This study was conducted in Plovdiv region, Bulgaria to describe the characteristics of hepatitis B infection several years after the introduction of hepatitis B vaccine. The data included a retrospective epidemiological analysis of 194 patients with hepatitis B viral markers who were admitted to the Department of Infectious Diseases, Parasitology and Tropical Medicine at the St. George University Hospital in Plovdiv (2007 – 2008). The study was based on official epidemiological data on the incidence rate of viral hepatitis B for the country and for the region of Plovdiv during 1998 – 2007. Serological (ELISA tests), epidemiological and statistical methods were employed. The incidence rate of acute viral hepatitis B showed a decreasing tendency. The disease is prevalent in the age groups 15-19 and 20-29. People from these age groups were born before 1992 when hepatitis B vaccination was included in the National Immunization Programme. Infection was predominant among males - 132 (68%). No difference was found in the average incidence rates between urban and rural populations; 13.9 cases per 100,000 for urban and 13.2 cases per 100,000 for rural residents. Acute viral hepatitis was the most common form of infection in 136 (70.1%) of the cases followed by 24 (12.4%) chronic infections. Most patients (160 or 82.5 %) were infected only with hepatitis B virus. Fifty (26%) patients belonged to high risk groups with the highest percentage among injecting drug users (IDUs). Social and economic status in Bulgaria and related migration, unemployment, high crime rate, sexual behaviour and injecting drug use are associated with the transmission of hepatitis B infection among certain social groups. Vaccination remains the only reliable method of prevention and should be provided not only to risk groups but to the population at large.
Hepatitis B virus (HBV) is prevalent worldwide. According to data from the World Health Organization, about one third of the world’s population has markers of past or current HBV infection. 360 million people have chronic infection and are at high risk for developing hepatic disease (hepatic cirrhosis or hepatic carcinoma) associated with the virus (1-3). Moreover, the infection has a wide clinical spectrum (4) and, due to the similar modes of transmission, association with other hepatic viruses is likely (5-8). The objective of this study was to conduct an epidemiological survey of patients with HBV infection and to describe the characteristics of infection in the period 1998-2007.
Materials and methods
Bulgaria is a country in Eastern Europe. The second largest city in Bulgaria is Plovdiv with a population of 345,249, while the population of the region of Plovdiv is 705,121. In 1982 Bulgaria started to register the different viruses associated with hepatitis. An acute hepatitis B case is considered confirmed only on the basis of supporting laboratory analysis; the presence of IgM antibodies against hepatitis B core antigen. Confirmed cases of chronic hepatitis B are only the cases in which HBsAg has been persistent for more than six months. There are three levels of surveillance system and infectious disease control (including hepatitis B) in Bulgaria:
- Peripheral level that registers and reports the new cases within 24 hours at an intermediary level.
- Intermediary level including regional inspectorates for public health protection and control in each of the 28 regions of the country that are responsible for the control of infectious diseases. Each case of hepatitis B virus is hospitalised, studied epidemiologically and reported daily to the National Centre for Health Information in Sofia.
- Central level is comprised of the Ministry of Health Care and the National Centre of Infectious and Parasitic Diseases in Sofia that receive weekly updated information for the country from the National Centre for Health Information.
Our study included a retrospective epidemiological analysis of 194 patients with hepatitis B viral markers who were admitted to the Department of Infectious Diseases, Parasitology and Tropical Medicine at the St. George University Hospital in Plovdiv (2007–2008). The study was based on official epidemiological data on the morbidity rate of viral hepatitis B for the country and for the region of Plovdiv during 1998 - 2007. Serological testing was performed at the Department of Microbiology and Immunology, Medical University, Plovdiv and at the Regional inspectorate for public health protection and control, Plovdiv. ELISA (Dia Sorin, Italy) was used for the analysis of viral hepatitis markers: HbsAg, anti–Hbc-IgM, anti-HCV, anti-HAV-IgM and anti-HDV. All ELISA tests were performed and interpreted according to the manufacturer’s instructions. Data was analyzed by descriptive and analytical methods. Frequency distribution was employed in which our hypothesis was tested in a unidimensional alternative distribution to compare the relative percentages of cases with acute and chronic hepatitis B infection by gender, age, clinical diagnosis and place of residence. The Student’s t-test was performed with a level of α -error 0.001. Epidemiological measurements were presented as:
Number of new cases of acute hepatitis B in a specified time and place
Incidence rate = -------------------------------------------------------------------------------------------- х 100,000
Average number of population for the same time and place
Number of deaths of acute hepatitis B in a specified time and place
Mortality rate = ------------------------------------------------------------------------------------- х 100,000
Average number of population for the same time and place
Number of deaths caused by acute hepatitis B in a specified time and place
Case fatality rate (CFR) = ----------------------------------------------------------------------------------------------- х 100
Number of diagnosed cases of acute hepatitis B for the same time and place
Results and Discussion
Comparing the data on incidence rate of acute viral hepatitis B cases for Bulgaria and for Plovdiv region over a ten year period (1998-2007), it is obvious that the incidence rate demonstrated a decreasing trend; 20.7 cases per 100,000 in 1998 to 9.8 cases per 100,000 in 2007 for the country, and from 28.9 cases per 100,000 in 1998 to 10.1 cases per 100,000 in 2007 for the Plovdiv region. This trend reflects the inclusion in 1992 of hepatitis B vaccination in the National Immunization Programme for all newborns. The immunization coverage (three doses) of hepatitis B vaccine among infants in the country during 2008 was 95.7% and 96% for the Plovdiv region. However, the incidence rate for Plovdiv was higher than the national average (Figure 1). Similar findings have been reported for mortality rates and case fatality rates (CFR) (Figure 2 and Figure 3).
These findings may be associated with the presence of larger clusters of injecting drug users (IDUs) in the big cities (Sofia and Plovdiv). According to expert estimates, the number of IDUs ranges from 6,000-10,000 in each city. IDUs are a susceptible group for infection with hepatitis viruses and HIV (9). Plovdiv is also known for its ethnic diversity with the gypsy community constituting the largest ethnic minority (13% of the entire city population). The gypsy community is more susceptible to these infections than other minorities in the country probably due to a wide spectrum of interrelated factors including high unemployment rates, low levels of sanitation and education, lack of social skills and motivation for social integration, prostitution, high crime rates, drug abuse, high mobility, refusing vaccination etc. (9). Their families are large with pronounced focal infection (several people in a family are chronic HBsAg carriers). Some resort to self-treatment, do not seek timely medical help and are later admitted into the Department of Infectious Diseases in grave condition with pronounced cytolysis and bilirubinemia in a precoma stage. Information about the death of a person due to hepatitis B is spread in their community and causes fear that, in conjunction with the educational activities, reduces the mortality rate and CFR for several years.
According to health experts, the percentage of sexually transmitted infections among gypsies is high, thus facilitating the transmission of more serious pathogens such as hepatitis B and HIV (9).
Figure 1. Incidence rate (per 100,000 population) of acute hepatitis B in Bulgaria and Plovdiv region, 1998-2007
Figure 2. Mortality rate (per 100,000 population) of acute hepatitis B in Bulgaria and Plovdiv region, 1998-2007
Using the above mentioned data from 2007 to 2008, a retrospective analysis was conducted of 194 hospitalized patients who received treatment at the Department of Infectious Diseases, Parasitology and Tropical Medicine (St. George University Hospital, Plovdiv). All patients had markers for hepatitis B infection; 136 cases of acute hepatitis B (HBsAg-positive and anti-HBc-IgM-positive), 24 cases of chronic B hepatitis (HBsAg-positive and anti-HBc-IgM-negative) and 34 cases of hepatitis B co-infection with other hepatotropic viruses (Table 1). The patients’ median age was 28 years (±15 years; 4 months to 80 years). The percentage of hepatitis B cases was highest in the age groups 15-19 and 20-29 years; 52 (26.8%) and 70 (36.1%) of the cases, respectively, (p>0.05) (Fig.4). Data for Bulgaria are similar (10). People in these age groups were born before hepatitis B vaccination was included in the National Immunization Programme. Epidemiological analysis demonstrated nearly equal infection rates among children and adults prior to the inclusion of hepatitis B vaccination (11). Recent studies show that young people are susceptible to sexually transmitted viral infections due to the growing number of those who are sexually active before the age of 15 years and due to their promiscuity (12).
Figure 3. Case fatality rate of acute hepatitis B in Bulgaria and Plovdiv region, 1998-2007
Figure 4. Distribution of patients positive for hepatitis B serological markers by age, 2007-2008 (n=194)
Among hospitalized patients, 132 (68%) were men and 62 (32%) were women (p<0.001). The disease incidence rate among men was 19.4 cases per 100,000 and among women was 8.5 cases per 100,000. The incidence rate among men was twice as high as among women and this ratio has been maintained for years. The predominance of infection among men has been documented by other authors as well (13-15). Most researchers associate this tendency with the higher prevalence of IDUs among men and with viral transmission via homosexual intercourse. Data indicates that the anal mucosa is more susceptible to infection with HBV than HIV (15).
The 194 patients were assigned into 8 groups according to clinical history, the course of hepatitis B infection and the serological profile (Table 1).
Table 1. Distribution of patients positive for hepatitis B serological markers
Among the hospitalized patients, 136 (70.1%) had acute hepatitis B infection and 24 (12.4%) had chronic hepatitis B infection (p<0.001). Men were predominant in both groups; 82 (60.3%) and 19 (79.2%), respectively. Patients with chronic viral infection, although limited in our study, are at a high risk of developing complications such as hepatic cirrhosis and hepatic cancer. The risk of liver cancer of them is 100 times higher than among healthy subjects (16, 17). Moreover, chronic carriers serve as reservoirs of infection (18) because all HBsAg-positive patients, regardless of their HBeAg status, demonstrate a certain level of viremia (19).
Serological testing revealed that most of the patients (160 cases; 82.5%) were only infected with HBV. Co-infection with other hepatitis viruses was seen in 34 patients (17.5%). The percentage of co-infections was 4.5 times lower and just single cases were present in the groups (Table 1). Among these patients, 30 (88 %) were infected with two viral agents and 4 (12%) with three viral agents. Another study conducted in Plovdiv region during 1999-2000 reported a high level of HBV and HCV co-infection among healthy populations (20). According to data from a Bulgarian study including patients with chronic hepatic states, HBV and HCV mixed infections were found in 3.8% of the cases (7). In our study, the percentage of mixed infections was two times higher (7.7%). According to literature, in patients with chronic hepatitis B, the level of co-infection with HCV ranges from 9% to 30% depending on the geographical region (5, 8). Therefore, co-infections with HBV and HCV are not uncommon especially in highly endemic geographic areas and among patients at high risk of parenteral infection. The risk of developing liver cancer is high among patients with HBV and HCV co-infection (5, 21, 22).
Seven cases (3.6%) with HBV and HAV co-infection were found in our study and all were registered during the HAV outbreak in 2006-2007. Four patients were infected with three hepatitis viruses, HBV, HCV and HDV. All of the patients were males and IDUs, and one was a prisoner.
Our data showed that most patients with hepatitis B viral infection are residents of Plovdiv or other urban areas; 145 (75%) residents in urban compared to 49 (25%) residents in rural areas. However, a comparison of average incidence rates in urban and rural areas showed no differences; 13.9 cases per 100,000 versus 13.2 cases per 100,000 respectively. This observation is associated with the fact that most rural residents travel to the big cities for business, work or educational purposes. Urbanization, increased contacts among people and densely populated areas facilitate the transmission of hepatitis B infection in large cities.
Among the 194 hospitalized patients, only 50 (26%) belonged to high risk groups and/or had risk factors (Table 2). In the remaining 74%, the mode of transmission was not determined because patients were unwilling to reveal personal information especially regarding sexual orientation, behaviour and illicit drug use. Similar high rates have been reported by other authors (23). Taking into account the knowledge about the most common mode of transmission, we suggest a sexual route of transmission in the majority of cases.
Table 2. Distribution of the patients according to the risk factors (n=50)
* Five prisoners were included in our study but 4 used heroin and were therefore included in the IDUs risk group / пять заключенных были включены в наше исследование, но четверо из них употребляли героин, и мы отнесли их к группе ПИН
Among these 50 patients, 21 (42%) were injecting drug users (heroin). Their age ranged from 17 to 41 years. Co-infection with another hepatitis virus was confirmed among 17 (81%). Co-infections with more than one hepatitis virus are frequent among drug users (24, 25). Drug abuse presents a serious health and social problem worldwide. According to official sources, the percentage of heroin drug abusers in Bulgaria is growing by 2,000-3,000 people annually (9). Other studies in Bulgaria established a high level of HCV and HBV among IDUs; 59% to 70% are infected with HCV and 5-6 % with HBV. The percentages are higher among the 25-34 years age group due to the longer duration of injecting drug use (26, 27).
Prisoners are another risk group. Among the five prisoners in our study, four were drug users. They were aged 23-41, with low education and unemployed. Three of the prisoners were co-infected with other hepatitis viruses. National surveys show a high percentage of HCV (13.5%) and HBV (11.8%) infection among prisoners in Bulgaria (12). It is likely that this tendency will remain unchanged in the future as these groups are frequently exposed to illicit drugs (26). The high proportion of infected individuals in this group might be associated not only with illicit drug use but also tattooing (24, 28).
Health care professionals are another risk group. Among our patients there were three (6%) health care professionals; one doctor, a nurse and a medical assistant. All three had acute hepatitis B and were not immunized. It is well known that the risk of viral transmission from health care workers to patients is low whereas the risk of transmission from patients to health care workers is moderate (6 to 35% after a needle stick) (29). Immunization of health care workers with recombinant hepatitis B vaccine is mandatory as well as post-exposure prophylaxis with hepatitis B immune globulin (HBIG) according to WHO recommendations (30).
Ten of the 50 patients (20%) with risk factors provided a history of contact with HBV carriers in their families. This illustrates the presence of family foci of infection similar to foci observed with hepatitis A. In these cases transmission of HBV occurs through sexual or close contact and sharing of blood-contaminated personal belongings. HBV is resistant in the surrounding environment and may survive in dry blood at room temperature for more than 7 days (31). Immunization of family members is recommended when a HbsAg carrier is identified.
The introduction of mandatory screening of blood and blood products in Bulgaria during the 1990s significantly reduced the transmission of HBV via transfusion. However, the window period of infection as well as the presence of mutant HBV (G145R) strains presents a diagnostic problem (HbsAg and anti-HBc-negative patients) and may allow infected blood or blood products to be used (32, 33). Seven of our patients (14%) had a history of blood transfusion 6 months before hospitalization and four of these patients had a history of surgical interventions. Another seven (14%) of our patients reported previous surgery and/or dental procedures. A direct causality is difficult to prove as cases are sporadic and there was no temporal or special relationship among them. However, the potential risk requires strict control and high quality disinfection procedures at medical facilities.
- The incidence rate of acute viral hepatitis B shows a decreasing tendency. The disease is prevalent among persons in the age groups 15-19 and 20-29 who have not been subject to mandatory vaccination.
- The social and economic status in Bulgaria and related migration, unemployment, high crime rate, risk sexual habits, injecting drug use favour the transmission of HBV infection among certain social groups.
- Vaccination remains the only reliable prevention method. Vaccination should be made available to risk groups and the population at large.
- WHO /V&B/01.28. Department of Vaccines and Biologicals. Hepatitis B immunization.
- Shepard CW, Simard EP, Finelli L et al. Hepatitis B Virus Infection: Epidemiology and Vaccination. Epidemiologic Reviews 2006; 28: 112-25.
- WHO Information Office: Fact Sheet WHO/204;2000.
- Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001; 34: 1225-41.
- Ibarra RT. Treatment of HBV- HCV coinfection. Annals of Hepatology 2006; 5 (suppl.1): 49-52.
- Mitre HP, de Mendonça JS de. Co-Infection with Hepatitis B Virus and Hepatitis C Virus. Braz J Infect Dis 2007; 11 (suppl.1): 33-5.
- Ivanova L, Russev V. Chronic liver diseases and parenterally transmitted hepatitis viruses. European Journal of Inflammation 2007; 5: 1-6.
- Liaw YF. Role of hepatitis C virus in dual and triple hepatitis virus infection. Hepatology 1995; 22: 1101.
- National Strategy for HIV and STD prevention and control. 2001-2007, Ministry of Health. Bul/98/005, Sofia, 2002.
- Kozuharova M,Vladimirova N, Kurchatova A, Marinova L. Acute infectious diseases in Bulgaria in 2005-2006 (main epidemiological parameters). National Centre of Infectious and Parasitic Diseases, Information Bulletin. 2008; 4-5.
- Georgiev P. Eradication and elimination of infectious diseases. Sofia, 1992,101-4.
- National Strategy for HIV and STD prevention and control. 2008-2015, Ministry of Health, Sofia, 2008.
- Lima G. Hepatitis B in Portugal. Euro Surveill 1999;3(27):pii=1374.
- Rantala M, van de Laar MJ. Surveillance and epidemiology of hepatitis B and C in Europe – a review. Euro Surveill 2008;13(21):pii=18880.
- Tepper ML, Gully PR. Lovers and Livers: Hepatitis B as an STD. The Canadian Journal of Human Sexuality, Special Issue: STDs and Sexual/Reproductive Health 1997; 6.
- Baltadjiev I, Popivanova N. HBV infection - pathological factors and viral persistence factors. Infectology 2008; 45: 3-8.
- Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56.
- Karmali S, Amato-Gauci A, Ammon A et al. Communicable disease in Europe. Health Systems and the Challenge of Communicable Disease 2008; 75-94.
- Ganem D, Prince AM. Hepatitis B Virus Infection- Natural History and Clinical Consequences. N Engl J Med 2004; 350: 1118-29.
- Atanasova M, Haydouchka I, Zlatev S et al. Prevalence of antibodies against hepatitis C virus and hepatitis B coinfection in healthy population in Bulgaria. A seroepidemiological study. Minerva Gastroenterol Dietol 2004; 50: 89-96.
- Crockett S, Keeffe EB. Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection. Annals of Clinical Microbiology and Antimicrobials 2005; 4: 13.
- Liu Z. Hou J. Hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection. Int J Med Sci 2006; 3: 57-62.
- Ferraz M., Yoradjian A. Et al. Epidemiology of acute hepatitis B in a university hospital in Sao Paulo, Brazil: retrospective study of two five-year periods. Sao Paulo Med. J. 1998; 116: 1695-99.
- Twisselmann B. Prevalence of antibodies to hepatitis B, hepatitis C, and HIV in Irish prisoners. Euro Surveill 2000;4(28):pii=1568.
- Tefanova V, Tallo T, Kutsar K et al. Urgent action needed to stop spread of hepatitis B and C in Estonian drug users. Euro Surveill 2006;11(4):pii=2883.
- Annual report of the national committee on narcotics. Drugs and drug abuse in Bulgaria, 2004, Sofia.
- Boykinova O, Stoilova Y, Novakov S. Incidence and prevalence of HCV infection in the Thracia region in Bulgaria for 15 years period. Problems of Inf and Paras Dis 2008; 36: 8-10.
- Babudieri S, Longo B, Sarmati L et al. Correlates of HIV, HBV and HCV infections in a prison inmate population: Results from a multicentre study in Italy. J of Med Virol 2005; 73: 311-7.
- Infection Control: Basic Concepts and Training. IFIC, 2003.
- WHO. Immunization, Vaccines and Biologicals. Hepatitis B vaccine. Available from: http://www.who.int/vaccines/en.hepatitisb.shtml
- WHO: Global Alert and Response (GAR). WHO/CDS/CSR/LYO/2002.2 : Hepatitis B. Available from: http://www.who.int/csr/disease/hepatitis/en/index.html
- Pillonel J, Laperche S. Trends in risk of transfusion-transmitted viral infections (HIV, HCV, HBV) in France between 1992 and 2003 and impact of nucleic acid testing (NAT). Euro Surveill 2005;10(2):pii=519.
- Zhu QR, Lü Q, Yu H et al. Hepatitis B virus S gene mutants in infants infected despite immunoprophylaxis. Clin Med J 2001; 114: 352-4.