Anneke van Vuuren

Sustained HBeAg and HBsAg Loss After Long-term Follow-up of HBeAg-Positive Patients Treated With Peginterferon α-2b

BACKGROUND & AIMS The aim of this study was to evaluate the long-term sustainability of response in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with pegylated interferon (PEG-IFN) alpha-2b alone or in combination with lamivudine. METHODS All 266 patients enrolled in the HBV99-01 study were offered participation in a long-term follow-up (LTFU) study. Patients were treated with PEG-IFN alpha-2b (100 mug/wk) alone or in combination with lamivudine (100 mg/day) for 52 weeks. Initial response was defined as HBeAg negativity at 26 weeks posttreatment. For the LTFU study, patients had one additional visit after the initial study (mean interval, 3.0 +/- 0.8 years). RESULTS Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A-infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001). CONCLUSIONS HBeAg loss after treatment with PEG-IFN alpha-2b alone or in combination with lamivudine is sustained in the majority of patients and is associated with a high likelihood of HBsAg loss, particularly in genotype A-infected patients. Therefore, PEG-IFN alpha-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy.

Early on‐treatment prediction of response to peginterferon alfa‐2a for HBeAg‐negative chronic hepatitis B using HBsAg and HBV DNA levels

Peginterferon alfa‐2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B (CHB). This study investigated the role of early on‐treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg‐negative patients receiving peginterferon alfa‐2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow‐up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa‐2a, n = 53, versus peginterferon alfa‐2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa‐2a treatment for HBeAg‐negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on‐treatment adjustments of peginterferon therapy for HBeAg‐negative CHB. (HEPATOLOGY 2010)

Serum HBsAg Decline During Long-term Potent Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B and Prediction of HBsAg Loss

Nucleos(t)ide analogues strongly inhibit viral replication in chronic hepatitis B (CHB) infection, but knowledge of their long-term effect on serum hepatitis B surface antigen (HBsAg) levels and HBsAg loss is lacking. Seventy-five CHB patients with virological response (VR) to ETV or TDF were included. HBsAg decline 2 years after VR was most pronounced in HBeAg-positive patients. Age, alanine aminotransferase, and HBeAg loss were associated with HBsAg decline in HBeAg-positive patients. Predicted median time to HBsAg loss was 36 years for HBeAg-positive and 39 years for HBeAg-negative patients. Thus, most patients treated with ETV and TDF will probably need decades of therapy to achieve HBsAg loss.

A Randomized Trial of Peginterferon α-2a With or Without Ribavirin for HBeAg-Negative Chronic Hepatitis B

OBJECTIVES:Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon α-2a with ribavirin might improve sustained response rates.METHODS:Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon α-2a 180 μg weekly plus placebo) or combination therapy (peginterferon α-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients.RESULTS:At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline −3.9 vs. −2.6 log copies/ml, P<0.001 and −0.56 vs. −0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia.CONCLUSIONS:Treatment with peginterferon α-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.

Diagnostic Yield Improves With Collection of 2 Samples in Fecal Immunochemical Test Screening Without Affecting Attendance

BACKGROUND & AIMS The fecal immunochemical test (FIT) is superior to the guaiac-based fecal occult blood test in detecting neoplasia. There are not much data on the optimal number of FITs to perform. We conducted a population-based trial to determine attendance and diagnostic yield of 1- and 2-sample FIT screening. METHODS The study included 2 randomly selected groups of subjects aged 50-74 years (1-sample FIT, n=5007; 2-sample FIT, n=3197). The 2-sample group was instructed to collect fecal samples on 2 consecutive days. Subjects were referred for colonoscopy when at least 1 sample tested positive (≥50 ng hemoglobin/mL). RESULTS Attendance was 61.5% in the 1-sample group (2979 of 4845; 95% confidence interval, 60.1%-62.9%) and 61.3% in the 2-sample group (1875 of 3061; 95% confidence interval, 59.6%-63.0%; P=.84). In the 1-sample group 8.1% tested positive, and in the 2-sample group 12.8% had at least 1 positive test outcome and 5.0% had 2 positive test outcomes (P<.05). When the mean from both test results in the 2-sample group was used, 10.1% had a positive test outcome (P<.05). The detection rates for advanced neoplasia were 3.1% in the 1-sample group, 4.1% in the 2-sample group with at least 1 positive test outcome, 2.5% when both test results were positive, and 3.7% among subjects with the mean from both test results being positive. CONCLUSIONS There is no difference in attendance for subjects offered 1- or 2-sample FIT screening. The results allow for the development of efficient FIT screening strategies that can be adapted for local colonoscopy capacities, rather than varying the cut-off value in a 1-sample strategy.

Attendance and Yield Over Three Rounds of Population-Based Fecal Immunochemical Test Screening

OBJECTIVES:Fecal immunochemical test (FIT) screening for colorectal cancer (CRC) requires timely successive rounds for an optimal preventive effect. However, data on attendance and trend in yield over multiple rounds of FIT screening are limited. We therefore conducted a consecutive third round of FIT screening in a population-based CRC screening trial.METHODS:Average-risk subjects aged 50–74 years were approached for three rounds of 1-sample FIT (OC-sensor) screening. Subjects with a hemoglobin level ≥50 ng/ml (≥10 μg Hb/g) feces were referred for colonoscopy. Subjects with a positive FIT in previous rounds were not re-invited for FIT screening.RESULTS:In the first round, 7,501 subjects were invited. The participation rate was 62.6% in the first round, 63.2% in the second round, and 68.3% in the third round (P<0.001). In total, 73% (5,241/7,229) of all eligible subjects participated in at least one of three rounds. The positivity rate was significantly higher in the first (8.4%) round compared with the second (6.0%) and third (5.7%) screening rounds (P<0.001). The detection rate of advanced neoplasia (AN) declined from the first round to subsequent rounds (round 1: 3.3%; round 2: 1.9%; and round 3: 1.3%; P<0.001). The positive predictive value for AN was 40.7% in the first screening round, 33.2% in the second screening round, and 24.0% in the third screening round (P<0.001).CONCLUSIONS:Repeated biennial FIT screening is acceptable with increased participation in successive screening rounds, and >70% of all eligible subjects participating at least once over three rounds. The decline in screen-detected AN over three screening rounds is compatible with a decreased prevalence of AN as a result of repeated FIT screening. These findings provide strong evidence for the effectiveness of FIT screening and stress the importance of ongoing research over multiple screening rounds.

Comparison of non-invasive assessment to diagnose liver fibrosis in chronic hepatitis B and C patients

Abstract Objective. Chronic viral hepatitis B and C cause liver fibrosis, leading to cirrhosis. Fibrosis assessment is essential to establish prognosis and treatment indication. We compared seven non-invasive tests, separately and in combination, in chronic hepatitis patients to detect early stages of fibrosis according to the Metavir score in liver biopsy. Material and methods. Galactose and methacetin breath tests (GBT and MBT), biomarkers (hyaluronic acid (HA), aspartate aminotransferase platelet ratio index (APRI), FibroTest, and Fib-4) and transient elastography (TE) were evaluated in 89 patients. Additionally, 31 healthy controls were included for evaluation of breath tests and biomarkers. Results. Serum markers (HA, APRI, FibroTest, and Fib-4) and elastography significantly distinguished non-cirrhotic (F0123) from cirrhotic (F4) patients (p < 0.001, p = 0.015, p < 0.001, p = 0.005, p = 0.006, respectively). GBT, HA, APRI, FibroTest, Fib-4, and TE detected F01 from F234 (p = 0.04, p = 0.011, p = 0.009, p < 0.001, p < 0.001, and p < 0.001, respectively). A combination of different tests (TE, HA, and FibroTest) improved the performance statistically, area under the curve (AUC) = 0.87 for F234, 0.92 for F34, and 0.90 for F4. Conclusion. HA, APRI, FibroTest, Fib-4, and TE reliably distinguish non-cirrhotic and cirrhotic patients. Except for MBT, all tests discriminate between mild and moderate fibrosis. As single tests: FibroTest, Fib-4, and TE were the most accurate for detecting early fibrosis; combining different non-invasive tests increased the accuracy for detection of liver fibrosis to such an extent and thus might be acceptable to replace liver biopsy.

Cost-effectiveness of one versus two sample faecal immunochemical testing for colorectal cancer screening

Objective The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT. Design The MISCAN–colon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive. Results Within an exemplary screening strategy, biennial FIT from the age of 55–75 years, one-sample FIT provided 76.0–97.0 life-years gained (LYG) per 1000 individuals, at a cost of €259 000–264 000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3–12.4 additional LYG compared with one-sample FIT at an extra cost of €50 000–59 000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT. Conclusion If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round.

Are Fecal Immunochemical Test Characteristics Influenced by Sample Return Time? A Population-Based Colorectal Cancer Screening Trial

OBJECTIVES:Fecal immunochemical tests (FIT) are preferred over guaiac-based fecal occult blood testing as colorectal cancer (CRC) screening tool. However, hemoglobin (Hb) degradation over time may influence FIT outcome. We therefore evaluated the effect of sample return time on FIT performance characteristics in a population-based CRC screening trial.METHODS:A representative random sample of the Dutch population (n=17,677), aged 50–74 years, was invited for FIT screening (OC-Sensor Micro; cutoff ≥ 50 ng Hb/ml). Sample return time was defined as the interval in days between fecal sampling and FIT laboratory delivery. Moreover, a random sample of positive FITs were selected to be stored at room temperature and re-tested every 3–4 days.RESULTS:In total, 8,958 screenees fulfilled our inclusion criteria. The mean sample return time was 3 days (± 3). Overall, 792 screenees (8.8%) had a positive test. Between the sample return time groups, the positivity rate (PR) varied between 7.7 and 9.0%. No statistically significant associations were found between PR or detection rate (DR) and the different sample return time groups (P value=0.84 and 0.76, respectively). For the laboratory experiment, 71 positive FITs were stored at room temperature and re-tested with standard intervals. The mean daily fecal Hb decrease was 5.88% per day (95% confidence interval 4.78–6.96%). None of the positive FITs became negative before 10 days after fecal sampling.CONCLUSIONS:This population-based CRC screening trial demonstrates that both the PR and DR of FITs do not decrease with prolonged sample return times up to 10 days. This means that a delay in sending the FIT back to the laboratory, of up to at least 1 week, does not necessitate repeat sampling in case of a negative test result. These data support the use of FIT-based screening as a reliable tool for nationwide CRC screening programs.

Tumor pyruvate kinase isoenzyme type M2 and immunochemical fecal occult blood test: performance in screening for colorectal cancer.

Objectives Immunochemical fecal occult blood test (FOBT) and determination of tumor pyruvate kinase isoenzyme type M2 (TuM2-PK) in stool samples may be valuable new screening tools for colorectal cancer (CRC). The aim of this study was to compare the accuracy of fecal TuM2-PK testing with immunochemical FOBT in patients with CRC or adenomas. Methods A total of 52 patients with CRC were analyzed, 47 with colorectal adenomas, and 63 matched controls with a normal colonoscopy. Nineteen additional patients with inflammatory bowel disease were tested to determine influence of inflammation. Stool samples were analyzed with two immunochemical FOBTs, Immo-care and OC-Light, and with a commercial enzyme-linked immunosorbent assay for TuM2-PK. Results In patients with CRC, the sensitivity of TuM2-PK, Immo-care and OC-Light was respectively 85, 92 and 94%. In patients with adenomas, the sensitivity was respectively 28, 40 and 34%. Specificity for these tests was 90% for TuM2-PK and 97% for both immunochemical FOBTs. All tests showed a high positivity rate in patients with inflammatory bowel disease (79% for TuM2-PK and Immo-care, and 89% for OC-Light). Conclusion Both immunochemical FOBTs appear valuable and are sensitive tests for CRC screening. TuM2-PK does not have supplemental value for screening for CRC because of a lower sensitivity and specificity. None of these tests is sensitive enough for detection of advanced adenomas. Patients with inflammatory bowel disease should be excluded from CRC screening when using immunochemical FOBT or TuM2-PK.