Special developments in the management of Hepatitis C. Disclosures

Transcription

1 Special developments in the management of Hepatitis C Sandeep Mukherjee,MD Division of Gastroenterology CHI Health and Creighton University Medical Center Omaha, NE Sandeep.Mukherjee@alegent.org Disclosures Speaker: Abbvie pharmaceuticals, Merck, Gilead Advisory board: Gilead Section editor for Hepatology: Dynamed Plus 1

2 Selected topics for discussion Update on newest drugs (US only) HCV-HIV coinfected patients Role of fibroscan Selecting patients for hepatoma surveillance with ultrasound HBV reactivation with DAA therapy HCV Genome Simeprevir Paritaprevir with ritonavir Grazoprevir Glecaprevir Voxilaprevir Ledipasvir Ombitasvir Elbasvir Daclatasvir Velpatasvir Pibrentasvir Sofosbuvir (NUCi) Dasabuvir (non- NUCi) 2

3 Update on newest drugs DAA s -used in all HCV patients including compensated cirrhosis (Child-Turcotte-Pugh class A) EXCEPT decompensated cirrhotics (class B,C) 2 new pan-genotypic protease inhibitors approved in 2017: VOXILAPREVIR AND GLECAPREVIR New NS5A inhibitor 2017:PIBRENTASVIR New NS3/N4AProtease inhibitors VOXILAPREVIR Substrate: CYP3A4,2C8 Substrate and Inhibitor: OATP1B1,1B3, P- gp,bcrp Coformulaled with Sofosbuvir and Velpatasvir Indication: salvage therapy (ie not for naïve patients) 3

4 New NS3/NS4A protease inhibitors GLECAPREVIR Minimal metabolism, biliary excretion Interaction with digoxin when given with pibrentasvir? more favorable DDI profile > previous protease inhib ;minimal interactions with: Ca antagonists, combination antiretorviral regimens Substrates of CYP3A,2D6,2C19,2C9 Protease inhibitors-clinical pearls Be careful of DDIs via CYP3A4 activation/inhibition Other common CYP inhibitors: antiarrhythmics, calcium antagonists, statins GRAZAPREVIR (near pangenotypic, CYP3A4 and OATP1B1/3 substrate) BUT. DDIs differ from other protease I (Csa and HIV protease inhibitors inc. levels due to OATP1B1/3 inhibition) 4

5 NS5A Replication complex inhibitors All substrates of P-gp protein and CYP 3A4 (LEDIPASVIR NOT CYP3A4 substrate) DDIs limitations with certain statins, anti-tb medications, certain HIV regimens Acid milieu for ledipasvir and velpatasvir NS5B Inhibitors Sofosbuvir and dasabuvir Sofosbuvir-backbone of many DAA regimens P-gp substrate (avoid use with inducers) Important DDI with amiodarone-should be held for at least 8 wks before starting SOF. 5

6 HCV-HIV coinfected patients No longer difficult to treat population Global estimate of co-infected patients 2,300,000 Advanced liver disease accounted for 13% of all deaths among HIV+ patients before DAA USA:HCV is the leading cause of liver disease and related mortality in coinfected patients Platt et al. Lancet Infectious Diseases 2016;16: HCV-HIV coinfected patients DAA vs interferon-based treatment: higher cure rates, better tolerance, improved safety Benefits well-established Meta-analysis of 31 studies (33,360 patients with HCV infection and coinfections) SVR associated with 50% risk reduction in allcause mortality (74% if cirrhotic;79% coinfected population). Simmons et al. Clin Inf Dis 2015;61:

7 DDIs in HCV-HIV coinfected patients Briefly discuss DDIs with commonly used DAA s SOFOSBUVIR (SOF) LEDIPASVIR (LDV) DACLATASVIR (DAC) ELBASVIR (ELB) GRAZOPREVIR (GZP) DDIs in HCV-HIV coinfected patients SOFOSBUVIR (NS5B nucleotide polymerase inhibitor, P-gp substrate) Avoid with TIPRANIVIR (induces P-gp) LEDIPASVIR (NS5A inhibitor, fixed dose with SOF, inhibitor of P-gp) LDV unaffected by raltegravir, rilpivirine but tenofovir DF levels can increase (not with tenofovir alafenamide) 7

8 DDIs in HCV-HIV coinfected patients SIMEPREVIR(NS3/4A protease inhibitor)- inhibits CYP 1A2 and 3A4 (intestinal),p-gp Do not use with efavirenz (CYP3A4 inducer),etravine, HIV protease inhibitors, cobicistat, ritonavir and nevirapine Can be used with rilpivirine, raltegravir,dolutegravir DDIs in HCV-HIV coinfected patients DACLATASVIR (NS5A inhibitor used with SOF)- metabolized by CYP3A and inhibits P-gp Avoid with CYP3A inducers (efavirenz,etravine, nevirapine) No clinical relevant interactions between tenofovir and DCV ELBASVIR (NS5Ai) and GRAZOPREVIR (protease i)- substrates of CYP3A and P-gp Avoid with CYP inducers (efavirenz) and inhibitors 8

9 SVR rates with DAA s in HCV monoinfection and HCV/HIV coinfection HCV monoinfection HCV/HIV coinfection 12 wk regimen, genotype 1 LDV/SOF 99% (211/214) 96% (332/355) DCV + SOF 100% (41/41) 97% (123/127) PTV/RTV/OBV/DSV 96% (455/473) 94% (29/31) + RBV EBR/GZP 95% (273/288) 95% (179/189) Sikavi et al. Hepatology 2018;67: Duration of treatment 8 vs 12 weeks German multicenter study(gecco-01): 210 monoinfected and 35 coinfected patients treated for 8 wk with LDV/SOF* Overall SVR 93.5% and 96.4% for coinfected 996 coinfected patients,no cirrhosis and HCV RNA < 6 million iu/ml treated with LDV/SOF for 8 vs 12 wks** SVR 94.6% (8 wks) vs 95.3% (12 wks) *Ingiliz P, et al. Clin Infect Dis 2016;63: **Bhattacharya D, et al. Clin Infect Dis 2017;64:

10 Reinfection rates among HCV/HIV coinfected individuals after SVR Meta-analysis of 8534 patients, 49 studies 5 yr reinfection rate among monoinfected patients % (high risk: prisoners, injection drug users) vs 21.8% in coinfected pts Hill et al. Clinc Infect Dis 2016;62: HCV/HIV Coinfected patients- a summary 1. Review HAART prior to HCV treatment to avoid DDIs 2. Similar SVR rates between mono and coinfected patients in clinical trials and recent real-world data 3. However, barriers to treatment include drug and alcohol use, mental illness, homelessness, incarceration affect SVR and reinfection 4. Care does not end after achieving SVR 10

11 Non invasive assessment of hepatic fibrosis Biomarkers APRI (>1.5) Fibrosis-4 (0-6) Fibrosure (USA)/Fibrotest > 0.75 Others Imaging Fibroscan (> 14 kpa) Magnetic resonance elastography Fibroscan 11

12 Hepatoma surveillance in HCV Anecdotal reports of increased incidence after SVR* Not verified in recent large retrospective study. 22,500 patients treated with DAA (19,518 with SVR; 2982 without SVR) 39.0% had cirrhosis. There were 271 new cases of HCC, including 183 in patients with SVR ** Compared with patients without SVR, those with SVR had a significantly reduced risk of HCC (0.90 vs 3.45 HCC/100 person-years; adjusted hazard ratio, 0.28, 95% CI= ). Patients with cirrhosis had the highest annual incidence of HCC after SVR (1.82 vs 0.34/100 person-years in patients without cirrhosis; adjusted hazard ratio, % CI, ). Cirrhotic patients still at risk of HCC despite SVR and require surveillance Non-cirrhotic patients with advanced fibrosis (F3) or high FIB-4 and obesity may also benefit from HCC surveillance *Conti F, et al. J Hepatol 2016;65: **Kanwal F, et al. Gastroenterology 2017;153:

13 HBV reactivation with DAA treatment Small risk of HBV reactivation with DAA-29 cases between Nov 2013 and Oct died;1 required liver transplant HBV screening required prior to DAA treatment Management of HBV reactivation during DAA not standardized Bersoff-Matcha s, et al. Ann Int Med 2017:166:792-8 HBV reactivation with DAA treatment 1 ST study to prospectively evaluate risk of HBV flares during DAA treatment for HCV Open-label, n=111 (Asian patients), 61% HCV G1b,12 weeks of LVR/SOF with 100% SVR HBV DNA<20 iu/ml: n=37 (31 or 84% had quantifiable HBV DNA until 12 wk post EOT) HBV DNA >20 iu/ml: n=74 (39 or 53% had >1 log rise until wk 12 post EOT) 5 pa ents with rising HBV DNA had ALT of whom 3 started treatment 1 pt had HBV reactivation from wk 8, ALT at 48 wk post EOT started treatment wk 53 Liu CJ, et a;. Gastroenterology 2018;154:

14 Mechanism of HBV reactivation during DAA treatment Invivo gen website HBV reactivation with DAA treatment Mechanism(s)? Lower HBsAg and higher IP-10 levels in HCVdominant HBV/HCV-coinfected patients: suggest HCV suppresses HBV DNA replication and also HBsAg production by immune mechanisms Most patients in Liu s study did not develop clinical complications and minority required treatment However, may need to follow up patients longer than 12 wk post EOT Wiegand SB, et al. Clin Microbiol Dis 2015;21:1-9 14

15 Conclusion AASLD/IDSA guidelines-living document which is periodically updated HCV/HIV coinfected patients have comparable SVRs to monoinfected patients but also have unique challenges Increasing use of non-invasive testing (liver biopsies rarely performed) Patients with cirrhosis need hepatoma surveillance after SVR HBV/HCV patients-need to be monitored during and after DAA therapy for HBV reactivation 15