Four-year Outcomes After Cessation of Tenofovir in Immune-tolerant Chronic Hepatitis B Patients.

GOALS: To study the long-term outcome after cessation of antiviral therapy in immune-tolerant patients. BACKGROUND: Experience in the treatment of immune-tolerant chronic hepatitis B is scanty. Some immune-tolerant patients may receive temporary antiviral therapy, such as for prevention of vertical transmission at pregnancy or prophylaxis for chemotherapy. STUDY: This was a follow-up study of a phase 2 trial at 2 centers. Immune-tolerant patients received tenofovir disoproxil fumarate and/or emtricitabine for 4 years and were followed for another 4 years after treatment cessation. Virological relapse was defined as hepatitis B virus (HBV) DNA>2000 IU/mL; clinical relapse was defined as HBV DNA>2000 IU/mL; and alanine aminotransferase (ALT)>2 times the upper limit of normal. RESULTS: In total, 20 patients stopped treatment and were followed up for 206±14 weeks. All patients developed virological relapse at posttreatment week 4 (HBV DNA, 7.07±1.45 log IU/mL). A total of 10 (50%) patients developed clinical relapse at 15±11 weeks (highest ALT, 1149 U/L). In total, 11 (55%) patients were restarted on antiviral therapy; 4 achieved complete HBV DNA suppression and 1 achieved hepatitis B e antigen (HBeAg) seroconversion. Among the 9 patients not restarted on therapy, 2 patients had HBeAg seroconversion with normal ALT and HBV DNA of 7.12 and 1.62 IU/mL, respectively. The remaining 7 untreated patients continued to have positive HBeAg, high HBV DNA, and normal ALT. CONCLUSIONS: Rapid virological relapse is universal and clinical relapse is common after stopping antiviral therapy in patients with immune-tolerant chronic hepatitis B. HBeAg seroconversion is rare regardless of treatment reinitiation.

Cost-effectiveness of the highly effective direct-acting antivirals in the treatment of chronic hepatitis C in Hong Kong.

BACKGROUND AND AIM: In Asia-Pacific where cost is a major concern, peginterferon plus ribavirin (PR) often remain as the standard of care in chronic hepatitis C (CHC) treatment, while the direct-acting antivirals (DAAs) are commonly recommended as retreatment. Newer DAAs can achieve a sustained virological response (SVR) of nearly 100% with pan-genotypic coverage, that is "Highly Effective DAAs." We aimed to investigate the most desirable cost range for the Highly Effective DAAs using Hong Kong as an example. METHODS: Markov modeling was performed using PR as the reference strategy. The cost-effectiveness of the Highly Effective DAAs was compared with sofosbuvir-PR (first-line and rescue) and boceprevir-PR therapies. A 50-year-old genotype 1b hepatitis C virus (HCV) infected treatment-naïve patient with METAVIR F3 was used as the base case scenario to reflect the commonest HCV genotype in Hong Kong. RESULTS: The use of PR would incur a lifetime cost of US$35,854 and effectiveness of 14.85 quality-adjusted life-year (QALY). Sofosbuvir-PR as first-line treatment was dominated by other regimes. If Sofosbuvir-PR rescue therapy was used, the drug cost of Highly Effective DAAs should be set below US$43,553, with a cost-effectiveness ratio (CER) of US$3035/QALY compared with PR. In regions where Boceprevir-PR was still used as first-line therapy, the desirable drug cost of Highly Effective DAAs would be below US$56,985 to achieve a CER of US$5427/QALY. CONCLUSIONS: The most desirable costs of the Highly Effective DAAs would be below US$43,553 if Sofosbuvir-PR rescue therapy is used and below US$56,985 if Boceprevir-PR therapy is used.

Adverse effects of vitamin D deficiency on outcomes of patients with chronic hepatitis B.

BACKGROUND & AIMS: Vitamin D is an immunomodulator that might be involved in the pathogenesis of viral hepatitis. We investigated the effects of vitamin D deficiency on long-term outcomes of patients with chronic hepatitis B (CHB). METHODS: We performed a prospective cohort study of 426 patients with CHB (65% male; mean age, 41 ± 13 years), who were enrolled from 1997 through 2000. Serum levels of 25-hydroxycholecalciferol (25(OH)D3) were measured on study enrollment (baseline). Patients were followed for 159 ± 46 months until last clinic visit or death; approximately 33% received antiviral therapy during the follow-up period. The primary outcome was a clinical event (hepatocellular carcinoma, complications of cirrhosis, or death). RESULTS: At baseline, the patients' mean serum level of hepatitis B virus DNA was 5.0 ± 2.1 log10 IU/mL; their mean level of 25(OH)D3 was 24.3 ± 9.4 ng/mL, and 348 patients (82%) had vitamin D deficiency (<32 ng/mL). Serum levels of 25(OH)D3 did not correlate with cirrhosis or viral load. Ninety-seven patients (22.8%) developed clinical events by a mean time of 118 ± 60 months after study enrollment. Patients who developed clinical events had lower baseline serum levels of 25(OH)D3 (23.2 ± 10.4 ng/mL) than patients who did not (28.2 ± 9.3 ng/mL, P < .001). Low baseline serum 25(OH)D3 was an independent factor associated with clinical events after adjustment for sex, age, and cirrhosis. The adjusted hazard ratio of vitamin D deficiency for clinical events was 1.90 (95% confidence interval [CI], 1.06-2.43; P = .04). The 15-year cumulative incidence rate of clinical events among patients with vitamin D deficiency was 25.5% (95% CI, 23.1%-27.9%), compared with 11.1% (95% CI, 7.4%-14.8%) in patients with normal serum levels of 25(OH)D3. CONCLUSIONS: Vitamin D deficiency is common among patients with CHB and is associated with adverse clinical outcomes.

Cost effectiveness of response-guided therapy with peginterferon in the treatment of chronic hepatitis B.

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.

Current developments in nucleoside/nucleotide analogues for hepatitis B.

There had been remarkable development in nucleos(t)ide analogues (NAs) and evolution in treatment strategies in last 15 years. Currently, there are five NAs available for chronic hepatitis B treatment, namely lamivudine, telbivudine and entecavir (nucleoside analogues), adefovir dipivoxil and tenofovir disoproxil fumarate (nucleotide analogues). The advantages of relatively infrequent side effects and easy administration per oral make NAs popular treatment options. The major drawback of earlier generation NAs is the risk of emergence of drug resistance. Current international guidelines recommend the use of more potent agents with high genetic barriers to resistance including entecavir and tenofovir as first line chronic hepatitis B treatment. However, there is no consensus regarding the subsequent treatment regimens in patients with suboptimal responses to NAs. De novo combination therapy of two NAs, response-guided therapy and roadmap concept in NAs with subsequent switch or add-on therapy can also potentially improve treatment efficacy and avoid resistance.

Efficacy of entecavir switch therapy in chronic hepatitis B patients with incomplete virological response to telbivudine.

BACKGROUND: The roadmap concept suggests the use of on-treatment HBV DNA to guide treatment strategy of chronic hepatitis B patients treated by telbivudine. Our aim was to validate the roadmap approach of entecavir switch therapy in patients with incomplete response to telbivudine. METHODS: Consecutive chronic hepatitis B patients on telbivudine monotherapy were studied. Incomplete virological response was defined as detectable HBV DNA after 6-12 months of treatment. Maintained virological response was defined as undetectable HBV DNA until the last follow-up. RESULTS: Among the 79 patients on telbivudine, 39 (49%) had undetectable HBV DNA after 6-12 months of telbivudine treatment and 40 (51%) had incomplete virological response. In total, 33 incomplete responders switched to entecavir at 11 months (6-23), and 26 (79%) achieved maintained virological response after 25 months (4-46). Low HBV DNA level before switch therapy was the independent factor associated with maintained virological response to entecavir (P=0.01). A total of 24 of 25 (96%) patients with HBV DNA<2,000 IU/ml, versus 2 of 8 (25%) patients with HBV DNA≥2,000 IU/ml, had maintained virological response after switching to entecavir. Although rtM204I and/or rtL180M was detected in 3 of 7 patients with incomplete virological response to entecavir, none of the patients with HBV DNA<2,000 IU/ml during telbivudine treatment harboured these amino acid substitutions. CONCLUSIONS: Roadmap approach using entecavir switch at month 6-12 among incomplete responders to telbivudine is recommended if the HBV DNA is <2,000 IU/ml at the time of switching.

Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis.

UNLABELLED: Entecavir is a potent antiviral agent with high genetic barrier to resistance, hence it is currently recommended as first-line antiviral therapy for chronic hepatitis B (CHB). The aim of this study was to investigate the efficacy of entecavir on clinical outcomes and deaths. It was a retrospective-prospective cohort study based on two cohorts of patients. The entecavir cohort included consecutive CHB patients who had received entecavir 0.5 mg/day for at least 12 months. The historical control cohort included untreated patients recruited since 1997 who underwent routine clinical care. The primary outcome was the 5-year cumulative probability of hepatic events, defined as any cirrhotic complications, hepatocellular carcinoma (HCC), and/or liver-related mortality. A total of 1,446 entecavir-treated patients (72% men; age, 51 ± 12 years; follow-up, 36 ± 13 months) and 424 treatment-naïve patients (65% men; age, 41 ± 13 years; follow-up, 114 ± 31 months) were studied. Overall, there was no difference in hepatic events between the entecavir and control cohorts. Among patients with liver cirrhosis (482 entecavir-treated, 69 treatment-naïve), entecavir-treated patients had reduced risks of all clinical outcomes when compared with treatment-naïve patients with cirrhosis after adjusted for model for end-stage liver disease score: hepatic events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.34-0.78; P = 0.002), HCC (HR, 0.55; 95% CI, 0.31-0.99; P = 0.049), liver-related mortality (HR, 0.26; 95% CI, 0.13-0.55; P < 0.001), and all-cause mortality (HR, 0.34; 95% CI, 0.18-0.62; P < 0.001). Entecavir-treated patients with cirrhosis who failed to achieve undetectable hepatitis B virus DNA (105/482 [22%]) had comparable risk of hepatic events as the untreated patients. CONCLUSION: Entecavir therapy reduces the risks of hepatic events, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had maintained viral suppression.

Association between anthropometric parameters and measurements of liver stiffness by transient elastography.

BACKGROUND & AIMS: We investigated the association between anthropometric parameters and results of liver stiffness measurements (LSMs) by transient elastography in healthy subjects and patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We analyzed anthropometric and LSM data from 658 healthy subjects (37% male; mean age, 47 ± 11 years; body mass index [BMI], 21.8 ± 3.0 kg/m(2); LSM, 4.4 ± 1.6 kPa) and 247 patients with biopsy-proven NAFLD (50% male; mean age, 48 ± 11 years; BMI, 28.6 ± 6.5 kg/m(2); LSM, 9.6 ± 8.7 kPa). Healthy subjects were defined as individuals without viral hepatitis, alcoholic liver disease, or NAFLD. We investigated associations between anthropometric parameters, including BMI and waist circumference, and LSM. RESULTS: LSMs were slightly higher among healthy subjects with BMIs ≤ 18.5 kg/m(2) (n = 84, 4.8 ± 1.5 kPa) and BMIs of 25-29.9 kg/m(2) (n = 76, 5.3 ± 2.2 kPa) than those with BMIs of 18.5-24.9 kg/m(2) (n = 492, 4.5 ± 1.9 kPa; P = .16 by analysis of variance). Among patients with NAFLD of Brunt fibrosis stage 0 or 1, LSMs were lowest among those with BMIs of 18.5-24.9 kg/m(2) (stage 0: n = 34, 5.5 ± 2.2 kPa; stage 1: n = 18, 7.2 ± 3.8 kPa). LSMs were higher among those with BMIs of 25-29.9 kg/m(2) (stage 0: n = 41, 6.1 ± 1.3 kPa; stage 1: n = 26, 7.9 ± 3.5 kPa) and highest for those with BMIs ≥30 kg/m(2) (stage 0: n = 13, 8.5 ± 2.2 kPa; stage 1: n = 22, 11.7 ± 5.2 kPa) (P < .001 and P = .002, respectively, by analysis of variance). High BMI was independently associated with high LSM, in addition to fibrosis stage, among patients with NAFLD. Patients with different waist circumferences had comparable LSMs. CONCLUSIONS: BMI ≥30 kg/m(2) is associated with higher LSMs in patients with NAFLD, after adjusting for fibrosis stage.

Gastroprotective therapy does not improve outcomes of patients with Helicobacter pylori-negative idiopathic bleeding ulcers.

BACKGROUND & AIMS: We performed a prospective cohort study to investigate the effects of gastroprotective agents (such as proton pump inhibitors or histamine-2 receptor antagonists) on long-term clinical outcomes of patients with Helicobacter pylori-negative idiopathic bleeding ulcers. METHODS: Patients with H pylori-negative idiopathic bleeding ulcers were recruited from a single center from April 2002 to March 2009 (n = 663). Age- and sex-matched patients with H pylori-positive bleeding ulcers were used as controls (n = 633). After ulcers had healed, 566 patients in the H pylori-negative idiopathic ulcer cohort received gastroprotective agents at clinicians' discretion, whereas controls received no gastroprotective agent after H pylori eradication therapy. Patients were followed until September 2011 for end points that included recurrent ulcer bleeding and all-cause mortality. RESULTS: During the exposed period of 534 person-years, the incidence rates of recurrent ulcer bleeding and death were 3.8 (95% confidence interval [CI], 2.6-5.4) and 21.8 (95% CI, 18.8-25.3) per 100 person-years among the patients given gastroprotective agents, compared with incidence rates of 2.4 (95% CI, 1.6-3.5; P = .08) and 13.8 (95% CI, 11.9-16.0; P < .001) per 100 person-years, respectively, during the unexposed period of 1588 person-years. Use of gastroprotective agents was not associated with mortality, after adjusting for confounders (hazard ratio, 1.1; 95% CI, 0.6-1.7). Incident rates of recurrent ulcer bleeding and death were significantly higher in patients with H pylori-negative idiopathic ulcers (2.9 and 17.0 per 100 person-years, respectively) than in controls (1.1 and 5.9 per 100 person-years, respectively; P < .001). CONCLUSIONS: Gastroprotective agents do not reduce the risk of recurrent bleeding or mortality for patients with H pylori-negative idiopathic bleeding ulcers.

Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is associated with cardiovascular risk. The aim of this study was to determine the role of fatty liver in predicting coronary artery disease and clinical outcomes in patients undergoing coronary angiogram. METHODS: This was a prospective cohort study carried out in a University hospital. Consecutive patients who underwent coronary angiogram had ultrasound screening for fatty liver. Significant cardiovascular disease was defined as ≥50% stenosis in at least one coronary artery. The primary outcome was a composite end point comprising cardiovascular deaths, non-fatal myocardial infarction and the need for further coronary intervention during prospective follow-up. RESULTS: Among 612 recruited patients, 356 (58.2%) had fatty liver by ultrasonography, 318 (52.0%) had elevated serum alanine aminotransferase and 465 (76.0%) had significant coronary artery disease. Coronary artery disease occurred in 84.6% of patients with fatty liver and 64.1% of those without fatty liver (p<0.001). After adjusting for demographic and metabolic factors, fatty liver (adjusted OR 2.31; 95% CI 1.46 to 3.64) and alanine aminotransferase level (adjusted OR 1.01; 95% CI 1.00 to 1.02) remained independently associated with coronary artery disease. At a mean follow-up of 87±22 weeks, 30 (10.0%) patients with fatty liver and 18 (11.0%) patients without fatty liver reached the composite clinical end point (p=0.79). CONCLUSIONS: In patients with clinical indications for coronary angiogram, fatty liver is associated with coronary artery disease independently of other metabolic factors. However, fatty liver cannot predict cardiovascular mortality and morbidity in patients with established coronary artery disease.

Piperacillin/tazobactam Induced Myelosuppression.

UNLABELLED: Neutropenia, secondary to immune destruction or maturation arrest, is the most commonly described adverse haematological effect of beta-lactam antibiotics. We describe a case of reversible pancytopenia, with evidence of hypocellular marrow, after a prolonged course of piperacillin/tazobactam for 26 days. KEYWORDS: Piperacillin; Tazobactam; Myelosuppression; Neutropenia.

A hospital clinic-based survey on traditional Chinese medicine usage among chronic hepatitis B patients.

OBJECTIVES: To survey the pattern of traditional Chinese medicine usage among chronic hepatitis B patients. DESIGN: Self-administered questionnaire survey. SETTING: Hepatitis clinic at a university hospital in Hong Kong. MAIN OUTCOME MEASURES: Proportion of chronic hepatitis B patients who have ever used traditional Chinese medicine for the treatment of chronic hepatitis B and factors associated with the use. RESULTS: Three hundred and sixty-two patients completed the survey (response rate 93%). One hundred and sixteen (32%) patients reported history of traditional Chinese medicine usage. One hundred and five (91%) patients felt that Chinese medicine had few or no side effects. Most (81%) patients did not inform their physicians on Chinese medicine usage. On multivariate analysis, recent travel to Mainland China, perceived active hepatitis and family members with chronic hepatitis B were independent factors associated with the use of Chinese medicine. CONCLUSIONS: Chronic hepatitis B patients commonly use traditional Chinese medicine. As patients seldom inform the physicians about the use of Chinese medicine, doctors should explicitly enquire about this because of potential therapeutic implications.