15
CHAPTER II
LITERATURE REVIEW
A. History/Etiology of Hepatitis B virus (HBV)
In 1965, Nobel Laureate Dr. Baruch Blumberg discovered the hepatitis B virus. Hepatitis B virus is a DNA virus which belongs to the Hepadnaviridae family of viruses. It was formerly called also as "Australia Antigen," just after blood of an Australian aborigine. The viral core is made up of a nucleocapsid, hepatitis B core antigen (HBcAg), the DNA of hepatitis B viruses, and DNA polymerase, Hepatitis B surface antigen (HBsAg), a virion polypeptide, coats the nucleocapsid.
The same gene (HBeAg) encodes the hepatitis B core antigen (HBcAg) and the hepatitis B e antigen (HBeAg). Although the hepatitis B virus genotype has eight variations, they are not employed in clinical practice to determine the severity of infection. In small levels, the Hepatitis B virus could be identified in serum, sperm, vaginal mucus, saliva, and tears25
Hepatitis B Virus spread is mainly by parenteral and percutaneous exposures include transfusions of blood and , (IDU) with sharp material like needles, syringes, also injuries that is due to other tools in healthcare proffessionals,and also hemodialysis. However, the parenteral route continues to be the most common mode of transmission both worldwide and locally. IDU, MSM, professionals in healthcare who have been exposed to infected body fluids which was infected, requiring regular and it was found that recurrent blood transfusions, people who do sex with many partners, partners who carry the HBV, individuals that were born in endemic places, everything is risky, HBV infection is a high risk in all of these places26. World Health Organization reported that virus can also be transmitted perinatally, occurring in infants of
16 HBeAg positive women. These children have a 70 to 90 percent chance of becoming infected, and 90 percent of those infected go on to develop chronic HBV infection according to the findings of world health organization.
Individuals who have both HIV and HBV are more prevalent due to the same method of transmission and similar risk factors, with the effectiveness of antiretroviral therapy (ART), AIDS-related opportunistic infections have been reduced, In contrast, liver-related mortality has risen to become the second-largest cause of death in Individuals who are infected with HIV.
Infection alters the natural course of HBV, increasing the risk of cirrhosis, hepatocellular cancer, and mortality from liver disease; it is now easier than ever to treat co-infected individuals thanks to the availability of powerful antiviral medicines that are active against both HIV. and HBV, as well as streamlined treatment algorithms, However, inadequate response, insufficient viral suppression, long-term antiviral treatment side effects, and antiretroviral therapy's possible hepatotoxicity remain significant obstacles 27.
B.Epidemiology of Hepatitis B virus
Chronic HBV is prevalent in various regions of the globe, varies substantially. this prevalence be divided in 3 major ones including the High, the middle, and the lower endemicity as indicated in the previous studies28
a)Geographical distribution of HBV infection
The report release by WHO concerning the Western pacific region and Africa have indicated that these two regions are the one with the highest HBV prevalence compared to other WHO regions where, the prevalence in western pacific region was 6.2 percent and in Africa was 6.1 percent, it is approximated that 3.3% in Eastern Mediterranean region, 2 percent in Southeast
17 Asia and 1.6 percent of the general population in European region. The report revealed that the prevalence of this HBV in America was 0.7 percent .
Figure2 1: Figure showing the Geographic distribution of HBV infection, as HBsAg prevalence. the source of the figure is referenced as 29
b).High Endemicitys
The frequency of HBV infection varies greatly around the world, Hepatitis B is quite common in developing nations, and Southeast Asia, China, Sub-Saharan Africa, and the Amazon Basin are examples of areas with enormous people. At minimum 8% of the community is chronically infected with HBV, and 70-95 percent of the population has tested for HBV in the past or now.
The majority of these patients happen during childhood or infancy. There really is no proof of acute HBV disease in children since most infections are asymptomatic, while chronic liver disease and liver cancer are frequent in adults29.
18 c)Intermediate Endemicity
Hepatitis B is common in portions of Eastern and Southern Europe, the Middle East, Japan, and South America. Between ten percent and sixty percent of the population is infected, with two to seven percent of them being chronically infected. Since most infections occur in youths and adulthood, severe HBV infection is common in these locations; nevertheless, infections in newborns and children result in a significant number of chronic disease rates. Babies, early life, and grownup illnesses are all possible transmission systems in such areas29.
d). Low Endemicity
Many developed countries like (Western Europe, Australia, part of the North America) it has been shown that HBV endemicity is minimal n these region mentioned above. The population infected by HBV in these areas is 5 up to 7%, among these 0.5 up to 2 % are being chronique carriers, High number of HBV infections is found in children below twenty years of age and found in groups like injectable drug users ,homosexuals and patients who demand frequent blood transfusions or hemodialysis, as well as health care providers30
HBsAg is characterized as high prevalence when it is above 8%, and characterized as intermediate when it is between 2 up to 7% , low when it below 2 %, These distinct groups are essential for determining the most common patterns of virus spread and effect, knowing these groups helps to find the population burden of HBV virus ,the spread of HBV is frequent in many countries of Asian Region and Sub-Saharan region of Africa, resulting in consequences such as liver cancer, where chronically infected patients of HBV are more than 8 percent of the population. Most of these people became infected during birth or in childhood when chance of contractinf the disease was high, Vertical transmission appears to be more prevalent in Asia
19 more than it can be in Africa, in Asia the higher proportion of ladies are highly infectious at young age, perhaps because of HBV genotypes that increase the likelihood of high HBeAg high levels and high HBV DNA levels during reproductive years In high-prevalence populations, the major effect of baby vaccination anti-HBV is most significant, not only has reduced HBsAg dramatically in such people where universal baby immunization was established early, but there is significant proof that liver cancer have also decreased within age cohorts that was allowed for free vaccine, HBsAg prevalence in children under five have decreased from 9.7% up to 1%
in china, the intervention that was done in Gambia proved that, newborn vaccination was 95%
effective in avoiding chronic HBV infection 30 C. Hepatitis B virus infection
Chronic or acute hepatitis B infections are both due to Hepatitis B virus, according to the world health organization , Some people may experience vomiting, greyish skin, weariness, black urine, and stomach pain due to an acute infection, Symptoms usually takes little weeks, and the early infection are rarely fata,. Symptoms might appear anywhere between 30 and 180 days after contamination around, 90% of those contaminated at birth acquire Chronic HBV, when comparing this to lower than ten percent of those infected with the age greater than 5. People who are chronically infected by HBV do not have symptoms, but cirrhosis and liver cancer can occur later. Cirrhosis or liver cancer affects around a quarter of people with chronic illnesses9. The virus spreads through contact with infectious blood o but thus virus can also be transmitted by body fluids of the infected individuals. In places where hepatitis B is prevalent, infection can occur by contact of the blood of others in childhood is the main pathway of transmitting this disease. Drugs injected intravenously and doing sec are the main source of this infection in
20 where the disease has not been diagnosed, blood transfusion with others factors like, dialysis, the people who live or have lived with an infected person, when people travel to countries with high rates of transmission these are all factors that can make someone be infected by HIBV, Tattooing was involved in many infected cases in the years of 1980s. The following factors do not spread HBV infection: hugging ,holding hands, kissing, ,coughing ,sneezing, sharing eating utensils, The disease can be controlled 30 to 60 days after exposure according to the previous studies that were done31
D. Pathogenesis of hepatitis b virus
Some studies report that HBV is not a cytopathic virus. Liver cell abnormalities that occur due to HBV infection are caused by the body's immune reaction against HBV-infected hepatocytes with the aim of eliminating the HBV. Clinic followed by recovery. Meanwhile, in some patients the immune response failed to destroy the infected liver cells so that the HBV is still replicating. In the case of chronic hepatitis B, the immune response is present but not perfect so that only necrosis occurs in liver cells containing HBV and there are still infected liver cells that do not undergo necrosis, so the infection can spread to other cells. In healthy carriers the immune response is completely ineffective so that there is no infected liver necrosis and the virus continues to replicate without clinical symptoms32.
E. Epidemiological risk factors for HBV co-infection in HIV/AIDS patients.
Blood transfusions, recycling of needles and contaminants during medical procedures, piercing or tattooing, sharing needles with drug users (IDU), sexually transmission, perinatal transmission, and men who have sex with men, are all known risk factors for HBV infection in
21 Indonesia (MSM.), Immunocompromised people, hemodialysis patients, tissue and organ transplants, and healthcare transmission are all examples of promiscuous heterosexuals33
Hepatitis B virus (HBV) and HIV are one of the many public health problems because of the similarity transmission methods of HBV and HIV, based on world health organization report, more than 37.-7 296 million people worldwide have HIV and HBV respectively.
Together these diseases progression reduces HBV clearance and severely impairs cell immune response to the HBV antigens. It also accelerates the process of disease progression and liver fibrosis and increasing serious disease problems, On the other hand, HBV infection is a very important factor in disease progression and treatment of patients with HIV. In other words, it significantly adds to the problems associated with liver toxicity after treatment with antiretroviral drugs . As a result, these cases show a significant decrease survival rates compared to patients infected with HIV or the HBV virus mono infection,the differences between the prevalence rates of infection in the different studies reflect the importance of the role. predisposes to adverse conditions in different countries or different parts of the same country34 , Some of the factors involved in concurrent development of these two infections include :
1) intake of intravenous injection drugs, 2) study area/district,
3) tattooing,
4) sharing hygiene tools
5) un protected sexual intercourse, 6) history of imprisonment
7) marital status
22 Previous research reported that intravenous drug use, tattooing, illegal sex, and history of imprisonment are independently related to high risks of concurrent infections, Undoubtedly, the distribution of infected syringes plays a major role in the spread of this disease in populations with high HBV transmission rates and prisons, because prison is a place where needles often used and various diseases such as HBV and HIV are very common in prison . In addition, un injected drug user who go to prison are more likely to convert and start doing that once they are there34.
F. Hepatits B virus coinfection with HIV/AIDS
About 5 percent to 10 percent of Individuals who have with HIV in US they are also infected by HBV. Chronic HBV develop faster to liver cancer, cirrhosis, in people who have both HIV and HBV compared to people with HIV alone.Chronic HBV has no impact on the evolution of HIV infection, HIV reduction, or CD4 T cell (CD4) cell reactions after the commencement of antiretroviral drugs. However, ARV toxicity or more liver-related complications linked with increased HBV activity after starting or stopping dual-acting ARVs may affect HIV treatment in HBV / HIV Co-infected patients35.
There is evidence that co-infection with HBV and HIV increases the risk of mortality in HIV/AIDS patients. HBV infection can make HIV patients on antiretroviral therapy more challenging to treat, resulting in toxicity; the progression is about two times more likely to occur among patients with co-infection compared to those with HIV infection alone 27.
About 1 percent of HBV sufferers (2.7 million individuals) are also HIV positive. The worldwide incidence of HBV infection in HIV-infected patients, on the other hand, is 7.4 percent. The
23 World Health Organization (WHO) has advised medication for all individuals who are diagnosed with H.I.V. infection, irrespective of their phase of illness, since 2015. Tenofovir, that's included in 1st HIV disease treatments, is indeed helpful against H.I.V and HBV13
G. Clinical presentation of hepatitis B
Symptoms of hepatitis B vary widely from asymptomatic to symptomatic severe, such as vomiting blood and coma. In acute hepatitis the symptoms are very mild and if there are symptoms, then the symptoms are like flu symptoms. The symptoms are: mild fever, nausea, weakness, loss of appetite, yellow eyes, urine dark color, diarrhea and muscle aches. In a minority of symptoms can be severe and fulminant hepatitis occurs which results in death.
Infection Hepatitis B acquired in the perinatal period and in infants is usually asymptomatic and can become chronic in 90% of cases36.
Approximately 30% of hepatitis B infections occurs in adults will cause jaundice and at 0.1-0.5%
can develop into fulminants. In adults 95% of cases will recover perfectly characterized by the disappearance of HBsAg and the emergence of anti HBs.Chronic infection is characterized by persistence of HBsAg and anti-HBc and serum HBV DNA can be detected for more than 6 months using non-PCR. In chronic hepatitis B, there are 3 phases, namely the immunotolerant phase, the replicative phase, and integration phases. In the immunotolerant phase, HBsAg . will be obtained and HBeAg in serum and high HBV DNA titer but ALT normal. In this phase, symptoms can occur and an increase in aminotransferases occurs which will be followed by the presence of anti-HBe (seroconversion). In phase non-replicative will find low HBV DNA and positive anti-HBe. Phase This non-replicative state is often also referred to as an inactive patient state can also occur in this situation resolution of hepatitis B so that HBsAg does not detected
24 again. In some patients HBeAg ,seroconversion may also be found caused by mutations in the virus. In this group of patients it is also possible to find an increase in HBV DNA levels accompanied by ALT elevation36.
If a person is infected with hepatitis B at an older age, usually Symptoms of inflammation are brief and symptoms of the disease are not severe. In phase nonreplicative hepatitis B virus replication can still be found but very little because it is suppressed by the patient's immune response. Some patients with negative antigen can become active again but with the e antigen remains negative. So there are 2 types of chronic hepatitis B, namely chronic hepatitis B with HBeAg positive and chronic hepatitis B with HBeAg negative. Patient who have perinatal infection can also become chronic hepatitis with A positive HBeAg is accompanied by an increase in ALT but after time quite a long time (10-20/year) HBeAg seroconversion will usually be followed by an improvement in the condition biochemistry and histology. Seroconversion of e antigen to e antibody can occur in 50-70% of patients with elevated ALT within 5-10 years after being diagnosed. Usually this will happen to people of the same age further, and women and their ALT are high 36.
In general, when seroconversion occurs, the symptoms of hepatitis are also present become inactive even though in a small part there are still biochemical disturbances and histologic activity as well as increased levels of HBV DNA. Inactivated HBsAg infection characterized by HBsAg-positive, anti-HBe and undetectable HBV DNA and normal ALT. Even so, sometimes there are still a few signs inflammation on anatomic pathology examination. When seroconversion occurs After a long period of time, symptoms of abnormalities in the preparation can also be found anatomic pathology36.
25
H. Laboratory diagnosis of hepatitis B
In symptomatic acute hepatitis B, the serological pattern, HBsAg begins to appear at the end of the incubation period approximately 2-5 weeks before clinical symptoms and the titer will increase after clinical symptoms appear and persist for 1-5 month. Furthermore, the HBsAg titer will decrease and disappear with a decrease in clinical symptoms. Persistence of HBsAg after 6 months indicates a process will become chronic. Anti-HBs only appears at the convalescent stage, namely: some time after the disappearance of HBsAg, so there is a window period (window period) is the period of disappearance of HBsAg until the onset of anti-HBs. Anti-HBs will persist for a long time, 90% will persist for more than 5 years so that it can determine the stage of healing and the patient's immunity. On window period, Anti-HBc is an important marker of acute hepatitis B. Anti-HBc initially consists of IgM and a small amount of IgG. IgM will decrease and disappears within 6-12 months after recovery, while IgG will persist long and can be detected within 5 years after recovery. HBeAg occurs with or immediately after HBsAg.
Found it HBeAg shows a large number of viruses. HBeAg positive time frame shorter than HBsAg. If HBeAg is still there for more than 10 weeks after the onset of clinical symptoms, indicating the disease progressed to chronic. Seroconversion from HBeAg to anti-HBe is a good prognosis well that will be followed by healing the disease37.
In asymptomatic hepatitis B infection, serological examination shows: low levels of HBsAg and HBeAg for a short time, often even HBsAg was not detected. The disappearance of HBsAg is immediately followed by the appearance of anti-HBs with high titers and long maintained. Anti- HBc and anti-HBe also occur but not as high as anti-HBs titers. Five to ten percent who suffering from acute hepatitis B will progress to chronic hepatitis B. In this type HBsAg appears at the end
26 of the incubation period with high titers which will permanent and maintained for a long time and can be up to tens of years or a lifetime life. Anti-HBs will not appear in HBsAg sufferers, but on the contrary, anti-HBc consisting of IgM and IgG anti-HBc will be detected and fixed. for more than 2 years37.
Table2 1: Interpretation of Laboratory HBV tests results The results of serological
tets
HBsAg Total anti-HBc
IgM anti-HBc
Anti-HBs
Identified after
vaccination or for 3-6 months after receiving HBIG
negative negative negative positive
Positively incorrect which is also called false postive(susceptible) Infection that has occurred previously (resolved)
"Secondary" Inflammation that lasts a long time (unlikely to be infectious)
negative negative negative negative
Chronic infection positive positive negative negative
After recovering from a previous infection, immune to a new infection.
negative positive negative positive
Acute infection negative positive positive negative
Acute initial infection OR vaccination administration within a few week.
positive negative negative negative
Never infected Susceptible
negative negative negative negative
27
I.Diagnosis of Hepatitis B virus
The diagnosis of hepatitis B is made by biochemical examination and serological and, if necessary, histopathological examination. On In acute hepatitis B, there will be a greater increase in ALT than in acute hepatitis B with elevated AST with ALT levels 20-50 times normal. Found also anti-HBc IgM in the blood other than HBsAg, HBeAg and HBV DNA. In chronic hepatitis ALT elevation is about 10-20 Upper Limit Normal value with a de Ritis ratio (ALT/AST) of about 1 or more. In addition, IgM anti-HBc is also negative. The diagnosis of chronic hepatitis B is confirmed by anatomic pathology examination, in addition it is also possible with fibrotest examination. Imaging with ultrasound or a CT scan may be helpful if the process is advanced38. J. Prevention of hepatitis B virus (HBV)
General prevention of hepatitis B is in the form of a blood donor screening test with a test sensitive diagnosis, adequate-accurate instrument sterilization. Dialysis device used individually, and for patients with HVB, machine should be provided separately. Disposable needles are disposed off in a special place that does not penetrate the needle. Prevention for medical personnel is to always use gloves. Conducted counseling so that injection drug users do not use needles alternating, safe sexual behavior. Prevent microlesion contact, avoid use tools that can transmit HVB (toothbrush, comb), and be careful in treating open wounds. Screening pregnant women at the beginning and at third trimester of pregnancy, especially mothers who are at high risk of HVB infection. Mother Pregnant women with HVB (+) are treated in an integrated manner. Immediately after birth, the baby is immunized active and passive against HVB.
Screening high-risk populations infected with HVB (born in a hyperendemic area, homosexual,
28 heterosexual, multiple sex partners, medical personnel, dialysis patients, families of patients chronic HVB, and who have sexual contact with HVB patients39.
Immunization for HBV can be active or passive. For passive immunization Hepatitis B immune globulin (HBIg) is used, it can provide direct protection quickly for a limited period of 3-6 months. In adults HBIg administered within 48 hours of exposure to HBV. Active immunization is given mainly to newborns within 12 first hours. Vaccinations are also given to all infants and children, adolescents, who have never been immunized (catch up immunization), individuals who are at risk of exposure HBV based on the profession concerned, adults at risk infected with HBV, medical personnel and staff of mentally disabled institutions, hemodialysis patients (immunization is given before dialysis therapy is started), patients who need transfusions or blood products on a routine basis, in drug abuse, in homosexuals and bisexuals, commercial sex workers, infected people sexually transmitted disease (STD), heterosexuality with multiple partners, contact household and sexual contact with people with HVB, populations from areas with high incidence of HBV, liver transplant candidate. To reach the level of seroconversion high concentration and protective anti-HBs concentration (10 mIU/ml), immunization is given 3 times with a schedule of 0.1,6 months39.
K. HBV co-infection in HIV-positive populations
Worldwide, roughly 35.3 million people live with HIV, of these; 4 million HIV-positive people are co-infected with HBV. The global prevalence of HBV–HIV co-infection among HIV- infected people is 7.4 per cent. In Africa, it is approximated that 3.4 million individuals are co- infected with HBV and H.I.V. at a 15% rate. Furthermore, roughly 90% of HIV-infected people possess biological symptoms of prior HBV infection, with 5–15% having chronic HBV
29 infection. The proportion and risk factors of HBV–H.I.V. co-infection differ considerably based on geographical distribution. In Western Europe and North America, the prevalence of HBV–
H.I.V. co-infection is approximately 5%, whereas it is around 20% in emerging countries such as South-East Asia. Furthermore, according to various studies, the prevalence of HBV/HIV co- infection in Africa ranges from 2% to 30.6 per cent40.
L.Epidemioloical risk factors for HBV co-infection in HIV/AIDS patients
Hepatitis B infection is an infectious disease that is still a serious health problem. Until now, hepatitis B disease shows high morbidity and mortality worldwide. Hepatitis virus has infected 2 billion people in the world, and about 240 million of them become chronic and developing hepatitis B.cirrhosis of the liver, fulminant hepatitis, liver failure, or liver cancer and eventually death.1 An estimated 780,000 deaths due to Hepatis B Virus or HBV infection and 4.5 million new HBV infections occur annually worldwide. According to WHO, HBV can be found worldwide, but with a high level of endemicity which varies. Most of the world's population lives in countries with a high prevalence of HBsAg (≥ 8%) or intermediates (2 – 7%). Indonesia is a country with moderate to high endemicity of Hepatitis B, the second largest in the South East Asian Region (SEAR) after Myanmar with an HBsAg prevalence of 9.4% (range 2.5 – 36.1%) of the general population3.Some of the factors that affect the transmission of HBV are as follows:
Age: A person's age affects risk factors for hepatitis B transmission, the incidence of hepatitis B in infants or children may occur due to transplacental transmission of HBV, whereas in adolescents or adults it usually occurs due to transmission of hepatitis B through sexual history, sharing needles with hepatitis B sufferers when using drugs and blood transfusions. A person's age when exposed to hepatitis B can also affect the chronicity of the disease, infants have the
30 highest probability of progression from acute hepatitis B to chronic hepatitis B, which is 90%.
The risk will decrease as you get older. Approximately 20-50% of children aged 1-5 years are infected HBV will also be at risk of becoming chronic. The risk decreases to 6-10% in someone who is infected with HBV at the age of more than 5 years. 25% of adult patients will die after being infected with chronic HBV since childhood, while 90% of adult patients with hepatitis B infection will die. recovered and the virus will disappear for a vulnerable time of 6 months3. Gender: In one study, data were obtained when men had a higher risk of hepatitis B infection, this is most likely related to the risk of drug use through needles used by HBV-infected people or tattooing with unsterilized needles.Sexual history: Hepatitis B virus is more easily transmitted through sexual contact especially unprotected sex as in HIV virus. Hepatitis B virus can be found in vaginal fluids, saliva, and semen. Oral sex or anal sex is one way of transmitting the hepatitis B virus through sexual intercourse. The hepatitis B virus cannot be transmitted by holding hands or touching an infected person. Transmission through kissing may occur because the virus is present in the saliva, especially if the patient's partner has sores in his mouth. The risk of being infected with hepatitis B increases with the number of sexual partners you have.- History of drug use through needles and blood transfusions Hepatitis B infection can be transmitted through HBV-infected needles, this can occur in drug users who take turns in using needles, as well as making piercings or tattoos with unsterile needles. This infection can also occur through direct contact with the blood of patients containing HBV such as in blood transfusions, so that the virus can enter the recipient's bloodstream and cause infection41.
Transmission routes and risks factors for HIV and hepatitis B is similar, expected regionally, subpopulations are most susceptible to each disease, as well as to different risks, as a result, countries differ in the rate of HIV / HBV. It is involved in the distribution of HIV and local
31 hepatitis, the double-blind study showed that, while this is true for studies in Europe, it is not useful for research studies in Africa or Asia, due to the high prevalence of HBV in many parts of Africa and Asia42.
There are various risk factors for acquiring HBV co-infection in HV/AIDS patients among others are :individual characteristics like (age, body mass index, sex), marital status geographical location, current ART regime, , ART duration, HIV viral load, key population category, education level, and CD4+Tcell count were all mentioned as risk factors for acquiring HB co-infection in HV/AIDS patients41.
M. Treatment of HIV/HBV Co-infection
HIV treatment guidelines recommend all HIV/HBV co-infected patients receives treatment for HBV, regardless of HBV activity, treatment is typically with agents that have dual activity against HIV and HBV, this include-Tenofovir+ FTC ,FTC is also called the Emtricibine ,the use of 3TC also called Lamivudine or FTC alone against HBV is contraindicated due to low barrier to resistance43
