Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM. METHODS: MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies. RESULTS: 156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I2=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I2=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I2=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2-F4), while 14.95% (95% CI 11.03% to 19.95%, I2=99.00%) had advanced fibrosis (F3-F4). CONCLUSION: This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD. PROSPERO REGISTRATION NUMBER: CRD42022360251.

A Meta-analysis on Associated Risk of Mortality in Nonalcoholic Fatty Liver Disease.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) affects much of the worldwide population and poses a significant burden to the global healthcare. The rising numbers of individuals with NAFLD and instances of mortality point toward the importance of understanding the association causes of mortality in NAFLD. This meta-analysis aimed to seek the associations of NAFLD with all-cause, cardiovascular disease (CVD)-related, liver-related, and cancer-related mortality. METHODS: MEDLINE and Embase were searched for articles relating to causes of mortality between NAFLD and non-NAFLD. The DerSimonian and Laird random-effects model was used to analyze adjusted hazard ratios (HR), and a sensitivity analysis was conducted to reduce heterogeneity through a graphical display of study heterogeneity. RESULTS: Fifteen studies involving 10 286 490 patients were included. Individuals with NAFLD exhibited an increased risk of all-cause mortality (HR, 1.32; 95% CI, 1.09-1.59; P < .01; I2 = 96.00%), CVD-related mortality (HR, 1.22; 95% CI, 1.06-1.41; P < .01; I2 = 81.00%), and cancer-related mortality (HR, 1.67; 95% CI, 1.15-2.41; P < .01; I2 = 95.00%). However, no significant association was found between liver-related mortality and NAFLD (HR, 3.58; 95% CI, 0.69-18.46; P =.13; I2 = 96.00%). The sensitivity analysis conducted with graphic display of heterogeneity and only population-based studies found similar results. CONCLUSION: NAFLD was associated with an increased risk of all-cause, CVD-related, and cancer-related mortality but not liver-related mortality. The finding is likely because of low fibrosis prevalence in the community. However, the significant burden in other causes of mortality beyond the liver points to a need for multidisciplinary efforts to reduce the mortality risks.

Complete alcohol abstinence increases the risk of NAFLD but not severity. A population analysis with transient elastography.

BACKGROUND & AIMS: As the global prevalence of non-alcoholic fatty liver disease (NAFLD) continues to rise, ubiquity of alcohol use has also prompted discussion regarding the potential interactions between the two. This study aims to examine the effects of modest alcohol consumption on the prevalence and complications of NAFLD in a multi-ethnic population. METHODS: This study analyses the 2017-2018 cycles of NHANES that examined liver fibrosis and steatosis with vibration controlled transient elastography. A coarsened exact matching was conducted to reduce confounding. Logistic regression was done with a multivariate model to assess the relationship between alcohol consumption (modest drinkers and non-drinkers) and risk of NAFLD and its complications. RESULTS: 2,067 individuals were found to have NAFLD and 284 NAFLD patients had a total history of alcohol abstinence. After coarsened exact matching, the prevalence of NAFLD was 49% (CI: 0.41 - 0.58) in non-drinkers and 33% (CI: 0.26 - 0.41) in modest drinkers. Non-drinkers had twice the odds of NAFLD compared to modest drinkers (OR: 1.99, CI: 1.22 - 3.22, p<.01) after adjustment for confounders. There were no significant differences in the odds of significant fibrosis, advance fibrosis, cirrhosis, cardiovascular disease and stroke between non-drinkers and modest drinkers. The odds of malignancy in non-drinkers were almost significantly less than modest drinkers (OR: 0.28, CI:0.08 - 1.02, p=.053). CONCLUSION: Interestingly, modest alcohol consumption is associated with decreased odds of NAFLD. Further investigations are required to examine the relationship between alcohol consumption and NAFLD and subsequently the potential impact on NAFLD management.

APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy.

BACKGROUND & AIM: Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation. METHODS: All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation. RECOMMENDATIONS: We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.

An expert review on the use of tenofovir alafenamide for the treatment of chronic hepatitis B virus infection in Asia.

Asia has intermediate-to-high prevalence and high morbidity of hepatitis B virus (HBV) infection. The use of guideline-recommended nucleos(t)ide analogs with high barrier to resistance, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), is one of the key interventions for curbing HBV infection and associated morbidity in Asia. However, there are some challenges to the use of ETV and TDF; while ETV is associated with high resistance in lamivudine (LAM)-exposed (especially LAM-refractory) patients; bone and renal safety issues are a major concern with TDF. Hence, a panel of twenty-eight expert hepatologists from Asia convened, reviewed the literature, and developed the current expert opinion-based review article for the use of TAF in the resource-constrained settings in Asia. This article provides a comprehensive review of two large, phase 3, double-blind, randomized controlled trials of TAF versus TDF in HBeAg-negative (study 0108) and HBeAg-positive (study 0110) chronic HBV patients (> 70% Asians). These studies revealed as follows: (1) non-inferiority for the proportion of patients who had HBV DNA < 29 IU/mL; (2) significantly high rate of normalization of alanine aminotransferase levels; (3) no incidence of resistance; and (4) significantly better bone and renal safety, with TAF vs. TDF up to 144 weeks. Considering the benefits of TAF, the expert panel proposed recommendations for optimizing the use of TAF in Asia, along with guidance on specific patient groups at risk of renal or bone disease suitable for TAF therapy. The guidance provided in this article may help clinicians optimize the use of TAF in Asia.

High sustained virologic response in genotypes 3 and 6 with generic NS5A inhibitor and sofosbuvir regimens in chronic HCV in myanmar.

Exclusive HCV therapy clinical trials with genotype 6 patients in high prevalence areas have been sparse. We analysed the safety and efficacy of two generic, pangenotypic NS5A/NS5B combination oral DAA regimens, primarily in genotypes 3 and 6, in a real-world setting: (a) daclatasvir/sofosbuvir (DCV/SOF) ± ribavirin (RBV) and (b) Velpatasvir/sofosbuvir (VEL/SOF ± RBV). Between December 2015 and November 2017, data from 522 patients were analysed, 311 of whom were treated with DCV/SOF ± RBV for 12/24 weeks (genotype 3: n = 193, genotype 6: n = 89) and 211 were treated with VEL/SOF ± RBV for 12/24 weeks (genotype 3: n = 83, genotype 6: n = 77). Overall SVR rates were high for both DCV/SOF ± RBV (96.1%, n = 299/311) and VEL/SOF ± RBV (95.3%, n = 201/211), and there was a good adverse event profile. Treatment naïve status and inclusion of RBV (in advanced fibrosis/cirrhosis) were significant independent predictors of achieving SVR12, while type of DAA regimen was not predictive. In this large cohort of genotypes 3 (n = 276) and 6 (n = 166; n = 127 unique subtype of 6c-l), high SVR rates of 94.9% (n = 262/276) and 95.2% (n = 158/166), respectively, were noted. In conclusion, generic and pangenotypic DCV/SOF and VEL/SOF ± RBV regimens were highly effective and safe, in genotypes 3 and 6 chronic HCV in Myanmar. These efficacious pangenotypic regimens suggest that baseline genotype testing can be eliminated moving forward. While RBV may still be needed for those with advanced fibrosis/cirrhosis, in a global elimination strategy it would not be practical even if it does compromise SVR in a minority with difficult to treat characteristics.

International Liver Transplantation Society Asian Consensus on the Management of Hepatitis C Virus Infection in Resource Limited Setting-From Noncirrhotic to Decompensated Disease and After Liver Transplantation.

BACKGROUND: The population of Asia exceeds 4.4 billion people. Chronic hepatitis C virus (HCV) infection in Asia is characterized by specific distribution of genotypes, lack of access to specific therapeutic agents, relatively high cost of treatment, and lack of experienced healthcare providers. Clear consensus on the diagnosis, management, and monitoring of HCV infection specific to the Asian region is a major unmet need. The consensus guidelines documents that have been published to date by major medical societies presume access to an array of direct acting antiviral agents and diagnostic tests that are not broadly applicable to resource limited settings, including Asia. METHODS: To address the lack of an Asia-specific set of HCV treatment guidelines, we assembled a panel of 15 HCV experts in the field of hepatology from India, Indonesia, Myanmar, Vietnam, Pakistan, Philippines, and Mongolia convened in April 2017 to review the updated literature and provide recommendations on the diagnosis and management of chronic HCV infection that reflects local conditions. RESULTS: An evidence-based comprehensive compilation of the literature supported by the graded recommendations from the expert panel for the optimization of the diagnosis, pretreatment, on treatment, and posttreatment assessments, and management of chronic HCV infection has been presented in this article. CONCLUSIONS: With the evolving treatment landscape and addition of several new direct-acting antiviral agents and combination regimens into the therapeutic armamentarium, the current article may serve as a guide to the clinicians in optimizing the diagnosis and treatment selection for the management of chronic HCV infection in resource-limited settings.

Findings from a large Asian chronic hepatitis C real-life study.

There is a paucity of information on chronic hepatitis C (CHC) patients treated with direct antiviral agents (DAAs) in Asia. We invited Asia-Pacific physicians to collate databases of patients enrolled for CHC treatment, recording baseline clinical, virologic and biochemical characteristics, sustained virologic response at week 12 (SVR12) and virologic failure. SVR12 outcome was based on intention to treat (ITT). Multivariate analysis was used to assess independent risk factors for SVR12 using SPSS version 20. A total of 2171 patients from India (n = 977), Myanmar (n = 552), Pakistan (n = 406), Thailand (n = 139), Singapore (n = 72) and Malaysia (n = 25) were collected. At baseline, mean age was 49 years, 50.2% were males, and 41.8% had cirrhosis. Overall, SVR12 was 89.5% and by genotype (GT) based on ITT and treatment completion, respectively, was 91% and 92% for GT1, 100% and 100% for GT2, 91% and 97% for GT3, 64% and 95% for GT4, 87% and 87% for GT6 and 79% and 91% for GT untested. Patients with cirrhosis had SVR12 of 85% vs 93% for noncirrhosis (P < 0.001) (RR 2.1, 95% CI 1.4-3.1, P = 0.0002). Patients with GT1 and GT3 treated with sofosbuvir/ribavirin (SR) had 88% and 89% SVR12, respectively, but those GT6 treated with sofosbuvir/ledipasvir (SL) had only 77.6% SVR12. Multivariate analysis showed absence of cirrhosis was associated with higher SVR12 (OR 2.0, 95% CI 1.3-3.1, P = 0.002). In conclusion, patients with GT1 and GT3 with/without cirrhosis had surprisingly high efficacy using SR, suggesting that Asians may respond better to some DAAs. However, poor GT6 response to SL suggests this regimen is suboptimal for this genotype.

Management of hepatitis C virus infection in the Asia-Pacific region: an update.

The Asia-Pacific region has disparate hepatitis C virus (HCV) epidemiology, with prevalence ranging from 0·1% to 4·7%, and a unique genotype distribution. Genotype 1b dominates in east Asia, whereas in south Asia and southeast Asia genotype 3 dominates, and in Indochina (Vietnam, Cambodia, and Laos), genotype 6 is most common. Often, availability of all-oral direct-acting antivirals (DAAs) is delayed because of differing regulatory requirements. Ideally, for genotype 1 infections, sofosbuvir plus ledipasvir, sofosbuvir plus daclatasvir, or ombitasvir, paritaprevir, and ritonavir plus dasabuvir are suitable. Asunaprevir plus daclatasvir is appropriate for compensated genotype 1b HCV if baseline NS5A mutations are absent. For genotype 3 infections, sofosbuvir plus daclatasvir for 24 weeks or sofosbuvir, daclatasvir, and ribavirin for 12 weeks are the optimal oral therapies, particularly for patients with cirrhosis and those who are treatment experienced, whereas sofosbuvir, pegylated interferon, and ribavirin for 12 weeks is an alternative regimen. For genotype 6, sofosbuvir plus pegylated interferon and ribavirin, sofosbuvir plus ledipasvir, or sofosbuvir plus ribavirin for 12 weeks are all suitable. Pegylated interferon plus ribavirin has been replaced by sofosbuvir plus pegylated interferon and ribavirin, and all-oral therapies where available, but cost and affordability remain a major issue because of the absence of universal health coverage. Few patients have been treated because of multiple barriers to accessing care. HCV in the Asia-Pacific region is challenging because of the disparate epidemiology, poor access to all-oral therapy because of availability, cost, or regulatory licensing. Until these problems are addressed, the burden of disease is likely to remain high.

Hepatitis C virus therapy with peg-interferon and ribavirin in Myanmar: A resource-constrained country.

AIM: To investigate peg-interferon (peg-IFN) and ribavirin (RBV) therapy in Myanmar and to predict sustained virologic response (SVR). METHODS: This single-center, open-label, study was conducted in Myanmar between 2009 and 2014. A total of 288 patients infected with HCV genotypes 1, 2, 3 and 6 were treated with peg-IFN alpha-2a (180 µg/wk) or alpha-2b (50 to 100 µg as a weight-based dose) and RBV as a weight-based dose (15 mg/kg/d). Treatment duration was 48 wk for genotypes 1 and 6, 24 wk for genotype 2, and 24 or 48 wk for genotype 3 based on rapid virologic response (RVR). Those co-infected with hepatitis B received 48 wk of therapy. RESULTS: Overall, SVR was achieved for 82% of patients and the therapy was well tolerated. All patients achieved SVR at equivalent rates regardless of HCV genotype (P = 0.314). Low fibrosis scores (P < 0.001), high baseline albumin levels (P = 0.028) and low baseline viral loads (P = 0.029) all independently predicted SVR. On the other hand, IL-28B TT and CC genotypes were not found to significantly predict SVR (P = 0.634; P = 0.618). Among those who completed treatment, the occurrence of RVR showed a > 96% positive predictive value for achieving SVR. Treatment duration did not significantly impact the likelihood of achieving SVR for patients infected with genotype 3 HCV (P = 0.371). The most common adverse events were fatigue (71%) and poor appetite (60%). Among patients with genotype 3 HCV, more patients in the 48-wk treatment group required erythropoietin than in the 24-wk treatment group (61.1% vs 49.2%). CONCLUSION: SVR rates were high with peg-IFN and RBV therapy in Myanmar. Fibrosis scores, baseline albumin, HCV RNA levels and RVR independently predicted SVR.

Current role of selective internal radiation with yttrium-90 in liver tumors.

An expert panel met to review the evidence for selective internal radiation therapy (SIRT) using yttrium-90 microspheres in hepatocellular carcinoma and metastases from colorectal cancer and neuroendocrine tumors. There is now convincing evidence for the safety and efficacy of SIRT in these situations albeit mostly from retrospective cohort studies. There are a number of ongoing prospective randomized controlled clinical trials investigating the role of SIRT in liver tumors; however, data from these trials are still several years away (although the SIRFLOX study has been recently published). In this evolving environment, published evidence and the authors' experience were used to summarize the current and potential role of SIRT in the management of hepatocellular carcinoma of intermediate or advanced stage and in liver-dominant metastatic colorectal cancer and metastatic neuroendocrine tumors.

Summary scores captured changes in subjects' QoL as measured by the multiple scales of the EORTC QLQ-C30.

OBJECTIVES: To examine the performance of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status/quality of life (QoL) scale and two summary scores to detect changes in the QoL profile over time, according to changes in the individual scales. STUDY DESIGN AND SETTING: Data came from 167 clinical trial patients with unresectable (advanced) hepatocellular carcinoma. The global health status/QoL scale of the questionnaire contained two items: overall health and overall QoL. Nordin and Hinz proposed summary scores for the questionnaire. A mixed-effect model was fitted to estimate trends in scores over time. RESULTS: Predominantly the individual scale scores declined over time; however, the global health status/QoL score was stable [rate of change = -0.3 per month; 95% confidence interval (CI): -1.2, 0.6]. Nordin's summary score, which gave equal weight to the 15 questionnaire scales, and Hinz's summary score, which gave equal weight to the 30 questionnaire items, showed a statistically significant decline over time, 3.4 (95% CI: -4.5, -2.4) and 4.2 (95% CI: -5.3, -3.0) points per month, respectively. CONCLUSION: In contrast to the global health status/QoL scale, the summary scores proposed by Nordin and Hinz detected changes in subjects' QoL profile described by the EORTC QLQ-C30 individual scales.

Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine.

Induction of curative immune responses by therapeutic vaccination in chronic viral infections such as chronic hepatitis B (CHB) is expected to be facilitated by reduction of viral load by antiviral treatment. In this open label, controlled, randomized study, 195 patients with HBeAg positive CHB were randomized to receive 12 doses of HBsAg with AS02B adjuvant candidate vaccine plus lamivudine daily for 52 weeks or lamivudine daily alone. The combined administration of vaccine and lamivudine was safe and well tolerated, but did not improve the HBe seroconversion rate (18.8%) when compared to treatment with lamivudine alone (16.1%) (p=0.6824). Despite induction of a vigorous HBsAg-specific lymphoproliferative response, cytokine production and anti-HBs antibodies, therapeutic vaccination with an adjuvanted HBsAg vaccine administered concomitantly with lamivudine did not demonstrate superior clinical efficacy in HBeAg positive CHB patients as compared to lamivudine therapy alone.

Possible correlation between iron deposition and enhanced proliferating activity in hepatitis C virus-positive hepatocellular carcinoma in Myanmar (Burma).

BACKGROUND: The aim of this study was to survey the effect of deposited iron on the cell kinetics of hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) in Myanmar (Burmese) patients. METHODS: Formalin-fixed and paraffin-embedded liver tissues from 34 Myanmar patients with HCC were used. To detect iron deposition, Prussian blue staining was performed. Cell proliferation and apoptosis were assessed by Ki-67 staining and by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) assay, respectively. HCV RNA was detected by in situ hybridization, and HCV protein, Fas and Fas ligand (FasL) were localized by immunohistochemistry. To identify the subtype of lymphocytes, CD8 was used as a surface marker. RESULTS: Iron deposition was found in 43% of the HCC cases, and was heavier in moderately differentiated HCC than in well-differentiated HCC. The Ki-67 labeling index (LI) in cancer cells was higher in Prussian blue-positive-HCC than in -negative HCC (3.8 +/- 2.2 vs 1.5 +/- 1.7, mean +/- SD; P=0.0067), whereas there was no significant difference between these groups in TUNEL LI. HCV protein was localized in cancer cells, and was found in 89% of the patients. In addition, Fas was expressed in HCC cells, and FasL was localized in HCC cells as well as in infiltrating CD8+ T lymphocytes. The frequency of apoptosis of HCC cells was correlated significantly with the population density of infiltrating CD8+ T lymphocytes. CONCLUSIONS: Our results indicated that, in Myanmar patients with HCC, iron deposition might accelerate hepatocarcinogenesis, by promoting cancer cell proliferation, without affecting the Fas/FasL apoptotic system.

International collaborative survey on epidemiology of hepatitis E virus in 11 countries.

We conducted seroepidemiological studies on antibody prevalence to hepatitis E virus (HEV) in 5,233 sera from 11 countries to ascertain the present state of HEV infection on a global basis. The prevalence of anti-HEV IgG increased with age in these tested countries, but the rate of antibody positivity was over 20% in the 16-30 year-old group in most of the participating countries, except for Japan, the USA, and Spain. Of patients with acute hepatitis of unknown etiology from Nepal, 56% (14/25) were positive for the IgM class of anti-HEV antibody. In addition, HEV RNAs in the serum from 3 Nepali patients who had the IgM antibody were detected by nested PCR and all of the HEV genes isolated belonged to genotype 1. Our results indicate that HEV is spreading worldwide, not only in developing countries, but also in more industrialized countries than previously thought.

Genotype C of hepatitis B virus can be classified into at least two subgroups.

A genomic characterization of hepatitis B virus (HBV) was done for 56 pre-S1/pre-S2 genes and 10 full-length HBV genotype C isolates from five Asian countries. Phylogenetic analysis of the pre-S1/pre-S2 genes revealed two major groups within genotype C: one for isolates from southeast Asia including Vietnam, Myanmar and Thailand (named HBV/C1) and the other for isolates from Far East Asia including Japan, Korea and China (named HBV/C2). This finding was confirmed by phylogenetic analysis based on the full-length sequence of 32 HBV genotype C isolates, including 22 from database entries. Two isolates from Okinawa, the island off the southern end of Japan, formed a different branch. Specific amino acid sequence changes were identified in the large S protein (amino acids 51, 54, 60, 62 and 73) and P protein (amino acids 231, 233, 236, 248, 252 and 304). Our results indicate that genotype C of HBV can be classified into at least two subgroups.

High prevalence of hepatitis B virus pre-s mutant in countries where it is endemic and its relationship with genotype and chronicity.

It has been reported that hepatitis B virus (HBV) mutants carrying mutations in the pre-S region can be found in infected patients. In this study, we investigated the prevalence of the HBV variant with the pre-S mutant in different geographic regions, including countries with low and high levels of endemic HBV infection, and analyzed the correlation with clinical findings. We examined 387 HBV DNA-positive serum samples from individuals among 12 countries, consisting of Vietnam, Myanmar, Thailand, China, Korea, Nepal, Japan, Russia, Spain, United States, Bolivia, and Ghana. HBV pre-S mutants were detected in 71 (18.3%) of 387 serum samples tested. This mutant was the most prevalent in Vietnam (36%), followed by Nepal (27.3%), Myanmar (23.3%), China (22.4%), Korea (14.3%), Thailand (10.5%), Japan (7.7%), and Ghana (4.3%). In contrast, no case with this mutation was found in Russia, Spain, United States, and Bolivia. Among the HBV deletion mutations, 15.5% (11 of 71) occurred in the pre-S1 and 46.5% (33 of 71) in the pre-S2 regions. Eight (11.3%) cases had a mutation in both the pre-S1 and pre-S2 regions. In addition, a point mutation at the pre-S2 starting codon was observed in 19 (26.7%) cases. The detection rate of the HBV mutant in patients with hepatocellular carcinoma was significantly higher than in other patients (P < 0.05). Furthermore, these mutants were found more frequently in genotype B (25%) and genotype C (24.5%) than in the other genotypes (P < 0.05). Our results indicated that there was a high prevalence of HBV pre-S mutation in regions of endemic HBV infection in Asia. Furthermore, the pre-S mutation appeared to be correlated with hepatocellular carcinoma and HBV genotypes.

Facilitating the WHO expanded program of immunization: the clinical profile of a combined diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b vaccine.

BACKGROUND: Vaccines are important weapons in the fight against infectious diseases. The World Health Organization (WHO) Expanded Program on Immunization (EPI) has been extended to include recommendations for hepatitis B and Haemophilus influenzae type b (Hib) vaccinations. The WHO has recommended that combined vaccines be used where possible, to reduce the logistic costs of vaccine delivery. This paper reviews the efficacy, safety and cost-effectiveness of Tritanrix-HB/Hib, the only commercially available combined diphtheria, tetanus, whole cell pertussis, hepatitis B and conjugated Hib vaccine. METHODS: The immunogenicity and reactogenicity results of five published clinical trials involving Tritanrix-HB/Hib in a variety of immunization schedules and countries were reviewed. Based on these data and cost-effectiveness studies, an assessment of its suitability for use in national immunization programs was made. RESULTS: Tritanrix-HB/Hib has shown excellent immunogenicity in clinical trials using a variety of schedules, with no reduced immunogenicity observed for any of the components of the combined vaccine. It has similar reactogenicity to DTPw vaccines alone. Pharmacoeconomic analyses have shown combined DTP-HB/Hib vaccines to be cost-effective compared to separate vaccines. CONCLUSIONS: Replacement of DTPw vaccination by Tritanrix-HB/Hib can be done without modifying the existing national immunization programs. This should facilitate widespread coverage of hepatitis B and Hib vaccinations and their rapid incorporation into the EPI.

High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial.

In the Asia-Pacific region and elsewhere, almost 85% of patients with hepatocellular carcinoma (HCC) are inoperable at diagnosis and have a dismal prognosis. Tamoxifen (TMX) is believed to inhibit HCC positive for estrogen receptor (ER), but most HCCs are ER negative. Results of previous phase 3 trials in inoperable HCC have been conflicting and inconclusive. At higher doses, however, TMX inhibits HCC through ER-independent mechanisms. A multicenter randomized controlled trial was performed to assess the role of high-dose TMX versus placebo (P) in the treatment of patients with inoperable HCC with respect to survival and quality of life (QoL). A total of 329 patients from 10 centers in 9 countries in the Asia-Pacific region enrolled in a double-blind randomized controlled trial of TMX 120 mg/d (TMX120) against P as a control arm with an intermediate dosage of TMX 60 mg/d (TMX60) to assess possible dose response. An independent data monitoring committee reviewed all aspects of the trial. QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Three-month survival rates for the P, TMX60, and TMX120 groups were 44%, 41%, and 35%, respectively, with a statistically significant trend difference in survival across the 3 treatment regimens (P =.011). There was a significantly higher risk of death in the TMX120 group compared with the P group (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). Adverse drug reactions were reported in 3% (9 patients), and 8 patients were lost to follow-up. In conclusion, TMX does not prolong survival in patients with inoperable HCC and has an increasingly negative impact with increasing dose. No appreciable advantage to QoL with TMX was observed.