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Management of HCV 2023 -Adem.pptx
1. Management of hepatitis c
virus infection
presenter: Dr. Adem. S (R3)
Moderator Dr Ahmed. A (MD,Internist)
Dr. Abdikadir (MD,Gastroenterologist)
1/5/2024 1
3. INTRODUCTION
• HCV infection is one of the common causes of CLD
worldwide.
• It was labeled as “non-A, non-B hepatitis” (In 1960s)
• Identified as Hepatitis C virus in 1989
• ~71 million individuals chronically infected worldwide
• Combination therapy with DAAs has altered the treatment
landscape dramatically
• Is the only chronic viral infection that can be cured by
antiviral therapy
1/5/2024 3
4. VIROLOGY
HEPATITIS C VIRUS,
• Is a linear, single-strand, positive-sense, 9600-
nucleotide RNA virus
• HCV is the only member of the genus
Hepacivirus in the family Flaviviridae.
• The HCV genome contains a single gene that
codes for a virus polyprotein of ~3000 amino
acids, which is cleaved after translation to yield
10 viral proteins.
• 50- to 80-nm virus particles
1/5/2024 4
6. Viral Replication and Life Cycle
• Hepatocytes are the major site of viral replication.
• HCV entry ivnvolves the attachment of envelope proteins E1 and E2 to cell
surface molecules.
• The expression and function of CD81, a member of the tetraspan
superfamily, is essential for HCV entry into hepatocytes.
• In addition, human scavenger receptor class B type 1, a selective
importer of cholesteryl esters from HDL into cells, has been shown to
interact with E2 and is also essential for HCV entry.
• CD81 and scavenger receptor class B type 1 are required early in the
process of viral entry, claudin-1, on hepatocytes, and occludin are
required later in the cell entry process
1/5/2024 6
8. HCV Genotypes and quasipecious
8
Genotype
Subtype
Isolate
Quasispecies
30 – 50%
15 – 30%
5 – 15%
1– 5%
Classification % Nucleotide difference
• There are 6 major HCV genotypes
• Subtypes designated by
letters (e.g. a, b, etc.)
• Different Genotypes are
associated with:
Treatment options
Treatment duration
Treatment outcomes
• GT1/4 were hardest to treat with
IFN-based regimens, but very
effectively treated with DAAs
• GT3 (especially with cirrhosis) is
the most difficult to treat with
DAAs
Within an individual
1/5/2024
10. Phylogenetic analysis revealed that
the predominant was genotype 4
(77.6%) followed by 2 (12.2%),1
(8.2%), and 5 (2.0%)
Seven subtypes were identified (1b,
1c, 2c, 4d, 4l, 4r and 4v), with
4d(34.7%), 4r (34.7%) and 2c (12.2%)
as the most frequent subtypes
genotype 4 is considered to be
difficult to treat
1/5/2024 10
11. Epidemiology
• The worldwide prevalence of HCV infection, is estimated to be
1%,
• more than 71 million people infected chronically.
• The overall worldwide prevalence increased from 1990 to
2010.
• Marked geographic variation exists, with infection rates
ranging from 0.1% in the Netherlands, Fiji, and Samoa, to
0.9% in the USA, 6.3% in Egypt, and 7% in Gabon.
•
• The prevalence is higher in males (2.1%) than in females
(1.1%), and in African Americans (3%) than in whites (1.5%).
1/5/2024 11
12. Ethiopia
1/5/2024 12
• MOH 2022
• Majorities of the study
subjects were female
(Range, 48- 73.4% of the
study population).
• The prevalence of HCV
among adult HIV infected
population was ranging
from 3.1% to 10.5%
• Overall, the prevalence
of HCV infection among
all the subjects was 4.9%.
13. Transmission
• Percutaneous (blood transfusion and needlestick
inoculation)
• Transmission Blood transfusion (before the introduction of
screening)
• Injection drug use
• Chronic hemodialysis is also associated with increased
rates of HCV infection
• Nosocomial transmission
• Occupational transmission
• Procedures involved in folk medicine (eg, scarification,
cupping), tattooing, body piercing, and commercial
barbering,
1/5/2024 13
14. Cont.
• Nonpercutaneous Transmission
• Sexual transmission of HCV can occur
• Perinatal transmission of HCV infection is low
• Transmission from breastfeeding is negligible to small
• Sporadic HCV Infection
1/5/2024 14
16. Pathogenesis
• Chronic hepatitis develops in 50% to 90% of persons with
acute HCV infection
• Determinants of persistence of HCV include
the evasion of immune responses through several viral
mechanisms;
inadequate induction of the innate immune response;
insufficient induction or maintenance of an adaptive
immune response;
the production of viral quasispecies;
the induction of immunologic tolerance or exhaustion.
1/5/2024 16
17. Mechanism of hepatocellular injury
• VIRAL MECHANISM
• the immune response is essential in preventing viral
persistence, in those without viral clearance the immune
response mediates hepatic cell destruction and fibrosis
• In chronically infected patients, the pathogenesis of liver
damage is largely immune mediated.
• In a small subset of immunocompromised HCV-infected
patients , however, a syndrome termed fibrosing
cholestatic hepatitis develops
• Such cases are thought to result from direct viral
hepatotoxicity of infected cells,
– viral levels are typically greater than 30 million
copies/mL and hepatocytes contain enormous
concentrations of virus and viral proteins
1/5/2024 17
18. Cont.
• Immune-Mediated Mechanisms
• HCV infection elicits an immune response in the host that
involves both an initial innate response and a subsequent
adaptive response.
• The innate response is the first line of defense against the virus
and includes
• such as natural killer (NK) cell activation and cellular antiviral
mechanisms triggered by pathogen-associated molecular
patterns recognized by the cell .
• NK cells, as the effector cells of the innate immune system,
also produce TNF-β and IFN-α, cytokines that are critical for
dendritic cell maturation and subsequent induction of adaptive
immunity.
1/5/2024 18
19. Cont.
• NK cells can also attack virus-infected cells directly, as do
other immune cells by different effector molecules
• Subsequently, however, the virus initiates a number of
mechanisms that undermine the ability of the host to
control the infection.
• NK cells do not adequately activate dendritic cells, and as
a result, the priming of CD8 + and CD4 + T cells in HCV-
infected patients is inadequate.
• Cross-reactivity between viral antigens and host
autoantigens has been invoked to explain the
association between hepatitis C and a subset of
patients with autoimmune hepatitis and antibodies to
liver-kidney microsomal (LKM) antigen (anti-LKM)
1/5/2024 19
20. Pathology
The typical morphologic lesions of all types of viral hepatitis
are similar and consist of
1. Pan-lobular infiltration with mononuclear cells .
the mononuclear infiltration consists primarily of small
lymphocytes, although plasma cells and eosinophils
occasionally are present.
2. hepatic cell necrosis,
3. hyperplasia of Kupffer cells, and
4. variable degrees of cholestasis.
In uncomplicated viral hepatitis, the reticulin framework is
preserved.
1/5/2024 20
21. Cont.
In hepatitis C, the histologic lesion is often remarkable for
• a relative paucity of inflammation,
• a marked increase in activation of sinusoidal lining cells and
• lymphoid aggregates,
• the presence of fat (more frequent in genotype 3 and linked
to increased fibrosis),
• bile duct lesions - biliary epithelial cells appear to be piled up
without interruption of the basement membrane.
1/5/2024 21
22. Clinical manifestations
Acute Hepatitis C
• HCV accounts for an estimated 20% of cases of acute
hepatitis.
• the majority of patients remain asymptomatic during the
acute phase and most infected persons do not become
aware of their disease.
• HCV RNA becomes detectable in serum within 7 to 21 days
after viral transmission.
• longer incubation periods can occur, especially in cases in
which only a small amount of virus has been transmitted
(15-160 days).
1/5/2024 22
23. Cont.
• HCV RNA levels rise rapidly in serum after infection,
followed by a delayed increase in serum ALT levels 4 to 12
weeks after infection.
• Serum ALT levels frequently reach values more than 10
times the upper limit of normal, with concomitant rises in
the serum bilirubin level in some individuals .
• Some patients also develop clinical symptoms 2 to 12
weeks after viral transmission
1/5/2024 23
24. Cont.
• most of the clinical symptoms are nonspecific. includes
fatigue, nausea, abdominal pain, loss of appetite, mild fever,
itching, myalgia.
• Jaundice, which is the most specific liver-related symptom,
develops in 50% to 84%.
• ALF caused by HCV has been reported in only single cases, in
contrast to infections with other hepatotropiviruses
• coinfection with HBV or HIV/alcoholic -more apparent and
severe presentation.
1/5/2024 24
26. Cont.
The rate of viral persistence after acute infection ranges
from 45% -90%.
Risk factors for persistence,
• Older > younger
• Male > female
• Blood transfusion > PWID (source of infection)
• Size of inoculum
• Immune status of the host
• African Americans > whites (race)
• Asymptomatic > symptomatic
1/5/2024 26
27. Cont.
Chronic Hepatitis C
• Most patients with chronic hepatitis C are asymptomatic
before the onset of advanced hepatic fibrosis.
• often complain of nonspecific symptoms such as fatigue,
vague abdominal pain, or depression and score lower in
all aspects of health-related quality of life
• Serum ALT levels are usually elevated in patients with
chronic HCV infection.
1/5/2024 27
28. Cont.
• The ALT level may remain normal for prolonged periods of
time in about 20% of cases, although transient elevations
occur even in these cases.
• Persistently normal ALT levels are more common in
women, and such cases typically are associated with lower
serum HCV RNA levels and
• less inflammation and fibrosis on liver biopsy specimens.
• Less common symptoms may include arthralgias,
paresthesias, myalgias, sicca syndrome, nausea, anorexia,
and difficulty with concentration
1/5/2024 28
33. Diagnosis
• Several immunologic and molecular assays are used to detect
and monitor HCV infection.
• Anti-HCV usually persists for many years in patients after
spontaneous resolution of infection or an SVR following
antiviral therapy.
• Anti-HCV titers may decline over time, however, and can
become undetectable 5 to 20 years after HCV clearance.
• Serologic assays are used initially for diagnosis, whereas
virologic assays are required for confirming infection,
monitoring response to treatment, and evaluating
immunocompromised patients.
1/5/2024 33
34. Indirect assays
• EIAs detect antibodies against different HCV antigens
• The third-generation EIAs detect antibodies against HCV
core, NS3, NS4, and NS5 antigens as early as 7 to 8 weeks
after infection, with sensitivity and specificity rates of 99%.
• Despite ongoing viral replication, serologic test results can
be negative in patients who are on hemodialysis or are
immunocompromised.
• patients who are anti-HCV positive should undergo HCV
RNA testing to determine if they have active viremia or
have cleared the infection.
1/5/2024 34
35. Direct assays
• Quantitative, highly sensitive, “real-time” HCV RNA tests
represent the state of the art for determining HCV viremia
in anti HCV–positive persons.
• The lower limit of detection of most assays varies from 10
to 15 IU/mL.These assays have a linear dynamic range of 1
to 7 log10 IU/mL and are the preferred testing method in
practice.
• The advantages of these very sensitive tests include
positivity within 1 to 3 weeks after acute infection and
detection of low-level residual infection during antiviral
therapy.
• A cheaper and faster alternative to nucleic acid testing for
HCV RNA to confirm HCV viremia is the HCV core antigen
assay. but with major limitations in sensitivity.
1/5/2024 35
38. HCV Genotype
1/5/2024 38
Identifying the genotype and subtype of HCV is important because some
DAA regimens are only recommended for certain HCV genotypes and
subtypes.
The most accurate approach uses PCR methodology and direct sequencing
of the NS5B or E1
PCR amplification of the 5′ noncoding region of the HCV genome.
A line-probe assay (INNO-LiPA) using genotype-specific probes for reverse
transcription of the 5′ portion of the HCV genome is the most popular
commercial assay for HCV genotyping.
39. LIVER BIOPSY
AND
NONINVASIVE
ASSESSMENT
OF FIBROSIS
1/5/2024 39
• The presence or absence of cirrhosis also
influences the choice and duration of
treatment
• Therefore, an assessment of the degree of
liver injury is recommended in all patients
with HCV infection
43. cont.
Goal of HCV therapy
• The goal of therapy is to cure HCV infection
• Prevent the complications of HCV-related liver and
extrahepatic diseases
• Improve quality of life and remove stigma
• Prevent onward transmission of HCV (treatment as
prevention or “TasP”).
1/5/2024 43
44. TREATMENT: WHOM TO TREAT
– All patients with HCV infection must be considered for therapy
– Treatment should be considered without delay in patients with:
• Significant fibrosis or cirrhosis
• Significant extra-hepatic manifestations
– Rx is not recommended in patients with limited life expectancy
due to non-liver-related comorbidities. (<12month)
1/5/2024 44
45. Endpoint of HCV therapy
• The endpoint of HCV therapy is an SVR,
• defined by undetectable HCV RNA in serum or plasma 12
weeks (SVR12) or 24 weeks (SVR24) after the end of
therapy, by a sensitive molecular method with a lower
limit of detection ≤15 IU/ml
• Undetectable HCV core antigen 12 or 24 weeks after the
end of therapy can be used as an alternative to HCV RNA
testing to define SVR12 and SVR24, respectively, in
patients with detectable HCV core antigen before
treatment.
1/5/2024 45
46. Drugs
Interferon
• IFN-based regimens became the cornerstone of antiviral
therapy for HCV infection in the late 1980s.
• IFNs are naturally occurring glycoproteins that exert a wide
array of antiviral, antiproliferative, and immunomodulatory
effects.
• Pegylated IFNs consist of IFN bound to (PEG) of varying
length. The large size of the molecule increases the half-life of
the IFN, thereby allowing once-weekly dosage.
• Pegylated IFNs replaced standard IFN, used in the past, and
resulted in a significant increase in the SVR.
• The use of IFN has been succeeded by IFN-free DAA
regimens.
1/5/2024 46
47. Cont.
Ribavirin
• RBV is an oral guanosine analog with activity against DNA
and RNA viruses.
• is still used with some DAA regimens in more difficult to
treat patients, such as genotype 3, cirrhosis, and prior
treatment failure.
• RBV generally is well tolerated, although it results in a
dose-dependent hemolytic anemia.
• The dose administered is based on the patient’s weight,
and the patient’s Hgb level must be monitored during
treatment.
1/5/2024 47
48. Cont.
Direct-acting antivirals
• Novel DAAs against HCV include compounds that target the
HCV NS3/NS4A protease, the HCV NS5A protein, and the HCV
NS5B polymerase.
• These drugs inhibit HCV replication by interfering with the
respective steps in the HCV life cycle.
An ideal DAA regimen should have
Activity against all HCV genotypes; have high antiviral
potency
Good oral bioavailability, allowing once daily dosing;
Possess few drug-drug interactions (DDIs); be well tolerated
with minimal toxicity;
Have a high barrier to resistance.
1/5/2024 48
53. Sofosbuvir/velpatasvir
1/5/2024 53
• fixed-dose combination (FDC) of a pangenotypic NS5A inhibitor and
sofosbuvir. It was approved both by the (FDA) and (EMA) in 2016.
• In clinical trials it is associated with high efficacy against infections with
• Genotypes 1–6, HIV/HCV coinfection,
• Persons on opioid agonist maintenance therapy (OAMT) persons
with compensated or decompensated cirrhosis
• High efficacy with genotype 4 non-A/D subtypes, which are endemic
in some regions of sub-Saharan Africa
54. Glecaprevir/pibrentasvir
1/5/2024 54
• FDC containing a pangenotypic NS3/4A protease inhibitor with a
pangenotypic NS5A inhibitor. The FDA and EMA approved it in 2017
• IN clinical trials it is associated with high efficacy against infections
with
• Genotypes 1–6 and compensated cirrhosis
• Persons with renal insufficiency and end-stage renal disease
• The regimen is contraindicated in persons with decompensated
cirrhosis (Child–Pugh Class C) because of high exposure to the
protease inhibitor.
55. Sofosbuvir/daclatasvir
1/5/2024 55
• Was approved by the EMA in 2014 and by the FDA in 2015.
• Clinical trials reported high efficacy of the combination of daclatasvir and
sofosbuvir in infections with
• genotypes 1–6,
• persons with decompensated liver disease,
• liver transplant recipients and those with HIV/HCV coinfection .
• less effective against genotype 4 non-A/D subtypes,endemic in some
regions of sub-Saharan Africa, genotypes 1 and 3 which frequently contain
RAS in the NS5A
64. Simplified HCV Treatment for Treatment-
Naive Adults
1/5/2024 64
The current update to the simplified treatment algorithms features
Reduced pretreatment and on-treatment clinician intervention
Expanded eligibility of persons who can be treated using these approaches.
Suggest that a minimal on treatment monitoring approach ( four
components)
No pretreatment genotyping,
Dispensing the entire treatment course at entry,
No scheduled ontreatment visits or laboratory monitoring,
Remote contact at week 4 to assess DAA adherence and SVR at
week 24)
67. DAAS Recommendation without
cirrhosis
1/5/2024 67
• Recommended DAA regimens for this simplified treatment
approach include
• Glecaprevir (300 mg)/pibrentasvir (120 mg) FOR 8 weeks
• Sofosbuvir (400 mg)/velpatasvir (100 mg) ) taken with food FOR
12 weeks
68. Simplified for HCV treatment among HCV
treatment-naive adults with compensated
cirrhosis
1/5/2024 68
69. Treatment recommendations compensated
cirrhosis
1/5/2024 69
• Recommended DAA regimens for this simplified treatment approach
include of
• Glecaprevir (300 mg)/pibrentasvir (120) mg taken with food FOR 8 weeks
genotypes 1 through 6 with SVR12 was 98%
• Sofosbuvir (400 mg)/velpatasvir (100 mg) FOR 12 weeks for genotypes 1,
2, 4, 5, or 6. SVR12 was 96 %
• Sofosbuvir/velpatasvir/voxilaprevir may be used as an alternative regimen
for persons with genotype 3 for 12 weeks SVR 12 was 96%
71. TREATMENT GUIDLINE FOR
DECOMPENCATED CIRRHOSIS
1/5/2024 71
• Pretransplant antiviral therapy for patients with:
• Compensated cirrhosis and HCC
• Decompensated cirrhosis but no HCC when the MELD score is relatively
low (eg,20) ,SPHN that warrant prompt transplantation
• Decompensated cirrhosis and HCC when expected wait time for
transplantation is > 3- 6M
• Defer antiviral therapy until post-transplant for patients with
• Advanced decompensated cirrhosis with an anticipated wait time <
3months
• Decompensated cirrhosis and HCC with an anticipated wait time < 3 to
6months
•
72. DAAs for Decompensated cirrhosis
1/5/2024 72
• Sofosbuvir-velpatasvir plus weight-based ribavirin for 12 weeks
(100 % SVR)
• Ledipasvir-sofosbuvir plus weight based ribavirin for 12 weeks
(SVR 97% )
• FOR ribavirin contraindicated we can use rebavirin free for 24
weeks
75. Retreatment
1/5/2024 75
• WHY virologic failure ?
• Adherence
• Administration
issue
• Drug interactions
• IS it relapse or treatment
failure ?
• Role of genetics testing
76. Sofosbuvir-based Regimen Failure
1/5/2024 76
• Generally, persons who have experienced treatment failure with a
sofosbuvir-based regimen should be retreated
• Sofosbuvir/ velpatasvir / voxilaprevir for 12 weeks
• Glecaprevir/pibrentasvir for 16 weeks can be used as an alternative
retreatment regimen .
• Sofosbuvir/ velpatasvir/ voxilaprevir FOR genotype 3 infection and
compensated cirrhosis for whom the addition of weight-based ribavirin to
the regimen for 12 weeks is recommended.
77. Glecaprevir/ Pibrentasvir Failure
1/5/2024 77
• Glecaprevir/pibrentasvir plus ribavirin and sofosbuvir for 16 wks is
a recommended retreatment option.
• Glecaprevir (300 mg)/pibrentasvir (120 mg) plus sofosbuvir (400
mg) and twice daily weight-based ribavirin
79. Special populations
1/5/2024 79
Acute HCV Infection
• The recommendation that persons with confirmed acute HCV
infection (HCV RNA–positive) should be treated the same as
those with chronic HCV infection without awaiting possible
spontaneous clearance
• treatment of this key population is critical to both HCV
prevention and elimination
80. Cont.
1/5/2024 80
HCV in pregnancy
• Although there have been no published large-scale clinical trials
to evaluate the safety of DAA therapy during pregnancy,
smaller studies and case series have not demonstrated any
safety concerns .
• The Guidance Panel suggests that DAA treatment may be
considered during pregnancy on a case-by-case basis after a
discussion of potential risks and benefits
82. Cont.
TREATMENT OF HBV-HCV coinfection
• HBV and HCV coinfection may result in an accelerated
disease course.
• HCV is considered to be the main driver of disease.
• Persons coinfected with HBV and HCV can be treated with
the same antiviral therapy for HCV; SVR rates are likely to be
similar to those in HCV-monoinfected persons.
• There is risk of HBV reactivation- may require treatment
with concurrent anti-HBV antiviral therapy.
1/5/2024 82
83. Cont.
TREATMENT OF HCV/CKD PATIENTS
• Chronic hepatitis C is independently associated with the development of
chronic kidney disease.
• A meta-analysis demonstrated that chronic HCV infection was associated
with a 51% increase in the risk of proteinuria and a 43% increase in the
incidence of CKD.
• There is also a higher risk of progression to end-stage renal disease
(ESRD) in persons with chronic HCV infection and CKD, and an increased
risk of all-cause mortality in persons on dialysis
1/5/2024 83
87. Indications for discontinuation
• A ≥10-fold increase in ALT activity at any time during
treatment
• An increase in ALT < 10-fold that is accompanied by any
weakness, nausea, vomiting, jaundice, or significantly
increased bilirubin, ALP, or INR
• ASYMPTOATIC increases in ALT <10-fold should be closely
monitored with repeat testing at 2-weeks intervals and if
levels remain persistently elevated should be discontinued
Check basic lab tests (CBC, Cr with eGFR, liver enzymes and
bilirubin at week 4 of treatment with any regimen.
1/5/2024 87
88. Prevention
• Early treatment
• Halt transmissions
vaccine
• Currently, hepatitis C vaccination is not feasible practically.
• Genotype and quasispecies viral heterogeneity, as well as
rapid evasion of neutralizing antibodies by this rapidly
mutating virus, conspire to render HCV a difficult target for
immunoprophylaxis with a vaccine.
1/5/2024 88
89. References
• Sleisinger and fordtan 11th gastroenterology and hepatology
• HARRISON’S PRINCIPLES OF INTERNAL MEDICINE, 21 TH EDITION
• Hepatitis C Guidance 2023 Update: IDSA & AASLD
• Hepatitis C Guidance 2022 Update: IDSA & AASLD
• EASL Hepatitis C management guideline 2021
• UP To Date 2023
1/5/2024 89
blood mononuclear cells, B cells, T cells, and dendritic cells hepatocytes are the major site of viral replication.
The other pre-treatment assessment that is optional is to assess the genotype of the patient, so I’d like to just review some basics around the diversity of HCV and its relevance for clinical management.
#Intravenous drug use is the most common route of transmission for genotype 4 infection in Europe while unsafe medical practice cause most cases in endemic countries. In Ethiopia, although we did not assess the risk concerning genotype 4 in the present study, we suggest that sharing contaminated needles and razor blades during tattooing, body piercing, scarification, and circumcision may be the main mode of transmission, as these are common practices particularly in rural Ethiopia.
Finally, cross-reactivity between viral antigens (HCV NS3 and
NS5A) and host autoantigens (cytochrome P450 2D6) has been
invoked to explain the association between hepatitis C and a subset
of patients with autoimmune hepatitis and antibodies to liver-kidney
microsomal (LKM) antigen (anti-LKM)
Liver cell damage consists of
hepatic cell degeneration and necrosis,
cell dropout,
ballooning of cells, and
acidophilic degeneration of hepatocytes (forming so-called Councilman or apoptotic bodies).
Hepatic cell regeneration is present, as evidenced by numerous mitotic figures, multinucleated cells, and “rosette” or “pseudo-acinar” formation.
the rate of spontaneous clearance is higher in symptomatic patients in whom jaundice develops during acute infection than in those who remain asymptomatic
Several immunologic and molecular assays are used to detect and monitor HCV infection.
The presence of anti-HCV in high titer in serum ([EIA] ratio > 9) indicates exposure to the virus but does not differentiate among acute, chronic, and resolved infection
If viremia needs just to be confirmed, however, HCV core antigen testing is a reasonable alternative to HCV RNA testing.
Regimen selection Depends on:
Efficacy(>90%SVR)
Duration
Adverse effect profile
Potential drug interactions
History of previous treatment
Stage of fibrosis
Insurance and financial issue
Both ribavirin and pegylated interferon require dose adjustment in persons with renal failure