HEPATITIS B NEWS
Year : 2009 | Volume
: 6 | Issue : 1 | Page : 141--156
Hepatitis B: News from the research world
Paramasivan Piramanayagam1, Gourdas Choudhuri1, Shivaram Prasad Singh2,
1 Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014, India
2 Department of Gastroenterology, Sriram Chandra Bhanja Medical College, Cuttack - 753 007, India
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014
Despite the development of an effective vaccine, hepatitis B is still the leading cause of chronic viral hepatitis across the world, especially in developing countries, with over 400 million people across the world estimated to be harboring the infection. This section of the journal highlights a few important articles on hepatitis B viral infection published recently and discusses the significance of their results and conclusions. We do hope that this review would enable treating hepatologists, physicians and students to comprehend the significance of these specially selected articles better, which would result in better comprehension and management of different aspects of chronic hepatitis B viral infection encountered in clinical practice.
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Piramanayagam P, Choudhuri G, Singh SP. Hepatitis B: News from the research world.Hep B Annual 2009;6:141-156
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Piramanayagam P, Choudhuri G, Singh SP. Hepatitis B: News from the research world. Hep B Annual [serial online] 2009 [cited 2020 Sep 28 ];6:141-156
Available from: http://www.hepatitisbannual.org/text.asp?2009/6/1/141/76911
Despite the development of an effective vaccine, hepatitis B is still the leading cause of chronic viral hepatitis across the world, especially in developing countries, with over 400 million people across the world estimated to be harboring the infection. 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 with development of novel potent antiviral agents made available for treatment. However, a lot more remains to be achieved through not only research but also by generating public awareness and motivating governments before we can hope to conquer this virus.
Research on hepatitis B virus infection and its sequelae continues to toss up new information that helps us understand and manage HBV infection related problems better. In this chapter, we have selected nine articles on hepatitis B viral infection from the many articles published during the last 12 months. 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 an abstract of the article, critical appraisal relevant to the article's results and conclusions has been added. We hope that this review would enable physicians, students and everyone involved in research on HBV and management of HBV infection appreciate the significance of these special articles.
McMahon BJ, Dentinger CM, Bruden D, Zanis C, Peters H, Hurlburt D, et al. Antibody levels and protection after hepatitis B vaccine: Results of a 22-year follow-up study and response to a booster dose. J Infect Dis 2009;200:1390-6.
Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
The duration of protection in children and adults (including health care workers) resulting from the hepatitis B vaccine primary series is not clear. The authors decided to determine the long-term protection afforded by hepatitis B vaccine, and Alaska natives who were administered plasma-derived hepatitis B vaccine when they were >6 months of age were tested for antibody to hepatitis B surface antigen (anti-HBs) after 22 years. Besides, those who had levels of <10 mIU/mL were further administered one dose of recombinant hepatitis B vaccine and were evaluated on the basis of anti-HBs assay at 10-14 days, 30-60 days, and after 1 year. It was seen that of the 493 participants, 60% (298) had an anti-HBs level ≥10 mIU/mL. A booster dose was administered to 164 persons, and 77% responded with an anti-HBs level ≥10 mIU/mL at 10-14 days, reaching 81% by 60 days. Response to the booster dose correlated positively with younger age, peak anti-HBs response after primary vaccination, and the presence of detectable anti-HBs before boosting. Considering persons with an anti-HBs level ≥10 mIU/mL at 22 years and those who responded to the booster dose, protection was demonstrated in 87% of the participants. No new acute or chronic hepatitis B virus (HBV) infections were identified.
The authors concluded that the protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 22 years. Booster doses are not needed.
This is a landmark study on the long-term efficacy of hepatitis B vaccination programs and provides much awaited answer to the need for booster vaccination for hepatitis B. When this cohort referred to in this study was recruited in 1981, HBV infection was hyperendemic among Alaskan natives with a prevalence of HBsAg of 8.2%. However, the introduction of hepatitis B vaccination as a routine childhood immunization coupled with a large-scale catch-up program involving all age groups has virtually eliminated new hepatitis B infections in Alaska. Further, the incidence of acute symptomatic hepatitis B too has fallen from 1200 cases per 100,000 population in 1981 to 0 case per 100,000 population since 1994. A potential limitation of the study is that the population received the primary hepatitis B vaccination series with the plasma-derived vaccine, which is no longer used. However, since antibody response and vaccine effectiveness in this and other populations that received the plasma-derived vaccine are similar to those demonstrated in populations vaccinated with recombinant vaccines beginning in the late 1980s, these findings should be applicable to persons who received either vaccine type. However, the veracity of extending these findings to persons immunized with recombinant hepatitis B vaccines ideally needs confirmation by long-term studies similar to this one. The results of this study are highly relevant to health care workers, including those vaccinated with plasma-derived vaccine in the early 1980s, and to children and adolescents who were vaccinated during catch-up hepatitis B vaccination programs in the 1990s. In view of the strong evidence presented by this study, hepatitis B vaccine booster doses are not currently indicated.
Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology 2008;48:1460-6.
Victorian Liver Transplant Unit, Austin Health, Victoria, Australia
Prior to effective prophylaxis, liver transplantation for hepatitis B virus (HBV) related disease was frequently complicated by recurrence, which could be severe and rapidly progressive. Combination hepatitis B immunoglobulin (HBIG) and lamivudine prophylaxis reduces this rate of recurrence to <5% at 5 years; however, HBIG administration is costly and inconvenient. The authors conducted a multicenter randomized study of adefovir dipivoxil substitution for low-dose intramuscular (IM) HBIG in patients without HBV recurrence at least 12 months post-transplantation for HBV related disease. Thirty-four patients were randomized, 16 to adefovir (1 patient withdrew consent at 3 months and is not considered in the results) and 18 to continue HBIG. All the patients continued lamivudine. Groups were well matched by age, sex, and time since transplantation (median 4.5 years), and background virological risk for HBV recurrence (30% of patients in the adefovir group, 24% in the HBIG group having detectable HBV DNA at transplantation). All patients were alive at study completion without recurrence. One patient in the adefovir group became hepatitis B surface antigen positive at 5 months but was persistently HBV DNA undetectable via polymerase chain reaction (sensitivity 14 IU/mL) over the following 20 months. Median creatinine was not significantly changed over the course of the study in either group. One patient in the adefovir group with a background of diabetic and hypertensive nephropathy (baseline creatinine 150 ΅mol/L) developed increased creatinine leading to dose reduction and ultimately cessation of adefovir at 15 months. Yearly cost of combination adefovir/lamivudine prophylaxis was $8290 versus $13,718 IM HBIG/lamivudine. The authors concluded that compared with combination HBIG plus lamivudine prophylaxis, combination adefovir plus lamivudine provides equivalent protection against recurrent HBV infection, but with better tolerability and less cost.
Recurrence of hepatitis B occurred in up to 95% when liver transplantation was done for hepatitis B related liver disease. With introduction of post-transplant lamivudine and IV HBIG prophylaxis, the recurrence rates have reduced to 5% over 5 years. The duration of post-transplantation prophylaxis is unclear. So, the current practice is to continue lamivudine and HBIG prophylaxis indefinitely. This incurs huge cost of HBIG and monthly intravenous pricks for patients. This study was done to evaluate the efficacy of replacing HBIG with adefovir in preventing post-transplantation recurrence. All patients were treated with HBIG and lamivudine for at least 12 months post-transplantation and then were randomized to either lamivudine and adefovir or lamivudine and HBIG (IM). In this randomized controlled trial, none in either of the treatment groups had HBV recurrence (over a median follow-up of 4.5 years) as defined by detection of HBsAg and detectable HBV DNA. One patient in adefovir and lamivudine combination arm had HBsAg positivity but undetectable HBV DNA. One patient in adefovir arm developed progressively increasing creatinine requiring discontinuation of adefovir. This study proves the efficacy of combination antivirals in preventing HBV recurrence in transplant patients.
Wong GL , Wong VW , Choi PC , Chan AW , Chim AM , Yiu KK , et al. Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B. Gut 2009;58:111-7. Epub 2008 Oct 2.
Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, Shatin, Hong Kong, China
Metabolic syndrome is associated with non-alcoholic steatohepatitis and cryptogenic cirrhosis. Whether metabolic syndrome affects the severity of chronic hepatitis B (CHB) is unclear. The authors aimed to study the relationship between metabolic syndrome and the risk of liver cirrhosis in patients with CHB. The authors prospectively recruited patients with CHB from primary care and hospital clinics for liver stiffness measurement (LSM) with transient elastography to diagnose early cirrhosis. Probable cirrhosis was defined as LSM ≥13.4 kPa. They analyzed a subgroup of patients with paired LSM and liver biopsies to validate the accuracy of LSM. Exactly 1466 patients had reliable LSM and 134 (9%) patients had adequate liver biopsy. Also, 188 (13%) patients had metabolic syndrome. Histological liver cirrhosis was present in 32/134 (24%) patients. Histological liver cirrhosis was more common among patients who had metabolic syndrome (38%) versus those who did not have (11%, P < 0.001). The specificity of probable cirrhosis on LSM for histological cirrhosis was 94%. Probable cirrhosis was present in 187 (13%) patients. Metabolic syndrome was more prevalent in patients with probable cirrhosis (24%) than those without cirrhosis (11%, P < 0.001). After adjustment for anthropometric, biochemical and virological factors, metabolic syndrome remained an independent factor associated with probable cirrhosis [odds ratio 1.7, 95% confidence interval (CI) 1.1-2.6]. The odds ratios of probable cirrhosis were 1.4 (95% CI 0.9-2.3), 2.6 (95% CI 1.7-4.3), 4.1 (95% CI 2.4-7.1), 4.0 (95% CI 1.9-8.4) and 5.5 (95% CI 1.8-16.7) in patients with one, two, three, four and five components of metabolic syndrome, respectively. The authors concluded that metabolic syndrome is an independent risk factor of liver cirrhosis in CHB.
Metabolic syndrome is characterized by a constellation of findings including impaired fasting glucose, hypertension, increased waist circumference, hypertriglyceridemia and low serum high density lipoprotein (HDL) cholesterol. It is a manifestation of insulin resistance. The association with metabolic syndrome is well established in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Patients of hepatitis C, who have hepatic steatosis due to the metabolic syndrome, respond poorly to interferon therapy. The role of metabolic syndrome in chronic HBV infection had not been explored. This prospective study throws interesting insight into the link between metabolic syndrome and fibrosis in chronic HBV infection. Liver fibrosis was studied by two different methods - liver biopsy (n = 134) and transient elastography (n = 1466). As for the criteria for diagnosing metabolic syndrome, the Asian parameters were used, as the study was conducted in Hong Kong. Cirrhosis was documented in 24% of liver biopsies. It was found in 12/23 (52%) of those with metabolic syndrome as compared to 20/111 (18%) in those without metabolic syndrome. In multivariate analysis, presence of metabolic syndrome, obesity (BMI > 25 kg/m 2 ), male gender, and hypoalbuminemia independently predicted cirrhosis. Similar results were also obtained in those whose liver stiffness was measured by transient elastography. Interestingly, serum alanine aminotransferase (ALT) was an independent predictor of fibrosis when assessed by transient elastography but not by histology. The higher liver stiffness in those who had raised ALT was probably related to hepatic necroinflammation rather than fibrosis. This study also highlights the limitation (overestimation of fibrosis during active hepatitis flare) of transient elastography when used for assessment of liver fibrosis in postnecrotic cirrhosis.
Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg seroclearance in CHB in Asian patients: Replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135:1192-9. Epub 2008 Jul 16.
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
The study was designed to assess the virological, histologic, and clinical outcome in chronic hepatitis B (CHB) patients with hepatitis B surface antigen (HBsAg) seroclearance. The authors determined the age of HBsAg seroclearance that is associated with a lower risk for hepatocellular carcinoma (HCC) in 298 CHB patients (median follow-up 108 months). The following virological and histologic features were also determined: liver stiffness (n = 229), liver histology, serum HBV DNA levels over time (n = 265), intrahepatic HBV DNA with covalently closed circular DNA (cccDNA) levels, and messenger RNA (mRNA) expression. The median age of HBsAg seroclearance was 49.6 years. Seven (2.4%) patients developed HCC. Cumulative risk for HCC was higher in patients with HBsAg seroclearance at age ≥50 years compared with those with HBsAg seroclearance at age <50 years (P = 0.004) years. Of these two groups of patients, 29.5% and 7.9%, respectively, had significant fibrosis by liver stiffness measurement (P = 0.001), and 15.4% of patients had mild histologic fibrosis. Intrahepatic total HBV DNA and cccDNA were detected in 100% and 79.3% of patients, respectively. All patients had undetectable surface and precore/pregenomic RNA transcripts. One (9.1%) patient had X mRNA expression. Serum HBV DNA were detectable in 13.4%, 6.1%, and 3.7% of patients within 1, 5-10 and >10 years after HBsAg seroclearance, respectively, and 82.1% patients had persistently normal alanine aminotransferase levels. The authors concluded that HBV persisted at low replicative and transcriptional levels after HBsAg seroclearance. HBsAg seroclearance at age <50 years was associated with a lower risk for the development of HCC.
HBsAg seroclearance is considered as one of the most important events in the natural history of hepatitis B. It is the holy grail of treatment of CHB. There are limited studies on long-term outcomes after HBsAg seroclearance. HBsAg seroclearance has been associated with low replicative state. It is well known that despite HBsAg seroclearance, cccDNA persists in liver. It was not known if HBsAg seroclearance would equate with negligible risk of progression to HCC, particularly, in the presence of cccDNA. In this long-term follow-up study, 298 patients were followed up for a median 9 years after HBsAg seroclearance. Median age at HBsAg seroclearance was 49 years (range 4-84 years). HBsAg seroclearance was associated with sustained biochemical (82%) and serum virological improvement (96%). Intrahepatic cccDNA was detectable in 80%. HBV X gene expression was documented in 9%. HCC developed in 7 (2.4%) patients at a median age of 70 years. All these patients had HBsAg seroclearance after the age of 50 years. Median time from HBsAg seroclearance to development of HCC was 43 months (8-65 months). Thus, HBsAg seroclearance is associated with low levels of intrahepatic HBV replication and a persistent risk of HCC.
Hassan MM, Li D, El-Deeb AS, Wolff RA, Bondy ML, Davila M, Abbruzzese JL. Association between hepatitis B virus and pancreatic cancer. J Clin Oncol 2008;26:4557-4562.
Departments of Gastrointestinal Medical Oncology, Epidemiology, and Gastroenterology, Hepatology, and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are considered to be hepatotropic and are a major cause of hepatocellular carcinoma. However, little is known about the role of HBV and HCV infections in other malignancies. This study aimed to determine whether HBV and HCV infections increase the risk for pancreatic cancer development. At The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls were recruited for the study. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). The positive samples were retested by two confirmatory tests. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). Anti-HCV was positive in seven cases (1.5%) and nine controls (1%), while anti-HBc was positive in 36 cases (7.6%) and 28 controls (3.2%). The estimated AORs and 95% CIs were as follows: anti-HCV-positive: 0.9 (95% CI 0.3-2.8); anti-HBc-positive: 2.5 (95% CI 1.5-4.2); anti-HBc-positive/anti-HBs-positive: 2.3 (95% CI 1.2-4.2), and anti-HBc-positive/anti-HBs-negative: 4 (95% CI 1.4-11.1). Risk modification by past exposure to HBV was observed among diabetics (AOR 7.1; 95% CI 1.7-28.7). The authors concluded that past exposure to HBV may be associated with pancreatic cancer development. They further suggested that these findings should be confirmed by other studies which may offer insights into the etiology of pancreatic cancer and may even suggest the need to consider prevention of HBV reactivation among patients with HBV related pancreatic cancer during chemotherapy.
The authors report of a finding of an association between hepatitis B infection and the risk of pancreatic cancer in a large-scale case-control study. A recent, large, prospective cohort study from Korea involving 664 cases of pancreatic cancer had however shown no association between pancreatic cancer and hepatitis B. Hassan et al. have, however, reported a twofold to threefold increased risk of pancreatic cancer in those who tested positive for hepatitis B core antibody (anti-HBc). However, in this study, none of the patients, and only one individual in the control group, tested HBsAg positive; the reported association with pancreatic cancer pertains to anti-HBc rather than to HBsAg positivity.
It is thus not clear why resolved or occult HBV infection would be associated with elevated pancreatic cancer risk, as suggested by these findings, when readily detectable chronic infection is not. On account of these dilemmas, the potential association between HBV infection and pancreatic cancer should be interpreted with caution. Evaluation of pancreatic cancer specimens for the presence of hepatitis B DNA could shed further light on this.
Papatheodoridis GV, Manesis EK, Manolakopoulos S, Elefsiniotis IS, Goulis J, Giannousis J, Bilalis A, Kafiri G, Tzourmakliotis D, Archimandritis AJ. Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B virus infection? Hepatology 2008;48:1451-9.
2 nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Athens, Greece
The diagnosis of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B indicating therapeutic intervention currently requires serum hepatitis B virus (HBV) DNA ≥2000 IU/mL. The study evaluated the severity of liver histology and the presence of histological indication for treatment in patients with HBeAg-negative chronic HBV infection, focusing on those with low viremia and/or normal alanine aminotransferase (ALT). In total, 399 patients with increased ALT and detectable serum HBV DNA (chronic hepatitis B patients) and 35 cases with persistently normal ALT and HBV DNA >2000 IU/mL (inactive carriers) were included. Histological indication for treatment (grading score ≥ 7 and/or stage ≥ 2 in Ishak's classification) was found in 91% (185/203), 82% (75/91), 75% (47/63), and 62% (26/42) of chronic hepatitis B patients with HBV DNA ≥200,000, 20,000-199,999, 2000-19,999, and <2000 IU/mL, respectively (P < 0.001). Histological indication for treatment was more frequent in chronic hepatitis B patients with persistently elevated ALT (86% or 275/321), but it was also found in 74% (58/78) of those with transiently normal ALT (P = 0.025). All inactive carriers had HBV DNA <20,000 IU/mL. Histological indication for treatment was present in 17% (6/35) of inactive carriers always due to moderate (stage 2) fibrosis without active necroinflammation. The study concluded that HBeAg-negative chronic HBV patients with persistently or transiently increased ALT and HBV DNA ≥20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such cases with HBV DNA <20,000 IU/mL and even <2000 IU/mL. In contrast, minimal histological lesions are observed in the majority of HBeAg-negative patients with persistently normal ALT and HBV DNA >2000 IU/mL, who may not require immediate liver biopsy and treatment but only close follow-up.
Treatment of HBeAg-negative chronic HBV infection is a difficult clinical problem. Treatment guidelines as outlined by AASLD advise treatment only for those with raised [2Χ upper normal limit (ULN)] ALT and high HBV DNA load (>10,000 copies/mL). These cutoff values have been decided arbitrarily. The DNA cutoff was lowered for HBeAg-negative hepatitis as compared to HBeAg-positive patients. This study prospectively evaluated liver histopathological changes in those with HBeAg-negative hepatitis (ALT >2 Χ ULN) and different DNA levels ranging from <10,000 copies/mL to >10,000,000 copies/mL. Histopathological changes considered to be indications of treatment include necroinflammatory score ≥7 and/or fibrosis score ≥2. Histological indication for treatment was observed in 86% of patients with DNA levels above the presently accepted cutoff (>10,000 copies/mL). This validates the lowering of cutoff for HBeAg-negative hepatitis. Interestingly, 62% of HBeAg-negative hepatitis (2Χ ULN) ALT and HBV DNA <10,000 copies/mL also had significant fibrosis and necroinflammatory scores which would merit treatment. This study raises important questions on whether the cutoff for initiating treatment has to be lowered further in this subset. The study is also reassuring for HBeAg-negative patients with persistently normal ALT but high HBV DNA load (>10,000 copies/mL), in whom only 17% had significant fibrosis or necroinflammation which would merit treatment. So, in this subgroup, liver biopsy may not lead to change of management in majority and follow-up with ALT alone may suffice.
Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442-55.
Hτpital Beaujon, Assistance Publique Hτpitaux de Paris, University of Paris 7 and INSERM Unitι 773, Centre de Recherches Claude Bernard sur les Hepatites Virales, Clichy, France
Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. In two double-blind, phase 3 studies, the authors randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of <400 copies/mL (69 IU/mL) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies/mL), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P < 0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P < 0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P < 0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P = 0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P = 0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. It was concluded that among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48.
Lamivudine was one of the first oral antivirals used for hepatitis B treatment since 1996. In the past 15 years, four more antivirals have found place in management of hepatitis B. Lamivudine and telbivudine have genetic barrier for resistance and long-term use is limited by emergence of drug resistance. Entecavir is shown to be most potent in viral suppression with least drug resistance in treatment-naοve patients. Tenofovir is a nucleotide analogue that has been used extensively in HIV patients. This study is the first large-scale, phase 3 RCT comparing tenofovir with adefovir in immunocompetent individuals with chronic HBV infection. In this double-blind study, 266 HBeAg +ve patients and 375 HBeAg -ve patients with compensated liver disease who showed Knodell necroinflammatory score ≥3 were randomized to tenofovir DF 300 mg OD or adefovir 10 mg OD for 48 weeks. Histology was repeated at 48 weeks. A composite of DNA suppression <400 copies/mL and improvement of Knodell inflammatory score by 2 points was the primary end point. In this study conducted in North America, Europe, Australia, which included the Whites predominantly, tenofovir showed significantly better response than adefovir. Both drugs showed similar histological improvement. Tenofovir had significantly better virological suppression than adefovir. None of the patients on tenofovir had renal dysfunction. Tenofovir has now been approved as one of the first line antivirals for treatment of chronic hepatitis B. Long-term resistance rates with tenofovir will be eagerly awaited and will decide the success of this molecule.
Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, Lin TH, Hsiao HH, Young JH, Chang MC, Liao YM, Li CC, Wu HB, Tien HF, Chao TY, Liu TW, Cheng AL, Chen PJ. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: A randomized trial. Hepatology 2008;47:844-53.
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
Lamivudine is effective in controlling hepatitis B virus (HBV) reactivation in HBV carrying cancer patients who undergo chemotherapy, but the optimal treatment protocol remains undetermined. In this study, HBV carriers with newly diagnosed non-Hodgkin's lymphoma (NHL) who underwent chemotherapy were randomized to either prophylactic (P) or therapeutic (T) lamivudine treatment groups. Group P patients started lamivudine from day 1 of the first course of chemotherapy and continued treatment until 2 months after completion of chemotherapy. Group T patients received chemotherapy alone and started lamivudine treatment only if serum alanine aminotransferase (ALT) levels elevated to greater than 1.5-fold of the upper normal limit (ULN). The primary endpoint was incidence of HBV reactivation during the 12 months after starting chemotherapy. During chemotherapy, fewer group P patients had HBV reactivation (11.5% vs. 56%, P = 0.001), HBV related hepatitis (7.7% vs. 48%, P = 0.001), or severe hepatitis (ALT more than 10-fold ULN) (0 vs. 36%, P < 0.001). No hepatitis related deaths occurred during protocol treatment. Prophylactic lamivudine use was the only independent predictor of HBV reactivation. After completion of chemotherapy, the incidence of HBV reactivation did not differ between the two groups. Two patients, both in group P, died of HBV reactivation related hepatitis, at 173 and 182 days, respectively, after completion of protocol treatment. When compared with an equivalent group of lamivudine-naοve lymphoma patients who underwent chemotherapy, therapeutic use of lamivudine neither reduced the severity of HBV related hepatitis nor changed the patterns of HBV reactivation. It was concluded that prophylactic lamivudine use, but not therapeutic use, reduces the incidence and severity of chemotherapy related HBV reactivation in NHL patients.
A competent immune response is required to limit HBV replication. In the setting of hematological malignancies, immune response is deranged due to (i) disease and (ii) chemotherapy. HBV related liver injury can occur during or after chemotherapy. During chemotherapy, HBV replication can increase manifold and cause liver injury. After completion of the chemotherapy, reconstitution of normal immune response can cause vigorous immune response on infected hepatocytes, resulting in liver injury. Liver injury can range from mild asymptomatic elevation in transaminases to fatal liver failure. The presence of liver enzyme abnormalities limits continuation and completion of chemotherapy. In the past, antivirals were used only after abnormalities in liver function tests were documented (therapeutic use). Multiple case series and two small randomized controlled trials had shown prophylactic use of lamivudine (from the time of institution of chemotherapy) to be useful in preventing HBV reactivation and hepatitis. The present study, largest RCT on this issue, was stopped after interim analysis because it showed that prophylactic lamivudine therapy was associated with significantly lower incidence of HBV reactivation and hepatitis during chemotherapy. There was no difference between the treatment groups in HBV reactivation and hepatitis in the year following chemotherapy.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB, Colonno RJ. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naοve patients is rare through 5 years of therapy. Hepatology 2009;49:1503-14.
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Development of virus resistance has emerged as a major challenge during the long-term treatment of chronic hepatitis B. Once patients with chronic hepatitis B virus (HBV) infection develop antiviral resistance, they lose the benefits of therapy and may even be predisposed to development of further resistance. Entecavir (ETV) has emerged as a major antiviral agent in the fight against HBV infection and reports regarding emergence of resistance to this agent are disconcerting. ETV resistance (ETVr) can result due to HBV reverse transcriptase substitutions at positions T184, S202, or M250, which especially emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V_L180M. This paper is a result of comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years by the team at Bristol-Myers Squibb Pharmaceutical Research Institute at Wallingford. The emerging data have been summarized in this paper. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (>300 copies/mL) from years 1 through 5. In addition, genotyping was also performed on isolates from patients experiencing virological breakthrough (>1 log10 rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virological breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The surveillance data over 5 years of therapy showed that while in the nucleoside-naοve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virological breakthrough was only 1.2% and 0.8%, respectively, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved <300 copies/mL HBV DNA subsequently developed ETVr. The authors concluded that long-term monitoring confirmed low rates of resistance in nucleoside-naοve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance and felt that the findings justified use of ETV as a primary therapy that would enable prolonged treatment with potent viral suppression and minimal resistance.
The results of this study have demonstrated sustained efficacy of entecavir during long-term treatment of chronic hepatitis B. During long-term monitoring, the investigators observed low rates of resistance in nucleoside-naοve patients during 5 years of ETV therapy, commensurate with potent viral suppression, high genetic barrier to resistance, and impaired fitness of ETVr viruses. The findings of this study also support the use of ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance. Besides, another advantage with its use was that in spite of the diminished susceptibility of LVDr virus to ETV and a reduced genetic barrier compared to the wild-type virus, ETV continued to exhibit potent antiviral activity.