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  • claudine intexas
    Mar 27, 2006
      From E-Medicine

      The identification of the hepatitis C virus (HCV) in the late 1980s was a substantial but minute step into the understanding of the virus. Its complex and evasive nature continues to pose significant risk of morbidity and mortality in the hosts it infects. Worldwide, HCV accounts for about 40% of cases of chronic liver disease. The complications of infection can be devastating, as most persons with HCV develop chronic infection. The painstaking progress of treating these patients has been made possible primarily through the use of the interferon family. The recent formulation of pegylated interferon (PEG-IFN) in combination with ribavirin has provided promising results in these patients. This combination has led to sustained viral response (SVR) rates of up to 60%. This recent advancement of therapy has given new hope to physicians who treat people who are infected with HCV.
      The prevalence of HCV among Americans has been reported at 2% of the total population. This percentage is heavily disputed. Strong sentiment exists that a considerable number of people are infected but undiagnosed. The analysis of the Third National Health and Nutrition Examination Survey (NHANES III) data showed that the highest risk factor for transmission was repeated exposure to blood. It is among this subset of individuals with repeated exposure that unfortunately high risk stratifications have been identified.
      Subpopulations with high HCV prevalence must be identified. These infected persons may serve as epidemiological mediators that perpetuate the spread of the disease.
      Intravenous drug users
      Because HCV is a blood-borne disease, with transmission occurring primarily through exposure to infected blood via parenteral or percutaneous routes, a history of intravenous drug use (IDU), even once in a lifetime, is considered a major risk factor. The prevalence of HCV among this population is around 90%, with infectivity usually occurring rapidly after initial exposure of drug injection. In the United States, IDU accounts for 60% of all new HCV infections, primarily through the sharing of syringes or drug paraphernalia. Intranasal drug use may also spread infection. The use and sharing of contaminated instruments (ie, straws) might be an alternative vehicle for spreading infection through the nasal mucosa. Patients who contracted HCV through IDU who receive treatment may indeed achieve SVR; however, their high-risk behavior poses a significant risk for reinfection.
      Persons infected with HIV
      HIV and HCV share the same route of transmission; this is well documented. Co-infection with HCV is thought to occur in 15-40% of individuals infected with HIV. The prevalence of HCV among patients with HIV who used intravenous drugs is estimated to be as high as 90%. The presence of HIV has been shown to further accelerate the rate to fibrosis, to cause higher HCV RNA viral loads, to cause higher incidence of cirrhosis and hepatocellular carcinoma (HCC), and to cause higher rates of vertical transmission compared with patients infected with HCV but not with HIV. Studies evaluating the combination of ribavirin with PEG-IFN have shown lower SVR in this patient population. SVR rates in treatment groups of patients who are monoinfected with HCV are about 54-63%; in the population of patients co-infected with HIV and HCV, SVR rates range from 12-40%. Patients infected with HIV and HCV genotype 1 are found to have consistently lower SVR rates than patients with other HCV genotypes, which
      is consistent with the overall HCV population.
      The implementation of highly active antiretroviral therapy (HAART) has been shown to further accelerate HCV replication. However, the presence of HCV has not been shown to accelerate HIV progression to AIDS. Rates of hospital deaths from end stage liver disease range from 17-45% in these patients. Early studies in the mid 1990s found that the presence of HCV had no effect on the progression of HIV to AIDS. These initial findings were revisited because of the implementation of HAART. The results again show that HCV does not pose a risk in increasing HIV disease progression and that HAART response was no different in HCV seropositive patients than in HCV seronegative patients. The treatment of HCV in patients co-infected with HIV and HCV should not be attempted unless the patients are stable with regard to their HIV status. Treatment of HCV is absolutely contraindicated in patients with AIDS.
      Recipients of blood transfusions prior to July 1992
      Patients with a history of blood transfusion prior to July 1992 should be identified and tested. The prevalence of non-A, non-B or posttransfusion hepatitis after open heart surgery before July 1992 was around 10% after receiving a blood transfusion. The implementation of nucleic acid screening reduced the risk of transfusion-associated infection for HCV to approximately 1 in 2 million blood units from repeated donors. This represents a significant reduction from rates of 1 in 276,000 using anti-HCV techniques alone. Recipients of solid organ or tissue transplants have risk levels similar to those of persons who received blood transfusions prior to July 1992. Hemophiliacs with a history of receiving blood products, especially from the early 1970s to the mid 1980s, are at increased risk; their prevalence of HCV is 75-90%.
      Persons who receive hemodialysis
      HCV prevalence in patients with chronic renal insufficiency who receive hemodialysis varies widely. The range has been estimated from 5-85% worldwide but eventually may exceed 95%. Approximately 85% of these patients have aminotransferase levels within the reference range, and some of them have negative test results for HCV antibodies but positive test results for HCV RNA.
      Incarcerated persons
      The prevalence of HCV among incarcerated persons has been reported as possibly 10-fold higher than that in the general population. Among incarcerated persons, females have a higher HCV prevalence than males.
      Infants of mothers with HCV
      Mothers have been shown to transmit HCV to their newborns. Mothers who had high viral loads at the time of delivery and those co-infected with HIV and HCV were at highest risk for transmitting the infection.
      Persons with particular unexplained findings
      Unexplained abnormal aminotransferase levels may be an indication of HCV infection. Cryoglobulinemia, membranoproliferative glomerulonephritis, and porphyria cutanea tarda may represent evidence of HCV infection.
      Persons with advanced liver disease
      Persons who have indications of advanced liver disease such as palmar erythema, ascites, peripheral edema, abdominal collaterals, splenomegaly, jaundice, and spider angiomas are at higher risk for having HCV.
      Persons exposed to blood
      Health care professionals, emergency staff, and public safety workers are at high risk for HCV after a needlestick injury or mucosal exposure to blood from an individual with HCV.
      Despite the high prevalence of HBV and HCV worldwide, this form of co-infection remains uncommon in the United States, particularly in the absence of HIV infection. Unfortunately, optimal treatment regimens have not been established. Four studies on this topic are worth mentioning.
      Guptan et al treated 14 co-infected patients with 6 MU IFN alfa 3 times/wk for 6 months and reported undetectable HBV DNA in 71% of patients and undetectable HCV RNA in 29% of patients. However, this small study was not randomized and 7 patients had comorbidities that may have influenced treatment outcome. In 2001, Villa et al randomized 30 co-infected patients to 6 MU IFN alfa versus 9 MU IFN alfa 3 times/wk for 6 months. All patients were HBV surface antigen–positive and HCV RNA–positive and underwent pretreatment and posttreatment biopsies. The authors reported that a high dose of standard IFN could clear HBV and HCV in 31% of patients versus none in the lower-dose group. Furthermore, improved histologic scores were noted in 29% of the higher-dose group versus none in the other group, suggesting a new role for high-dose IFN.
      Liu et al used standard IFN and ribavirin. They discovered that SVR was achieved at rates comparable with patients with HCV alone, and they reported that up to 21% of patients lost HBV surface antigen. Given the increasing efficacy of PEG-IFN over standard IFN, these investigators are currently conducting a multicenter study using PEG-IFN and ribavirin in patients co-infected with HBV and HCV. Recently, Chuang et al performed a case-control study of 126 patients (42 cases, 84 controls) to investigate the effectiveness of IFN-alfa and ribavirin. The authors reported that SVR to HCV was similar between cases and controls. However, HCV responders had significantly higher rates of HBV DNA resurgence than HCV nonresponders during and after treatment, which suggests reciprocal viral interference between HCV and HBV after therapy.
      Sexual partners of individuals with HCV
      The sexual partners of known infected patients are at a relatively low risk of transmission (2-5%). Whether having multiple sexual partners poses a higher risk is unclear. The National Institutes of Health (NIH) and Centers for Disease Control (CDC) recommendations for screening these individuals are not consistent.
      Persons exposed to nonsterile needle equipment
      Individuals with tattoos and body piercings might be considered at high risk if their body art was performed in a nonsterile environment.
      Most patients infected with HCV remain asymptomatic; approximately 10-20% develop symptoms such as fatigue, abdominal pain, myalgia, and arthralgia. The hepatic enzyme levels are within the reference range in 30-40% of those patients. The diagnostic yield in these cases depends on carefully obtaining a detailed history and thoroughly evaluating laboratory test results.
      Unequivocally, the criterion standard of screening tools remains the detection of antibody against HCV (anti-HCV) using an enzyme-linked immunosorbent assay (ELISA), also known as enzyme immunoassay (EIA). The third generation of this test is highly sensitive (>97% after 6 mo) and highly specific (99% in immunocompetent patients) but cannot be used to distinguish between previous exposure with recovery or current viral activity. Immunocompromised individuals, such as patients with HIV, with a strong history for potential exposure require further testing for HCV RNA detection using polymerase chain reaction (PCR). PCR must be used after positive results for anti-HCV, as well.
      The recombinant immunoblot assay (RIBA) can serve as the confirmatory test of EIA but is seldom used. Perhaps the greatest indication to use this test is when a patient has a positive test result for anti-HCV and a negative result for HCV RNA. A negative RIBA test result indicates that the anti-HCV positive result by ELISA was false-positive, and no further testing is recommended.
      Additional laboratory and radiological evaluations include the following:

      Determine the levels of the hepatic enzymes, including alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, bilirubin levels, albumin levels, and prothrombin time. Thrombocytopenia and leucopenia are indicative of cirrhosis.
      Perform an ultrasound of the liver to identify changes that suggest cirrhosis or coexistent pathologies, such as fatty liver.
      Following the diagnosis of cirrhosis, perform a computed tomography (CT) scan for cancer screening. Also obtain a baseline alpha-fetoprotein level in all patients with cirrhosis.
      Test for other hepatotropic viruses (eg, hepatitis A [HAV], hepatitis B [HBV]) because HBV and HCV share the same mode of transmission and further vaccination should be pursued.
      Genotyping is required if treatment is planned, as the 6 different HCV genotypes guide treatment duration.
      Liver biopsy may offer additional information regarding the activity (inflammation) and the stage (fibrosis) of the disease, though the utility of this procedure has been questioned for patients with genotypes 2 and 3.
      Patients at high risk for HCV should be educated about lifestyle modifications. In particular, instruct them to avoid alcohol consumption and educate them about the mode of transmission, including the risk of spreading the infection to household persons or sexual partners. Abstinence from illicit drug use is essential. Treatment options should be tailored specifically to each patient and should be thoroughly explained on a case-by-case basis.
      Persons co-infected with HIV and HCV
      The results from the AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) recently showed that patients co-infected with HIV and HCV obtain more beneficial outcomes when treated with a combination of ribavirin and PEG-IFN. The 868 patients in the APRICOT study were randomized into 3 treatment arms for 48 weeks and were stratified by HCV genotype, antiretroviral treatment, ALT level, liver biopsy findings, and CD4 cell count. The results showed that the group receiving PEG-IFN plus ribavirin achieved SVR of 40%. Those receiving interferon (IFN) plus ribavirin achieved SVR of 12%, and those receiving PEG-IFN plus placebo achieved SVR of 20%. Of those infected with genotype 1, SVR rates were 29% with PEG-IFN plus ribavirin, 14% with IFN plus ribavirin, and 7% with PEG-IFN plus placebo. Patients with genotypes 2 and 3 achieved SVR of 62%, 36%, and 20% in the corresponding treatment arms. Similar results were obtained in the AIDS Clinical Trials Group (ACTG) study that
      randomized 132 individuals to receive PEG-IFN plus ribavirin or IFN plus ribavirin. They, too, found that SVR was higher in the group receiving PEG-IFN plus ribavirin (27%) than in the group receiving IFN plus ribavirin (12%). Of the patients who received PEG-IFN plus ribavirin, those with genotype 1 achieved SVR of only 14% while all other genotypes showed a 73% SVR. The use of HAART in both the APRICOT and ACTG study did not seem to affect SVR.
      Persons who contracted HCV through IDU
      The treatment of HCV in patients who use illicit drugs, as in other patients, is determined jointly by the patient and physician based on individualized risk-benefit assessments. Successfully rehabilitated intravenous drug users, even those receiving methadone maintenance therapy, can be treated. The decision to treat patients who remain active users of intravenous drugs is more difficult. Major concerns include adherence to treatment protocol, psychologic side effects, and the possibility of reinfection. Although these important issues must be addressed, none warrants categorically excluding all active or recent drug users from therapy; the final decision is to be made on a case-by-case basis. Individuals who have a strong desire to be treated and who commit to the recommendations and antiviral regimens should be treated.
      Patients with other conditions
      The same treatment principles apply in patients with and without hemophilia. Although patients with hemophilia carry a higher risk of bleeding during pretreatment, this risk can be minimized in coordination with the hematologists.
      Patients with end-stage renal disease are candidates for interferon monotherapy, likely at a reduced dose. Ribavirin is contraindicated in these patients.
      Patients with devastating symptomatology related to extrahepatic disease must be treated. Maintenance therapy may be required.
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