perhaps all oralChallenging adverse events May be better toleratedHigh likelihood of resistance with May not generate resistancetreatment failure Pangenotypic or at least moreCurrent PIs only effective forgenotype 1 Higher barrier to resistance with some classesPossibility of resistance with pooradherence
Challenging Patients for Whom TreatmentWith Current Options Less Than Optimal Cirrhosis (all genotypes) Injection-drug users Decompensated cirrhosis – Methadone substitution Null responders Thalassemics Pretransplantation Children Posttransplantation IFN contraindicated Renal failure IFN intolerant – Impaired renal function Those on “edge” of society – Dialysis Psychiatric comorbidity – Renal transplantation recipients
Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis No SVR 100 SVR 80 Patients With Liver Complications (%) 60 40 20 0 0 24 48 72 96 120 144 168 Mos Pts at Risk, n 759 702 634 527 345 207 34 124 119 116 108 70 41 12Bruno S, et al. Hepatology. 2007;45:579-587.
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 100 Per protocol 85 86 86 ITT 79 Undetectable HCV RNA (%) 78 80 71 60 53 51 40 20 n/N = 145/ 145/ 224/ 224/ 219/ 219/ 177/ 177/ 276 285 265 282 254 281 205 251 0 Wk 4 Wk 8 Wk 12 Wk 16Hezode C, et al. AASLD 2012. Abstract 51.
CUPIC: Efficacy of Boceprevir in Cirrhotics ~ 60% of patients treated with BOC-based therapy had undetectable HCV RNA at Wk 16 of ongoing therapy 100 Per protocol ITT Undetectable HCV RNA (%) 80 71 61 58 61 60 40 37 37 20 1 1 n/N = 2/ 2/ 55/ 55/ 88/ 88/ 89/ 89/ 155 155 149 150 144 151 126 146 0 Wk 4 Wk 8 Wk 12 Wk 16Hezode C, et al. AASLD 2012. Abstract 51.
The First-Generation Protease Inhibitors:Where Are We Now? Telaprevir and boceprevir are harbingers of important treatment advance Improved SVR rates in both naive and experienced patients Certain patients (advanced disease) require therapy imminently and should be treated now Others may be motivated to be treated now—opportunities for cure, candidates for shortened therapy, and/or personal reasons For many, the choice is not clear The advent of triple therapy changes the way treatment discussed with patients – Clinicians must educate and advocate for patients to choose the correct course of treatment
Factors That InfluenceOutcomes With HCV Therapy
ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR Data from TVR12 + pegIFN-α2a/RBV arm only 100 90 79 78 78 71 74 71 73 75 62SVR (%) 50 25 n/ 118/ 152/ 64/ 207/ 226/ 45/ 45/ 48/ 16/ N = 149 213 82 281 290 73 50 68 22 0 1b 1a < 800,000 ≥ 800,000 F0-2 F3/F4 CC CT TT Genotype HCV RNA (IU/mL) Fibrosis IL28B* *IL28B testing was in whites only.1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
IL28B Genotype Predicts Likelihood of Eligibility for Shortened Therapy SPRINT-2: BOC + ADVANCE: T12 + PegIFN-α2b/RBV  PegIFN-α2a/RBV * 100 100 89 78 80 80 60 60 57 52 45 40 40 20 20 % T GRr o y ili b gl E % T GRr o y ili b gl E n/ 117/ 158/ n/ 39/ 39/ 10/ N= 132 304 N= 50 68 22 f t i i f t i i 0 0 CC CT/TT CC CT TT *IL28B testing in ADVANCE was in whites only.1. Poordad F, et al. Gastroenterology. 2012;143:608-618. 2. Jacobson IM, et al. EASL 2011. Abstract1369. ( (
IL28B Genotype Should Not Be Used to Exclude Patients From Therapy If patients have favorable CC genotype – Likelihood of SVR is high with pegIFN/RBV alone, but triple therapy may allow shorter therapy and, in one TVR study, higher SVR rates If patients have unfavorable CT/TT genotype – Likelihood of SVR is higher with triple therapy than with pegIFN/RBV – 59% to 71% in SPRINT-2 – 71% to 73% in ADVANCE* Limited value of IL28B genotyping in treatment-experienced patients – Most have unfavorable TT or CT genotype *IL28B testing in ADVANCE was in white Americans only.1. Jacobson IM, et al. EASL 2011. Abstract 1369. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.
Lead-in Strategy Can Help DetermineWhom to Treat 4 wks of pegIFN/RBV lead-in before BOC (or TVR) – Lowers HCV RNA burden – May identify rapid responders who may not need DAA – Allows assessment of IFN responsiveness – Provides useful information regarding likelihood of SVR with addition of DAA – Provides insight into tolerability of pegIFN/RBV backbone – Elucidates hematologic response to pegIFN/RBV, especially in “marginal” patients; make needed dose adjustments before addition of DAA
Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts PegIFN-α2b/RBV* A > 1 log10 decrease in HCV RNA at Wk 4 of therapy is the strongest BOC + pegIFN-α2b/RBV predictor of SVR RGT* SPRINT-2 and RESPOND-2 Combined BOC + pegIFN-α2b/RBV 100 48 wks* 81 81 82 82 80 75 75 76 67 60 SVR (%) 50 50 44 40 40 37 32 24 20 4 5 1/ 1/ n/N= 0/ 2/ 2/ 56/ 83/ 58/ 27 19/ 20/ 37/ 83/ 109/ 20 6/ 10/ 13/ 23/ 26/ 2 3 4 75 102 72 51 45 117 111 133 25 25 26 28 34 0 < 1 log ≥ 1 log < 1 log ≥ 1 log < 1 log ≥ 1 log CC CT TT *BOC was administered with pegIFN-α2b in these trials.Poordad F, et al. Gastroenterology. 2012;143:608-618.
Preparing for Treatment: Possibilities ofDrug–Drug Interactions
Both BOC and TVR Have Potential forMany Drug–Drug Interactions BOC TVR – Strong inhibitor of – Substrate of CYP3A CYP3A4/5 – Inhibitor of CYP3A – Partly metabolized by CYP3A4/5 – Substrate and inhibitor of P-gp – 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)
Medicines That Are Contraindicated With BOC and TVR Drug Class* Contraindicated With BOC Contraindicated With TVR Alpha 1-adrenoreceptor Alfuzosin Alfuzosin antagonist Anticonvulsants Carbamazepine, phenobarbital, N/A phenytoin Antimycobacterials Rifampin Rifampin Antiretrovirals EFV, all RTV-boosted PIs DRV/RTV, FPV/RTV, LPV/RTV Ergot derivatives Dihydroergotamine, ergonovine, Dihydroergotamine, ergonovine, ergotamine, methylergonovine ergotamine, methylergonovine GI motility agents Cisapride Cisapride Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum HMG CoA reductase Lovastatin, simvastatin Lovastatin, simvastatin inhibitors Oral contraceptives Drospirenone N/A Neuroleptic Pimozide Pimozide PDE5 inhibitor Sildenafil or tadalafil when used for Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN treatment of pulmonary arterial HTN Sedatives/hypnotics Triazolam; orally administered Orally administered midazolam, midazolam triazolam *Studies of drug–drug interactions incomplete.1. Boceprevir [package insert]. July 2012. 2. Telaprevir [package insert]. October 2012.
Preparing for Treatment:Management of Adverse Events
Adverse Effect Management: Anemia Recommendation: anemia should be managed initially by reducing the RBV dose Do not dose reduce DAA or stop and then restart Do not discontinue pegIFN/RBV and continue DAA Monitor closely if Hb falls < 10 g/dL ESA agents are unlabeled for HCV anemia – May be effective as a secondary anemia management strategy1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
EPO and RBV Dose Reduction for Anemia Lead to Similar SVR Rates in BOC Patients Nested study within randomized trial of genotype 1 HCV therapy-naive patients receiving 4 wks of lead-in with pegIFN-α2b/RBV and then either 44 wks of triple therapy or RGT (24-44 wks) 100 ∆ -0.7% (95% CI: -8.6 to 7.2)* 80 71 71 SVR (%) 60 40 20 n/N = 178/249 178/251 0 RBV DR EPO *Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort. 82% of RBV dose reduction group vs 62% in EPO group did not require secondary anemia interventionPoordad F, et al. EASL 2012. Abstract 1419.
Predictive Value of Anemia for SVR With BOC or TVR In phase III trials, anemia positive predictor of SVR with BOC but not TVR EOTR, relapse, and SVR comparable between RBV DR and EPO arms in treatment-naive patients who developed anemia during BOC/PR therapy SPRINT-2* ADVANCE and ILLUMINATE† 100 100 Hb ≥ 10 g/dL Hb < 10 g/dL 80 72 80 73 74 58 SVR (%) 60 60 40 40 20 20 0 n/N = 212/363 263/363 0 n/N = 384/524 267/361 *Data from BOC/48 and BOC RGT arms. † Data from T12/PR arm only.1. Sulkowski MS, et al. Hepatology. 2012;[Epub ahead of print]. 2. Poordad F, et al. DDW 2011. Abstract 626.
Adverse Effect Management:Rash and Anorectal Symptoms Rash management – Mild to moderate rash can be treated with oral antihistamines, topical steroids – Systemic steroids are not recommended – For severe rash, many practitioners will stop TVR alone and follow for 1 wk to see if the rash improves – If not, stop all 3 drugs – Important to have “go-to” dermatologist; vigilance with rash is key Anorectal symptom management – Fiber, loperamide, hydrocortisone, pramoxine topical cream, topical lidocaine
Managing Major Adverse Effects ofPegIFN Depression – Assess mood, sleep, suicidal thoughts – Consider SSRI to treat baseline or new depression – Refer to mental health services to follow high-risk patients during treatment Influenzalike symptoms – Acetaminophen, hydration – Reduce dose of IFN if necessary Neutropenia, thrombocytopenia: monitor CBC frequently Others: GI upset, hair loss, insomnia, injection-site reactions
Helping Patients Adhere to ComplexRegimens PegIFN/RBV + BOC or TVR = very complex regimen – BOC 800 mg TID: 12 pills/day with food – TVR 750 mg TID: 6 pills/day with high-fat meal – RBV (2-6 pills/day) and weekly pegIFN injection Adherence enhanced by a combination of – Patient education and motivation – Reducing pill burden when possible – Shortening therapy when appropriate – Prompt adverse effect management
Optimizing Current HCV Therapy With PIs Plus PegIFN/RBV
Strategies to Enhance Current Therapy With PegIFN/RBV Plus PI for GT1 Pts Shorter therapy may be possible for certain patients – Investigational T12/PR12 regimens for IL28B CC patients PR alone for IL28B CC patients? – Being evaluated in phase III trial vs BOC + pegIFN-α2a/RBV Potential for BID dosing of TVR – OPTIMIZE: TVR 1125 mg BID noninferior to TVR 750 mg every 8 hrs (both with pegIFN-α2a/RBV) in treatment-naive GT1 patients – SVR12 in 74% vs 72% of patients, respectively – No increase in adverse events1. Buti M, et al. AASLD 2012. Abstract LB-8.
Naives: key pointsTriple therapy with first-generation PIs in naïve Gt 1 CHC patients:• improves survival by about 4 years• is cost-effective, with an ICER per LYG below € 12,000• is strongly influenced by the IL28B CC prevalence and theensuing likelihood of RVR and SVR, but also by the pricing ofBOC and TVR• is optimised by allocating patients according to IL28B and/or RVR based strategies- An individualized treatment strategy can avoid triple therapy in 25-33% of naive HCV G1 patients
Re-treatment with P/R of treatment-experienced patients FULL PAPERSOverall SVR rate after retreatment: 16.1% (CI 6-33%) EASL and AASLD Guidelines recommend that G1 HCV patients failing to eradicate HCV on P/R ABSTRACTS should not be retreated with P/R alone Cammà C, et al. J Hepatol. 2009 Oct;51(4):675-81.
Re-treatment with P/R plus a 1 st generation PI of treatment-experienced patientsPhase 3 RCTs (BOC: RESPOND-2, PROVIDE: TVR:REALIZE) show that TT achieves SVR in about 30%-75% ofexperienced G1 CHC patients, with SVR rates progressivelydecreasing from :• Relapse (RR)• Partial responders (PAR) (HCV-RNA drop >2 log at week 12, but never not detectable)• Null responders (NR) (HCV-RNA drop < 2 log at week 12).
Cost-effectiveness of Boceprevir orTelaprevir for previously treated patients with Gt 1 CHC Competing strategiesResponse to Response Strategyprevious P/R to lead-in • RR • BOC LEAD IN • BOC-POOR§ • PAR • TVR LEAD IN • BOC-GOOD* • NR • TVR NO LEAD IN • TVR-POOR § • TVR-GOOD* *>1Log drop at week 4 of DT §<1Log drop at week 4 of DT Cammà C, et al. J Hepatol, in press
ICERs According to Profile of Previous Response and Severity of Liver Fibrosis 20000 18000 16000 TVR 14000 BOC 12000ICER for LYG 10000 8000 6000 4000 2000 0 F3-F4 F3-F4 F3-F4 CHC CHC CHC CHC CHC RR PAR NR RR GOOD PAR POOR NR Cammà C, et al. J Hepatol, in press
CAVEATS• Efficacy data from registration trials• Inconclusive data on cirrhosis• Aggregate rather than individual patient data• Analysis limited to direct medical costs• Time horizon = 20 years
Approval of triple therapy for reimbursement in Italy: basic principles (presumably) followed by AIFA• Local disease epidemiology and cost issues do not allow universal use of triple therapy (TT) in Italy• Patients with F3/F4 fibrosis deserve priority for TT• Selected patients with F0/F2 fibrosis may benefit from TT• Some non-responders should not be retreated with currently available therapies• Boceprevir and telaprevir are equally effective• Only Centers who meet specific requirements are allowed to prescribe TT• HCV monoinfected and HCV/HIV coinfected patients should both receive access to TT• TT after OLT can only be used off-label (law 648/96)
Approval of triple therapy for reimbursement in Italy: basic principles (presumably) followed by AIFA • IL28b status and virological features (baseline viral load and HCV subtype) are weak predictors at the individual level of RVR and SVR and cannot be used to pre-assign to TT or P/R • Response to a lead-in phase (P/R alone for 4 weeks>1 log drop in HCV RNA from baseline) is the strongest predictor of SVR*, and its absence of appearance of RAVs, hence a lead-in period is enforced for both boceprevir and telaprevir to: – Rule-in naïve patients in need of TT – Rule-out treatment experienced patients with a low likelihood of response to TT * Proven for boceprevir, assumed for telaprevir
Approval of triple therapy for reimbursement in Italy: AIFA criteria for naive Gt 1 patients Fibrosis Triple therapy (P/R Dual therapy Comments stage with Boc or Tpv) (P/R) F0, F1, F2 RVR* negative RVR* positive Lead-in not needed for F3, F4 All patients None telaprevir * RVR: at least 1 log10 drop after 4 weeks of P/R
Approval of triple therapy for reimbursement in Italy: AIFA criteria for treatment exp. Gt 1 patientsRR: relapsers; PR: partial responders; NR: null responders; UK: unknown pattern Fibrosis stage Triple therapy (P/R with Dual Comments Boc or Tpv) therapy (P/R) RR: all PR: all F0, F1, F2 NR: only if RVR* positive None UK: only if RVR* positive Lead-in not F3, F4 All patients None needed for telaprevir * RVR: at least 1 log10 drop after 4 weeks of P/R
Approval of triple therapy for reimbursement in Italy: potential critical issue • AIFA criteria are partly hypothetical: • Lead-in largely unproven for telaprevir • No statements about indications for treatment (Do all patients with F0/F2 fibrosis deserve therapy? What policy for informed deferral)? • Assimilating an unknown response to null response may be unsound • Unclear diagnostic criteria for fibrosis • Efficacy in terms of cost reduction may be insufficient • 20% of naïve patients • 30-40% of treament experienced patients • Selection of Centers for treatment is delegated to regional Health Authorities, who are also empowered to impose further restrictions
Characteristics of HCV DAA classes Characteristic Protease Nucleos(t)ide Non-nucleoside NS5a inhibitors inhibitors polymerase polymerase inhibitors inhibitors Potency High, variable Moderate-high, Variable, variable High, multiple among HCV consistent across across HCV genotypes geno/subtypes geno/subtypes geno/subtypes Barrier to Low High Very low Low resistance 1a < 1b 1a = 1b 1a < 1b 1a < 1b DDI potential High Low Variable Low-moderate Toxicity Rash Mitochondrial Variable Variable Anemia nucleos(t)ide ↑ Bilirubin interactions (ART, RBV)Pharmacokinetics Variable: QD to QD Variable: QD to QD TID TID Comments 2nd generation Pis: Single target Allosteric Multiple mode of better barrier, active site inhibition, many action pangenotypic targets
No cross resistance between classes: a combination of DAAs can eliminate RAVs Kieffer T, et al. J Antimicrob Chemother 2010;65:202–12R: resistant (>4-fold increase in EC50) Gao M, et al. Nature 2010;465:96–100; Lagrace L, et al. Hepatology 2010;52(4 Suppl):1205AS: susceptible (<4-fold change in EC50) Lenz O, et al. Hepatology 2010;52(4 Suppl):709A; Zeuzem S, et al. Hepatology 2010;52(4 Suppl):400A
HCV therapy: hopes and hypes….• Interferon-free• >90% SVR• Once daily• High tolerability with low adverse event• Few drug-drug interactions• Short, fixed duration (12-24 weeks)• Pan-genotypic• High barrier to resistance or lack of cross resistance• Affordable
IL28B genotype has been associated with viral kinetics during IFN-free therapyINFORM-1 : Mericitabine (NI) + danoprevir (PI), 14 days, n = 15 Chu, Gastro , 2012
Investigational HCV Regimens in Phase III Clinical Trials •Regimens With 1 DAA •Regimens With 2 DAAs •IFN-Free Regimens + PegIFN alfa/RBV + PegIFN alfa/RBV Faldaprevir* (BI 201335, PI) Daclatasvir + asunaprevir* Sofosbuvir + RBV Daclatasvir* (BMS-790052, Sofosbuvir + GS-5885 NS5A) (FDC) ± RBV •New Interferons Daclatasvir + asunaprevir Sofosbuvir* (GS-7977, NI) Simeprevir* (TMC435, PI) PegIFN lambda-1a + RBV ABT-450/RTV + ABT-267 ± ABT-333 ± RBV Alisporivir* (CYP) On Hold PegIFN lambda-1a + Vaniprevir (MK-7009, PI) daclatasvir + RBV •Alternative Dosing TVR BID* (approved PI) *Studied with pegIFN-α2a. Studied with both pegIFN-α2a and pegIFN-α2b.ClinicalTrials.gov.
Future Role of Interferon What role may interferon play in future regimens? – Preventing resistance? For which sets of patients may IFN play a role? – Patients with cirrhosis? – Treatment-experienced patients? – Patients with resistance to DAAs? Will newer IFNs replace currently available agents? – EMERGE: IFN lambda may have comparable efficacy but fewer hematologic AEs vs pegIFN alfa1. Muir AJ, et al. AASLD 2012. Abstract 214.