Hepatitis C Virus Update LAUREN BESTE, MD MSC VA PUGET SOUND HEALTH CARE SYSTEM & UNIVERSITY OF WASHINGTON

Transcription

1 Hepatitis C Virus Update LAUREN BESTE, MD MSC VA PUGET SOUND HEALTH CARE SYSTEM & UNIVERSITY OF WASHINGTON

2 Disclosures None

3 Can we review everything about hepatitis C in 1hour?

4 But we can hit the highlights! (and a few other highyield topics) By the end of this talk, you should be able to: Identify risk factors for HCV infection Work up potential candidates for treatment Access resources for primary care based HCV treatment in your local area

5 Let s review chronic Hepatitis C Virus RNA virus, transmitted by blood Affects ~1% of US adults (INPUT actual #) #1 cause of cirrhosis and HCC in US CDC Progress toward viral hepatitis elimination.

6 The good news: HCV deaths declined for the first time (ever) in 2015 Bad news: still exceeds the deaths from all other reportable infectious diseases combined More bad news: new HCV infections are on the rise, esp. in high risk groups year olds American Indians/ Alaska Natives Whites CDC Progress toward viral hepatitis elimination.

7 HCV epidemiology is changing birth cohort used to account for 75% of chronic HCV infection Smith BD et al., MMWR: August 17, 2012: 61(RR04);1-18.

8 The new epidemic: 2002 vs Age distribution of newly reported confirmed cases of hepatitis C virus infection --- Massachusetts, 2002 and * N = 6,281; excludes 35 cases with missing age or sex information. N = 3,904; excludes 346 cases with missing age or sex information. CDC MMWR. 2011;60(17)

9 Rate of acute HCV increased overall from 2014 to 2015 CDC Progress toward viral hepatitis elimination.

10 Increase in HCV infections is linked to opioid crisis Data from CDC s hepatitis surveillance system and the Substance Abuse and Mental Health Services Administration s (SAMHSA) national database From 2004 to 2014 acute HCV increased 133% and admissions for opioid injection increased 93% Seen at national level and by state, age, race and ethnicity

11 Substantial, simultaneous increase in opioid admissions and acute HCV -CDC (2017)

12 HCV in pregnancy also on the rise Prevalence of maternal HCV infection increased 89%, from 1.8 to 3.4/1,000 live births (p<0.001), based on birth certificate data Patient-level characteristics associated with maternal HCV infection White race, rural county residence, cigarette smoking during pregnancy, having a high school education or less, concurrent HBV infection MMWR / May 12, 2017 / 66(18);

13 So what can PCPs do about HCV?

14 Recall: HCV screening is a 2-step process birth cohort AND risk factor-based screening 15-20% of people clear HCV spontaneously Step 1: antibody for screening Step 2: PCR for confirmation of viremia (or suspected acute infection)

15 Patient education is important! Patients report increased comfort with PCPs than with specialists when it comes to HCV PCPs often the first (or only) source of accurate information about HCV Zickmund S et al. J Gen Intern Med Oct;18(10):

16 Patient misconceptions abound HCV cannot be passed through casual contact (hugs, dishes, toilet seats, etc.) HCV is almost impossible to transmit via monogamous heterosexual contact HCV is still there if you Leave your needles out for 24 hours Bleach your needles Use a clean needle but share your cotton Etc., etc., etc.

17 HCV pre-treatment workup: Check for comorbidities HIV, HBV, HAV (need for vaccination) Substance use disorders NOT an absolute exclusion, but important to know about Psychosocial barriers Adherence, adherence, adherence

18 HCV pre-treatment workup: Fibrosis assessment Affects treatment duration; screening for complications (e.g., varices) Many options available! Labs Predictive risk indices Fibroscan Liver biopsy is rarely needed, if ever

19 Noninvasive Alternatives to Biopsy Serum indices Forns fibrosis index, APRI, FIB-4 Serological markers FibroTest, FibroSure, FibroSpect II Liver stiffness measurement Ultrasound elastography (FibroScan) MR elastography Colletta C, et al. Hepatology. 2005;42: Halfon P, et al. Am J Gastroenterol. 2006;101:

20 Advantages and Disadvantages of Hepatic Elastography Examination time < 5 mins Median value of 10 successful acquisitions Potential confounders: visceral adiposity, steatosis, cholestasis, nonfasting, user error

21 What can FibroScan measure? FibroScan Vibration-controlled transient elastography Expressed in kpa Measures stiffness Controlled Attenuation Parameter Expressed in db/m Measures steatosis VCTE Stiffness Fibrosis Correlate CAP Ultrasound Attenuation Rate Steatosis Correlate

22 Predictive Value of Elastography vs Serum- Based Tests Area Under the ROC Curve (Sensitivity vs 1 Specificity) for METAVIR Stage F0-1 vs F2-4 According to Different Fibrosis Assessment Methods [1] Assessment Method AUROC 95% CI APRI Elastography FibroTest FibroTest + Elastography Castera L, et al. Gastroenterology. 2005;128: Degos F, et al. EASL Abstract 96.

23 What about HCV treatment?

24 HCV regimen selection requires 3 key pieces of data HCV genotype HCV treatment history (DAA or interferon-based) Fibrosis status Adherence concerns are the biggest exclusion for HCV treatment

25 SVR Rate (%) SVR Rates in Patients With HCV > (gt1) IFN 6 mo IFN 12 mo IFN/RBV 6 mo IFN/RBV 12 mo PEG-IFN 12 mo PEG- IFN/RBV 12 mo PI/PEG- IFN/RBV 6-12 mo DAAs 8-12 weeks Adapted from Strader DB, et al. Hepatology 2004;39:

26 Modern DAA regimens are combinations of multiple drug classes Structural Domain Nonstructural Domain 5 UTR Core E1 E2 P7 NS2 NS3 4A 4B NS5A NS5B 3 UTR Protease Polymerase Ribavirin (RBV) NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non-NUC Inhibitors. Grazoprevir (GZR) Paritaprevir/Ritonavir (PTV/RTV) Simeprevir (SMV) Voxilaprevir (VOX) Glecaprevir (GLE) Daclatasvir (DCV) Elbasvir (EBR) Ledipasvir (LDV) Ombitasvir (OBV) Velpatasvir (VEL) Pibrentasvir (PIB) Sofosbuvir (SOF) Dasabuvir (DSV) Slide credit:

27 Combination DAA regimens available in 2018 NS3 Protease Inhibitor NS5A Replication Complex Inhibitors NS5B Nucleoside Inhibitors NS5B Nonnucleoside Inhibitors Brand Name Sofosbuvir Sovaldi Simeprevir Olysio Ledipasvir Sofosbuvir Harvoni Paritaprevir/ritonavir Ombitasvir Dasabuvir Viekira Paritaprevir/ritonavir Ombitasvir Technivie Daclatasvir Daklinza Grazoprevir Elbasvir Zepatier Velpatasvir Sofosbuvir Epclusa Voxilaprevir Velpatasvir Sofosbuvir Vosevi Glecaprevir Pibrentasvir Mavyret

28 What s new with Hepatitis C in 2018? Glecaprevir/Pibrentasvir (Mavyret) Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi) Previously-unfilled HCV treatment niches Pangenotypic option for renally impaired patients Patients who previously failed a regimen containing an NS5A inhibitor Shorter course treatment for all genotypes Reduced costs

29 Glecaprevir/ Pibrentasvir Indications Treatment of chronic HCV GT 1-6 Treatment of GT 1 patients who previously failed a regimen containing either an HCV NS5A inhibitor OR an NS3/4A PI Dosing 3 tablets (100mg/40mg) daily X 8-16 weeks Mavyret Prescribing Information 2017

30 Puoti M et al. Abstract SAT-233. EASL 2017 Pooled Data From SURVEYOR-1 and 2, EXPEDITION-4, and ENDURANCE 1, 2, 3 and 4 8 weeks of G/P is the optimal treatment duration for chronic HCV patients without cirrhosis

31 EXPEDITION- 1 G/P for 12 weeks is highly efficacious in HCV GT 1, 2, 4, 5, or 6 and compensated cirrhosis, with or without prior treatment (PRS) Forns X et al. EASL 2017

32 G/P approved for 12 weeks in GT3 patients, treatment naïve, with cirrhosis G/P approved for 16 weeks in GT3 patients, treatment experienced, with cirrhosis Wyles et al. AASLD 2016

33 Glicaprevir/ pibrentasvir takeaways Highly efficacious regardless of: Genotype Baseline HCV RNA Fibrosis stage (up to compensated cirrhosis) Previous treatment experience HIV-1 coinfection Baseline NS5A polymorphisms Post-transplant (liver or kidney) Cannot use in decompensated cirrhosis due to protease inhibitor component

34 Glicaprevir/ pibrentasvir takeaways Highly tolerable Few drug-drug interactions OK in renal impairment Duration Non-cirrhotic, treatment-naive patients (or peg/riba experienced) get 8 weeks Treatment-experienced GT3 with cirrhosis get 16 weeks Everybody else gets 12 weeks

35 Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi) NS5B inhibitor NS5A inhibitor NS3/4A inhibitor Sofosbuvir Velpatasvir (GS-5816) Voxilaprevir (GS-9857) Broad genotypic activity Retains activity against almost all clinically relevant resistance mutations

36 Overview of Sofosbuvir/ Velpatasvir/ Voxilaprevir FDA-approved for retreatment of prior NS5A and/or sofosbuvir failures (or both) Extremely efficacious, including in: Gt 1-4 Compensated cirrhosis Viral resistance mutations Dosing Sof 400mg/ Vel 100mg/ Vox 100mg once daily x 12 weeks 36

37 POLARIS 1,2 (naïve, cirrhotic),3 (exp, no cirrhosis),4 (no NS5A experience) Implications for noncirrhotic patients Effective in naïve patients, all genotypes Effective if prior DAA experience 12 weeks more effective than 8 weeks (data not shown) Flamm SL, EASL 2017 Abstract 424

38 POLARIS 1,2 (naïve, cirrhotic),3(te no cirrhosis),4 (no NS5A experience) Implications Effective in cirrhosis, all genotypes Need 12 weeks for cirrhosis 38

39 Summary of Sofosbuvir/ Velpatasvir/ Voxilaprevir Extremely efficacious, especially useful in prior DAA failures Tolerable; few drug-drug interactions Limitations Not recommended if CrCl<30ml/min, or decompensated cirrhosis

40 Older DAA combinations you will continue to see in 2018 Sofosbuvir/ velpatasvir +/- ribavirin for weeks Pangenotypic Efficacious in DAA-experienced patients Safe in Child-Pugh B/C patients (no protease inhibitor)

41 Costs of HCV treatment Sofosbuvir/ ledipasvir Glicaprevir/ pibrentasvir Sofosbuvir/ velpatasvir/ voxilaprevir $113,400 for 12 weeks $15,840 for 12 weeks $10,560 for 8 weeks $89,712 for 12 weeks Many insurance plans no longer cover sofosbuvir/ ledipasvir (aka Harvoni)

42 Treating your own HCV+ patients

43 Project ECHO (Extension for Community Health Outcomes) Originally designed to improve access to HCV care in rural New Mexico First piloted June 2003 now hundreds of academic, regional US, and international partners Now serving 40 conditions besides HCV

44 How ECHO works Brief didactic via teleconference, with CME PCPs present cases Multidisciplinary team decides on a treatment plan PCPs implements treatment plan and re-present at key milestones or if problems develop Everybody learns! Patients don t have to travel!

45 Equivalent HCV treatment outcomes for ECHO vs. academic med center Arora et al. NEJM 2011: 1-9.

46 Accelerated HCV treatment with ECHO Associated with increased HCV treatment in VHA vs usual care (n=38,753) Adjusted hazard ratio for HCV treatment 1.20 (95%CI ) P <.01 PCP-initiated treatment rate was 21.4% in ECHO group compared with 2.5% in controls (P <.01) No differences in SVR Beste et al. Am J Med (2017),

47 ECHO is cost-effective Based on Markov modeling, the incremental costeffectiveness ratio with Project ECHO versus usual care was $10,351 per QALY Well below the standard willingnessto-pay threshold of $50,000 per QALY Rattay et al. Gastroenterology December e2

48 Last but not least, PCPs enjoy ECHO! Arora Hepatology 2010; 52:

49 University of Utah s ECHO program covers Idaho utah.edu/echo/ It s free! And they have free CME every week for multiple programs (not just HCV)

50 General HCV treatment guidance HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C Updated continuously Available for download, online viewing, and mobile device

51 When is specialist support recommended for HCV treatment? Decompensated cirrhosis History of hepatocellular carcinoma Previous DAA experience HIV or HBV co-infection Renal failure/ dialysis

52 Conclusions The demographics of HCV are changing PCPs have a role to play in HCV care at all levels Support is available for primary-care based HCV treatment Consider ECHO

53 Thanks for your attention!

54 A few words on HCV in PWIDs

55 Bonus slides

56 Global prevalence of HCV in PWID is 60-80% 73 % 64 % 51 % 40 % 73 % 11% 67 % 41 % 55 % Nelson, Mathers, Cowie, et al. Lancet. 2001;378:

57 Why aren t more PWIDs treated? Provider concerns Treatment adherence Neuropsychiatric tolerability (less so in DAA era) Risk of reinfection Perpetuated stigma Poor linkage to care

58 The idea of scale-up Treating patients at highest risk of transmission is actually MORE cost effective compared to lowtransmission groups However, it will take decades to eliminate HCV if we rely on traditional harm reduction without increased antiviral therapy Martin NK et al. Clin Inf Dis 2013 (57 Suppl 2): S39-45

59 Treatment/Cure among PWID: Mathematical Modeling (Melbourne) Martin NK, Hepatology 2013

60 Relative reduction in prevalence in 10y with combinations of harm reduction and DAAs Martin NK, CID 2013; 57 (Suppl 2): S39-S45

61 Can we eliminate HCV? OST programs alone can reduce HCV transmission by 50-80% Parallel expansion of opioid substitution, buprenorphine, and needle and syringe exchange (NSP) are needed in conjunction with HCV treatment De vos AS et al. Addiction ; Vickerman P et al. Addiction: 2012; Hellard M et al. Hepatology Grebely J et al. Int J Drug Policy 2015 (26):

62 Can PWID succeed with antiviral treatment? IDU does not compromise adherence, completion, or SVR HCV treatment does not impact drug dependency or increase drug use OK to combine with methadone or suboxone Occasional drug use does not seem to impact adherence or SVR Grebely J et al. Int J Drug Policy 2015 (26):

63 Dore GJ et al. Annals Int Med. 2016; 165(9): C-EDGE CO-STAR trial EBV/ GZR for 12 weeks in PWID on stable opioid agonist therapy >3 months N=301, 13 countries Randomized, placebo controlled 3 groups: immediate treatment, deferred treatment (placebo x 12 weeks, then treatment), and placebo Active drug use (in addition to OAT) not excluded

64

65 Dore GJ et al. Annals Int Med. 2016; 165(9):

66 Active drug use was frequent

67 Dore GJ et al. Annals Int Med. 2016; 165(9): Results SVR 91.5% in ITG and 89.5% in DTG Adherence >95% of doses reported by 96.5% of patients >50% of each group had positive UDS at each visit No correlation with adherence or efficacy, regardless of which drug was positive Probable reinfection after treatment completion occured in 6 patients 4.6 (95%CI 1.7,10) reinfections per 100 person-years

68 Reinfection post-treatment In systematic review, the reinfection rate is per 100 person-years Reinfection does occur, but not as often as we think Harm reduction optimization Grady BP, Schinkel J, Thomas XV, Dalgard O. Hepatitis C virus reinfection following treatment among people who use drugs. Clin Infect Dis. 2013; 57(Suppl 2):S

69 Emerging models for reinfection prevention Injecting partners are reservoirs for reinfection Treat a friend approach PWID may be more likely to engage if linked to care by a friend Rolls DA et al. J Theor Biol Mar 21; 297():73-87.

70 My perspective Engagement in formal substance abuse program is strongly encouraged For people not in OAT, there is still a mathematical case for HCV treatment Need to ensure safe needle practices Patient needs to demonstrate adherence Need good primary care! Screening for HIV, TB, intimate partner violence, STIs Assess housing status, MH comorbidities Vaccinations (TDaP, Hav/ HBV, etc.)

71 HCV education & resources VA Hepatitis C Website Hepatitis C Online AASLD/ IDSA Treatment Guidelines