| Abstract|| |
Hepatitis B is the leading cause of chronic viral hepatitis across the world, especially in developing countries. Over 400 million people across the world are estimated to be harboring the infection. This section highlights a few important published articles on hepatitis B viral infection and discusses the significance of the results and conclusions of these articles. It is hoped that this review would enable treating physicians and students to comprehend the significance of these specially selected articles better, which should result in better understanding and management of patients with chronic hepatitis B viral infection.
Keywords: Hepatitis B, ultrasonography, cirrhosis, genotype A, genotype D, health care worker, immunization, insulin resistance, hepatic steatosis, lamivudine, entecavir, natural history, resistance
|How to cite this article:|
Piramanayagam P, Choudhuri G, Singh SP. Hepatitis B: News from the research world. Hep B Annual 2008;5:146-62
| Introduction|| |
Hepatitis B viral infection continues to be a major health problem across the world and over 400 million people are estimated to be harboring the infection. Although research on hepatitis B viral infection has added considerably to our understanding of the viral and host dynamics as well as treatment of chronic hepatitis B, a lot more remains to be achieved before we can hope to conquer this virus.
Research on this topic continues to toss up new information that helps us understand and manage this infection better. In this chapter, we have selected nine articles on hepatitis B viral infection from the many published in 2008. These articles enhance our understanding of the basic nature of this infection, throw new light on the natural history of this infection, or help us treat patients with chronic infection better. After each abstract, relevant comments have been added to highlight the reasons for selecting the article for this review. It is hoped that this review would enable physicians and students comprehend the significance of these special articles.
Chen YP, Dai L, Wang JL, Zhu YF, Feng XR, Hou JL. Model consisting of ultrasonographic and simple blood indexes accurately identify compensated hepatitis B cirrhosis. J Gastroenterol Hepatol. 2008;23:1228-34.
Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
Background and Aim: Several models for significant fibrosis or cirrhosis have been introduced for hepatitis C, but are seldom for hepatitis B. The present study retrospectively evaluates the relationship between ultrasonography (USG), blood tests and fibrosis stage to construct a model to predict compensated cirrhosis. Methods: A total of 653 patients with chronic hepatitis B who underwent liver biopsies, USG scanning and routine blood tests were retrospectively analyzed. The patients were divided into model set and validation set. Blood tests and USG indexes were analyzed statistically. An USG scoring system included liver parenchyma, gallbladder and hepatic vessel; splenomegaly was introduced. Results: There were significant differences between cirrhosis and other fibrosis stages in USG indexes of liver parenchyma, gallbladder, hepatic vessel, and splenomegaly. USG scores were significantly different between F4 and other fibrosis, and significantly correlated with fibrosis stage. Apart from alanine aminotransferase and alkaline phosphatase, blood tests and patient's age were correlated with fibrosis and found significantly different between patients with and without cirrhosis. The model for cirrhosis indexes which included USG score, patient's age, and variables including platelet, albumin, and bilirubin predicted cirrhosis with area under receiver-operator curve of 0.907 in the model set and 0.849 in the validation set. Using proper cut-off values, nearly 81% patients could be accurately assessed for the absence or presence of cirrhosis. Conclusion: The model with USG score, age of patient, blood variables of platelet, albumin, and bilirubin can identify hepatitis B cirrhosis with a high degree of accuracy. The application of this model would greatly reduce the number of biopsies.
Histology is the gold standard for diagnosis of chronic liver disease stage. However, since liver biopsy is invasive and can sometimes cause life threatening complications, researchers are constantly searching for an alternative simple, inexpensive and non- or minimally invasive method to assess the stage of chronic liver disease. There are a good number of studies attempting to diagnose cirrhosis or severe fibrosis in patients with chronic hepatitis C using blood tests and other simple indices with a reasonable sensitivity and specificity. However, similar studies on chronic HBV infection are scarce. In this article, Chen et al. have reported a novel model to predict compensated cirrhosis due to hepatitis B virus (HBV) infection using the findings of USG examination of liver and blood tests. They have combined the USG findings of liver, patient's age, blood platelet count, serum albumin and bilirubin levels to construct their model for cirrhosis index. Surprisingly, employing their novel model, the researchers could diagnose cirrhosis with a sensitivity of 81%, and specificity of 83%. Besides, importantly, the researchers had included only patients with early cirrhosis. Although the model appears to be a very useful non-invasive method to diagnose early cirrhosis due to HBV infection, this new model has to be validated and confirmed by others in a large group of chronic Hepatitis B patients. This could then be used to effectively screen and predict compensated cirrhosis, and obviate the need for liver biopsy in these patients. Besides, this is important for a clinician because the distinction of early compensated cirrhosis from precirrhotic chronic hepatitis due to HBV infection is important to decide the timing of antiviral therapy against HBV infection in order to prevent progression to uncompensated cirrhosis in patients with elevated serum alanine aminotransferase (ALT).
Wang CC, Hsu CS, Liu CJ, Kao JH, Chen DS. Association of chronic hepatitis B virus infection with insulin resistance and hepatic steatosis. J Gastroenterol Hepatol 2008;23:779-82.
Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
Background and Aim: Chronic viral infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may decrease tissue response to insulin, thereby causing insulin resistance. In addition, insulin resistance is associated with hepatic steatosis. However, whether these phenomena hold true for chronic hepatitis B virus (HBV) infection remains largely unknown. The present study therefore aimed to investigate the association of chronic HBV infection with insulin resistance and hepatic steatosis. Methods: A total of 507 subjects (243 men and 264 women; mean age 46.56 years) less than 60-years-old attending a health examination center were enrolled in the study. All the subjects were negative for antibodies against HCV and consumed less than 140 g alcohol/week. Demographic, anthropometric, clinical, and laboratory data were obtained for each subject. Insulin resistance index was determined using homeostasis model assessment (HOMA-IR). Hepatic steatosis was identified by ultrasound examination. Results: Of the 507 subjects, 50 (9.9%) were positive for hepatitis B surface antigen (HBsAg) and designated HBV carriers. All variables were comparable between HBV carriers and non-HBV carriers; only HBV carriers had significantly higher serum alanine aminotransferase and aspartate aminotransferase levels (P < 0.05). By multivariate linear regression, HBV carriers were not associated with insulin resistance. In addition, multivariate regression analyses showed that HBV carriers were not associated with the presence of ultrasonographic fatty liver. Conclusions: Chronic HBV infection does not seem to be associated with insulin resistance or hepatic steatosis in HBV carriers.
Hepatic steatosis is observed in at least one-quarter of individuals with chronic hepatitis B. In this context, it is important to understand the relationship between hepatic steatosis and chronic hepatitis b viral infection. In this study from Taiwan, the investigators attempted to study the association of chronic HBV infection with insulin resistance and hepatic steatosis, and observed that the indices of insulin resistance (HOMA-IR) were similar in both groups. Further, multivariate logistic regression analyses demonstrated that positive HBsAg status was also not identified as an independent predictor of fatty liver or insulin resistance. However, the investigators found strong correlations between hepatic steatosis and insulin resistance, BMI and triglyceride levels, as expected in the subjects with NAFLD. These findings are in line with other reports in patients with chronic hepatitis B that show an association between steatosis and insulin resistance. It would therefore be reasonable to conclude that host factors underlie hepatic fat accumulation in these patients who are HBsAg positive and, unlike chronic hepatitis C, chronic hepatitis B infection is not a disorder with heightened insulin resistance. However, it is also important to understand the impact of fatty liver on the natural history of chronic hepatitis B, and longitudinal studies on the impact of fatty liver on the natural history of chronic hepatitis B are lacking; prospective studies are needed to address this important issue.
Suzuki F, Toyoda J, Katano Y, Sata M, Moriyama M, Imazeki F, Kage M, Seriu T, Omata M, Kumada H. Efficacy and safety of entecavir in lamivudine-refractory patients with chronic hepatitis B: randomized controlled trial in Japanese patients. J Gastroenterol Hepatol 2008;23:1320-6.
Department of Hepatology, Toranomon Hospital, Tokyo, Japan
Background and Aim : Entecavir is a potent inhibitor of both wild-type and lamivudine-resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double-blind, multicenter study in Japan (ETV-052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine-refractory chronic hepatitis B infection. Methods: Eighty-four patients with chronic hepatitis B who were refractory to lamivudine therapy were switched from lamivudine to daily oral doses of 0.5 mg entecavir (41 patients) or 1 mg entecavir (43 patients) for 52 weeks. Results: The proportions of patients achieving the primary end-point (>or=2 log (10) reduction in HBV-DNA from baseline by polymerase chain reaction assay or undetectable HBV-DNA levels [<400 copies/ mL] at week 48) were 90 and 93% for entecavir 0.5 mg and 1 mg, respectively, with 33% of patients in each dosing group achieving < 400 copies/mL. The mean reduction in HBV-DNA from baseline was 3.58 and 3.75 log (10) copies/mL for entecavir 0.5 mg and 1 mg, respectively. High proportions of patients achieved alanine aminotransferase normalization at week 48 (0.5 mg 86%, 1 mg 78%). Histological improvement was observed in most patients (0.5 mg 52%, 1 mg 60%). Virological breakthrough (increase in HBV-DNA of >or=1 log (10) copies/mL from nadir) was observed in one patient but was not associated with selection of entecavir-associated resistance substitutions. Entecavir was well tolerated with no patients discontinuing study drug due to adverse events. Conclusions: These findings indicate that entecavir is safe and effective for the treatment of Japanese adults with lamivudine-refractory chronic hepatitis B.
Despite the development of novel antiviral agents, management of antiviral drug resistance has emerged as a major challenge in the management of patients with chronic hepatitis B. Emergence of resistant HBV strains leads to virological and biochemical breakthrough, and can further result in histological improvement deterioration during treatment, hepatic decompensation and death. In this article, Suzuki et al. have reported the results of a phase II randomized, double-blind trial comparing the efficacy and safety of 0.5 mg and 1 mg entecavir switch therapy in patients with chronic hepatitis B with confirmed genotypic lamivudine resistance. After 48 weeks of entecavir therapy, 90 and 93% of patients treated with 0.5 mg and 1 mg respectively achieved either a 2 log10 or more reduction in viral load from baseline or undetectable hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR).
Ideally, such studies should aim at achieving an undetectable viral load by sensitive PCR assays as a primary endpoint (less than 400 copies/mL). In hepatitis B e antigen (HBeAg)-positive patients, a complete virological response should be defined by achievement of undetectable viral load by PCR, together with biochemical response and HBeAg seroconversion. However, in this study, although rapid viral load reduction was achieved with the 1 mg dose for both groups, only one-third of the patients achieved undetectable viral load levels by PCR at week 48. Further, HBeAg seroconversion was similar (15-17%) in both groups. and a complete response was achieved in about 15% patients only. On-therapy virological breakthrough was observed in only one patient and was not attributable to the selection of recognized substitutions associated with entecavir resistance. However, routine sequencing was not performed on patients who failed to achieve the primary end-point by week 24. Patients with partial or inadequate responses at week 24 may be at increased risk of developing antiviral resistance and should be considered for additional therapy. It remains possible that patients in this study may already harbor mutations associated with entecavir resistance; it will be important to observe whether the initial responses reported here can be maintained for a longer term. Researchers have also reported data for week 48 with entecavir switch therapy in patients with confirmed lamivudine resistance. However, these patients require long-term antiviral therapy, and obviously no long-term conclusions can be drawn from the data. Previous experience with nucleoside monotherapy has revealed an alarming total of cumulative resistance rates. Hence, while the rate of antiviral resistance may initially be low, once established, a progressive rise in rates of resistance would be expected to occur. Once antiviral resistance is determined the initiation of salvage 'add on' treatment is dependent on the understanding of nucleos(t)ide analog resistance patterns. In vitro studies demonstrate that entecavir is less effective against lamivudine-resistant HBV strains in comparison to wild-type: 20-30-fold higher concentrations are required for polymerase inhibition. This is because lamivudine resistance already preselects two of the three mutations required for entecavir resistance. Virological breakthrough to entecavir requires at least three substitutions. Accumulating evidence from these settings suggest that entecavir switch is not an optimal treatment for patients with lamivudine resistance.
Baldick CJ, Eggers BJ, Fang J, Levine SM, Pokornowski KA, Rose RE, et al. Hepatitis B virus quasispecies susceptibility to entecavir confirms the relationship between genotypic resistance and patient virologic response. J Hepatol 2008;48:895-902.
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
Background/Aims : The efficacy of anti-viral therapy for chronic hepatitis B virus (HBV) is lost upon the emergence of resistant virus. Using more than 500 patient HBV isolates from several entecavir clinical trials, we show that phenotypic susceptibility correlates with genotypic resistance and patient virologic responses. Methods : The full-length HBV or reverse transcriptase gene is amplified from patient sera, sequenced, and cloned into an HBV expression vector. Entecavir susceptibilities of individual virus clones and patient quasispecies populations are analyzed in conjunction with the sequenced resistance genotype and the patient's virologic response. Results : Entecavir susceptibility decreased approximately eight-fold for isolates with various constellations of lamivudine resistance substitutions. The spectrum of additional substitutions that emerged during therapy, at residues rtT184, rtS202, or rtM250, displayed varying levels of entecavir susceptibility according to the specific resistance substitutions and the proportion of resistant variants in the quasispecies. Phenotypic analyses of samples associated with virologic breakthrough confirmed the role of these residue changes in entecavir resistance. Additional longitudinal phenotypic analyses showed that decreased susceptibility correlated with both genotypic resistance and increased circulating HBV DNA. Conclusions : HBV phenotypic analysis provides additional insight as part of a resistance monitoring program that includes genotypic analysis and quantification of circulating virus.
In this article, Baldick et al. present a comprehensive phenotypic analysis of 511 patient isolates collected from clinical trials of ETV therapy in nucleoside-naύve and in LVD-refractory hepatitis B patients.
The authors first investigated the correlation between genotypic resistance and ETV susceptibility using laboratory clones, and subsequently repeated the same studies using patient-derived clones. They observed that laboratory clones with rtM204V and rtL180M substitutions exhibited an eight-fold reduced ETV susceptibility. Further addition of rtT184L, rtS202G or rtM250V substitutions reduced ETV susceptibility by approximately 100-fold relative to wild-type HBV. Besides, in their study, they also showed that patient-derived clones displayed a similar relationship between genotypic and phenotypic resistance as compared to laboratory clones; however it was observed that the variability in ETV susceptibility was greater with patient derived clones. The implication of this observation is that phenotypic confirmation of newly identified putative drug-resistant mutations can be performed more expeditiously using laboratory clones as compared to phenotypic assays which are very cumbersome.
An important contribution of this study is the data on analysis of isolates from patients with virologic breakthrough but no detectable substitutions at rt184, 202 and 250 indicating that virologic breakthrough in these patients is probably due to non-compliance of medication and not due to unidentified mutations.
What is the implication of this observation on chronic hepatitis B management with nucleos(t)ide analogues?
In clinical practice, serum HBV DNA monitoring is the most practical method to detect virologic breakthrough, and in patients with virologic breakthrough, testing for genotypic resistance should be performed. Necessary modification should be instituted in patients found to have signature resistance mutations and medication compliance should be reinforced in patients with no detectable resistance mutations.
Kim SU, Han KH, Nam CM, Park JY, Kim do Y, Chon CY, Ahn SH. Natural history of hepatitis B virus-related cirrhotic patients hospitalized to control ascites. J Gastroenterol Hepatol 2008;23:1722-7.
Department of Internal Medicine, Yonsei University, College of Medicine, Seoul, South Korea
Background and Aim : Few studies have assessed the natural history of hepatitis B virus (HBV)-related cirrhotic ascites. We investigated the natural history of patients with HBV-related cirrhotic ascites hospitalized to control ascites and determined their prognosis, including survival rates and prognostic factors affecting survival. Methods : Between January 1996 and December 2005, 203 consecutive patients with HBV-related cirrhotic ascites were followed for a median of 80.7 months (range15-149) after their first significant ascitic decompensation that required hospitalization. Results : The mean age of all patients was 52.6 years. Male gender predominated (male/female, 138/65). A subgroup analysis of 165 patients who had ascitic decompensation as their first episode of hepatic decompensation revealed that gastrointestinal variceal bleeding developed after a median interval of eight months following ascitic decompensation in 31 (18.8%) patients, hepatic encephalopathy occurred at nine months in 53 (32.1%), spontaneous bacterial peritonitis appeared at 12.7 months in 24 (14.5%), hepatorenal syndrome occurred at 8.1 months in five (3%), and hepatocellular carcinoma was observed at 21.2 months in 10 (6.1%). The overall median survival was 12.4 months. The one and three-year survival rates were 50.7 and 18.7%. The prognostic factors that independently correlated with survival at the time of ascitic decompensation were Child-Pugh classification B/C (P = 0.030), serum white blood cell (WBC; P = 0.035), serum creatinine (Cr; P = 0.039), serum sodium (Na; P = 0.010), and antiviral therapy (P = 0.040). Conclusions : The prognosis of HBV-related cirrhotic patients with ascitic decompensation is poor. Child-Pugh class, serum WBC/Cr/Na, and antiviral therapy primarily influenced survival.
Guidelines for management of chronic hepatitis B should be based on natural history. However, the natural history of HBV-related cirrhosis and prognostic factors after the first episode of hepatic decompensation is less well known. HBV-related cirrhosis of the liver eventually progresses from the compensated to the decompensated phase which is characterized by ascites, variceal bleeding, encephalopathy and/or jaundice. Unfortunately, details of the natural history and the prognostic factors associated with disease progression after the onset of ascites remain to be elucidated.
In this article, published in the Journal of Gastroenterology and Hepatology, Dr. Kim and colleagues provide the natural history of hepatitis B cirrhosis following the first episode of ascites. Two hundred and three consecutive patients with HBV-related cirrhotic ascites were followed for a median of 81 months after the first significant episode of ascites requiring hospitalization; 19% developed gastrointestinal variceal bleeding after a median of 8.0 months, 32% developed hepatic encephalopathy at 9.0 months, 15% developed spontaneous bacterial peritonitis (SBP) at 13 months, 3.0% developed hepatorenal syndrome (HRS) at 8.1 months and 6.1% developed HCC at 21 months. While the median survival was 12 months, the one and three-year survival rates were 51 and 19%, respectively. Child-Pugh class, white blood cell (WBC) count, serum creatinine, serum sodium and antiviral therapy were the independent factors that influenced survival. While the study demonstrated that lamivudine therapy improved survival and influenced outcome in patients after the appearance of ascites, (which is in agreement with earlier reports), contrary to other studies, Dr Kim et al. also showed that detectable HBV DNA did not influence survival statistically. This difference might be attributable to the uncontrolled nature of the study.
A very important finding in this article is that most cirrhotic complications such as hepatic encephalopathy, variceal bleeding, SBP, and HRS are likely to develop within a year of ascitic decompensation. On the basis of these results, patients with ascites should be carefully monitored to determine the optimal time for liver transplantation. Besides, the results of this study can be used to design and carry out case-control or cohort studies which could further unravel the role of ascites volume and response to diuretics for prognosis in HBV-related cirrhotics. Randomized controlled trials can also be done to develop treatment paradigms that achieve early and continued suppression of serum HBV DNA, in renewed attempts to either prevent the occurrence of decompensated cirrhosis or impede its progression.
Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R, Bose S. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology 2008;134:1376-84.
Department of Gastroenterology, G. B Pant Hospital, New Delhi, India
Background and Aims : There is a paucity of data on hepatitis B virus (HBV) DNA levels and histologic lesions in patients with chronic HBV (CHBV) infection and persistently normal alanine aminotransferase (ALT) levels (PNALT). We studied the ALT, HBV DNA levels, and spectrum of histologic lesions in such patients. Methods : The study included 1387 incidentally detected asymptomatic hepatitis B surface antigen (HBsAg)-positive patients with ≥1-year follow-up and either PNALT (n = 189; hepatitis B e antigen [HBeAg(+)], 73; HBeAg(-), 116) or persistently or intermittently elevated ALT (PIEALT; n = 1198; HBeAg(+), 530; HBeAg(-), 668). Results: In the PIEALT and PNALT patients, baseline DNA ≥5-log copies/mL was seen in 73.8% and 60.3% in HBeAg(+) (P = 0.018) and 76% and 35.3% in HBeAg(-) (P < .001) patients and histologic fibrosis stage ≥2 in 65.5% and 40.2% in HBeAg(+) (P < .001) and 63.9% and 13.8% in HBeAg(-) (P < .001) patients, respectively. Approximately 21% of HBeAg(-) patients with PNALT and HBV DNA <5-log copies/mL had histologically active liver disease (histologic activity index ≥3 and/or fibrosis stage ≥2). Conclusions: A fair proportion of patients with CHBV infection with PNALT have HBV DNA ≥5-log copies/mL and significant histologic fibrosis. Use of ALT and HBV DNA levels without resorting to liver biopsy to define "inactive carrier state" in HBeAg (-) PNALT patients may miss histologically significant disease in a proportion of patients.
This study from India stresses the fact that labeling of HBV infected patients as "inactive carriers" based on ALT and HBV DNA levels may be misleading since a significant proportion of cases with normal ALT and low HBV DNA may have advanced liver disease if liver biopsy is performed. In the light of this article, would it be fair to withhold biopsy on the basis of normal ALT and low HBV DNA levels in asymptomatic HBV infected patients?
The study also questions lowering of the ALT cut off level to differentiate the really "inactive carriers" from those with active disease, with histological damage, who need to be treated.
Madan K, Batra Y, Jha JK, Kumar S, Kalra N, Paul SB, Singh R, Duttagupta S, Panda SK, Acharya SK. Clinical relevance of HBV DNA load in patients with chronic hepatitis B infection. Trop Gastroenterol 2008;29:84-90.
Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
Background: Hepatitis B virus (HBV) DNA detection and quantification play an increasing role in the assessment of disease activity and response to therapy. However, viremia levels which define various stages of HBV infection have not yet been established. Aim: To define viremia levels which describe various chronic hepatitis B virus (CHB) infection stages. Methods: In a retrospective study, stored sera samples of CHB infected patients registered at AIIMS liver clinic, from January 1996 to June 2005 were subjected to competitive, quantitative PCR analysis. Results: The median HBV DNA load was lowest among carriers and highest among patients with chronic hepatitis B [0 (0-8) vs. 7 (0-12) log10 copies/ml, respectively; p<0.05]. As compared to chronic hepatitis patients the DNA load was also lower among cirrhotics [7 (0-12) vs. 4.5 (0-8) log10 copies/ml, respectively; P<0.05] and hepatocellular cancer patients [7(0-12) vs. 0 (0-8) log10 copies/ml, respectively; P<0.05]. Patients with carriers had a DNA load which was significantly lower than e antigen negative CHB [0 (0-8) vs. 6 (0-10) log10 copies/ml; P<0.05] or e antigen positive CHB [0 (0-8) vs. 8 (0-12) log10 copies/ml; P<0.05]. A threshold of 3.5 log10 copies/ml had sensitivity and specificity of 83% and 58% respectively in differentiating carriers from e antigen negative CHB. There was a strong positive correlation of HBV DNA load with inflammatory grade (R=0.334; p=0.0001), fibrosis stage (R=0.276; P=0.001) and ALT levels (R=0.378; P=0.0001). About 82% (9/11) of those who lost e antigen showed a decline in HBV DNA level to <5 log10 copies/ml, whereas only 12.5% (1/8) of those who did not lose e antigen had a decline in DNA load below this level. Conclusions: HBV DNA viremia levels correlate positively with the inflammatory grade, fibrosis stage and ALT levels. Loss of e antigen shows a decline in the DNA load to below 5 log10 copies/ml in most patients. Further prospective studies employing repeated measurements are required to define a threshold to differentiate between HBV carriers and e antigen negative CHB.
HBV DNA detection and quantification form an integral part of diease assessment; of disease activity and response to therapy in chronic hepatitis B patients. This retrospective Indian study emphasizes the positive correlation between HBV DNA levels and inflammatory grade, fibrosis stage and ALT levels in patients with chronic hepatitis B. The study further highlights its finding that most patients who lose e antigen have a decline in DNA load to below 5 log 10 copies/ml, and also attempts to differentiate between "inactive HBV carriers" and e antigen negative chronic hepatitis B using HBV DNA threshold of 3.5 log10 copies/ml; although this threshold had a sensitivity of 83%, the specificity was quite low (58%). The authors rightly conclude that further prospective studies employing repeated HBV DNA measurements are required to define a suitable threshold to differentiate between HBV carriers and e antigen negative CHB.
Sukriti, Pati NT, Sethi A, Agrawal K, Agrawal K, Kumar GT, Kumar M, Kaanan AT, Sarin SK. Low levels of awareness, vaccine coverage, and the need for boosters among health care workers in tertiary care hospitals in India. J Gastroenterol Hepatol 2008;23:1710-5.
Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
Background and Aim: The risk of acquiring HBV infection through exposure to blood or its products is highest amongst health care workers (HCWs). Despite potential risks, a proportion of HCWs never gets vaccinated. India is second to China in the number of people with chronic HBV. This study aimed to investigate the vaccination practices and prevalence of HBV infection in HCWs in India. Methods: A total of 2162 HCWs were screened for the presence of serological markers of HBV and hepatitis C virus (HCV). Occult HBV infection was tested by detection of HBV-DNA for surface and core regions by nested polymerase chain reaction in HBsAg-negative and IgG anti-hepatitis core antigen-positive subjects. Results: Only 1198 (55.4%) of the 2162 HCWs screened had been vaccinated; and 964 (44.6%) were not vaccination-status conscious; of these HCWs, 600 (27.7%) had never been vaccinated and 364 (16.4%) were unaware of their vaccination status. Protective (> 10 IU/mL) anti-hepatitis B surface (anti-HBs) antigen titers were seen in only 61.7%. The anti-HBs titers were found to be lower with the passage of time; the median anti-HBs titers in subjects who were vaccinated > 10 years ago were significantly lower than those who had been vaccinated < 5 years ago (P < 0.001). One per cent of HCWs were HBsAg-positive, and 24.7% of 700 HCWs screened had past exposure (IgG-anti-HBc-positive). Occult HBV was detected in five per cent of 120 positive subjects with past exposure; all had anti-HBs titers > 10 IU/mL. Conclusions: Even today, 28% HCWs in India are unvaccinated and 17% are unaware of their vaccination status. This data suggests that use of hepatitis B immune globulin be mandatory in needle-pricked HCWs in India, and that implementation of awareness strategies is urgent. Since the anti-HBs titers decline in a fair proportion, there is justification for a booster dose of vaccine 10 years after primary vaccination to HCWs in India.
In this article, Sukriti et al. have reported on hepatitis B virus [HBV] vaccine coverage, duration of protective anti-HBs levels (>10 IU/mL), exposure frequencies and rates of HBV infection among HCWs in four large tertiary-care hospitals in North India. The study revealed that while only 55% of the HCW were vaccinated and 28% were never vaccinated, 17% were surprisingly not only unvaccinated but also unaware about the need for HBV vaccination. This is very pathetic since HCWs are at high risk for HBV infection because of exposure to infected blood and body fluids, particularly percutaneous injuries. In all developing countries, where HBV prevalence rate is higher, HBV vaccination rates among HCW have been reported to be unsatisfactory. Besides, in these countries, paramedics were more often unaware of HBV/HCV transmission resulting in lower HBV vaccination rate than doctors. Universal precautions too are suboptimal among HCW in these countries. In contrast, in economically advanced countries, a lower HBV prevalence, better HBV vaccine coverage among HCW, and optimal practice of universal precautions has reduced rates of HBV infection among HCW markedly. This study has aptly highlighted the need to focus our attention on HCWs especially paramedics who should be counseled at the time of entry into their training programs.
However, their recommendation that HCWs should be administered a booster dose after 10 years of initial HBV vaccination is controversial and not supported by any evidence. This is also in contravention to the recommendations of the European Consensus Group on Hepatitis B Immunity and the Steering Committee for the Prevention and Control of Infectious Disease in Asia (where HBV prevalence is high), who have neither recommended booster vaccination for HCW, nor recommended passive-active immunization for post-exposure prophylaxis to HCW vaccinees up to 15 years after primary HBV vaccination. Finally, protection against HBV in HCW has been documented after 15-18 years of HBV vaccination without any booster or post-exposure prophylaxis.
Studies have shown that when HCWs are followed up for 15 years after HBV vaccination, although 30% had no detectable anti-HBs they possess B-cell memory as documented by either an amnestic antibody response or positive enzyme-linked immunosorbent spot results. Further, long-term studies in hyper-endemic areas have demonstrated that immunological memory remains intact for over 10 years post vaccination, so that initial vaccination confers protection against HBV infection even after anti-HBs declines below detectable levels. Hence the recommendation on booster vaccination does not appear sustainable.
Madan K, Batra Y, Sreenivas V, Mizokami M, Tanaka Y, Chalamalasetty SB, Panda SK, Acharya SK. HBV genotypes in India: do they influence disease severity? Hepatol Res 2009;39:157-63.
Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
Aims: Association of HBV genotypes (especially A and D) with severity of liver disease is controversial. We studied the influence of HBV genotypes on liver disease severity among Indian patients. Methods: We selected 247 HBV infected patients (42 acute hepatitis, 87 carriers, 44 chronic hepatitis B[CHB], 35 liver cirrhosis [LC] and 40 hepatocellular carcinoma [HCC]). Genotyping of stored sera was performed using genotype-specific enzyme-linked immunosorbent assay (ELISA) and restriction fragment length polymorphism (RFLP). The distribution of genotypes in disease states of differing clinical, histological and biochemical severity were compared. Results: The most common genotype was D (162/237, 68.3%), followed by A (61, 25.7%) and C (14, 5.9%). The distribution of HBV genotypes between patients with acute hepatitis and CHB (carriers + CHB + LC + HCC), or between carriers and disease states (CHB + LC + HCC), or between mild chronic infection (carriers + CHB) and complications of chronic HBV infection (LC + HCC) was similar. Eighty-seven patients had liver biopsy; the median histological activity index (HAI) and fibrosis stage at baseline were similar between genotype groups (four (1-9) genotype A [n = 28]), three (2-4) genotype C (n = 4) and four (1-10) genotype D (n = 55); P = 0.33 for HAI score; (0.5 (0-6) genotype A, 0.5 (0-4) genotype C and 1 (0-6) genotype D; P = 0.92 for fibrosis stage). Response to therapy was similar between the genotypes. Conclusion: Clinical, histological severity and therapeutic responses are similar among patients with HBV genotypes A and D.
This is a very interesting study on the association of HBV genotypes with severity of liver disease in the Indian population which harbors roughly 10% of the world's HBV infected population. Two earlier studies from Delhi and Lucknow in Northern India had earlier produced conflicting opposing results. While Prof. Sarin's study associated genotype D with more severe and progressive disease, the study from Lucknow concluded that genotype A was more often associated with ALT elevation, HBeAg positivity, absence of anti-HBe and cirrhosis of liver than was genotype D. Paradoxically, the study from Prof. Acharya and workers from New Delhi failed to show any influence of the two frequent Genotypes [A and D] in determining either the disease severity or response to antiviral therapy. The result of this study which has larger number of patients than the earlier studies highlights the problems with conclusions based on small numbers. It is clear that we need further prospective data, preferably pooled from all over the country, before any meaningful conclusions can be made on this issue. The analyses should also take into account other variables, especially viral load on the severity, outcome and response to therapy.
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014
Source of Support: None, Conflict of Interest: None