hepatitisc-230507225140-296062d3 (1)

Clinical Case
07/14/2024
• A 62-year-old woman reported to your clinic for complaints of
tiredness, fatigue, anorexia, and weakness.
• There was past history of knee joint replacement in India, 5 years
back where he received a blood transfusion during that operation
and of course , injections too.
• On Physical examination, nothing was remarkable except slight
anemia and mild Jaundice
• Laboratory values:
 AST 650 IU/mL, ALT 950 IU/mL , SCr 0.9 mg/dL,
Dr. Afzal Haq Asif

 Bilirubin: 2.9.0 mg/dL, albumin 2.5 g/dL.
• What is most probable cause/causes of patient’s problem
• Which further investigation you suggest to reach final
diagnosis 1
Clinical Case
07/14/2024
• HBs Ag, Anti HBs were found negative
• Anti HCV were positive
 What other tests needed to confirm diagnosis and for treatment
• USG: Liver size a little decreased, no nodule or cirrhotic changes

• A liver biopsy has revealed necro-inflammation and bridging fibrosis.
• What is final diagnosis ?
What is the best course of action?
Dr. Afzal Haq Asif

•
 What is most recent practices regarding Pharmacotherapy for this case
 What general measure you will advise to community to protect against
such diseases? Vaccination?
2
Hepatitis C
AASLD/IDSA recommendations-2018.Updates: 2021
ACCP-Updates-2022
Pharmacotherapy handbook 2021, 11 th Edition
07/14/2024
ILO’s
• At the end of the session, the attendee will
be able to
 Define the acute and chronic viral hepatitis C
 Diagnose based upon clinical and lab data
 Design therapeutic objectives
 Design therapeutic and follow up evaluation
plan for patient
 Resolve drug related problems of patient
 Educate the patient to improve therapeutic
Dr. Afzal Haq Asif
outcome
4
HCV
07/14/2024
HCV is a single stranded RNA virus
Genus Hepa-civirus, (HCV)
Family Flavi-viridae
Characterized by a high spontaneous mutation rate
11 genotypes (90 sub-types) , (1a, 1,b, 2a, 3b etc)
• USA:
• Genotype 1 (subtypes 1a, 1b, and 1c) 70%–75%.
Dr. Afzal Haq Asif
• Genotypes 2 (subtypes 2a, 2b, and 2c) and 3 (3a and 3b) are less common
• KSA:
• Genotype 4 is common
• Ia And Ib less common
• Genotype 2, 3, 5 and 6 are least common
5
07/14/2024
Genotype %age
HCV genotype 1 is
Genotype 4 (16.8%)
the most prevalent Genotype 3 (17.9%),
and
worldwide (49.1%),
Genotypes 5 and 6
Dr. Afzal Haq Asif
Genotype 2 (11.0%). are responsible for

the remaining < 5%.
6
Transmission
07/14/2024
Mainly blood-borne (transfusion, intravenous drug abuse)
High risk: Transfusion, intravenous drug abuse
Low risk:
• Hemodialysis continuous
• Snorting cocaine or other drugs
• Occupational exposure needle stick , health workers
•
Dr. Afzal Haq Asif
Body piercing and acupuncture with unsterilized needle

• Tattooing
• From pregnant mother to child
• Nonsexual household contacts (rare)
• Sharing razors and/or toothbrushes
• Sexual transmission
7
07/14/2024
Pathogenesis:
replication in
Liver cells
Dr. Afzal Haq Asif

8
07/14/2024
Pathogenesis
Direct cell injury due to viral replication
• Genotype 1 is associated with higher viral replication,

• Genotype 1b associated with more progressive liver disease
Immune mediated cell injury:

Dr. Afzal Haq Asif
• CD8+ and CD4+ lymphocytes in portal, peri-portal, and

lobular areas in patients with HCV infection
9
Clinical Presentation
07/14/2024
Acute: less than 6 months

• Usually asymptomatic;
• if Symptoms do appear, they are generally nonspecific: fatigue, weakness, anorexia,
and jaundice; typically appear within 4–12 hours after exposure.
• Rapid progression to fulminant liver disease is infrequent.
• Diagnosis of acute infection is extremely rare.
Chronic: more than 6 months

• Most chronically ill patients with HCV infection remain asymptomatic for years,
presenting with symptoms during the fifth and sixth decades of life
• Most who present for medical attention have chronic infection;
• Anorexia, abdominal pain, fever, jaundice, malaise, nausea,
• Symptoms associated with hepatocellular carcinoma and liver cirrhosis.
Dr. Afzal Haq Asif
• Extrahepatic disease (e.g., cryoglobulinemia, glomerulonephritis) may also be

present.
• The level of virus in the serum (HCV RNA) is not highly correlated with stage of
disease.
10
Dr. Afzal Haq Asif 07/14/2024
11
07/14/2024
Dr. Afzal Haq Asif
• Pol, S., Vallet-Pichard, A. & Hermine, O. Extrahepatic cancers and
chronic HCV infection. Nat Rev Gastroenterol Hepatol 15, 283–
290 (2018). 12
07/14/2024
HCV infection: course of disease
• Asymptomatic: 30%
• Moderate to severe hepatitis in 30% <20 years of age
• Acute:
 Antibodies against HCV (anti-HCV) in the blood indicate
infection. About 15% to 45% of patients have acute
hepatitis C that resolves without any further complication
• Chronic:
 In 70% of cases: when infection persists for more than 6
months and viral replication is confirmed by HCV RNA
levels, because of Ineffective host immune system, with
cytotoxic T lymphocytes unable to eradicate the HCV,
 Approximately 55% to 85% of chronic cases progress to
mild, moderate, or severe hepatitis (Child-Pugh score)
 In 15% to 30% Persistent damage to hepatic cells leading to
cirrhosis after several decades of infection
Dr. Afzal Haq Asif
 Factors for cirrhosis: obesity, diabetes, heavy

alcohol use, male sex, and coinfections with HIV or
HBV. Age over 40 years at the time of infection
 5-year mortality with compensated cirrhosis 9%,
 5-year mortality with Decompensated cirrhosis
50%
 Once cirrhosis is confirmed, the risk of developing HCC is
about 2% to 4% per year
13
07/14/2024
Course of the  Hepatocellular Carcinoma in
Disease,
HCV infection
 1% to 4% of patients per year
during the first 5 years after
cirrhosis develop
hepatocellular carcinoma
 7% after 5 years of cirrhosis
 14% at 10 years;
 Higher in men
Dr. Afzal Haq Asif

 Higher in older patients
14
07/14/2024
Spontaneous resolution
• HCV infection spontaneously clears in 20% to 50% of
patients
• Clearance of acute HCV infection occurs within 6 months

of the estimated time of infection (median, 16.5 weeks) in
at least 2/3 of patients who spontaneously clear HCV.
• Only 11% of those who remain viremic at 6 months will

spontaneously clear the infection at a later time
• Patients who have spontaneously cleared should not be

treated with antiviral therapy.
• However, they should be counseled about the possibility of

reinfection and tested routinely for this development if risk
behaviors are ongoing
Dr. Afzal Haq Asif

• Transient suppression of viremia can occur in those with
acute HCV infection, even among those who progress to
chronic infection.
• Thus, a single undetectable HCV RNA test result is

insufficient to declare spontaneous clearance
15
Extra-hepatic
07/14/2024
manifestations
• Rheumatoid arthritis
• Glomerulonephritis
• Cryo-globenemia
Dr. Afzal Haq Asif
16
07/14/2024
Diagnosis
• Clinical Signs and symptoms: not suggestive, unless
thorough history and Labs
• Serum anti-HCV antibodies:

 99% sensitivity and specificity..indicate HCV
 can be detected 8–12 weeks post exposure
• Serum HCV RNA: can be detected 2 weeks post

exposure
 Quantitative: used for
 Confirmation of Diagnosis
 Monitoring response to therapy
 Qualitative: only to confirm diagnosis
 50 IU/ml: 100 copies/mL to confirm
Dr. Afzal Haq Asif
diagnosis 98% specificity
• Liver biopsy: for cirrhosis, prognosis
• ALT: Non specific
• Genotype: for treatment duration and response

17
Hepatitis C
Prevention
AASLD, (American Association for the Study of Liver Diseases)
2018/2021
07/14/2024
Who should be screened

• Persons who have injected illicit drugs in the recent and remote past
• Persons with conditions of a high prevalence of HCV infection

including:
 With HIV infection
 With hemophilia who received clotting factor prior to 1987
 Who have ever been on hemodialysis
 With unexplained abnormal aminotransferase levels
 Immigrants from countries with a high prevalence of HCV
infection
• Prior recipients of transfusions or organ transplants prior to July

1992:
 Persons who were notified that they had received blood from a
donor who later tested positive for HCV infection
 Persons who received a transfusion of blood or blood products
Dr. Afzal Haq Asif
 Persons who received an organ transplant
• Children born to HCV-infected mothers
• Health care, emergency medical and public safety workers after a

needle stick injury or mucosal exposure to HCV-positive blood
• Current sexual partners of HCV-infected persons
19
07/14/2024
Prevention
• No Vaccine is available
• Risk factor modification
 Intravenous drug abuse: treatment with oral
methadone
 Sexual contact: appropriate barrier
contraception
 Avoid blood exposure: Occupational (universal
precautions) or other contact
 Avoid sharing toothbrushes or razors or
Dr. Afzal Haq Asif
receiving a tattoo
• HAV and HBV vaccine to prevent further

progression of liver disease
20
Educate about the following
07/14/2024
Avoid sharing toothbrushes and dental or shaving equipment
Cover any bleeding wound to prevent possibility of others coming

into contacted with infected blood
Counsel to avoid using illicit drugs and enter substance abuse

treatment
Counsel to avoid reusing or sharing syringes, needles, or any

supplies for those continuing to use injectable drugs •
Avoid donating blood

Dr. Afzal Haq Asif
In those coninfected with HIV, consider using barrier precautions

to prevent sexual transmission
Proper cleaning of contaminated surfaces with a dilution of 1 part

household bleach to 9 parts water
21 Always wear gloves when cleaning up blood spills

Treatment
guidelines-2018/2021 updates
Goals of Therapy
07/14/2024
Acute:
• Eradicate HCV infection in acute

• To prevents the development of chronic HCV infection
Chronic:
• Attain Sustained Virologic Response (SVR) inChronic

• Undetectable HVC RNA, after therapy completion
Decrease HCV associated morbidity and mortality
Normalize biochemical markers

Dr. Afzal Haq Asif
Improve clinical symptoms
Prevent progression to cirrhosis and HCC
Prevent development of end stage liver disease

23
07/14/2024
General recommendations
• To assist with making the best treatment
decision for each patient each
recommendation is classified as follows:
 Recommended – Favored for most patients
 Alternative – Optimal in a particular subset of
patients
 Treatment regimens and length vary according to
HCV genotype and prior treatment history.
 Patients of acute HCV should promptly start HCV
treatment.
 The initiation of treatment should not be delayed
waiting spontaneous clearance.
Dr. Afzal Haq Asif

 Why to treat Acute HCV:
 Reducing risk of spread of HCV to others,
 Decreased chances to develop chronic phase
24
New Regimen -
2018 / 21
guidelines-2018 updated Aug 2021
07/14/2024
Dr. Afzal Haq Asif
Strength and level of Evidence
26
07/14/2024
 A patient is presumed to have cirrhosis if
they have a FIB-4 score >3.25 (
https://www.hepatitisc.uw.edu/page/clini
cal-calculators/fib-4
) or
Pretreatment
 Any of the following findings from a
previously performed test.
Transient elastography indicating
cirrhosis (eg, FibroScan stiffness
Assessment:
>12.5 kPa)
https://www.mskcc.org/cancer-care Cirrhosis
/patient-education/understanding-y
our-fibroscan-results
Dr. Afzal Haq Asif

Noninvasive serologic tests above
proprietary cutoffs indicating
cirrhosis (eg, FibroSure, Enhanced
Liver Fibrosis Test, etc)
Clinical evidence of cirrhosis (eg,
liver nodularity and/or
splenomegaly on imaging, platelet
count
27
28
07/14/2024
Pretreatment Assessment: Medication & Labs

 Potential drug-drug interaction assessment: Drug-
drug interactions can be assessed using drug
interaction checker.
 Education: Educate the patient about proper

administration of medications, adherence, and
prevention of reinfection.
 Pretreatment laboratory testing:

Any time prior to starting antiviral therapy:
Quantitative HCV RNA (HCV viral load) HIV
Dr. Afzal Haq Asif
antigen/antibody test
Hepatitis B surface antigen
At start and Within 6 weeks of initiating
treatment: Complete blood count (CBC) Hepatic
function panel (ie, albumin, total and direct
bilirubin, alanine aminotransferase [ALT],
aspartate aminotransferase [AST]) Calculated
glomerular filtration rate (eGFR)
29
On-Treatment
07/14/2024
Monitoring
• Inform patients taking diabetes medication of the potential for
symptomatic hypoglycemia.
• Monitoring for hypoglycemia is recommended.
• Inform patients taking warfarin of the potential for changes in

their anticoagulation status.
• Monitoring INR for subtherapeutic anticoagulation is

recommended.
• No laboratory monitoring is required for other patients.
Dr. Afzal Haq Asif

• An in-person or telehealth/phone visit may be scheduled, if
needed, for patient support, assessment of symptoms, and/or
new medications
30
07/14/2024
Post-Treatment Assessment
of Cure
• At 12 weeks or later following completion of
therapy
 Assessment of quantitative HCV RNA
 Hepatic function panel
• Objective:
 To confirm HCV RNA is undetectable (virologic cure)
 Transaminase normalization.
Dr. Afzal Haq Asif

• Assessment for other causes of liver disease is
recommended for patients with elevated
transaminase levels after achieving SVR.
31
07/14/2024
Treatment Naïve
Genotype 1-6
Dr. Afzal Haq Asif

32
Classes of DAA
Three classes of approved DAAs: (NS: N terminal Serine)
NS3/4A protease inhibitors,
Glecaprevir
Peritaprevir
07/14/2024
Grazipasvir
Semiprevir
Voxila-previr
NS5A inhibitors, NS5A): a zinc-binding and proline-rich hydrophilic phosphoprotein that plays
a key role in Hepatitis Cvirus RNA replication
Pi-brin-tasvir
Ledipasvir
Vel-pa-tas-vir
Daclatasvir
Ombitasvir
Elbasvir
Polymerase inhibitors (nonnucleoside inhibitors and nucleotide inhibitors). NS5B
Polymerase inhibitotrs
So-fos-bu-vir
Dasabuvir
Protease inhibitors
33
Dr. Afzal Haq Asif

Ritonavir
Treatment Regimens: DAA Drugs
07/14/2024
 Followingare most commonly prescribed new
drug regimens for almost all the genotypes (1-6):
1. Albas-vir + Grazo-pre-vir
2. Gleca-pre-vir + Pi-bren-tas-vir
3. Ledi-pas-vir + So-fos-bu-vir
4. Sofosbuvir + Vel-pa-tas-vir
 Following are available in fixed dose

combination
Ledi-pas-vir/sofosbuvir (Harvoni)
Elbasvir/grazoprevir (Zepatier)
Ombitasvir/paritaprevir/Ritonavir/Dasabuvir
(Viekira Pak)
Ombitasvir/paritaprevir/Ritonavir (Technivie)
Dr. Afzal Haq Asif

Sofosbuvir/velpatasvir (Epclusa)
 Commonly used for 8 or 12 weeks
34
Treatment Recommendations for Chronic HCV Infection in Treatment-Naive
07/14/2024
Patients with or without Compensated Cirrhosis
Geno Recommended Therapies without Cirrhosis Recommended Therapies with

Compensated Cirrhosis
type
1a EBR (50 mg)/GZR (100 mg)a × 12 wk EBR (50 mg)/GZR (100 mg)a × 12 wk GLE
GLE (300mg)/PIB (120mg) x 8 wk (300mg)/PIB (120mg) x 12 wk LDV (90
LDV (90 mg)/SOF (400 mg) × 12 wkb mg)/SOF (400 mg) × 12 wk SOF (400
SOF (400 mg)/VEL (100 mg)× 12 wk mg)/VEL (100 mg)× 12 wk
1b EBR (50 mg)/GZR (100 mg) × 12 wk EBR (50 mg)/GZR (100 mg) × 12 wk
GLE (300mg)/PIB (120mg) x 8 wk GLE (300mg)/PIB (120mg) x 12 wk LDV
LDV (90 mg)/SOF (400 mg) × 12 wkb (90 mg)/SOF (400 mg) × 12 wk SOF (400
SOF (400 mg)/VEL (100 mg)× 12 wk mg)/VEL (100 mg)× 12 wk
Dr. Afzal Haq Asif

2 GLE (300mg)/PIB (120mg) x 8 wk SOF (400 mg)/VEL (100 mg)× 12 wk
SOF (400 mg)/VEL (100 mg)× 12 wk GLE (300mg)/PIB (120mg) x 12 wk
See guidelines for treatment recommendations after failure of PEG therapy or direct-acting antivirals.
a
Not recommended for genotype 1a if baseline NS5A RASs for elbasvir are detected.
b
For patients who are non-black, HIV uninfected, and whose HCV RNA <6 million IU/mL, can use 8 week duration of therapy.
c
If NS5A RAS for Y93H is present, add ribavirin to the regimen or sofosbuvir/velpatasvir/voxilaprevir should be considered.
EBR = elbasvir; GLE = glecaprevir; GZR = grazoprevir; LDV = ledipasvir; PIB = pibrentasvir; SOF = sofosbuvir; VEL = velpatasvir. 35
07/14/2024
Genotype Recommended Therapies without Cirrhosis Recommended Therapies with Compensated
Cirrhosis
3 GLE (300mg)/PIB (120mg) x 8 wk SOF (400 GLE (300mg)/PIB (120mg) x 12 wk

mg)/VEL (100 mg)× 12 wk SOF (400 mg)/VEL (100 mg)× 12 wk
4 GLE (300mg)/PIB (120mg) x 8 wk SOF (400 GLE (300mg)/PIB (120mg) x 12 wk

EBR (50 mg)/GZR (100 mg) × 12 wk LDV EBR (50 mg)/GZR (100 mg) × 12 wk LDV (90
(90 mg)/SOF (400 mg) × 12 wk mg)/SOF (400 mg) × 12 wk
5 or 6 GLE (300mg)/PIB (120mg) x 8 wk SOF (400 GLE (300mg)/PIB (120mg) x 12 wk

LDV (90 mg)/SOF (400 mg) × 12 wk LDV (90 mg)/SOF (400 mg) × 12 wk
Dr. Afzal Haq Asif

See guidelines for treatment recommendations after failure of PEG therapy or direct-acting antivirals.
a
Not recommended for genotype 1a if baseline NS5A RASs for elbasvir are detected.
b
For patients who are non-black, HIV uninfected, and whose HCV RNA <6 million IU/mL, can use 8 week duration of therapy.
c
If NS5A RAS for Y93H is present, add ribavirin to the regimen or sofosbuvir/velpatasvir/voxilaprevir should be considered.
EBR = elbasvir; GLE = glecaprevir; GZR = grazoprevir; LDV = ledipasvir; PIB = pibrentasvir; SOF = sofosbuvir; VEL = velpatasvir.
36
07/14/2024
Key Points
 Ifpatient exposed to INF/INF+ Ribavirin before, no change in
therapy
 Ifpatient exposed to DAA, (Sofosbubir) containing therapy,

add Voxi-la-pre-vir to the regimen, now it will be 3 drugs for
same duration
 Ifpatient has compensated cirrhosis, usually no change in

therapy
 Ifpatient has decompensated cirrhosis, add ribavirin to 2

DAA’s. But if patient is ineligible for Ribavirin, increase
Dr. Afzal Haq Asif

duration of 2 drug regimen to 24 weeks or as per guidelines
 Weight based ribavirin dose means: for less than 75 kg, dose
is 1000 mg, if more than 75 kg dose is 1200 mg
37
Simplified Regimen
07/14/2024
 Forall genotype: Treatment Naïve Patients and
without cirrhosis
Glecaprevir (300 mg) / pibrentasvir (120 mg) to be
taken with food for a duration of 8 weeks
Sofosbuvir (400 mg) / velpatasvir (100 mg) for a
duration of 12 weeks
 For
all genotype: Treatment Naïve and with
compensated cirrhosis
Genotype 1-6:
Glecaprevir (300 mg) / pibrentasvir (120 mg) taken
with food for a duration of 8 weeks
Genotype 1, 2, 4, 5, or 6: Not 3
Sofosbuvir (400 mg)/velpatasvir (100 mg) for a
Dr. Afzal Haq Asif

duration of 12 weeks
 NOTE: Patients with genotype 3 require baseline NS5A

resistance-associated substitution (RAS) testing.
Those without Y93H can be treated with 12 weeks of
sofosbuvir/velpatasvir.
If Y93H is present, see HCV guidance for treatment
recommendations. 38
07/14/2024
HCV Therapy and CKD
For patients with chronic HCV infection and
chronic kidney disease (CKD) stage 1, 2, or 3, the
following drug regimens do not require dose
adjustments
Daclatasvir 60 mg
Simeprevir 150 mg
Sofosbuvir 400 mg
Daily fixed-dose combination of elbasvir (50
mg)/grazoprevir (100 mg)
Daily fixed-dose combination of glecaprevir
(300 mg)/pibrentasvir (120 mg)
Dr. Afzal Haq Asif

Fixed-dose combination of ledipasvir (90
mg)/sofosbuvir (400 mg)
Fixed-dose combination of sofosbuvir (400
mg)/velpatasvir (100 mg)
Fixed-dose combination of sofosbuvir (400
mg)/velpatsavir (100 mg)/voxila-pre-vir (100
mg)
39
Genotype 1
Treatment-Naïve

40
41
42
43
44
Genotype 2
Treatment-Naïve

45
46
47
Genotype 3
Treatment-Naïve

48
49
50
Genotype 4
Treatment-Naïve

51
52
53
07/14/2024
Treatment-Naïve
Genotype 5 or 6
Dr. Afzal Haq Asif

54
55
07/14/2024
Treatment-
Experienced
Genotype 1
Dr. Afzal Haq Asif

56
07/14/2024
Dr. Afzal Haq Asif
RASs: Resistance Associated substitutions: Mechanism of Resistance of antiviral
drugs 57
58
59
60
61
62
+Voxilaprevir

63
+Voxilaprevir

64
+Voxilaprevir

65
07/14/2024
Treatment-
Experienced
Genotype 2
Dr. Afzal Haq Asif

66
67
68
69
07/14/2024
Treatment-
Experienced
Genotype 3
Dr. Afzal Haq Asif

70
71
72
+Voxilaprevir

73
07/14/2024
Treatment-Experienced
Genotype 4
Dr. Afzal Haq Asif

74
75
76
+Voxilaprevir

77
07/14/2024
Treatment-
Experienced
Genotype 5 or 6
Dr. Afzal Haq Asif

78
79
+Voxilaprevir

80
Patients with
decompensated
Cirrhosis
ADD ribavirin , if not increase duration to 24 hr
82
83
84
85
86
87
88
Drug Interactions
AASLD -2018 /2021
Drug interactions
AASLD 2018 /21
91
92
Pharmacology
Sofosbuvir (Sovaldi) NS5B
07/14/2024
polymerase inhibitor
• Indications:
 HCV genotypes 1, 2, 3, and 4, including those with:
 Hepatocellular carcinoma
 HCV/HIV co-infections
• Dosing: 400-mg tablet once daily with or without food

 No dosing recommendations for glomerular filtration rate (GFR)
less than 30 mL/minute
 Dose of ribavirin with Sofosbuvir
 should be reduced when used with sofosbuvir 600 mg daily
 Discontinue Ribaviren if hemoglobin is less than 8.5 g/dL
 Reduce the ribavirin dose if there is a greater than 2-g/dL
decrease in hemoglobin during any 4-week period, and
 Discontinue if hemoglobin is less than 12 g/dL, despite 4 weeks
at reduced dose.
 If GFR 30–50 mL/minute, use alternating doses of 200 and 400
Dr. Afzal Haq Asif
mg daily;
 If GFR less than 30 mL/minute or if end-stage renal
disease/hemodialysis, reduce to 200 mg/day
• Adverse effects: Fatigue, headache
• Drug interactions:
 Avoid use with potent P-glycoprotein inducers. Avasimibe,
carbamazepine, phenytoin, rifampin, St John’s
wort,tipranavir/ritonavir
94  Concentrations are significantly affected by anticonvulsants
(carbamazepine, phenytoin, phenobarbital, and oxcarbazepine),
Ledipasvir
07/14/2024
 Ledipasvir; approved in combination with sofosbuvir
(Harvoni)
 FDA indication (approved October 2014):
 Treatment of chronic HCV genotype 1 and 4 infection
as a fixed dose combination with sofosbuvir.
 Not recommended to administer with other products
containing sofosbuvir
 Dose and administration
 One tablet (90 mg of ledipasvir and 400 mg of
sofosbuvir) by mouth once daily with or without food
 No dose adjustments required for mild or moderate
renal impairment. Safety and efficacy is unknown in
those with severe renal impairment (CrCl < 30 mL/
minute) or end-stage renal disease and in dialysis.
Dr. Afzal Haq Asif

 No dose adjustments required for mild, moderate, or
severe hepatic impairment (Child Pugh Class A, B,
or C). Safety and efficacy is unknown in those with
decompensated cirrhosis.
 Formulations: Oral; 90 mg ledipasvir and 400-mg
sofosbuvir tablet
 Treatment duration: Depends on patient population; Usually
12 weeks
95
07/14/2024
Ledipasvir
• Adverse events
 The most notable adverse events
include fatigue, headache, nausea,
diarrhea, and insomnia.
 Laboratory abnormalities
 Bilirubin elevations: Greater than 1.5
times ULN in 3%, <1%, and 2% of
subjects treated for 8, 12, and 24
Dr. Afzal Haq Asif

weeks, respectively
 Lipase elevations: Asymptomatic,
transient, greater than 3 times ULN in
<1%, 2%, and 3% of subjects treated
for 8, 12, and 24 weeks, respectively
 Creatine kinase: may increase
96
07/14/2024
NS5A/B inhibitor combination
sofosbuvir /velpatasvir (Epclusa)
• Indication: Genotype 1–6 infection
• Dosing: sofosbuvir 400 mg /velpatasvir 100 mg fixed-dose

combination tablet once daily for 12 weeks. Weight-based
ribavirin is added if decompensated cirrhosis is present with
HCV genotypes 1–4.
• Adverse effects: headache and fatigue
• Drug interactions
 Contraindicated with inducers of P-gp and moderate to
potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g.,
Dr. Afzal Haq Asif

rifampin, St. John’s wort, carbamazepine), which can
decrease plasma concentrations of sofosbuvir and/or
velpatasvir.
 Avoid use of amiodarone and sofosbuvir because of
symptomatic bradycardia.
97
07/14/2024
NS3/4A inhibitor Grazoprevir
combined with
NS5A inhibitor elbasvir (Zepatier)
• Indication: Geonotypes 1 or 4 infection with or without
ribavirin
• Dosing: Grazoprevir 100 mg / elbasvir 50 mg fixed-dose

combination tablet once daily for 12 or 16 weeks.
 Testing for NS5A resistance-associated substitutions (RASs)
is recommended. If RASs are present, treatment duration
should be extended to 16 weeks, and ribavirin should be
coadministered.
 Renal dose adjustment is not necessary, including patients
receiving hemodialysis.
Dr. Afzal Haq Asif

• Adverse effects
 ALT elevations: Check ALT at baseline, 8 weeks of therapy,
and 12 weeks of therapy if 16 week duration is indicated
 Contraindicated in Child-Pugh class B or C).
 Headache, fatigue
 Contraindicated in combination with OATP1B1/3 inhibitors
(Organic anion-transporting polypeptide, strong CYP3A
inducers, and efavirenz
98
Substrates of OATP: Organic anion-
transporting polypeptide
07/14/2024
• Atorvastatin (Lipitor®) - OATP1B1,
• Lovastatin (Mevacor®) - OATP1B1
OATP1B3
• Methotrexate (Rheumatrex®) - OATP1B1,
• Bilirubin - OATP1B1, OATP1B3 OATP1B3
• Bosentan (Tracleer®) - OATP1B1 • Olmesartan (Benicar®) - OATP1B1,
OATP1B3
• Digoxin (Lanoxin®) - OATP1B3
• Paritaprevir (Viekira Pak™) - OATP1B1,
• Empagliflozin (Jardiance®) - OATP1B1, OATP1B3
OATP1B3
• Pitavastatin (Livalo®) - OATP1B1,
• Ezetimibe (Zetia®) - OATP1B1 OATP1B3
• Fexofenadine (Allegra®) - OATP1B1, • Pravastatin (Pravachol®) - OATP1B1,
OATP1B3, OATP1A2, OATP2B1 OATP2B1
• Fluvastatin (Lescol®) - OATP1B1 • Repaglinide (Prandin®) - OATP1B1
• Glyburide (DiaBeta®) - OATP1B1 • Rifampin - OATP1B1, OATP1B3 -
Dr. Afzal Haq Asif

• Rosuvastatin (Crestor®) - OATP1B1,
• Irinotecan (Camptosar®) - OATP1B1
OATP1B3
• Telmisartan (Micardis®) - OATP1B3 • Simvastatin (Zocor®, Zetia®) - OATP1B1
• Valsartan (Diovan®) - OATP1B1, • Thyroxine (Synthroid®, Levoxyl®) -
OATP1B3 OATP1B1
99
07/14/2024
NS3/4A and NS5A inhibitor combination
glecaprevir and pibrentasvir (Mavyret)
• Indications
 Genotype 1–6 infection with or without compensated cirrhosis (Child-
Turcotte-Pugh A)
 Genotype 1 infection in patients who have previously been treated
with either an NS5A inhibitor or an NS3/4A inhibitor, but not both
• Dosing: glecaprevir 100 mg / pibrentasvir 40mg fixed dose combination

tablet, three tablets once daily with food for:
 Eight weeks for genotype 1–6 treatment-naive patients without
cirrhosis
 Twelve weeks for genotype 1–6 treatment-naive patients with
compensated cirrhosis
Dr. Afzal Haq Asif

 Eight to 16 weeks for patients previously treated, depending on prior
regimen
• Adverse effects: headache, fatigue, nausea
• Drug interactions: Avoid use with P-gp or CYP3A inducers, because this
can reduce the concentration of glecaprevir and pibrentasvir
(carbamazepine, efavirnez, St. John’s wort). It is contraindicated with
atazanavir or rifampin.
10
NS5B/A polymerase inhibitors
07/14/2024
sofosbuvir (Sovaldi) and
sofosbuvir/ledipasvir (Harvoni)
• Indications
 Sofosbuvir: HCV genotypes 1, 2, 3, and 4, including those with
hepatocellular carcinoma meeting Milan criteria and those with
HCV/HIV coinfections
 Sofosbuvir/ledipasvir: genotype 1, 4, 5, or 6 infection
• Dosing: 400-mg tablet once daily with or without food

 Sofosbuvir renal dosing: no dosing recommendations for
glomerular filtration rate (GFR) less than 30 mL/minute
 Dose reductions for ribavirin
 When used with sofosbuvir according to U.S. prescribing
information, ribavirin 600 mg daily is recommended for
patients with no cardiac disease if hemoglobin is less than 10
Dr. Afzal Haq Asif

g/dL, and recommendations are to discontinue if hemoglobin is
less than 8.5 g/dL. In patients with stable cardiac disease,
reduce the ribavirin dose if there is a greater than 2 g/dL
decrease in hemoglobin during any 4-week period, and
discontinue if hemoglobin is less than 12 g/dL, despite 4 weeks
at reduced dose.
 When used with sofosbuvir according to the 2016
AASLD/Infectious Diseases Society of America (IDSA)
guidelines: For GFR 30–50 mL/minute, use alternating doses of
200 and 400 mg daily; for GFR less than 30 mL/minute or with
end-stage renal disease or hemodialysis, reduce to 200 mg/day. 10
07/14/2024
NS5B/A polymerase inhibitors sofosbuvir
(Sovaldi) and sofosbuvir/ledipasvir (Harvoni)
(Continued)
• Adverse effects: fatigue, headache

 Avoid use with potent P-glycoprotein
inducers.
 Concentrations are significantly affected by
anticonvulsants (carbamazepine, phenytoin,
phenobarbital, and oxcarbazepine), rifabutin,
rifampin, St. John’s wort, and tipranavir/
Dr. Afzal Haq Asif

ritonavir.
 Avoid using with amiodarone because of
symptomatic bradycardia. The mechanism
of this interaction is not known.
10
07/14/2024
Ribavirin adverse effect
monitoring
• Oral nucleoside analog
• Available as 200-mg tablets (Copegus) or capsules (Rebetol)
• Adverse Effect
 Hemolytic anemia:
 Upto 10% of patients (usually within 1–2 weeks of initiating
therapy):
 decrease dose to 600 mg/day when hemoglobin drops to 10 g/dL
or less, and discontinue when hemoglobin drops to 8.5 g/dL or
less
 May worsen underlying cardiac disease;
Dr. Afzal Haq Asif

 Monitor complete blood cell count (CBC) at baseline, 2 weeks, 4
weeks,
 Decrease dose to 600 mg/day if hemoglobin drops more than 2 g/dL
in any 4-week period during treatment.
 May use epoetin or darbepoetin to stimulate red blood cell
production, improve anemia
103
Ribavirin adverse effect
07/14/2024
monitoring
• Teratogenicity: Category X drug;
 Requires a negative pregnancy test at baseline and every
month up to 6 months after treatment,
 Use of two forms of barrier contraception during
treatment and for 6 months after treatment.
• Contraindicated in patients with a creatinine

clearance (CrCl) less than 50 mL/minute
• pancreatitis, pulmonary dysfunction (dyspnea,
Dr. Afzal Haq Asif

pulmonary infiltrate, and pneumonitis), insomnia,
irritability or depression (often referred to as “riba
rage”), and pruritus.
104
HIV and HCV co infection
07/14/2024
• 30% HIV patient also have HCV infection
• Rapid progression of liver damage
• SVR is lower as compared to HVC alone
• A threshold CD4 count of at least 350 cells/μL has been suggested for
initiation of antiviral therapy;
• Treatment is not recommended if CD4 counts lower than 200

cells/mL.
• Adverse effects are more common:

 Anemia with Ziduvodine and Ribavirin combination
 Mitochondrial toxicity, pancreatitis, liver failure, and death ; more
common with Didanosine and Ribavirin combination
Dr. Afzal Haq Asif

• ???? Liver transplant
• Assignment: Please read the following and prepare for exam:
• http://www.hcvguidelines.org/full-report/unique-patient-populations-
patients-hivhcv-coinfection
105
Liver Transplant. Is this a
07/14/2024
solution?
• Most common indication in US:
 Hepatitis C virus–related end-stage liver disease
• Outcome:
 Recurrence is essential outcome
 Progression of liver disease is accelerated, Within 5
years after transplantation, 20% to 40% of liver
allografts progress to cirrhosis;
 60% to 70% of cirrhotics experience hepatic
decompensation within 3 years
Dr. Afzal Haq Asif

 Response rates to pegIFN and ribavirin treatment after
liver transplant are lower than for patients in the
pretransplant setting,
 Drug toxicity remains a limiting factor. 1/3 require
discontinuation
106
Patient care and
07/14/2024
education-1
• Educate patient for risk factors for acquiring hepatitis
• Educate patient about hepatotoxic drugs
• Educate regarding vaccination against A & B
• Obtain thorough PMH regarding psychiatric, cardiac,

endocrine and renal disorders
• Assess fro adverse effects periodically
• Encourage for medication compliance to increase SVR
Dr. Afzal Haq Asif

• Encourage fluid intake to avoid dehydration
• Educate all women of child bearing age, and men who are
able to father a child to use 2 forms of contraception
during and 6 months after therapy
107
Patient care and
07/14/2024
education contd-2
• Provide patient education:
 How to prevent viral hepatitis
 Importance of taking all medication daily at
scheduled time
 Adverse effects of medications
 How to self administer pegylated interferon
injection correctly
 Importance of appropriate disposal of used
Dr. Afzal Haq Asif

injection
108
Monitoring
07/14/2024
Before Therapy
• Before initiating HCV therapy
 The following laboratory tests are
recommended any time before therapy
initiation:
 HCV genotype and subtype, quantitative
HCV viral load (if quantification will
influence therapy duration may need to
obtain laboratory measurement within a
few weeks of therapy initiation).
 Assess potential for drug-drug

Dr. Afzal Haq Asif
interactions.
 The following laboratory tests are
recommended within 12 weeks of
therapy initiation:
 CBC, INR, hepatic function panel,,
calculated GFR.
11
07/14/2024
Monitoring During and after Therapy

• Assessment of medication adherence,
• monitoring of adverse effects,
• potential for drug-drug interactions.
• The following laboratory tests are recommended

within 4 weeks of initiation therapy:
 LFT, CBC, creatinine concentration, calculated
GFR, hepatic function panel. Consider
increasing the frequency if regimen contains
medications with increased likelihood for drug-
related toxicities, such as ribavirin (may need
to obtain CBC more often for example).
HCV quantitative viral load

Dr. Afzal Haq Asif
•
 After 4 weeks of therapy and
 12 weeks after therapy is completed.
 At the end of treatment and
 24 weeks after therapy is completed.
111
07/14/2024
When to discontinue anti-
viral therapy…
• Monitor HCV quantitative viral load .
 If HCV quantitiative viral load is detectable at week 4 of
treatment, repeat test after an additional 2 weeks (i.e.,
treatment week 6).
 If threatment week 6 viral load has increased by greater
than 10-fold (>1 log10 IU/mL), it is recommended to
discontinue therapy.
Dr. Afzal Haq Asif

11
07/14/2024
• Pregnancy-related issues
while receiving ribavirin
 Women of childbearing
potential should have serum
pregnancy test before initiation
of therapy if regimen contains
ribavirin. For pregnant on
 Contraception use and possible
RBV
pregnancy should be assessed
during therapy at appropriate
intervals and for 6 months
Dr. Afzal Haq Asif

after the completion of
treatment for women of
childbearing potential and for
female partners of men who
receive ribavirin.
11
07/14/2024
References
• AASLD Guidelines Nov 2018, (American
Association for the Study of Liver Diseases)
guidelines-2018/2021
• Pharmacotherapy Handbook 11the ed. 2021
Dr. Afzal Haq Asif

114
Click icon to add picture
07/14/202
Thank
You
Very
Much
Dr. Afzal Haq Asif

116

hepatitisc-230507225140-296062d3 (1)

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

hepatitisc-230507225140-296062d3 (1)

Uploaded by

Copyright:

Available Formats

Clinical Case

Dr. Afzal Haq Asif

• USG: Liver size a little decreased, no nodule or cirrhotic changes

Dr. Afzal Haq Asif

HCV is a single stranded RNA virus

Genus Hepa-civirus, (HCV)

Characterized by a high spontaneous mutation rate

11 genotypes (90 sub-types) , (1a, 1,b, 2a, 3b etc)

Genotype 2 (11.0%). are responsible for

Mainly blood-borne (transfusion, intravenous drug abuse)

High risk: Transfusion, intravenous drug abuse

Body piercing and acupuncture with unsterilized needle

Dr. Afzal Haq Asif

• Genotype 1 is associated with higher viral replication,

Immune mediated cell injury:

• CD8+ and CD4+ lymphocytes in portal, peri-portal, and

Acute: less than 6 months

Chronic: more than 6 months

• Extrahepatic disease (e.g., cryoglobulinemia, glomerulonephritis) may also be

• Moderate to severe hepatitis in 30% <20 years of age

 Factors for cirrhosis: obesity, diabetes, heavy

Dr. Afzal Haq Asif

• Clearance of acute HCV infection occurs within 6 months

• Only 11% of those who remain viremic at 6 months will

• Patients who have spontaneously cleared should not be

• However, they should be counseled about the possibility of

Dr. Afzal Haq Asif

• Thus, a single undetectable HCV RNA test result is

• Serum anti-HCV antibodies:

• Serum HCV RNA: can be detected 2 weeks post

diagnosis 98% specificity

• Liver biopsy: for cirrhosis, prognosis

• ALT: Non specific

• Genotype: for treatment duration and response

Who should be screened

• Persons with conditions of a high prevalence of HCV infection

• Prior recipients of transfusions or organ transplants prior to July

 Persons who received an organ transplant

• Children born to HCV-infected mothers

• Health care, emergency medical and public safety workers after a

• Current sexual partners of HCV-infected persons

• HAV and HBV vaccine to prevent further

Avoid sharing toothbrushes and dental or shaving equipment

Cover any bleeding wound to prevent possibility of others coming

Counsel to avoid using illicit drugs and enter substance abuse

Counsel to avoid reusing or sharing syringes, needles, or any

Avoid donating blood

In those coninfected with HIV, consider using barrier precautions

Proper cleaning of contaminated surfaces with a dilution of 1 part

21 Always wear gloves when cleaning up blood spills

• Eradicate HCV infection in acute

• Attain Sustained Virologic Response (SVR) inChronic

Decrease HCV associated morbidity and mortality

Normalize biochemical markers

Improve clinical symptoms

Prevent progression to cirrhosis and HCC

Prevent development of end stage liver disease

Dr. Afzal Haq Asif

Dr. Afzal Haq Asif

Pretreatment Assessment: Medication & Labs

 Education: Educate the patient about proper

 Pretreatment laboratory testing:

• Monitoring for hypoglycemia is recommended.

• Inform patients taking warfarin of the potential for changes in