This guideline has been approved by the Saudi Association for the Study of Liver diseases
and Transplantation and represents the position of the Association.
These practice guidelines have been written to assist physicians and other health
care providers to aid in the recognition, diagnosis, and management of chronically
infected hepatitis C virus (HCV) patients. They are based on a formal review and analysis
of published literature on the topic that impact the management of chronic HCV infection,
and the experience of the authors in hepatitis C. In addition, various international
practice guidelines and consensus documents on management of chronic hepatitis C were
considered in the development of these guidelines. The recommendations contained herein
suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects
of care related to the disease.
Our understanding of the natural history of HCV infection and the potential for therapy
of the resultant disease is continuously improving. However, despite the increasing
knowledge, areas of uncertainty still exist and therefore clinicians, patients, and
public health authorities must continue to make choices on the basis of the evolving
evidence. Therefore, these guidelines are intended to be flexible and may be updated
periodically as new information becomes available.
MATERIALS AND METHODS
The Saudi Association for the Study of Liver diseases and Transplantation (SASLT)
formed a task force to evaluate the current epidemiology, trends in, and management
of the hepatitis C virus (HCV) infection in Saudi Arabia. A majority of the members
of the committee were hepatologists.
The first step was a broad literature search of published literature on every aspect
of the epidemiology, natural history, risk factors, diagnosis and management of HCV.
All available literature on the topic was examined critically, and the available evidence
was then classified according to its importance.
The contents of the resulting document, including the recommendations contained in
it, have been discussed in detail and agreed upon by members of the SASLT task force.
The document was also reviewed by a content expert from another country and valuable
additional input was incorporated. Subsequently, and after review by the board of
directors, the guidelines were approved and endorsed by SASLT.
All recommendations in these guidelines are based on the best available evidence,
and tailored to patients treated in Saudi Arabia. They are graded on the basis of
evidence.
The purpose of these guidelines is to improve HCV patient care in the Kingdom, and
to promote and improve the multidisciplinary care required in the treatment of these
patients. They are intended for use by physicians, and also offer recommended approaches
to the diagnosis, treatment and prevention of HCV.
Grading of recommendations
Grade A
Recommendation based on at least one high quality randomized controlled trial or at
least one high quality meta-analysis of methodologically sound randomized controlled
trial.
Grade B
Recommendation based on high quality case-control or cohort studies or a high quality
systematic review.
Grade C
Recommendation based on non-analytic studies (case reports or case series).
Grade D
Recommendation based on expert opinion only.
GOALS OF THESE GUIDELINES
These are as follows:
To provide a concise, evidence-based review of the diagnosis and management of chronic
HCV infection in Saudi Arabia.
To help initiate plans to prevent HCV infection in the population.
To achieve early and accurate diagnosis of patients with HCV infection.
To provide an evidence-based approach for the management of HCV-infected patients.
To facilitate appropriate and timely referrals between primary, secondary, and tertiary
care providers.
To identify gaps in the knowledge and understanding of the incidence of HCV in Saudi
Arabia that require further research.
EPIDEMIOLOGY
Prevalence and incidence
HCV infection is a leading cause of cirrhosis, liver failure and liver cancer worldwide,
making it a major public health issue. The World Health Organization (WHO) estimates
a worldwide prevalence of 3%. Each year, three to four million people are newly diagnosed
with HCV, and it remains endemic in many countries of the world.[1–3] According to
the WHO, there are at least 21.3 million HCV carriers in Eastern Mediterranean countries,
a figure close to the combined number of estimated carriers in the Americas and Europe.
A large, cross-community, population-based survey from different regions of Saudi
Arabia was performed among children aged 1-10 to estimate the prevalence of HCV in
Saudi children. Out of 4,496 children, 39 (0.90%) tested positive for HCV antibodies.
However, the survey was performed using a first generation Enzyme-linked Immunosorbent
Assay (ELISA) kit that is known to produce false-positives.[4]
As a part of a hepatitis B virus (HBV) vaccination follow-up study, children were
also tested for HCV serology using a more reliable third generation ELISA test coupled
with a Recombinant Immunoblot Assay (RIBA) for confirmation.[5] This study showed
the prevalence of HCV antibodies to be higher in adolescents than in younger children:
from 0.04% in 1997 (children aged 1-12 years), to 0.22% for adolescents aged 16-18
years in 2008 (unpublished results), a trend possibly related to different exposures
to risk in different age groups. This increasing prevalence with age was also reported
by Fakeeh et al.: 4.49% in < 15 years olds, 2.05% in 15-21 year olds, 5.10% in 25-34
year olds, 8.64% in 35-44 year olds, 15.0% in 45-54 year olds, and 11.9% in ≥ 55 year
olds in a cohort of outpatient's attendees and hospital-admitted patients.[6] However,
these seemingly high rates are not generalizable as the patient population was not
representative of the country in general. The Saudi Ministry of Health (MOH) report
found a much higher proportion of HCV infection in adults (23,950/11,878,260) when
compared to patients younger than 15 years old (998/8,186,369), despite similar mean
population sizes. Memish et al, reported an almost 45-fold higher annual incidence
of seropositivity in those ≥ 15 years vs. children < 15 years of age.[7]
The prevalence in the general population is generally considered uncertain, since
most studies were conducted more than 10 years ago.[6
8–10] HCV has been reported to be on the decline over the past decade, although it
remains a major public health concern in the country.
While HCV infection has been a reportable disease in Saudi Arabia since 1990, the
level of reporting compliance is unknown, hence epidemiologic estimates may be inaccurate.
However, blood donors are screened, and pre-marital testing for HCV infection has
been mandatory since January 2008. It is estimated that well over one million individuals
have already been screened. Nested data, not confirmed by PCR-based testing, reported
from the General Directorate for Communicable Diseases, Riyadh region, revealed a
HCV sero-prevalence of 0.33%.[11] A large community-based study reporting the actual
prevalence of HCV in Saudi Arabia has not yet been undertaken. However, a summary
report compiled by the WHO mentions 437,292 official reports of HCV infections among
persons living in Saudi Arabia, giving an estimated prevalence of about 1.8%.[12]
A study by the Saudi MOH of all of all reported cases in Saudi Arabia from January
1995 to December 2005 showed considerable differences in the number of cases reported
to the MOH per region. The highest prevalence occurred in Al Baha and Jeddah (0.32%),
and the lowest in Jizan (0.016%) and estimated the prevalence rate among children
< 15 years to be 0.012% and that among adults to be 0.202%.[13] These results are
mirrored by earlier studies undertaken in the country. For example, blood screening
results taken from 528 blood donors in the Jeddah region reported a prevalence of
1.7% infection, whereas another study of 557,815 Saudi adult residents in the Riyadh
province found 1.1% anti-HCV prevalence.[14
15]
A recent viral hepatitis surveillance study reported an annual average incidence of
seropositivity of 78.4 per 100,000 of the population served by the National Guard
Health Affairs (NGHA) hospitals in the Central, Eastern, and Western regions of the
country.[7] HCV incidence decreased by 30% over the eight-year study period. Prevalence
rates from Saudi blood donor screening centres range from 0.4-1.1%.[16–18]
Gender has not emerged as a sizeable factor in HCV infections in Saudi Arabia. Only
one study found a higher prevalence of HCV among men compared with women, though the
significantly higher age of the men could have contributed to this difference.[6]
On the other hand, a community-based study of equal numbers of men and women did not
find any gender differences in infection rates.[8] A retrospective study in the Eastern
Province did not find any significant differences in HCV infection between men and
women either.[19] In two further separate reports, the prevalence of HCV infection
was not shown to differ between men and women.[7
20]
A recent systematic review of studies published in indexed sources, as well as from
non-indexed sources, such as the MOH website, estimated that the prevalence of HCV
in Saudi Arabia was at 1-1.9% among adults.[21]
Genotypes
In Saudi Arabia, genotype 4 HCV is most prevalent, followed by genotype 1. In the
largest genotype study on 1013 Saudi nationals, HCV G1 accounts for 25.9%, G2 for
4.3%, G3 for 2.9%, G4 for 60%, G5/G6 for 0.3% and 6.3% were of mixed genotype. In
addition, 81.1% of all HCV patients are older than 41 years of age, and males account
for 55.3% in G1, and 44.9% in G4 cases.[21] (I. Altraif et al., unpublished data).
Genotypes 2a/2b has been documented in the eastern region and genotype 5 in the western
region of the country, with genotypes 3 and 6 being extremely rare.[6
14
22–25] The most common subtypes of genotype 4 HCV among Saudis are 4c/4d followed
by subtypes 4h, 4e, and 4a.[14
26]
Risk factors
The primary source of HCV transmission is parenteral exposure to HCV-infected blood
or blood products.
Hemodialysis
Patients on hemodialysis are particularly at risk of contracting HCV. In Saudi Arabia,
hemodialysis is the most commonly used form of renal replacement therapy, and the
number of patients receiving hemodialysis treatment has been increasing dramatically.[17
18
27] At the same time, the incidence of new infection, and the prevalence of HCV has
increased in this patient population over the past three decades, and it is now estimated
to be 7-9% and 15-80%, respectively.[17] Additionally, there was a surge in endemicity
in the mid-1990s, from 41% to 55%, appearing simultaneously with the sudden expansion
of hemodialysis services, due to a significant increase in the number of patients
with end-stage renal disease across the country.[17
27]
In recent years, based on more available data, and countrywide figures from the Saudi
Centre for Organ Transplant, the HCV prevalence rate has remained constant at 50%,
even though the demand for dialysis services continues to rise, perhaps as a reflection
of better adherence to infection prevention and control policies and practices.[17
27] In fact, a recent single-centre study that adopted strict infection control guidelines
reported a zero incidence of infection for the entire duration of 5 years that 36
sero-negative hemodialysis patients were followed.[28] Another investigational study
followed the epidemiology of HCV in a dialysis unit after methods to reduce prevalence
of the virus were set in place.[29] These practices included strict adherence to universal
infection control precautions, separation of HCV-positive patients from the negative
ones, and using specially designated machines for the HCV-negative hemodialysis patients.
Periodic testing revealed no sero-conversions and a reduced prevalence of HCV RNA-positive
patients to 6.5% within the unit.
A study by Abu-Aisha et al. recommended the delegation of specific hemodialysis machines
for anti-HCV-positive cases.[30] Soyannwo et al. also determined that machine isolation
policies, rather than blood transfusions, lead to wide-spread variations in the prevalence
of HCV among different dialysis centres in Saudi Arabia.[31] Several studies have
also referred to patient isolation as an important factor in preventing transmission
of viral hepatitis in hemodialysis units.[32–34] For instance, a specially designed
centre with complete isolation of HCV-negative and HCV-positive patients resulted
in the annual incidence of HCV infection dropping significantly from 2.4% to 0.2%.[34]
Intravenous drug users
Acquisition of Hepatitis C by intravenous drug users constitutes only a small percentage
of the total HCV infection cases in Saudi Arabia, despite the continued rise in number
of IV drug users.[13
35] Recent examination of the prevalence of viral infection among 344 Saudi injecting
drug users reported a 38% HCV RNA detection rate with a predominant genotype of 1b.[35]
An earlier study showed that the HCV infection among IV drug users in a Jeddah detoxification
center was 69%.[36]
Other risk factors
Additional potential risk factors for HCV transmission include exposure to an infected
sexual partner, or multiple sexual partners, and perinatal exposure.[37] Few studies
have been done on these topics, and the available data are conflicting. One study
concluded that intrafamilial transmission was a major route of transmission among
the Saudi population,[38] while two others showed that neither intrafamilial[39] nor
perinatal[13] transmission are risk factors for HCV infection in Saudi Arabia. Further
studies need to be undertaken to explore modes of transmission of HCV in the local
population.
Other forms of transmission such as bloodletting and traditional tattooing have been
suggested.[40] In addition, a study by Al Faleh et al., has documented a history of
prior blood transfusion in 14.8% of infected patients.[14] The low prevalence of HIV
in the Saudi population relegates it as a risk factor of marginal importance in the
local setting.[18
41
42] Other high risk group patients such as patients with thalassemia major and hemophilia
have a prevalence rate of 70% and 78.6%, respectively.[10
41] A prevalence of 15.9% has been reported in patients with sexually-transmitted
diseases[42] and high risk behavior.
Recommendations
HCV testing is recommended for (Grade B)
Individuals with a history of intravenous drug use.
Patients with conditions associated with a high prevalence of HCV infection, including
those.
With HIV infection
With hemophilia, who received clotting factor concentrates before 1987
Who ever underwent hemodialysis
With unexplained abnormal aminotransferase levels
Prior recipients of transfusions or organ transplants, including those.
Who were notified that they had received blood from a donor who later tested positive
for HCV infection
Who received a transfusion of blood or blood products before July 1992
Who underwent an organ transplant before July 1992
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.
Sexual partners of HCV-infected persons.
Individuals found to have HCV infection should be counseled regarding prevention of
the spread of the virus to others. They should be informed that transmission occurs
through contact with their blood, and they should therefore be informed about how
to take precautions against the possibility of such exposure (Grade B).[43]
NATURAL HISTORY
The HCV is one of the most important Flaviviridae infections in humans, and is the
second most common cause of viral hepatitis.[44] HCV has six major genotypes, which
are indicated numerically (1 to 6) according to the international Simmonds classification.[45]
HCV infection can present as an acute hepatitis, chronic hepatitis, extra-hepatic
manifestation, or as cirrhosis and its complications. Acute hepatitis is usually asymptomatic,
not commonly encountered in general clinical practice and rarely leads to hepatic
failure. Natural history studies suggest that 55-85% of persons with acute hepatitis
C will go on to develop chronic HCV infection, while the remaining 15-45% of patients
with acute hepatitis C will spontaneously clear the virus without developing any long-term
complications and require no further treatment. Those having persistent infection
for more than six months are defined as chronic hepatitis C.[46] Of these, 5-20% have
been reported to develop cirrhosis over a period of 20 to 25 years.[47–49] The high
figure of 20% of chronic HCV patients developing cirrhosis may not reflect the true
rate in the general population of HCV-infected persons, since these studies were done
in tertiary-care hospitals and may have had referral bias. A very small portion of
chronic HCV patients (0.5% to 0.74% per year) spontaneously clear their virus.[50]
Patients with HCV-induced cirrhosis have a risk of about 30% over 10 years for developing
end-stage liver disease, and about 1-4% risk per year for developing hepatocellular
carcinoma (HCC).[51
52]
The 10-year risk of cirrhosis is less than 10% in patients with mild chronic hepatitis,
44% in those with moderate hepatitis, and 100% in those with severe hepatitis with
bridging fibrosis.[53]
Evolution of chronic HCV infection to cirrhosis is a primary concern. Factors that
accelerate the rate of progression include excessive alcohol intake, existing HIV
and/or HBV, a longer duration of HCV infection, males, and those patients acquiring
the infection when under the age of 40, or who acquire it through blood transfusion
rather than through drug use by injection.[53–58] An important predictor of the future
progression of liver disease and the need for HCV treatment is more-than-portal fibrosis
on liver biopsy (Metavir ≥2 or Ishak ≥3).[55
59
60]
Due to the long course of hepatitis C, the exact risk of cirrhosis is very difficult
to determine, and figures differ from study to study and between populations. Data
from Egypt has suggested a possible relationship between HCV genotype 4 and HCC, where
the vast majority of patients have genotype 4.[61–66] Such data is not available in
Saudi Arabia and its relevance in the local setting needs to be further explored.
The Saudi Observatory Liver Disease (SOLID) registry has recently been established
through a national funding initiative termed as the National Plan for Science and
Technology, under the auspices of King Abdulaziz City for Science and Technology in
Riyadh. The SOLID registry functions on a nationwide basis, with a constantly expanding
list of participating centers. The registry aims to prospectively accrue demographic,
clinical and treatment-related data in patients with HCV and other liver diseases.
It is at present the only longitudinal, hospital-based, research database in the region.
Deaths related to chronic HCV are usually caused by complications of decompensated
cirrhosis and HCC. The onset of decompensation is associated with a rapid decline
in survival rates. The 5-year survival rate for patients with compensated cirrhosis
is as high as 90%, compared to 50% for those with decompensated cirrhosis.[67–69]
CLINICAL FEATURES OF HCV INFECTION
Infection with HCV can result in both acute and chronic hepatitis, each with a different
spectrum of clinical manifestations.
Acute HCV
Acute HCV infection is usually asymptomatic. However, approximately 25% of patients
with acute HCV present with jaundice, and less than 33% develop non-specific symptoms
such as nausea, vomiting, abdominal pain, and fatigue orarthralgia. Less common symptoms
include fever and rash. In patients who experience the symptoms of acute hepatitis,
the illness typically lasts for 2-12 weeks. The incubation period from infection to
onset of symptoms can range from 2 to 12 weeks.[70
71]
HCV RNA typically becomes detectable in serum 7 to 21 days after exposure, and can
be detected at high levels at the onset of jaundice.[71]
Aminotransferase levels become elevated approximately 6-12 weeks after exposure, and
can be more than 15 times the upper limit of normal.[72]
Anti-HCV becomes detectable approximately 7-10 weeks after the onset of infection.
Fulminant hepatic failure due to acute HCV infection is very rare. It may be more
common in patients with underlying chronic hepatitis B virus infection.[73]
Chronic HCV
In chronic hepatitis C, the disease may continue to appear to resolve both biochemically
and histologically, followed by intermittent or constant elevation of serum transaminases.
Most patients with chronic infection are asymptomatic or have only mild nonspecific
symptoms, and do not have physical signs of liver disease, as long as cirrhosis itself
is not present.[74]
Extrahepatic manifestation of HCV
Patients with these syndromes can be divided into those with a higher degree of association,
and those with a more moderate or mild association with HCV. The most prevalent extra-hepatic
diseases with the highest degree of association with HCV are the essential mixed cryoglobulins
with a clinical triad of weakness, arthralgia and palpable purpura. Renal disease
can also be associated with chronic HCV, particularly membranoproliferative glomerulonephritis.[75
76]
The other diseases include noncryoglobulinemic systemic vasculitis, splenic lymphoma
with villous lymphocytes, fatigue, porphyria cutanea tarda, sicca syndrome, and autoantibodies
production. The extra-hepatic manifestations that share mild-degree certainty of association
with HCV infection include B-cell non-Hodgkin lymphoma, autoimmune thrombocytopenia,
pruritus, and type II diabetes mellitus. The other diseases such as autoimmune thyroiditis,
lichen planus are less likely to be associated with HCV.[77
78]
Most extra-hepatic manifestations of chronic HCV infection are immunological, and
a chronic level of infection seems to be necessary for their development. Molecular
study of the unique way in which the HCV virus interacts with the human immune system
is slowly beginning to provide plausible explanations of the pathogenic role of HCV
in some of these syndromes, but many patho-genetic links remain completely obscure.[79]
Cirrhosis and hepatocellular carcinoma
Patients with normal serum transaminases activity have a lower fibrosis progression
rate (15%) than those patients with elevated enzymes.[80]
Cirrhosis can be missed clinically, as most cirrhotic patients are asymptomatic as
long as hepatic decompensation and HCC does not occur. The HCV-related compensated
cirrhosis is usually discovered during screening of blood donors, premarital screening
or at the time of routine laboratory testing.[59
67]
A wide spectrum of nonspecific symptoms can be noted in patients with compensated
and decompensated cirrhosis, including fatigue in 75%, abdominal pain in 24%, and
anorexia in 13%.[81]
Less than 50% of cirrhotic patients have clinical and laboratory results that support
the presence of cirrhosis like hepatomegaly and/or splenomegaly, spider angiomata,
palmar erythema, testicular atrophy, or gynaecomastia, caput medusa, elevated serum
bilirubin concentration, hypoalbuminemia, or low platelet counts.
Among patients with compensated cirrhosis, the annual risk of decompensation is 3.9%.
The clinical presentation can be dramatic after hepatic decompensation, and manifests
itself with ascites in 48%, variceal bleeding in 22-32%, hepatic encephalopathy in
5-8%, jaundice in 6%, or a combination of these complications in 17% of patients.
Patients with hepatic decompensation may also develop lower extremity edema, pruritus,
sexual dysfunction, easy bruising, muscle wasting and muscle cramps.
Patient with HCV-related cirrhosis are at risk of HCC, and the estimated risk, described
in various reports, has varied from 0-3% per year. The suspicion of HCC development
should be high in those patients who present with rapid clinical decompensation with
ascites, hepatic encephalopathy and bleeding from portal hypertension. Ultrasound
of the abdomen at 6 months intervals is the recommended test that can be used for
early detection of HCC in patients with HCV cirrhosis.[67
82]
Recommendations
The Saudi Observatory Liver Disease Registry (SOLID) is a valuable source of data
for HCV in Saudi Arabia, and efforts must be made to improve patient registration
and the utilization of the registry (Grade D).
Large epidemiologic studies are needed to further define the epidemiologic features
and natural history of HCV infection in Saudi Arabia (Grade D).
Patients with significant fibrosis caused by HCV are at significant risk for disease
progression (Grade A).
Patients with cirrhosis caused by hepatitis C are at high risk for the development
of HCC and these patients should be regularly screened to detect the onset of early
HCC (Grade A).
LABORATORY TESTING
Alanine aminotransferase and aspartate aminotransferase
Liver chemistries are an insensitive means of assessing fibrosis. Elevations of alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate the presence
of liver disease, but does not determine the type, the cause of the liver disease,
or correspond to the degree of damage on liver biopsy.[83] Additionally, viral genotype
and/or viral load do not correlate with the amount of liver injury.[84] In 341 anti-HCV
positive patients in the study by Silini et al., 49% had persistently normal or nearly
normal ALT levels and of those 70% had circulating HCV RNA; while on histology a large
number of them had mild chronic hepatitis.[85] Therefore, if there is a suspicion
of HCV infection in patients with a persistently normal ALT level, they should be
tested for HCV-RNA. The use of routine liver tests to screen for chronic hepatitis
C virus infection is of limited value in cases of anti-HCV and PCR positives.[86]
Other studies have shown that transaminase levels can be helpful in predicting the
severity of liver disease, with higher levels associated with more advanced histology,
but they are usually of limited value in an individual patient.[58
87] With levels fluctuating from normal to abnormal over time, the value of monitoring
transaminases is limited. Additionally, the results of routine liver tests correlate
poorly with both necro-inflammatory and fibrosis scores found on liver biopsy.
Serologic assays
Detection of the anti-HCV antibody is used for screening for HCV infection. The two
enzyme immunoassays (EIAs) commonly used are Abbott HCV EIA 2.0 (Abbott Laboratories,
Abbott Park, IL) and ORTHO® HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics, Raritan,
NJ). The enhanced chemi-luminescence immunoassay (CIA) VITROS® Anti-HCV assay, (Ortho-
Clinical Diagnostics, Raritan, NJ) is also used for the same purpose. The specificity
of third generation EIAs for detection of anti-HCV is greater than 99%;[88] at the
same time, they are reproducible and inexpensive.[43] The recombinant immunoblot assay,
Chiron RIBA HCV 3.0 SIA (Chiron Corporation, Emeryville, CA) is more specific, and
is a supplemental assay to confirm the results of EIA testing.[89
90] The specificity is extremely high for third generation EIA, that exceeds particular
signal/ cutoff ratios (e.g., >3.8 for the above mentioned Ortho and Abbott EIA tests).[91
92] Its high sensitivity and specificity may obviate the need for a confirmatory immunoblot
assay in the patient with HCV infection. However, a positive RIBA is not diagnostic
of active HCV infection, since up to 45% of patients will clear HCV spontaneously
after acute infection, while remaining anti-HCV positive.[46]
The hepatitis C virus antibodies revealed by ELISA are detectable within three to
15 weeks of infection. The third-generation anti-HCV enzyme immunoassay (EIA) can
detect HCV antibodies as early as 6–8 weeks after exposure.[93] Anti-HCV antibodies
can be detected in 80% of HCV patients within 15 weeks after exposure, in > 90% within
5 months after exposure, and in > 97% up to 6 months after exposure. Overall, HCV
antibody tests have a strong positive predictive value for exposure to the hepatitis
C virus.
One of the newest assays, the Murex HCV Ag/Ab combination assay combines the detection
of anti-HCV antibodies with the detection of core antigen in a single assay, which
significantly reduces the window period from infection to detection when compared
with conventional serological HCV antibody screening assays.[94]
Second- and third-generation tests, which have included more antigens from the better-conserved
regions of the viral genome, have high sensitivity and specificity for detection for
all genotypes. Use of this technique runs the risk of false-negative results of less
than 5%.[95] If a reaction with two or more of the antigens is seen, the RIBA test
is considered positive.[96] Reaction with only one antigen gives an indefinite test
result; only about 10% of these patients are HCV-RNA-positive.[97] The recombinant
viral antigens from HCV are used in all commercial assays, and consequently false-negative
results are less likely, due to amino-acid heterogeneity. False positive results are
more likely to occur when testing is performed among populations where the prevalence
of hepatitis C is low. False negative results are more likely in patients who have
not yet developed antibodies (seroconversion), have an insufficient level of antibodies
to be detected, immunocompromised individuals who may never develop antibodies to
the virus, in the presence of hypo- or aggammaglobulinemia, and in patients on hemodialysis.[98–100]
Molecular assays
The presence of the virus is tested by using molecular nucleic acid testing methods,
such as polymerase chain reaction (PCR), transcription mediated amplification (TMA),
or branched DNA (b-DNA). All HCV nucleic acid molecular tests have the capacity to
detect the presence of the virus and to measure the amount of the virus present in
the blood (the HCV viral load).
Historically, qualitative assays have been shown to be more sensitive than quantitative
assays. Most recently, available real-time polymerase chain reaction (PCR) has shown
the ability to detect even a small amount of HCV RNA (<10 (IU)/ml) and to accurately
quantify HCV RNA levels up to 107 IU/ml. Their dynamic quantification range adequately
covers clinical needs for diagnosis and monitoring.[101–103] With transcription mediated
amplification (TMA) assays, the sensitivity is up to 10-50 IU/mL.[104] A highly sensitive
assay with a lower detection limit is considered appropriate for monitoring during
therapy. All available assays have excellent specificity, namely in the range of 98%
to 99%.
The international standard for HCV RNA nucleic acid is well accepted for uniformity,[44]
and is now preferred over viral copies.[105
106] The hepatitis C virus is usually detectable in the blood by PCR within one to
three weeks of infection.[93] However, more recently HCV antigen assays (HCV core
antigen) has significantly reduced the window period (i.e., period prior to the detection
of an antibody).[107–111] The assay based on the detection of the HCV core protein
(Trak-C; Ortho Clinical Diagnostics) has proposed an alternative to PCR, but it suffers
from lack of sensitivity.[112]
For monitoring purposes, it is important to use the same laboratory test before and
during therapy. Traditionally, qualitative tests are more sensitive, but with a lower
limit of detection 5 IU/mL [Table 1].[113]
Table 1
Qualitative assays for detection of HCV RNA
Viral RNA testing is indicated when there is clinical suspicion of HCV, transaminase
levels are high, and antibody testing is negative.[84]
An approach based on the HCV core protein and specific anti-HCV antibody detection
(Monolisa HCV Ag-Ab Ultra; Bio-Rad Laboratories, Marnesla-Coquette, France) has recently
been developed for the diagnosis of hepatitis C.[114
115]
Reverse transcription of the viral RNA, followed by amplification of complementary
DNA (RT-PCR) has a role in diagnosis, monitoring and evaluation of therapy. Its disadvantages
are the risk of contamination, and false-negative results when samples are not handled
correctly. Quantitative measurements have revealed that the level of viraemia correlates
with the severity of disease and reacts inversely with the response to therapy. Quantification
can be done by quantitative PCR assays or by branched DNA (bDNA) techniques.[116]
In PCR, sensitivity is higher, but bDNA has better reproducibility.[116] The lower
limit of detection for earlier versions of these PCR tests has been around 600 IU/mL.
More recent versions are more sensitive, with a broader dynamic range from around
5-25 IU/mL to > 108 IU/mL, depending on the laboratory of origin.[83]
Genotype assay
HCV genotype and subtype can be determined via various methods, including direct sequence
analysis, reverse hybridization, and genotype-specific real-time PCR.[117] Genotyping
is useful in epidemiological studies, selecting therapy, predicting likelihood of
response to therapy and determining the optimal duration of treatment. Up to 80% of
patients with HCV genotype 2 and 3 respond favorably to antiviral therapy. Several
methods are available for genotyping: (a) serologically identifying the specific peptide
by ELISA,[118] (b) sequencing of PCR products, (c) use of type-specific primers and
(d) restriction fragment length polymorphism. Several commercial assays are available
to determine HCV genotypes, using direct sequence analysis of the 5′ non-coding region.
These include the Trugene 5′NC HCV Genotyping kit (Siemens Healthcare Diagnostics
Division, Tarrytown, NY). A reverse hybridization analysis using genotype specific
oligonucleotide probes located in the 5′non-coding region, INNO-LiPa HCV II, (Innogenetics,
Ghent, Belgium), and Versant HCV Genotyping Assay 2.0 (Siemens Healthcare Diagnostics
Division, Tarrytown, NY). The analysis of conserved 5′NCR allows the determination
of 3 major groups, types 1, 2, and 3,[119
120] with type specific primers,[121] on the basis of restriction fragment length
polymorphisms (RFLP's)[122] or with sequence specific DNA probes (genotyping).[123]
Phylogenetic analysis of the NS5 region has allowed the classification of HCV into
6 major genetic types and a number of subtypes. So far, there has been no overlap
in sequence variability between the different classes with nucleotide homologies of
88-100% between isolates, 74-86% between subtypes, and 56-72% between types.
Incorrect typing among the major genotypes is rare (< 3%) and mixed genotypes are
known to occur, but are uncommon. Occasionally (< 5%), tested samples cannot be genotyped.
This usually results from low viral levels, issues with the PCR amplification step
of the assay, or extreme nucleotide variability within the HCV genome.[124]
Noninvasive tests to asssess liver fibrosis
The use of non-invasive tests to assess liver fibrosis is not yet recommended. However,
various non-invasive tests are being investigated for staging the degree of liver
fibrosis. These tests may be used to decide whether or not to initiate antiviral therapy,
and to monitor the effects of such therapy.[125]
Standard liver biochemical tests (liver function and coagulation studies) and radiological
imaging of the liver are not sufficiently sensitive to diagnose evolving hepatic fibrosis
and early stages of cirrhosis, though it may be helpful in advanced cirrhosis.[125]
A number of studies employing a variety of indirect markers of liver fibrosis (FibroSure
and FibroStat), including standard liver chemistries, platelet count, prothrombin
index, and lipoprotein A1 concentrations, have been published recently. These tests
have gained acceptance in Europe as alternatives to liver biopsy.[126
127]
The commonly used non-invasive tests are the aspartate aminotransferase (AST)-to-platelet
ratio index (APRI),[128] the Forns index,[129] FIB-4,[130
131] Fibroindex,[132] FibroTest,[133] FibroMeter,[134] and Hepascore.[135] The main
advantage of APRI, the Forns index, and FIB-4 over other non-invasive tests is that
they are based on readily available blood tests, and are easily accessible.
The Forns index is based on platelet count, gamma glutamyl transpeptidase (GGT), age,
and cholesterol.[129] Forns score = 7.811 - 3.131 × ln [number of platelets (109/L)]
× 0.781 ln [GGT (U/L)] + 3.467 × ln [age (years)] - 0.014 [cholesterol (mg/dl)].[133]
The Forns index was found to be slightly more accurate than the aspartate aminotransferase-platelet
ratio index and FIB-4 in predicting significant fibrosis and cirrhosis.[132]
The APRI Score (AST platelets ratio index) is a serological marker alternative to
liver biopsy, and it has been found to be both satisfactorily sensitive and specific.[136]
The APRI formula was proposed by Wai et al.[130] and the APRI score is calculated
as follows: [(AST/upper normal limit of AST) ×100) / number of platelets (109/L).[137]
The results obtained are then used to plot two Receiver Operating Characteristic (ROC)
curves to determine the best cutoff point for advanced fibrosis (F3 and F4). A second
point on the curve is established for moderate and advanced fibrosis (F 2, 3, and
4).
The FIB-4 was originally developed to predict significant fibrosis and cirrhosis among
human immunodeficiency virus (HIV)/HCV co-infected patients in the APRICOT study.[131]
The FIB-4 formula includes the alanine aminotransferase (ALT) level, the aspartate
aminotransferase (AST) level, platelet count and age: FIB-4 score = [age (years) ×
AST (U/L)]/(number of platelets (109/L) × ALT (U/L) ½],[130
131] and appears to be a strong predictor of de-compensated cirrhosis or death.[137]
In fact, both FIB-4 and APRI have been shown to have the highest positive predictive
value only in cases with the most severe stages of liver fibrosis (LF).[138] For these
reasons, rather than using FIB-4 and APRI as substitutes for liver histology at a
single time-point for comparison of LF among different individuals, these markers
can be used to determine associated risk factors for possible LF progression.[139]
In a study by Güzelbulut et al., the Forns index, APRI and FIB-4 were all found to
be accurate noninvasive blood tests for the prediction of the presence or absence
of significant fibrosis and cirrhosis in half of the patients studied. Although they
all demonstrated similar levels of accuracy, the Forns index performed slightly better
than the APRI and the FIB-4 both in the prediction of significant fibrosis and cirrhosis.
The main advantage of these tests is that they are easily reproducible, with readily
available blood tests. Consequently, the use of a combination of some or all of these
tests may circumvent the need for liver biopsy.[140]
FibroTest/ActiTest
FibroTest/ActiTest estimates liver fibrosis and necrotic inflammation. These tests
are validated,[141] and recommended in Europe. ActiTest is a modification of the FibroTest
that incorporates ALT, and measures both necro-inflammatory activity, and liver fibrosis
of viral origin (HBV and HCV).[142] The diagnostic value of FibroTest/ActiTest is
the same for the intermediate and extreme grades of liver fibrosis. The diagnostic
value is independent of ethnic origin, sex, genotype, viral load, or presence of co-morbidities.
ActiTest is validated for the initial diagnosis, monitoring both treated and untreated
patients.
The ActiTest result is presented as a score of 0 to 1, proportional to the significance
of the activity, with a conversion to the METAVIR system (from A0 to A3). To facilitate
the visual interpretation, the result is accompanied by a colored graph showing the
level of severity as follows:
Green (minimal or absent)
Orange (moderate)
Red (significant)
The use of FibroTest has been validated for the diagnosis of fibrosis in both treated
and untreated patients. In 2006, the French National Authority for Health (HAS) recommended
the use of FibroTest as a first-line assessment tool for fibrosis in patients with
untreated chronic hepatitis C.
When serological markers and transient elastography are used alone or together, the
results obtained are comparable to those of the liver biopsy itself.[142
143] The use of biochemical markers of liver fibrosis (FibroTest) and necrosis (ActiTest)
can be recommended as an alternative to liver biopsy for the assessment of liver injury
in patients with chronic hepatitis C and both have been shown to accurately identify
patients with mild fibrosis or cirrhosis. However, they have been shown to be less
effective in discriminating moderate and severe fibrosis.[126]
Histology
Liver biopsy still remains the only gold standard test for evaluating stages of fibrosis,
and, when combined with clinical and laboratory findings, is also a reliable means
of assessing prognosis, thus helping to provide information about the need to initiate
therapy. Currently, the American Association for the Study of Liver Disease (AASLD)
recommends that, regardless of the level of ALT, a liver biopsy is advised for patients
with genotypes 1 and 4. However, biopsy is not mandatory in order to initiate therapy.[45]
Histology outcomes can vary from showing only mild changes to those of chronic active
hepatitis and cirrhosis,[144] depending on the duration and severity of the disease.
Histological changes indicative of chronic HCV disease are lymphoid aggregates in
portal and bile duct areas, together with steatosis of hepatocytes. A combination
of at least two of these features is seen in about 70% of all cases. Immunohistochemical
techniques can detect HCV proteins in liver biopsy, and HCV-RNA can be detected with
in situ PCR or bDNA techniques.
For evaluation of histo-pathological abnormalities and progression, quantitative scores
have been developed for estimating the degrees of inflammation (grading) and of fibrosis
(staging). The ‘histological activity index’ (HAI) of Knodell[145] is widely used,
but has some drawbacks. Several adaptations have been proposed, (e.g., Scheuer[146]),
mainly to separate inflammation from fibrosis scores, as each of these parameters
has a distinct value for the prognosis of the disease and for evaluating the effect
of therapy.
METAVIR score stage assessment for fibrosis classification in chronic hepatitis C
The scores are as follows:
F0: No fibrosis
F1: Portal and periportal fibrosis with no septum
F2: Portal and periportal fibrosis with rare septum
F3: Portal and periportal fibrosis with many septa
F4: Cirrhosis
Necroinflammatory activity
The activity (or grade) estimates the lesions by measuring portal inflammation and
hepatocellular necrosis.
METAVIR score assesses grading for activity as follows:
A0: No activity
A1: Minimal activity
A2: Moderate activity
A3: Severe activity
Recommendations
Conditions for these recommendations are:
Clinical signs and symptoms of chronic HCV are nonspecific, the liver chemistry and
radiographic findings poorly corroborate with the activity and extent of the damage
to the liver in early and late stages of the HCV infection. Diagnosis of HCV infection
is based on detection of anti-HCV antibodies by enzyme immunoassay and HCV RNA by
a sensitive molecular method (lower limit of detection <50 IU/ml), ideally a real-time
PCR assay. The diagnosis of chronic hepatitis C is based on the detection of HCV infection
(positive anti-HCV antibodies and HCV RNA) in a patient with signs of chronic hepatitis.
Rarely, in profoundly immunosuppressed patients, anti-HCV antibodies may not be detected,
but HCV RNA is always present.
Patients with suspected HCV infection should be tested for anti-HCV by an up-to-date
(currently, third generation) ELISA test (Grade B).
Immunosuppressed patients may require a test for HCV RNA, if hepatitis is present,
but anti-HCV antibodies are undetectable (Grade B).
The measurement of HCV RNA concentrations in serum and identifying the HCV genotype
are recommended and should be used to determine the duration of treatment (Grade A).
Liver fibrosis can be broadly established by means of either biochemical or hematological
tests like ALT, AST, prothrombin time, platelets, APRI, AST/ALT ratio, Forns Index;
those that include specific indirect markers of liver fibrosis, such as a-2macroglobulin;
those that incorporate only direct markers of liver fibrosis (MP3), or combinations
of direct and indirect markers (Hepascore, FibroMeter). Sufficient evidence exists
to support the view that algorithms perform well in the detection of significant fibrosis
(METAVIR score F2-F4). Thus, their use in patients with chronic hepatitis C can be
recommended for this purpose (Grade A).
Liver biopsy is valuable for assessing the status and level of liver inflammation,
the potential progression of fibrosis and the presence or absence of cirrhosis. It
is not mandatory, and should only be considered in patients who are hesitant about
HCV treatment, in order to make decisions regarding urgency of treatment. Standard
histological scoring systems by a suitably experienced pathologist should be used
to encourage uniformity of histological reports. In addition, the risks and benefits
of liver biopsies should first be carefully explained to the patient (Grade B).
TREATMENT OF CHRONIC HCV PATIENTS
Since interferon-alpha (IFN-α) was first introduced for treatment of non-A and non-B
hepatitis 2 decades ago, therapy for chronic carriers of the hepatitis C virus has
improved dramatically. Historically, standard IFN monotherapy will lead to a sustained
virological response (SVR) in less than 15% of patients. With the addition of ribavirin
(RBV), and later the substitution of pegylated IFN-alpha (peg-IFN-α) for the standard
IFN, the SVR rate significantly improved. Treatment with combined peg-IFN and RBV
may result in SVR in 42% to 52% of genotype 1 infected patients, 70% to 80% of genotype
2 or 3 infected patients and 54-68% of genotype 4 infected patients.
The use of combinations of peg-IFN and RBV are thus considered the current standard
of care for the treatment of chronic hepatitis C (CHC). The purpose of anti-HCV therapy
is the eradication of HCV infection, in order to prevent the occurrence of complications
and death. All HCV patients with compensated chronic liver disease who have had no
previous treatment for HCV, are willing to be treated, and have no contra-indication
to peg-IFN-α or RBV should be considered for treatment, regardless of their baseline
ALT level.
Pre-treatment predictors of response are useful for advising patients on their chance
of viral eradication. Positive pre-treatment predictors of response to peg-IFN and
RBV include the HCV genotypes 2 and 3, low baseline HCV RNA levels (genotypes 1 and
4 < 600,000 IU/mL, genotypes 2 and 3 < 400,000 IU/mL), IL-28B polymorphism CC type,
absence of bridging fibrosis or cirrhosis, younger age (< 40 years), and those with
a body mass index of < 30 Kg/m2. Negative pre-treatment predictors include advanced
hepatic fibrosis, HIV co-infection, and the presence of insulin resistance with or
without diabetes, obesity, non-viral hepatic steatosis and possibly low vitamin D
levels.[147
148]
Table 2 summarizes the various definitions of virological responses obtained during
dual antiviral therapy with peg-IFN and RBV.
Table 2
Virological response obtained during dual antiviral therapy with pegylated interferon
and ribavirin
Indications and contraindications of antiviral therapy
Treatment with peg-IFN-α and RBV is cost effective, even for patients showing early
stages of liver fibrosis.[149
150] A reasonable candidate for HCV therapy is an adult patient who is 18 years old
or older, has HCV viremia, and displays evidence of chronic hepatitis with at least
F2 fibrosis, or a well-compensated cirrhosis (total serum bilirubin < 25 μmol/l; INR
< 1.5; serum albumin > 34 g/L, no hepatic encephalopathy or ascites). Candidates should
also have good hematological indices before starting antiviral therapy. Preferable
pre-treatment hematological indices should be the following: hemoglobin level above
12 g/dl; neutrophil count above 1500 /mm3 and platelet count above 75,000 mm. Absolute
contraindications to the use of peg-IFN-α and RBV include uncontrolled autoimmune
diseases, co-morbid conditions that markedly limit life expectancy, history of hypersensitivity
to peg-IFN or RBV, pregnancy, or unwillingness to use birth control during and for
six months after treatment, severe cardiac disease, severe pulmonary disease, uncontrolled
psychiatric conditions, and uncontrolled seizure disorders. Certain patient groups
such as HIV/HCV co-infection and liver transplant patients with HCV infection should
be treated at tertiary hospitals with facilities for HIV care, or liver transplant
programs, respectively.
Recommendations
Eradication of HCV infection is the primary purpose of antiviral therapy (Grade A).
Patients with chronic HCV infection who have had no prior therapy and have compensated
liver disease should be evaluated and considered for anti-HCV therapy (Grade B).
Treatment regimen and antiviral side effects
Two pegylated IFN-α are available in Saudi Arabia, namely, peginterferon alfa-2b (PegIntron®),
with a 12-kd linear polyethylene glycol (PEG) covalently linked to the standard interferon
alfa-2b molecule, and peginterferon alfa-2a (Pegasys®) with a 40-kd branched PEG covalently
linked to the standard interferon alfa-2a molecule.[151]
In the Individualized Dosing Efficacy versus Fixed Dosing to Assess Optimal Peg-IFN
Therapy (IDEAL) trial, 3070 genotype 1 infected patients were randomized to one of
the two-pegylated IFN, and no difference in SVR was obtained between the two formulations.
The rate of SVR was 40.9% with peg-IFN-α2a (Pegasys®) and 39.8% with peg-IFN-α2b (PegIntron®).[152]
The preference as to which of them to use will therefore depend on their availability
at a particular hospital or patient preference.
Ribavirin (a guanosine nucleoside analogue) is an important component of HCV dual
and triple (direct-acting antiviral agents) therapy. It improves viral clearance,
decreases relapse rates, and improves rates of SVR when used in combination with peginterferon,
as compared with peginterferon monotherapy.
When a patient is being evaluated for HCV therapy, it is important to assess all pre-existing
medical problems, such as diabetes, hypertension, and weight, and to screen all candidates
for symptoms of depression and coronary artery disease. An acceptable plan for monitoring
patients on antiviral therapy would include monthly visits during the first 12 weeks
of treatment, followed by visits at three-month intervals until the end of therapy.
At each visit, adherence to treatment, and the presence of any side effects should
be reviewed. Laboratory monitoring should include measurements of the complete blood
count and differential (if leucopenia has developed), ALT, AST, ALP, bilirubin (total
and direct), INR, and Albumin every 4 weeks on treatment. Thyroid function (represented
by Thyroid Stimulating Hormone (TSH)) should be measured every 12 weeks, and at six
months after completing antiviral therapy. The monitoring of treatment effectiveness
is based on repeated measurements of HCV RNA levels. With genotypes 1 and 4, HCV RNA
level should be measured at baseline and in weeks 4, 12, and 24 (if HCV RNA positive
at week 12) and week 48 of treatment. With genotypes 2 and 3, HCV RNA level should
be measured at baseline, in weeks 4, 12 (if HCV RNA is positive at week 4), and 24.
With all genotypes, HCV RNA should be ordered 24 weeks after documenting End of Treatment
response (ETR) to verify the achievement of SVR. A sensitive real-time PCR-based assay
with a lower limit of detection of 50 IU/ml should be used. The same assay should
be used in each patient to determine HCV RNA at different time points, in order to
ensure consistency of results.[153]
Recommendations
In chronic HCV non-genotype 1 infected patients with normal renal function, combination
therapy with pegylated IFN-α and ribavirin is considered the standard of care (Grade
A).
After initiating combination antiviral therapy, patients should be seen at monthly
intervals in the first three months, and then every two to three months until the
end of treatment. Patients who have completed the treatment regimen should be seen
six months after the end of treatment. Individualized close follow up should be planned,
based on the severity of any adverse events (Grade D).
Adverse events associated with pegylated interferon and ribavirin
Pegylated interferon-related adverse events are the primary reason for patients discontinuing
treatment. It is estimated that 10% to 14% of patients may discontinue treatment due
to adverse events associated with the use of IFN.[154
155] The most common of these are influenza-like side effects such as fatigue, headache,
aching bones, myalgia, fever and rigors. Neuropsychiatric side effects may also manifest
them selves in 22% to 31% of patients. These side effects include depression, anxiety,
irritability and rarely psychosis. In addition, neutropenia (absolute neutrophil count
(ANC) below 1500 mm3) is a frequent laboratory abnormality, occurring in 18% to 20%
of patients, and severe neutropenia, that is, ANC < 500 mm3, may be observed in 4%
of patients. Despite the decline of the neutrophil count, serious infections are not
related to the degree of neutropenia.[156
157] The use of peg-IFN can also induce autoimmune disorders, such as autoimmune thyroiditis,[158]
or could aggravate pre-existing autoimmune disorders.
The most common side effect related to RBV is hemolytic anemia. Anemia can be observed
in approximately one-third of patients. Dose adjustment for anemia (hemoglobin level
< 10 g/dL) may be required in 9% to 15%. Other side effects associated with RBVcould
include mild lymphopenia, hyperuricemia, itching, rash, cough and nasal stuffiness.
RBV is teratogenic in animals, and therefore strict birth control should be practised
in patients being treated with peg-IFN-α and RBV during treatment and for six months
following its discontinuation.
Management of adverse events related to antiviral therapy
Table 3 summarizes common strategies used in ameliorating antiviral adverse events.
Neutropenia and thrombocytopenia are common adverse events reported when peg-IFN-α
is administrated. The dose of pegylated interferon should be reduced if the ANC falls
below 750/mm3, or if the platelet count falls below 50,000/mm3. When using peg-IFN-α
2a, the dose may be reduced from 180 to 135 μg/week, and then to 90 μg/week. When
using pegylated IFN-α 2b, the dose may be reduced from 1.5 to 1.0 μg/kg/week and then
to 0.5 μg/kg/week. Peg-IFN-α 2b should be stopped if the platelet count is < 25,000.
Once neutrophil or platelet counts rise again, treatment can be re-started, but a
reduced dose should be administered. There is no evidence to support the routine use
of granulocyte colony stimulating factor (G-CSF, Filgrastim) to reduce the rate of
infections or improve SVR rates. Serious infections may occur in 3% to 5% of patients,
irrespective of neutrophil count.[156
157] The use of granulocyte colony-stimulating factors should therefore be reserved
for managing only the most severe neutropenia which is not initially responsive to
peg-IFN dose reduction.
Table 3
Summary of management of other adverse effects of Peginterferon/Ribavirin
Eltrombopag is an orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis.[159]
It allowed successful treatment of HCV when given for 12 weeks to patients who had
baseline thrombocytopenia (20,000 to 70,000 mm3). However, thrombopoiesis- stimulating
drugs are not generally recommended for the management of thrombocytopenia, as there
is still a lack of sufficient data on their role in improving SVR rates, as well as
a potential risk of precipitating portal vein thrombosis.
Although anemia is most commonly related to RBV, Peg-IFN also contributes to anemia
by its effect on bone marrow suppression. It manifests itself early, within the first
2 weeks of administration, with a mean maximum hemoglobin reduction of 3 g/dL in first
6-8 weeks that could be associated with an improved chance of achieving SVR.[160]
A decrease in hemoglobin of 1.5 g/dL at week 2 of therapy has been associated with
the risk of severe anemia and the need for treatment interruption. If significant
anemia occurs (hemoglobin < 10 g/ dl) the dose of RBV should be adjusted downward,
by 200 mg at a time. RBV administration should be stopped if the hemoglobin level
falls below 8.5 g/dl. However, RBVdose reductions to levels less than 60% will significantly
decrease the likelihood of obtaining SVR. Recombinant erythropoietins (rEPO) can therefore
be used to maintain or improve hemoglobin levels, in order to avoid significant ribavirin
dose reductions or interruptions. rEPO can be administered when the hemoglobin level
falls below 10 g/dl. The hemoglobin level should be assessed 2 weeks after initiating
rEPO. The rEPO dose should be reduced if the increase in hemoglobin is more than 1
g/dl, and stopped if the hemoglobin level rises to over 12 g/dl. The hemoglobin level
should then be re-assessed 4 weeks later. The dose should again be reduced if the
hemoglobin increase is more than 2 g/dl, compared to 4 weeks earlier. If the hemoglobin
level falls again below 12 g/dl, erythropoietin therapy can be re-started at 50% of
the initial dose. If the hemoglobin level rise is less than 1 g/dl at 4 weeks of administration
and no other cause of anemia is found, the rEPO dose can be increased. However, few
studies have prospectively evaluated the impact of rEPO on SVR rates. rEPO use was
associated with an improved rate of SVR when higher doses of RBV(~15 mg/kg/day, 1,000–1,600
mg/day) were initiated, but showed no impact on SVR with standard ribavirin dosing.[161
162]
The use of hematological growth factors is associated with increased cost of treatment
for chronic hepatitis C.[163] In addition, rEPO has been associated with serious side
effects, including cardiovascular and/or thromboembolic events, pure red cell aplasia,
progression of certain cancers, and death.[164]
Antiviral treatment should be stopped immediately in cases of a hepatitis flare (ALT
levels above 10 times normal), or if a serious bacterial infection occurs at any site
in the body, regardless of neutrophil counts.
Interferons can induce or exacerbate depression. There are two distinct depressive
syndromes that can develop while receiving interferon, namely, a depression-specific
syndrome (mood, anxiety, cognitive complaints), and neurovegetative syndrome, (fatigue,
anorexia, pain and psychomotor slowing). Depression-specific symptoms are responsive
to serotonergic antidepressants, whereas neurovegetative symptoms are not. Antidepressant
therapy maybe prescribed in a prophylactic approach to patients in whom pre-treatment
screening indicates possible positive symptoms of depression. Success in reducing
the incidence of depression without an impact on the SVR during treatment has been
reported.[165] IFN-induced sleep deprivation manifested together with irritability
and anxiety should not be confused with depression, and should be managed with anxiolytics.[166]
Early consultation and follow up with a psychiatrist is desirable whenever psychiatric
symptoms are suspected.
Recommendations
The peg-IFN-α and RBV should be temporarily interrupted if the ANC falls below 500/mm3,
or hemoglobin falls below 8.5 g/dl respectively (Grade A). The combination of peg-IFN-α
and RBV should be stopped if severe hepatitis flare or severe sepsis occur (Grade
C).
The use growth factors is associated with an increased cost of therapy and a lack
of sufficient evidence towards improvement of sustained virologic response (SVR) (Grade
B). When deciding to use recombinant erythropoietin (EPO) and G-CSF, an 80% or more
of RBV and peg-IFN-α dose should be maintained during the course of therapy so that
the benefit of adherence can be achieved (Grade D).
Peg-IFN-α- induced neutropenia does not correlate with increased frequency of infection
episodes (Grade C). The use of granulocyte colony-stimulating factor (G-CSF) does
not reduce the rate of infections (Grade C)
Improving treatment success rates
Before starting antiviral therapy, patients must be instructed about the schedule
and the side effects to be expected during treatment. Patients should also be instructed
about preventive and therapeutic measures to ease these side effects. Adherence to
an antiviral treatment regimen is generally defined as taking ≥80% of treatment regimen
for ≥80% duration of therapy. In order to maintain maximum exposure to each drug after
dose reductions and hence, improve the response rate, a full dose should be resumed
whenever possible.[167] Diabetes control, weight reduction for obese[168] and reduction
of or abstention from alcohol intake are important measures to consider before initiating
antiviral therapy.
Recommendations
In order to optimize SVR rates, complete adherence to both peg-IFN-α and RBV regimens
should be emphasized (Grade B).
Pre-treatment weight reduction in obese individuals and good control of diabetes mellitus
may increase the chance of SVR (Grade B).
TREATMENT OF CHRONIC HCV NAÏVE PATIENTS
Genotypes 1 and 4 HCV infection
The SVR reported by registration trials for peg-IFN-α was 46% and 42% in patients
with HCV genotype 1 treated with peg-IFN-α 2a or peg-IFN-α 2b and RBV, respectively.[154
155] The reported SVR rates using peg-IFN-α and weight based RBV in large prospective
trials of genotype 4 were 54% to 68%.[169–171] The optimal treatment regimen for HCV
infection with genotypes 1 and 4 is peg-IFN-α based RBV (13- 15 mg/Kg/day) divided
into two doses, for a duration of 48 weeks. The dose of peginterferon alfa-2a (Pegasys®)
is 180 μg subcutaneously per week, and the dose of peginterferon alfa-2b (PegIntron®)
is 1.5 μg/kg subcutaneously per week. Direct acting antiviral agents (Boceprevir and
Telaprevir) have recently been approved for use as triple therapy in chronic HCV genotype
1 infected patients[172
173] (See section on triple therapy of HCV genotype 1).
Recommendations
Treatment with peginterferon plus ribavirin should be planned for 48 weeks; the dose
for peg-IFN-α 2a (Pegasys®) is 180 μg subcutaneously per week, and for peg-IFN-α 2b
(PegIntron®) is 1.5 μg/kg subcutaneously per week together with weight- based (13-15mg/kg/day)
RBV (Grade A).
Genotypes 2 and 3 HCV infection
In patients infected with HCV genotypes 2 and 3, the reported SVR is 76% and 82% of
cases treated with peg-IFN-α 2a plus RBV, and peg-IFN-α 2b plus RBV, respectively.[154
155] A recent meta-analysis showed higher SVR rates in genotype 2 than in genotype
3 infected patients treated for 24 weeks (74% vs. 69%, respectively).[174] Treatment
with peg-IFN plus RBV should be administered for 24 weeks, using a fixed dose of RBV
at 800 mg per day. However, those with a BMI beyond 25 or those who have baseline
factors suggesting low responsiveness (high viral load, insulin resistance, metabolic
syndrome, severe fibrosis or cirrhosis) should receive a weight-based dose of RBV,
similar to genotypes 1 and 4.[175]
Recommendations
Treatment with peg-IFN plus RBV should be planned for 24 weeks; the dose for peg-IFN-α
2a(Pegasys®) is 180 μg subcutaneously per week, and for peg-IFN-α 2b (PegIntron®)
is 1.5 μg/kg subcutaneously per week, together with 800 mg RBV (Grade A).
Adequate RBV doses at 15 mg/kg should be administrated to patients with genotypes
2 and 3 who have baseline factors that predict low responsiveness to peg-IFN, such
as obesity and cirrhosis (Grade D).
Genotype 5 and 6 HCV infection
Patients with genotypes 5 and 6 infections are under-represented in trials of peg-IFN
and RBV, due to their limited distribution globally. In the non-randomized retrospective
studies of genotype 5 that are limited to small numbers of patients, the reported
SVR, using 24-48 weeks non-pegylated and pegylated IFN and RBV, was 48% to 60%.[176–178]
The reported SVR rate in HCV-6 patients treated with a 48-week regimen of peg-IFN
and RBV varies between 66% and 86%.[179–181] There are insufficient data to determine
the optimal treatment regimen for genotypes 5/6, and further studies are needed. Until
robust data are available, the treatment regimen for patients with genotype 5 / 6
infections should follow the recommendations for patients with genotype 1 and 4 infections,
using peg-IFN and a weight-based dosage of RBV, over a period of 48 weeks.
Recommendations
Treatment with peg-IFN plus ribavirin should be planned for 48 weeks; the dose for
peg-IFN-α 2a (Pegasys®) is 180 μg subcutaneously per week, and for peg-IFN-α 2b (PegIntron®)
is 1.5 μg/kg subcutaneously per week, together with a weight-based dosage of RBV (Grade
C).
Direct-acting antivirals in treatment naïve patients
In many patient populations, the outcome of standard HCV therapy with peg-IFN-α and
RBV is not satisfactory. The advanced knowledge of the structures of HCV polymerases
and proteases has meant that structure-based drug design can be used to develop direct
inhibitors to these enzymes. This category of antivirals is called “direct-acting
antivirals” (DAAs).
Currently, many drugs at different stages of development are under investigation.
Of these, Telaprevir and Boceprevir are NS3/4A protease inhibitors. Each has been
the subject of several large recently completed multicenter phase 3 clinical trials,
and they have subsequently been added to some international institutional guidelines
for the treatment of HCV genotype 1.
The efficacy of telaprevir in combination with peg-IFN-α 2a and RBV in the treatment
of naïve HCV genotype 1 patients has been evaluated in several phase 2 and 3 studies.
A landmark phase 3 (ADVANCE) trial,[173] evaluated the efficacy of telaprevir with
peg-IFN-α 2a and RBVin 1088 treatment-naïve patients with genotype 1 chronic HCV.
Patients were randomly assigned to one of three different treatment regimens. SVR
rates were significantly higher (69% to 75%, versus 44%) in patients who received
a regimen containing telaprevir, in comparison with a standard of care treatment regimen.
The most commonly encountered adverse events in the telaprevir-based groups were pruritus,
rash, and anemia.
Another (ILLUMINATE) trial,[182] was a phase 3 non-inferiority trial, designed to
evaluate differences in SVR rates between a 24-week period and a 48-week period of
telaprevir-based therapy in patients who had an extended rapid virologic response
(eRVR; HCV RNA < 25 IU/mL at both weeks 4 and 12). In this trial, a total of 540 treatment-naïve
patients with HCV genotype 1were included. The overall SVR rate was 72%, and an eRVR
was achieved in 65%. Among patients with an eRVR, the SVR rate in the 24-week treatment
group (92%) was non-inferior to the SVR rate in the 48-week treatment group (88%).
Boceprevir is another NS3/ 4A protease inhibitor. Its efficacy against HCV genotype
1 was evaluated in several trials. A phase 3 SPRINT-2 trial studied boceprevir in
combination with peg-IFN-α 2b and RBV in 1097 treatment naive genotype 1 HCV patients.[172]
All patients received a 4-week lead-in of peg-IFN-α 2b and RBV. They were subsequently
randomly assigned to 3 groups: group 1 (the control group) received placebo plus peg-IFN/RBV
for an additional 44 weeks, group 2 received boceprevir plus peg-IFN/RBV for 24 weeks,
and those with a detectable HCV RNA level between weeks 8 and 24 received placebo
plus peg-IFN/RBV for an additional 20 weeks, group 3 received boceprevir plus peg-IFN/RBV
for 44 weeks. SVR was achieved in 125 of the 311 patients (40%) in group 1, in 211
of the 316 patients (67%) in group 2 (P < 0.001), and in 213 of the 311 patients (68%)
in group 3 (P < 0.001).
These drugs appear promising in the treatment of HCV genotype 1. However, they are
limited by their proven efficacy against HCV genotype 1 only; in addition, concerns
about their side effects and long term resistance profile exist. Preclinical data
suggests that, with the currently used dosages, boceprevir might not be effective
in HCV genotype 4. In a proof-of-concept study, telaprevir has shown activity against
HCV genotype 4 during 15 days monotherapy or in combination with peg-IFN and RBV when
compared to peg-IFN, RBV and placebo.[183]
Recommendations
The combination of peg-IFN/RBV is the approved standard of care for chronic hepatitis
C, especially non-genotype1 (Grade A)
The most effective regimen for treating HCV genotype 1 is the use of triple therapy,
with boceprevir or telaprevir in combination with peg-IFN/RBV (Grade A)
Clinical trials of HCV antiviral therapy in Saudi Arabia
When peg-IFN was internationally introduced, early, multiple trials were performed
in Saudi Arabia. Shobokshi et al., treated 180 HCV genotype 4 patients in a randomized
open label multicenter trial. The first group received 180 μg peg-IFNα 2a weekly,
plus 800 mg/day RBV for 48 weeks, the second group received peg-IFN monotherapy, and
the third group was treated with standard IFN-α 2a 4.5 MU TIW plus 800 mg/day of RBV.
At the end of the follow up, SVR was seen in 50% of the patients in the peg-IFN combination
therapy group, compared with 28% in the peg-IFN monotherapy group, and 30% in the
standard IFN combination group.[184] Al Faleh et al., randomized 96 patients with
fixed doses of either 100 μg of peg-IFN-α 2b plus 800 mg/day of ribavirin or standard
IFN plus RBV combination therapy. SVR was achieved in 43.8% of patients in the peg-IFN
arm and in 29.2% of patients in the standard IFN arm. These results did not achieve
statistical significance, probably because of the relatively small sample size.[185]
A retrospective study by Al Ashgar et al., was performed on peg-IFN-α 2a and RBV in
335 patients with chronic hepatitis C, of whom 54.5% were genotype 4, and 22.15% genotype
1. The SVR was 55.1%.[186] Another retrospective study by Dahlan et al., on 240 patients
who received peg-IFN-α- 2a or peg-IFN-α- 2b with standard dose of RBV, undertaken
between 2003-2007, found that 64% of patients with genotype 4 had SVR.[187]
Response-guided therapy of chronic HCV infection
The rapidity with which a patient clears HCV RNA during therapy has very important
implications for predicting the likelihood of a response to treatment, for determining
the optimal duration of treatment, and as a stopping rule for antiviral therapy. In
patients infected with HCV genotype1 and 4-6, HCV RNA levels should be assessed at
the following times: baseline, week 4, week 12, and at the end of treatment. Week
24 HCV RNA testing is indicated in patients who do not obtain negative HCV RNA at
week 12, i.e., in partial early virological responders (pEVR). In patients infected
with HCV genotypes 2 and 3, HCV RNA levels should be obtained at baseline, week 4
and week 24. Week 12 HCV RNA level should be tested in patients who do not achieve
rapid virological response (RVR). All HCV patients who achieve end of treatment response
(ETR) should have their HCV RNA level tested six months after completing antiviral
therapy, in order to establish whether SVR has been achieved, or relapse has taken
place.
Rapid virological response
A rapid virologic response (RVR) is defined as having undetectable HCV RNA in serum
after the first 4 weeks of antiviral therapy. The achievement of an RVR identifies
those patients who are most sensitive to IFN, and is highly predictive of obtaining
an SVR, independent of genotype and treatment regimen; an SVR rate of 91% is reported.[188]
Approximately 20% of persons with HCV genotypes 1 and 4 infections and 66% with HCV
genotype 2 and 3 infections achieve an RVR.[189
190]
Early virologic response and delayed virological response
Early virologic response (EVR) is defined as a greater than 2-log drop in viral load
at 12 weeks of therapy. An EVR is sub-classified into a complete EVR (cEVR), defined
as undetectable HCV RNA in serum at 12 weeks of therapy, and a partial EVR (pEVR),
defined as a greater than 2-log decrease in the level of HCV RNA in serum at week
12 of therapy.
Approximately 97% to 100% of treatment-naive patients with HCV genotype 1 infection
who do not achieve EVR, fail to obtain an SVR.[191
192] In contrast, an EVR is less accurate in predicting an SVR. A complete EVR is
a better predictor of an SVR than a 2-log reduction in HCV RNA. The clinical utility
of an EVR is less useful in persons with HCV genotype 2 and 3 infections, since the
majority clear virus by week 12 and respond to treatment. In patients with detectable
HCV RNA (≥50 IU/ml) at week 24, i.e., partial virological response, treatment should
then also be stopped, due to a small chance of SVR (1–3%).[192
193] Delayed virological response (DVR), also known as slow virological response,
is defined as a more than 2 Log10 drop in HCV RNA level at week 12 (pEVR) but with
an undetectable level at week 24, and maintained undetectability to the end of treatment.
Stopping rules for combination therapy with peginterferon and ribavirin
All HCV patients who have null response [defined as > 2 log reduction in HCV RNA level
at week 12 but detectable viral load (>50 IU/ml) at week 24] must abandon antiviral
therapy.
INDIVIDUALIZED TREATMENT DURATION ACCORDING TO ON-TREATMENT VIROLOGIC RESPONSE
Shortening the duration of antiviral therapy based on RVR
It may be possible to shorten the duration of treatment for patients with genotypes
1 or 4 who achieve an RVR, from 48 to 24 weeks.[194
195] Treatment for those patients with genotypes 2 or 3 who achieve an RVR, could
possibly be shortened to 16 weeks from 24.[196–199] However, a large,multicenter international
trial[199] randomly assigned 1469 patients with HCV genotypes 2 or 3 to receive 180
μg of peg-IFN-α 2a weekly, plus 800 mg of RBV daily for a period of either 16, or
24 weeks. The SVR rate was significantly lower in patients treated for 16 weeks than
in those treated for 24 weeks (62% vs. 70% respectively). In addition, among those
patients treated for 16 weeks only, there was a higher relapse rate (31% versus 18%).
Shortening the duration of antiviral therapy across all genotypes should not be attempted
if patients have any of the following negative predictors: high viral load (genotypes
1 and 4 > 600,000 IU/ mL, genotypes 2 and 3 >400,000 IU/mL), advanced fibrosis of
≥F3 on metavir, insulin resistance, metabolic syndrome, and non-viral steatosis or
HIV co-infection.
Extension of duration of antiviral therapy based on DVR
Strategies to improve SVR rates in patients who achieve undetectable HCV RNA between
weeks 12 and 24 of therapy, delayed virologic response (DVR), or so-called slow responders,
may include extension of duration of therapy for another 24 weeks. For patients with
genotypes 1 and 4 infection who have DVR, consideration could be given to extending
treatment to a duration of 72 weeks, with the intention of minimizing the risk of
relapse.[200–204] However, in the era of direct acting antiviral therapy, all genotype
1 infected patients are expected to undergo triple therapy, and therefore extension
of the treatment for another 24 weeks would probably not be necessary, due to the
normally impressive SVR rate obtained with triple therapy. In patients with genotypes
2/3 infection with no RVR, treatment of 48 weeks duration is advised.[175] Insufficient
data exist for other genotypes.
Recommendations
A highly sensitive quantitative HCV RNA PCR with a lower limit of detection of 50
IU/ml or less should be used when treating HCV infection (Grade A).
Before initiating antiviral therapy, patients must have genotyping performed. Knowledge
of the HCV genotype will determine the dose of ribavirin and treatment duration (Grade
A).
Antiviral therapy must be discontinued if patients fail to achieve more than 2 log
reduction in HCV RNA at week 12 of treatment (Null response) (Grade A). Patients who
achieve more than 2 Log reduction in HCV RNA at week 12 but remain detectable (≥50
IU/ml) at week 24 should discontinue treatment(partial response) (Grade A).
Shortening the duration of antiviral therapy in patients who achieve RVR should also
be attempted in patients who lack pretreatment negative predictors (Grade B).
Extension of antiviral therapy to 72 weeks should be considered in HCV genotype 1
and 4 patients if delayed virological response is obtained (Grade A). Similarly, patients
with genotypes 2 and 3 who have no RVR with pre-treatment negative predictors may
be considered for extention of the treatment to 48 weeks (Grade C).
RE-TREATMENT OF EXPERIENCED CHRONIC HCV PATIENTS
Poor adherence to antiviral regimen by patients, and inappropriate dose reductions
can both contribute to low response rates. Significantly, 20% to 50% of patients treated
with peg-IFN and RBV will not achieve an SVR.
Null responder and partial responder
Approximately one third of patients treated with peg–IFN and RBV are unable to obtain
negative viremia before week 24. These patients may be either null responders, or
partial responders. The decision to engage on a repeated course of therapy must be
individualized for each patient in the light of potential benefits, when options are
limited, and the chances for success quite low. Non-responders to previous non-peg-IFN
can be retreated with peg-IFN-α -2a or 2b and RBV. Re-treatment with peg-IFN and RBV
has been shown to result in an SVR rate of 40% among patients who were previously
treated with IFN monotherapy, but this rate dropped to 10% in those who had previously
received combination therapy with non-peg-IFN and RBV.[205–207] Re-treatment of patients
who failed to respond fully to a previous full treatment regimen of peg-IFN-α/ RBV
with the same or a different peg-IFN regimen, showed disappointing results, and is
not recommended.[208] Given the unfortunate SVR rate for re-treatment of HCV patients,
all non-responders genotype 1 and relapsers to previous peg-IFN treatment should be
considered for triple therapy using protease inhibitors.[209
210] Re-treating non-responders for a longer duration improved response rates, although
in general the rates remained disappointingly low. In the REPEAT trial,[211] extension
of peg-IFN-α 2a therapy to 72 weeks in patients who had previously been treated with
peg-IFN-α 2b (the study included all genotypes, but genotype1 was the predominant
one) showed an SVR rate of 16%, compared with 8% of those who received 48 weeks of
treatment. The major limitation of the REPEAT study was that 64% of patients had an
unknown response to their previous peg-IFN therapy. Non-genotype 1 patients with DVR
in the first cycle of treatment who have evidence of inadequate exposure to either
peg-IFN-α or RBV (due to dose adjustments or poor adherence during the first course
of therapy) could be considered for re-treatment with peg-IFN-α and RBV. Non-responders
to peg-IFN and RBV with baseline cirrhosis should generally undergo screening and
surveillance for HCC and varices.
Relapsers
The reported relapse rate after treatment with peg-IFN-α and RBV is approximately
15–25%. Patients who relapsed after treatment with standard IFN-based regimens responded
to re-treatment with peg-IFN-α and RBV in 32–53% of cases.[206] Re-treatment with
peg-INF-α 2a of patients who relapsed after prior peg-IFN and RBV was reported in
a small, open-label, multicentre trial, which included 28 relapsers, of whom 68% then
achieved SVR.[211] All genotype 1 patients who have relapsed after a previous peg-IFN
course should be considered for re-treatment with triple therapy using protease inhibitors.[208
209]
Recommendations
HCV patients with non-genotype 1infection experiencing prior non-response or relapse
after non-peg-IFN therapy with or without RBV, or previously treated with peg-IFN
monotherapy, may be considered for a second course of therapy with peg-IFN plus RBV
(Grade B).
HCV patients with non-genotype 1 infection who had previously shown a null or partial
response pattern, where an adequate dose of peg-IFN and RBV had been administered
during the first course of antiviral therapy, should not be subjected to another course
of combination therapy using same or different peg-IFNs (Grade B). These patients
should be followed up for progression of liver disease and could wait for new, more
effective protease inhibitors (Grade C)
Non-responder or relapsers patients with genotype 1 HCV infection after treatment
with either peg-IFN or non-peg-IFN should be considered for re-treatment with a triple
therapy regimen, using direct acting antiviral agents (Grade A).
Role of maintenance antiviral therapy in non-responders
Studies assessing the role of peg-IFN as a maintenance strategy for non-responders[212
213] failed to demonstrate any significant reduction in the clinical endpoints such
as progression of fibrosis, HCC, or death.
Recommendations
Maintenance therapy with peg-IFN is not recommended for patients with bridging fibrosis
or cirrhosis who have previously failed a course of peg-IFN and RBV (Grade A).
DIRECT-ACTING ANTIVIRALS IN TREATMENT-EXPERIENCED HCV PATIENTS
With the arrival of new, direct-acting antiviral (DAA) drugs like telaprevir and boceprevir,
which have been shown to be more effective than re-treatment with a standard regimen,
re-treatment of prior non-responders is now promising.
Recently, two phase 3 studies have evaluated telaprevir. The first was in a prior
non-responders, PROVE 3 (Protease Inhibition for Viral Evaluation) study, and the
second, the REALIZE study (Re-treatment of Patients with Telaprevir-based Regimen
to Optimize Outcomes).[210] In both trials, results after re-treatment of prior non-responders
with different telaprevir regimens in combination with peg-IFN-α 2a and RBV were superior
to those for re-treatment with peg-IFN-α 2a and RBV alone.
The SVR rates ranged from 51% to 66% in the regimens containing triple therapy (telaprevir,
peg-IFN and RBV), and better response rates were demonstrated in relapsers when compared
to non-responders. In these trials, the SVR rates ranged from 69% to 88% in prior
relapsers, while lower SVR rates in non-responders of 29% to 39% were observed. The
majority of patients in these trials had genotype 1 infection.
Boceprevir addition also showed similar improvements in response rates for treatment-experienced
individuals. The addition of boceprevir to peg-IFN and RBV resulted in significantly
higher rates of SVR in previously treated patients with chronic HCV genotype 1 infection,
when compared with those on a regimen of peg-IFN and RB Valone.[209]
In a phase 3 trial (RESPOND-2), boceprevir was evaluated in prior partial responders
or relapsers with peg-IFN and RBV; however, null responders were not included in this
trial. A 4-week lead-in phase of peg-IFN and RB Vand response-guided therapy was required
with different regimens of boceprevir and with peg-IFN-α 2b and RBV. SVR rates were
higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control
group (21%, P < 0.001).
A retrospective analysis of null responders (defined as < 1.0 log10 IU/mL reduction
in HCV RNA after 4 weeks of peg-IFN-α 2b/RBV) to peg-IFN and RBV from the two lead-in
groups of the SPRINT-1 trial was conducted. Following the lead-in phase, patients
received 24 or 44 weeks of boceprevir plus peg-IFN-α 2b/RBV. An SVR was achieved in
25% and 55% of null responder patients treated with 24 or 44 weeks of triple therapy.
Although this analysis pertains to null responders assessed after only 4 weeks of
peg-IFN and RBV, the majority of these patients would have failed to achieve an SVR.
These findings suggest that the additional use of protease inhibitors are not the
answer for this difficult-to-treat population.
There are ongoing trials with other DAAs that could suggest further solutions for
the treatment of non-genotype 1 HCV patients with prior non-response.[214
215]
Recommendations
Patients with HCV genotype-1 who have failed prior standard therapy with peg-IFN-α
and RBV, can be treated with triple therapy with boceprevir or telaprevir, together
with peg-IFN-α and weight-based RBV (Grade A).
TREATMENT OF ACUTE HEPATITIS C
Identification of clinical acute HCV infection is uncommon, since, most of the time
it has a subclinical course with mild or no symptoms. When clinically suspected, a
patient with possible acute HCV should be tested as soon as possible for HCV RNA,
since the antibody testing requires several weeks for sero-conversion.
In the absence of a recent negative HCV test, discriminating between acute HCV and
recently discovered chronic HCV is difficult. Spontaneous clearance of acute HCV infection
can occur in up to 30% of cases, so the decision to treat or to delay treatment should
weigh the possible chance of spontaneous resolution and the cost and possible side
effects of treatment. In most instances, clearance will occur in the first 12 weeks,
and the presence of symptoms predictive of spontaneous clearance can occur in about
30% of patients.[216
217]
Treatment of acute HCV has been shown to reduce the development of chronic HCV infection;
however, there is no consensus on the optimal treatment regimen. Therapy begun before
12 weeks have passed since diagnosis is associated with a better chance of SVR.[218]
Standard IFN alfa is effective in improving biochemical outcomes, and achieving sustained
virologic clearance in 32% of IFN-treated patients, versus only 4% of control group
patients.[219] Several clinical trials have shown that the treatment of hepatitis
C infection during the acute phase is associated with high SVR rates ranging between
75% and 95%.[220] Twelve trials were analyzed (414 patients) in a meta-analysis. The
use of standard interferon appeared to significantly increase the SVR (risk difference
49%; 95% confidence interval 32.9-65%) in comparison to patients on no treatment.[221]
Several studies have evaluated the use of peg-IFN. Once weekly peg-IFN-α 2b monotherapy
(1.5 μg /kg per week) for a period of 12 weeks was evaluated in a major study of 129
subjects with acute HCV. The SVR rates were 95%, 92%, and 76% with treatment onset
at 8, 12, and 20 weeks, respectively. The overall SVR rate was 87%.[218] Patients
infected with genotypes 2, 3, and 4 showed better SVR rates than those infected with
genotype 1. The role of combination therapy with RBV is not well established, and
probably does not improve SVR; however, it might be considered in cases where chronic
infection is suspected.[222
223]
The impact of the duration of therapy with 12 weeks vs. 24 weeks on SVR rate has also
been evaluated in several case series, but no definitive recommendation can be made
about the optimal length of treatment needed for acute hepatitis C. It is however,
advisable to treat for 24 weeks.[224]
Recommendations
There is no clear evidence on the optimum timing for the start of acute HCV therapy,
but treatment can be delayed up to 12 weeks after acute onset of hepatitis to allow
for spontaneous resolution (Grade B).
Treatment with either standard IFN or peg-INF-α monotherapy for 24 weeks is recommended;
however, peg-INF-α is preferable because of its convenience in administration (Grade
B)
TREATING SPECIAL POPULATIONS
Treatment of patients with severe liver disease
Patients with hepatitis C-compensated cirrhosis need to be treated to prevent complications,
especially in the absence of contraindications. Indeed both large cohort studies and
meta-analyses have shown that an SVR in patients with advanced fibrosis is associated
with a significantly decreased incidence of clinical decompensation and HCC. However,
the SVR rates with interferon-based therapy are lower in patients with advanced fibrosis
than in those with mild to moderate fibrosis.[154
155
225] In the study done by Heathcote et al. on patients with compensated cirrhosis,
it appeared that the SVR was reached in 30% of those treated with peg-IFN-α 2a alone,[226]
and in another study by Helbeling et al. after they added two different doses of RBV
(1,000 to 1,200 mg per day or 600 to 800 mg. per day), an SVR was achieved in 52%
and 38% of patients respectively.[227] Dose reduction was necessary in 78% and 57%
of subjects, and serious adverse events developed in 14% and 18% respectively of the
two groups.
Patients with advanced fibrosis usually have low leukocyte and platelet counts secondary
to portal hypertension and hypersplenism and need close monitoring for side effects
of medication. Medication-related hematological side effects may contraindicate therapy,
and it is more evident (vs. frequent) and anticipated in cirrhotic than in non-cirrhotic
patients.[228] The use of growth factors might be useful in treating patients with
advanced fibrosis, which offers the possibility of treatment with full doses of interferon-based
therapy, the eradication of pre-transplantation HCV, and the lower likelihood of post-transplantation
infection.[229–231] Some studies on patients with decompensated cirrhosis preliminary
to liver transplantation have been done. In the earliest reported study, done by Crippin
et al. in 2002, over half of considered patients were found ineligible because of
cytopenias.[232] In 2007, Iacobellis et al. carried out a controlled study,[233] in
which peg-IFN-α 2b, was given in doses of 1.0 μg /kg body weight per week, and RBV
in doses of 800 to 1000 mg daily for 24 weeks; 44% and 7% of patients with genotypes
2 or 3 and genotypes 1 or 4, respectively developed SVR. Treatment was tolerated in
41% reduced in 39% and discontinued in 20%. Over a 30-month follow-up period, only
23% of patients with an SVR decompensated, while 83% of the control group and 62%
of the non-responder group developed decompensation. The conclusion of this study
was that in decompensated cirrhotics, HCV clearance by therapy is lifesaving and reduces
disease progression.[229
234
235] Approximately 75% of patients rendered HCV RNA negative at the time of transplantation,
remain negative post-transplantation. Surveillance for HCC and portal hypertension
should be done regularly, irrespective of SVR achievement, which in turn translates
to a decreased rather than an abolished risk when HCV infection has been eradicated.
Recommendations
Compensated cirrhotics should be treated to prevent future complications (Grade A).
Treatment should be started carefully, with close monitoring for side-effects, and
lower dosages might be used once the patient has been placed on a liver transplant
list, aiming for HCV clearance prior to transplantation. However, this approach is
applicable in only around 50% of patients, and tolerance is poor, particularly in
patients with decompensated cirrhosis (Grade C).
Cirrhotics should undergo regular surveillance for HCC, irrespective of SVR (Grade
B).
Post-Liver transplantati on recurrence
Treatment of established graft lesions with peg–IFN and RBV combination therapy results
in a SVR in around 30% of patients.[236] Most studies initiated therapy at least 6
months post-operatively, in order to optimise patient tolerance and to enable the
addition of RBV.[237]
Since the first deceased donor liver transplantation (DDLT) took place in 1990, more
than 300 DDLTs have been performed in Saudi Arabia. More recently, more than 200 living
donor liver transplantations (LDLTs) have been performed in Saudi Arabia. However,
there is inadequate documentation of the natural history of HCV re-infection after
liver transplantation in the Kingdom and worldwide.[238]
HCV infection recurrence is universal in patients, and tends to be more aggressive
when there is detectable HCV RNA at the time of liver transplantation.[229] The course
of HCV-related liver disease is accelerated in liver transplant recipients, and almost
6% to 23% of patients develop cirrhosis after a median of 3.4 years.[239–241]
Successful therapy has been shown to have a positive impact on both graft and patient
survival.[242] Rates of SVR have been lower than those achieved in the non-transplant
setting. Possible reasons for this difference include high HCV viral load post-LT,
a higher frequency of genotype 1 patients, poor tolerance of treatment after LT, and
the need for frequent dose reductions. Treating a patient pre-emptively before the
biochemical and histological recurrence of hepatitis seems attractive theoretically,
because of low viral levels but the results were not encouraging. The safety efficacy
and patient tolerance of peg-IFN-α alone, or associated with RBV, given pre-emptively,
have been evaluated in two randomized trials, with SVR rates of 8%[243] and 18%,[244]
respectively. Although peg-IFN-α 2a[245] or 2b[244] plus RBV were deemed safe and
were reasonably well tolerated, both demonstrated very poor efficacy early post-LT.
Only 40% to 60% of patients are candidates because of the high doses of immunosuppressive
drugs used, underlying cytopenias, mild renal dysfunction and the presence of other
medical problems during this early period post-liver transplantation, all of which
can have an impact on efficacy. Monotherapy with standard or pegylated IFN is not
advised because of poor SVR rates, as reported in several randomized controlled trials.[243
246
247] Small, uncontrolled, trials of peg-IFN plus RBV report SVR rates of 18% to 19%.
The presence of significant fibrosis or portal hypertension one year after transplantation
is predictive of rapid disease progression and graft loss.[244] Most transplant centers
prefer to delay therapy until recurrent disease is confirmed, either by persistently
raised ALT levels unexplained by other causes, or by the demonstration of significant
fibrosis on liver biopsy (Metavir and IASL stage ≥2 or Batts-Ludwig and Ishak stage
≥3).[248] The decision to treat should therefore take into consideration the benefit
of good SVR rates versus the risks inherent in achieving these (precipitate acute
cellular rejection and side effect of therapy). The threshold for performing a liver
biopsy should be low, in order to assist treatment decisions, and whenever liver tests
worsen during the course of antiviral therapy, to diagnose this, and to use it to
further influence treatment decisions. Data on post-transplant HCV genotype 4 treatment
is scarce. A single center in Saudi Arabia reported twenty-five patients infected
with HCV genotype 4 infections that were treated with peg-IFN-α 2a at a dose of 180
μg/week in addition to 800 mg/day of RBV (the dose was adjusted within the tolerated
range of 400-1,200 mg). Pre-treatment liver biopsies were obtained from all patients.
Biochemical and virological markers were assessed before, during, and after treatment.
Twenty-two patients (88%) achieved EVR (12 patients tested negative for HCV-RNA).
Fifteen (60%) and fourteen patients (56%) achieved an ETR, and a SVR, respectively.
Five patients had advanced pre-treatment liver fibrosis. Pre-treatment ALT was elevated
in 24 patients (96%). The most common adverse effects were flu-like symptoms and cytopenia.
Eighteen patients (72%) required erythropoietin alpha and/or granulocyte-colony stimulating
factors as a supportive measure. One patient developed severe rejection complicated
by sepsis, renal failure, and death. Other adverse effects included depression, mild
rejection, impotence, itching, and vitiligo.[249] No studies using protease inhibitors
in the post-transplant setting have yet been published but are ongoing; however, other
drug interactions with immuno-suppressants is of major concern and needs to be taken
into consideration.[250]
Recommendations
Once chronic hepatitis C recurrence has been documented histologically after liver
transplantation, cautious treatment by an experienced physician should be started
(Grade A).
Urgent initiation of treatment in patients with significant fibrosis one year after
transplantation that predicts rapid disease progression and graft loss (Grade B).
Liver biopsy while on treatment is indicated, if liver enzymes worsen, to rule out
graft rejection, although it is rare (Grade C).
HIV co-infection
Approximately 25% of HIV-infected persons in the western world have chronic HCV infection.[38]
No clear data from Saudi Arabia on treating such group seems to exist. Progression
of liver disease is accelerated in patients with HIV-HCV co-infection, in particular
in those with a low CD4-positive cell count and impaired immune function. For this
reason, early antiretroviral therapy should be considered in patients with HIV HCV
co-infection.[251] Patients with HIV should be tested for the presence of HCV by doing
anti-HCV and HCV RNA tests, especially in those patients with HIV and unexplained
abnormalities in liver function tests and enzymes. The treatment regimen is the same
as that for patients without HIV co-infection. The dose of RBV should always be weight-based,
and the duration of treatment up to 48 weeks, which could be extended in some genotype
1 patients to 72 weeks. Co-administration of RBV with didanosine (ddI) should be avoided
to prevent mitochondrial toxicity and fatal lactic acidosis. Anemia is more pronounced
during therapy with IFN plus RBV when the patient is also taking zidovudine (AZT).
This suggests that there is a cumulative myelo-suppressive effect of IFN plus AZT
that further reduces erythropoiesis that could compensate for the acute RBV-induced
hemolysis.[252] HIV patients with decompensated cirrhosis should be assessed for liver
transplantation if no contraindication exists.
Recommendations
Treatment regimen is the same in HIV co-infected and non-HIV infected patients but
the dose of ribavirin should always be weight-based (Grade B).
Treating HCV in co-HIV infected patients may require longer treatment duration (72
weeks for genotype 1 and 48 weeks for genotypes 2 and 3) (Grade B).
Before using RBV, the physician should make sure that patients are not on AZT, or
ddI (Grade C).
HBV co-infection
In HBV endemic areas, co-infection with HBV and HCV can be seen in people who have
a high risk of parenteral infections, such as injection drug users,[253] patients
on hemodialysis,[254] patients undergoing organ transplantation[255] and HIV-positive
individuals.[256] In patients with HCV-HBV co-infection, HCV is usually the main driver
of chronic hepatitis activity. Although it may fluctuate, the HBV DNA level is often
low or undetectable. Due to the variety of virological profiles in HBV/HCV co-infection,
it is important to assess the dominant virus prior to initiating therapy, and after
hepatitis delta virus infection has been excluded. The HCV dominant virus should be
treated with peg-IFN-α and RBV following the same rules as mono-infected patients.
The SVR rates in this group are broadly comparable or even higher than those in HCV
mono-infected patients.[257
258] There is a potential risk of HBV reactivation during or after HCV clearance.[259]
In that case, or if HBV replication is detectable at a significant level, concurrent
HBV nucleoside/nucleotide analogue therapy may be indicated.
Recommendations
Treatment regimen is the same as for mono-infected patients (Grade B).
Concurrent HBV nucleoside/nucleotide analogue therapy is indicated if there is a significant
HBV replication at any stage, pre-, peri- and post-HCV clearance (Grade C).
Treatment of patients with renal disease
Chronic renal disease represents a global health problem. Chronic HCV infection is
prevalent in patients with end-stage renal disease (ESRD) on hemodialysis (HD), and
in renal transplant recipients, with significant impact on morbidity and mortality.
The prevalence rates reported in HD patients in Middle Eastern countries are 68% in
Saudi Arabia with a range of 14.5% to 94.7%, 26% in Oman, and 80% in Egypt.[251] Patients
with HCV infection and chronic renal disease are prone to develop diabetes mellitus[260]
and denovo glomerulonephritis post-transplantation. Additionally, HCV-infected subjects
have a shorter graft survival after renal transplantation, due to increased risk of
severe infection and liver disease deterioration.[261] Accordingly, there is a general
belief that these patients should be treated before transplantation.[262] Treatment
with current standard combination therapy is challenging in patients with ESRD, due
to its tolerability. Liver biopsy may be needed before treating those patients, because
of the discrepancy between the level of the ALT and the extent of histologic damage
that is noted in such patients.[263] At present, therapy for hepatitis C in patients
with ESRD is controversial, and should be considered only in patients waiting for
renal transplantation, those with significant liver disease, and minimal comorbid
conditions that may affect survival, and in patients with acute hepatitis C. The therapeutic
regimen varies with the severity of the kidney disease. Persons with creatinine clearance
of more than 60 ml/minute can be treated like those patients without kidney disease.
RBV is cleared by the kidneys; therefore hemodialysis patients have been treated with
peg-IFN-α monotherapy.[264] Since peg-IFN-α 2a is cleared through the liver and peg-IFN-α2b
primarily through the kidneys,[265] there could be a theoretical accumulation of peg-IFN-α
2b when used in hemodialysis, although hemodialysis does not appear to affect clearance.[245
266] Even though this has not been formally compared, no obvious differences are observed
clinically. Most experts support the cautious use of peg-IFN-α, adjusting the dose
to the level of renal dysfunction.
Although the current practice is to administer the full dose of peg-IFN-α, the recommended
starting doses for this group are peg-IFN-α 2b, at 1 μg /kg subcutaneously once weekly
or peg-IFN-α 2a, 135 μg subcutaneously once weekly. In the absence of RBV, SVR rates
are substantially lower, and careful patient selection and side effect management
are important. Most studies used a 6-month post therapy SVR as the end point for successful
therapy. Overall, 40% of HCV treated patients had an SVR, including 31% for genotype
1, a rate greater than that reported for IFN monotherapy.[187] In a single-center
study of Saudi hemodialysis patients, peg-IFN-α 2a was found to be well tolerated,
and hematological disturbances appeared to be the most important adverse effects.[267]
At the end of therapy, a response rate of up to 76%, with 69% sustained response was
obtained with Peg-IFN-α 2a therapy. In an earlier study by Huraib et al., HCV RNA
became negative in 76% of patients after 12 weeks of treatment, in 88% after 12 months
of treatment, and in 71% of the patients, 6 months after completion of therapy. Of
13 patients who underwent liver biopsies after 6 months of therapy, 11 patients (85%)
showed histological improvement.[268]
However, the use of peg-IFN and RBV in dialysis patients is hampered by fairly common
side effects. Combination treatment with peg-IFN-α and RBV might be considered by
experienced physicians and used with caution in those with creatinine clearance below
50 ml/minutes,[269] with individualized RBV dosing of 200-800 mg/day, and titrating
the dose based on creatinine clearance and hemoglobin level decline during the first
few weeks of therapy. These patients may need substantial hematopoietic support, as
suggested by few preliminary studies.
HCV post renal transplantation
HCV has been recognized as one of the major causes of morbidity and mortality, and
indicates a poor prognosis for patient and graft survival in renal transplantation.
It is also associated with an increased risk of cirrhosis and its complications. Treatment
of chronic HCV infection with peg-IFN-α and RBV in renal transplant recipients is
associated with a risk of acute or chronic cellular rejection, resulting in graft
loss and reduced patient survival.[270] Accordingly, routine interferon-based antiviral
treatment post-renal transplant should be considered only for selected patients, and
those who develop post-transplantation fibrosing cholestatic hepatitis.[271] Subjects
being considered for renal transplantation should be treated for hepatitis C prior
to transplantation.
The largest retrospective study on 19 patients with stable graft function and absence
of cirrhosis was reported by Aljumah et al., between October 2003 and December 2008,
where the patients received peg-IFN-α 2a/2b and RBV for 48 weeks, with a SVR rate
of 42.1%. Only one patient had graft rejection (5.3%).[272] The result was encouraging,
and another prospective protocol involving 28 adult renal transplant recipients at
two centers in Saudi Arabia, ≥12 months after transplant surgery with confirmed HCV
and evidence of histological disease (METAVIR ≥A2/F2; ≥F3=17) were recruited in a
pilot open-label trial and given peg-IFN-α 2a (135–180 μg/week, based on GFR) plus
RBV (200–1200 mg/day, based on GFR). Safety and laboratory assessments were performed
weekly for 4 weeks, then 2-weekly for 8 weeks, and then 6-weekly for 36 weeks. Renal
biopsy was performed in patients with a 20% increase in serum creatinine from pre-treatment
levels. Twenty seven patients completed at least 12 weeks of therapy, and 21 completed
all study assessments. Dose reductions of peg-IFN and RBV were required in 36% and
54%, respectively for hematological side effects. Overall, 55.6%, 38.5% and 19% achieved
EVR, end-of-treatment response and SVR, respectively. None of the patients experienced
any rejection episodes during or 24 weeks after therapy and the authors concluded
that peg-IFN/RBV therapy in renal recipients is safe, but has limited efficacy in
the treatment of chronic HCV, and as such larger prospectively conducted multicenter
studies in this population subset are needed.[273]
Treatment of patients with cryoglobulinemia-associated glomerulonephritis
Cryoglobulinaemia refers to the presence of abnormal immunoglobulins in the serum,
which have the unusual property of precipitating at temperatures below 37°C and re-dissolving
at higher temperatures. Cryoglobulins (CGs) are classified, on the basis of their
clonality, into three types. Type II CGs and type III CGs (mixed cryoglobulinaemia)
are highly prevalent in patients with chronic HCV infection. Mixed cryoglobulinaemia
(MC) can be found in 29-54% of patients with HCV infection according to different
studies.
MC can be associated with systemic vasculitis, renal impairment and peripheral neuropathy.
Treatment of HCV related cryoglobulinemia is challenging, and should be restricted
to symptomatic patients in order to avoid unnecessary complications like exacerbation
of vasculitis in patients with cryoglobulinemia-associated glomerulonephritis during
treatment by interferon.[274
275] Improvement of clinical MC is reported in 50% to 70% of patients receiving antiviral
therapy based on IFN-α and RBV, and correlates with the reduction of HCV RNA concentrations.[276
277]
Antiviral therapy should thus be considered as the first line therapeutic approach
in HCV-infected patients with MC-related disorders. However, with multi-organ involvement,
antiviral therapy may be have to be limited due to the severity of a specific MC-related
disorder, treatment failure, side effects or contraindications. In such cases, other
therapeutic strategies, such as immuno-suppresion and/or plasmapheresis should be
considered.
Persons with progressive renal failure generally require treatment with immunosuppressive
therapy, steroids and plasmapheresis.[278] The role of IFN-based antiviral therapy
can be considered for those with mild to moderate kidney disease, or after controlling
the acute flare with immunosuppressive agents.[279] Most of the studies regarding
the treatment of MC are small and uncontrolled, thus there is no evidence-based data
on which to base firm recommendations. It is therefore suggested that persons with
moderate proteinuria and slowly progressive kidney disease can be managed by means
of a regimen of one year of low dosage RBV (200 mg-800 mg/d) in combination with IFN-α
or peg-IFN-α, and in most cases this is well tolerated by HCV patients, and leads
to SVR and significant improvement of GFR.[280]
Recommendations
Liver biopsy should be individualized if the decision is made to treat HCV in a chronic
renal disease patient (Grade C).
The same standard combination antiviral therapy can be used to treat persons with
chronic HCV infection and mild renal disease (GFR >60 mL/minute) (Grade C).
Non-hemodialysis patients with severe renal disease can be treated cautiously with
reduced doses of both peg-IFN (alpha-2a, 135 μg/week; alpha-2b, 1 μg/kg/week) and
RBV (200-800 mg/day) (Grade C).
Patients on hemodialysis can safely be treated with peg-IFN-monotherapy (Grade A).
Combination treatment with individualized doses of RBV can be considered in selected
patients (Grade C).
Patients on a renal transplant list should be treated prior to transplantation to
avoid the risk of treatment-induced acute graft rejection post-transplantation (Grade
B).
Treatment is recommended post-renal transplant only in selected patients and those
with fibrosing cholestatic hepatitis (Grade C).
Patients with cryoglobulinemia and mild to moderate proteinuria or slowly progressive
renal disease can be treated with either standard IFN or reduced doses of peg-IFN-α
and RBV (Grade C).
Patients with cryoglobulinemia and marked proteinuria with evidence of progressive
renal disease or an acute flare of cryoglobulinemia can be treated with rituximab,
cyclophosphamide plus methylprednisolone, or plasma exchange, followed by interferon-based
treatment once the acute process has subsided (Grade C).
Alcohol and drug abuse
Chronic alcohol consumption in patients with chronic hepatitis C is associated with
an accelerated fibrosis progression, cirrhosis, and an increased risk of HCC.[281]
SVR rates are lower in patients with alcohol abuse.[281] Patients regularly consuming
alcohol should not be excluded from treatment, but should receive counseling to stop
their consumption, and additional support to improve regimen-adherence during therapy.
Illicit injection drug use is the predominant mode of HCV transmission and little
data are available on the treatment of active drug users. Patients should be drug-free
for at least 6 months before treatment, and close monitoring by an experienced multidisciplinary
team of hepatologists and addictologists to be sure that they will adhere to treatment
and regular follow- up visits is necessary.[282]
Recommendations
Alcohol consumption should be strongly discouraged (Grade A).
Patients on stable maintenance substitution can be treated for HCV in an interdisciplinary
team who need to also consider their slightly reduced SVR-rates when compared to conventional
HCV patients, as the treatment should be individualized (Grade B).
Illicit drug users should continue receiving support and counseling parallel to HCV
treatment (Grade C)
Treatment of persons with psychiatric illnesses
The increasing use of IFN for treating patients with hepatitis C has resulted in recognition
of and increasing concern about the psychiatric side effects that can result from
treatment. These effects can occur either shortly after beginning IFN therapy, or
later, as a result of continued treatment. Patients may report some psychiatric illness
during the course of their treatment, such as depression, anxiety, and occasional
suicidal ideation, and a high percentage of previous drinkers and drug users tend
to relapse. A combination of some or all of these factors would lead to an argument
against treating this population. Significant depressive symptoms occur in 21% to
58% of IFN-treated patients. Case studies have demonstrated that pharmacologic interventions
are beneficial in reducing iatrogenic psychiatric symptoms, while allowing patients
to maintain IFN therapy.[283]
Former or current drug abuse and mental disorders are considered risk factors. In
addition, reports of suicide attempts during IFN-α therapy and the risk of reinfection
has led to the opinion that the use of IFN-α is contra-indicated for patients with
a preexisting mental disorder, ongoing opiate abuse, or methadone substitution. As
a consequence, most of these patients remain untreated, despite fulfilling the medical
criteria for antiviral treatment of chronic hepatitis C.
However, a recent prospective controlled trial[284] provided evidence that treatment
of chronic hepatitis C infection with peg-IFN-α and RBV is possible in different subgroups
of “difficult-to-treat” psychiatric patients, and treating them in interdisciplinary
treatment units in order to optimize adherence and response rates and to manage side
effects is recommended. Most psychotropic agents are thought to be safe. However,
consideration should be given to drug interactions and dose modification in patients
with advanced liver disease.
Recommendations
Patients with HCV infection and concomitant mental and psychiatric disorders can be
considered for treatment using the currently approved regimens (Grade C).
Treatment of hepatitis C infection in patients with psychiatric disorders should be
undertaken only with the support of a multi-disciplinary team that should include
psychiatric counseling services prior to therapy (Grade C).
Hemoglobinopathies
Thalassemia major, which requires frequent blood transfusions, and sickle cell disease
are among the common hemoglobinopathies that challenge the physician. These patients
have higher incidence of anemia and iron accumulation when treated with standard combination
Hepatitis C therapy. They can however, be treated with standard combination therapy,
but these complications should be carefully managed with growth factors, blood transfusions,
and iron chelation therapy when needed.[285] Chronic HCV infection is frequent in
individuals with sickle cell anemia (SCA). They have life-long anemia, chronic hemolysis,
and at times also have hematological crises, which can worsen the anemia and require
chronic transfusions. The HCV antibody positivity is directly related to the number
of transfusions given, and on average the prevalence rate in transfused patients is
more than 10%. It is known that the combination of iron overload and HCV can lead
to a more rapidly progressive liver disease. The treatment of HCV in sickle cell patients
poses a challenge to clinicians. A novel approach described by some is the pre-treatment
of these patients with hydroxyurea to increase fetal hemoglobin, therefore decreasing
the severity of RBV-related hemolysis. Individual cases have been successfully treated
with a combination of peg-IFN-α and RBV. In one study in Saudi Arabia, fifty-two patients
with SCA and HCV were treated over a period of 7 years. All were treated with peg-IFN
and a standard dose of RBV for 24 weeks for those with genotype 2 and 3 infections,
and for 48 weeks for those with genotype 1 and 4 infections. Only 8 were receiving
hydroxyurea at the time of treatment. All tolerated the treatment well and none experienced
a decrease in their Hb, which required blood transfusion before, during or after therapy.
There were no hematological side effects attributable to RBV at the usual recommended
dose. Thirty-seven (71.2%) achieved SVR. The authors showed that patients with SCA
and HCV can be treated with peg-IFN and RBV at the usual recommended dose, including
those who are not receiving hydroxyurea. The conclusion from this study was that treating
HCV infection in SCA patients is considered to be safe and effective, and the response
rates in these patients are comparable to those of patients without SCA.[286]
In addition, a case series from the western province of Saudi Arabia enrolled 8 patients
with chronic HCV infection and SCA, who were treated with peg-IFN-α-2a and RBV for
one year. All 8 patients had a cEVR. Seven out of the 8 patients had an ETR of whom,
5 achieved SVR. Hemoglobin concentrations measured at 1, 3, 6, 9, and 12 month intervals
during their treatment showed no significant changes from those measured at baseline.
The study was able to conclude that treatment of chronic HCV hepatitis in patients
with SCA with peg-IFN-α-2a anc[287]
Recommendations
Patients with hemoglobinopathies can be treated with combination therapy, but need
careful monitoring for hematologic side effects (Grade C).
CONCLUSIONS
The SASLT guideline for HCV provides a concise, updated, evidence-based review of
the diagnosis and management of chronic HCV infection in Saudi Arabia. This may help
to initiate plans to prevent HCV infection in the population, to bring about early
and accurate diagnosis of patients, and to facilitate appropriate and timely referrals
between primary, secondary, and tertiary care providers. This guideline also aims
to help identify gaps in the knowledge and understanding of the incidence of HCV in
Saudi Arabia requiring further research. As noted above there is a large population
of patients with few therapeutic options, and DAA therapy has become the focus of
investigations and once additional information is available, this guideline needs
to be updated.
Disclosures
Dr. Sanai is a consultant for advises, is on the speakers’ bureau of and received
grants from Bristol-Myers Squibb. He has been a consultant for and advised Scherring-Plough
and Merck Sharp and Dohme, is on the speakers’ bureau of and received grants from
Roche and Glaxo- SmithKline. Dr. Altraif is a consultant and advises Scherring-Plough,
Merck Sharp and Dohme and Roche, and has received grant support from Roche. Dr. Alghamdi
is on the speakers’ bureau of Bristol-Myers Squibb, Roche and Merck Sharp and Dohme.
Dr. Alswat advises and is on the speakers’ bureau of Merck Sharp and Dohme. Dr. Alfaleh
has been a consultant for Schering Plough and has received grant support from Schering
Plough.