Management of Chronic Hepatitic C Virus Genotype 4 Infection

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Arab Journal of Gastroenterology www.arabjg.eg.net 38
Review Article Management of Chronic Hepatitic C Virus Genotype 4 Infection
Gamal Esmat, Maissa El Raziky
Tropical Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Key Words Chronic hepatitis C, epidemiology, screening, diagnosis, therapy
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Corresponding Author
http://www.arabjg.eg.net/2007_part2/article_no.1.pdf
Gamal Esmat, MD, Tropical Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt,
Tel.: 202236847524, Fax: 20223682774, E-mail: gesmat@gamalesmat.com
InTRoDuCTIon
Hepatitis C virus (HCV) accounts for a sizable proportion of cases of chronic liver disease, liver disease deaths and cases
of hepatocellular carcinoma and represents the most common indication for liver transplantation (LTx). Projections based on the
current prevalence of infection and anticipated rates of progression suggest that the morbidity and mortality as well as the medical care
costs attributable to HCV infection will escalate alarmingly during the next two decades1.Six major genotypes1–6 and more than 50 subtypes of HCV have been described2. In general, HCV genotype 4 (HCV4) is predominant in Africa and the Middle East 3. In Egypt, where hepatitis C is highly endemic (up to 15% of the population), 91% of the patients were infected with HCV44.Many studies confrm that HCV4 is the predominant HCV genotype in Saudi Arabia5,6 and Kuwait7. Small studies from Africa suggest that HCV4 is the predominant genotype on that continent8,9. Although HCV4 represents 1–3% of the hepatitis C infections in Western countries, some studies report an unexplainably more prevalent HCV4 in some European countries as in Southern Spain10, Southern Italy11 and France12. Most HCV4 patients in these studies were intravenous drug abusers.SCREEnInG Hepatitis C has many characteristics that render it potentially suitable for screening. In fact, it causes signifcant morbidity, high risk groups are identifable as a target population and the screening test is effcient. The testing strategy utilizes the antibody test which has excellent specifcity and sensitivity, if we exclude some false negative cases in acute infections and in the immunocompromised state. In these situations the diagnosis can be made with HCV RNA by using amplifcation techniques. For the majority of patients, the usual approach is to test them initially for the antibody and then to use HCV RNA to detect viraemia13. But problems arise in the defnition of the target population. In fact, generalized population screening is not endorsed by international guidelines, although some recommend screening population of high prevalence countries. Opportunistic screening (case fnding) of individuals with classic risk factors, such as transfusion before 1992 and drug addiction, is the most frequently used strategy14. Arguments against population screening are that nearly half of the detected patients will have normal alanine aminotransferase (ALT) and a slowly progressing disease15, that many patients will harbor conditions contraindicating antiviral treatment and that many persons with mild disease will have deterioration in their quality of life after knowing the result of the test16
. These drawbacks limit the effectiveness of a mass screening program and render it not cost effective14. The optimal method to detect HCV infection, according to all international guidelines, is therefore to screen individuals with identifable risk factors: Intravenous drug use (past and present), populations with high HCV prevalence, injections with reusable glass syringes, blood transfusion or organ transplantation before 1992 (or by known HCV positive donor), administration of clotting factors before 1997, hepatitis B virus infection, clinical or biochemical evidence for chronic liver disease, percutaneous exposures to HCV, history of sexually transmitted disease, history of invasive procedures or haemophilia, children born to HCV positive mothers, health care workers performing procedures at risk of transmission to the patient and stable sexual partners of HCV positive patients17-21. Multiple large community-based studies from Egypt have shown a strong association between a history of receiving parenteral antischistosomal therapy (in the 1960s and 1970s) and the prevalence of anti-HCV antibody (anti-HCV)22–24. Rao et al. reported that among Egyptians residing in the Nile delta region, the prevalence of HCV was 38% in patients who reported no history of schistosomiasis and 68% in individuals with a history of parenteral antischistosomiasis treatment (P <0.0001)23. Many publications suggest that parenteral antischistosomiasis treatment had a major role in the spread of HCV throughout Egypt. This intensive transmission established a large reservoir of chronic HCV infection, responsible for the high prevalence of HCV infection and current high rates of transmission. Egypt’s mass campaigns of
parenteral antischistosomiasis treatment may represent the world’s largest iatrogenic transmission of blood-borne pathogens24.

Arab J Gastroenterol 2007; 8(2): 38-43ISSN 1687-1979G. Esmat and M. El Raziky- Management of Chronic HCV Genotype 4 39 PRETREATMEnT DIAGnoSTIC EVALuATIon Pretreatment diagnostic consideration Seropositive persons for anti-HCV in the presence of HCV RNA and compensated liver disease are considered as potential candidates for antiviral therapy21 . Currently, antiviral therapy is not recommended for patients with decompensated liver cirrhosis or history of severe uncontrolled psychiatric disorder17 . Patients with marked leucopoenia or thrombocytopoenia may not tolerate interferon (IFN) and patients with marked anaemia, cardiovascular or cerebrovascular disease, or renal failure may not tolerate ribavirin, which causes dose-dependent haemolytic anaemia22 . Testing for ALT and aspartate aminotransferase (AST) levels is an important component of the diagnostic evaluation in patients with chronic HCV, although elevation of ALT and AST levels is not a requirement for therapy21 . Virologic tests for monitoring therapy Quantitative testing for HCV RNA with an amplifcation assay provides both a baseline level to monitor virologic response and a prognostic indicator of the likelihood of response. Patients with very high levels of HCV RNA respond less well to antiviral therapy than do those with lower levels. These assays are valuable for demonstration of early virologic response (EVR) that is a 2-log 10 reduction in HCV RNA levels within 12 weeks of initiating therapy21 . Genotyping Although the genotype is a strong predictor of response to therapy and can affect the duration, however in a country like Egypt, where more than 90% of HCV cases are of genotype 44 , genotyping may be revaluated for its cost-effectiveness. Patients with genotype 4, are intermediate in responsiveness to therapy between those of genotype 1 and genotypes 2 and 3, and are treated for a full 48 weeks with full dose ribavirin like patients with genotype 125 . Liver biopsy Despite its complications and interpretation errors, liver biopsy remains the gold standard for determining histologic grade and stage to assess the current status of the liver and to provide prognostic information for future disease progression26 . In most studies, the degree of liver fbrosis is an important predictor of response to therapy. Patients with mild degree of fbrosis respond better to treatment than patients with higher fbrosis stage27 . If he biopsy specimen shows mild histologic disease, progression may be suffciently slow to justify monitoring without therapeutic intervention17 . Steatosis has been shown to be a negative predictor of response to antiviral therapy28 . Persistently normal serum ALT As patients with persistently normal ALT levels generally do not progress histologically, they are candidates for antiviral therapy or for monitoring without intervention as determined on an individual basis and is infuenced by patient’s factors such as motivation, histologic activity and fbrosis20 . Counseling to avoid transmission of HCV

HCV-infected persons should be counseled to avoid sharing toothbrushes and dental or shaving equipments and be cautioned to cover any bleeding wound in order to keep their
blood away from others and advised not to donate blood, body organs other tissues or semen.
Persons should be counseled to stop using illicit drugs, avoid reusing or sharing syringes or needles, to clean the injection site with a new alcohol swab and dispose safely syringes and
needles after use.
HCV-infected persons should be advised that the risk of sexual transmission is low and that the infection itself is not a reason to change sexual practices (i.e. those in long-term relationships need not starting using barrier precautions and others should always practice “safer” sex)13.
Approach to patients with anti-HCV
When anti-HCV is present, a single determination of ALT level gives limited information about the severity of the underlying liver disease. Patients who initially have a normal ALT should
undergo three measurements over a six months period to confrm persistence of normal ALT levels.
When anti-HCV is present and ALT is normal, qualitative HCV RNA determination should be performed. If HCV RNA is negative, the presence of anti-HCV is probably due to past infection while if HCV RNA is positive, annual follow-up is proposed, but no treatment is considered and liver biopsy is not indicated.
When anti-HCV is present and ALT is elevated, a qualitative
HCV RNA determination is indicated in order to confrm the
presence of HCV.
A quantitative HCV RNA determination (which is less sensitive than the qualitative) and genotyping is only indicated when treatment is considered.
Liver biopsy is not recommended in patients with normal transaminases. In contrast, a liver biopsy is highly recommended before considering treatment in order to determine the infammatory activity and the degree of fbrosis (staging) and to exclude other liver diseases. When it is decided not to treat, a follow-up biopsy is planned after three to fve years in order to determine the evolution of the disease29.
TREATMEnT oF CHRonIC HCV4 InFECTIon
Therapy for chronic HCV4 infection has evolved substantially during the past decade. The goal of treatment is to prevent sequels of HCV infection; this is mainly achieved by elimination of the virus. Accordingly, treatment responses are dependent on the results of HCV RNA testing. Infection is considered eradicated when there is a sustained virologic response (SVR) defned as the absence of detectable HCV RNA in serum at the end of treatment and 6 months later. Persons who achieve a SVR always have a dramatic earlier
reduction in the HCV RNA level defned in some studies as a 2-log drop or loss of HCV RNA 12 weeks into therapy, referred to as an early virologic response (EVR). Continued absence of detectable virus at termination of treatment is referred to as end of treatment response (ETR). A patient is considered to have relapsed when HCV RNA becomes undetectable on treatment but is detected again after discontinuation of treatment. Persons in whom HCV RNA levels remain stable on treatment are considered non responders, while those whose HCV RNA levels decline (e.g. by >2 logs), but never become undetectable, are referred to as partial responders. Improvement in liver histology, including improvement in fbrosis, has been recorded particularly in those with a SVR to therapy13.
Initial therapy with IFN alpha monotherapy had limited
success30,31
. Ribavirin monotherapy was shown to be ineffective32.
But the addition of ribavirin and later the pegylation of IFN led to marked improvements in response rates. The current standard of care, therefore, is pegylated IFN (PEG-IFN) with ribavirin33.
IFn alpha and Ribavirin
An Egyptian study randomized 52 HCV4 patients to receive either IFN-α-2b 3 million Unit (MU) TIW or IFN plus 1000mg/day of ribavirin for 24 weeks. Approximately 30% in each arm had cirrhosis. The SVR rates were 20% in the combination arm and 8% in the IFN monotherapy arm34. Koshy et al. treated 112 non-cirrhotic HCV4 patients with either 5 MU of IFN-α-2b TIW (52 patients) or IFN plus ribavirin 1000mg/day for body weight <75kg or 1200mg/day for body weight >75kg. Sustained viral response was observed in only 8% of patients in the monotherapy group versus 42% in the combination group (P =0.0001)35. The same group also reported on 26 HCV4 cirrhotic patients treated with either IFN or IFN plus ribavirin combination therapy in similar doses. No SVR was observed in the IFN monotherapy group compared to 14% in the combination therapy group7.
Al Faleh et al.36conducted a prospective open label trial on 97 patients from Saudi Arabia. Genotyping was available for 76 patients; 55% had genotype 4. Sixty eight patients were non-responders to previous IFN monotherapy while 29 patients were treatment-naïve. Patients were treated with IFN-α-2b 3 MU TIW plus ribavirin 1000mg daily for 6 months. End-of-treatment virologic response (ETVR) was 28% in the previously treated group and 58% in the naïve patients, while SVR was 5% and 12%, respectively. When the 40 patients with genotype 4 were analyzed, the ETVR was 43% and the SVR was 16%. One possible explanation for the surprisingly low SVR in the naïve patients compared to the previously treated patients is that more than 70% of the naïve patients had a high or medium viral load. Furthermore, the treatment duration was only 6 months, which may explain the relatively high ETVR compared to the low SVR36.A small Italian study reported on 18 HCV4 patients treated with IFN-α-2b 5–6 MU TIW plus ribavirin 1000–1200mg/day for 48 weeks37.Three patients had cirrhosis and seven had been treated previously with IFN monotherapy. Only 33% had an ETVR and 11% had a SVR33.
PEG - IFn
There is a very limited number of patients with genotype 4 infection in the large multicenter HCV treatment trials. As a subgroup of the large phase two and three trials including 1205 hepatitis C patients, Sherman et al. reported on the results of 16 patients with HCV4. Five patients received treatment with IFN-α-2a and 11 patients were treated with PEG-IFN-α-2a weekly for 48 weeks42. Four patients had cirrhosis. No patient treated with standard IFN achieved ETVR or SVR, whereas of the patients treated with PEG-IFN 73% showed ETVR and 45% had a SVR38.
PEG - IFn and Ribavirin
The addition of the synthetic guanosine analogue ribavirin to IFN was a major breakthrough in the treatment of HCV infection. Diago et al. reported preliminary results on 49 HCV4 patients from North America and Europe. In the frst trial, 13 patients were treated with PEG-IFN-α-2a plus ribavirin 1000–1200mg/day for 48 weeks, while in the second trial 36 patients were treated in one of four groups:
PEG-IFNα-2a plus 800mg of ribavirin or 1000–1200mg of ribavirin for 24 weeks or 48 weeks. Among patients who were treated with PEG-IFN plus 1000–1200mg of ribavirin, 79% achieved a SVR.
Patients treated with ribavirin at a dose of 800mg for 48 weeks or ribavirin 1000–1200mg for 24 weeks achieved slightly lower SVR of 63% and 67%, respectively. No SVR was seen in patients treated with ribavirin 800 mg/day for 24 weeks39.
Shobokshi et al. treated 180 HCV4 patients in a randomized open label multicenter trial40. The frst group received PEG-IFNα-2a 180mg weekly plus ribavirin 800mg/day 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 ribavirin 800mg/day. ETVR was 67% in the PEG-IFN combination arm compared to 59% in the monotherapy arm and 37% in the standard IFN combination arm. At the end of 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 arm. Patients who did not acheive a signifcant response at 12 weeks of therapy showed no SVR40.
Al Faleh et al. randomized 96 patients to be treated with either 100 mg of PEG-IFN-a-2b plus 800mg/day of ribavirin or standard IFN plus ribavirin combination therapy. ETVR was 70% in the PEG-IFN arm compared with 52% in the standard IFN arm41. SVR was achieved in 43.8% of patient in the PEG-IFN arm and in 29.2% of patients in the standard IFN arm. These results did not achieve statistical signifcance, probably because of the relatively small sample size41.
Esmat et al. reported results from a randomized trial involving 200 patients, 90% of them had HCV4. Forty eight patients were randomized to receive PEG-IFN-α-2b 100mg/week plus 800–
1000mg of ribavirin based on body weight or standard IFN plus ribavirin for 48 weeks. Patients receiving PEG-IFN achieved 45% SVR compared to 38% in the IFN group37.
In a study from Kuwait where PEG-IFN-α-2b was used, Hasan et al. enrolled 66 patients in a prospective open label study. In this study, a higher (currently standard) dose of ribavirin, that is 1000–1200mg/day, was used. This resulted in much higher ETVR and SVR of 77% and 68%, respectively42.
From the studies of Diago39and Hasan42, we can conclude that high dose ribavirin, that is 1000–1200 mg/day, should be used in HCV4 patients, irrespective of the type of PEG-IFN used.G. Esmat and M. El Raziky- Management of Chronic HCV Genotype 4 41Monitoring response to antiviral therapy
Baseline and twelfth week monitoring of HCV RNA levels should be performed with the same quantitative amplifcation assay. An EVR, during the frst 12 weeks of therapy, is a valuable laboratory milestone. In the absence of an EVR, the likelihood of a SVR is 0 to 3%. If the only goal of therapy is to achieve a SVR therapy can be discontinued after 12 weeks if an EVR is not achieved. Potentially, histologic beneft may happen even in the absence of a SVR. For documentation of a ETR or a SVR, a more sensitive quantitative assay with a lower limit of 50 IU/ml, if available, or a qualitative HCV RNA assay is recommended1.
Follow up after treatment
Once treatment has been decided for a particular patient, routine follow up is planned. Pre-treatment baseline laboratory values should be obtained including complete blood count, complete metabolic panel, INR and HCV viral load. Patients should return two weeks after initiation of therapy and subsequently every four weeks. At these encounters the above routine laboratory studies should be obtained as well to monitor for signs of adverse effects
due to the drugs. The decision to continue treatment after week 12 would then be determined based on EVR, tolerance to drugs, laboratory profles and the pre-treatment assessment of the severity of liver disease. During each follow up, signs and symptoms of possible adverse effects should be evaluated. If treatment is continued in the presence of adverse effects, dose adjustments can be considered. On the other hand, a particular adverse effect can be treated or monitored without lowering dosages depending on its severity. Once the course of treatment is completed, a qualitative HCV viral load must be obtained to document end of ETR. The same test should be done 6 months later to evaluate for SVR.
Frequent haematologic monitoring is necessary to identify marked anaemia, neutropaenia and thrombocytopaenia; monitoring of thyroid stimulating hormone level is indicated to identify hypothyroidism or hyperthyroidism1.
Contraindications for IFn therapy43
Major uncontrolled depressive illness or severe uncontrolled psychiatric disorder, patients with decompensated liver cirrhosis, with marked leucopaenia or thrombocytopaenia or marked
anaemia, patients with severe concurrent disease such as severe hypertension, poorly controlled diabetes, obstructive pulmonary disease, cardiovascular or cerebrovascular diseases or renal failure, kidney, heart or lung transplantation recipient, autoimmune hepatitis, untreated hyperthyroidism, pregnant or unwilling/unable to comply with adequate contraception, under three years of age and known hypersensitivity to drugs used to treat HCV.
Special percautions
Age older than 70 years, neutropoenia (neutrophil count <1500cells/µL), thrombocytopoenia (<85,000/µL), organ transplantation, history of autoimmune disease and presence of thyroid antibodies are situations needing special caution.
Adverse events
The incidence and types of side effects of PEG-IFN alpha plus ribavirin are similar to those identifed for IFN plus ribavirin; they tend to be more severe in the initial weeks of treatment: Those typically associated with IFN alpha, such as neutropaenia, thrombocytopaenia, depression, hypothyroidism and hyperthyroidism, irritability, concentration and memory disturbances, visual disturbances, fatigue, muscle aches, headaches, nausea and vomiting, skin irritation, low grade fever, weight loss, insomnia, hearing loss, tinnitus, interstitial fbrosis and hair thinning. “Flu-like” symptoms and depression seem to occur signifcantly less frequently with PEG-IFN alpha-2a plus RBV than with interferon alpha-2b plus ribavirin44.
Those typically associated with ribavirin, include haemolytic anaemia, fatigue, itching, rash, sinusitis, birth defects or gout.
Deaths reported in association with treatment include suicide, myocardial infarction, sepsis and stroke. Ribavirin is contraindicated in pregnancy, necessitating strict precautions and contraception in women of childbearing age and their sexual partners and in HCV-infected men with female partners of childbearing age. It should be avoided in patients with ischaemic cardiovascular and cerebrovascular disease and with renal insuffciency13.
HCV and schistosomiasis
Concomitant HCV and Schistosoma mansoni infection is common in Egypt and has a severe impact on the course of liver disease in this population45. In acute hepatitis, spontaneous resolution is associated with vigorous and persistent HCV-specifc CD4 Th1 and CD8 cytotoxic T cell responses46. A predominant Th2 profle, induced by S. mansoni infection, probably antagonizes and downregulates the antiviral activities of Th1 cytokines. This may result in increased viral replication and more aggressive progression to fbrosis. Coinfected patients had signifcantly high HCV RNA titres and an inverse relationship between virus load and CD4 T-cell responses, particularly during the early phase of chronic evolution. This favours liver damage and progression of disease47. Dual infections of schistosomiasis and viral infections
display signifcant infuences on host immune reactions including cytokine shift pattern alteration45. It also has an impact on response to anitiviral therapy. Thus screening for active schistosomiasis and treating the infection prior to initiating IFN/ribavirin therapy is mandatory.
FACToRS ASSoCIATED WITH RESPonSE To InTERFERon AnD RIBAVIRIn
From studies using regular IFN, Al Faleh et al. found that a high pretreatment viral load was the most important negative predictive factor for response to therapy followed by an advanced histological stage30. Similar results were found in some of the studies in Egyptians using pegylated interferon37,42.
In contrast, Koshy et al. did not fnd any signifcant pretreatment variables that would predict treatment response35.

Relapsers and nonresponders1

Patients in whom HCV RNA is undetectable during and at the end of therapy but reappears again after completion of therapy (relapsers) are likely to respond and experience a relapse again with
a subsequent course of the same therapy. The chance of achieving Arab J Gastroenterol 2007; 8(2): 38-4342
a SVR in relapsers, however, may be as high as 40 to 50% if re-treatment is pursued with more effective therapy. If this group of patients is to be re-treated, ideally, a different, more effective
regimen should be used. Therapy with PEG-IFN and ribavirin should be strongly considered for patients who experienced a relapse after a course of standard IFN/ribavirin combination therapy, while a longer duration of therapy in patients who experienced a relapse after 12 months of treatment with PEG-IFN plus ribavirin is of unproven effcacy.
For nonresponders to a previous course of standard IFN monotherapy, re-treatment with PEG-IFN plus ribavirin can increase the frequency of responsiveness to approximately 20%; for nonresponders to a previous course of standard IFN plus ribavirin, re-treatment with PEG-IFN plus ribavirin can increase the frequency of responsiveness to approximately 10%. Expectations for responsiveness to re-treatment are lower in patients with genotype 1, cirrhosis, high baseline HCV RNA levels and black ethnicity. Such factors, in addition to patient’s tolerance to previous therapy and severity of underlying liver disease, should be taken into consideration when making individualized decisions about the re-treatment of prior nonresponders.

HCV infection after liver transplantation
In patients with chronic HCV who are candidates for transplantation, recurrent infection of the allograft is universal following transplantation and probably occurs at the time of reperfusion.
Viraemia starts to rise from day 7 and most patients will develop acute HCV4-12 weeks post-transplant. Following transplant, pre-emptive treatment (<6 months) post transplant is only within
clinical trials. Treatment of established reccurrence ( >6 months) should be considered in severe disease, the preferred regimen is at least 48 weeks PEG-IFN plus ribavirin. Over-immunosuppression
should be avoided in the early post-transplant period and rapid steroid withdrawal in the later post-transplant period48.
Liver transplantation for HCV induced cirrhosis
The outcome of patients transplanted for HCV is variable. HCV cirrhosis whether alone or mixed with schistosomiasis was the main indication for LTx. A 77.6% survival after a median follow up
period of 4.6 years was reported49.
ConCLuSIon
The natural history of HCV4 seems to be generally similar to other HCV genotypes, but the suggestion that it is associated with a worse prognosis after liver transplantation is questionable. Regular IFN monotherapy results are poor (in the range of 10-15%). Non-pegylated IFN plus ribavirin combination therapy showed variable results, but approximately 35-40% of patients achieve SVR after 48 weeks of treatment. The use of PEG-IFN combination therapies should result in improved response rates, ranging from 40% to 70%. Thus PEG-IFN, higher doses of ribavirin and a 48 weeks duration of therapy give the patient the best chance for a higher SVR.
ACKnoWLEDGMEnTS
The authors acknowledge the efforts of Dr. Naglaa Zayed, lecturer of Tropical Medicine Department, Cairo University and Dr. Mohammed El Kassas, tropical medicine specialist at TMRI, for
their help in preparing this review.
Competing interests: None
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