SPECIAL COMMUNICATION - PRACTICE GUIDELINES
|Year : 2012 | Volume
| Issue : 7 | Page : 1-32
|SASLT practice guidelines: Management of hepatitis C virus infection
Abdullah S Alghamdi1, Faisal M Sanai2, Mona Ismail3, Hamdan Alghamdi4, Khalid Alswat5, Adel Alqutub6, Ibrahim Altraif4, Hemant Shah7, Faleh Z Alfaleh5
1 Department of Medicine, Gastroenterology Unit, King Fahad General Hospital, Jeddah, Saudi Arabia
2 Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City, and King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs; Liver Disease Research Center, National Plan for Science and Technology, King Saud University, Riyadh, Saudi Arabia
3 Department of Medicine, Division of Gastroenterology, King Fahad Hospital of the University, College of Medicine, University of Dammam, Dammam, Saudi Arabia
4 Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City, and King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
5 Liver Disease Research Center, National Plan for Science and Technology; Department of Medicine, Gastroenterology unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia
6 Department of Medicine, Gastroenterology Unit, King Fahad Medical City, Riyadh, Saudi Arabia
7 Division of Gastroenterology, University Health Network, University of Toronto, Toronto, Ontario, Canada
Click here for correspondence address and email
|Date of Web Publication||18-Sep-2012|
Keywords: Hepatitis C, prevalence, fibrosis, histology, treatment, pegylated interferon, direct acting antiviral, response
|How to cite this article:|
Alghamdi AS, Sanai FM, Ismail M, Alghamdi H, Alswat K, Alqutub A, Altraif I, Shah H, Alfaleh FZ. SASLT practice guidelines: Management of hepatitis C virus infection. Saudi J Gastroenterol 2012;18, Suppl S1:1-32
|How to cite this URL:|
Alghamdi AS, Sanai FM, Ismail M, Alghamdi H, Alswat K, Alqutub A, Altraif I, Shah H, Alfaleh FZ. SASLT practice guidelines: Management of hepatitis C virus infection. Saudi J Gastroenterol [serial online] 2012 [cited 2015 Nov 30];18, Suppl S1:1-32. Available from: http://www.saudijgastro.com/text.asp?2012/18/7/1/101155
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
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.
Recommendation based on high quality case-control or cohort studies or a high quality systematic review.
Recommendation based on non-analytic studies (case reports or case series).
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. ,, 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. 
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.  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.  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. 
The prevalence in the general population is generally considered uncertain, since most studies were conducted more than 10 years ago. ,,, 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%.  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%.  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%.  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. ,
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.  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%. ,,
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.  On the other hand, a community-based study of equal numbers of men and women did not find any gender differences in infection rates.  A retrospective study in the Eastern Province did not find any significant differences in HCV infection between men and women either.  In two further separate reports, the prevalence of HCV infection was not shown to differ between men and women. ,
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. 
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.  (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. ,,,,, The most common subtypes of genotype 4 HCV among Saudis are 4c/4d followed by subtypes 4h, 4e, and 4a. ,
The primary source of HCV transmission is parenteral exposure to HCV-infected blood or blood products.
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. ,, 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.  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. ,
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. , 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.  Another investigational study followed the epidemiology of HCV in a dialysis unit after methods to reduce prevalence of the virus were set in place.  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.  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.  Several studies have also referred to patient isolation as an important factor in preventing transmission of viral hepatitis in hemodialysis units. ,, 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%. 
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. , 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.  An earlier study showed that the HCV infection among IV drug users in a Jeddah detoxification center was 69%. 
Other risk factors
Additional potential risk factors for HCV transmission include exposure to an infected sexual partner, or multiple sexual partners, and perinatal exposure.  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,  while two others showed that neither intrafamilial  nor perinatal  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.  In addition, a study by Al Faleh et al., has documented a history of prior blood transfusion in 14.8% of infected patients.  The low prevalence of HIV in the Saudi population relegates it as a risk factor of marginal importance in the local setting. ,, Other high risk group patients such as patients with thalassemia major and hemophilia have a prevalence rate of 70% and 78.6%, respectively. , A prevalence of 15.9% has been reported in patients with sexually-transmitted diseases  and high risk behavior.
- 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). 
| Natural History|| |
The HCV is one of the most important Flaviviridae infections in humans, and is the second most common cause of viral hepatitis.  HCV has six major genotypes, which are indicated numerically (1 to 6) according to the international Simmonds classification. 
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.  Of these, 5-20% have been reported to develop cirrhosis over a period of 20 to 25 years. ,, 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.  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). ,
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. 
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. ,,,,, 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). ,,
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. ,,,,, 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. ,,
| 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 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. ,
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. 
Aminotransferase levels become elevated approximately 6-12 weeks after exposure, and can be more than 15 times the upper limit of normal. 
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. 
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. 
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. ,
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. ,
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. 
Cirrhosis and hepatocellular carcinoma
Patients with normal serum transaminases activity have a lower fibrosis progression rate (15%) than those patients with elevated enzymes. 
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. ,
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%. 
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. ,
- 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.  Additionally, viral genotype and/or viral load do not correlate with the amount of liver injury.  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.  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.  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. , 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.
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%;  at the same time, they are reproducible and inexpensive.  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. , 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). , 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. 
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.  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. 
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%.  If a reaction with two or more of the antigens is seen, the RIBA test is considered positive.  Reaction with only one antigen gives an indefinite test result; only about 10% of these patients are HCV-RNA-positive.  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. ,,
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 10 7 IU/ml. Their dynamic quantification range adequately covers clinical needs for diagnosis and monitoring. ,, With transcription mediated amplification (TMA) assays, the sensitivity is up to 10-50 IU/mL.  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,  and is now preferred over viral copies. , The hepatitis C virus is usually detectable in the blood by PCR within one to three weeks of infection.  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). ,,,, 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. 
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]. 
Viral RNA testing is indicated when there is clinical suspicion of HCV, transaminase levels are high, and antibody testing is negative. 
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. ,
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.  In PCR, sensitivity is higher, but bDNA has better reproducibility.  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. 
HCV genotype and subtype can be determined via various methods, including direct sequence analysis, reverse hybridization, and genotype-specific real-time PCR.  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,  (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, , with type specific primers,  on the basis of restriction fragment length polymorphisms (RFLP's)  or with sequence specific DNA probes (genotyping).  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. 
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. 
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. 
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. ,
The commonly used non-invasive tests are the aspartate aminotransferase (AST)-to-platelet ratio index (APRI),  the Forns index,  FIB-4, , Fibroindex,  FibroTest,  FibroMeter,  and Hepascore.  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.  Forns score = 7.811 - 3.131 × ln [number of platelets (10 9 /L)] × 0.781 ln [GGT (U/L)] + 3.467 × ln [age (years)] - 0.014 [cholesterol (mg/dl)].  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. 
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.  The APRI formula was proposed by Wai et al. and the APRI score is calculated as follows: [(AST/upper normal limit of AST) ×100) / number of platelets (10 9 /L).  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.  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 (10 9 /L) × ALT (U/L) ½], , and appears to be a strong predictor of de-compensated cirrhosis or death.  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).  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.  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. 
FibroTest/ActiTest estimates liver fibrosis and necrotic inflammation. These tests are validated,  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).  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:
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.
- Green (minimal or absent)
- Orange (moderate)
- Red (significant)
When serological markers and transient elastography are used alone or together, the results obtained are comparable to those of the liver biopsy itself. , 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. 
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.  Histology outcomes can vary from showing only mild changes to those of chronic active hepatitis and cirrhosis,  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  is widely used, but has some drawbacks. Several adaptations have been proposed, (e.g., Scheuer  ), 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
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
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/m 2 . 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. ,
[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|
Click here to view
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. , 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 /mm 3 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.
Treatment regimen and antiviral side effects
- 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).
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. 
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®).  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. 
Adverse events associated with pegylated interferon and ribavirin
- 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).
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. , 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 mm 3 ) is a frequent laboratory abnormality, occurring in 18% to 20% of patients, and severe neutropenia, that is, ANC < 500 mm 3 , may be observed in 4% of patients. Despite the decline of the neutrophil count, serious infections are not related to the degree of neutropenia. , The use of peg-IFN can also induce autoimmune disorders, such as autoimmune thyroiditis,  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/mm 3 , or if the platelet count falls below 50,000/mm 3 . 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. , 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|
Click here to view
Eltrombopag is an orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis.  It allowed successful treatment of HCV when given for 12 weeks to patients who had baseline thrombocytopenia (20,000 to 70,000 mm 3 ). 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.  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. ,
The use of hematological growth factors is associated with increased cost of treatment for chronic hepatitis C.  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. 
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.  IFN-induced sleep deprivation manifested together with irritability and anxiety should not be confused with depression, and should be managed with anxiolytics.  Early consultation and follow up with a psychiatrist is desirable whenever psychiatric symptoms are suspected.
Improving treatment success rates
- The peg-IFN-α and RBV should be temporarily interrupted if the ANC falls below 500/mm 3 , 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).
- he 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)
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.  Diabetes control, weight reduction for obese  and reduction of or abstention from alcohol intake are important measures to consider before initiating antiviral therapy.
- 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. , The reported SVR rates using peg-IFN-α and weight based RBV in large prospective trials of genotype 4 were 54% to 68%. ,, 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 , (See section on triple therapy of HCV genotype 1).
Genotypes 2 and 3 HCV infection
- 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).
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. , 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).  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. 
Genotype 5 and 6 HCV infection
- 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).
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%. ,, The reported SVR rate in HCV-6 patients treated with a 48-week regimen of peg-IFN and RBV varies between 66% and 86%. ,, 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.
Direct-acting antivirals in treatment naïve patients
- 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).
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,  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,  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.  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. 
Clinical trials of HCV antiviral therapy in Saudi Arabia
- 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)
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.  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.  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%.  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. 
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.  Approximately 20% of persons with HCV genotypes 1 and 4 infections and 66% with HCV genotype 2 and 3 infections achieve an RVR. ,
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. , 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%). , Delayed virological response (DVR), also known as slow virological response, is defined as a more than 2 Log 10 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. , Treatment for those patients with genotypes 2 or 3 who achieve an RVR, could possibly be shortened to 16 weeks from 24. ,,, However, a large,multicenter international trial  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. ,,,, 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.  Insufficient data exist for other genotypes.
- 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. ,, 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.  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. , Re-treating non-responders for a longer duration improved response rates, although in general the rates remained disappointingly low. In the REPEAT trial,  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.
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.  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.  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. ,
Role of maintenance antiviral therapy in non-responders
- 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).
Studies assessing the role of peg-IFN as a maintenance strategy for non-responders , failed to demonstrate any significant reduction in the clinical endpoints such as progression of fibrosis, HCC, or death.
- 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).
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.
| Direct-acting Antivirals in Treatment-Experienced HCV Patients|| |
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).  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. 
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. ,
- 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. ,
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.  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.  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%.  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. 
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%.  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. ,
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. 
- 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. ,, 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,  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.  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.  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. ,, 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.  In 2007, Iacobellis et al. carried out a controlled study,  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. ,, 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.
Post-Liver transplantati on recurrence
- 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).
Treatment of established graft lesions with peg-IFN and RBV combination therapy results in a SVR in around 30% of patients.  Most studies initiated therapy at least 6 months post-operatively, in order to optimise patient tolerance and to enable the addition of RBV. 
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. 
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.  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. ,,
Successful therapy has been shown to have a positive impact on both graft and patient survival.  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%  and 18%,  respectively. Although peg-IFN-α 2a  or 2b  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. ,, 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.  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).  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.  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. 
- 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).
Approximately 25% of HIV-infected persons in the western world have chronic HCV infection.  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.  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.  HIV patients with decompensated cirrhosis should be assessed for liver transplantation if no contraindication exists.
- 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).
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,  patients on hemodialysis,  patients undergoing organ transplantation  and HIV-positive individuals.  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. , There is a potential risk of HBV reactivation during or after HCV clearance.  In that case, or if HBV replication is detectable at a significant level, concurrent HBV nucleoside/nucleotide analogue therapy may be indicated.
Treatment of patients with renal disease
- 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).
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.  Patients with HCV infection and chronic renal disease are prone to develop diabetes mellitus  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.  Accordingly, there is a general belief that these patients should be treated before transplantation.  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.  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.  Since peg-IFN-α 2a is cleared through the liver and peg-IFN-α2b primarily through the kidneys,  there could be a theoretical accumulation of peg-IFN-α 2b when used in hemodialysis, although hemodialysis does not appear to affect clearance. , 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.  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.  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. 
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,  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.  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.  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%).  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. 
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. , 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. ,
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.  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.  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. 
Alcohol and drug abuse
- 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).
Chronic alcohol consumption in patients with chronic hepatitis C is associated with an accelerated fibrosis progression, cirrhosis, and an increased risk of HCC.  SVR rates are lower in patients with alcohol abuse.  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. 
Treatment of persons with psychiatric illnesses
- 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)
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. 
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  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.
- 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).
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.  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. 
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 
- 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.
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.
| References|| |
|1.||Butt AA. Hepatitis C virus infection: The new global epidemic. Expert Rev Anti Infect Ther 2005;3:241-9. |
|2.||Soriano V, Peters MG, Zeuzem S. New therapies for hepatitis C virus infection. Clin Infect Dis 2009;48:313-20. |
|3.||Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med 2007;356:1445-54. |
|4.||Al-Faleh FZ, Ayoola EA, al-Jeffry M, al-Rashed R, al-Mofarreh M, Arif M, et al. Prevalence of antibody to hepatitis C virus among Saudi Arabian children: A community-based study. Hepatology 1991;14:215-8. |
|5.||Alfaleh F, Alshehri S, Alansari S, Aljeffri M, Almazrou Y, Shaffi A, et al. Long-term protection of hepatitis B vaccine 18 years after vaccination. J Infect 2008;57:404-9. |
|6.||Fakeeh M, Zaki AM. Hepatitis C: Prevalence and common genotypes among ethnic groups in Jeddah, Saudi Arabia. Am J Trop Med Hyg 1999;61:889-92. |
|7.||Memish ZA, Knawy BA, El-Saed A. Incidence trends of viral hepatitis A, B, and C seropositivity over eight years of surveillance in Saudi Arabia. Int J Infect Dis 2010;14:e115-20. |
|8.||Al-Faleh FZ, Ramia S, Arif M, Ayoola EA, al-Rashed RS, al-Jeffry M, et al. Profile of hepatitis C virus and the possible modes of transmission of the virus in the Gizan area of Saudi Arabia: A community-based study. Ann Trop Med Parasitol 1995;89:431-7. |
|9.||Al Nasser MN. Intrafamilial transmission of hepatitis C virus (HCV): A major mode of spread in the Saudi Arabia population. Ann Trop Paediatr 1992;12:211-5. |
|10.||Bahakim H, Bakir TM, Arif M, Ramia S. Hepatitis C virus antibodies in high-risk Saudi groups. Vox Sang 1991;60:162-4. |
|11.||Alswaidi FM, O'Brien SJ. Is there a need to include HIV, HBV and HCV viruses in the Saudi premarital screening program on the basis of their prevalence and transmission risk factors? J Epidemiol Community Health 2010;64:989-97. |
|12.||WHO. World Health Organization Regional Committee for the Eastern Mediterranean; The growing threats of hepatitis B and C in the Eastern Mediterranean Region: A call for action. 2009. Available from: http://www.emro.who.int/rc56/media/pdf/EMRC5603en.pdf. [Last accessed on 2011 Apr 9]. |
|13.||Madani TA. Hepatitis C virus infections reported in Saudi Arabia over 11 years of surveillance. Ann Saudi Med 2007;27:191-4. |
|14.||Shobokshi OA, Serebour FE, Skakni LI. Hepatitis C genotypes/subtypes among chronic hepatitis patients in Saudi Arabia. Saudi Med J 2003;24 Suppl 2:S87-91. |
|15.||Abdelaal M, Rowbottom D, Zawawi T, Scott T, Gilpin C. Epidemiology of hepatitis C virus: A study of male blood donors in Saudi Arabia. Transfusion 1994;34:135-7. |
|16.||Al-Faleh FZ. Changing pattern of hepatitis viral infection in Saudi Arabia in the last two decades. Ann Saudi Med 2003;23:367-71. |
|17.||Karkar A. Hepatitis C in dialysis units: The Saudi experience. Hemodial Int 2007;11:354-67. |
|18.||Huraib S, al-Rashed R, Aldrees A, Aljefry M, Arif M, al-Faleh FA. High prevalence of and risk factors for hepatitis C in haemodialysis patients in Saudi Arabia: A need for new dialysis strategies. Nephrol Dial Transplant 1995;10:470-4. |
|19.||Al-Tawfiq JA, Anani A. Profile of viral hepatitis A, B, and C in a Saudi Arabian hospital. Med Sci Monit 2008;14:CR52-6. |
|20.||El-Hazmi MM. Prevalence of HBV, HCV, HIV-1, 2 and HTLV-I/II infections among blood donors in a teaching hospital in the Central region of Saudi Arabia. Saudi Med J 2004;25:26-33. |
|21.||Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, et al. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31 Suppl 2:61-80. |
|22.||Al-Faleh FZ, Huraib S, Sbeih F, al-Karawi M, al-Rashed R, al-Mofleh IA, et al. Hepatitis C virus genotypes in patients with chronic liver disease and haemodialysis patients from Saudi Arabia. J Viral Hepat 1995;2:293-6. |
|23.||Bosmans JL, Nouwen EJ, Behets G, Gorteman K, Huraib SO, Shaheen FA, et al. Prevalence and clinical expression of HCV-genotypes in haemodialysis-patients of two geographically remote countries: Belgium and Saudi-Arabia. Clin Nephrol 1997;47:256-62. |
|24.||Shobokshi OA, Serebour FE, Skakni L, Al-Saffy YH, Ahdal MN. Hepatitis C genotypes and subtypes in Saudi Arabia. J Med Virol 1999;58:44-8. |
|25.||Al-Traif I, Handoo FA, Al-Jumah A, Al-Nasser M. Chronic hepatitis C. Genotypes and response to anti-viral therapy among Saudi patients. Saudi Med J 2004;25:1935-8. |
|26.||Abdo A, Lee S.Management of hepatitis C virus genotype 4.J Gastroenterol Hepatol 2004;19:1233-9. |
|27.||Saudi Center for Organ Transplantation Annual Report. Available from:http://www.scot.org.sa. [Last cited in 2006]. |
|28.||Mohamed WZ. Prevention of hepatitis C virus in hemodialysis patients: Five years experience from a single center. Saudi J Kidney Dis Transpl 2010;21:548-54. |
|29.||Hussein MM, Mooij JM. Methods used to reduce the prevalence of hepatitis C in a dialysis unit. Saudi J Kidney Dis Transpl 2010;21:909-13. |
|30.||Abu-Aisha H, Mitwalli A, Huraib SO, Al-Wakeel J, Abid J, Yousif KI, et al. The effect of chemical and heat disinfection of the hemodialysis machines on the spread of hepatitis C virus infection: A prospective study. Saudi J Kidney Dis Transpl 1995;6:174-8. |
|31.||Soyannwo MA, Khan N, Kommajosyula S, Abdel Rahman AR, Khadaji M, Sing R, et al. Hepatitis C antibodies in haemodialysis and pattern of end-stage renal failure in Gassim, Saudi Arabia. Afr J Med Med Sci 1996;25:13-22. |
|32.||Saxena AK, Panhotra BR, Sundaram DS, Naguib M, Venkateshappa CK, Uzzaman W, et al. Impact of dedicated space, dialysis equipment, and nursing staff on the transmission of hepatitis C virus in a hemodialysis unit of the middle east. Am J Infect Control 2003;31:26-33. |
|33.||Al-Jiffri AM, Fadag RB, Ghabrah TM, Ibrahim A. Hepatitis C virus infection among patients on hemodialysis in jeddah: A single center experience. Saudi J Kidney Dis Transpl 2003;14:84-9. |
|34.||Karkar A, Abdelrahman M, Ghacha R, Malik TQ. Prevention of viral transmission in HD units: The value of isolation. Saudi J Kidney Dis Transpl 2006;17:183-8. |
|35.||Madani TA. Trend in incidence of hepatitis B virus infection during a decade of universal childhood hepatitis B vaccination in Saudi Arabia. Trans R Soc Trop Med Hyg 2007;101:278-83. |
|36.||Iqbal N. Substance dependence. A hospital based survey. Saudi Med J 2000;21:51-7. |
|37.||Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centre for Disease Control and Prevention. MMWR Recomm Rep 1998;47(RR-19):1-39. |
|38.||Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C Virus prevalence among patients infected with human immunodeficiency virus: A cross-sectional analysis of the US adult AIDS clinical trials group. Clin Infect Dis 2002;34:831-7. |
|39.||Arif M, al-Swayeh M, al-Faleh FZ, Ramia S. Risk of hepatitis C virus infection among household contacts of Saudi patients with chronic liver disease. J Viral Hepat 1996;3:97-101. |
|40.||Altraif I. Hepatitis C acquisition in Saudi Arabia: Are the majority of cases without risk factor? Ann Saudi Med 1995;15:428-30. |
|41.||Arif MA, Al-Faleh FZ, Ramia S. Schistosomiasis as a possible risk factor for acquiring hepatitis C virus (HCV) infection among Saudis. Saudi J Gastroenterol 1997;3:74-7. |
|42.||Bakir T. Age-specific prevelance of antibody to hepatitis C virus (HCV) among the Saudi population. Saudi Med J 1992;13:321-4. |
|43.||Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147-71. |
|44.||Leiveven J. (October-November 2004) Pegasys / RBV improves fibrosis in responders, relapsers and nonresponders with advanced fibrosis. In: 55 th Annual Meeting of the American Association for the Study of Liver Disease: 2 Boston, MA, USA. |
|45.||Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, Brechot C, et al. A proposed system for nomenclature of hepatitis C viral genotypes. Hepatology 1994;19:1321-4. |
|46.||NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consensus and State-of-the-Science Statements 2002;19 (3):1--46. 2002. PMID 14768714. |
|47.||Strader DB, Seeff LB. The natural history of chronic hepatitis C infection. Eur J Gastroenterol Hepatol 1996;8:324-8. |
|48.||Seeff LB, Hoofnagle JH. National institutes of health consensus development conference: Management of hepatitis C: 2002. Hepatology 2002;36 (5 Suppl 1):S1-2. |
|49.||Seeff LB, Buskell-Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med 1992;327:1906-11. |
|50.||Scott JD, McMahon BJ, Bruden D,Sullivan D, Homan C, Christensen C, et al. High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives.Clin Infect Dis2006;42:945-52. |
|51.||Fattovich G, Giustina G, Degos F, Diodati G, Tremolada F, Nevens F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol 1997;27:201-5. |
|52.||Stadhouders PH, Cooreman MP. Chronic hepatitis C virus disease: An evaluation of procedures for diagnosis and treatment. Neth J Med 1997;51:213-24. |
|53.||Adinolfi LE, Utili R, Andreana A, Tripodi MF, Marracino M, Gambardella M, et al. Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C. Dig Dis Sci 2001;46:1677-83. |
|54.||Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 1999;30:1054-8. |
|55.||Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-32. |
|56.||Harris DR, Gonin R, Alter HJ, Wright EC, Buskell ZJ, Hollinger FB, et al. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med 2001;134:120-4. |
|57.||Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ. Long-term clinical and histopathological follow-up of chronic post transfusion hepatitis. Hepatology 1991;14:969-74. |
|58.||Sanai FM, Helmy A, Dale C, Al-Ashgar H, Abdo AA, Katada K, et al. Updated thresholds for alanine aminotransferase do not exclude significant histological disease in chronic hepatitis C. Liver Int 2011;31:1039-46. |
|59.||Yano M, Kumada H, Kage M, Ikeda K, Shimamatsu K, Inoue O, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334-40. |
|60.||Fontaine H, Nalpas B, Poulet B, Carnot F, Zylberberg H, Brechot C, et al. Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C. Hum Pathol 2001;32:904-9. |
|61.||Freedman L, Edwards B, Ries L, Young Je, editors. Cancer Incidence in Four Member Countries (Cyprus, Egypt, Israel, and Jordan) of the Middle East Cancer Consortium (MECC) Compared with US SEER. Bethesda, MD: NIH Pub. No. 06-5873; 2006. |
|62.||Magnitude of hepatocellular carcinoma in Egypt [database on the Internet]. Available from: http://www.nci.edu.eg.[Last cited on 2011 Apr24]. |
|63.||Bhattacherjee V, Prescott LE, Pike I, Rodgers B, Bell H, El-Zayadi AR, et al. Use of NS-4 peptides to identify type-specific antibody to hepatitis C virus genotypes 1, 2, 3, 4, 5 and 6. J Gen Virol 1995;76 (Pt 7):1737-48. |
|64.||Angelico M, Renganathan E, Gandin C, Fathy M, Profili MC, Refai W, et al. Chronic liver disease in the Alexandria governorate, Egypt: Contribution of schistosomiasis and hepatitis virus infections. J Hepatol 1997;26:236-43. |
|65.||Kamal S, Madwar M, Bianchi L, Tawil AE, Fawzy R, Peters T, et al. Clinical, virological and histopathological features: Long-term follow-up in patients with chronic hepatitis C co-infected with S. mansoni. Liver 2000;20:281-9. |
|66.||Lehman EM, Wilson ML. Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: A systematic review and meta-analysis. Int J Cancer 2009;124:690-7. |
|67.||Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology 1997;112:463-72. |
|68.||Hu K-Q, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. Hepatology 1999;29:1311-6. |
|69.||Planas, R, Ballesté, B, Alvarez, MA, Rivera M, Montoliu S, Galeras JA, et al. Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200 patients. J Hepatol 2004;40:823-30. |
|70.||Williams IT, Sabin K, Fleenor M, Judson F, Mottram K, Poujade J, et al. Current patterns of hepatitis C virus transmission in United States: The role of drugs and sex (Abstract). Hepatology 1998;28:497A. |
|71.||Orland JR, Wright TL, Cooper S. Acute hepatitis C. Hepatology 2001;33:321-7. |
|72.||Esteban JI, Genesca J, Alter HJ. Hepatitis C: Molecular biology, pathogenesis, epidemiology, clinical features, and prevention. Prog Liver Dis 1992;10:253-82. |
|73.||Chu CM, Yeh CT, Liaw YF. Fulminant hepatic failure in acute hepatitis C: Increased risk in chronic carriers of hepatitis B virus. Gut 1999;45:613-7. |
|74.||Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999;29:908-14. |
|75.||Sterling RK, Bralow S. Extrahepatic manifestations of hepatitis C virus. Curr Gastroenterol Rep 2006;8:53-9. |
|76.||Altraif IH, Abdulla AS, al Sebayel MI, Said RA, al Suhaibani MO, Jones AA. Hepatitis C associated glomerulonephritis.Am J Nephrol 1995;15:407-10. |
|77.||Sène D, Limal N, Cacoub P. Hepatitis C virus-associated extrahepatic manifestations: A review. Metab Brain Dis 2004;19:357-81. |
|78.||Gordon SC. Extrahepatic manifestations of hepatitis C. Dig Dis1996;14:157-68. |
|79.||Mayo MJ. Extrahepatic manifestations of hepatitis C infection. Am J Med Sci 2003;325:135-48. |
|80.||Mathurin P, Moussalli J, Cadranel JF, Thibault V, Charlotte F, Dumouchel P, et al. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity. Hepatology 1998;27:868-72. |
|81.||Tong MJ, El-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463-6. |
|82.||Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26(3 Suppl1):34S-8S. |
|83.||Novello AC. New York state department of health clinical guidelines for the medical management of hepatitis C. state of New York, Department of Health; 2005:1-27. Available from http://nastad.org/Docs/Public/Resource/2006711_NYS_HepC_Mgt_Guidelines.pdf. [Last cited on 2012 August10]. |
|84.||Shiffman ML, Diago M, Tran A, Pockros P, Reindollar R, Prati D, et al. "Chronic hepatitis C in patients with persistently normal alanine transaminase levels. Clin Gastroenterol Hepatol 2006;4:645-52. |
|85.||Silini E, Bono F, Cividini A, Cerino A, Bruno S, Rossi S, et al. Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities. Hepatology 1995;21:285-90. |
|86.||Alberti A, Morsica G, Chemello L, Cavalletto D, Noventa F, Pontisso P, et al. Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV. Lancet 1992;340:697-8. |
|87.||Haber M, West A, Haber A, Reuben A. Relationship of aminotransferases to liver histologicalstatus in chronic hepatitis C. Am J Gastroenterol 1995;90:1250-7. |
|88.||Colin C, Lanoir D, Touzet S, Meyaud-Kraemer L, Bailly F, Trepo C. Sensitivity and specificity of third-generation hepatitis C virus antibodydetection assays: An analysis of the literature. J Viral Hepat 2001;8:87-95. |
|89.||Dufour DR, Talastas M, Fernandez MD, Harris B, Strader DB, Seeff LB. Low-positive anti-hepatitis C virus enzyme immunoassay results: An important predictor of low likelihood of hepatitis C infection. Clin Chem 2003;49:479-86. |
|90.||Alter MJ, Kuhnert WL, Finelli L. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. Centre for Disease Control and Prevention. MMWR Recomm Rep 2003;52:1-13. |
|91.||Pawlotsky JM, Lonjon I, Hezode C, Raynard B, Darthuy F, Remire J, et al. What strategy should be used for diagnosis of hepatitis C virus infection in clinical laboratories? Hepatology 1998;27:1700-2. |
|92.||Stramer SL, Caglioti S, Strong DM. NAT of the United States and Canadian blood supply. Transfusion 2000;40:1165-8. |
|93.||Ramia S, Eid-Fares J. Distribution of hepatitis C virus genotypes in the Middle East. Int J Infect Dis 2006;10:272-7. |
|94.||Dean L, Perry K. Evaluation of Murex HCV Ag/Ab Combination, Report PER06007. Available from: http://www.hpamidas.org.uk/documents/reports/HCV/Murex_HCV_AgAb_Report_v8_FINAL.pf. [Last cited on 2007 Feb]. |
|95.||Vrielink H, Zaaijer HL, Reesink HW, van der Poe1 CL, Cuypers HT, Lelie PN. Sensitivity and specificity of three third-generation anti-hepatitis C virus ELISAs. VOX Sang 1995;69:14-7. |
|96.||Sjogren MH. Serologic diagnosis of viral hepatitis. Gastroenterol Clin North Am 1994;23:457-77. |
|97.||Courouce AM, Janot C. Recombinant immunoblot assay first and second generations on 732 blood donors reactive for antibodies to hepatitis C virus by ELISA. VOX Sang 1991;61:177-80. |
|98.||Thio CL, Nolt KR, Astemborski J, Vlahov D, Nelson KE, Thomas DL. Screening for hepatitis C virus in human immunodeficiency virus-infected individuals. J Clin Microbiol 2000;38:575-7. |
|99.||Kalantar-Zadeh K, Miller LG, Daar ES. Diagnostic discordance for hepatitis C virus infection in hemodialysis patients. Am J Kidney Dis 2005;46:290-300. |
|100.||Chamot E, Hirschel B, Wintsch J, Robert CF, Gabriel V, Deglon JJ, et al. Loss of antibodies against hepatitis C virus in HIV-seropositive intravenous drug users. Aids 1990;4:1275-7. |
|101.||Vermehren J, Kau A, Gartner BC, Gobel R, Zeuzem S, Sarrazin C. Differences between two real-time PCR-based hepatitis C virus (HCV) assays (RealTime HCV and Cobas AmpliPrep/Cobas TaqMan) and one signal amplificationassay (Versant HCV RNA 3.0) for RNA detection and quantification. J Clin Microbiol 2008;46:3880-91. |
|102.||Chevaliez S, Bouvier-Alias M, Pawlotsky JM. Performance of the Abbott Real-Time PCR assay using m2000(sp) and m2000(rt) for hepatitis C virus RNA quantification. J Clin Microbiol 2009;47:1726-32. |
|103.||Fytili P, Tiemann C, Wang C, Schulz S, Schaffer S, Manns MP, et al. Frequency of very low HCV viremia detected by a highly sensitive HCV-RNA assay. J Clin Virol 2007;39:308-11. |
|104.||Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastroenterology 2002;122:1554-68. |
|105.||Saldanha J, Lelie N, Heath A. Establishment of the first international standard for nucleic acid amplification technology (NAT) assays for HCV RNA.WHOCollaborative Study Group. Vox Sang 1999;76:149-58. |
|106.||Pawlotsky JM, Bouvier-Alias M, Hezode C, Darthuy F, Remire J, Dhumeaux D. Standardization of hepatitis C virus RNA quantification. Hepatology 2000;32:654-9. |
|107.||Courouce AM, Le Marrec N, Bouchardeau F, Razer A, Maniez M, Laperche S, et al. Efficacy of HCV core antigen detection during the preseroconversion period. Transfusion 2000;40:1198-202. |
|108.||Alzahrani AJ, Obeid OE. Detection of hepatitis C virus core antigen in blood donors using a new enzyme immunoassay. J Fam Community Med 2004;11:103-7. |
|109.||Alzahrani AJ. Analysis of HCV core antigenemia in Saudi Drug users. Saudi Med J 2005;26:1645-6. |
|110.||Fabrizi F, Lunghi G, Aucella F, Mangano S, Barbisoni F, Bisegna S, et al. Novel assay using total hepatitis C virus (HCV) core antigen quantification for diagnosis of HCV infection in dialysis patients. J Clin Microbiol 2005;43:414-20. |
|111.||Takahashi M, Saito H, Higashimoto M, Atsukawa K, Ishii H. Benefit of hepatitis C virus core antigen assay in prediction of therapeutic response to interferon and ribavirin combination therapy. J Clin Microbiol 2005;43:186-91. |
|112.||Alados-Arboledas JC, Calbo-Torrecillas L, Lopez-Prieto MD, de Francisco-Ramirez JL, de Miguel-Sastre C. Clinical assessment of Monolisa HCV Ag-Ab ULTRA (Bio-Rad) in a general hospital. Enferm Infecc Microbiol Clin 2007;25:172-6. |
|113.||Ghany MG, Strader DB, Thomas DL, Seeff LB. AASLD practice guidelines, diagnosis, management and treatment of hepatitis C: An update. Hepatology 2009;49:1335-74. |
|114.||Laperche S, Le Marrec N, Girault A, Bouchardeau F, Servant-Delmas A, Maniez-Montreuil M, et al. Simultaneous detection of hepatitis C virus (HCV) core antigen and anti-HCV antibodies improves the early detection of HCV infection. J Clin Microbiol 2005;43:3877-83. |
|115.||Ansaldi F, Bruzzone B, Testino G, Bassetti M, Gasparini R, Crovari P, et al. Combination hepatitis C virus antigen and antibody immunoassay as a new tool for early diagnosis of infection. J Viral Hepat 2006;3:5-10. |
|116.||Gretch DR, Corazon dela Rosa MT, Carithers RL, Willson RA, Williams B, Corey L. Assessment of hepatitis C viremia using molecular amplification technologies: Correlations and clinical implications. Ann Intern Med 1995;123:321-9. |
|117.||Chevaliez S, Pawlotsky JM. Diagnosis and management of chronic viralhepatitis: Antigens, antibodies and viral genomes. Best Pract Res Clin Gastroenterol 2008;22:1031-48. |
|118.||Simmonds P, Rose KA, Graham S, Chan SW, McOmish F, Dow BC, et al. Mapping of serotype-specific, immunodominant epitopes in the NS-4 region of hepatitis C virus (HCV): Use of type-specific peptides to serologically differentiate infections with HCV types 1, 2 and 3. J Clin Microbiol 1993;31:1493-503. |
|119.||Bukh J, Purcell R, Miller R. At least 12 genotypes of hepatitis C virus predicted by sequence analysis of the putative E1 gene of isolates collected worldwide. Proc Natl Acad Sci USA 1993;90:8234-8. |
|120.||Simmonds P, Smith DB, McOmish F, Yap PL, Kolberg J, Urdea MS, et al. Identification of genotypes of hepatitis C virus by sequence comparisons in the core, E1 and NS-5 regions. J Gen Virol 1994;75:1053-61. |
|121.||Okamoto H, Sugiyama Y, Okada S, Kurai K, Akahane, Y, Sugai Y, et al. Typing hepatitis C virus by polymerase chain reaction with type-specific primers: Application to clinical surveys and tracing infectious sources. J Gen Virol 1992;73:673-9. |
|122.||McOmish F, Chan SW, Dow BC, Gillon J, Frame WD, Crawford RJ, et al. Detection of three types of hepatitis C virus in blood donors: Investigation of type-specific differences in serologic reactivity and rate of alanine aminotransferase abnormalities. Transfusion 1993;33:7-13. |
|123.||Stuyver L, Rossau R, Wyseur A, Duhamel M, Vanderborght B, van Heuverswyn H, et al. Typing of hepatitis C virus isolates and characterization of new subtypes using a line probe assay. J Gen Virol 1993;74:1093-102. |
|124.||Germer JJ, Rys PN, Thorvilson JN, Persing DH. Determination of hepatitis C virus genotype by direct sequence analysis of products generated with the Amplicor HCV test. J Clin Microbiol 1999;37:2625-30. |
|125.||Afdhal NH, Nunes D. Evaluation of liver fibrosis: A concise review. Am J Gastroenterol 2004;99:1160-74. |
|126.||Poynard T, Imbert-Bismut F, Munteanu M, Messous D, Myers RP, Thabut D, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol 2004;3:8-10. |
|127.||Poynard T, Munteanu M, Imbert-Bismut F. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clin Chem 2004;50:1344-55. |
|128.||Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518-26. |
|129.||Forns X, Ampurdanes S, Llovet JM, Aponte J, Quintó L, Martínez-Bauer E, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002;36:986-92. |
|130.||Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, et al. FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and FibroTest. Hepatology 2007;46:32-6. |
|131.||Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317-25. |
|132.||Koda M, Matunaga Y, Kawakami M, Kishimoto Y, Suou T, Murawaki Y, et al. Fibroindex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C. Hepatology 2007;45:297-306. |
|133.||Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: A prospective study. Lancet 2001;357:1069-75. |
|134.||Calès P, Oberti F, Michalak S, Hubert-Fouchard I, Rousselet MC, Konaté A, et al. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology 2005;42:1373-8. |
|135.||Adams LA, Bulsara M, Rossi E, DeBoer B, Speers D, George J, et al. Hepascore: An accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem 2005;51:1867-73. |
|136.||Borsoi Viana MS,Takei K, Collarile Yamaguti DC, Guz B, Strauss E. Use of AST platelet ratio index (APRI Score) as an alternative to liver biopsy for treatment indication in chronic hepatitis C. Ann Hepatol 2009;8:26-31. |
|137.||Cozzi Lepri A, Prosperi M, Lo Caputo S, et al. Fib4 is an independent predictor of serious liver disease among HIV-infected patients with or without HBV/HCV co-infection in the Icona foundation study. Italian Conference on AIDS and Retroviruses Brescia, Italy. Infection 2010;38(Suppl 1):73. |
|138.||Tural C, Tor J, Sanvisens A, Pérez-Alvarez N, Martínez E, Ojanguren I, et al. Accuracy of simple biochemical tests in identifying liver fibrosis in patients co-infected with human immunodeficiency virus and hepatitis C virus. Clin Gastroenterol Hepatol 2009;7:339-45. |
|139.||Mendeni M, Focà E, Gotti D, Ladisa N, Angarano G, Albini L, et al. Evaluation of liver fibrosis: Concordance analysis between noninvasive scores (APRI and FIB-4) evolution and predictors in a cohort of HIV-infected patients without hepatitis C and B infection. Clin Infect Dis 2011;52:1164-73. |
|140.||Güzelbulut F, Cetinkaya ZA, Sezikli M, Yaºar B, Ozkara S, Övünç AO. AST-platelet ratio index, Forns index and FIB-4 in the prediction of significant fibrosis and cirrhosis in patients with chronic hepatitis C. Turk J Gastroenterol 2011;22:279-85. |
|141.||Halfon P, Munteanu M, Poynard T. "FibroTest-ActiTest as a non-invasive marker of liver fibrosis". Gastroentérol Clin Biol 2008;32(6 Suppl 1):22-39. |
|142.||Poynard T, Ngo Y, Munteanu M, Thabut D, Massard J, Moussalli J, et al. Biomarkers of liver injury for hepatitis clinical trials: A meta-analysis of longitudinal studies. Antivir Ther 2010;15:617-31. |
|143.||Castera L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis. J Viral Hepat 2009;16:300-14. |
|144.||Goodman ZD, Ishak KG. Histopathology of hepatitis C virus infection. Semin Liver Dis 1995;15:70-81. |
|145.||Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431-5. |
|146.||Scheuer PJ. Classification of chronic viral hepatitis: A need for reassessment. J Hepatol 1991;13:372-4. |
|147.||Kau A, Vermehren J, Sarrazin C. Treatment predictors of a sustained virologic response in hepatitis B and C. J Hepatol 2008;49:634-51. |
|148.||Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: A genome-wide association study. Gastroenterology 2010;138:1338-45. |
|149.||Grieve R, Roberts J, Wright M, Sweeting M, DeAngelis D, Rosenberg W, et al. Cost effectiveness of interferon or peginterferon with ribavirin for histologically mild chronic hepatitis C. Gut 2006;55:1332-8. |
|150.||Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Muhlberger N, Wright D, et al. Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C. J Viral Hepat 2010;17:34-50. |
|151.||Zeuzem S, Welsch C, Herrmann E. Pharmacokinetics of peginterferon. Semin Liver Dis 2003;23(Suppl 1):23-8. |
|152.||McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580-93. |
|153.||Chevaliez S, Bouvier-Alias M, Brillet R, Pawlotsky JM. Overestimation and under-estimation of hepatitis C virus RNA levels in a widely used real-time polymerase chain reaction-based method. Hepatology 2007;46:22-31. |
|154.||Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet 2001;358:958-65. |
|155.||Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82. |
|156.||Roomer R, Hansen BE, Janssen HL, de Knegt RJ. Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. Hepatology 2010;52:1225-31. |
|157.||Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K, et al. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002;36:1273-9. |
|158.||Deutsch M, Dourakis S, Manesis EK, Gioustozi A, Hess G, Horsch A, et al. Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alfa therapy. Hepatology 1997;26:206-10. |
|159.||McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007;357:2227-36. |
|160.||Sulkowski MS, Shiffman ML, Afdhal NH, Reddy KR, McCone J, Lee WM, et al. Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. Gastroenterology 2010;139:1602-11. |
|161.||Pockros PJ, Shiffman ML, Schiff ER, Sulkowski MS, Younossi Z, Dieterich DT, et al. Epoetin alfa improves quality of life in anemic HCV infected patients receiving combination therapy. Hepatology 2004;40:1450-8. |
|162.||Shiffman ML, Salvatore J, Hubbard S, Price A, Sterling RK, Stravitz RT, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology 2007;46:371-9. |
|163.||Del Rio RA, Post AB, Singer ME. Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination therapy. Hepatology 2006;44:1598-606. |
|164.||Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008;299:914-24. |
|165.||Schaefer M, Sarkar R, Knop V, Effenberger S, Friebe A, Heinze L, et al. Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: A randomized trial. Ann Intern Med. 2012;157:94-103. |
|166.||Schaefer M, Mauss S. Hepatitis C treatment in patients with drug addiction: Clinical management of interferon-alpha-associated psychiatric side effects. Curr Drug Abuse Rev 2008;1:177-87. |
|167.||McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype- 1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061-9. |
|168.||Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for non-response to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-44. |
|169.||Moucari R, Ripault MP, Martinot-Peignoux M, Voitot H, Cardoso AC, Stern C, et al. Insulin resistance and geographical origin: Major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4. Gut 2009;58:1662-9. |
|170.||Khattab M, Eslam M, Sharwae MA, Shatat M, Ali A, Hamdy L. Insulin resistance predicts rapid virologic response to peginterferon/ribavirin combination therapy in hepatitis C genotype 4 patients. Am J Gastroenterol 2010;105:1970-7. |
|171.||Derbala MF, El Dweik NZ, Al Kaabi SR, Al-Marri AD, Pasic F, Bener AB, et al. Viral kinetic of HCV genotype-4 during pegylated interferon alpha 2a: Ribavirin therapy. J Viral Hepat 2008;15:591-9. |
|172.||Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al.; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-206. |
|173.||Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-16. |
|174.||Andriulli A, Mangia A, Iacobellis A, Ippolito A, Leandro G, Zeuzem S. Meta-analysis: The outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis. Aliment Pharmacol Ther 2008;28:397-404. |
|175.||EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2011;55:245-64. |
|176.||D'Heygere F, George C, Van Vlierberghe H, Decaestecker J, Nakad A, Adler M, et al. Efficacy of interferon-based antiviral therapy in patients with chronic hepatitis C infected with genotype 5: a meta-analysis of two large prospective clinical trials. J Med Virol. 2011;83(5):815-9. |
|177.||Antaki N, Hermes A, Hadad M, Ftayeh M, Antaki F, Abdo N, et al. Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus genotype 5. J Viral Hepat 2008;15:383-6. |
|178.||Bonny C, Fontaine H, Poynard T, Hézode C, Larrey D, Marcellin P, et al. Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study. Aliment Pharmacol Ther 2006;24:593-600. |
|179.||Nguyen MH, Trinh HN, Garcia R, Nguyen G, Lam KD, Keeffe EB. Higher rate of sustained virologic response in chronic hepatitis C genotype 6 treated with 48 weeks versus 24 weeks of peginterferon plus ribavirin. Am J Gastroenterol 2008;103:1131-5. |
|180.||Li F, Ng TL, Tai LF, et al. High response rate of combination therapy of pegylated interferon and ribavirin in treating chronic hepatitis C with genotype 6A in Hong Kong Chinese. Hepatol Int 2009;3:164. |
|181.||Antaki N, Marcellin P. What is the safe duration of therapy for patients infected with HCV genotype 6? Nat Clin Pract Gastroenterol Hepatol 2009;6:78-9. |
|182.||Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011;365:1014-24. |
|183.||Khattab MA, Ferenci P, Hadziyannis SJ, Colombo M, Manns MP, Almasio PL, et al. Management of hepatitis C virus genotype 4: Recommendations of an international expert panel. J Hepatol 2011;54:1250-62. |
|184.||Shobokshi OA, Serebour FE, Skakni L, Al Khalifa M. Combination therapy of peginterferon alfa-2a (40KD) (PEGASYS(r)) and ribavirin (COPEGUS(r)) significantly enhance sustained virological and biochemical response rate in chronic hepatitis C genotype 4 patients in Saudi Arabia. Hepatology 2003;38(4 Suppl. 1):636A. |
|185.||Alfaleh FZ, Hadad Q, Khuroo MS, Aljumah A, Algamedi A, Alashgar H, et al. Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int 2004;24:568-74. |
|186.||Al Ashgar H, Khan MQ, Helmy A, Al Swat K, Al Shehri A, Al Kalbani A, et al. Sustained virologic response to peginterferon alpha-2a and ribavirin in 335 patients with chronic hepatitis C: A tertiary care center experience. Saudi J Gastroenterol 2008;14:58-65. |
|187.||Dahlan Y, Ather HM, Al-ahmadi M, Batwa F, Al-hamoudi W. Sustained virological response in a predominantly hepatitis C virus genotype 4 infected population. World J Gastroenterol 2009;15:4429-33. |
|188.||Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Goncales FL Jr, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005;43:425-33. |
|189.||Ferenci P, Laferl H, Scherzer TM, Gschwantler M, Maieron A, Brunner H, et al.; Austrian Hepatitis Study Group. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008;135:451-8. |
|190.||Dalgard O, Bjoro K, Ring-Larsen H, Bjornsson E, Holberg-Petersen M, Skovlund E, et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008;47:35-42. |
|191.||Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43:954-60. |
|192.||Berg T, Sarrazin C, Herrmann E, Hinrichsen H, Gerlach T, Zachoval R, et al. Prediction of treatment outcome in patients with chronic hepatitis C: Significance of baseline parameters and viral dynamics during therapy. Hepatology 2003;37:600-9. |
|193.||Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645-52. |
|194.||Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97-103. |
|195.||Kamal SM, El Kamary SS, Shardell MD, Hashem M, Ahmed IN, Muhammadi M, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: The role of rapid and early virologic response. Hepatology 2007;46:1732-40. |
|196.||Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609-17. |
|197.||von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T, et al. Peginterferon-alpha-2a (40 kDa) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005;129:522-7. |
|198.||Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh MY, et al. A randomized study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut 2007;56:553-9. |
|199.||Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124-34. |
|200.||Berg T, von Wagner M, Nasser S, Sarrazin C, Heintges T, Gerlach T, et al. Extended treatment duration for hepatitis C virus type 1: Comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006;130:1086-97. |
|201.||Pearlman BL, Ehleben C, Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology 2007;46:1688-94. |
|202.||Farnik H, Lange CM, Sarrazin C, Kronenberger B, Zeuzem S, Herrmann E. Meta-analysis shows extended therapy improves response of patients with chronic hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 2010;8:884-90. |
|203.||Ferenci P, Laferl H, Scherzer TM, Andreas Maieron A, Hofer H, Stauber R, et al. Peginterferon a-2a/ribavirin for 72 weeks reduces relapse among Hepatitis C type 1 and 4 patients with early virologic responses. Gastroenterology 2010;138:503-12. |
|204.||Sanchez-Tapias JM, Diago M, Escartin P, Enríquez J, Romero-Gómez M, Bárcena R, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006;131:451-60. |
|205.||Taliani G, Gemignani G, Ferrari C, Aceti A, Bartolozzi D, Blanc PL, et al. Pegylated interferon alfa-2b plus ribavirin in the re-treatment of interferon- ribavirin non-responder patients. Gastroenterology 2006;130:1098-106. |
|206.||Shiffman ML, Di Bisceglie AM, Lindsay KL, Morishima C, Wright EC, Everson GT, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126:1015-23; |
|207.||Jacobson IM, Gonzalez SA, Ahmed F, Lebovics E, Min AD, Bodenheimer HC Jr, et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the re-treatment of chronic hepatitis C. Am J Gastroenterol 2005;100:2453-62. |
|208.||Cheruvattath R, Rosati MJ, Gautam M, Vargas HE, Rakela J, Balan V. Pegylated interferon and ribavirin failures: Is re-treatment an option? Dig Dis Sci 2007;52:732-6. |
|209.||Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-17. |
|210.||McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292-303. |
|211.||Yoshida EM, Sherman M, Bain VG, Cooper CL, Deschênes M, Marotta PJ, et al.;Pegasys Study Group. Re-treatment with peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have relapsed or not responded to a first course of pegylated interferon-based therapy. Can J Gastroenterol 2009;23:180-4. |
|212.||DiBisceglie A, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359:2429-41. |
|213.||Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, et al.; EPIC3 Study Group. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C. Gastroenterology 2011;140:1990-9. |
|214.||Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H, et al. Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders. Hepatology 2012;55:742-8. |
|215.||Jensen DM, Wedemeyer H, Herring RW, Ferenci P, Ma MM, Zeuzem S, et al. High rates of early viral response, promising safety profile and lack of resistance related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study. Hepatology 2010;52:360A. |
|216.||Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A, et al. Acute hepatitis C: High rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003;125:80-8. |
|217.||Santantonio T, Sinisi E, Guastadisegni A, Casalino C, Mazzola M, Gentile A, et al. Natural course of acute hepatitis C: A long-term prospective study. Dig Liver Dis 2003;35:104-13. |
|218.||Kamal SM, Fouly AE, Kamel RR, Hockenjos B, Al Tawil A, Khalifa KE, et al. Peginterferon alfa-2b therapy in acute hepatitis C: Impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:632-8. |
|219.||Poynard T, Regimbeau C, Myers RP, Thevenot T, Leroy V, Mathurin P, et al. Interferon for acute hepatitis C. Cochrane Database Syst Rev 2002;CD000369. |
|220.||Kamal SM. Acute hepatitis C: A systematic review. Am J Gastroenterol 2008;103:1283-97. |
|221.||Licata A, Di Bona D, Schepis F, Shahied L, Craxí A, Cammà C. When and how to treat acute hepatitis C? J Hepatol 2003;39:1056-62. |
|222.||Deterding K, Gruner NH, Wiegand J, Galle P, Spengler U, Hinrichsen H, et al.; The Hep-Net Acute-HCV Study group. Early versus delayed treatment of acute hepatitis C: The German HEP-NET acute HCV III study-a randomized controlled study. J Hepatol 2009;50(Suppl 1):S380. |
|223.||Santantonio T, Wiegand J, Gerlach JT. Acute hepatitis C: Current status and remaining challenges. J Hepatol 2008;49:625-33. |
|224.||Kamal SM, Moustafa KN, Chen J, Fehr J, Abdel Moneim A, Khalifa KE, et al. Duration of peginterferon therapy in acute hepatitis C: A randomized trial. Hepatology 2006;43:923-31. |
|225.||Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al.; PEGASYS international study group. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C-A randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55. |
|226.||Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673-80. |
|227.||Helbling B, Jochum W, Stamenic I, Knopfli M, Cerny A, Borovicka J, et al. HCV-related advanced fibrosis/cirrhosis: Randomized controlled trial of pegylated interferon alpha-2a and ribavirin. J Viral Hepat 2006;13:762-9. |
|228.||Schmid M, Kreil A, Jessner W, Homoncik M, Datz C, Gangl A, et al. Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon alpha mono and combination therapy regimens. Gut 2005;54:1014-20. |
|229.||Garcia-Retortillo M, Forns X, Feliu A, Moitinho E, Costa J, Navasa M, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology 2002;35:680-7. |
|230.||Ghobrial RM, Steadman R, Gornbein J, Lassman C, Holt CD, Chen P, et al. A 10-year experience of liver transplantation for hepatitis C: Analysis of factors determining outcome in over 500 patients. Ann Surg 2001;234:384-93;discussion 393-394. |
|231.||Neumann UP, Berg T, Bahra M, Puhl G, Guckelberger O, Langrehr JM, et al. Long-term outcome of liver transplants for chronic hepatitis C: A 10-year follow-up. Transplantation 2004;77:226-31. |
|232.||Crippin JS, McCashland T, Terrault N, Sheiner P, Charlton MR. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl 2002;8:350-5. |
|233.||Iacobellis A, Siciliano M, Perri F, Annicchiarico BE, Leandro G, Caruso N, et al. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: A controlled study. J Hepatol 2007;46:206-12. |
|234.||Forns X, Garcia-Retortillo M, Serrano T, Feliu A, Suarez F, de la Mata M, et al. Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation. J Hepatol 2003;39:389-96. |
|235.||Carrion JA, Martinez-Bauer E, Crespo G, Ramirez S, Perez-del-Pulgar S, Garcia-Valdecasas JC, et al. Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: A retrospective study. J Hepatol 2009;50:719-28. |
|236.||Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int 2012;32 Suppl 1:120-8. |
|237.||Alsatie M, Chalasani N, Kwo PY. Management of hepatitis C infection after liver transplantation. Drugs 2007;67:871-85. |
|238.||Al-Sebayel M, Khalaf H, Al-Sofayan M, Al-Saghier M, Abdo A, Al-Bahili H, et al. Experience with 122 consecutive liver transplant procedures at king faisal specialist hospital and research center. Ann Saudi Med 2007;27:333-8. |
|239.||Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, et al. HCV-related fibrosis progression following liver transplantation: Increase in recent years. J Hepatol 2000;32:673-84. |
|240.||Neumann UP, Berg T, Bahra M, Seehofer D, Langrehr JM, Neuhaus R, et al. Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J Hepatol 2004;41:830-6. |
|241.||Yilmaz N, Shiffman ML, Stravitz RT, Sterling RK, Luketic VA, Sanyal AJ, et al. A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C virus following liver transplantation. Liver Transpl 2007;13:975-83. |
|242.||Berenguer M, Palau A, Aguilera V, Rayon JM, Juan FS, Prieto M. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant 2008;8:679-87. |
|243.||Chalasani N, Manzarbeitia C, Ferenci P, Vogel W, Fontana RJ, Voigt M, et al. Peginterferon alfa-2a for hepatitis C after liver transplantation: Two randomized, controlled trials. Hepatology 2005;41:289-98. |
|244.||Shergill A, Khalili M, Bollinger K, Roberts J, Ascher N, Terrault N. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C infected patients undergoing liver transplantation. Am J Transplant 2005;5:118-24. |
|245.||Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, et al. Pegylated interferon-alpha2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000;68:556-67. |
|246.||Sheiner PA, Boros P, Klion FM, Thung SN, Schluger LK, Lau JY, et al. The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation.Hepatology 1998;28:831-8. |
|247.||Singh N, Gayowski T, Wannstedt CF, Shakil AO, Wagener MM, Fung JJ, et al. Interferon-alpha for prophylaxis of recurrent viral hepatitis C in liver transplant recipients: A prospective, randomized, controlled trial. Transplantation 1998;65:82-6. |
|248.||Gane EJ, Lo SK, Riordan SM, Portmann BC, Lau JY, Naoumov NV, et al. A randomized study comparing ribavirin and interferon alfa monotherapy for hepatitis C recurrence after liver transplantation. Hepatology 1998;27:1403-7. |
|249.||Al-Hamoudi W, Mohamed H, Abaalkhail F, Kamel Y, Al-Masri N, Allam N, et al. Treatment of genotype 4 hepatitis C recurring after liver transplantation using a combination of pegylated interferon alfa-2a and ribavirin. Dig Dis Sci 2011;56:1848-52. |
|250.||Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011;54:20-7. |
|251.||Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauerbruch T, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet 2003;362:1708-13. |
|252.||Bräu N, Rodriguez-Torres M, Prokupek D, Bonacini M, Giffen CA, Smith JJ, et al. Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon a-2b+ full-course vs. 16-week delayed ribavirin. Hepatology 2004;39:989-98. |
|253.||Pallas JR, Farinas-Alvarez C, Prieto D, Delgado-Rodriguez M. Coinfections by HIV, hepatitis B and hepatitis C in imprisoned injecting drug users. Eur J Epidemiol 1999;15:699-704. |
|254.||Reddy GA, Dakshinamurthy KV, Neelaprasad P, Gangadhar T, Lakshmi V. Prevalence of HBV and HCV dual infection in patients on hemodialysis. Indian J Med Microbiol 2005;23:41-3. |
|255.||Aroldi A, Lampertico P, Montagnino G, Passerini P, Villa M, Campise MR, et al. Natural history of hepatitis B and C in renal allograft recipients. Transplantation 2005;79:1132-6. |
|256.||Zhou J, Dore GJ, Zhang F, Lim PL, Chen YM; TREAT Asia HIV Observational Database. Hepatitis B and C virus coinfection in The TREAT Asia HIV Observational Database. J Gastroenterol Hepatol 2007;22:1510-8. |
|257.||Potthoff A, Manns MP, Wedemeyer H. Treatment of HBV/HCV coinfection. Expert Opin Pharmacother 2010;11:919-28. |
|258.||Potthoff A, Wedemeyer H, Boecher WO, Berg T, Zeuzem S, Arnold J, et al. The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the efficacy of pegylated interferon-alpha 2b and ribavirin in patients with HBV/HCV co-infection. J Hepatol 2008;49:688-94. |
|259.||Potthoff A, Berg T, Wedemeyer H; HEP-NET B/C Coinfection Study Group. Late hepatitis B virus relapse in patients co-infected with hepatitis B virus and hepatitis C virus after antiviral treatment with pegylated interferon-a2b and ribavirin. Scand J Gastroenterol 2009;44:1487-90. |
|260.||Kamar N, Mariat C, Delahousse M, Dantal J, Najjar AA, Cassuto E, et al. Diabetes mellitus after kidney transplantation: A French multicentre observational study. Nephrol Dial Transplant 2007;22:1986-93. |
|261.||Choy BY, Chan TM, Lai KN. Recurrent glomerulonephritis after kidney transplantation. Am J Transplant 2006;6:2535-42. |
|262.||Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation. National kidney foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med 2003;139:137-47. |
|263.||Contreras AM, Ruiz I, Polanco-Cruz G, Monteon FJ, Celis A, Vazquez G, et al. End-stage renal disease and hepatitis C infection: Comparison of alanine aminotransferase levels and liver histology in patients with and without renal damage. Ann Hepatol 2007;6:48-54. |
|264.||Peck-Radosavljevic M, Boletis J, Besisik F, Ferraz ML, Alric L, Samuel D, et al. Low-dose peginterferon alfa-2a (40KD) is safe and produces a SVR in patients with chronic hepatitis C and end-stage renal disease. Clin Gastroenterol Hepatol 2011;9:242-8. |
|265.||Rostaing L, Chatelut E, Payen JL, Izopet J, Thalamas C, Ton-That H, et al. Pharmacokinetics of alphaIFN-2b in chronic hepatitis C virus patients undergoing chronic hemodialysis or with normal renal function: Clinical implications. J Am Soc Nephrol 1998;9:2344-8. |
|266.||Fabrizi F, Dixit V, Martin P, Messa P. Combined antiviral therapy of hepatitis C virus in dialysis patients: Meta-analysis of clinical trials. J Viral Hepat 2011;18:e263-9. |
|267.||Alsaran K, Sabry A, Shaheen N. Pegylated interferon alpha-2a for treatment of chronic HCV infection in hemodialysis patients: A single Saudi center experience. Int Urol Nephrol 2010;43:865-73. |
|268.||Huraib S, Tanimu D, Romeh SA, Quadri K, Al Ghamdi G, Iqbal A, et al. Interferon-alpha in chronic hepatitis C infection in dialysis patients. Am J Kidney Dis 1999;34:55-60. |
|269.||Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat 2006;13:316-21. |
|270.||Martin P, Fabrizi F. Hepatitis C virus and kidney disease. J Hepatol 2008;49:613-24. |
|271.||Toth CM, Pascual M, Chung RT, Graeme-Cook F, Dienstag JL, Bhan AK, et al. Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha therapy. Transplantation 1998;66:1254-8. |
|272.||Aljumah AA, Saeed MA, Al Flaiw AI, Al Traif IH, Al Alwan AM, Al Qurashi SH, et al. Efficacy and safety of treatment of hepatitis C virus infection in renal transplant recipients. World J Gastroenterol 2012;18:55-63. |
|273.||Sanai F, Bzeizi KI, Almeshari KA, Mousa D, Ashgar H, ALshoail G, et al. Peginterferon alpha- 2a plus ribavirin combination treatment in chronic hepatitis C post-renal transplant patients: An interim analysis. Transplantation 2010;90(Suppl 2):222. |
|274.||Cid MC, Hernandez-Rodriguez J, Robert J, del Rio A, Casademont J, Coll-Vinent B, et al. Interferon-alpha may exacerbate cryoblobulinemia-related ischemic manifestations: An adverse effect potentially related to its anti-angiogenic activity. Arthritis Rheum 1999;42:1051-5. |
|275.||Dore MP, Fattovich G, Sepulveda AR, Realdi G. Cryoglobulinemia related to hepatitis C virus infection. Dig Dis Sci 2007; 52:897-907. |
|276.||Calleja JL, Albillos A, Moreno-Otero R, Rossi I, Cacho G, Domper F, et al. Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinaemia. Aliment Pharmacol Ther 1999;13:1179-86. |
|277.||Zuckerman E, Keren D, Slobodin G, Rosner I, Rozenbaum M, Toubi E, et al. Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinaemia with ribavirin and interferon- alpha. J Rheumatol 2000;27:2172-8. |
|278.||Kamar N, Rostaing L, Alric L. Treatment of hepatitis C-virus-related glomerulonephritis. Kidney Int 2006;69:436-9. |
|279.||Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265-71. |
|280.||Bruchfeld A, Lindahl K, Stahle L, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003;18:1573-80. |
|281.||Anand BS, Currie S, Dieperink E, Bin EJ, Shen H, Ho SB, et al.; VA-HCV-001 Study Group. Alcohol use and treatment of hepatitis C virus: Results of a national multicenter study. Gastroenterology 2006;130:1607-16. |
|282.||Edlin BR. Prevention and treatment of hepatitis C in injection drug users. Hepatology 2002;36:S210-9. |
|283.||Trask PC, Esper P, Riba M,Redman B. Psychiatric side effects of interferon therapy: Prevalence, proposed mechanisms, and future directions. J Clin Oncol 2000;18:2316-26. |
|284.||Schaefer M, Hinzpeter A, Mohmand A, Janssen G, Pich M, Schwaiger M, et al. Hepatitis C treatment in "difficult-to-treat" psychiatric patients with pegylated interferon-alpha and ribavirin: Response and psychiatric side effects. Hepatology 2007;46:991-8. |
|285.||Harmatz P, Jonas MM, Kwiatkowski JL, Wright EC, Fischer R, Vichinsky E, et al.; Thalassemia Clinical Research Network. Safety and efficacy of pegylated interferon alpha-2a and ribavirin for the treatment of hepatitis C in patients with thalassemia. Hematologica 2008;93:1247-51. |
|286.||Issa H. Safety of pegylated interferon and ribavirin therapy for chronic hepatitis C in patients with sickle cell anemia. World J Hepatol 2010;2:180-4. |
|287.||Ayyub MA, El-Moursy SA, Khazindar AM, Abbas FA. Successful treatment of chronic hepatitis C virus infection with peginterferon alpha-2a and ribavirin in patients with sickle cell disease. Saudi Med J 2009;30:712-6. |
Abdullah S Alghamdi
Department of Medicine, King Fahad General Hospital, PO BOX 50505 (450), Jeddah
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Epidemiology of viral hepatitis in Saudi Arabia: Are we off the hook
| ||Abdo, A.A. and Sanai, F.M. and Al-Faleh, F.Z. |
| ||Saudi Journal of Gastroenterology. 2012; 18(6): 349-357 |