Update on HCV therapy

Nicolas Intagliata, MD

Gastroenterology and Hepatology

University of Virginia

In the beginning there was…

Hoofnagle NEJM 1986

Patient case

60 year old man referred for genotype 1 HCV on

routine testing.

Has no idea how or when he may have acquired it

Past Medical History

Obesity, HTN, dyslipidemia

Social History

Denies ETOH use, current smoker

Physical Exam – 70kg, No stigmata (spider

angioma, palmar erythema, ascites, liver edge)

Blood work

AST – 78, ALT – 88

Alk Phos – 102, T. Bili – 0.8

INR – 1.2

WBC – 5.5, Hgb – 12, Plts – 120

Viral load 1,000,000 and genotype 1

Important questions

What is HCV and what does it mean for my

patient?

What tests to order before tx or referral?

What does curing HCV do for my patient over

the short/long term?

What are the therapies available/coming?

After successful therapy…then what?

What is the cost to society?

Epidemiology

CDC estimates

Incidence 0.3/100,000

Prevalence estimates of approximately

1.0% of the population

~ 3.2 million people with chronic HCV

Peak prevalence in people born

between 1945-1965

80% of all chronic infections in this

group www.cdc.gov

Still a lot undiagnosed…

Worldwide Genotype Distribution

Messina et al. Hepatology 2014

What is Hepatitis C?

RNA flavivirus (7 genotypes) Can produce acute or chronic hepatitis Tattoos, IVDA, prison time, transfusions, intranasal

cocaine, sex?

Many patients do not know exposure

*IMPORTANT CONCEPT*

Positive antibody does not equate to chronic hepatitis (15-20% clear virus on own)

Check VL to corroborate suspicions

Exposure and clearance does not mean immunity

What does HCV do?

• 100 people

• 80 people

• 20 people?

What do we gain with treatment?

Reduce transmission

Prevent cirrhosis

Reverse fibrosis

Reduce complications

Improve transplant

outcomes

Bruno et al. Hepatology 2007.

History of HCV therapy

Heim. Nature Reviews 2013

Direct acting agents for all, with

Interferon for none.

deLemos and Chung TMM 2014

Drugs in the pipeline…

Pawlotsky Gastroenterology 2014

Many important factors to consider

Degree of fibrosis or evidence of cirrhosis May not be obvious- examination and labs can help

Imaging, elastography? and biopsy

Insurance

Ability to maintain compliance

Drug interactions

Comorbidity

Prior history of therapy Prior exposure/failure to interferon and ribavirin?

Naïve, responder, relapser, non-responder

Prior exposure to protease inhibitors?

Prior exposure to sofosbuvir?

Sofosbuvir (Sovaldi®)

Mechanism- nucleoside/tide analogue

Associated trials (MANY!)

COSMOS

LONESTAR

Currently approved by FDA (Sept. 2014)

SOF+RIB for G2 for 12 weeks/ for G3 for 24 weeks

SOF+LDV for G1 (October 2014)

Off label use for G1:

SOF+SIM for 12-24 weeks +/- ribavirin

(INF+SOF+RIB for G1 for 12 weeks)

Simeprevir (Olysio®)

Mechanism- protease inhibitor

Associated trials

COSMOS

Currently approved by FDA for treatment in G1

INF+SIM+RIB

Off label use for G1:

SOF+SIM for 12-24 weeks +/- ribavirin

Ledipasvir + Sofosbuvir (Harvoni®)

Approved October 2014, combined one pill

Almost immediately available on market

Is 1st line therapy for genotype 1 patients now

Population Medication Duration (weeks)

Treatment naïve w/ or w/o

cirrhosis

Harvoni (led/sof) 12

Treatment experienced w/o

cirrhosis

Harvoni (led/sof)

12

Treatment experienced w/

cirrhosis

Harvoni (led/sof)

24

Viekira Pak® (4 or 5 drugs)

Approved December 2014

Ombitasvir, paritaprevir, ritonavir, dasabuvir +/-

ribavirin

Population Medication Duration (weeks)

GT1a, w/o cirrhosis Viekira Pak + riba 12

GT1a, w/ cirrhosis Viekira Pak + riba 24

GT1b, w/o cirrhosis Viekira Pak 12

GT1b, w/ cirrhosis Viekira Pak + riba 12

Basic Guide

Genotype 1 (and 4 for the most part)

Options

Harvoni (led/sof)

Viekira Pak

Sim/Sof

(Interferon-based strategies)

Genotype 2

Options

Sofosbuvir and ribavirin

(Interferon-based therapies)

Genotype 3

Sofosbuvir and ribavirin for 24 weeks

COSMOS trial

SIM+SOF with or without ribavirin

HCV G1, naïve and non-responders, all fibrosis

levels

2 Cohorts; 4 groups ~30 in triple therapy

(SIM/SOF/RIB, ~15 in dual SIM/SOF

154 (92%) of 167 of patients in the ITT

population achieved SVR12

90% in 24 week cohort

94% in 12 weeks cohort

Lawitz et al. Lancet 2014

COSMOS trial

Why is this study important?

Incorporated early from abstract

Before actual publication

First all oral regimen for G1!

High rate of efficacy

Low rate of side effects

Off label use of medications

HIGHLY EXPENSIVE

LONESTAR trial

G1, naïve and previously

treated, some cirrhosis

SOF+LDV for 8 or 12

weeks (+/- RIB)

100% end of treatment

response!

98/100 patients achieved

SVR!

Lawitz et al. Lancet 2014

LONESTAR

Why is this study important?

High rate of efficacy with LDV/SOF

8 weeks effective in naïve, non-cirrhosis

Low rate of adverse events

Offers hope to the population from 2011

who have failed 1st generation protease

inhibitors

ION-3 Trial

LDV+SOF

Evaluated naïve non-

cirrhotics

Concluded that 8 weeks

of LDV+SOF results in

very high rates of cure

No additional benefit with

the addition of ribavirin,

nor extending therapy for

12 weeks Kowdley et al. NEJM 2014

Genotype 2

Currently FDA approved

SOF/RIB 12 weeks

Several trials have been conducted

Many patients cured on INF/ribavirin in past!

Take home message:

HIGH RATES OF CURE with SOF/RIB for 12

Reasonable to extend to 16 weeks in

cirrhotics?

Genotype 3

Current FDA approved regimen

SOF/RIB for 24 weeks

Data least impressive overall, but still good

Some consider this the “new genotype 1”

Future therapies on the horizon!

Back to our case

Middle aged, asymptomatic with some signs of

cirrhosis/portal hypertension

Should we treat and with what?

Do they have cirrhosis?

Before this mattered tremendously…

Maybe, but does it change therapy?

It changes prognosis and need for surveillance

We should treat…

Treatment is costly

Rationing therapy is inevitable

High risk groups:

Advanced fibrosis

Well-compensated

cirrhosis

Immunosuppressed,

post-transplant

Resected HCC

Hagan et al. Hepatology 2014

Simeprevir one

month $23,889

12 weeks= $71,667

Sovaldi one month $30,240

12 weeks= $90,720

Harvoni one month $31,651

12 weeks= $94,953

Viekira Pak one month

$29,995

12 weeks= $89,982

Financial issues

Guidelines for “triaging” patients

http://www.hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy

Important concepts

Acute, chronic, clearance

Tests we order:

CBC, BMP, Hepatic Panel, INR

Viral load, genotype

Is cirrhosis present?

May not change treatment, but changes prognosis and future management especially HCC! Ultrasound Elastography vs. liver biopsy

Guidelines

AASLD/IDSA joint guidelines

www.hcvguidelines.org

Updated routinely and provide excellent

resource, especially for special patient

populations

Treatment effects:

The regression to the mean

The future looks bright, but important lessons from

clinical research must be remembered

Real patients behave differently!

Side effects will emerge

Hezode et al. Gastroenterology 2014

Resistance may emerge

Re-infection may become a problem

Antibody does not confer protection!