Hepatitis C: the 2015 Perspective for the Family Medicine Practitioner

Hepatitis C: the 2015 Perspective for the Family Medicine Practitioner Annie Luetkemeyer, MD Division of HIV,ID & Global Medicine San Francisco General Hospital

Disclosures I have received research grant support to UCSF related to HCV from the following: Abbvie Bristol Myers Squibb (BMS) Gilead Pfizer Merck ACTG (NIH)

Evidence clearly supports treatment in all HCV-infected persons except those with limited life expectancy (less than 12 months) due to non liver related comorbid conditions www.hcvguidelines.org

Relevance to Family Practice HCV has undergone a revolution: All oral, highly effictive therapy now available for essentially ALL patients, even the most complex Evidence supports treating all HCV+ patients, regardless of degree of hepatic fibrosis Regardless of whether or not you are or become an HCV treater, important to discuss the changing landscape with our primary care patients

HCV: The big picture in 2015 Relevance to family practice Preparing for HCV treatment Our current HCV arsensal What populations remain special in 2015? Monitoring on therapy and after therapy

Glossary DAA: Directly Acting Agents Fibrosis Staging: Metavir F0-F4 HCV Genotype: strain of HCV (1-6), not a drug resistance test P/R: Pegylated interferon (PEG) + Ribavirin (RBV) RAVs : Resistance associated variants SVR: Sustained virologic response (= cure)

Resources http://www.hcvguidelines.org Management guidelines from IDSA and AASLD http://www.hep-druginteractions.org Free downloadable app http://www.hepatitis.va.gov/provider/index.asp Great patient information

Our patient 32 yo man, former IDU, now on methadone, establishing care in your clinic. HCV Antibody+ PMH: none, Meds: Methadone Labs: AST 35/ALT 33 Alb 3.9. INR 1.1

HCV Ab+: next steps Confirm viremia with HCV RNA Screen and vaccinate if indicated for HAV & HBV Reduce alcohol consumption Reduce forward transmission risk Drug use avoid sharing needles or nasal straws Sexual counseling: MSM or HIV infected partner Household precautions: no shared toothbrushes or razor

HCV Genotype Genotypes 1-6 Can impact disease progression Genotype 3: associated with steatohepatitis Impacts selection and response to therapy Easiest to Cure: 2>4 1 (1b>1a) Genotype 1: most common in US (70%) 70% 1a

Fibrosis Evaluation Key to assess for advanced fibrosis Impacts decision to screen for HCC and varices Informs risk of decompensation and mortality Affects HCV treatment response, choice of therapy, and treatment initiation timeline If initial evaluation does not show fibrosis, suggest repeating in 3-5 years, if not cured of HCV in the interim Do NOT need q 6-12 month imaging for HCC surveillance if non-cirrhotic HCV+

Serologic markers Platelets, INR, Albumin Fibrosis assessment Serologic tests: APRI, Fib- 4, FibroSure/Test Physical Exam Palmar erythema, telangectasia, gynecomastia, splenomegaly Imaging: Ultrasound reasonable first step CT and MRI usually unnecessary- would avoid radiation and save as follow-on tests Transient Elastography: Fibroscan Excellent option when available -now FDA approved Biopsy: rarely necessary FREE! APRI= (AST/ASTULN)/Plts

Case #1 continued HCV RNA: 7 million IU/ml Genotype 1a Plts 210, INR 1.0, Albumin 4.1 APRI= 0.4 HAV Immune Hep B S Ab neg, S Ag neg, Core Ab Neg Ultrasound: no evidence of cirrhosis Should you move forward with HCV treatment in this non-cirrhotic patient?

Whom to treat Evidence clearly supports treatment in all HCV-infected persons except those with limited life expectancy (less than 12 months) due to non liver related comorbid conditions www.hcvguidelines.org

More information % of Patients with Positive Urine Drug Screen 70 60 50 40 30 20 10 0 Tells you he still occasionally smokes and shoots speed Adherent to appointments and motivated to treat HCV Time Point Any drug use of 8 classes* Any drug use of 7 classes (excl. cannabinoids) Cannabinoids Benzodiazepines Opiates Cocaine Amphetamines Dore AASLD 2015 #42 Despite substantial drug use during treatment, 96.5% of patients missed 3 doses during 12 weeks

Drug procurement Limited access to expensive HCV drugs has impacted DAA use 2014-15 analysis, 4 states, 2350 HCV patients 16% denied Medi-caid: 46% denied Progress toward improved access Medi-Cal 7/15: Removed restrictions limiting treatment to those with advanced fibrosis HIV+, Women childbearing age, IDU, MSM Worlwide: scale up of generic production Lo Re AASLD 2015 LB-5

HCV Arsenal & Principals of therapy

Assaleh Liver Int 2013:

Protease inhibitors: -PREVIRs eg. simeprevir Assaleh Liver Int 2013

NS5B Polymerase inhibitors: -BUVIRs : Nucleoside inhibitors: ex. Sofosbuvir Non- Nucleoside inhibitors (NNI): ex. Dasabuvir

NS5A Inhibitors: -ASVIRs e.g Daclatasvir Ledipasvir Ombitasvir

Current DAA combinations NS5b Nucleotide based therapy NS5b Nuke Backbone SOFOSBUVIR One drug from 2 nd class NS5a Protease inhibitor Ribavirin Triple therapy without a NS5b Nuke NS5a NS5b Non-Nuke Protease inhibitor

Current DAA combinations NS5b Nucleotide based therapy NS5b Nuke Backbone SOFOSBUVIR One drug from 2 nd class NS5a Protease inhibitor Ribavirin Sofosbuvir/ Ledipasivir FDC Triple therapy without a NS5b Nuke NS5a NS5b Non-Nuke Protease inhibitor

Current DAA combinations NS5b Nucleotide based therapy NS5b Nuke Backbone SOFOSBUVIR One drug from 2 nd class NS5a Protease inhibitor Ribavirin Sofosbuvir+ Simeprevir +/- Ribavirin Triple therapy without a NS5b Nuke NS5a NS5b Non-Nuke Protease inhibitor

Current DAA combinations NS5b Nucleotide based therapy NS5b Nuke Backbone One drug from 2 nd class NS5a SOFOSBUVIR Protease inhibitor Ribavirin Triple therapy without a NS5b Nuke Sofosbuvir+ Ribavirin Increasingly 2 nd line NS5a NS5b Non-Nuke Protease inhibitor

Current DAA combinations NS5b Nucleotide based therapy NS5b Nuke Backbone SOFOSBUVIR One drug from 2 nd class NS5a Protease inhibitor Ribavirin Triple therapy without a NS5b Nuke NS5a NS5b Non-Nuke Protease inhibitor PrOD : Pariteprevir/ ombitasvir/ ritonavir, dasabuvir +/- Ribavirin

Current DAA combinations NEW in 2015 NS5b Nucleotide based therapy NS5b Nuke Backbone One drug from 2 nd class SOFOSBUVIR NS5a Protease inhibitor Ribavirin Daclatasvir: Pangenotypic NS5a Triple therapy without a NS5b Nuke NS5a NS5b Non-Nuke Protease inhibitor

2015 Landscape Now have highly effective all oral therapy for all genotypes Ribavirin still has a role in some regimens GT2, DAA failures, decompensated cirrhotics PEG-interferon rarely used Still an alternative indication for GT2 and GT3 patients Adapted from EASL Guidelines, 2015

Current Treatment principles HCV Genotype matters (for now) Most current regimens not pan-genotypic Easiest to Cure: 2>4 1 (1b>1a) Cirrhotic GT3 remains as a hard to treat population Harder to treat populations may need longer therapy and/or addition of ribavirin Cirrhotic patients Prior Treatment failures (even if not with DAA) Treatment now possible for almost everyone including decompensated cirrhotics, HCC, renal failure and pre/post liver transplant

Options for our patient Genotype 1a, non-cirrhotic, treatment naive LDV/SOF Regimens Dose No Cirrhosis PTV/RTV/OBV + DSV + RBV ( PrOD ) QD fixed-dose combo LDV (90mg)/SOF (400mg) QD fixed-dose combo PTV (150mg)/RTV (100mg)/OBV (25mg) + BID DSV (250mg) + wtbased RBV x12 wks x12 wks LDV/SOF PrOD Kowdleny NEM 2014 (ION-3) Feld, et al. NEJM 2014. (SAPPHIRE-I);

Current GT1 Options LDV/SOF Pros One pill daily Can shorten to 8 weeks if HCV RNA < 6 million Cons Caution with PPI s ( if must use, limit to 20 mg day WITH LDV/SOF) Cannot be given if CrCl < 30 PrOD Pros Can be given in severe renal insufficiency or HD Cons BID dosing Contains ritonavir (associated with GI side effects) Ribavirin required if GT1a New warning in cirrhotics

$83,300 vs. $94,500 for 12 weeks

Back to our patient Starts LDV/SOF x 12 weeks You check in with him every 2 weeks regarding adherence Week 4 lab check: HCV RNA at week 4 is < limit of detection LFTs have normalized, Creatinine remains normal 12 weeks after completing treatment, HCV RNA is undetectable -> Cured!

After the cure HCV Ab may remain positive for life Future HCV screening will need to be HCV RNA Counsel about Reinfection Drug use: shared needles, works, snorting straws Sexual contact through men having sex with men (MSM)- risk highest in HIV+ men If cirrhotic, continue to screen for hepatocellular carcinoma with q 6-12 month imaging

Unique Populations Excellent Cure rates HIV Cirrhotics (longer therapy or RBV) IDU/opioid agonists Good options but still can do better Renal Failure/HD Cirrhotic Genotype 3 Decompensated cirrhotics DAA treatment failures

Coming soon NS5b Nucleotide based therapy NS5b Nuke Backbone One drug from 2 nd class SOFOSBUVIR NS5a Protease inhibitor Ribavirin Sofosbuvir/ Velpatsvir FDC Pangenotypic Mid-2016 Triple therapy without a NS5b Nuke NS5a NS5b Non-Nuke Protease inhibitor Coming Soon Protease inhibitor NS5a Grazoprevir + Elbasvir Zepatier Pangenotypic Use in renal failure/hd Approval anticipated early 2015

The Next Generation Triple therapy with an NS5b (Nuke) NS5b (Nuke) NS5a Protease inhibitor Gilead & Merck actively developing triple therapy Goal: One size fits all, pangenotypic treatment Salvage regimen for prior failures

Conclusions We have to tools to cure HCV in the majority of HCV patients, including those with most complex disease HCV treatment is well tolerated and relatively straightforward for most patients The field continues to evolve with improved pangenotype regimens and treatment for hardest to treat groups. In order realize the tremendous potential of HCV DAAs, we will need primary care providers to identify HCV and discuss treatment readiness as well as large cadre of HCV treaters, including primary care based treatment

Resources AASLD/IDSA HCV Guidelines: http://www.hcvguidelines.org EASL 2015 Guidelines: http://www.easl.eu/medias/cpg/hepc- 2015/Full-report.pdf University of Liverpool HCV Drug interaction database: http://www.hep-druginteractions.org Patient education resource VA HCV website http://www.hepatitis.va.gov/provider/index.asp