Serial Monitoring and Hyperimmunoglobulin versus Standard of Care to Prevent Congenital Cytomegalovirus Infection: A Phase III Randomized Trial.

INTRODUCTION: Nonrandomized studies support the potential of cytomegalovirus hyperimmunoglobulin (CMV-HyperIg) in preventing maternofetal CMV transmission, but prospective interventional studies show equivocal results. We pre-sent a prospective phase-III international randomized open-label trial on the potential effect of CMV-HyperIg following serial monitoring of CMV serostatus. METHODS: CMV-seronegative pregnant women (gestational age [GA] <14 weeks) were 1:1 randomized to monthly CMV-serostatus monitoring and CMV-HyperIg upon seroconversion (treatment), or routine prenatal care with CMV-serostatus testing at end of pregnancy (control). Ethical considerations required that control subjects with confirmed seroconversion be offered Cytotect®. The primary endpoint was the proportion of fetuses/newborns with congenital CMV infection. Secondary endpoints included neonatal CMV disease and safety during the 24-month follow-up. RESULTS: The treatment arm counted 4,800 randomized subjects: 52 seroconverted (median GA 24 [11-35] weeks), of which 45 completed follow-up. The control arm counted 4,735 randomized subjects: 42 seroconverted, of which 34 completed follow-up (evaluable data for 28 newborns) and 8 subjects chose off-label Cytotect®. Congenital CMV rates were 13/28 newborns (46.4% [CI 27.51; 66.13]) vs. 16/45 newborns (35.6% [CI 21.87; 51.22]) in control and treated arms, respectively (p = 0.46). Newborn CMV disease was mostly mild and spontaneously resolving. There were no major safety concerns. The target sample was not reached within an acceptable time frame. CONCLUSIONS: Serial monitoring of CMV serostatus with CMV-HyperIg treatment was associated with a mild nonsignificant reduction in the vertical CMV transmission rate. Studies on the optimal preventive strategy are hampered by epidemiological and ethical challenges and should focus on GA-dependent transmission rates and accurate dating of infection.

Recurrence of Hepatitis B Infection in Liver Transplant Patients Receiving Long-Term Hepatitis B Immunoglobulin Prophylaxis.

BACKGROUND Long-term real-world data are relatively sparse regarding recurrence of chronic hepatitis B virus (HBV) infection after liver transplantation using hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogue (NUC) prophylaxis. MATERIAL AND METHODS Data from 371 adults transplanted for HBV-related disease at 20 European centers and given HBIg for ³12 months ± NUC therapy were analyzed retrospectively. RESULTS HBIg comprised Hepatect® (iv HBIgB; n=299), subcutaneous Zutectra® (sc HBIg, n=236), and other HBIg preparations (n=130); 93.5% received NUC therapy. Mean follow-up was 6.8±3.5 years. The primary efficacy variable, freedom from HBV recurrence, occurred in 95.7% of patients (95% CI [93.1%, 97.5%]). The observed incidence of recurrence was 16/371 (4.3%) (annual rate 0.65%); 5/16 patients with recurrence had discontinued HBIg and 7/16 had anti-HBs <100 IU/l. Excluding these 7 patients, the HBV recurrence rate was 2.4%. The recurrence rate while on HBIg therapy was 1 per 2069 months. In patients who discontinued HBIg, risk of HBV recurrence versus sc HBIg users was increased by 5.2-fold (1 per 1 603 versus 1 per 8379 treatment months). The annual rate of HBV-related hepatocellular carcinoma (HCC) recurrence was 1.7%. CONCLUSIONS These results support the long-term use of HBIg with NUC therapy as an effective management strategy to minimize risk of HBV recurrence and virus-related complications after liver transplantation.

Early Introduction of Subcutaneous Hepatitis B Immunoglobulin Following Liver Transplantation for Hepatitis B Virus Infection: A Prospective, Multicenter Study.

BACKGROUND: Subcutaneous administration of hepatitis B immunoglobulin (HBIg) is effective in preventing hepatitis B virus (HBV) recurrence after liver transplantation, but early conversion to subcutaneous administration is undocumented. METHODS: In a prospective study, patients transplanted for terminal liver disease due to HBV infection who were HBV DNA-negative at transplant were switched by week 3 posttransplantation from intravenous to subcutaneous HBIg (500 or 1000 IU weekly or fortnightly, adjusted according to serum anti-HBs trough level) if they were HBsAg- and HBV-DNA negative at time of switch. All patients concomitantly received nucleos(t)ide analogue antiviral therapy. Primary endpoint was failure rate by month 6, defined as serum anti-HBs of 100 IU/L or less or HBV reinfection despite serum anti-HBs greater than 100 IU/L. RESULTS: Of 49 patients treated, 47 (95.9%) continued treatment until month 6. All patients achieved administration by a caregiver or self-injection by week 14. No treatment failures occurred. Mean anti-HBs declined progressively to month 6, plateauing at a protective titer of approximately 290 IU/L. All patients tested for HBV DNA remained negative (45/45). Only 1 adverse event (mild injection site hematoma) was assessed as treatment-related. CONCLUSIONS: Introduction of subcutaneous HBIg administration by week 3 posttransplantation, combined with HBV virostatic prophylaxis, is effective and convenient for preventing HBV recurrence.

Compliance and tolerability of subcutaneous hepatitis B immunoglobulin self-administration in liver transplant patients: a prospective, observational, multicenter study.

BACKGROUND: Subcutaneous self-administration of hepatitis B immunoglobulin (HBIg) prophylaxis is preferred by patients, but compliance with the assigned regimen in routine practice is undocumented. MATERIAL AND METHODS: A prospective, observational, 18-week, open-label, single-arm, multicenter study assessed compliance and tolerability in maintenance liver transplant patients self-administering subcutaneous HBIg at home according to local practice. RESULTS: Sixty-one patients were analyzed (median follow-up 18 weeks, range 14.0-27.9 weeks), with 961/1006 injections (95.5%) administered at home during the study. Other than in 4 patients, HBIg was prescribed for weekly administration (500 IU/L, n=39; 1000 IU/L, n=18) at study entry. Eighteen patients (29.5%) were assigned a dose lower than recommended in the Summary of Product Characteristics. The primary variable of compliance failure, defined as ≥ 1 hepatitis B surface antibody (anti-HBs) serum trough level <100 IU/L, occurred in 4 patients (6.6%; 95% CI 1.8%, 15.9%), 3 of whom were receiving a dose below that recommended for their body weight. Anti-HBs levels exceeded 100 IU/L in all patients at the final visit. Mean (SD) anti-HBs level at the first and final study visits was 248 (97) IU/L and 255 (104) IU/L, respectively. Patient compliance was graded good or very good by physicians in 91.8% of cases. No patients tested positive for HBsAg or HBV-DNA. Four patients experienced ≥ 1 adverse drug reactions, none of which was serious. No patient discontinued HBIg due to adverse events. CONCLUSIONS: Subcutaneous HBIg home-based self-administration under routine, real-life conditions is well-tolerated and associated with high compliance and maintaining protective anti-HBs serum concentration.

Ablation of nonneoplastic Barrett's mucosa using argon plasma coagulation with concomitant esomeprazole therapy (APBANEX): a prospective multicenter evaluation.

BACKGROUND: Complete reversal of Barrett's epithelium (BE) achieved by treatment with argon plasma coagulation (APC) is variable. The aim of this prospective study was to evaluate the effectiveness of high-power APC in a multicenter trial. METHODS: In seven study centers, 60 patients (mean age 57, range 27-77) with nonneoplastic BE (length 1-8 cm) were recruited for treatment with high-power APC (90 W) in combination with esomeprazole 80 mg/day. Video endoscopy, chromoendoscopy, and four-quadrant biopsies (4QB) were carried out during baseline endoscopy and regular intervals. The effect of ablation was classified as complete remission (CR), partial remission, or minor response. RESULTS: Fifty-one of the 60 patients completed ablation therapy. Three patients were lost to follow-up (FU). After a mean of 2.6 APC sessions (range 1-5) and a mean FU of 14 months (range 12-32), CR was achieved in 37 of 48 patients (77%). Major complications occurred in five of 51 patients (9.8%). CONCLUSIONS: Complete ablation of BE can be achieved in a high percentage of patients even in a multicenter design using high-power APC. However, APC has a relevant morbidity. Therefore, ablation of nonneoplastic BE cannot be recommended generally because incidence of cancer in BE is low.