HCV ECHO® WESTERN STATES

Original presentation by: Date prepared:

HCV Screening, Management, and Treatment Guidelines

Paulina Deming, PharmD, PhC Associate Professor of Pharmacy-College of Pharmacy Project ECHO University of New Mexico Health Sciences Center Brad Moran, PharmD Chief of Pharmacy Fort Peck Service Unit IHS

October 5, 2018

Agenda

1. Recognize and stage a patient’s level of liver disease using common laboratory tests and imaging

2. Describe new therapeutic options for the treatment of chronic HCV

3. Recognize and assess the clinical significance of common drug-drug interactions with oral-HCV therapies

4. Use national algorithms and guidelines to guide treatment strategies for patients with HCV infection

HCV ECHO® WESTERN STATES

Conflict of Interest Disclosure Statement

Hepatitis

• Spread via blood-to-blood contact

usually asymptomatic

• Leading cause for liver transplantation in the US

• ~75-80% of acute infections become chronic chronic infection- detection of virus 6 months post-exposure

• No vaccine available

• Prevalence is 1.6% of US population

Hepatitis C is a Global Health Problem Estimated 170 million persons with HCV infection worldwide

World Health Organization 2008 (http://www.who.int/ith/es/index.html)

> 10% 2.5%-10%

1%-2.50%

Prevalence of infection

NA

• Persons born between 1945-1965

• Received blood transfusion or organ donation prior to 1992

• Current or former injection drug users

• Chronic hemodialysis patients

• Any known blood exposure to HCV-positive blood

• Persons with HIV

• Children born to HCV-infected mother

Risk Factors for HCV Infection

CDC Testing Algorithm for Chronic HCV

Hepatitis C Genotypes

74%

15%

7% 4%

Prevalence in US population

Genotype 1

Genotype 2

Genotype 3

Genotypes 4-6

Alter MJ et al. N Engl J Med 1999; 341:556-62

• 6 major genotypes (1-6), most with subtypes

• Genotype 1

- GT 1b different than GT 1a

• GT 2 easier to treat than GT 3

• GT 3 associated with higher mortality, steatohepatitis

Hepatitis C Epidemiology-Fort Peck

Reservation

173

423

502

841

744

661

531

715

432

0

100

200

300

400

500

600

700

800

900

2010 2011 2012 2013 2014 2015 2016 2017 *2018

HCV AB TESTS PERFORMED 2010-2018

FPSU HCV Epidemiology

816

562

254

93

0

100

200

300

400

500

600

700

800

900

HCV Ab+ Chronic HCV Spontaneous clearance

number of living patients *no confirmatory

HCV Ab+ by age group

2

200

292

153

116

51

2

0 50 100 150 200 250 300 350

17 and younger

18-29

30-39

40-49

50-59

60-69

70+

Age

Gro

up

# patients

Natural history following initial infection with HCV

Time 20-25 years 25-30 years

HCV is Not Just a Liver Disease

Common Symptoms of HCV in Absence of Cirrhosis

• Fatigue

• Impaired cognitive function (brain fog)

• Migratory arthralgia or myalgia

• Depression

Extrahepatic Manifestations of Chronic HCV

• Renal Disease • Lymphomas • Neuropathy • Dermatologic

Manifestations • Diabetes • Neurological

Impairments

• Baseline studies

• Screening for other causes of liver disease

• Vaccinations

• Staging of Liver Disease

• Special considerations for cirrhotic patients:

– Monitoring for hepatocellular carcinoma

– Evaluation for cirrhosis related complications

– Referral for liver transplantation

• Assessment and management of alcohol and substance abuse

Overview: Routine Evaluation and Follow Up of Persons with Chronic HCV

• HCV Therapies

• Special populations

• Choosing a regimen

• Common side effects and laboratory abnormalities

• Drug-drug interactions

• Monitoring of patients on HCV therapy

• Monitoring of patients after HCV therapy

Overview: Part 2- HCV Therapy

• HCV genotype and subtype

• Quantitative HCV RNA

• HIV antibody

• Hepatitis A serology (IgG or total)

• Hepatitis B serology (HBsAg, anti-HBs, anti-HBc)

• Alpha-fetal protein (AFP)

• Abdominal ultrasound with measurement of spleen size

Baseline Studies in Persons with Chronic HCV

• Complete blood count with differential

• Comprehensive metabolic panel including serum creatinine

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, serum albumin

• International normalized ratio (INR)

Baseline Studies in Persons with Chronic HCV

• Complete blood count with differential

• Comprehensive metabolic panel including serum creatinine

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, serum albumin

• International normalized ratio (INR)

Identify changes consistent with cirrhosis; identify anemia especially if requiring ribavirin therapy

Evaluate renal function for choosing appropriate HCV therapy

Recognize level of inflammation and liver injury

Assess hepatic synthetic function

• Thrombocytopenia (<150 thousand)

– Due to portal hypertension caused by cirrhosis

– Portal hypertension causes:

Platelets to become “stuck” in spleen

More platelets damaged/destroyed

• Neutropenia

– Cirrhosis can cause bone marrow suppression

Why is the CBC Important to Understand Liver Disease Severity?

• Elevations in AST or ALT useful for measuring liver cell injury

– What is normal AST or ALT? 40 IU/mL

– Studies suggest this is too high and normal should be lower and different for men vs. women

– Healthy ALT is <30 IU/mL for men and <19 IU/mL for women

• Elevations in conjugated bilirubin suggest liver disease

• Loss of liver’s ability to synthesize (lack of synthetic function) can be seen with:

– Low serum albumin

– Prolonged prothrombin time (elevated INR)

– Important to look at trends in labs over time

Abnormalities in Hepatic Panel

Baseline Studies in Persons with Chronic HCV

• HCV genotype and subtype

• Quantitative HCV RNA

• HIV antibody

• Hepatitis A serology (IgG or total)

• Hepatitis B serology (HBsAg, anti-HBs, anti-HBc)

• Alpha-fetal protein (AFP)

• Abdominal ultrasound with measurement of spleen size

Determine appropriate HCV therapy and treatment duration; demonstrate chronic HCV

Share similar routes of transmission; determine need for HAV and/or HBV vaccination; determine risk for HBV reactivation

Evaluate for cirrhosis; screen for hepatocellular carcinoma

• Hepatitis A

– Check HAV antibody (total or IgG)

• Hepatitis B

– Check hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs; total or IgG), and hepatitis B core antibody (anti-HBc)

– Labs needed irrespective of vaccination

Other Viral Hepatitis

Hepatitis B Serologies

Test Result Interpretation

HBsAg Anti-HBc Anti-HBs

Negative Negative Negative

Susceptible to HBV

HBsAg Anti-HBc Anti-HBs

Negative Positive Positive or Negative

Previous exposure to HBV.These patients are not immune or “protected” and frequently have subclinical infection and are at risk for reactivation with immunosuppression. There is no role to vaccinate (or boost) these patients.

HBsAg Anti-HBc Anti-HBs

Negative Negative Positive

Immune to HBV due to HBV vaccine

HBsAg Anti-HBc IgM anti-HBc Anti-HBs

Positive Positive Positive Negative

Acute HBV infection

HBsAg Anti-HBc IgM anti-HBc Anti-HBs

Positive Positive Negative Negative

Chronic HBV infection

• FDA warning issued 2016 following 24 reported cases of HBV reactivation in patients treated with HCV DAAs – 2 deaths

– 1 liver transplant

• Mechanism of reactivation unclear – HCV DAAs do not have immunosuppressive effects

• Current recommendations are to “evaluate patients for potential coinfection of HCV and HBV”

HBV Reactivation Risk in HCV

• HAV

• HBV

• Pneumococcal vaccine for all patients with chronic liver disease, including on-going alcoholism

• Annual flu

Vaccinations

Disease States Potentiating

Fibrosis

Fibrosis

NAFLD Alcohol NASH

Viral Hepatitis HIV

Autoimmune

Practice guidelines: http://www.aasld.org/practiceguidelines/Pages/default.aspx

Natural history following initial infection with HCV

Time 20-25 years 25-30 years

• Presence or history of ascites or esophageal varices

• Low platelet count (<150,000 mm3)

• APRI > 1.0

• FIB-4 > 3.25

• Fibrosure > 0.72

• Imaging with evidence of cirrhosis (nodular contour of liver or evidence of portal hypertension)

• Liver biopsy with F3 or F4 fibrosis

• Transient elastography consistent with advanced fibrosis/cirrhosis

Findings Suggestive of Advanced Fibrosis/ Cirrhosis

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

Use an upper limit of normal of 40

https://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4

Child-Pugh Classification of Cirrhosis for Drug Dosing

1 Point 2 Points 3 Points

Encephalopathy None Moderate Severe

Ascites Absent Mild-Moderate

Severe/ Refractory

Bilirubin (mg/dL) < 2 2 - 3 > 3

Albumin (g/dL) > 3.5 2.8 - 3.5 < 2.8

INR

(PT Prolongation sec over control)

<1.7

(0-4)

1.7-2.3

4-6

>2.3

(>6)

Note: Child Pugh Score is calculated only for patients with cirrhosis

Child-Pugh Interpretation of Hepatic Function in a Patient with Cirrhosis

C-P Score (Class) Liver Function

5-6 (A) Mild Dysfunction

7-9 (B)

Moderate Dysfunction Moderate dose reduction (~25%)

for drugs that are mostly hepatically metabolized

> 9 (C)

Severe Dysfunction Significant dose reduction (~50%)

for drugs that are mostly hepatically metabolized

• Liver biopsy is not reliable gold standard

– Sampling error leads to misinterpretation in 10-15% of cases

– Can miss the diagnosis of cirrhosis

– Invasive procedure with complications

– Expensive

– Poor patient acceptance

– Interpretation has significant inter observer variability

Liver Biopsy is Gold Standard but…

Seeff LB, et al. Clin Gastroenterol Hepatol. 2010;8:877–883. The French METAVIR Cooperative Study Group. Hepatology. 1994;20:15-20

• Incidence of HCC is estimated at 2-8% per year in patients with chronic HCV and advanced fibrosis/cirrhosis

• All patients with cirrhosis should be screened for HCC and continue with HCC surveillance every 6 months (indefinitely)

– Abdominal ultrasound plus AFP

– Biomarkers

– MRI or CT for suspicious lesions or concerns for HCC

Hepatocellular Carcinoma

Compensated cirrhosis

Decompensated cirrhosis

Death Chronic liver

disease

Development of complications:

• Variceal hemorrhage

• Ascites

• Encephalopathy

• Jaundice

Natural History of Chronic Liver Disease

• Physical exam for edema, muscle wasting, encephalopathy, and/or ascites

• Endoscopy for presence of esophageal varices and need for esophageal banding/prophylaxis

• Additional info at AASLD guidelines: https://www.aasld.org/publications/practice-guidelines-0

Evaluating Patients with Cirrhosis: Related Complications

Source: Ginés P, et al. Hepatology 1987; 7:122-8.

Patients with Cirrhosis Decompensation Shortens Survival

60 40 80 100 120 140 160

0

40

60

80

20

20 0

100

Months

All patients with cirrhosis

Decompensated cirrhosis

180

Median survival~ 9 years

Median survival~ 1.6 years

Pro

ba

bilit

y o

f S

urv

iva

l

• Periodic assessment of cirrhotic patients using a validated prognostic tool such as MELD score (Model for End-Stage Liver Disease) can predict mortality and is used as indicator for liver transplantation

• Patients with a score of 15 or higher should be considered for evaluation of liver transplant

Indications for Referral to Hepatologist and for Liver Transplantation

MELD Calculator and Interpretation

https://www.hepatitisc.uw.edu/page/clinical-calculators/meld

• No indications to withhold HCV therapy based on active alcohol or substance use

• Tobacco- can increase risk of HCC

• Marijuana- daily use associated with increased fibrosis

• Alcohol- hepatotoxic

Alcohol and On-going Substance Abuse

Disease States Potentiating

Fibrosis

Fibrosis

NAFLD Alcohol NASH

Viral Hepatitis HIV

Autoimmune

Patient should be counseled on maintaining a healthy diet and normal BMI (<25 kg/m2)

• Mental health assessment – Patients with HCV

have higher rates of depression

– Underlying depression can affect medication adherence

• Coffee and tea may be liver protective

• Statins may be hepatoprotective and may decrease the risk of HCC

When Will There Be Good News?

Jaruvongvanich V., et al. 2017. Clin Res Hepatol Gastroenterol.

• The following labs should be current within the past 12 months*:

– HCV-RNA Quant

• Patients must have documentation of the following labs:

– HCV GT and subtype

– HBsAg, anti-HBs, anti-HBc (irrespective of vaccine history)

– HAV Ab (unless documentation of vaccination)

– HIV Ab

Summary: Pre-Treatment Laboratories

(within 60 days of start of treatment)

*For non-cirrhotic, treatment naïve patients with genotype 1, an HCV-RNA within 6 months of starting therapy must be available for consideration of an 8 week course of treatment.

• CBC with differential

• Chem 7

• Liver enzymes: ALT, AST, alkaline phosphatase

• Liver function tests: albumin, total and direct bilirubin, INR

• Vitamin D 25-OH

• Urine or serum pregnancy test for women of childbearing capacity (ribavirin only)

• Alpha fetoprotein (if cirrhosis)

• HIVRNA and CD4 count (if HIV infected)

• VERY LIMITED

• Prior to using sofosbuvir/velpatasvir in patients with HCV GT3 who have cirrhosis and/or are treatment experienced – RAS testing for HCV GT3- looking for Y93 mutation

• All patients with HCV GT1a when considering use of elbasvir/grazoprevir require pre-treatment resistance testing for NS5A resistance associated substitutions (RASs)

Pre-Treatment Resistance Testing

Changes in HCV Therapy

• Cure

– Defined as sustained virologic response (SVR)

• Improvements in liver function

– Improvements in fibrosis, reversal of cirrhosis?

– Prevent decompensation

• Improvements in extrahepatic manifestations of HCV

• Prevent deaths due to liver disease complications

• Prevent liver cancer

• Reduce rates of liver cancer recurrence

Goals of HCV Therapy

• Direct Acting Antivirals

– Oral

– Short durations

– Minimal side effects

– Minimal laboratory abnormalities

– High cure rates

Differences in Therapy

• Interferon Based

– Injectable

– Long duration of treatment

– High side effect profile

– Multiple laboratory abnormalities

– Low cure rates

• Treatment naïve (TN): no prior HCV therapy

• Treatment experienced (TE): prior HCV therapy- important to clarify which prior treatment

– Interferon

– Direct acting antivirals only

• Sustained virologic response (SVR): cure, defined as undetectable HCV RNA at least 12 weeks after end of treatment (EOT)

– Durable

• Relapser: patient who achieves an undetectable HCV RNA on treatment but has a detectable HCV RNA after treatment is completed

Treatment Terminology

The Evolution of Highly Effective Treatment

IFN

6 mos

PegIFN

RBV

12

mos

IFN

12

mos

IFN/

RBV

12

mos

2001

1998

2011

Standard

IFN

RBV PegIFN

1991

BOC

and

TPV

PegIFN/

RBV/

BOC or

TPV

6-12

mos

IFN/

RBV

6 mos

6

16

34

42

55

70+

0

20

40

60

80

100

2013

SOF

89+

SMV

80+

PegIFN/

RBV/

SMV

24-48

wks

PegIFN/

RBV/

SOF

12-24

wks

2014

LDV/

SOF

>90 >90

PrOD

LDV/

SOF

8-12

wks

PrOD

+

RBV

12-24

wks

EBR/

GZR

12-16

wks

SOF

+

DCV

12

wks

DCV+

SOF

EBR/

GZR

2016

>90 >90

SOF/

VEL >90

SOF/

VEL

12

wks

SOF/

VEL/

VOX

2017

GLE/

PIB

>90 >90

GLE/

PIB

8-12

wks

SOF/

VEL/

VOX

12

wks

HCV Direct Acting Antivirals (DAAs)

Target NS3/4A: Protease Inhibitors (-previr)

NS5A: Replication Complex Inhibitors (-asvir)

NS5B: Polymerase Inhibitors (-buvir)

Boceprevir Telaprevir Simeprevir Paritaprevir Grazoprevir Glecaprevir Voxilaprevir

Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatavir Pibrentasvir

Nucleotide: Sofosbuvir Non-nucleoside: Dasabuvir

Pulled from market

HCV Direct Acting Antivirals (DAAs) Generic Name Brand Name

Elbasvir/ Grazoprevir Zepatier®

Glecaprevir/Pibrentasvir Mavyret®

Ledipasvir/Sofosbuvir Harvoni®

Paritaprevir/ritonavir/Ombitasvir Technivie®

Paritaprevir/ritonavir/Ombitasvir with Dasabuvir Viekira Pak®

Sofosbuvir/ Velpatasvir Epclusa®

Sofosbuvir/ Velpatasvir/Voxilaprevir Vosevi®

Other Therapies

Ribavirin Ribasphere®, RibaPak®, Copegus®, Rebetol®

Single Agent Therapies

Daclatasvir Daklinza®

Sofosbuvir Sovaldi®

• Patients who are treatment naïve and non-cirrhotic have very high SVR rates

• Underlying cirrhosis can decrease SVR

• Medication adherence

What Predicts Treatment Success or Failure?

Overview of HCV Therapies

• Joint guidelines of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA)

• Updated frequently- check online for most current version of guidelines

• Available at: http://www.hcvguidelines.org/

• Combination of – NS5B polymerase inhibitor

(Sofosbuvir);

– NS5A inhibitor (ledipasvir)

• Administration – One tablet once daily with

food or without food

– Requires acidic environment for absorption

• Indicated for GT 1 and 4 for 12 weeks

Ledipasvir/Sofosbuvir

Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.

• Patients without cirrhosis

• Patients with cirrhosis, including Child’s class A, B or C cirrhosis

• Restricted to patients with glomerular filtration rates greater than 30 mL/min/1.73 m2

• Approved for use in children 12 yo and older or 35 kg and above

Who Can Be Treated with Ledipasvir/Sofosbuvir?

0

20

40

60

80

100

ION-1 GT 1 treatment-naïve

including cirrhotics

ION-3 GT 1 treatment-naïve

non-cirrhotic

ION-2 GT 1 treatment-experienced

including cirrhotics and PI failures

99 97 98 99 94 93 95 94 96 99 99

LDV/SOF LDV/SOF+RBV

12 Weeks 24 Weeks 12 Weeks 24 Weeks 12 Weeks

Efficacy Summary

ION Phase 3 Program (ION-1, ION-2, ION-3)

SVR

12

(%

)

Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print] Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print] Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]

8 Weeks

107/ 111

102/ 109

108/ 109

110/ 111

211/ 217

211/ 214

212/ 217

215/ 217

202/ 215

201/ 216

206/ 216

Error bars represent 95% confidence intervals.

• 97% (1886/1952) overall SVR rate

• Fixed-dose combination of sofosbuvir (NS5B inhibitor) and velpatasvir (NS5A inhibitor)

• Approved for chronic HCV genotypes 1, 2, 3, 4, 5, or 6 for 12 week duration of therapy

Sofosbuvir/Velpatasvir

Epclusa [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.

• Patients without cirrhosis

• Patients with cirrhosis, including Child’s class A, B or C cirrhosis

• Restricted to patients with glomerular filtration rates greater than 30 mL/min/1.73 m2

Who Can Be Treated with SOF/VEL?

64

SVR12 by Cirrhosis Status or Treatment History

ASTRAL-1: SOF/VEL STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients

Error bars represent 95% confidence intervals.

Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med. 2015. DOI: 10.1056/NEJMoa1512610

99 99 99 99 99

0

20

40

60

80

100

SV

R12 (

%)

618/624 496/501 120/121 418/423

Non-Cirrhotic Treatment-

Naïve Treatment-

Experienced

200/201

Total Cirrhotic

• Combination of – Glecaprevir an NS3/4A protease

inhibitor

– Pibrentasvir an NS5A inhibitor

• Dosage and administration: 3 tablets once daily with food

• Indicated for 8 weeks in patients without cirrhosis; 12 weeks if cirrhotic

Glecaprevir/Pibrentasvir

Glecaprevir-Pibrentasvir for 8 or 12 weeks in Non-Cirrhotic GT 1 ENDURANCE-1: Baseline Characteristics

Source: Zeuzem S, et al. AASLD 2016.Abstract 253.

99.1 100 99.7 100

0

20

40

60

80

100

ITT-PS ITT-PS-PP

Pati

en

ts (

%)

wit

h S

VR

12

GLE-PIB x 8 Weeks GLE-PIB x 12 Weeks

332/335 331/332 331/331 332/332

ITT-PS population: ITT excluding patients with HIV coinfection or treatment experience with sofosbuvir

ITT-PS-per protocol (PP) population: ITT-PS excluding patients with premature discontinuation of study drug,

virologic failure before Week 8, and missing SVR12 data

Glecaprevir-Pibrentasvir in Treatment-Naïve Non-Cirrhotic GT 3

ENDURANCE-3 Study: Results

ION-3: SVR 12 by Treatment Duration and Regimen (ITT Analysis)

Source: Foster G, et al. EASL 2017. Abstract GS-007.

95 97 95

0

20

40

60

80

100

GLE-PIB SOF + DCV GLE-PIB

Pati

en

ts w

ith

SV

R 1

2 (

%)

222/233

12-Week Regimens

111/115 149/157

8-Week Regimen

GLE-PIB = glecaprevir-pibrentasvir; SOF = sofosbuvir; DCV = daclatasvir

ITT = Intent-to-treat

Glecaprevir-Pibrentasvir in Genotype 1-6 with Renal Disease EXPEDITION-4: Results

SVR12 by Type of Analysis

Source: Gane E, et. al, AASLD 2016. Abstract 935.

98 100

0

20

40

60

80

100

ITT mITT

Pa

tie

nts

wit

h S

VR

12

(%

)

1 discontinuation

1 lost to follow-up

102/104 102/102

ITT, intent-to-treat analysis; mITT, modified intent-to-treat analysis

• Combination of – NS5B polymerase inhibitor

(Sofosbuvir);

– NS5A inhibitor (Velapatasvir);

– NS3/4A protease inhibitor (Voxilaprevir)

• Administration – One tablet once daily with

food

• Indicated for patients who previously failed DAA therapy

Sofosbuvir/Velpatasvir/Voxilaprevir

Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.

• Patients without cirrhosis

• Patients with Child’s class A cirrhosis (compensated cirrhosis)

• Not recommended in patients with Child’s Class B or C cirrhosis

• Restricted to patients with glomerular filtration rates greater than 30 mL/min/1.73 m2

Who Can Be Treated with SOF/VEL/VOX?

96 99 93

0

20

40

60

80

100

SV

R1

2,

%

Overall* No Cirrhosis Cirrhosis

SVR12 Results Overall and by Cirrhosis Status

POLARIS-1: SOF/VEL/VOX for 12 Weeks in NS5A Inhibitor-Experienced HCV GT 1–6

Bourliere M, AASLD 2016, Oral 194

253/263

6 relapses 1 on-treatment failure** 2 withdrew consent 1 LTFU

* p <0.001 for superiority compared with prespecified 85% performance goal for SOF/VEL/VOX

** Exposure was consistent with non-adherence

140/142 113/121

1 withdrew consent 1 LTFU

6 relapses 1 on-treatment failure** 1 withdrew consent

99 98 97 100 100 100 100 93 96 94 100

0

93 86

0

20

40

60

80

100

Overall GT 1 GT 1a GT 1b GT 2 GT 3 GT 4/5/6

*1/1 patient with GT unknown achieved SVR12; †4/4 patients with GT 1 other (cirrhosis, n=2; no cirrhosis, n=2) achieved SVR12; ‡Includes only GT 4 patients.

SV

R12, %

Overall GT 1a GT 2 GT 3 GT 4/5/6 GT 1b GT 1

16 16

12‡

14 52 56

31 33

49† 51

113 121

5 5

29 29

15 15

22 22

66 68

97†

99 140* 142

SVR12 by Genotype and Cirrhosis Status

POLARIS-1: SOF/VEL/VOX for 12 Weeks in NS5A Inhibitor-Experienced HCV GT 1–6

Data on file, Gilead Sciences

Cirrhosis No Cirrhosis

72

100 92 100 96 100 94 100 100 94 100

0

20

40

60

80

100

GT 1a GT 1b GT 2 GT 3 GT 4

SV

R12, %

Cirrhosis No Cirrhosis

SOF/VEL/VOX 12 Weeks Overall SVR12 97%

SOF/VEL 12 Weeks Overall SVR12 90%

93 93 94 95

0

81 100 100

77

0 0

20

40

60

80

100

GT 1a GT 1b GT 2 GT 3 GT 4

7 7

22 23

18 18

12

13 37 37

12 12

29 31

13 13

11

11 16 17

21 22

16 17

14

15 26 28

23 30

16 16

7

7 13 16

SVR12 by Genotype and Cirrhosis Status

POLARIS-4: SOF/VEL/VOX or SOF/VEL for 12 Weeks in Non-NS5A Inhibitor DAA-Experienced HCV GT 1–4

Data on file, Gilead Sciences 73

• Still utilized in combination with other HCV therapies in more difficult to treat patient populations and/or when specific RAS concerns exist

• Well-known to cause toxicity profile

– Hemolytic anemia

Occurs within 1-2 weeks and peaks after 4-6 weeks

Can see increase in indirect bilirubin

– Teratogenic

Pregnancy category X

Ribavirin

• Overall very well tolerated

• Most commonly reported side effects: – Headache

– Fatigue

– Nausea

– Diarrhea (reported with voxilaprevir)

Side Effect Profile of DAAs

• Overall not common

• Most common laboratory abnormalities: – ALT elevations

Concomitant use of ethinyl-estradiol with glecaprevir/pibrentasvir

– Bilirubin elevations

Many DAAs inhibit bilirubin transporters

– Anemia with concomitant use of ribavirin

Ribavirin causes hemolytic anemia

Laboratory Abnormalities with DAAs

Rapid Viral Decline

Rapid Improvements in Inflammation

Ribavirin Induced Hemolytic Anemia

• In patients with cirrhosis

– Avoid NSAIDs

– Acetaminophen preferred for short-term pain management at <2 grams per day

What About Medications in Patients with HCV?

• In patients undergoing HCV therapy

– Avoid herbals

– Verify potential drug interactions using Liverpool website

• Statins:

– Interactions vary by DAA and statin

• Acid suppressive therapy:

– Ledipasvir and velpatasvir require acidity for absorption – greatest concern with velpatasvir

• Avoid amiodarone

– Amiodarone with sofosbuvir and other DAA: Serious symptomatic bradycardia

Other Main Drug Interaction Concerns for DAAs

• Carbamazepine

• Oxcarbazepine

• Phenytoin

• Phenobarbital

• Rifampin

• Expected to ↓ concentrations

• DO NOT USE WITH HCV THERAPY!

Major Drug-Drug Interactions for all Direct Acting Antivirals

www.hep-druginteractions.org Also available as an app: hepichart

Use of HCV Therapies in Special Populations

Use of HCV DAAs in Renal Insufficiency and Cirrhosis

Ledipasvir/sofosbuvir

Elbasvir/grazoprevir

Sofosbuvir/ velpatasvir

Sofosbuvir/ velpatasvir/ voxilaprevir

Glecaprevir/ pibrentasvir

Use in renal impairment or end-stage renal disease?

> 30 mL/min

Safe to use in all levels of renal impairment including dialysis

> 30 mL/min

> 30 mL/min

Safe to use in all levels of renal impairment including dialysis

Use in cirrhosis?

Childs Class A, B or C

Child Class A Childs Class A, B or C

Child Class A

Child Class A

Treatment Flowsheet Example

Treatment Flowsheet Example: With Ribavirin

• AASLD/IDSA HCV Treatment Guidelines:

– Available at: http://www.hcvguidelines.org

• HCV Drug Interactions (University of Liverpool):

– Available at: http://www.hep-druginteractions.org

• Educational material, clinical calculators, HCV therapy summaries (University of Washington)

– Available at: http://www.hepatitisc.uw.edu

Resources

HCV ECHO® WESTERN STATES

End of Presentation

Questions?

Ong et al., Am J Med 2003; 114:188

Poor Correlation of Ammonia Levels With Presence or Severity of Encephalopathy

Venous total ammonia mmol/L

0

400

350

300

250

200

150

100

50

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Severity of Hepatic

Encephalopathy

POOR CORRELATION OF AMMONIA LEVELS WITH PRESENCE OR SEVERITY OF HEPATIC ENCEPHALOPATHY

Can Active Drug Users Adhere to HCV Therapy and Achieve Cure?

Immediate Treatment Group Deferred Treatment Group

Mean Drug Adherence (%)

SVR12, n/m (%)

Mean Drug Adherence (%)

SVR12, n/m (%)

All patients 99.3 184/201 (91.5) 99.6 85/95 (89.5)

Patients with positive UDS at Day 1

Opioids 99.1 37/44 (84.1) 99.6 16/19 (84.2)

Amphetamine 99.9 9/10 (90) 99.2 5/6 (83.3)

Cocaine 97.5 19/20 (95) 99.2 8/10 (80)

Benzodiazepines

99.7 46/51 (90.2) 99.5 23/26 (88.5)

Cannabinoids 99.7 56/60 (93.3) 99.6 24/27 (99.6)

Dore et al. Ann Intern Med. 2016;165:625-634.

n= number of all randomized patients achieving SVR12; m= number of all randomized patients with positive UDS for the indicated drug at day 1