Debate: To Treat Now or Not to Treat Now. Age, Disease Stage, Resistance, and Comorbidities

Transcription

1 Debate: To Treat Now or Not to Treat Now Age, Disease Stage, Resistance, and Comorbidities

2 Moderator: Raymond T. Chung, MD Associate Professor of Medicine, Harvard Medical School Director of Hepatology and the Liver Center, Massachusetts General Hospital Discussant: Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine and Pediatrics Columbia University College of Physicians & Surgeons Director, Center for Liver Disease and Transplantation New York-Presbyterian Hospital Discussant: John F. Reinus, MD Professor of Clinical Medicine Albert Einstein College of Medicine Chief of Clinical Hepatology Montefiore Medical Center

3 Preamble º In 2013, we ve witnessed substantial improvements in treatment for genotype 1 HCV, with SVR rates 30% higher than seen previously and the ability to shorten therapy: PEG/RBV/TVR PEG/RBV/BOC º There have been corresponding increases in AEs, SAEs, and overall intolerability º SVR rates have diminished in those with advanced fibrosis, particularly cirrhosis, and those with prior null response to PEG-IFN/RBV º Tolerability concerns are heightened for those with cirrhosis

4 Preamble º Dramatic data regarding the success of all oral DAAs further promises to change the landscape, with e90% SVR rates possible º So...

5 Do We Treat Now or Do We Not Treat Now? º Whom do we treat now, if we do treat at all? º Importance of disease stage in decision making º Utility of biopsy vs. noninvasive staging º Do we confine treatment to patients with cirrhosis or bridging fibrosis? º What about treatment-experienced patients? º If we treat, what about a lead-in approach to stratify? º What about other baseline factors age, race, VL, IL28B?

6 Do We Treat Now or Do We Not Treat Now? º What about the specter of resistance? º Should we push clinical trials as a third way? Is this feasible? º What about genotypes 2 or 3? Do we treat now or wait on them, too? º What do our patients want? Does SVR rate matter most? Or avoidance of IFN? How much do duration, pill burden, and DDIs matter? º Given current time lines for approvals, can we justify much more widespread deferrals? º What about use of approved agents in unapproved combinations?

7 Treatment of HCV Now Git-R-Done! Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine and Pediatrics Columbia University College of Physicians & Surgeons Director, Center for Liver Disease and Transplantation New York-Presbyterian Hospital

8 HCV Treat Now Cure today is always better than cure tomorrow Benefits of waiting Higher cure rate Lower side effects So the question is always how much better and how much longer is the wait The answer is better and soon but the benefit is not equal for all

9 SVR Improves Long-Term Outcomes = 80% SVR rate = 60% SVR rate = 40% SVR rate % cirrhosis % liver-related death proportion of population treated proportion of population treated Davis GL, et al. Gastroenterol. 2010;138(2):

10 Predictors of Response Viral Factors HCV genotype HCV G1 subtype HCV RNA levels Based on these factors a group of patients can be selected who have ~90% cure rate with 24 weeks of therapy Host Factors Adherence BMI Age Fibrosis Race Sex IL28B genotype Response to therapy

11 SPRINT-2: Influence of Patient and Virus Characteristics on SVR with BOC SVR (%) Genotype HCV RNA (IU/mL) Fibrosis* IL28B *Using the Metavir fibrosis score. Poordad F, et al. N Engl J Med. 2011;364(13): ; Poordad F, et al. Gastroenterol. 2012;143:

12 ADVANCE: Influence of Baseline Patient and Virus Factors on SVR with TVR SVR (%) Genotype HCV RNA (IU/mL) Fibrosis a IL28B b a Using the Metavir fibrosis score; b IL28B testing was in Caucasians only. Jacobson IM, et al. N Engl J Med. 2011;364(25): ; Jacobson IM, et al. EASL Abstract 1369.

13 REALIZE Study: TVR for Retreatment of HCV SVR (%) T12PR48 = TVR + PR administered for 12 weeks followed by 36 weeks PR for 12 weeks followed by PR for 32 weeks; SOC = PR administered for 48 weeks; LI-T12PR48 = patients assigned to the lead-in group received PR for 4 weeks, followed by TVR for 12 weeks, and PR for a total of 48 weeks. Zeuzem S, et al. N Engl J Med. 2011;364(25):

14 RESPOND-2: SVR in Relapsers and Non-Responders with BOC SVR (%) *Patients with detectable HCV RNA level at Week 8 received placebo and PR for an additional 12 weeks. All 3 groups received PR 4 weeks (lead-in period). BOC/PR = boceprevir + pegifn/rbv; Control = received placebo + PR for 44 weeks. Bacon BR, et al. N Engl J Med. 2011;364(13):

15 OPTIMIZE Phase III: TVR BID vs TVR Q8h in Treatment-Naïve GT1 OPTIMIZE: SVR12 rates with TVR 1,125 mg BID noninferior to TVR 750 mg every 8 hours (q8h) Similar safety and tolerability profile in both treatment arms Outcome (%) TVR BID + PR (n = 369) TVR q8h + PR (n = 371) All Patients (n = 740) SVR12 (ITT) SVR12 (per protocol) Relapse a On-Treatment Virologic Failure b a Patients with HCV RNA < 25 IU/mL at planned treatment end assessed for relapse. b Patients who experienced virologic breakthrough or met virologic stopping rule. Buti M, et al. AASLD Abstract LB-8.

16 What s Coming? ~1 year Interferon Sparing regimens + DAA with ~90% SVR weeks Fewer side effects, easier dosing IFN-free fo easy to treat GT2,? 3, 2+ years Interferon-free multiple DAA s with ~90% SVR Multiple regimens based on GT and other factors Fewer side effects?ribavirin

17 Limitations of Emerging Trials Several agents from different classes discontinued due to AEs Phase 3 for IFN-free not done for most drugs Trials on patients with cirrhosis and other special populations needed Time line and costs issues remain unknown, particularly for IFN-free Rx

18 Patients with Good Outcome: Characteristics of a Easy-to-Treat Patient Naïve or prior relapse to IFN Mild Fibrosis HCV genotype 1b IL-28B CC Low viral load Under 40 years old No NAFLD Risk factors (Thin, nondiabetic) These patients need to wait 1 year to save 12 weeks of IFN and longer for the last 12!

19 New and Emerging Strategies: Clinical Considerations Recent recommendations from the CDC emphasize the importance to screen and early diagnosis of HCV infection Newly diagnosed patients with chronic HCV infection still require comprehensive counseling For patients who are candidates for therapy Initiate treatment with currently available therapy easy or advanced disease naïve or relapse Defer treatment until availability of new antiviral agents with the potential for increased efficacy, decreased adverse events, and shorter duration of therapy over existing regimens

20 To Treat or Not to Treat : DON T John F. Reinus, MD Professor of Clinical Medicine Albert Einstein College of Medicine Chief of Clinical Hepatology Montefiore Medical Center

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22 When planning therapy of a disease Goal: What is the desired result in this patient? Effectiveness: Can the desired result be achieved? Disease prognosis: What is the prognosis without therapy? Benefit: Will the desired result benefit the patient? Safety: What are the risks of treating? Contraindications: Is the patient able to receive treatment? Tolerability: Can the patient tolerate therapy? Alternative treatment: Is there another more suitable therapy?

23 HCV genotype 1 treatment response rates Genotype 1 SVR IFN 12% IFN/RBV 35% Peg-IFN RBV 44% Protease Peg-IFN RBV 70% 2nd Generation DAAs >90% Schaefer EA, et al. Gastroenterology 2012;142:1340 Ghany MG, et al. Hepatology 2009;49:1335 Ghany MG, et al. Hepatology 2011;54:1433

24 When planning therapy of a disease Goal: What is the desired result in this patient? Effectiveness: Can the desired result be achieved? Disease prognosis: What is the prognosis without therapy? Benefit: Will the desired result benefit the patient? Safety: What are the risks of treating? Contraindications: Is the patient able to receive treatment? Tolerability: Can the patient tolerate therapy? Alternative treatment: Is there another more suitable therapy?

25 5- and 20-year probabilities of progression to different stages of fibrosis in HCV infection Terrault, et al. Clinical Gastroenterology and Hepatology 2008;6: YEAR PROGRESSION 20-YEAR PROGRESSION Estimated median time of progression from F0 to cirrhosis was 79 years!

26 Will the patient benefit from treatment? What is the prognosis with liver disease? What is the prognosis without liver disease?

27 When planning therapy of a disease Goal: What is the desired result in this patient? Effectiveness: Can the desired result be achieved? Disease prognosis: What is the prognosis without therapy? Benefit: Will the desired result benefit the patient? Safety: What are the risks of treating? Contraindications: Is the patient able to receive treatment? Tolerability: Can the patient tolerate therapy? Alternative treatment: Is there another more suitable therapy?

28 Adverse events in 157 patients treated with telaprevir at Montefiore and Mt. Sinai Bichoupan K, et al. AASLD 2012; Abstract 1755 Hgb < 8.5 g/dl 35 (20%) RBC transfusion 18 (11%) Severe rash 15 (9%) Severe fatigue 54 (31%) Skin burning 24 (14%) Anorectal burning 39 (24%) Hypokalemia 30 (17%) AKI 27 (16%) Depression 10 (6%) Hospital admission 28 (16%) Other* 18 (10%) Early telaprevir discontinuation due to adverse event: MMC + MSMC Advance + Realize (n=157) (n=629) P 21% 13% 0.01 *Other: diarrhea, dehydration, infection, arrhythmia, decompensation

29 BCP: pharmacokinetic interactions Data courtesy of Dr. Mark S. Sulkowski, Johns Hopkins School of Medicine Effect on ART Effect on BCP ART AUC C MIN AUC C MIN Recommendation Efavirenz 20% 19% 44% Do not prescribe ETR;NVP;RPV Do not prescribe Atazanavir/r 35% 49% No Change Do not prescribe Darunavir/r 44% 59% 29% 35% Do not prescribe Lopinavir/r 34% 43% 44% 35% Do not prescribe Raltegravir No Change No Change Standard BCP dose

30 When planning therapy of a disease Goal: What is the desired result in this patient? Effectiveness: Can the desired result be achieved? Disease prognosis: What is the prognosis without therapy? Benefit: Will the desired result benefit the patient? Safety: What are the risks of treating? Contraindications: Is the patient able to receive treatment? Tolerability: Can the patient tolerate therapy? Alternative treatment: Is there another more suitable therapy?

31 HCV drugs in late-stage clinical development NS3/4A Nucleotide NS5B NS5A Protease Polymerase Replication-Complex Inhibitors Inhibitors Inhibitors FDA Approved Telaprevir Boceprevir Phase III ABT-450 Sofosbuvir Daclatasvir (Clinical Trial) (ABT450/r + ABT267 (Sof + GS RBV) (Dac + P/RBV) + ABT333 + RBV) (Sof + RBV) (Dac + Asunaprevir) Asunaprevir (Asun +Daclatasvir) Faldaprevir (Fal + P/RBV) Simeprevir (Sim + P/RBV)

32 Oral 12-week therapy of geno-1 HCV: efficacy Sofosbuvir, Ledipasvir, Ribavirin Treatment Naive (n=25) Null Responder (n=9) Week 1 11/25 (44%) 0/9 (0%) Week 2 22/25 (88%) 4/9 (44%) Week 4 25/25 (100%) 8/9 (89%) Week 12 25/25 (100%) 9/9 (100%) SVR 4 25/25 (100%) 9/9 (100%) SVR 12 25/25 (100%) 9/9 (100%) Gane E, et al. AASLD, EASL

33 Oral 12-week therapy of geno-1 HCV: safety Sofosbuvir, Ledipasvir, Ribavirin Treatment Naive (n=25) Null Responder (n=9) Anemia 5/25 (20%) 0/9 (0%) Depression 2/25 (8%) 0/9 (0%) Headache 1/25 (4%) 0/9 (0%) URI 0/25 (0%) 0/9 (0%) Fatigue 0/25 (0%) 2/9 (22%) Sprain 0/25 (0%) 0/9 (0%) Gane E, et al. AASLD, EASL

34 Oral 12-week therapy of geno-1 HCV: safety Sofosbuvir, Ledipasvir, Ribavirin Treatment Naive (n=25) Null Responder (n=9) PT > 3X ULN 0/25 (0%) 0/9 (0%) PT 1.5-3X ULN 2/25 (8%) 0/9 (0%) Hematuria? 9/25 (36%) 0/9 (0%) Hgb 7-9 g/dl 5/25 (20%) 2/9 (22%) ALT > 5X ULN 0/25 (0%) 0/9 (0%) TB > 2.6X ULN 0/25 (0%) 0/9 (0%) Gane E, et al. AASLD, EASL

35 Just say NO to drugs Goal and Effectiveness: While the goal is cure, many patients still cannot be treated successfully with currently available drugs. Prognosis and Benefit: Most patients have a benign shortterm prognosis and do not need to be treated immediately. Safety and Tolerability: Current therapy has many severe side effects that make it difficult for patients to complete treatment. Alternative Therapy: Numerous new, vastly superior drugs will be available in the near future.

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