Hepatitis C: A New Era In Treatment And Cure

Adam Deising, DOLCDR MC USN

Director of HepatologyDepartment of GastroenterologyNaval Medical Center San Diego

Disclosures I have no financial disclosures

I will be discussing some treatments that are not FDA approved and that are still in development

Objectives Discuss the basic epidemiology and natural history of HCV and identify

which groups are at risk

Briefly review prior treatment therapies and current recommended available therapies with specific concentration on interferon-free treatments

Discuss new and upcoming treatment strategies in treatment naïve, experienced and difficult to treat populations

Epidemiology and General StatisticsFirst identified in 1989, previously known as “non-A/non-B” viral

hepatitis

Leading chronic blood-borne pathogen in the US

Worldwide, 130 – 170 million are chronically infected 2.7 – 4 million infected in the US alone Prevalence in US veterans 2x than general population (2.8% vs 1.3%)1

Currently the leading underlying cause for liver transplantation and major factor for rising incidence of HCC**

1. Backus LI et al. Public Health Matters 2012

Distribution of Fibrosis

VirologySingle stranded RNA member of the Flaviviridae family

3 structural proteins and 7 non-structural (NS) proteins

Six genotypes (1 – 6) with various subtypes

Degree of viral loads do no predict stage of fibrosis or overall prognosis

NS3/4A inhibitorsBoceprevir*Teleprevir*SimeprivirABT-450MK-5172

NS5B inhibitorSofosbuvirDasabuvir

NS5A inhibitorLedipasvirDaclatasvirOmbitasvirMK-8742

NS3 inhibitorAsunaprevir

MESSINA ET AL. HEPATOLOGY, 2014 ahead of print

Natural HistoryIncubation of HCV virus ranges from 2 – 23 weeks (mean 7.5

weeks)

Infected patients rarely present with acute clinical symptoms—most present with chronic elevation of liver enzymes

HCV RNA detected within 2 weeks of infection, HCV-Ab lags by 4-8 weeks

Loomba R et al. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes. Aliment Pharmacol Ther. 2011 Mar;33(5):559-65.

Factors That Increase Risk of Progression to CirrhosisHistologic stage at diagnosis

Duration of infection

Alcohol consumption >50g/day

Steatosis

Age > 40 years at the time of infection

Co-infection with HIV or HBV

Risk of TransmissionBlood-borne pathogen, transmission mainly through

percutaneous exposure to blood

IV and intra-nasal drug use is most common means of transmission

Less common is needle stick injury, vertical transmission (~5%, highest risk in mother with high HCV titer + HIV), sexual (except MSM, which is high risk)

Who To Screen?2012 CDC recommendation to perform at least a one time screen of all

patients born b/w 1945-1965 50% of patients were under-reporting their previous high risk behavior Patients in this birth cohort account for 3/4 of current infections

Yearly screening for persons who continue to inject drugs and HIV+ men who continue to have unprotected sex with men

Periodic testing should be offered to others with ongoing risk factors for exposure to HCV

AASLD / IDSA guidelines for HCV

How To Screen?All persons with risk for HCV should be initially tested for a HCV

antibody (anti-HCV) If positive, it is recommended to proceed with a quant HCV RNA (detect

RNA 25 IU/ml or lower) RNA obtained in HCV Ab negative patients who are immunocompromised

or if acute HCV is suspected

Genotype HCV RNA + patients

Test for HIV and HBV to evaluate for co-infection (+/- RPR for high risk behavior)

Basic recommendations:Minimal alcohol use (NO alcohol for those with cirrhosis)

Vaccinate against HAV and HBV, if not already immune

Flu vaccine yearly

Education on how to prevent transmission to others

Evaluation for evidence of advanced fibrosis Liver biopsy, imaging with US or MRI, non-invasive markers of fibrosis (Fibrosure,

fibroscan, MRI elastography)

TreatmentBrief overview of where we were

Pre-2011: PEG/Riba2011: PEG/Riba + PI (TEL and BOC) for GT1 diseaseNOV/DEC 2013: Simeprevir and Sofosbuvir on the market

Multiple new medications are on the way

All oral, interferon-free therapy may (will) become standard of care

Current Available Treatment Options

Slide c/o Dr. Alexander Kuo, MD UCSD

Interferon Intolerant or Ineligible

Molina et al. IAS July 2014, Melbourne

Simeprevir + Sofosbuvir +/- RBV, to Treat Chronic Infection With HCV GT 1 in non-responders to PEG-IFN and RBV and Treatment-Naive

Patients: The COSMOS Study

Lawitz et al. Lancet. Published online 7/28/14

Sim/Sof/RBV x 24 Sim/Sof x 24 Sim/Sof/RBV x 12 Sim/Sof x 12 Overall

Group 1: patients discontinued treatment for non-virologic reasons or missing data at time of assessment. SVR = 19/20 (95%) with these patients excluded

PRESS RELEASE: OCTOBER 10, 2014

Ledipasvier (NS5A) + Sofosbuvir (NS5B) Treatment naïve, GT 1a + 1b, up to 20% cirrhosis

SVR 99% SVR >99%

Treatment naïve, GT1a/1b, no cirrhosis

202/215 (94%) 201/216 (93%) 208/216 (96%)

Previous exposure to PEG/RBV or PEG/RBV/PI, ~20% cirrhotic, GT 1a/1b

Prescribing Guidelines for SOF/LDV

Genotype 2

Treatment naïve, non-cirrhotic—Sofosbuvir + weight based RBV x 12 weeks FISSION, POSITRON, VALENCE trials: 201/214 patients achieved SVR = 94%

Treatment experienced +/- cirrhosis x 12 weeks (VALENCE trial)

Genotype 3

Sofosbuvir + RBV x 12 weeks: SVR ~60%

Extending SOF + RBV x 24 weeks (VALENCE trial)

Genotype 3

SOF + PEG + RBV x 12 weeks 38/39 (97%) SVR in treatment naïve patients 10/12 (83%) SVR in treatment experienced with/without cirrhosis**

“For many patients with genotype 3, the adverse effects and increased monitoring requirements of PEG make this less acceptable than the recommended regimen of sofosbuvir plus weight-based RBV” (AASLD/IDSA HCV Guidance)

Sofosbuvir + Ledipasvir in GT 3 + 4 SOF/LDV x 12 weeks in treatment naïve GT3 patients +/- Ribavirin1

SOF/LDV alone: SVR12 = 64% (16/25) SOF/LDV/Riba: SVR12 = 100% (26/26)

Ongoing trials for GT4 disease ION-4: phase 3 trial of LDV/SOF x 12 weeks in GT 1 or GT4 + HIV co-infection2

French trial, phase 2 of LDV/SOF in treatment naïve and experienced with GT4 and GT53

1. Gane, E et al. LDV/SOF fixed-dose combination is safe and effective in difficult to treat populations including GT3 patients, decompensated GT1 patients and GT1 patients with prior sofosbuvir experience. Oral presentation#6: 49 th annual meeting of EASL, April 9-13 2014, London, UK

2. Clinical trials.gov NCT020736563. Clinical trials.gov NCT0208

Upcoming Treatment Options

Slide c/o Dr. Alexander Kuo, MD UCSD

Treatment naïve, non-cirrhotic patients ABT-450 = NS3/4A; Ombitasvir = NS5A inhibitor; Dasabuvir = NS5B inhibitor

Treatment naïve or experienced (PEG-IFN + Riba), all patients with Childs A cirrhosis. Patients with thrombocytopenia (>/= 60K), low albumin and major depression included.

Exclusions: Childs B + C, prior treatment with Telaprevir or Boceprevir

1:1 stratified to receive either 12 or 24 weeks of treatment

Primary endpoint is SVR 12

Difficult To Treat Populations

HCV and HIV co-infected Minimal drug-drug interaction with sofosbuvir and ART therapies

Tipranavir/ritonavir: decrease sofosbuvir concentration Simeprevir: more drug-drug interactions SOF/LDV: Tipranavir/ritonavir: decrease SOF/LED concentration, several others containing

HIV PI/ritonavir + tenofovir (all can increase tenofovir concentration)

Post-liver and kidney transplant Both can be safely treated with sofosbuvir and simeprevir containing regimens SOF/LDV likely safe based on preliminary data No significant interaction with sofosbuvir and CNI, purine antagonists or mTOR inhibitors Co-administration not recommended with simeprevir and cyclosporine

Childs B + C patients—should be referred for clinical trials Currently not recommended to treat these with interferon based therapy or

simeprevir based therapy due to the risk of further decompensation Sofosbuvir + Ribavirin can be considered for those who require immediate

treatment for up to 48 weeks of therapy Decompensated, pre-transplant Hepatocellular carcinoma who may be transplanted in the near future

SOF/LDV currently being studied in pre-transplant decompensated patients and post-transplant patients, including those with fibrosing cholestatic hepatitis (SOLAR-1 and SOLAR-2)1

1. Clinicaltrials.gov NCT01938430 and NCT02010255

Who Can’t We Treat (yet)? Renal disease

Sofosbuvir, ledipasivr and simeprevir studied in CKD with GFR ≥ 30 and is safe Abbvie regimen also safe in patients with mild to moderate CKD Not studied in ESRD on HD or GFR ≤ 30, thus treatment with new DAAs is not

recommended in this population unless enrolled in a trial Studies are underway and more to come

Treatment of Acute Hepatitis C Infection

PRESS RELEASE: OCTOBER 8 2014 HCV-Ab and RNA recommended if suspicious for acute HCV

ALF secondary to acute HCV is rare (< 1% of ALF cases), those suspected of ALF should be evaluated by a transplant center

Monitor for serological clearance for 3-6 months and treat with DAA therapies per the treatment recommendations for chronic HCV infection

PEG-IFN + Riba for 16 weeks (GT 2 and 3) to 24 weeks (GT 1) can still be used for those who are interferon eligible. SVR = ~82% when treated within 12 weeks of acute HCV diagnosis

So, do we now treat everyone?

What about the cost?

Show Me The Money! Cost is an issue

What have we been paying? PEG-IFN/Riba x 48 weeks ~$36,000 PEG-IFN/Riba/TEL ~$86,000 PEG-IFN/Riba/BOC ~$72,000

Simeprevir + Sofosbuvir x 12 weeks ~$150,0001

Sofosbuvir + Ledipasvir: $63,000 (8 weeks); $94,500 (12 weeks)

Other DAA regimens ????—To be determined1 Hagan et al. Hepatology 2014;60:37-45

Cost of liver transplant: ~$550,000

Expect a pricing competition

Cost of therapy will likely remain high for some time

Are there regulations on who we should not treat right now?

What Do the HCV Guidance Recommendations Say? August 11 2014, HCV guidance recommendations were updated:

Treatment is recommended for patients with chronic HCV infection.

Treatment is assigned with the highest priority for those patients with advanced fibrosis (F3), those with compensated cirrhosis (F4), liver transplant recipients, and patients with severe extrahepatic HCV manifestations (Table 1)

Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatic HCV complications are given high priority (Table 1)

Conclusions: Hepatitis C is now a curable disease for the vast majority of people

Treatment of HCV will decrease overall morbidity and mortality for these patients, decrease rates of HCC and HCV-related liver transplants

Prior null responders and those with cirrhosis are still the toughest to treat, some regiments may be better than others

Genotype 3 is now the new Genotype 1

More treatment options are on the way (very very soon!) and thus the treatment landscape will change within the next 6 months

Conclusions: Cost is an issue and insurance companies may force people with indolent

disease to wait

Prediction: At some point HCV treatment may be in the hands of primary care

Up to date information can be found on the AASLD website or www.hcvguidelines.org

Am I going to be out of a job in 10-15 years?

NASH—A Persistent Hurdle!

• Daclatasvir (NS5A inhibitor) + Sofosbuvir x 24 weeks in GT 2 and 3• Daclatasvir + Sofosbuvir +/- Ribavirin for 12 or 24 weeks

• Naïve and prior treatment failures with TEL or BOC included,• F0 - F4 included

• SVR 12 for GT 2 + 3• GT 2: 92% (24/26)• GT 3: 89% (16/18)

• SVR GT 1: 98% (164/167); 1a (98% ,129/132) 1b (100%, 35/35)• SVR achieved in 84/85 who received 24 weeks and 80/82 who received 12

weeks • Addition of Ribavirn had no effect on SVR