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Background: HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy., Aim: To evaluate the use of serum biomarkers to predict HBeAg loss., Methods: HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated., Results: HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm., Conclusions: Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Daniel Q. Huang Advisory board: Eisai, Gilead. Liang Shen nil; Wah Phyo nil; Gavin Cloherty Employee of Abbott Diagnostics; Emily K. Butler Employee of Abbott Diagnostics; Mary C. Kuhns Employee of Abbott Diagnostics; Anne L. McNamara Employee of Abbott Diagnostics; Vera Holzmayer Employee of Abbott Diagnostics; Jeffrey Gersch Employee of Abbott Diagnostics; Mark Anderson Employee of Abbott Diagnostics; Wei Lyn Yang: Advisory board: Gilead, Abbie, Bristol Myers Squibb, MSD; Jing Hieng Ngu Advisory Board: Gilead Sciences; Speakers Bureau: Abbvie; Jason Chang nil; Jessica Tan nil; Taufique Ahmed nil; Yock Young Dan Advisory Board: BMS, Gilead, Novartis, Abbvie, MSD; Speaker's Bureau: Sanofi Aventis, Siemens; Research grants: BMS, Novartis and Johnson & Johnson; Yin Mei Lee nil; Guan Huei Lee nil; Poh Seng Tan nil; Htet Toe Wai Khine nil; Amy Tay nil; Seng Gee Lim: Advisory Board: Gilead Sciences, Roche, GSK, Janssen, Grifols, Assembly, Arbutus, Abbott, Sysmex. Speakers Bureau: Gilead Sciences, Abbott, Sysmex, Roche, GSK. Educational/research funding: Abbott, Gilead Sciences., (Copyright © 2024. Published by Elsevier B.V.)

Background: Biomarkers such as quantitative HBsAg (qHBsAg), quantitative hepatitis B virus (HBV) core-related antigen (qHBcrAg) and HBV RNA may be useful in predicting HBsAg loss in patients with chronic hepatitis B (CHB) undergoing antiviral therapy., Aim(s): Our study evaluated qHBsAg, HBV RNA and qHBcrAg as a posthoc analysis of a randomized clinical trial of peginterferon±NA to determine their utility in predicting HBsAg loss., Methods: CHB patients who completed therapy with 48weeks peginterferon alpha2b ± nucleoside analogue therapy (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBsAg loss. The predictive ability of qHBsAg, qHBcrAg, HBV RNA and other variables were investigated by univariate and multivariate logistic models for HBeAg-negative patients by odds ratios, area under the curve (AUC), sensitivity, specificity, and positive and negative likelihood ratios (LR)., Results: HBsAg loss occurred in 15/114(13%) HBeAg-negative CHB patients who completed 48 weeks of peginterferon. At baseline, qHBsAg was superior to HBcrAg and HBV RNA with AUC 0.916, 0.649 and 0.542, respectively. Using multivariate analysis, the model comprising treatmentarm, age, gender, baseline qHBsAg, HBcrAg and HBV RNA, weeks 4 & 8 qHBsAg had the highest AUC(0.98), but the univariate model with week 8 qHBsAg <70 IU/mL had AUC 0.96. Hence, the contributions of variables other than qHBsAg were marginal. HBV RNA and qHBcrAg were weak predictors of HBsAg loss. Kinetics of the novel markers showed only qHBsAg had a good relationship with HBsAg loss while HBV RNA had a marginal relationship and HBcrAg did not change at all, and none had a good relationship with viral rebound., Conclusions: On-treatment biomarker predictors were better than baseline ones, and the best predictor of HBsAg loss at 72 weeks was week 8 qHBsAg <70 IU/mL., (© 2020 John Wiley & Sons Ltd.)

Background: Combination therapy with HBIG and NAs has reduced HBV recurrence post LT. Despite its efficacy, costs of HBIG remain prohibitive. With high-potency NAs, HBIG's use has been questioned. We aim to evaluate the efficacy and safety of HBIG-free regimens in patients transplanted for HBV-related liver disease., Methods: A review of LT patients at the National University Hospital, Singapore from 2001 to 2015 was performed. Patients transplanted for HBV were divided by antiviral treatment received: high- or low-potency NAs, or a combination of HBIG with high-potency NAs. Post-transplant outcomes were reviewed till data censure. Primary outcome was recurrence of HBV viremia post-transplant, while secondary outcomes were HBsAg sero-clearance, graft survival and mortality., Results: Among 58 patients, 51 (88%) had persistent HBV viral suppression. Patients on a high-potency agent had significantly higher viral suppression compared to those on a low-potency agent (97% vs 72%, p = 0.02). This was also seen in patients with VL detectable at transplant (100% vs 50%, p < 0.01). None of the 16 patients with VL detectable at transplant and treated with high-potency agents developed recurrence. 42 patients (72%) achieved persistent HBsAg sero-clearance. Although this was higher in the high-potency NA-only group, it was not statistically significant (p = 0.56). There were no graft failures or mortalities attributed to HBV recurrence., Conclusion: With the use of high-potency agents, HBIG may not be necessary in the treatment of patients transplanted for HBV-related liver disease, even in the presence of detectable VL at time of transplant.

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., (© 2018 John Wiley & Sons Ltd.)

Between 80 and 115 million people worldwide are chronically infected with hepatitis C virus, with 60%-90% of these being undiagnosed. Untreated chronic hepatitis C (CHC) is associated with progressive liver disease, cirrhosis, hepatocellular carcinoma and liver-related mortality. A number of extrahepatic manifestations are also reported in CHC patients, further adding to the burden of the disease. CHC also impacts patients in terms of lower health-related quality of life, higher levels of fatigue and reduced productivity. Furthermore, the later stages of disease are costly for both healthcare systems and society. Pegylated-interferon (PEG-IFN)+ribavirin (RBV), for many years the mainstay of treatment, leads to sustained virological response (SVR) in 40%-70% of patients. However, a substantial number of patients are ineligible for treatment, and many patients fail to achieve SVR with this regimen. Furthermore, PEG-IFN+RBV leads to impairment of patient-reported outcomes during treatment, and most patients suffer from adverse events, associated with poor adherence, treatment discontinuation and treatment failure. The approval of second-generation direct-acting antivirals (DAAs) has revolutionized the treatment of CHC patients. All-oral, PEG-IFN and RBV-free regimens have higher efficacy rates, shorter treatment durations, fewer adverse events, higher adherence rates and improvement in PROs from as early as Week 4, compared to PEG-IFN+RBV regimens. The aim of this article is to review the evidence for HCV infection as a systemic disease, summarizing the impact of hepatitis C and its treatments on clinical, patient and economic outcomes, with a focus on data from Asia and Japan specifically., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Aim: The high cost of chronic hepatitis C (HCV) direct-acting antivirals (DAAs) poses significant financial challenges for health payers, especially in Asia. A personalized treatment strategy based on individualized probability of virological response using oral DAAs as second-line therapy would seem practical but has not been studied., Methods: We performed a Markov model to project health outcomes and costs for patients with genotype 1 HCV through 10 treatment strategies over a lifetime period. The implication of retreatment was also incorporated to reflect real-life situation., Results: Using boceprevir and peginterferon/ribavirin (BOC/PR, the least costly treatment) as a base case, the all-oral therapies such as ombitasvir/paritaprevir/ritonavir-dasabuvir are cost-effective with an incremental cost-effective ratio of $US50 828. However, the all-oral DAAs would no longer be cost-effective compared with conventional therapies if retreatment were taken into account. A road map strategy using rapid virological response to guide use of BOC/PR and sofosbuvir/PR had the most favorable incremental cost-effective ratio ($US27 782) relative to BOC/PR. Nevertheless, the trade-off with the cost-effectiveness of the road map strategy is an increased number of liver-related deaths compared with all-oral DAAs (52 vs 10-20 per 10 000 patients) by incorporating retreatment., Conclusions: The 12-week all-oral DAAs were cost-effective options using conventional drug-to-drug comparison. However, they cease to be cost-effective when treatment strategies incorporating DAA retreatment for interferon failures are incorporated. HCV management can be optimized by adopting individualized treatment algorithm providing a practical solution to health payers to make oral DAAs accessible to those who need them most., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

HCV in the East is a complex scenario with prevalence rates of 0.5% to as high as 4.7%, and variable distributions of genotypes, with a dominance of genotype 1b in East Asia, genotype 3 in South Asia and South East Asia, and genotype 6 in Indochina. Approvals for the new oral directing antiviral agents (DAAs), in the East have been very slow, but ultimately will be achieved by 2019, consequently, pegylated interferon and ribavirin are still widely used. Nonetheless the main issues are the problems of screening and linkage to management, and the considerable barriers to access HCV care., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To examined the efficacy and safety of treatment with boceprevir, PEGylated-interferon and ribavirin (PR) in hepatitis C virus genotype 1 (HCVGT1) PR treatment-failures in Asia., Methods: The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures. Participating physicians were invited to contribute data from their patients: baseline characteristics, on-treatment responses, sustained virological response at week 12 (SVR12), and safety were collected and analysed. Multivariate analysis was performed to determine predictors of response., Results: 150 patients were enrolled from Australia, Malaysia, Singapore and Thailand (Asians = 86, Caucasians = 63). Overall SVR12 was 61% (Asians = 59.3%, Caucasians = 63.5%). SVR12 was higher in relapsers (78%) compared with non-responders (34%). On-treatment responses predicted SVR, with undetectable HCVRNA at week 4, 8 and 12 leading to SVR12s of 100%, 87%, and 82% respectively, and detectable HCVRNA at week 4, 8 and 12, leading to SVR12s of 58%, 22% and 6% respectively. Asian patients were similar to Caucasian patients with regards to on-treatment responses. Patients with cirrhosis (n = 69) also behaved in the same manner with regards to on-treatment responses. Those with the IL28B CC genotype (80%) had higher SVRs than those with the CT/TT (56%) genotype (P = 0.010). Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR. Serious adverse events occurred in 18.6%: sepsis (2%), decompensation (2.7%) and blood transfusion (14%). Discontinuations occurred in 30.7%, with 18.6% fulfilling stopping rules., Conclusion: Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80% if they have good on-treatment responses; however, discontinuations occurred in 30% because of virological failure or adverse events.

The prevalence of hepatitis C virus (HCV) in Asia is 0.5% to 4.7%, with three different genotypes predominating, depending on the geographic region: genotype 1b in East Asia, genotype 3 in South and Southeast Asia, and genotype 6 in Indochina. Official approval for direct-acting antiviral agents (DAAs) in Asia lags significantly behind that in the West, such that in most countries the mainstay of therapy is still pegylated interferon and ribavirin (PR). Because the interleukin-28B genetic variant, associated with a high sustained virologic response (SVR), is common in Asians, this treatment is still acceptable in Asian patients with HCV infections. A roadmap for HCV therapy that starts with PR and takes into account those DAAs already approved in some Asian countries can provide guidance as to the best strategies for management, particularly of genotype 1 and 3 infections, based on SVR rates. Sofosbuvir and PR are likely to be the initial therapies for genotype 1 and 3 disease, although in the former these drugs may be suboptimal in patients with cirrhosis (62% SVR) and the extension of treatment to 24 weeks may be required. For difficult to treat genotype 3 infections in treatment-experienced patients with cirrhosis, a combination of sofosbuvir and PR result in an 83% SVR and is, therefore, currently the optimal treatment regimen. Treatment failure is best avoided since data on rescue therapies for DAA failure are still incomplete.

Background & Aims: The high prevalence of chronic hepatitis B in Asian countries produces a substantial economic burden. Peginterferon has immunomodulatory effects and a finite course for treatment of hepatitis B, but also a high cost and side effects. The recent introduction of a 12-week stopping rule (stopping treatment after 12 weeks) has increased its appeal as a first-line treatment for hepatitis B. We aimed to determine the cost effectiveness of the 12-week stopping rule for peginterferon in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients., Methods: We used Markov modeling, with data from the Hong Kong population, to compare the cost effectiveness of peginterferon therapy with a 12-week stopping rule vs conventional therapy (48 weeks) and with other antiviral agents., Results: For HBeAg-positive patients, stopping peginterferon therapy after 12 weeks had the lowest cost-effectiveness ratio (CER), of $9501/quality-adjusted life-year (QALY), compared with no treatment, making it the most cost-effective option. Conventional (48-week) peginterferon treatment had a CER of $9664/QALY. For HBeAg-negative patients, entecavir had the lowest CER ($34,310/QALY). Entecavir was more cost effective than either peginterferon strategies (CERs of $37,423/QALY for 12 weeks of peginterferon and $38,474/QALY for 48 weeks of treatment)., Conclusions: The 12-week stopping rule increases the cost effectiveness of peginterferon therapy, and is the most cost-effective treatment for HBeAg-positive patients. The need for long-term antiviral therapy for HBeAg-negative patients makes entecavir the most cost-effective strategy., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients infected with chronic HCV genotype 1 experience liver complications as the disease progresses. This study aims to project the long-term reduction of liver complications and cost-effectiveness of treatment strategies, including co-administrating boceprevir (BOC) with pegylated interferon-α2b (PEG-IFN) and ribavirin compared with standard of care (SOC) of PEG-IFN and ribavirin only., Methods: A Markov model was created to estimate the expected costs and quality-adjusted life-years (QALYs) associated with treatment strategies outlined in the BOC package insert in Singapore. Patient characteristics were from pivotal trials, the transition probabilities and QALYs were estimated from publications, and the pharmaceutical and health status costs were obtained from a public hospital in Singapore. The threshold of cost-effectiveness was chosen as 65,000 SGD for this study., Results: For treatment-naive patients, BOC is highly cost-effective compared with SOC (179 SGD/QALY) and cost-saving for patients who have failed prior treatment, due to higher QALYs from better sustained virological response (SVR) and lower costs from avoidance of complications. Sub-group analyses show that BOC is cost-effective for non-cirrhotic treatment-experienced patients and null responders. It out-performs SOC for treatment-naive non-cirrhotic and cirrhotic patients who have failed prior treatment. Even after adjusting for higher prevalence of favourable IL28B genotype in Asians, BOC is cost-effective compared with SOC. Only untreated cirrhotic patients showed inconclusive cost-effectiveness for BOC., Conclusions: Compared with SOC, BOC prevents more HCV liver complications from HCV genotype 1, particularly in patients who have failed previous SOC. Improved SVR and shortened duration of treatment result in BOC being potentially cost-saving or cost-effective in an Asian population.

Entecavir switch is one of the treatment options for lamivudine-resistant hepatitis B (HBV) patients in Asia. This study examined the outcome of patients with different baseline resistance genotypes in a cohort study. In this study, 14 patients with chronic HBV were treated with entecavir 1 mg/day for 5 years. Enrolment criteria include: documented lamivudine resistant mutations, treatment with adefovir 10 mg/day for at least 24 weeks, and Child-Pugh score <7. Most had previous failed adefovir therapy and compensated cirrhosis of the liver. Clinical outcomes, liver biochemistries, and HBV DNA were monitored regularly. Patients with virologic breakthrough were rescued with add-on adefovir. At the end of the treatment period, the mean HBV DNA fell from 5.92 × 10(6) (baseline) to 3.67 × 10(1)  IU/ml. The presence of a HBV polymerase rtM204V mutation at the baseline was found to be the major risk factor for adverse outcomes. Compared to the patients with the rtM204I mutant, patients with the rtM204V mutant had increased risk of virologic breakthrough (80% vs. 0%, P = 0.010) requiring add-on adefovir, slower virologic responses (log rank test, P = 0.0011), failure to reach undetectable HBV DNA levels (60% vs. 0%, P = 0.045), and higher risk of entecavir-resistance (60% vs. 0%, P = 0.045). All the patients with rtM204I and rtA181 mutants had undetectable HBV DNA from 18th month. In summary, lamivudine-resistant HBV patients with the rtM204V mutation have the highest risk of developing entecavir resistance, and entecavir monotherapy should be avoided. Those with the rtM204I and rtA181V mutations may have lower risks, but regular surveillance for viral breakthrough is required., (Copyright © 2012 Wiley Periodicals, Inc.)

Goals: To determine the clinical outcome of chronic hepatitis B cirrhotics on antiviral therapy., Background: The long-term outcome of hepatitis B cirrhotics on therapy remains to be characterized., Methods: A large clinic cohort of chronic hepatitis B cirrhotic patients were enrolled in a treatment program of lamivudine ± adefovir therapy. Patients were analyzed for clinical outcomes, and predictors of these outcomes were evaluated by multivariate analysis. Clinical outcomes of ascites, encephalopathy, hepatocellular carcinoma (HCC), and progression in Child-Pugh score, Model for End-stage Liver Disease score, and mortality were assessed. Data were analyzed by Kaplan-Meier graphs, log-rank test, and Cox regression., Results: Of 143 chronic hepatitis B cirrhotics, 19.6% had decompensated cirrhosis. At 5 years, the mean survival was 83.6%, development of ascites, HCC, encephalopathy, and deterioration in Child-Pugh score were 7.0%, 15.9%, 10.8%, and 16.9%, respectively. The overall progression of liver-related complications was 32.8% at 5 years. Multivariate analysis showed that ascites, albumin ≤28 g/L, Child-Pugh score ≥7.9, Model for End-stage Liver Disease score ≥10.9 were significantly associated with liver-related complications. Low albumin and low hepatitis B virus DNA were independent factors for liver-associated mortality. Lamivudine resistance did not affect mortality or liver disease progression. When stratified by Child-Pugh status, the mean survival of those with Child C cirrhosis was worse than Child A and B cirrhosis (P<0.001, log-rank test). Early deaths (≤12 mo) were due to liver failure or sepsis, whereas deaths ≥12 mo were mainly due to HCC., Conclusion: Decompensated chronic hepatitis B cirrhotics may suffer early mortality despite antiviral treatment, and therefore should be considered for early liver transplantation.

Aim: To investigate the accuracy of serum alanine aminotransferase (ALT) in diagnosing lamivudine resistance and factors that contributed to abnormal serum ALT., Methods: This was a retrospective study of chronic hepatitis B patients on lamivudine therapy who were followed for 3-mo with liver function tests and hepatitis B virus (HBV) DNA measurement. Lamivudine resistance was defined as HBV DNA ≥ 1 log from nadir on at least 2 occasions, confirmed by genotyping. Serum ALT levels in patients with lamivudine resistance were compared to serum ALT levels in those without lamivudine resistance., Results: There were 111 patients with and 117 without lamivudine resistance. The area under the receiver operating characteristic of serum ALT to diagnose lamivudine resistance was 0.645 ± 0.037. Serum ALT > 42.5 U/L gave the best diagnostic accuracy with sensitivity = 61%, specificity = 60%, positive predictive value = 60%, negative predictive value = 61%, positive likelihood ratio = 1.53 and negative likelihood ratio = 0.65 for predicting lamivudine resistance, missing 39% of resistant patients. Using other serum ALT cutoffs, diagnostic accuracy was lower. By multivariate analysis, baseline abnormal serum ALT was associated with abnormal ALT during resistance (OR = 5.98, P = 0.003), and males were associated with serum ALT flares during resistance (OR = 8.9, P = 0.016)., Conclusion: Serum ALT is inadequate for diagnosing lamivudine resistance and has implications where viral resistance testing is suboptimal and for reimbursement of rescue therapy.

Hepatitis B immunoglobulin with lamivudine prophylaxis (LAM/HBIG) is effective in preventing Hepatitis B (HBV) recurrence posttransplant but is expensive and inconvenient. Lamivudine-resistant HBV, which has limited the usefulness of lamivudine monoprophylaxis in transplant, can now be effectively controlled with adefovir dipivoxil. We performed a cost-effectiveness analysis on the strategies of lamivudine prophylaxis with adefovir rescue(LAM/ADV) compared to combination LAM/intravenous fixed high-dose HBIG prophylaxis(LAM/ivHBIG) or LAM/intramuscular HBIG prophylaxis(LAM/imHBIG). Markov modeling was performed with analysis from societal perspective. Probability rates were derived from systematic review of the literature and cost taken from MEDICARE database. Outcome measures were incremental cost-effectiveness ratio(ICER) and cost to prevent each HBV recurrence and death. Analysis was performed at 5 years posttransplant as well as at end of life expectancy (15 years). Combination LAM/ivHBIG cost an additional USD562,000 at 15 years, while LAM/imHBIG cost an additional USD139,000 per patient compared to LAM/ADV. Although there is an estimated increase in recurrence of 53% with LAM/ADV and 7.6% increased mortality at the end of life expectancy (15 years), the ICER of LAM/ivHBIG over LAM/ADV treatment is USD760,000 per quality-adjusted life-years and for LAM/imHBIG, USD 188,000. Cost-effectiveness is most sensitive to cost of HBIG. Lamivudine prophylaxis with adefovir dipivoxil salvage offers the more cost-effective option for HBV patients undergoing liver transplant but with higher recurrence and death rate using a model that favors LAM/HBIG. Lowering the cost of HBIG maintenance will improve cost-effectiveness of LAM/HBIG strategy. In conclusion, a tailored approach based on individual risks will optimize the cost-benefit of HBV transplant prophylaxis.

Combination therapy between two immunomodulators used for treatment of chronic hepatitis B was explored based on reported therapeutic efficacy of interferon-alpha, and thymosin-alpha1 as monotherapeutic agents to determine if combination therapy was superior to interferon alone. This double-blinded, randomized, placebo-controlled trial compares the addition of thymosin-alpha1, 1.6 microg taken three times per week (combination therapy) or thymosin placebo (monotherapy) to lymphoblastoid interferon (Wellferon), 5 million international units (MIU) taken three times per week, for 24 weeks. Entry criteria included positive hepatitis B e antigen (HBeAg); alanine aminotransferease (ALT) > or = 1.5 x upper normal limit, but < or = 10 x upper normal limit; positive HBV DNA; absence of cirrhosis; treatment naivety and no co-morbid factors. A total of 98 HBeAg-positive patients were recruited, of which 48 were randomized to combination therapy and 50 to monotherapy. The primary endpoint was the loss of HBeAg at 72 weeks. The secondary endpoints were HBeAg seroconversion, normalization of ALT, loss of HBV DNA and improvement in histology. The HBeAg loss was 45.8% and 28.0% for combination therapy and monotherapy, respectively (difference, 17.8%; 95% CI -1.2%-35.3%, P = 0.067). There was a trend towards HBeAg loss when using combination therapy. There were also no statistically significant differences between the different therapies with respect to the secondary endpoints of HBeAg seroconversion, changes in histology, normalization of ALT or loss of HBV DNA. In conclusion, this trial showed a 17.8% improvement in HBeAg loss rates using combination therapy over interferon monotherapy. This could clinically indicate a potential important difference that would need confirmation in subsequent trials.