Hepatitis C in HIV Women: Pardigm Shift with all oral Therapies

Transcription

1 Hepatitis C in HIV Women: Pardigm Shift with all oral Therapies Mamta K. Jain, M.D., M.P.H. UT Southwestern Medical Center

2 Financial Disclosure Research Grants: Gilead Sciences AbbVie Pharmaceuticals Merck Janssen Bristol-Myers Squibb Boehringer Ingelheim GlaxoSmithKline Pfizer Advisory Board/Speaker s Program Gilead Sciences AbbVie Pharmaceuticals Boehringer Ingelheim

3 Hepatitis C virus (HCV) Family Flaviviridae with 7 genetic types Enveloped, positive sense, single stranded RNA

4 Sources of Infection for Persons with Hepatitis C Injecting drug use 60% Sexual 15% Transfusion 10% (before screening) Unknown 10% *Nosocomial; Health-care work; Perinatal Other* 5% Source: Centers for Disease Control and Prevention

5 HCV Epidemiology Most common blood-borne infection in US 35.8% of HCV infections are in women

6 New Epidemic: Headlines Heroin and Pill Abuse Stir a Battle Cry in Vermont (ABC News) Heroin Makes a Comeback: This Time, Small Towns are Increasingly Beset by Addiction, Drug-Related Crimes (US News & World Report) Hidden America: Heroin Use Has Doubled, Spreading to Suburbs (ABC News) Aggressive pill enforcement pushes young suburbanites to heroin (Akron Beacon Journal)

7 Prisoners: High Prevalence of HCV Prevalence of HCV in correctional settings 10-41% Higher prevalence in those who were IDU A study of 6,342 inmates of which 55% were screened for HCV (n=3470), 21% had acute HCV. Diagnosed inmates had a mean age 29, 63% female and 91% were Caucasian Testing and treating HCV in correctional settings could have a large impact on HCV incidence and prevalence Spaulding et al. Top Antivir Med 2013;21:27-35 Kim et al. Hepatology 2013;57:

8 HCV Mother to Child Transmission 4% risk of HCV transmission from mother to child in women with HCV Risk 19.4% if mother is HIV/HCV infected Increased risk of mother to child transmission among those with high HCV viral loads Roberts Hepatology 2002: S

9 HCV Mother to Child Transmission HCV can be found in breast milk But breastfeeding does not promote HCV transmission Prasad Am J Perinatol 2013:

10 HCV Screening Baby Boomers IDU Multiple sexual partners Not recommended to screen all pregnant women

11 HCV Natural History Women have increased clearance of HCV compared to women Women have slower progression to cirrhosis Kenny-Walsh N Engl J Med 1999: Levine Clin Gastroenterol Hepatol 2006:

12 HCV Mortality Exceeds HIV The Increasing Burden of Mortality From Viral Hepatitis in the United States Between 1999 and 2007 Ly et al. Ann Intern Med. 2012;156:

13 Why Should We Treat HCV? Pros Treatment is curative Reduce risk of liver related mortality Reduce risk of new infections/transmission Cons Long latency; asymptomatic phase Cost Small proportion will progress to ESLD Risk of re-infection high

14 SVR and All-Cause Mortality Among Pts With Chronic HCV and Advanced Hepatic Fibrosis van der Meer et al. JAMA 2012; 308:

15 SVR% Evolving HCV Treatment Paradigm IFN 24 weeks 13 IFN 48 weeks 48 weeks 24 weeks 12 weeks 43 IFN+ RBV 28 weeks SVR 56 Peg- IFNa+RBV 48 weeks 75 TVR/BOC+ Peg-IFNa+ RBV 90 SOF +Peg- IFNa+RBV 12 weeks 99 oral therapy for 12 wks or less

16 HCV Treatment Response by Gender Small study of 70 patients treated with pegylated interferon and ribavirin Lower SVR in women Difference persisted after adjustment for age, race, genotype, prior treatment, duration of therapy, and fibrosis stage Discontinuation rate were higher in women than men due to adverse events Simoes Womens Health Issues 2015:

17 HCV Life Cycle and DAA Targets Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA LD ER lumen LD Virion assembly Translation NS3/4 and polyprotein protease processing inhibitors ER lumen Membranous web LD NS5B polymerase RNA inhibitors replication Nucleoside/nucleotide Nonnucleoside NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:

18 Medications used in Phase 2 and 3 Trials: The Future? NS3/4A Protease Inhibitors boceprevir (TID) telaprevir (TID) simeprevir (QD) asunaprevir (BID)* danoprevir/r (BID) paritaprevir(qd) grazoprevir (QD) GS9451 (QD) NS5B Polymerase Inhibitor sofosbuvir (QD) dasabuvir (BID) setrobuvir (BID) deleobuvir (BID) BMS (BID) mericitabine (BID) GS9669 (QD) NS5A inhibitor daclatasvir (QD)* ledipasvir ( QD) ombitasavir(qd) elbasvir (QD) PI-688 (QD) * Not available in US

19 GENOTYPE 1

20 Treatment Naive Preferred Sofosbuvir/ledipasvir (FDC) (Harvoni ) Dosing 1 pill once a day Duration 12 weeks Treatment naïve with or without cirrhosis * 8 wks allowed for treatment naïve, non cirrhotic with < 6 million copies Be careful with shorter duration may be at risk for higher relapse

21 Genotype 1 Naïve Treatment Experienced / / / / / / / / weeks 24 weeks sof/ldv sof/ldv +rbv 0 12 weeks 24 weeks SOF/LDV SOF/LDV+ RBV Afdhal N et al. N Engl J Med 2014;370: Afdhal N et al. N Engl J Med 2014;370:

22 ION-4: LDV/SOF in HIV/HCV HIV/HCV Phase 3: ION 4 Wk 0 Wk 12 Wk 24 N=335 LDV/SOF SVR12 Phase 3, multicenter, open-label study (NCT ) HCV GT 1 or 4 patients in US, Canada, and New Zealand Broad inclusion criteria HCV treatment-naïve or treatment-experienced 20% with compensated cirrhosis Platelets 50,000/mm 3 ; hemoglobin 10 mg/dl, CrCl 60 ml/min HIV-1 positive, HIV RNA <50 copies/ml; CD4 cell count >100 cells/mm 3 ART regimens included FTC/TDF with EFV, RAL or RPV Naggie et al, CROI 2015, Oral #LB-152

23 SVR12 (%) SVR12: Overall, TN vs TE and by Cirrhosis Status Overall Naïve vs Experienced Cirrhosis Status / / / /268 63/67 LDV/SOF 12 Weeks Naïve Experienced No Cirrhosis Cirrhosis Among those who were treatment-experienced with cirrhosis, 98% (46/47) achieved an SVR12 Naggie et al, CROI 2015, Oral #LB-152

24 SVR12 (%) SVR12 by Subgroup and Baseline Characteristics % 96% 95% 100% 96% 96% 96% 100% 99% 90% / /276 56/59 36/36 285/ /250 74/77 8/8 215/ /115 Overall Male Female BL HCV BL HCV GT 1a GT 1b GT 4 Non-black Black RNA RNA < 800K 800K Statistically significant in multivariate analysis Naggie et al, CROI 2015, Oral #LB-152

25 HCV Genotype 1: 3D naïve or experienced Genotype 1a Paritaprevir/ritonavir+ ombitasavir (once daily)+ dasabuvir (bid) + weight-based ribavirin bid Duration 12 weeks if no cirrhosis Duration 24 weeks if with cirrhosis Genotype 1b Paritaprevir/ritonavir+ ombitasavir (once daily)+ dasabuvir (bid) No ribavirin Duration 12 weeks if no cirrhosis Duration 24 weeks if with cirrhosis

26 Sustained Virologic Response at 12 Weeks after the End of Treatment. Ferenci P et al. N Engl J Med 2014;370:

27 HIV/HCV 3D HIV/HCV 12 wk + RBV 24 wk + rbv /31 29/32 SVR 12 Sulkowski JAMA 2015;313:

28 HCV Genotype 1: Simeprevir/Sofosbuvir Sofosbuvir and simeprevir ± ribavirin Once daily 12 weeks if non-cirrhotic 24 weeks if cirrhotic

29 Real World HIV/HCV: Sim/Sof Del Bello. 22 nd CROI February 23-26, 2015; abstract 647

30 GENOTYPE 2

31 Genotype 2 IFN eligible Regimen duration Preferred Yes or No Sof 400mg daily+ wt based RBV daily 12 weeks Alternative None

32 SVR12 (%) SVR12 (%) VALENCE GT2 12-Wk Treatment (n = 73) n/n = 0 29/30 2/2 30/33 7/8 0 Naive, Noncirrhotic Naive, Cirrhotic Exp d Noncirrhotic No increase in AEs seen with longer duration treatment AEs seen consistent with RBV Exp d, Cirrhotic Zeuzem S, et al. AASLD 2013.

33 SVR12 (%) SVR12 (%) FUSION: SVR12 With Sofosbuvir + RBV by Genotype and Fibrosis Level Sofosbuvir + RBV 12 wks 100 Sofosbuvir + RBV 16 wks n/n = 25/26 23/23 6/10 7/9 14/38 25/40 5/26 14/ No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Genotype 2 Genotype 3 Nelson D, et al. EASL Abstract 6. Reproduced with permission.

34 GENOTYPE 3

35 SVR12 (%) SVR12 (%) SVR % Sofosbuvir and Ribavirin for 24 weeks : VALENCE GT3 24-Wk Treatment (n = 250) n/n = 0 86/92 12/13 87/100 27/45 Naive, Noncirrhotic Naive, Cirrhotic Exp d Noncirrhotic Exp d, Cirrhotic No increase in AEs seen with longer duration treatment AEs seen consistent with RBV Zeuzem S, et al. AASLD 2013.

36 SVR12 (%) LONESTAR-2: Sofosbuvir + P/R for 12 Wks in Treatment-Exp d GT2/3 HCV Pts Single-arm trial of pts with treatment failure on P/R Approximately 50% with compensated cirrhosis Primary endpoint: SVR12 Pts with GT2 or GT3 HCV and previous treatment failure with P/R (N = 47) Sofosbuvir 400 mg QD + PegIFN 180 µg once wkly + RBV 1000 mg or 1200 mg/d Wk n/n = 96 22/23 GT /24 GT3 Lawitz E, et al. AASLD Abstract LB-4. Reproduced with permission. Similar rates of SVR12 in pts with and without cirrhosis

37 GENOTYPE 4

38 Genotype 4 Sofosbuvir/ledipasvir 12 weeks Synergy trial of 21 genotype 4 38% treatment experienced 33% with cirrhosis 20/21 had SVR 12

39 Genotype 4: 3D Pearl-1 42 treatment naïve and 49 treatment experienced with genotype 4 3D+ ribavirin for 12 weeks 91/91 achieved SVR12

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41 SVR12 (%) SVR12 (%) NEUTRINO: (SOF/Peg/RBV) for 12 wks (alternative) SVR12 According to Genotype SVR12 According to Fibrosis Level n/n = 261/292 27/28 7/7 GT 1 GT 4 GT 5, /273 43/54 No Cirrhosis Cirrhosis Lawitz E, et al. EASL 2013.

42 Sim/Sof with or without RBV for 12 wks (alternative) No clinical data Simeprevir has activity against genotype 4 Only for treatment naive

43 GENOTYPE 5&6

44 SVR12 (%) SVR12 (%) Sofosbuvir/Pegylated Interferon/Ribavirin: NEUTRINO SVR12 According to Genotype SVR12 According to Fibrosis Level n/n = 261/292 27/28 7/7 GT 1 GT 4 GT 5, /273 43/54 No Cirrhosis Cirrhosis Lawitz E, et al. EASL 2013.

45 Genotype 6: sofosbuvir/ledipasivir for 12 weeks for Treatment Experienced and Naive 120 SVR SVR /25 Genotype 6

46 SIDE EFFECTS

47 Interferon Side Effects Symptoms/lab abnormality flu-like symptoms dehydration Fatigue Cytopenia Depression Rash Hair loss Neuropathy Thyroid abnormality Retinopathy Management Increase water intake Decrease interferon if ANC<500 Plt<50K Other severe symptoms Treat irritability/depression with SSRI Treat rash with topical steroid cream

48 Ribavirin Side Effects Symptoms/lab abnormality Anemia Rash Insomnia Cough Management Hmg<10: decrease ribavirin to 600mg topical steroids Dose reduction Avoid use with AZT (anemia); drug interaction with DDI and D4T

49 Ribavirin Category X Women of child-bearing potential must have urine pregnancy test while on treatment and for 6 months after completion of treatment Must use 2 forms of birth control

50 Sofosbuvir Side Effects When used with ribavirin Fatigue Headache Drug-drug interactions Amiodarone symptomatic bradycardia P-gp inducers (rifampin, St. John s wort, etc) Anti-convulsants

51 Simeprevir Side Effects Simeprevir/peg/rbv Rash (photosensitivity) Pruritus Nausea Simeprevir and sofosbuvir Fatigue Headache Nausea Do not use in Child B or C cirrhotics

52 Simeprevir: drug-drug interactions Inducers/inhibitors of CYP3A can impact drug levels Digoxin Antiarrhythmics Anticonvulsants Erythromycin Clarithromycin Azoles rifampins HIV medications Can not use Cobicistat NNRTIs PIs Can use Rilpivirine Raltegravir dolutegravir

53 Sofosbuvir/ledipasvir Side Effects Fatigue Headache Drug-Drug interactions Amiodarone PPI P-gp inducers (rifampin, St. John s wort) Boosted PI and truvada increase tenofovir levels Do not use with cr cl <30

54 Ombitasvir/ paritaprevir/ ritonavir plus dasabuvir: side Effects Fatigue Nausea* Pruritus* Other skin reactions Insomnia* Asthenia *most common AE without ribavirin

55 Ombitasvir/ paritaprevir/ ritonavir plus dasabuvir: drug-drug interactions Risk of ALT elevation with ethinyl estradiolcontaining medications (in 1%) Cyp3a, UGT1A1, BCRP, OATP1B3 HIV medications Can use with atanzanvir/r (do not give ritonavir) Raltegravir dolutegravir Darunavir/r Decreased levels of darunavir; need more data

56 Conclusion HCV treatment has become shorter, with fewer side-effects, and with improved response (cure!) HIV/HCV patients have drug-drug interactions which may require change in HIV medications

57 Thank you! For more information