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Infection with Hepatitis C Virus Genotype 4 in the United States
 
 
  Journal of Clinical Gastroenterology 2004; 38(1):68-71
 
Andre C. Lyra, MD; Sunil Ramrakhiani, MD; Bruce R. Bacon, MD; Adrian M. Di Bisceglie, MD
 
From the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, St. Louis, MO.
 
Background: Hepatitis C virus genotype differences seem to be of considerable clinical significance because they affect responses to antiviral therapy. HCV genotype 4 is rare in the United Sates and there are few published data regarding response to therapy in patients with HCV genotype 4 infection.
 
Objectives: To assess epidemiologic factors associated with HCV genotype 4 infection in United States and to describe the response rate to therapy with the combination of alpha interferon and ribavirin.
 
Methods: All hepatologists in our Division were asked for information about patients they had treated with HCV genotype 4. In addition, we searched the computer database from Saint Louis University Hospital in the last 40 months (1999 to 2002). Twenty HCV genotype 4 patients were identified. A retrospective chart review was performed to collect information about their demographics, risk factors for acquisition of infection, baseline laboratory studies and response to antiviral therapy.
 
Results: A risk factor for exposure to HCV was noted in 14 cases (70%); 12 patients had a history of illicit drug use, whereas a history of blood transfusion was detected in three cases; 1 patient had both risk factors. Only 4 of 20 individuals had fibrosis stage 3 or 4 on liver biopsy. Seventeen patients were treated, 14 of whom completed therapy; 10 patients were sustained responders.
 
Conclusions: As with other HCV genotypes, most patients with HCV genotype 4 in the United States acquire the infection through intravenous drug use, liver disease is often mild to moderate in severity and 59% of our patients had a sustained virologic response after combination therapy with interferon and ribavirin.
 
PATIENTS and METHODS
 
Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with the prevalence of anti-HCV in the general population of the United States being 1.8%. 1 This corresponds to an estimated 3.9 million individuals having been infected with HCV. The striking genetic heterogeneity of the RNA genome of HCV is well recognized. This genetic diversity extends to include 6 major genotypes, over 80 subtypes and minor variants referred to as "quasispecies". 2 The occurrence of HCV genotypes tends to vary with geographic region. Thus, HCV genotype 1 accounts for approximately two-thirds of HCV-infected individuals in the United States. The next most common is genotype 2 (14%), followed by genotype 3 (6-8%). 3, 4 In one study the prevalence of HCV genotype 4 infection among 438 patients from 10 tertiary referral centers across the United States was 1.1%. 3
 
HCV genotype differences seem to be of considerable clinical significance because they affect responses to antiviral therapy. In particular, it is well known that patients infected with HCV genotypes 2 and 3 respond much better to antiviral therapy than those infected with genotype 1. 5 HCV genotype 4 appears to be prevalent in the Middle East and Central Africa, where it has been reported to be frequently associated with cirrhosis and a poor response to interferon. 6, 7 There are few published data from the United States regarding response to therapy in patients with HCV genotype 4 infection. The aim of the present study is to assess epidemiologic factors associated with HCV genotype 4 infection in the United States and to determine the response to therapy with the combination of alpha interferon and ribavirin.PATIENTS AND METHODS
 
We retrospectively studied patients with HCV genotype 4 infection who were referred to Saint Louis University. All hepatologists in our Division were asked for information about patients they had treated with HCV genotype 4. In addition, we searched the computer database from Saint Louis University Hospital in the last 40 months (1999 to 2002). There were 1250 tests for HCV genotyping that were performed during this period; 8 patients (0.6%) were found to have genotype 4. In total, we were able to identify 20 patients who were infected with HCV genotype 4. All had anti-HCV and HCV RNA detectable in serum. A retrospective chart review was performed to collect information about their demographics, risk factors for acquisition of infection, baseline laboratory studies including liver biopsy results, and response to antiviral therapy.
 
Serum HCV RNA levels and HCV genotyping assays were performed by 2 commercial clinical laboratories. HCV RNA levels were determined in most cases using the Amplicor HCV version 1.0 kit from Roche (Branchburg, NJ), however the results are not comparable between the 2 laboratories. In 12 cases, the HCV was genotyped by sequencing and phylogenetic analysis of PCR products from the NS5B region; and in 8 cases HCV genotyping was performed by restriction fragment length polymorphisms (RFLP) analysis of 5` untranslated region (5`UTR).
 
Sixteen patients were treated with interferon and ribavirin in combination at standard doses (alpha interferon 3 million units 3 times a week and ribavirin 1,000 to 1,200 mg per day based on body weight). One of these 16 patients was a previous non-responder to interferon mono-therapy. Two patients were treated with pegylated interferon and ribavirin. The other 2 patients were not treated. HCV RNA was assessed at baseline and at 3, 6, 12, and 18 months after starting treatment. Patients who still had detectable HCV RNA by PCR at 6 months were defined as non-responders and their therapy was stopped. Patients who had undetectable HCV RNA by PCR at 6 months were treated for an additional 6 months. Sustained biochemical and virologic response was defined as normal ALT and negative HCV RNA 6 months after therapy was stopped.
 
RESULTS
 
The baseline demographics, liver biopsy, and laboratory data from these patients are summarized: risk factors—55% IDU (n=11), cocaine snorting 10% (n=2), 30% (n=6) >1 million copies/ml; mean ALT 95 U/L (range 15-202); stage of fibrosis—11 stage 2, 5 stage 1, 2 stage 3, 2 stage 4. Fourteen patients were white, most of them born in the United States. Four patients were African American, 1 was an Egyptian who had immigrated to the US approximately 30 years ago, and 1 was a black woman from Zaire who had just immigrated to the United States. They were all adults and half were men. A risk factor for exposure to HCV was noted in 14 cases (70%); a history of illicit drug abuse including intravenous drug use and snorting cocaine was obtained from 12 patients, whereas a history of blood transfusion was detected in 3 cases; 1 patient had both illicit drug use and blood transfusion as risk factors. In the patient of Egyptian nationality, the patient from Zaire, and in 4 other patients, no source of HCV infection could be identified. HCV RNA was detectable in serum of all cases, but because 2 different laboratories performed the assays mean values could not be calculated. The baseline HCV RNA was above 1 million copies per ml in 6 patients. Most of the patients had mild to moderate liver disease on biopsy and only 4 individuals had bridging fibrosis or cirrhosis present. Interestingly, one of these patients with cirrhosis was the subject of Egyptian nationality. He has since developed hepatocellular carcinoma.
 
Thirteen patients have completed 6 to 12 months of therapy. An additional patient completed 8 months of treatment and then discontinued therapy because of side effects. Two patients discontinued therapy a few weeks after starting due to adverse reactions, whereas 1 patient was lost to follow-up. Two patients were not treated and another is still on the second month of treatment with pegylated interferon and ribavirin. Seven of the 14 individuals who completed treatment (50%) had undetectable HCV RNA at 3 months of therapy. Ten of the 14 patients (71%) are sustained responders whereas 4 were non-responders (29%). When excluding from analysis the patient who is still on the second month of therapy, overall 10 of 17 treated patients (59%) had a sustained virologic response. Interestingly, the patient who was treated for only 8 months was a sustained responder, and 1 patient with cirrhosis at liver biopsy who was an African American also had a sustained response after using the combination of pegylated interferon and ribavirin. The subject who was re-treated with combination therapy was a sustained responder also. Sustained responders frequently had baseline serum HCV RNA levels below 1 million copies/ml and negative HCV RNA by qualitative PCR at 3 months of therapy. In addition, 8 out of 10 sustained responders had hepatic stage of fibrosis 1 or 2. On the other hand, 3 out of 4 non-responders had baseline serum HCV RNA levels higher than 1 million copies/ml and all 4 had detectable HCV RNA at 3 months of therapy. Of note, the patient of Egyptian nationality was a non-responder.
 
DISCUSSION
 
We describe patients infected with HCV genotype 4 who seem to be different from those in countries from the Middle East where this genotype is prevalent. Thus, most of our patients were white, born in the United States and 12 of 20 (60%) appeared to have acquired HCV through illicit drug abuse, including intravenous drug use and snorting cocaine. Reports from Western European countries have also encountered a high rate of HCV transmission through intravenous drug use in subjects with HCV genotype 4. Therefore, in a study from Spain 10 of 11 individuals found to be infected with this HCV genotype were intravenous drug users. 8 In French populations, 36% to 65% of HCV genotype 4 infections have occurred through intravenous drug abuse. 9, 10 On the other hand, in a study from Kuwait where there was a high proportion of subjects of Egyptian nationality, none of the patients was an intravenous drug user. 11
 
In addition, most patients in this small cohort had mild to moderate liver disease and only 4 had bridging fibrosis or cirrhosis present. This is also in contrast to studies from the Middle East and Africa where HCV genotype 4 is frequently associated with cirrhosis. Interestingly, the only patient of Egyptian nationality from our study had no identifiable source of the HCV infection and had cirrhosis at liver biopsy.
 
Our patients had a remarkably high rate of response to antiviral therapy with the combination of interferon and ribavirin. Thus, 10 of 14 (71%) individuals who completed approximately 12 months of therapy had a sustained virologic response. Interestingly, 4 of these 9 responders had normal ALT levels before treatment, however, these are baseline levels and we are not aware of other ALT measurements in the 6 months preceding the start of therapy. On the other hand, in the study from Kuwait, the sustained virologic response rate of individuals with HCV genotype 4 who completed combination therapy was 42%, whereas in a study from Egypt it was 21%. 11, 12 Other previous studies of antiviral treatment have also shown a poor response rate with interferon therapy alone. 6, 13 The reasons for the better response to therapy in our patients are unclear but might be related to the differences in populations mentioned previously. Therefore, our patients are from a different ethnic background and appear to have had a different source of HCV infection in comparison to patients from the Middle East.
 
Differences in ethnicity have been described to interfere with response to therapy for hepatitis C viral infection. Thus, African Americans seem to have a worse overall response to interferon treatment than whites. 14 Moreover, most of our patients had mild to moderate histologic liver disease, low HCV viral load before treatment, and one of the sustained responders was treated with pegylated interferon, which has been reported to improve the response rate to combination therapy. Possibly, the association of all these factors favored the response to treatment. It is also important to consider the possibility of patient selection bias secondary to the small number of subjects. Nevertheless, it should be noted that HCV genotype 4 is rare in the United States with the prevalence being reported to be as low as 1.1% among subjects who are referred to tertiary centers. In our center, the incidence rate seemed to be around 0.6% in a 3-year period. Therefore, the few cases that are described here probably reflect reasonably well the patients infected with HCV genotype 4 who are referred to our center.
 
In conclusion, we report 20 patients who were infected with HCV genotype 4 and were evaluated in Saint Louis University. Most of these individuals acquired the infection through intravenous drug use, had mild to moderate histologic liver disease, and had a sustained virologic response after combination therapy with interferon and ribavirin.
 
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