Hepatitis C (HCV) is one of the major public health problems worldwide. Infection with HCV proceeds to chronicity in more than 80% of cases and even recovery does not protect against subsequent re-exposure to the virus. In 20-40% cases hepatitis C infection leads to end-stage liver diseases: cirrhosis and hepatocellular carcinoma after 15-20 years of HCV infection. According to recent estimations, there are about 180 million people worldwide, carrying the HCV virus, and this number is growing constantly. HCV infection is the most common chronic blood-borne infection in the USA and certain other countries. The major risk behavior that has been found to be associated with HCV transmission in several populations is injecting drug use. Different studies revealed HCV infection rates ranging from 60% to 90% among intravenous drug users. Health care workers, who are exposed to blood in the workplace, are at risk from infection from blood-borne pathogens, including HCV, although the prevalence of HCV infection among health care workers is not high, averaging 1-2%. There is evidence of an association between the exposure to multiple sex partners and the acquisition of hepatitis C. However, very low prevalence of HCV infection has been reported by studies of long-term monogamous partners of patients with chronic hepatitis C virus infection.
Most patients with acute HCV infection develop chronic infection. During the acute stage of infection the patient may remain completely asymptomatic. Serum HCV RNA is essential for measuring the level of infection and for monitoring the effects of treatment.
HCV isolates from around the world can be separated into at least 6 major genotypes, each with a number of subtypes. The virus genotype has been found to be a predictor of response to interferon treatment in most published studies. Differences in the severity of disease produced by different virus genotypes are, currently, not clear enough. Some studies have found that serum levels of alanine aminotransferase are higher in individuals infected with type 1 or type 3, yet others failed to show the same relationship.
Investigation of blood-borne hepatitis (hepatitis C and B) showed that Hepatitis C is now an emerging and expanding public health problem for Georgia. High prevalence of Hepatitis C has been found in persons who inject drugs (58%). A recent prevalence study (1997-1998) of blood donors in Georgia showed 7.8% seroprevalence of HCV. Widely disseminated injecting drug use and common needle sharing among IDUs, use of unsterile equipment in medical facilities and inadequate testing of donated blood increase the risk of Hepatitis C dissemination in Georgia. For these reasons Hepatitis C infection is considered by the Ministry of Health of Georgia to be a problem of the highest priority.
Therefore, there is an acute need for investigation of hepatitis C epidemiology, including molecular epidemiology in Georgia for assessment of spreading patterns of this infection in the country and population groups that are at high risk of hepatitis C virus infection.
The problem of the relation of the natural history of Hepatitis C infection with host, viral and environmental factors is yet to be completely solved. To define the correlation of the outcome of acute hepatitis with molecular characteristics of the virus, host genetic factors and viral load dynamics are especially interesting.
A cross sectional study of the general population of Georgia will be designed to obtain a comprehensive picture of the epidemiology and clinical course of hepatitis C virus infection in the country. The objectives of the study are:
· To determine the prevalence of HCV infection in the general population of Georgia;
· To assess the risk behaviors potentially related to HCV infection;
· To assess the association of HCV prevalence with risk behavior and demographic characteristics;
· To investigate molecular characteristics of HCV types circulating in Georgia;
· To determine the association between viral molecular characteristics and host genetic factors with clearance or chronicity and the natural history of HCV infection in Georgia;
· To study the clinical course of HCV infection in treated and non-treated patients and the relationship of treatment effectiveness with virologic parameters.
A cross-sectional study design will be used. 2000 persons from the general adult population of Georgia will be enrolled in the study. The study subjects will be recruited by multi-stage cluster sampling in the capital of Georgia, Tbilisi.
The fieldwork team will visit households to interview the selected study subjects. This team will include an interviewer and a qualified person for blood drawing. The interviewer will briefly explain the goal and design of the study to the individuals. If the study subject is willing to participate in the study, a questionnaire will be administered. Demographic data and self-reported drug use, sexual behavior and history of exposure to blood or blood products will be obtained by questionnaires. Blood will be drawn for each study subject for testing for HCV antibodies.
For each sub-population and for the total study population the refusal rate will be calculated (the numerator – the number of people who decline to be interviewed, after being randomly selected, the denominator - the number of people who are randomly selected at the site).
HCV antibody screening will be performed by the third-generation ELISA method. The presence of HCV antibodies will be confirmed by the more specific Recombinant Immunoblot Assay (RIBA). Patients with confirmed HCV antibodies will be included in the follow-up. Follow-up visits will be scheduled every 6 months for the group of patients with chronic HCV. For patients with acute HCV the follow-up visits will be scheduled every two weeks during the first 3 months, once a month during the next 3 months and every 6 months thereafter.
At each visit patients will be tested for HCV RNA by qualitative PCR to confirm the presence of chronic infection. To determine HCV viral load dynamics, quantitative RNA PCR will be performed.
Patients will be differentiated into two major groups: patients with acute hepatitis C and patients with chronic hepatitis C at the moment of inclusion in the study. As the number of patients with acute hepatitis revealed by cross-sectional study is not expected to be high, the patients with acute HCV infection will be added to this group recruited from the infectious disease clinic. The chronic HCV group will be divided in two subgroups: patients under combination antiviral therapy and patients without treatment. Clearance or carriage of the virus will be assessed by HCV RNA PCR analysis.
In the group of patients with HCV infection the HCV genotypes will be identified by the second-generation LiPA assay. It will allow discrimination of types 1-6 and subtypes 1a, 1b, 2a/c, 2b, 2d, 2i, 3a-c, 4a-h, 5a, 6a, and 10a. As a consequence of its high sensitivity for capturing minor sequence variants, the LiPA proved to be particularly useful for the detection of clinically relevant mixed infections with different HCV genotypes.
All specimens with an indeterminate result at the LiPA analysis stage and selected specimens for quasispeaces detection and molecular evolutionary analysis will be submitted for sequencing.
HLA typing will be performed by a PCR-based technique.
The Georgian AIDS & Clinical Immunology Research Center has considerable experience in autoimmune and viral hepatitis. Main activities in this field include: laboratory diagnostics of viral and autoimmune hepatitis, modern treatment of patients with autoimmune and viral hepatitis, clinical and laboratory monitoring of these patients, study of the immunological disorders in patients with hepatitis C, prevalence of autoantibodies in patients with chronic viral hepatitis, autoimmune complications of the treatment of chronic hepatitis C with Interferon-a.
As a result of the study precise estimates of HCV prevalence in the general population of Georgia will be obtained and risky behavior correlates will be identified.
For the first time in Georgia molecular characteristics of various Hepatitis C virus isolates will be identified.
On the basis of a comparative study of HCV types and subtypes, the pattern of HCV infection in Georgia will be characterized. Detection of only one HCV type, represented by numerous subtypes, will indicate long-term endemic infection, while the detection of various types, represented by only a few subtypes, will be suggestive of a recent spread of HCV.
The relation between the clinical outcome of acute and chronic hepatitis C and viral load, molecular characteristics and host immune factors will be defined.
Recommendations will be developed for prevention interventions of HCV infection.
The response to treatment and correlation of host genetic and immunologic factors with treatment effectiveness will be identified.
