Hepatitis C

Is treatment in primary care possible/feasible (desirable)?

Objectives

• Understand the unique characteristics of HCV• Understand the complications of HCV

infection• Know who is at risk and who should be

screened• Describe treatment history and future options• Understand who should be treated and by

whom

What is the Hepatitis C Virus?

• HCV was identified in 1989 – RNA virus– Prior: 90% of post transfusion ‘non A/non B’

hepatitis– Incubation rate for acute HCV 15-160 days but not

usually associated with acute symptoms or illness– Thought to be directly cytopathic to the

hepatocyte• HBV: T-lymphocytes are thought to mediate liver injury

Hepatitis B vs C• HCV:– Up to 80% develop chronicity• The rest will likely continue to test HCV Ab+• BUT immunity is not inferred

• HBV:– if acquired as adult, only 20% develop acute

symptoms (can be severe)– Only 5-10% develop chronic virus• The remainder are immune

• HCV is a diverse virus– 6 genotypes identified (with subtypes)• Genotype 1 most common in US• Genotype 2 - YEA! – He has genotype 2!!• Genotype 3 more in far east• Genotype 4 in Africa and middle east, increased

frequency in Europe• Genotype 5 in South Africa• Genotype 6 in Hong Kong, Vietnam and AustraliaGenotype 1 is the nemesis of treaters, researchers and pharmaceutical manufacturersIL28B genetic polymorphism? – Huh?

Who Should Be Screened?• Persons born between 1945-1965• Persons who currently inject

drugs or who have injected drugs in the past, even once or in the distant past

• Recipients of clotting factor concentrates before 1990s

• Recipients of blood transfusion or donated organs before July 1992

• Long term hemodialysis patients

• Persons with known exposures to HCV (e.g., healthcare workers after needle sticks, recipients of blood or organs from a donor who later tested positive for HCV)

• HIV-infected persons• Children born to infected mothers • Patients with signs or symptoms

of liver disease (e.g., abnormal liver enzyme tests)

• Donors of blood, plasma, organs, tissues or semen

Birth Cohort

• Per the CDC, anyone born between 1945 and 1965 should be screened, regardless of risk factor

• “According to data from 1999 to 2008, three fourths of patients in the United States living with HCV infection were born between 1945 and 1965” (US Preventative Task Force web site) – grade B recommendation

Incidence of HCV

• Estimates in 2005: 185 million people globally infected(1)

• In United States, from a high of 250,000 new cases annually (1980s), down to 17,000 new cases annually(3)

– Per CDC, current overall incidence 0.3 per 100,000

• (1) Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST

• Hepatology. 2013;57(4):1333• (2) Surveillance for acute viral hepatitis--United States, 2006. Wasley A, Grytdal S, Gallagher K, Centers

for Disease Control and Prevention (CDC) MMWR Surveill Summ. 2008;57(2):1

Why Do We Care

• New cases are declining• Infections from 1960s, 70s, 80s are suffering

the consequences and complications– Cirrhosis– Hepatocellular Carcinoma– Diminished quality of life

Symptoms of HCV

• Typically asymptomatic • Symptoms often not attributed to HCV• Most common: fatigue– Along with anemia and thyroid issues, put HCV in

differential• Also nausea, anorexia, myalgias, arthralgias,

weakness• Rarely debilitating

Quality of Life

• Even without specific symptoms of the virus, HCV diminishes health related quality of life(4)

• Successful treatment improves quality of life

• (3) Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment• Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F Hepatology. 2005: 41(4): 790

Extrahepatic manifestations of HCV

• A study of 321 patients with chronic HCV, 38% had extrahepatic manifestations (4)

– Dermatologic: purpura, porphyria cutanea tarda, psoriasis– Rheumatologic: arthropathies– Other: neuropathies, uveitis

– (4) Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d'Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l'Hepatite C.

– Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, Yamamoto AM, Camproux AC, Hausfater P, Musset L, Veyssier P, Raguin G, Piette JC

– Medicine (Baltimore). 2000;79(1):47.

Natural History of HCV Infection

Acute HCV

Chronic HCV55 to 85%

Stable75 to 95%

Cirrhosis5 to 25%

Stable

HCC or Decompensation

1-3% /yr

Resolved15 to 45%

Complications of advanced liver disease

• Cirrhosis – once advanced fibrosis has developed, risk of progression to cirrhosis ~10% /year– Synthetic failure

• Hypoalbuminemia• Jaundice• Prolonged bleeding time

– Portal Hypertension• Ascites, peripheral edema• Varices and bleeding• encephalopathy

– Hepatocellular carcinoma

Complications continued

• Hepatitis C accounts for nearly one-third of deaths annually from hepatocellular carcinoma in US

• Higher risk of death from complications of decompensated cirrhosis

Factors associated with disease progression

• Acquiring the virus after age 40• Male• Blood transfusion may be a higher risk• Steatosis• ALCOHOL– Maintaining abstinence (hx of abuse) can improve

histology in the presence of chronic virus

Burden of Disease

• In a study present at The Liver Meeting in 2011, the annual health care costs of a patient with hepatitis C (without cirrhosis) is nearly $18,000. (5)

• According to the United Network for Organ Sharing (UNOS)' Transplant Living Web site, the estimated U.S. average in 2011 of billed charges per liver transplant is $577,100. – ~$25,000 annually for anti-rejection drugs(5)Disease burden in patients with chronic hepatitis C virus (HCV) infection in a United States (US) private health insurance claims database analysis from 2003 to 2010 - (11/15/11) AASLD Nov 5-9 2011 SF, SC Gordon,1 PJ Pockros,2 NA Terrault,3 RS Hoop,4 A Buikema,5 D Nerenz,1 FM Hamzeh4 1Henry Ford Health System, Detroit, MI, USA; 2Scripps Clinic Torrey Pines, La Jolla, CA, USA; 3University of California at San Francisco, San Francisco, CA, USA; 4Genentech, South San Francisco, CA, USA; 5i3 Innovus, San Francisco, CA, USA

Still wondering why we treat?

Treatment objectives

• Sustained viral response (SVR) – CURE!• Avoid complications of cirrhosis and/or

hepatocellular carcinoma• Success measured by – No viremia– Normalized ALT – Improved histology • Decreased necroinflammatory action• Stable or improved level of fibrosis

• Success measured by – No viremia– Normalized ALT – Improved histology – Decreased necroinflammatory action– Stable or improved level of fibrosis

Evolution of Treatment(or how I have tortured 100s of unsuspecting

souls over the years)

Medieval

• Standard interferon alpha, monotherapy– Mechanism of action: stimulates immune

response– FDA approved in 1991– Subcutaneous injection TIW• 50% respond with normalized ALT and undetectable

viral load but

– 24 week course ~ 12% success rate– 48 week course ~ 24% success rate

Addition of Ribavirin

• 1998 FDA approval for combination therapy with interferon

• Mechanism of action: decreases replication by inhibiting pro (?)

• Ribavirin oral agent, interferon still TIW SQ• 35% cure rate – VERY exciting

Pegylation

• Polyethylene glycol added to the interferon• Improved half-life• Allowed for weekly SQ combined with daily

ribavirin• Cure rates increased to ~40% in genotypes

1,4,5,6• ~70% in genotypes 2,3

Side effects of Peg/RBV

• Fatigue• Anemia

– May require Procrit or transfusion– Dose reductions decrease response

• pancytopenia• insomnia• Hyper somnolence• Alopecia (rarely irreversible(• Dyspnea• Cough• fatigue• Nausea• Diarrhea• Arthralgias• Depression• fatigue

• Anxiety• suicidal ideation• Exacerbation of autoimmune disease• Dry skin• Pruritus +/- rash• Thyroid dysfunction (+/- reversible)• Retinal hemorrhage• fatigue• uveitis• Leukocytoclastic vasculitis• Prophyria cutanea tarda• Migraine• Polyarteritis nodosum• Worsening of diabetes• Teratogenicity (RBV)

Newer Agents

• Protease inhibitors approved May 2011• Direct Acting Anti-virals– Approved for genotype 1 only– NS 3/4A inhibitors with activity against HCV

encoded serine protease required for cleavage of viral polyprotein= no replication

– Telaprevir and Boceprevir: very similar efficacy– $$$$$– SVR increased to >70%

Treatment regimens

• Boceprevir– Treatment course 28-48

wks depending on response

– 200 mg 4 every 7-9 hours (with food)

– RBV 200 mg 4-6 divided BID

– Pegylated interferon alfa• Weekly SQ

• Telaprevir– Treatment course 24-48

wks depending on response

– 375 mg 2 TID every 7-9 hours with 20g fat

– RBV 200 mg 4-6 divided BID

– Pegylated interferon alfa• Weekly SQ

BUT more side effects

• More anemia• More pruritus• More fatigue• Dysgeusia• Anal/rectal complaints– Anal pruritus– Diarrhea (fire-rrhea)– Hemorrhoids– Anal pain

• More rash• Mild, moderate, severe• Serious: • SJS• TEN: Toxic Epidermal

Necrolysis• DRESS: Drug reaction

with eosinophilia and systemic symptoms

Patient Selection

Your most important (and often most difficult) decision

• Not everyone wants treatment

• Not everyone needs treatment

• Some patients should not be treated

• Everyone should be evaluated and know their status

AASLD Recommendations(6)

• At least 18 years of age and• HCV RNA + and• Liver biopsy showing significant fibrosis and• Compensated liver disease and• Acceptable hematologic and biochemical

indices and• Willing to be treated and adhere to treatment

requirements

AASLD continued

• Individualize Decision to Treat(6)

– Failed previous therapy– Current alcohol or illicit substance users– No or mild fibrosis by liver biopsy– Coinfection with HIV– Chronic renal disease– Decompensated cirrhosis– Liver transplant recipients

Contraindications to HCV Therapy(7)

• Uncontrolled depressive illness, psychosis, or epilepsy• Untreated anemia• Autoimmune hepatitis or other autoimmune condition known

to be exacerbated by interferon• Untreated thyroid disease• Pregnancy or unwillingness to comply with adequate

contraception• Severe concurrent medical disease

• (7) Ghany MG, et al. Hepatology. 2009;49:1335-1374. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. June 2011.

• Lab markers of concern:– Albumin <3.7 can predict decompensation on

treatment even if biopsy does not reflect cirrhosis– Platelets <75

Preparing Patients for Therapy

• Clear understanding of treatment options• Review, explain, review, explain side effects and

management (consent form to treat?)• Clear description of treatment protocol, duration

and administration schedule for medications• Clear understanding of lab requirement and

office visit expectation– Free drug possible and no-charge office visit but labs

are not free

• Job related issues• Support system• Clear understanding of prognosis, predicted

response per treatment protocol• Your expectations regarding alcohol, drug use• This is a two way discussion – treatment is

elective, no matter how necessary you think it is– Reluctant patients are not adherent to therapy

New therapies on the horizon

• Will likely be multi-drug cocktails• Goals–High SVR–Pan genotypic–All oral–Clean SE profiles– Short duration of therapy– Smaller pill burden

Specific treatment targets

• NS3/4 A protease inhibitors• NS3 protease inhibitors• NS5A nonnucleoside inhibitor• NS5B nonnucleoside polymerase inhibitors• NS5B nucleotide polymerase inhibitors• NS5A inhibitor

American Companies

• Most with more than one compound– Gilead– Merck– AbbVie– Bristol-Myers Squibb– Janssen– Roche– Vertex– Kadmon

The end is near!

Final thoughts

• Screen per birth cohort/risk factor• If +HCV Ab – get genotype, viral load to

establish chronicity– If negative, repeat in 6 months to confirm– If positive and treatment not an option, don’t

check viral load yearly • HCV replicates 1 trillion virions daily: numbers fluctuate

dramatically and do not correlate with fibrosis or inflammation

• “The temporary normalization of ALT levels should not be equated with improvement of disease nor should it be used as a justification for not seeking treatment.” Melissa Palmer, MD (Dr Melissa Palmer’s Guide to Hepatitis & Liver Disease)

Markers of deterioration

• Albumin dropping less than 3.7 indicates worsening fibrosis and synthetic function

• Watch platelets• Monitor synthetic function– Increasing INR, bilirubin