Terapia epatite C, Risposta Virologica Sostenuta e Popolazioni Speciali nel 2018

Transcription

1 Terapia epatite C, Risposta Virologica Sostenuta e Popolazioni Speciali nel 2018 Facoltà di Medicina e Chirurgia Università Vita e Salute OSR-Milano Prof. C. Uberti-Foppa - Milano 25 ottobre 2018

2 The DAA era presents opportuniries for elimination but where do we go next.?

3 EASL Recommendations:Indications for Treatment of Chronic HCV in 2018 Who Should Be Treated?

4 Newly Reported HCV Cases (%) Newly Reported HCV Cases (%) Changing Epidemiology of HCV in the US 2007 (N = 41,037) 2015 (N = 33,454) Male Female Mostly baby boomers Male Female PWIDs: yrs of age Age (Yrs) Age (Yrs) Screening linkage to HCV care DAA treatment cascade must be operative in all those at risk Treatment of PWIDs plus harm reduction efforts essential part of elimination efforts California Department of Public Health. Chronic hepatitis C infections in California: cases newly reported through June

5 ODD Organ Transplants (n) Organ Transplants With Overdose Death Donors Prospective observational cohort study of transplant donors, recipient outcomes 19,897 transplants, 7313 ODDs examined ODDs: 1.1% of donors in 2000, 13.4% in % white 66.3% yrs of age 18.3% HCV infected Kidney Liver Heart Lung Yr Transplanted Durand CM, et al. Ann Intern Med. 2018

6 Potential benefits of treatment in PWID social benefits

7 SVR and PWID Sofosbuvir/Velpatasvir 12 weeks SVR 12 by Genotype in Patients on OST ASTRAL trials (non-opioid substitution therapy [OST], n = 984; OST, n = 51) evaluating the once-daily, pan-genotypic regimen of sofosbuvir/velpatasvir f or hepatitis Cvirus infection, OST did not impact completion, adherence, sustained virologic response (SVR12), or safety. SVR12 was 96% (95% confidence interval, 87%, >99%) in those receiving OST Grebely J

8 SVR and PWID Does use of oppiate substitution therapy affect SVR of DAAs? Grebely J, CID 2016

9 SVR and PWID ANCHOR Substudy:Colocation of HCV and Buprenorphine Substudy of single-arm HCV treatment trial in Washington, DC Endpoints: adherence to SOF/VEL, SVR12 rate; risk behaviors, HCV reinfection, HIV acquisition Patients with HCV infection and opioid use disorder with opioid injection in 3 mos before enrollment; no previous DAAs, no decompensated cirrhosis (N = 90) Wk 12 SOF/VEL + Buprenorphine* Follow-up to Wk 96 *Buprenorphine started between Wk 0-24 of SOF/VEL treatment initiation with followup for 1 yr at same center and with same provider as HCV treatment Rosenthal E, et al. EASL Abstract PS-092.

10 SVR and PWID ANCHOR Substudy: Efficacy of Colocalized Buprenorphine and DAA HCV treatment visit adherence high: 77% to 87% over 24 wks 90% to 95% received study drug Wk 24: Per Protocol 9% 2% 7% Wk 24: ITT 13% 2% 91% 76% 39 patients started MAT with 26 (67%) retained Patients receiving MAT significantly more likely to receive second SOF/VEL bottle and SOF/VEL at study visit vs those not receiving MAT HIV risk behavior decreased significantly from Day 0 of MAT to Wks 4, 12, and 24 (P =.003 for Wk 4 and 24 difference; P =.001 for Wk 12 difference) N = 46 (84%) No SVR Achieved SVR N = 55 (100%) Missed visit Awaiting results Died Rosenthal E, et al. EASL Abstract PS-092.

11 SVR and PWID Elbasvir/Grazoprevir: C-EDGE CO-STAR study Dore GJ et al Ann Intern Med 2016

12 SVR and PWID Co-STAR Part B: Assessment of Reinfection Risk in Patients on OAT Who Received EBR/GZR Observational study in which patients on OAT with GT1/4/6 HCV who received EBR/GZR in Co-STAR Part A were assessed for HCV reinfection and drug use for 3 yrs (N = 199) Part A: SVR12 rate of 91% with 12-wk EBR/GZR; 97% of patients had > 95% adherence During 24 months of available f/u, IDU was stable in PWID receiving OAT (15% to 26%) Part A: Through FW12 Incidence of Reinfection Part A: Part B: Through Through FW24 24 mos of f/u Subgroup Reinfection/ 100 PY (95% CI) Reinfections Rate: 2.3 per 100 PY 74 participants (37%) reported IDU 4.2 ( ) 125 participants (63%) reported NO IDU 0.4 ( ) Dore GJ et al Ann Intern Med 2016

13 SVR and PWID Strategies to Decrease HCV Reinfection Risk After SVR in High-Risk Groups Expect reinfection: logical consequence of treating high-risk groups Harm reduction access (NEP, OST): to reduce risk of reinfection Individual-level strategies: treatment of injecting partners Rapid scale-up: initial increase in reinfections, then control Access to retreatment: without stigma and discrimination

14 SVR and PWID Inadequate Harm Reduction Service Provision for PWIDs in Many States 18 states have highly underdeveloped harm reduction laws (including Alaska, Georgia, Michigan, Missouri, New Jersey, Texas, West Virginia) No laws authorizing syringe exchange program No steps taken to decriminalize possession/distribution of syringes No explicit allowance for retail sale of syringes without prescription Only 3 states (Massachusetts, New Mexico, and Washington) have laws that support full access to both syringe services programs and HCV-related treatment and preventive services for PWIDs Campbell CA, et al. MMWR Morb Mortal Wkl Rep. 2017;66:

15 SVR and PWID TraP Hep C: HCV Treatment as Prevention Program in Iceland Reduced Incidence in 2 Yrs New PWID and Incident HCV Infections at Vogur Addiction Hospital New IVD use New HCV infection 53% reduction in incidence of new HCV HCV PCR+ 43% 72% reduction from % Major scale up with reasonable cure rates Overall SVR: 90%; SVR for patients who completed treatment: 94% Dramatic reduction in community viral load and HCV incidence Yr Tyrfingsson T, et al. EASL Abstract PS-095.

16 SVR and PWID Impact of better linking of care to cure of PWID with DAAs: improved treatment and response can reduce transmission (TasP)

17 Hepatitis C in PWID The opioid epidemic is a stark reminder of the consequences of a societal problem that remained hidden for years, in part because of the stigma associated with drug use and the reluctance to confront it as a public health problem. The concurrent spread of HCV, if not controlled, will similarly have public health and financial repercussions for decades to come. Estimated number of new hepatitis B and Hepatitis C infections in the US by year Liang TJ, et al. N Engl J Med. 2018;378:

18 Heptitis C: elimination/eradication Bello inserire Quasi studenti fanno uso di eroina ev 10 o più volte al mese

19 HCV During Pregnancy and in Children

20 Newly Reported HCV Cases (%) Newly Reported HCV Cases (%) Changing Epidemiology of HCV in the US 2007 (N = 41,037) 2015 (N = 33,454) Male Female Mostly baby boomers Male Female PWIDs: yrs of age Age (Yrs) Age (Yrs) Screening linkage to HCV care DAA treatment cascade must be operative in all those at risk Treatment of PWIDs plus harm reduction efforts essential part of elimination efforts California Department of Public Health. Chronic hepatitis C infections in California: cases newly reported through June

21 Recent HCV Infection Increase Among Women of Reproductive Age in United States National Notifiable Diseases Surveillance System ,801 reproductive-aged women and 1859 children (aged 2-13 yrs) with HCV Number of reproductive-aged women with acute, past/present HCV doubled: 2006: 15, : 31,039 Wisconsin Electronic Disease Surveillance System and Wisconsin Medicaid Data Rate of HCV infection during pregnancy increased 93% from (1/368 to 1/192) Of 183 HCV-exposed infants, only 34% received recommended HCV testing Vertical transmission documented: 4%, ~ 15% with uncontrolled HIV coinfection Treat HCV in women of reproductive age before pregnancy is considered HCV treatment during pregnancy not recommended because of lack of safety/efficacy data. Ly KN, et al. Ann Intern Med. 2017;166: Watts T, et al. MMWR Morb Mortal Wkly Rep. 2017;66: ; AASLD/IDSA. HCV guidance. September 2017.

22 SVR and Children AASLD/IDSA Recommendations for Treating HCV-Infected Children If DAA regimens available for their age group, treatment is recommended for all HCV-infected children older than 3 yrs Defer if IFN-free regimens not available Extrahepatic manifestations or advanced fibrosis require early antiviral therapy to minimize future morbidity and mortality LDV/SOF or SOF + RBV FDA approved for age 12 yrs and older (SVR 98%) Multiple DAA regimens under investigation for ages 3-17 yrs AASLD/IDSA. HCV guidance. October 2018 Clinical Trials.gov, access october 2018

23 Diagnosis of Acute Hepatitis C (AHC) in HIV-infected MSM from 2003 to 2014 Martinez-Rebollar et al. Enferm Infec Microbiol Clin. 2015

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25 Risk Factors for HCV Acquisition in HIV+ MSM Platt et al 2016

26 SVR and HIV HIV-HCV coinfection

27 SVR and HIV Risk of DAA Therapy Failure in HIV/HCV Co-infection Multicenter cohort of HCV mono-infected and HIV/HCV co-infected subjects from 9 sites in Germany (N=1505, GECCO Cohort) SVR12 According to Cirrhosis Status and CD4 T-cell Count in HIV/HCV Co-infected Subjects Overall SVR rate was 95% Non-cirrhotic Cirrhotic 95% (1096/1156) in HCV mono- and 94% (329/349) in HIV/HCV co-infection In multivariate analysis in the HIV/HCV subgroup, only liver cirrhosis (OR 3.5 [95% CI: ]) remained significantly associated with non-svr. Early DAA initiation in co-infected patients before the onset of higher liver fibrosis/cirrhosis may allow for optimal viral eradication rates and substantially reduced morbidity and mortality. DAA, direct acting agents; SVR 12, sustained virologic response 12 weeks after therapy Boesecke C, et al. CROI Seattle, WA. Poster #551

28 HCV reinfection incidence and outcomes among HIV-positive MSM in Western Europe Reinfection is high Martin T. EASL 2016

29 Treatment as Prevention (TasP) = The Dutch Model Rapid DAA-HCV Therapy Uptake in HIV Patients & Decline in Acute HCV Infections Among HIV+ MSM Evaluation of outcomes in HIV/HCV coinfected patients with access to DAAs ATHENA Cohort all oral DAAs or PegIFN+SMV or SOF PegIFN±BOC or TVR Rapid uptake of all oral therapy after November 2015 DAHHS 1+2 Cohorts Acute HCV Diagnoses (n) PYFU Rate per 1000 PYFU Prevalence per year % 0.55% Majority (70%) of HIV/HCV coinfected patients are cured of HCV or expected to be, and the incidence of acute HCV has decreased significantly, most likely due to unrestricted access and use of HCV DAAs (AIDS Therapy Evaluation in the Netherlands) Boerekamps A, CID 2018

30 HCV Seroprevalence in US State Correctional Departments, Varan AK, et al. Public Health Rep. 2014;129: State Sex Period of Observations Median HCV Seroprevalence, % Indiana M & F Michigan New Mexico M F M F New York M & F North Dakota M & F Oregon M & F Pennsylvania M & F Washington M F

31 HCV Grossly Undertreated in Correctional Settings Among 41 states with reported data as of January 1, 2015: 106,266 (10%) inmates known to have HCV infection Only 949 (< 1%) of HCV-infected inmates receiving HCV treatment Assistance with transition to community healthcare providers upon release important for maintaining and enhancing gains achieved by HCV treatment in prison Beckman AL, et al. Health Aff (Millwood). 2016;35:

32 Public and Individual Health Benefits of HCV Treatment in Prison Prison System Decreased risk of HCV transmission within the prison Improved health of inmates Incarcerated Individual Cured of HCV Decreased risk of liver failure and liver cancer No more adverse events (eg, fatigue, depression) BENEFITS OF HCV TREATMENT Community Decreased risk of HCV transmission by prisoners following release Long-term cost savings

33 SVR and incarcerated Outcomes of treatment for HCV infection in the prison setting Mc Donald L- EASL 2017

34 Llerena S-ASSLD 2016 SVR and incarcerated JAILFREE-C Therapy: LDP/SOF for 8 or 12 wks

35 SVR and incarcerated SToP-C: HCV Treatment as Prevention Trial in 4 Australian Correctional Centers Surveillance phase (Oct 2014 Nov 2017): model number required to treat to show significant decrease in HCV incidence Treatment phase: 12 wks of SOF/VEL for all HCV-infected prisoners Current surveillance phase analysis includes 482 participants at risk of HCV (primary or reinfection) who had 1 follow-up visit; 388 py of follow-up HCV Infection Incidence/100 PY Overall 7.9 Primary infection 6.4 Reinfection 12.3 In those w/idu history but not during current imprisonment % CI Factors Associated With HCV Risk* ahr 95% CI Younger age, per 10 yrs History of injecting, but not in current imprisonment (vs no injecting) Injecting in current imprisonment (vs no injecting) In those injecting in current imprisonment *Cox proportional hazard model. Hajarizadeh B, et al. EASL Abstract THU-134.

36 SVR and CKD Elbasvir/Grazoprevir effectiveness in patients with CHC and chronic Kidney Disease: Real world experience from the TRIO Network Younossi Z- EASL 2017

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38 Key Take-Home Points HCV elimination will require innovation and focus on special populations PWIDs are driving new HCV infections in the US HCV treatment can provide benefit to the individual (cure) and society (prevention) Syndemic approaches are needed Women of reproductive age are driving new pediatric HCV infections HCV screening before and during pregnancy Corrections systems have high HCV burden and minimal treatment uptake Curative HCV treatment may prevent transmission in community after release

39 One of the last population in need of additional therapies to provide higher SVR rates - Decompensated Cirrhosis With Previous DAA Failure Remains challenging - Protease inhibitors cannot be given in decompensated cirrhosis - Regimen options: LDV/SOF +RBV for 24 wks DCV + SOF + RBV for 24 wks SOF/VEL + RBV for 24 wks

40 SVR and Decompensated Cirrhosis Decompensated Cirrhosis Genotype 2 or 3 Recommendation 2.1 We suggest that HCV-infected patients with decompensated cirrhosis with CTP Class B and/or MELD less than 20 on the waiting list for liver transplantation, who are without refractor portal hypertensive symptoms or other conditions requiring more immediate transplantation, should be treated with antiviral therapy ASTRAL- 4 Study (267 pts with decompensated cirrhosis) Terrault N, Transplantation 2017; HCV guidance May 24, 2018; Foster GR N Engl J Med 2015

41 Liver decompensation predicts ribavirin overexposure in hepatitis C virus patients treated with direct-acting antivirals Achievement of Rapid Virological Response (i.e., hepatitis C virus RNA undetectability within week 4 of treatment) was not associated with ribavirin plasma concentrations measured over the fist 8 wk Guardigni V. World J Hepatol 2017 December 8; 9(34):

42 Presence of NS5A RAVs correlates with progression of liver fibrosis and represents de novo selection of variants rather than transmission of drug resistance

43 Summary SVR and special populations The majority os so called controversies and special populations are in the eyes of the clinician and not in the reality

44 Summary SVR and special populations The majority os so called controversies and special populations are in the eyes of the clinician and not in the reality 2018 last population in need of additional therapies to provide higher SVR rates Decompensated Cirrhosis With Previous DAA Failure Remains challenging