hcv screening, management and guidelines - npaihb · hcv screening, management and guidelines...
TRANSCRIPT
HCV ECHO® WESTERN STATES
Original presentation by: Date prepared:
HCV Screening, Management and 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
January 30, 2017
OBJECTIVES
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
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
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
0
100
200
300
400
500
600
700
800
900
2010 2011 2012 2013 2014 2015 2016 2 0 1 7
HCV AB TESTS PERFORMED 2010-2017
FPSU HCV Epidemiology
777
526
251
0
100
200
300
400
500
600
700
800
900
HCV Ab+ Chronic HCV Spontaneous clearance
number of living patients
HCV Ab+ by age group
5
214
265
139
108
44
2
0 50 100 150 200 250 300
17 and younger
18-29
30-39
40-49
50-59
60-69
70+
Age
Gro
up
# patients
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 for 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
• 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)
• All patients with HCV GT1a when considering use of elbasvir/grazoprevir require pre-treatment resistance testing for NS5A resistance associated substitutions (RASs)
• All patients with HCV GT3 who have cirrhosis and/or are treatment experienced when using sofosbuvir/velpatasvir or sofosbuvir plus daclatasvir should have RAS testing for HCV GT3- looking for Y93 mutation
Pre-Treatment Resistance Testing
• Cure
– Defined as sustained virologic response (SVR)
• Improvements in liver function
– Improvements in fibrosis, reversal of cirrhosis?
• Improvements in extrahepatic manifestations of HCV
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
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®
Simeprevir Olysio®
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?
• 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
Ledipavir/Sofosbuvir
Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.
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
Elbasvir/ Grazoprevir (EBR/GZR)
• Fixed-dose combination tablet – 50 mg elbasvir (NS5A
replication complex inhibitor)
– 100 mg grazoprevir (NS3/4A protease inhibitor)
• Dosing: 1 tablet per day with or without food
• Approved Feb. 2016
Indicated for HCV genotypes 1 and 4
Patients with GT 1a require pre-treatment resistance testing If present, must add ribavirin and extend treatment duration to 16 weeks
• Increased risk of ALT elevations
– 5x ULN in 1% of patients
2% in women, Asian race, or patients aged 65 years or older
– Occurred at treatment week 8 or later
– Mostly asymptomatic
– Resolved with ongoing or completed therapy
– Monitor LFTs every 4 weeks or as clinically indicated
• Adverse effects:
– Fatigue, headache, and nausea
Laboratory Abnormalities and Adverse Effects
Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6 C-EDGE TN: Results
C-EDGE TN: SVR12 Results by Genotype
Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.
Slide courtesy of HCV Online; H. Nina Kim MD, MSc and David Spach MD
299/316 144/157 129/131 18/18 8/10
Primary efficacy analysis included all patients who received ≥1 dose of drug.
• Fixed-dose combination of sofosbuvir (NS5B inhibitor) and velpatasvir (NS5A inhibitor)
• Approved June 28, 2016 for chronic HCV genotypes 1, 2, 3, 4, 5, or 6 – Treatment naïve
– Treatment experienced (Peg-IFN/RBV with or without PI)
Sofosbuvir/Velpatasvir
Epclusa [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.
62
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 – NS5B polymerase inhibitor
(Sofosbuvir);
– NS5A inhibitor (Velapatasvir);
– NS3/4A protease inhibitor (Voxilaprevir)
• Administration – One tablet once daily with
food
• Approved July 18, 2017
Sofosbuvir/Velpatasvir/Voxilaprevir
Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.
• Patients with genotype 1, 2, 3, 4, 5, or 6 who were previously treated with an NS5A inhibitor
• Patients with genotype 1a or 3 infection previously treated without an NS5A inhibitor
– No advantage of using sofosbuvir/velpatasvir/voxilaprevir over sofosbuvir/velpatasvir for retreatment of patients with GT 1b, 2, 4, 5, or 6
Indications: DAA Treatment Experienced Patients
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
66
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 67
• Adverse reactions:
– Headache
– Fatigue
– Diarrhea
– Nausea
• Laboratory abnormalities: increases in total bilirubin
– Voxilaprevir can inhibit bilirubin transporters
Adverse Reactions and Laboratory Abnormalities
• Combination of – Glecaprevir an NS3/4A protease
inhibitor
– Pibrentasvir an NS5A inhibitor
• Dosage and administration: 3 tablets once daily with food
• Approved Aug. 3, 2017
Glecaprevir/Pibrentasvir
Glecaprevir/Pibrentasvir: Indications and Duration of Therapy
HCV Genotype Prior Treatment Experience
Without Cirrhosis With Compensated Cirrhosis
1,2,3,4,5,6 Naïve 8 weeks 12 weeks
1,2,4,5,6 Pegylated interferon, ribavirin and/or sofosbuvir
8 weeks 12 weeks
3 Pegylated interferon, ribavirin and/or sofosbuvir
16 weeks 16 weeks
1 NS3/4A (NS5A naïve) 12 weeks 12 weeks
NS5A (NS3/4A naïve) 16 weeks 16 weeks
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
• Adverse reactions reported:
– Headache, fatigue, nausea, diarrhea
– Rates similar to placebo
• Laboratory abnormalities:
– Serum bilirubin abnormalities in approximately 3% of patients
– Glecaprevir/pibrentasvir can affect bilirubin transporters
Adverse Reactions and Laboratory Abnormalities
• 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
Case
• This is a 61-year old male with hepatitis C, genotype 1a
• Currently on furosemide and spironolactone for ascites
• Recommended treatment: ledipasvir/sofosbuvir plus 1200 mg ribavirin for 12 weeks
• What is this person’s level of liver disease?
• What laboratory abnormalities do you anticipate on treatment?
• Overall very well tolerated
• Most commonly reported side effects: – Headache
– Fatigue
– Nausea
– Diarrhea (reported with voxilaprevir)
Summary: Side Effect Profile of DAAs
• Overall not common
• Most common laboratory abnormalities: – ALT elevations
Concomitant use of ethinyl-estradiol with PrOD or glecaprevir/pibrentasvir
Elbasvir/grazoprevir
– Bilirubin elevations
Many DAAs inhibit bilirubin transporters
– Anemia with concomitant use of ribavirin
Ribavirin causes hemolytic anemia
Summary: Laboratory Abnormalities with DAAs
• 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
• 44 yo female who is treatment naïve with HCV GT 1a
• Current medications:
– Amlodipine
– Atorvastatin
– Omeprazole
– Fluticasone nasal
Case Study: Managing Interactions
www.hep-druginteractions.org Also available as an app: hepichart
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
• 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
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