Hepatitis B virus in Pakistan: A systematic review of prevalence, risk factors, awareness status and genotypes

In Pakistan, there are estimated 7-9 million carriers of hepatitis B virus (HBV) with a carrier rate of 3-5%. This article reviews the available literature about the prevalence, risk factors, awareness status and genotypes of the HBV in Pakistan by using key words; HBV prevalence, risk factors, awareness status and genotypes in Pakistani population in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. One hundred and six different studies published from 1998 to 2010 were included in this study. Weighted mean and standard deviation were determined for each population group. The percentage of hepatitis B virus infection in general population was 4.3318% ± 1.644%, healthy blood donors (3.93% ± 1.58%), military recruits (4.276% ± 1.646%), healthcare persons (3.25% ± 1.202%), pregnant women (5.872% ± 4.984), prisoners (5.75% ± 0.212%), surgical patients (7.397% ± 2.012%), patients with cirrhosis (28.87% ± 11.90%), patients with HCC (22% ± 2.645%), patients with hepatitis (15.896% ± 14.824%), patients with liver diseases (27.54% ± 6.385%), multiple transfused patients (6.223% ± 2.121%), opthalmic patients (3.89% ± 1.004%) and users of injectable drugs (14.95% ± 10.536%). Genotype D (63.71%) is the most prevalent genotype in Pakistani population. Mass vaccination and awareness programs should be initiated on urgent basis especially in populations with HBV infection rates of more than 5%.


Introduction
Hepatitis B virus (HBV) infection is a major global health problem [1][2][3], especially in Asia, Africa, southern Europe and Latin America [4]. About 2 billion people are infected with HBV worldwide [2,4,5], and 400 million among them are suffering from chronic HBV infection [6]. Pakistan is highly endemic with HBV [7] with nine million people infected with HBV [8] and its infection rate is on a steady rise [9]. The reason may be the lack of proper health facilities, poor economical status and less public awareness about the transmission of major communicable diseases including HBV, HCV and HIV [6].
The clinical course and sequel of chronic hepatitis vary among individuals. Infection with HBV leads to a wide spectrum of clinical presentations, ranging from asymptomatic carrier state to acute self-limiting infection or fulminant hepatic failure, chronic hepatitis with progression to cirrhosis, and hepatocellular carcinoma (HCC) [2].
Studies are too limited to give a clear picture of the prevalence of HBV at the National level, especially among otherwise healthy individuals. Most previous studies targeted different small groups of individuals with some clinical indications therefore; these do not accurately reflect the overall prevalence in Pakistan [7,8]. The present article briefly presents the prevalence, risk factors associated with HBV transmission, awareness status and HBV genotypes prevalent in Pakistani population.

Literature Search and inclusion criteria
Articles were searched in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar by using keywords; Hepatitis B virus in Pakistan, Prevalence of HBV in Pakistan, HBV in Blood donors, Hepatitis B virus in general population, HBV in Pakistani healthcare workers, HBV in surgical patients, HBV infection in women and children, HBV infection in prisoners, HBV in diseased population in Pakistan, HBV in injection drug users, epidemiology of HBV in Pakistan, HBV genotypes in Pakistan and awareness about HBV in Pakistani population. Two hundreds and twenty nine different studies (articles/repots) were obtained from the literature search, out of which 106 published from 1998 to 2010 were included in the present review. Studies full filling the following criteria were included: 1) Samples were collected from Pakistani individuals. 2) An obvious description of the methods of detection of HBV infection and genotyping. 3) Information about the number of individuals studied and their residing area were reported. 4) Studies reporting risk factors and awareness status in Pakistani population were included to discuss the HBV prevalence in different population groups.

Analysis
Studies showing percent prevalence of HBV infection in different population are shown in table 1, 2, 3 and 4,  while table 5 shows the percentage of different genotypes prevalent in Pakistan. The percent prevalence in the different population groups are presented in mean ± standard deviation (with 95% confidence interval).
Formula used for determination of mean prevalence in each population group Formula used for determination of standard deviation (SD) in each population group Where "x" is the percent HBV prevalence reported in each study and "N" is the total number of studies in the population groups.
These studies show that Southern Punjab, Interior Sindh, District Tatta, Kurrum agency and some areas of Lahore have very high HBV prevalence of >5%, hence mass vaccination and awareness programs in these areas on urgent basis is suggested.

Surgical patients
Four different studies showed 7.397% ± 2.012% HBV prevalence rates in patients undergoing surgery [57][58][59][60]. The lack of routine serological screening in Pakistani hospitals prior to surgery is one of the factors responsible for increased disease transmission [59]. It is recommended that every case undergoing surgery should be screened for hepatitis B and C virus infections [61].

Intravenous drug users (IDU)
Pakistan is estimated to have 4 to 4.8 million drug users with 180,000 IDUs [83]. Strathdee et al. [84] observed significant increase in needle sharing in IDUs since 2001. Among them Afghan refugees have higher levels of needle sharing as compared to the local IDUs [85]. Two different reports showed a very high HBV prevalence of 14.95% ± 10.536% in injection drug users [86,87].

Patients with other diseases
Two different reports show the prevalence of HBV in ophthalmic patients to be 3.89% ± 1.004% [88,89], percent prevalence of HBV was 12.4% in patients on hemodialysis [90], 26% in psychiatric patients [91], 10.2% in patients advised for liver function tests [92], 1.5% in patients with dermatoses caused by lichen planus [93] and 2.02% in orthopedics patients [94]. High prevalence among psychiatric patients could be due to razor sharing, facial and armpit shaving from barbers and carelessness during injuries.

Genotypes
Hepatitis B virus exists in eight different genotypes (A-H) and its prevalence differs with differs by geography and ethnicity [95]. Ten different studies (Table 5) conducted at different regions of Pakistan showed that the most prevalent HBV genotype in Pakistan is genotype D with overall prevalence rate of 63.71% followed by genotype A (10.036%), genotype C (7.55%) and genotype B (5.335%) while untypable and mixed genotypes were 2.377% and 9.931%, respectively [1,7,8,87,[97][98][99][100][101][102]. The most detailed study recently conducted by Awan et al. [96] showed that the most emerging genotype in Pakistani population is genotype C with the prevalence rate of 27.66%, which is a bad news as it is more common in cirrhotic patients and is known to be associated with more severe liver diseases. Moreover, Previous studies also shows that genotype D have more severe disease, less responsive to interferon therapy as compared to genotype A and B and have higher HBV DNA levels. This genotype also has specific viral sequence patterns that may predict long-term response to lamivudine treatment [101]. However, further studies are needed to characterize prevalence of different genotypes, their relative severity and treatment response rates in Pakistani population.

Risk factors associated with HBV infection
History of dialysis for more than 2 years is a risk factor for dialysis patients [90]. Major risk factors for mother to infant transmission include increasing maternal age, number of pregnancies, repeated injections and addiction [51]; major risk factors in surgical patients include re-use of contaminated syringes, contaminated surgical instruments and blood products [59]; risk factors in pregnant women (antenatal) include ear and nose prick, history of jaundice among them or with their partner [49], history of blood transfusions, history of injections   ; in children key risk factors were injection in the past, surgical and dental procedures, blood transfusion, accidental cuts at barber shops and umbilical cord cut through unsterilized instruments at home [102]; in thalassaemic children there is a definite risk factor of repeated blood transfusion [79], while main risk factors among the obstetrical and gynecological population were unsafe surgery, injections and inadequately screened blood transfusions [45]. Qureshi et al. [103] compared male patients suffering from chronic hepatitis with healthy people as control and found very strong relationship of the HBV infection with history of dental treatment, surgery and history of taking injections. It is established fact that HBsAg does not cross the placental barrier however; the infection in children/ newborns may occur at the time of birth or soon after birth. The infants of HBV positive mothers must be vaccinated soon after birth and HBIG immediately within 24 hours of birth [54]. Relatively low prevalence in the female prostitutes (high risk group) reflects the effect of legal, social and religious constraints in Pakistani society [56]. Many of the Afghan refuges (most of them are children) are rag pickers who collect used syringes and needles dumped outside the hospitals and hence are one of the most vulnerable groups to viral hepatitis in Pakistan [104]. Most of these factors are easily preventable and need awareness in general population and the healthcare workers. Preventive strategies for HBV infection include healthy blood transfusion services along with safe sex [34], vaccination against HBV [40,103], shaving by barbers needs to be discouraged [103] and better training of healthcare workers [105]. Paid blood donation should be prohibited [85]. All patients needing surgery should be screened for viral hepatitis and there should be separate operation theatres facilities for these patients [94]. In addition reuse of razors in many barber shops that may spread hepatitis in a substantial number of individuals [106] and must be discouraged. Importantly, the most common risk factors and modes of HBV transmission in this country differ in importance in various community groups [23].
In Turkish population, HLA-A24 and Cw1 has been associated with low risk for HBV-related chronic liver disease and HLA-B13, B8, DR7, DR13 and DQ3 were found associated with high risk for chronic HBV infection [107]. However, there is no study that describes cellular or molecular mechanism of HBV infection in Pakistani population. Ali et al. [113] reported that 78.8% of the rural population of Faisalabad was unaware of viral hepatitis. In another study, Asif et al. [114] reported that only 17.6% of the rural population of Nowshera was aware of the fact that Hepatitis B and C are transmitted by a virus. Talpur et al. [115] stated that there is significant lack of knowledge and poor attitude towards HBV and HCV in surgical patients at Nawabshah area. We suggest aggressive public awareness programs especially in rural areas and people at high risk to decrease the burden of HBV infection in Pakistan.