Viral Hepatitis: Will new therapies deliver global impact?

Transcription

1 Viral Hepatitis: Will new therapies deliver global impact? Jordan J Feld MD MPH Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto

2 3 Main Points 1. HBV and HCV cause an enormous and sometimes under-recognized burden of disease 2. New agents will achieve control in almost everyone with HBV and cure in almost everyone with HCV 3. Eradication requires more than good drugs

3 3 Main Points 1. HBV and HCV cause an enormous and sometimes under-recognized burden of disease 2. New agents will achieve control in almost everyone with HBV and cure in almost everyone with HCV 3. Eradication requires more than good drugs

4 Hepatitis B - Some Sobering Facts Toronto Million people chronically infected - 2 billion with evidence of past infection - 600,000-1 million deaths annually (same as malaria!)

5 HCV: A major global public health problem million people infected No vaccine Leading indication for liver transplant

6 Potential Consequences of HCV Infection Healthy Liver Cirrhosis Liver Cancer 20% (at 20 yrs of infection) 1-4%/yr Slowly progressive over decades of infection Does this mean 80% do not have consequences? No! Cirrhosis risk 41% at 30 yrs lifetime risk 50-60% or higher Thein Hepatol 2008

7 A growing epidemic Projected 37% of HCV patients will develop cirrhosis in % of patients with hepatitis C in 2010 had cirrhosis Davis et al Gastroenterology 2010

8 Consequences differ with epidemiology HCV Prevalence Egypt Japan USA Australia 0 < Age [years] Incidence of HCV-related advanced liver disease Japan Egypt USA Australia Year 1. New Low prevalence IDU, low transmission, increasing burden 2. Old Low prevalence iatrogenic, low transmission, high burden 3. High prevalence iatrogenic, high spread, high/increasing burden Hajarizadeh Nat Rev Gastro & Hep 2013

9 HCV Global Burden: Prevalence & Absolute Numbers Different from HIV/HBV - Highest prevalence Africa (Egypt) - But largest absolute numbers in Asia - Burden greatest low/middle income countries Clin Microb Inf 2011

10 Not only a problem in developing countries Hepatitis C virus Streptococcal pneumonia Human papilloma virus Hepatitis B virus E. Coli HIV/AIDS Staphylococcus aureus Influenza C. Dificile Rhinovirus Respiratory syncytial virus Parainfluenza virus Group B Strep Group A Strep Haemophilus influenza Tuberculosis Legionella Chlamydia Adenovirus Gonorrhea Years of Life Lost Year-equivalents of reduced functioning Health Adjusted Life Years (HALYs) Kwong et al PLoS One 2012

11 Increasing HCV and decreasing HIV mortality Ly Ann Int Med 2012 CDC

12 Summary Point 1 HBV and HCV cause an enormous and sometimes underrecognized burden of disease Both HBV and HCV cause a large burden of illness 1. Cirrhosis/Liver failure 2. Liver cancer Global burden greatest in developing countries but increasing burden in most wealthy countries Burden increases markedly as the population ages

13 3 Main Points 1. HBV and HCV cause an enormous and sometimes under-recognized burden of disease 2. New agents will achieve control in almost everyone with HBV and cure in almost everyone with HCV 3. Eradication requires more than good drugs

14 HBV Therapy Immunotherapy Interferon Stimulates immune control of viral replication Direct Antivirals Nucleoside/nucleotide analogues Suppress viral replication

15 HBV therapy prevents bad outcomes 651 patients with F3/F4 randomized to LAM vs Placebo % with disease progression Placebo Lamivudine Liaw NEJM 2004

16 Long-term follow-up of Potent Nuc Therapy 375 HBeAg ve patients treated with ADV or TDF x 5 yrs Week 240: TDF-TDF 83% ADV-TDF 84% Overall: 83% Potent agents high rates of long-term viral suppression Marcellin P et al Lancet 2012

17 Undetectable HBV DNA after 1 Year on Therapy 80% 70% 60% 50% 40% 30% 20% 10% 0% 72% 76% 42% 21% 10% 0% PegIFN Lamivudine Adefovir Entecavir Tenofovir Placebo

18 But Loss of HBsAg after 1 30% Year of Therapy HBsAg Loss 20% 10% 0% 7% 1.1% 1.7% ~1% 3% 1% PegIFN Lamivudine Adefovir Entecavir Tenofovir Placebo The Problem: Therapy effective but must be taken long-term/indefinitely no cure

19 HCV: The Good News Sustained Virological Response (%) 100% 80% 60% 40% 20% 0% Standard Interferon % % Ribavirin 1998 Peginterferon % 42% 39% % IFN IFN IFN/R IFN/R PegIFN PegIFN/R 6 mo 12 mo 6 mo 12 mo 12 mo 12 mo

20 SVR is a durable endpoint 1,343 patients who achieved SVR followed for mean 3.9 yrs Late relapse is extremely rare SVR is truly a virological cure Swain Gastro 2010

21 Is SVR is a cure of liver disease? 286 pts with mild fibrosis and SVR after IFN therapy Follow-up post SVR (n=286) SVRs SVR (n=286) Patients Proportion of patients Survival Decompensation/HCC HCC Percent Survival % survival Matched Matched general General population Population Time [yrs] Time [yrs] [yrs] SVR stops progression of liver disease Normal survival in those with mild disease Veldt Gut 2002

22 What about patients with advanced disease? Long-term follow-up of 534 patients with F3/F4 post-treatment Liver Related LR-Mortality, Mortality % % year occurence occurrence SVR: 1.9% %(95%CI CI ) Non-SVR: non-svr: 27.4% ((5% (95%CI ) Non-SVR p<0.001 SVR Follow-up time, years SVR eliminates liver failure & liver-related death Van de Meer et al JAMA 2012

23 SVR Reduces All-Cause Mortality Long-term follow-up of 534 patients with F3/F4 post-treatment Overall Mortality, % year occurence occurrence SVR: 8.9% %(95%CI CI ) Non-SVR: non-svr: 26.0% 27.4% (95%CI ((5% CI ) Non-SVR p<0.001 SVR Follow-up time, years SVR is not a surrogate = reduced all-cause mortality Van de Meer et al JAMA 2012

24 Liver Cancer still occurs post-svr Long-term follow-up of 534 patients with F3/F4 post-treatment year occurence occurrence SVR: 5.1% %(95%CI ) CI ) Non-SVR: non-svr: 21.8% (95%CI ((5% CI ) HCC, % Non-SVR p<0.001 SVR Follow-up time, years However HCC curable if found early Surveillance necessary but effective Van de Meer et al JAMA 2012

25 Sustained Response 100% 80% 60% The Good News Standard Interferon Ribavirin 1998 Peginterferon 2001 The Bad News 55% This slide is 10 years old!!! 40% 34% 42% 39% % 6% 16% 0% IFN IFN IFN/R IFN/R PegIFN PegIFN/R 6 mo 12 mo 6 mo 12 mo 12 mo 12 mo

26 The Lifecycle - Lots of Targets Entry Inhibitors Polymerase Inhibitors Protease Inhibitors NS5A Inhibitors Manns Nat Rev 2007

27 Why has it taken so long? HCV HIV Remarkable Diversity BILN 2061 Born 2002 Died 2005 Toxicity of Early DAAs Schultz BMC Bioinformatics 2006

28 The Real Reason HCV Lobby HIV Lobby

29 Not just a theory Edlin Nature 2011 Number of people (millions) Dollars Spent (Billion USD)

30 Why is this the reality? HCV is a disease of the marginalized Edlin Nature 2011

31 Fortunately there has been progress Polymerase Inhibitors Protease Inhibitors NS5A Inhibitors Plus host inhibitors Alisporivir (cyclophilin), Miravirsen (mir122) Manns Nat Rev 2007

32 Very Rapid Progress 1 pill, OD, No AEs, ~100% SVR Perfectovir Efficacy Peg/RBV + BOC/TVR Peg/RBV + 2 nd gen DAA IFN-Free DAA Combos Peg/RBV Tolerability/Safety

33 17 HCV Trials in NEJM since 2012

34 PI + NS5A + NNI + RBV ABT-450/r + ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV x 12 wks Naive Treatment Failures (49% nulls) SVR12 (%) SVR12 (%) Feld J EASL 2014 Abst / 473 All 307/ 322 G1a 148/ 151 G1b / 297 All 166/ 173 G1a 119/ 123 G1b 5 drugs (3 pills) BUT 12 wks, 1 size fits all Very well tolerated (vs. placebo), few virologic failures Zeuzem S EASL 2014 Abst 01

35 How about a single pill? ION 1, 2 & 3: sofosbuvir (nuc) + ledipasvir (NS5A) FDC +/- RBV Naïve Prior Trt (incl PI) Failures SVR4 or 12 (%) / 214 S/L 211/ 217 S/L/R 12 wks 102/ 109 S/L 107/ 111 S/L/R 12 wks 108/ 109 S/L 110/ 111 S/L/R 24 wks 202/ 215 Highly effective single-tablet regimen No issues with resistance 201/ / 216 S/L S/L/R S/L 8 wks 12 wks Mangia EASL 2014, Afdahl EASL 2014, Kowdley EASL 2014

36 Perfectovir will soon be a reality No AEs >95% SVR IFN-free RBV-free No DDIs 6-12 weeks 1 pill OD Minimal/No Resistance

37 HBV Summary Point 2 New agents will achieve control in almost everyone with HBV and cure in almost everyone with HCV Long-term suppressive therapy No curative therapy Vaccination effective but under-utilized HCV SVR is a cure Dramatic progress On the cusp of interferon-free therapy

38 3 Main Points 1. HBV and HCV cause an enormous and sometimes under-recognized burden of disease 2. New agents will achieve control in almost everyone with HBV and cure in almost everyone with HCV 3. Eradication requires more than good drugs

39 Disease eradication is possible The end of small pox an incredible triumph

40 What is required to eradicate an infectious disease? 1. No animal reservoir 2. Treat and cure all those infected 3. Prevent all new (chronic) infections Sounds simple enough

41 What is required to eradicate an infectious disease? 1. No animal reservoir 2. Treat and cure all those infected 3. Prevent all new (chronic) infections

42 Non-human HCV? We only get it if you infect us! Rodent, equine and canine HCV But low/no risk of transmission to humans Drexler PloS Path 2013, Lyons Emerg Inf Dis 2012, Parera PLoS One 2012

43 What is required to eradicate an infectious disease? 1. No animal reservoir 2. Treat and cure all those infected 3. Prevent all new (chronic) infections

44 Treatment Shouldn t this be easy?

45 Under-diagnosis & Undertreatment Treatment Rate [%/year] Bubble Area: Viremic HCV Prevalence 0% 20% 40% 60% 80% 100% Diagnosis Rate Dore J Viral Hepatitis 2014

46 Why are treatment rates so low? Modeled data for non-va US population Diagnosis Access Treated SVR Should improve with IFN-free therapy but long way to go Yehia PLoS One 2014

47 Treatment uptake more important than rate of SVR! ~10% 34% 68% * * Assumes 30% dx & up to 25% rx d in Outcomes at Davis Gastroenterology 2010

48 Shown another way SVR in individuals SVR in the population Improved therapy of no benefit unless treatment rates increase Thomas Lancet 2010

49 Why are treatment rates so low? Patients Unaware of infection feel perfectly well Do not want treatment! Treatment very difficult even perfectovir Doctors Poor awareness late diagnosis and referral 57% of PCPs do not know HCV is curable! Few treaters hepatologists, GIs, IDs Will PCPs take up treatment like in HIV?

50 The payers position It costs what???? Limitations on access here and in most European countries

51 Costs for 12 weeks of Sofosbuvir 100,000 84,000 Cost in USD 80,000 60,000 40,000 67,000 66,000 55,000 20,000 0 US UK Germany Canada Iran India Burma Egypt Kenya Brazil Mozambique Estimated Production Cost This model has worked for HIV but pushback from US & other wealthy countries

52 Cost Considerations Curative therapy Short treatment Minimal monitoring Minimal infrastructure required Diagnosis of HCV does not equal liver disease Diagnosis requires confirmation of viremia Many patients with minimal liver disease Not all will progress Should we treat it as a liver disease or an infectious disease?

53 High Income Strategies Increase diagnosis rates Population screening Baby Boomers, other groups Initially treat only patients with liver damage (F2+) Access to non-invasive tools for staging (Fibroscan) Expand treater pool PCPs, prisons Very effective in HIV

54 Financial Models Standard model: Maximum $/pill High revenue in US Subsidize the rest of the world Lower treatment uptake elsewhere Options to Explore Lower $/pill Reduced revenue in US Greater global uptake? Similar total revenue Much greater global benefit Price per cure Encourages shorter therapy Concerns about adherence

55 Treat it like a house Amortize cost over many years (like HIV/HBV) Pill as house Payer Reduced budget impact Defer/discount costs Greater treatment uptake Industry Greater uptake Secured market Who will be take the lead on a new model of payment?

56 Low/Middle Income Countries What we can t afford to do

57 HIV: Major global success HIV therapy now available to millions in wealthy and resource-limited countries

58 Where have we failed? Need to avoid partitioning of funding We re all on the same team

59 HCV in Low/Middle income countries Increase diagnosis rates Lower than high income countries Low cost HCV RNA test confirmation of viremia/cure & on-treatment monitoring Accessible liver disease staging Serum panels,? Transient Elastography (Fibroscan) National & Global Strategic plans Drug pricing reform Consider cheaper non-perfectovir options Strong & effective lobby to make these needs a reality

60 HIV lobby = VERY effective

61 What did lobbying achieve?

62 Industry has a MAJOR role to play

63 We re learning

64 The world is listening

65 What is required to eradicate an infectious disease? 1. No animal reservoir 2. Treat and cure all those infected 3. Prevent all new (chronic) infections (?)

66 Prevention is the best medicine HBsAg Positivity (%) In Taiwan OR for Liver Cancer Age [years] HBV vaccination major success story 1 st cancer vaccine BUT implementation less than ideal Coverage only 75% Birth dose < 50% of countries 27% of neonates Required for global eradication Chang JNCI 2009 Ni Gastroenterology 2007

67 The Holy Grail An HCV vaccine Likely needed for true eradication 2 options Sterile immunity prevent infection - unlikely Increase clearance rate possible Less motivation with perfectovir around the corner will need non-pharma support

68 Treatment as prevention 96% reduction in HIV transmission Easier for HCV: Curable, defined treatment duration Cohen et al NEJM 2011

69 Treatment as prevention for HCV Implementation in IDU/incarcerated pop ns in wealthy countries likely highly effective Martin N, et al. J Hepatology 2011

70 Rate of new cases critical Effective treatment may be adequate The reality need to reduce transmission

71 Developing Countries Transmission largely through medical exposures Actually GOOD news! Much easier to buy new needles than to change behaviour but still very costly Added benefits beyond HCV transmission should be a priority!

72 The Vision for HCV Wealthy nations Broad access to PERFECTOvir for ALL patients Active case-finding efforts treatment by primary care MDs Prevent development of cirrhosis Prevent HCV-related mortality by treating cirrhotics Treatment as prevention better than a vaccine? Resource-limited regions Initially access to PERFECTOvir for patients presenting with advanced disease still effective Reduce medical transmission clean needles! Eradication will require a vaccine

73 The Bottom Line HCV is curable, HBV is controllable Cure/control saves lives Treatment is improving incredibly quickly Challenges differ in high vs. low/middle income Eradication will require a lot more than good drugs Increased diagnosis screening Access to care both developed & developing nations Reduced transmission IDU, iatrogenic Vaccine development and implementation

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