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Updates  in  Liver  Disease    for  Primary  Care  Prac6ce  

 Hepa66s  C  

and  Non-­‐Alcoholic  Fa>y  Liver  Disease  

 

Rena  K.  Fox,  MD  Professor  of  Medicine  

UCSF  Division  of  General  Internal  Medicine  

 

   

I  have  no  disclosures  

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Objectives: HCV and NAFLD

1.  Understand current HCV screening recommendations

2.  Review primary care evaluation of HCV patients including staging of liver disease

3.  Describe the currently available HCV treatments 4.  Highlight several HCV treatment issues:

monitoring, access, reinfection

5.  Recognize NAFLD prevalence and outcomes 6.  Understand NAFLD diagnosis and treatment

Prevalence  of  HCV  Infec6on  in  the    United  States  

•  >5.2  million  living  with  chronic  HCV  in  United  States  

–  Prevalence:  2%  

•  Chronic  HCV  cases  not  included    in  NHANES  es6mate  

–  Homeless  (n=142,761-­‐337,6100)  –  Incarcerated  (n=372,754-­‐664,826)  –  Veterans  (n=1,237,461-­‐2,452,006)  –  Ac6ve  military  (n=6805)  –  Healthcare  workers    

(n=64,809-­‐259,234)  –  Nursing  home  residents  (n=63,609)  –  Chronic  hemodialysis  (n=20,578)  –  Hemophiliacs  (n=12,971-­‐17,000)  

5.19  

1.9  

7.1  

3.8  

3.27  

0  

1  

2  

3  

4  

5  

6  

7  

8  

Total   Not  Included  NHANES  

NHANES  

Num

ber  o

f  Cases  (in  millions)  

Es6mated  HCV  Cases  

Conserva6ve  es6mate  

Chak  E,  et  al.  Liver  Int.  2011;  31:1090-­‐1101.  Center  for  Disease  Control  and  Preven6on.  Hepa66s  C  FAQs  for  Health  Professionals.  h>p://www.cdc.gov/hepa66s/HCV/HCVfaq.htm#sec6on2.  Accessed  November  19,  2013.  

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US HCV Prevalence by Birth Year

Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-18.

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0 1910 1920 1930 1940 1950 1960 1970 1980 1990

Year of Birth

1988-1994 1999-2002

Pre

vale

nce

(%)

Natural History of HCV Infection

Ward JW. Top Antivir Med. 2013;21:15-19.

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Projected Prevalence of Decompensated Cirrhosis and HCC Rises Through 2020

•  Although the overall prevalence of HCV infection is decreasing, the prevalence of cirrhosis is increasing

•  Decompensated cirrhosis more common after 1995 •  HCC rose steeply after 1990, predicted to peak in 2019 at 14,000/year

Adapted from Davis GL et al. Gastro. 2010; 138 (2): 513-521

Screening Recommendations –

CDC and USPSTF

q  Risk Based Screening: Screen adults at risk for HCV infection

q  Ever injected illegal drugs; received clotting factors made before 1987;

received blood/organs before July 1992; ever on chronic hemodialysis;

evidence of liver disease (elevated ALT); infants born to HCV infected

mothers; HIV infection

q  Birth Year Screening: Screen adults born 1945 through 1965

q  One-time testing for HCV without prior ascertainment of HCV risk factor

(strong recommendation, moderate quality of evidence)

Smith BD, et al. MMWR Morb Mortal Wkly Rep. 2012;61(RR04);1-18.

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Primary Care Evaluation of HCV Baseline Every 6 mos

*if cirrhosis* Annually As needed

HCV RNA (viral load) x

HCV Genotype x

CBC/Platelet x x x

PT/ INR x x x

BMP / LFTs x x x

HIV Ab x

HAV IgG x

HBsAg, HBsAb, HBcAb x

Fibrosure or Fib-4 x x

Cryoglobulins x

Abdominal US x x

Immunizations x

Staging and Assessment of Fibrosis

Why test for fibrosis? Determine treatment urgency Assess need for additional care Cirrhosis requires additional management

How to test for fibrosis? Gold standard: liver biopsy Serum markers– Fibrosure, APRI, Fib-4 Elastography (FibroScan®, MRE) Imaging may detect cirrhotic features

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APRI: AST to Platelet Ratio Index

http://www.hepatitisc.uw.edu/page/clinical-calculators/apri

FIB-4: Fibrosis 4

http://gihep.com/calculators/hepatology/fibrosis-4-score

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Cirrhosis Management in Primary Care

§  Counsel on alcohol, NSAIDS, immunizations §  Screen for HCC with US every 6 mos §  Calculate MELD

§  every 6 months if compensated §  every 3-4 months if decompensated

§  Screen for varices with EGD every 2 years §  Refer to GI for decompensation – ascites, varies,

portal HTN §  Refer for Transplant evaluation if MELD 10-15

HCV Treatment Aims to Achieve a Sustained Virological Response (SVR)

¨  SVR – the HCV RNA becomes undetectable during

treatment and remains undetectable

¨  SVR 12 – undetectable 12 weeks after treatment

¨  SVR 24 – undetectable 24 weeks after treatment

¨  <1% virologic relapse after SVR

¨  SVR is the definition of “cure” of the virus

¨  SVR has been associated with regression of fibrosis and

improved clinical outcomes

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Viral Cure (SVR) Associated With Reduced Risk of Death,Transplant and HCC §  Meta-analysis of over 23,000 patients from 129 studies

§  Achieving SVR vs. no SVR was associated with substantial benefits

§  62% to 84% reduction in all-cause mortality, 90% reduction in liver transplantation, 68% to 79% reduction in HCC

Hill AM, et al. AASLD 2014. Abstract 44.

5-Yr Risk of All-Cause Death by SVR

5-Yr Risk of HCC by SVR

SVR No SVR

General Cirrhotic Pts HIV- Coinfected Pts

Pts

Dea

d A

fter

5 Y

rs (

%)

20

10

5

0

4.5

10.5

3.6

11.3

1.3

10.0

General Cirrhotic Pts HIV- Coinfected Pts

Pts

With

HC

C A

fter

5 Y

rs (

%)

2.9

9.3

5.3

13.9

0.9

10.0

25

15

20

10

5

0

25

15

SVR No SVR

US  HCV  Treatment  Cascade  During  Interferon-­‐Ribavirin  Era  

0%  

10%  

20%  

30%  

40%  

50%  

60%  

Diagnosed   Referred  to  care   Treated   Successfully  Treated  

Holmberg  SD,  et  al.  New  Eng  J  Med.  2013;368:1859-­‐1861.    

50%  

32-­‐38%  

7-­‐11%  

5-­‐6%  

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The  New  Era:  Direct  Ac6ng  An6virals  (DAAs)  

Classes  of  DAAs  Exis6ng  Drugs  and  Drugs  in  Development  

NS3/4  Protease  Inhibitors  

Nucleos(t)ide    NS5B  Polymerase  Inhibitors  

Non-­‐nucleos(t)ide  NS5B  Polymerase  Inhibitors  

NS5A  Inhibitors  

Simeprevir   Sofosbuvir   Dasabuvir   Ledipasvir  

Paritaprevir/RTV   Mericitabine   Beclabuvir    (BMS-­‐791325)   Ombitasvir  

Grazoprevir    (MK-­‐5172)  

Daclatasvir    

Asunaprevir      

Elbasvir    (MK-­‐8742)  

Telaprevir   GS-­‐5816    

Boceprevir  

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Sofosbuvir (Sovaldi)

§  Approval Status: FDA approved December 6, 2013

§  Indication for HCV Monoinfection and HCV-HIV Coinfection - GT 1,4: Sofosbuvir + peginterferon + ribavirin (12 weeks) - GT 2: Sofosbuvir + ribavirin (12 weeks) - GT 3: Sofosbuvir + ribavirin (24 weeks)

§  Additional Indication for HCV Monoinfection - GT 1 (interferon ineligible): Sofosbuvir + ribavirin (24 weeks) - HCC and awaiting transplant: Sofosbuvir + ribavirin (up to 48 weeks)

§  Class & Mechanism - Nucleotide analog inhibitor of NS5B polymerase enzyme

§  Dosing: 400 mg PO once daily with or without food

§  Adverse Effects (AE) attributable to Sofosbuvir - Fatigue, headache

Ledipasvir-Sofosbuvir (Harvoni)

§  Approval Status: FDA approved October 10, 2014

§  Indications and Usage - Indicated for the treatment of chronic HCV genotype 1 in adults

§  Class & Mechanism - Ledipasvir: NS5A inhibitor - Sofosbuvir: Nucleotide analog NS5B polymerase inhibitor

§  Dosing: Ledipasvir-Sofosbuvir (fixed dose 90 mg/400 mg) One tablet orally once daily with or without food

§  Adverse Effects: Fatigue, headache

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ION-­‐1  Treatment  Naïve,  included  cirrho6cs  

Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) §  Approval Status: FDA approval on December 19, 2014

§  Indication: Genotype 1 chronic HCV infection, including compensated cirrhosis

§  Class & Mechanism

- Ombitasvir: NS5A inhibitor

- Paritaprevir: NS3/4A serine protease inhibitor

- Ritonavir: HIV protease inhibitor used as booster

- Dasabuvir: Non-nucleoside NS5B polymerase inhibitor

§  2 Tablets (3 tab in AM and 1 tab in PM):

§  Ombitasvir-Paritaprevir-Ritonavir (fixed dose 12.5/75/50 mg)

§  Dasabuvir: 250 mg

§  Adverse Effects (AE): fatigue, pruritus, and insomnia

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Viekira™  +/-­‐  Ribavirin    Phase  3  Trials  

Trial,  N   Genotype   Treatment  Hx   Cirrhosis   Regimen   SVR  

Sapphire  I  N=631  

GT1   Naïve   No   Viekira  +  RBV   96%  

Sapphire  II  N=394  

GT1   Experienced  with  Peg/Riba  

No   Viekira  +  RBV   96%  

Pearl  2  N=186  

GT1b   Experienced  with  Peg/Riba  

No   Viekira  +  RBV  Viekira  –  RBV  

96.6%  100%  

Pearl  3  N=419  

GT1b   Naïve   No   Viekira  +  RBV  Viekira  –  RBV  

99%  99%  

Pearl  4  N=3-­‐5  

GT1a   Naïve   No   Viekira  +  RBV  Viekira  –  RBV  

97%  90%  

Turquoise  2  N=380  

GT1   Naïve  and  Experienced  

Yes   Viekira  +  RBV  12wk  Viekira  +  RBV  24wk  

92%  96%  

Viekira=  PTV/RTV/OMV  +  DSV  

Daclatasvir (Daklinza)

§  Approval Status: Approved by United States FDA July 24, 2015

§  Indications and Usage - Indicated with sofosbuvir for the treatment of chronic HCV genotype 3 in adults

§  Treatment Course - For GT3: Daclatasvir 60 mg plus Sofosbuvir 400 mg once daily x 12 weeks - Both medications taken with or without food

§  Class & Mechanism - NS5A inhibitor

§  Dosing Preparations and Adjustments - Daclatasvir 60 mg and 30 mg tablets - No dosage adjustment with any degree of renal impairment - No dosage adjustment with mild, moderate, or severe hepatic impairment

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Ribavirin (Copegus, Rebetol, Ribasphere)

§  Mechanism: purine nucleoside analog

§  Approval Status: - First approved by FDA in 1998 - Multiple preparations subsequently FDA approved

§  Indications - In combination with other agents for all HCV genotypes

§  Dosing (brand dependent): - Fixed dose (800 mg PO per day in two divided doses) - Weight based (1000-1200 mg per day in two divided doses) - Weight based (800-1400 mg per day in two divided doses)

§  Drug Interactions - Use of ribavirin and didanosine can cause life-threatening toxicity - Use of ribavirin and azathioprine can cause azathioprine-related toxicity

§  Adverse Effects (AE) - Hemolytic anemia - Birth defects (pregnancy category X)

3 Major Factors in Choosing HCV Treatment Regimen

Genotype

Treatment History

Presence of cirrhosis

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Genotype 1- Treatment Naive Genotype Treatment

History Cirrhosis Status

Options Recommended

1 Naïve Non-cirrhotic

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir x 12 weeks 1a : Add Ribavirin 1b: No Ribavirin

Ledipasvir/Sofosbuvir x 12 weeks If baseline RNA < 6 million: 8 weeks

Cirrhotic, CTP A

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir x 12 weeks 1a : Add Ribavirin 1b: No Ribavirin

Ledipasvir/Sofosbuvir x 12 weeks (may add Ribavirin)

Cirrhotic, CTP B-C

Ledipasvir/Sofosbuvir + Ribavirin x 12 weeks start Ribavirin 600 mg/day, titrate up

Source: VA Treatment Considerations www.hepatitis.va.gov

Genotype 1- Treatment Experienced Genotype Treatment

History Cirhosis Status

Recommended Regimens

1 Experienced (Peg/Riba)

Non-cirrhotic

Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir x 12 wks 1a : Add Ribavirin 1b: No Ribavirin

Ledipasvir/Sofosbuvir x 12 wks (may add Ribavirin)

Experienced (Peg/Riba)

Cirrhotic, CTP A

Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir x 12 wks 1a : Add Ribavirin 1b: No Ribavirin

Ledipasvir/Sofosbuvir + Ribavirin x 12 wks Ledipasvir/Sofosbuvir x 24 wks

Experienced (Peg/Riba)

Cirrhotic, CTP B-C

Ledipasvir/Sofosbuvir + Ribavirin x 12 wks start Ribavirin 600 mg/day, titrate up

Source: VA Treatment Considerations www.hepatitis.va.gov

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Genotype 2 Genotype Treatment

History Cirhosis Status

Recommended Regimens

2 Naive Non-cirrhotic

Sofosbuvir + Ribavirin x 12 weeks

Cirrhotic Sofosbuvir + Ribavirin x 12 weeks

Experienced

Non-cirrhotic

Sofosbuvir + Ribavirin x 12 weeks

Cirrhotic Sofosbuvir + Ribavirin x 16 weeks

Source: VA Treatment Considerations www.hepatitis.va.gov

Genotype 3 Genotype Treatment

History Cirrhosis Status

Recommended Regimens

3 Naive Non-cirrhotic

Daclastasvir + Sofosbuvir x 12 wks Sofosbuvir + Ribavirin x 24 wks

Cirrhotic

Ledipasvir/Sofosbuvir + Ribavirin x 12 wks Sofosbuvir + Ribavirin x 24 wks

Experienced Non-cirrhotic

Daclastasvir + Sofosbuvir x 12 wks Sofosbuvir + Ribavirin x 24 wks

Cirrhotic Ledipasvir/Sofosbuvir + Ribavirin x 12 wks Sofosbuvir + Ribavirin x 24 wks

Source: VA Treatment Considerations www.hepatitis.va.gov

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Monitoring on HCV Treatment Baseline

4 wks 12 wks after finishing

Notes

Genotype X

HCV RNA X X X Or every 2 weeks until undetectable. Stop treatment if not undetectable by 6 wks

CBCD X X Every 2 weeks if on RBV

LFTs X X Stop if AST/ALT 10x

GFR X X Every 2 weeks if abnl or drug interactions

INR X

TSH (using IFN) X q 12 wks if using IFN

Source: hcvguidelines.org

HIV-HCV Co-infection §  Previously much lower SVR rates with Peg/Riba, compared to

HCV monoinfected patients

§  With DAAs, treatment and efficacy generally the same as HCV monoinfected

§  Caution with drug interactions- may require change of HIV or HCV regimen or dose adjustment

§  In general, least interactions with INSTIs

§  Dose adjust Daclatasvir with ATV/r, EFV, ETV

§  Ledipasvir and HCV PIs increase TDF- watch Cr

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Estimated Medication Cost Regimen Cost

Sofosbuvir + Ribavirin x 12 weeks $84,000

Ledipasvir/Sofosbuvir x 8 weeks $63,000

Ledipasvir/Sofosbuvir x 12 weeks $94,500

Ledipasvir/Sofosbuvir x 24 weeks $189,000

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir +/- Ribavirin x 12 weeks

$84,000

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir +/- Ribavirin x 24 weeks

$168,000

Incremental Costs of HCV

Patients with HCV

•  $9681 per patient per year

HCV with decompensated cirrhosis

•  $27,845 per patient per year

HCV with hepatocellular carcinoma

•  $43,671 per patient per year

HCV with liver transplant

•  $93,609 per patient per year

McAdam-Marx C, et al. J Manag Care Pharm. 2011;17(7):531-546.

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Patient adherence

§  Adherence is crucial §  Factors that may complicate adherence, such as

active substance use, depression, neurocognitive disorders, and lack of social support, should be noted

§  Address issues of adherence before initiating medications.

§  Providers should incorporate strategies for measuring and supporting adherence within their clinics.

Who to Treat

§  Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies owing to comorbid conditions.

§  Immediate treatment is assigned the highest priority for those patients with advanced fibrosis (Metavir stage F3), those with compensated cirrhosis (Metavir stage F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C.

VA Treatment Considerations www.hepatitis.va.gov; AASLD-IDSA Guidelines www.hcvguidelines.org

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What about Re-infection?

§  Has been demonstrated among MSM, IDU (Grebely, 2012; Inglitz, 2014., Sacks-Davis, 2013)

§  Studies show variable risk- May be associated with increased rate of spontaneous clearance (Grady, 2013)

§  Patient education needed before treatment

Summary: Update in Hepatitis C

SCREEN Implement birth cohort and risk based screening

STAGE

Stage liver disease for HCV patients and focus on treatment for those with evidence of advanced liver disease

PROVIDE PRIMARY CARE

Educate HCV patients, offer vaccinations, treat comorbidities, screen for HCC if cirrhotic

TREAT

Refer or Treat within Primary Care

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Clinical picture of NAFLD

AGA Guideline, Gastroenterology, 2002

¨  NAFLD a manifestation of metabolic syndrome

¤ Common cause of abnormal liver enzymes

¤  Increases risk for diabetes and coronary artery disease

¨  Hepatic fat (steatosis) in absence of significant alcohol consumption

¨  Generally clinically stable, asymptomatic ¤  Progression of fibrosis in approximately 1/3 patients ¤  Better prognosis than alcoholic hepatitis

¨  Liver enzymes elevated in 90%

Prevalence of NAFLD

¨  Most common liver disorder in Western industrialized countries

¨  Estimated prevalence of 20 – 40% percent of the general population .

¨  Among 400 US military personnel and their families (mean age 55) in Texas, prevalence of NAFLD 46 %.

¨  Prevalence was increased in men, older individuals, and those with hypertension, obesity or diabetes.

¨  Hispanics and diabetics at greatest risk for NAFLD and NASH

¨  Presence of NAFLD associated with lifestyle factors including minimal exercise and fast food consumption

Williams CD, et al. Gastroenterology. 2011;140:124-131.

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What is the difference between NAFLD and NASH?

¨  NASH is a subset of NAFLD

¨  Cannot distinguish NAFLD from NASH without histology

¨  NASH requires liver biopsy for diagnosis

¨  No imaging modality is able to differentiate between the benign or aggressive fatty liver

Williams CD, et al. Gastroenterology. 2011;140:124-131.

Other Causes of Hepatic Steatosis

§  Significant alcohol use §  Hepatitis C (particularly genotype 3) §  Wilson disease §  Lipodystrophy §  Starvation §  Parenteral nutrition §  Medications §  Reye syndrome §  Acute fatty liver of pregnancy §  HELLP syndrome §  Inborn errors of metabolism

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Diagnosis of NAFLD

Diagnostic criteria ¨  Hepatic steatosis on imaging or biopsy ¨  Exclusion of alcohol ¨  Exclusion of other causes of hepatic steatosis ¨  Note: Elevated AST, ALT is not required Recommended testing for other causes: ¨  Test for HCV, HBV, Serum gammaglobulin level,

antinuclear antibody, antismooth muscle antibody, and anti-liver/kidney microsomal antibody-1, iron studies

Management of NAFLD and NASH

¨  Management of the associated conditions ¨  Weight loss is the only treatment proven and safe ¨  Avoid alcohol ¨  Immunizations for chronic liver disease ¨  Optimize blood glucose control ¨  Statins are shown to be safe ¨  Vitamin E 400 IU/day if NASH and with no diabetes

or CAD ¨  Refer if biopsy has shown NASH

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Thank you

Resources www.hcvguidelines.org www.hepatitis.va.gov www.hepatitisc.uw.edu

www.aasld.org