Introduction
Hepatitis B is an infectious illness of the liver caused by hepatitis B virus (HBV) that affects hominoidea including humans and causes an inflammation called hepatitis originally known as serum hepatitis. The disease has caused epidemics in part of Asia and Africa and it is endemic in China (William, 2006). About a third of the world population has been infected at one point in their lives including 350 million who are chronic carriers (Alter, 2006). Studies done in Nigeria showed HBV carriage rate in the range of 9% to 39% (Ezegbudo, 2004). The virus can live for a long period of time away from the body meaning that it can be shared among household items like toothbrushes, razor, etc. (Petersa and Jose, 2006).
HBsAg is the surface antigen of hepatitis B virus. It indicates current hepatitis B virus infection. It is the serological hallmark of HBV infection and appears in serum 1-10 weeks after acute exposure to HBV (McGovern, 2009).
HIV is Human Immunodeficiency Virus, a lentivirus (slowly replicating virus) that causes the Acquired Immunodeficiency Syndrome (AIDS). HIV virus and hepatitis B virus have a worldwide distribution; however prevalence of both infections is greater in the developing world especially Asia and Africa. They are two most common chronic viral infections documented worldwide (Soriano, 2006). Both viruses are present in Nigeria and are a significant cause of mortality and morbidity. Hepatitis B virus share the same transmission route as HIV and these routes include; through blood transfusions, sharing of needles to inject drugs, sexual activities and also sharing of razors or toothbrushes (Masto, 2004).
A person who is infected with both HIV and hepatitis B virus is said to be HIV/HBV co-infected. The presence of infection markers to these two viruses obviously presents great risk to the recipient and because of the similarity in their mode of transmission; HIV and HBV often co-exist in the same patient. Some studies suggested that as many as 70%-90% of HIV positive people have evidence of past or current HBV infection (Lipiroth, 2007) while about 2.4 million are estimated to have chronic HBV infection (Bonacin, 2004). HBV co-infection in HIV positive individual is of utmost importance because of the underlying hepatic complications which have been shown to decrease the life expectancy in HIV infected populations (Chung, 2006).
In Nigeria, the seroprevalence of HIV/HBV infection has been studied in many parts of the country. Hepatitis B have been shown to occur in 10-70% of HIV infected individuals (Hadonu and Nwokedi, 2006). A cross sectional study of adult population of more than 18 years in Lagos show a seroprevalence rate of 10% (Lavanchy, 2004), Jos, Nigeria showed a prevalence rate of 16.7% (Idoko, 2009) while Niger Delta showed a prevalence of 9.7% of HBV among HIV infected persons (Ejele, 2004). Hepatitis B virus has a major impact on the natural history, diagnosis, progression, morbidity and mortality of HIV infection (McGovern, 2009). Symptoms of hepatitis B include loss of appetite, nausea, vomiting, dark urine, etc. Hepatitis B also causes liver inflammation and jaundice. It is a serious public health problem worldwide and one of the most common infectious disease globally.
Conceptual framework
Hepatitis B surface antigen was formerly called Australian antigen because it was first discovered in the serum of an Australian aborigine in 1963. The Australian antigen was discovered to be related to type B hepatitis by Okochi and Murakami in 1968 while Dane found virus-like particles in the serum of patients suffering from type B hepatitis in 1973. It was discovered by virologist Alfred Pince in 1968 to be part of the virus that caused serum hepatitis. Heptavax, a first generation hepatitis B vaccine in the 1980s was made from HBsAg extracted from the blood plasma of hepatitis patients. Current vaccines are made from recombinant HBsAg grown in yeast. HBsAg is the earliest sign of an active hepatitis B infection. It indicates current hepatitis B infection. This antigen may be present before symptoms of a HBV infection appear. If the antigen is present for more than 6 months, then it is a chronic HBV infection. HBsAg is present in the sera of patients with viral hepatitis with or without clinical symptoms. Its detection is used to establish a diagnosis of hepatitis B infection.
Hepatitis B virus is a major public health problem which is more prevalent in the developing countries (WHO, 2004). It is a resilient virus that can exist in almost any surface for about one month. Sodium hypochloride 0.5% (1:10 household bleach) destroys the HBV antigenicity within 3 minutes but the virus is stable at minus 20 degree centigrade for about 20 years (Brook, 2004). Human Immunodeficiency Virus (HIV) is a member of the retrovirus family that causes AIDS in humans. When CD4+ cell count declines below a critical level, cell mediated immunity is lost and the body becomes susceptible to opportunistic infections.
HIV and hepatitis B virus infections are two major viral infections worldwide. The presence of both viruses in a person presents a great risk to the recipient. The rate of progression and complications from viral hepatitis are accelerated in patients with HIV co-infection (Pouti, 2006). Incidence of hepatitis B virus in HIV individuals is common due to shared routes of transmission. In areas of low endemicity, HIV and HBV infections are usually acquired in adulthood through sexual or percutaneous transmission and in such areas such as America, Australia and Europe, the prevalence of chronic HBV is around 5-7% among HIV infected persons (Alter, 2006) while in countries with high endemicity, the main routes of transmission of HBV are perinatal or in early childhood. In these countries, HBV co-infection rate is around 10-20% (Lee and Nyirenda, 2008).
Structure and morphology
The hepatitis B virus belongs to the family hepadnaviridae and genus orthohepatodnavirus (Brook, 2004). It is the only hepadna virus causing infections in humans. It cannot yet be grown in an artificial medium but can be transmitted to certain primates such as chimpanzees in which it is able to replicate. Hepatitis B virus is divided into four (4) major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes present on its envelope protein and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome. The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus (Kramvis and Francois, 2005).
HBV infected cells produce multiple types of virus related particles. Electron microscopy of partially purified preparations of HBV shows three types of particles (Ganen, 2007).
- Double shelled particles with diameter of 42-47 nanometre (known as Dane particles after their discoverer).
- Spheres of about 22nm in diameter, usually present in a 10,000 to 100,000 fold excess over Dane particles.
- Relative to the complete virus or Dane particles, there are smaller quantity of filaments of 20nm in diameter and variable length often measuring about 200nm.
All these forms have a common antigen on their surfaces termed hepatitis B surface antigen (HBsAg) which is present in large quantity in the serum of the infected host. These viral particles in circulation allow for easy antigen detection (Ganen, 2007). The particles containing HBsAg are antigenically complex. Each contains a group of specific antigen a, in addition to two pairs of naturally exclusive sub determinants adw, ayw, adr and ayr (Brook, 2004). These subtypes have geographical predictions, for example in the United States of America, adw is the predominant subtype while in Africa, it is adr (Brook, 2004). There is no difference in the pathogenicity between subtypes due to the universal presence of the “a” determinant. Antibody to “a” determinants are used in the diagnostic assay kit for HBsAg detection.
The complete virus or Dane particles are the infectious virion of HBV (Ganen, 2007). Its outer shell is a lipoprotein envelope containing the viral surface glycoprotein. The inner core particle (Hepatitis B Core antigen) or nucleocapsid has a diameter of 25-27 nm and its major structural protein is the C protein. Within the core is the viral DNA, a protein kinase and a polymerase known to be centrally involved in genomic replication. The core also contains non particulate soluble antigen (HBeAg) derived from HBcAg by proteolytic self cleavage (Nassal, 2007). The viral DNA is a double stranded circular molecule. This molecule has an unusual structure in that its two DNA are not perfectly symmetrical. Replication of HBV occurs predominantly in the liver but also occurs in lymptocytes, spleen, kidney and pancreas. HBsAg is a product of S gene of the HBV genome and the prime constituent of hepatitis B particle forms (Brook, 2004). It is manufactured in the cytoplasm of infected hepatocytes in high quantities. The excess that did not combine with DNA to produce viral particles spills into the serum as 22 nm diameter spheres and filaments. Carriage of HBsAg is considered to be chronic when the patient has been HBsAg positive for 6 month or more.
The spheres and filaments are exclusively of HBsAg and host derived lipids, approximately 30% by weight. These particles lack nuclei acid and hence are non infectious. Nonetheless, in pure form, these particles are highly immunogenic and induce a neutralising anti-HBs (antibody to surface proteins) antibody response prior to the development of recombinant HBsAg preparations. 20 nm sphere as prepared fro the serum of HBV carriers served as HBV vaccine (Brook, 2004).
Signs and symptoms
Acute infection with hepatitis B virus is associated with acute viral hepatitis. An illness that begins with general ill-health, loss of appetite, nausea, vomiting, body aches, mild fever and dark urine and then progresses to development of jaundice. The illness lasts for a few weeks and then gradually improves in most affected people. A few people may have more severe liver disease and may die as a result (Terrault and Roche, 2005). Chronic infection with hepatitis B virus may be associated with a chronic inflammation of the liver (chronic hepatitis) leading to cirrhosis over a period of several years. This type of infection dramatically increases the incidence of hepatocellular carcinoma (liver cancer) (Rudolph, 2007). Chronic carriers are encouraged to avoid consuming alcohol as it increases the risk of cirrhosis and liver cancer. Symptoms outside of the liver are present in 1-10% of HBV infected people and occur in acute hepatitis B after preceding the onset of jaundice (Liang, 2009). The symptom often subsides shortly after the onset of jaundice but can persist throughout the duration of acute hepatitis B
Transmission of hepatitis B virus
Transmission of hepatitis B virus occurs when blood or body fluid of an infected person enters the body of a person who is not immune. HBV could be transmitted through the following ways;
- From mother to child mainly during and after birth accounting for 1-5% infection in Africa
- Use of unsterilized needles and syringes for injection.
- Transfusion of infected blood and blood products.
- Close body contact with patients with active infection, especially those with skin lesions like scabies and cuts that enable transfer of blood or body fluid.
- Unprotected sex with infected persons and human bites.
- Sharing of toothbrushes, razors, needles, nail and hair clippers
Studies in Nigeria have confirmed some of the routes outlined above. A figure of 2.8% has been documented as the rate of HBV transmission from Nigerian females to their offspring (Ezegbudo, 2004). Various studies in Nigeria showed that blood transfusion is an important source of HBV transmission while studies from north central Nigeria indicates that unprotected sex is implicated in the transmission of HBV (Mustapha, 2004). Other risk factors for developing HBV infection include working in a health care setting, tattooing and dialysis. However, hepatitis B virus cannot be spread by holding hands, sharing eating utensils or drinking glasses, sneezing or hugging.
Pathogenesis
Hepatitis B virus primarily interferes with the functions of the liver by replicating in liver cells known as hepatocytes. The virion bind to the host cell via the pre S domain of the viral surface antigen and are subsequently internalized by endocytosis.
During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. Although the innate immune response does not play a significant role in these processes, the adaptive immune response, in particular virus-specific cytotoxic T lymphocytes(CTLs), contributes to most of the liver injury associated with HBV infection. CTLs eliminate HBV infection by killing infected cells and producing antiviral cytokines, which are then used to purge HBV from viable hepatocytes.
Persistent HBV infection is characterized by a weak adaptive immune response thought to be due to low CD4+ cell count or inefficient CD4+ T cell priming early in the infection (Guidotti, 2006).
Epidemiology/Prevalence
Hepatitis B virus AND HIV have common routes of transmission but HBV is 100 times more infectious than HIV. Consequently, in some settings, up to two thirds of all HIV infected people have a blood marker for past or present HBV infections.
Homosexual or men who have sex with men show higher rates of HBV/HIV co-infection than heterosexuals (Konopnicki, 2005). Patients with HIV infection have a greater risk of getting infected with hepatitis B virus than HIV negative persons. Although spontaneous clearance of HBV acquired in adulthood occurs in 90% of immunocompetent individuals, HIV infected persons are half as likely as HIV uninfected persons to spontaneously clear HBV. Chronic HBV infection occurs in 5-10% of HIV infected individuals who are exposed to HBV, a rate 10 times higher than that of the general population (Alter, 2006). An estimated 4 million people worldwide are co-infected with HIV and chronic HBV but their prevalence varies with the population studied (Bonacini, 2004). Factors affecting the prevalence of chronic HBV include age at time of acquisition and mode of acquisition which varies geographically.
In the United States, HIV and HBV infection rates are highest among men who have sex with men and injection drug users. It is estimated that 10% of HIV infected individuals are HBV surface antigen positive in contrast to Asia and Sub-Saharan Africa. Where vertical and early childhood exposures are the most common modes of transmission respectively and overall HBV prevalence is higher at an estimated 20-30% (Hoffman, 2007). Several studies support an increased prevalence of HBV in HIV infected populations of Sub-Saharan Africa with more than 80% of HIV positive individuals in some of these countries carrying serum markers for HBV (Burnett, 2005).
In Nigeria, a country where hepatitis B virus and HIV infection prevalences are high, HBV occurs in 10-70% of HIV infected individuals (Iwalokun, 2006). Recent studies of HBsAg prevalence in Jos and Gombe among HIV infected persons was shown to be 25.9% (Ukaeje, 2005) and 26.5% (Mustapha, 2004) respectively. In a study carried out by Okocha, Oguejiofor and Odenigbo (2012) in Nnewi, a prevalence of 5.9% was obtained for HBsAg among HIV positive people. They also reported a prevalence of 5.6% for non-infected people. In the north central Nigeria, a prevalence of 10.7% was reported by Imuru and Adegoke (2008). In a study in Kano, a prevalence of 4.9% was reported by Abiodun and Ihongbe (2004). In a cohort of 260 HIV adult patients studied in National Hospital, Abuja, the prevalence was 11.5% (Adewole and Anteyi, 2009). In Ibadan, a prevalence of 11.9% was obtained by Otegbayo and Taiwo (2008). In Niger Delta region, a prevalence of 9.7% was also documented by Ejele and Erhabor (2004).
In Lagos Nigeria, a cross sectional study of HIV infected individuals aged 18 years and above carried out between the year 2006 and 2009 showed a prevalence rate of 10% (Lavanchy, 2004) while in Owerri, a study of the pediatric population was carried out and 139 HIV infected children demonstrated a prevalence of 5.8%. Higher rate of prevalence was found in females than in males with females having a prevalence of 65.6% while that of males was 34.4% (Otegbayo, 2008).
Endemicity
The prevalence of hepatitis B surface antigen varies geographically with high endemicity areas in south East Asia, Sub-Saharan Africa, the Amazon basin, parts of the Middle East, the Central Asia Republic and parts of Eastern Europe.
Areas of low endemicity include North America, Western and Northern Europe, Australia and Parts of South America.
Relationship between HIV and HBSAG
According to Puoti (2006) and Thio (2009), the rate of progression and complications from viral hepatitis are accelerated in patients with HIV infection after acquiring HBV infection. HIV infected individuals are 6 times more likely to develop chronic hepatitis B than HIV negative individuals. This is more likely to occur in HIV infected persons with lower CD4 cells count.
Decreased rates of clearance of HBsAg and increased HBV replication are also seen with higher HBV DNA viral load. In addition, HIV infected individuals are more likely to lose previously developed protective anti-HBs (antibody to hepatitis B surface antigen) and develop acute hepatitis B infection. This risk is also associated with lower CD4+ cell counts.
According to Drake (2004) and Bellini (2009), following the initiation of antiretroviral therapy (ART), immune reconstitution inflammatory Syndrome (IRIS) may occur which can lead to worsening liver disease including hepatitic decompensation. In addition after discontinuation of an ART Regimen containing antibody to hepatitis B virus agent (anti-HBV) reactivation of hepatitis B can occur.
- Impact of HBV on HIV
According to WHO (2011), on the management of hepatitis B and HIV co-infection, HBV co-infection with HIV has a major impact on the natural history, diagnosis, progression, morbidity and mortality of HBV infection.
In the early ART era, some studies showed an increased rate of HIV progression to AIDS among individuals with HBV infection (Chavel, 2007). Patients receiving antiretroviral therapy have an increased risk of hepatic flares when active treatment for both HIV and HBV is interrupted (Dore, 2010).
- Impact of HIV on HBV
HBV infection is more frequently seen and is associated with increased severity of liver disease in HIV infected patients. According to Weber (2006), patients co-infected with HIV and HBV especially those with low CD4+ cell count are at increased risk for liver related mortality.
The course of acute HBV may be modified in the presence of HIV infection with lower rates of spontaneous clearance of HBV. HIV increases the risk of cirrhosis and end stage liver disease in HBV infection (Theo, 2004).
Diagnosis of HBsAg
Given the elevated rates of HBV among individuals who are infected with HIV and the shared routes of transmission between the two viruses. All HIV infected individuals should be screened for HBV co-infection with HBsAg testing.
The test called assay for detection of hepatitis B virus infection involve serum or blood tests that detect either viral antigens (protein produced by the virus) or antibodies produced by the host. Interpretation of these assays is complex.
Hepatitis B surface antigen (HBsAg) is the first detectable viral antigen to appear during infection. It is frequently used to screen for the presence of hepatitis B virus. If it is found along with other specific antibodies, it means the person has a hepatitis B infection. However early in an infection, this antigen may not be present and it may be undetectable later as it is being cleared by the host. During this stage in which the host remains infected but is successfully clearing the virus, antibodies specific to the hepatitis B core antigen (anti-HBC lgm) may be the only serological evidence of disease. Therefore most hepatitis B diagnostic panel contain HBsAg and total anti HBC (both lgm and IgC).
If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by antibodies to the hepatitis B surface antigen (anti-HBs) and core antigen (anti-HBC). The time between the removal of HBsAg and appearance of anti-HBS is called the window period.
A person negative for HBsAg but positive for anti-HBs have either cleared an infection or has been vaccinated previously. Individuals who remains HBsAg positive for at least six months are considered to be hepatitis B carriers (Dean, 2006). Routine liver function test and serological assays for the detection of HBV antigens and antibodies should be performed to assess the phase of chronic hepatitis B. Liver biopsy is essential to confirm the diagnosis and to identify any intercurrent disease affecting the liver.
Prevention and control
There are broadly three strategies for dealing with hepatitis B virus infection in the developed countries, immunization for at risk population, antiviral drugs and immunostimulatory therapy for those affected.
Immunization is the most effective means of controlling HBV worldwide. The vaccine has an outstanding record of safety and efficacy and it is 95% effective in preventing development of the chronic carrier stage. In Africa, universal immunization at birth has been adopted. The vaccine is more effective in children and 95 per cent of the vaccinated have protective levels of antibody. The protection afforded by vaccination is long lasting.
In addition, HBV infection in Nigeria can be prevented or drastically reduced through health education of the general public on the various mode of transmission of HBV and preventive measures. Such measures include careful handling of blood and body fluids since they are potentially infectious. Also discouraging communal sharing of blade/sharp instrument used for shaving, barbing, manicure and body piercing and high level sexual networking.
WHO recommends universal screening of blood and plasma for HBsAg by sensitive method before transfusion. All those with a risk of exposure to body fluid such as blood should be vaccinated. Those at high risk of infection should be tested as there is effective treatment for those who have the disease. Testing to verify effective immunization is recommended and further doses of vaccine should be given to those who are not sufficiently immunized. The screening is highly recommended for the HIV infected persons. Patient’s positive for HBsAg should be tested for quantitative HBV DNA and screened for hepatitis B Delta antibodies (anti HDV). Hepatitis B vaccination is recommended in all HIV positive persons who are negative for HBsAg and anti-HBs.
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