Is hepatitis B immunoglobulin necessary in prophylaxis of hepatitis B recurrence after liver transplantation? A meta-analysis.
ABSTRACT: Application of nucleoside analogues and hepatitis B immunoglobulin (HBIG) has reduced hepatitis B virus (HBV) recurrence rate after liver transplantation (LT) dramatically. Recent data suggests therapy without HBIG is also effective. We sought to evaluate the necessity of HBIG in prophylaxis of HBV recurrence after LT.A meta-analysis was performed. PubMed/MEDLINE, Web of Knowledge and other databases were searched for eligible literatures. The major end points were recurrence rate, patient survival, and YMDD mutant. Risk difference (RD) or risk ratio (RR) was calculated to synthesize the results.Nineteen studies with a total of 1484 patients were included in this analysis. Application of HBIG was helpful to reduce HBV recurrence [P<0.001; RD?=?0.16; 95% confidence interval (CI)(0.12, 0.20)] and virus mutants [P<0.001; RR?=?3.13; 95%CI (1.86-5.26)], it also improved patients' 1-year [P?=?0.03; RD?=?0.08; 95%CI (0.01, 0.15)] and 3-year survival rates [P?=?0.005; RD?=?0.17; 95%CI(0.05, 0.28)]. No significant difference was found for patients' 5-year survival [P?=?0.46; RD?=?-0.06; 95%CI (-0.21, 0.10)]. Sub-group analysis showed that in patients with positive pre-operative HBV DNA status, HBIG was necessary to reduce HBV recurrence rate (P<0.001; RD?=?0.42; 95%CI (0.32, 0.52)). In patients with negative HBV DNA, combined therapy gained no significant advantages (P?=?0.18; RD?=?0.06; 95%CI (-0.03, 0.14)). Non-Lamivudine (non-LAM) antiviral drugs performed as well as combination therapy in prophylaxis of HBV recurrence after LT (P?=?0.37; RD?=?0.06; 95%CI (-0.02, 0.14)).HBIG with nucleoside analogues is helpful to reduce HBV recurrence and virus mutants. The necessity of HBIG in prophylaxis of HBV recurrence after LT when using new potent nucleoside analogues, especially for patients with negative pre-transplant HBV DNA status remains to be evaluated.
Project description:BACKGROUND:Recurrence of Hepatitis B Virus infection in patients undergoing liver transplanted (LT) is a serious and often fatal problem. Lamivudine (LAM) and Hepatitis B Immunoglobulin (HBIG) are widely used to manage hepatitis B recurrence after liver transplantation. However, the outcomes in patients are less elucidated. OBJECTIVES:The current study aimed to evaluate the YMDD motif mutations profile among the patients undergoing LT infected with HBV and treated with LAM/HBIG at least for one year. PATIENTS AND METHODS:Thirty patients with liver transplantation due to HBV were enrolled, while DNA level remained under detection limit of 50 IU/mL before transplantation and abnormal higher levels of liver enzymes after LT. The HBV genome detection was performed by two different Polymerase Chain Reaction methods following viral quantification by commercial Real-Time PCR. HbsAg detection, besides liver function tests were conducted as complementary assays. To assess nucleotide analogue mutations, the major part of polymerase gene (aa 80 - 240) was amplified by Nested-PCR, introduced to sequencing and subjected to phylogenetic analysis. RESULTS:Totally, according to the laboratory criteria there were 13 cases with detectable HBV genome, while the mean liver enzyme levels were higher in recurrent patients and HBsAg was detected only in four out of the 13 cases. Phylogenetic analysis demonstrated that all isolated genomes belonged to genotype D. Critical M204I mutation, as a proof for resistance to LAM, was detected among 46% of the subjects and natural entecavir resistance (S202I) was also distinguished in one subject. Viral quantification showed higher titer in LAM resistant group in comparison to the group with undetectable drug resistance mutant (P > 0.05). CONCLUSIONS:Although the patients carrying M204I mutation were more likely to show lack of responses to LAM therapy, LAM replacing by other nucleoside/tide analogs plus HBIG maybe still effective in decreasing hepatitis B recurrence after liver transplantation. However, it is suggested that drug resistance test should be considered by clinicians during therapeutic management to avoid the following viral breakthrough.
Project description:Background:Perinatal transmission is the main route of hepatitis B virus (HBV) transmission. While several measures have been attempted as means of preventing perinatal HBV transmission, the optimal strategy remains inconclusive. Methods:We conducted a comprehensive search, through December 2016, for randomized controlled trials (RCTs) that compared the following measures among pregnant women with HBV infection: placebo/none, active immunoprophylaxis (hepatitis B vaccine series starting at birth [HBVac]), passive-active immunoprophylaxis (hepatitis B immunoglobulin and vaccine [HBIG+HBVac]), prenatal HBIG administration (HBIG/HBIG+HBVac), and prenatal antiviral therapy (AVT/HBIG+HBVac). Direct, indirect, and network meta-analyses were performed for all treatment comparisons. Results:Fifteen RCTs involving 2706 infants of HBV carrier mothers were eligible for analysis. Network meta-analysis demonstrated similar results as direct and indirect comparisons. HBVac alone significantly reduced the risk of hepatitis B infection in infants of HBV carrier mothers (relative risk [RR], 0.32; 95% confidence interval [CI], 0.21-0.50). The combination of immunoglobulin with vaccine is superior to vaccine alone (RR, 0.37; 95% CI, 0.20-0.67). Prenatal HBIG administration and antiviral therapy offer further advantages over current passive-active immunoprophylaxis for infants of highly viremic (HBV DNA level higher than 2 × 105 IU/mL) mothers (RR, 0.47; 95% CI, 0.29-0.75; and RR, 0.31; 95% CI, 0.10-0.99, respectively). There was no significant publication bias. Conclusions:Based on the universal infantile vaccination program, HBIG for infants born to HBV carrier mothers further reduces transmission. For highly viremic mothers whose children are still at risk for transmission under current immunoprophylaxis, prenatal HBIG administration or antiviral therapy in late pregnancy may be considered if more long-term evidence supports its efficacy and safety.
Project description:Prophylactic administration of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NAs) is the standard treatment for controlling hepatitis B virus (HBV) recurrence after liver transplantation (LT). Since lifelong use of HBIG is expensive and inconvenient and the antibodies level in anti-hepatitis B surface (HBs) is not sustainable and stable, an alternative strategy is to produce anti-HBs antibodies by active immunization. Our present study aimed to prospectively investigate the efficacy and safety of procedural HBV vaccination in transplanted patients.Recipients who had undergone LT for hepatitis B related liver diseases more than one year before, with no evidence of HBV recurrence or rejection and normal liver function were enrolled. All subjects received the hepatitis B vaccine (40 ?g) by intramuscular injection at months 0, 1, 2, 6 and 12 after enrollment with continuous administration of NAs. The liver function and anti-HBs titers were measured before each vaccination and HBIG (400U) was administrated intramuscularly when anti-HBs titer was lower than 30 IU/L during the course. The results of routine blood tests, liver function, concentration of immunosuppressant, and HBV-DNA copies were monitored during the research. After completion of the vaccination procedure, recipients were regarded as responders if their anti-HBs greater than 30 IU/L were maintained for up to six months without using HBIG and vaccine.Twenty-seven patients were enrolled in this study and the average anti-HBs titer before vaccination was 19.86±14.80 IU/L. The average anti-HBs titer of the nine responders at the end of the follow-up was 57.14±22.75 IU/L, giving an overall response rate of 33.3% (9/27). There were no reports of reactivation of HBV, rejection, severe anaphylaxis or other adverse events. Responders and non-responders showed their significant difference in anti-HBs titers after the fourth vaccination (P<0.01). Moreover, the majority of non-responders (11/18, 63.64%) had high LY/EO rates (lymphocyte number/eosinophil number>15) while most responders (8/9, 88.89%) had low LY/EO rates at the beginning of vaccination (P = 0.019).Active immunization is an effective, cost-saving, and safe method for the prevention of HBV reactivation in patients transplanted for hepatitis B virus related liver diseases. The LY/EO rate may be a valuable indicator in selecting potential recipients for vaccination.
Project description:BACKGROUND:Mother-to-child transmission of hepatitis B virus (HBV) is the main cause of new infections worldwide. We aimed at assessing the percentage of infants successfully immunized in two major hospitals in Vientiane, Lao PDR where HB immune globulin (HBIg) is not available. METHODS:We studied a prospective cohort of chronically HBV infected pregnant women and their infants until 6 months post-partum from January 2015 to March 2017. All infants received HB vaccine at birth and 6, 10 and 14 weeks thereafter, and HBV status was assessed at 6 months of age. HBV surface gene sequencing was performed in infected mother-infant pairs. RESULTS:Of 153 mothers with HB surface antigen (HBsAg), 60 (39%) had detectable serum HBe antigen (HBeAg). HBeAg positive pregnant women were younger than those negative (median age 26 versus 28 years; p = 0.02) and had a significantly higher HBV viral load at delivery (median 8.0 versus 4.0 log10 IU/mL, p <0.001). Among the 120 infants assessed at 6 months of age, 5 (4%) were positive for HBsAg and had detectable HBV viral load by polymerase chain reaction. All were born to mothers with HBeAg and viral load >8.5 log10 IU/mL. However, only four (3.3%, 95% CI 0.5% to 7.0%) had a virus strain closely related to their mother's strain. HBV surface gene mutations were detected in 4 of the 5 infected infants. Anti-HBs antibody levels were below 10 IU/L in 10 (9%) uninfected infants at 6 months of age. CONCLUSIONS:Mother-to-child transmission occurred less frequently than expected without the use of HBIg. Adding HBIg and/or maternal antiviral prophylaxis may have prevented some of these infections. The observation of unsatisfactory levels of anti-HBs antibodies in 9% of the uninfected infants at 6 months highlights the need for improvement of the universal immunization procedures.
Project description:Antiviral drugs have been recommended as prophylaxis for the reactivation of hepatitis B virus (HBV) infection in cancer patients undergoing chemotherapy. However, screening and antiviral prophylaxis for lung cancer remain controversial because of insufficient evidence.In this study, we investigate the absolute risk for HBV reactivation and the prophylactic effects of antiviral drugs in hepatitis B surface antigen (HBsAg)-positive lung cancer patients during chemotherapy.We searched Pubmed, Embase, Cochrane, Web of Science and SinoMed from inception until 28 November 2016, and identified all potential relevant references with or without prophylactic use of antiviral therapy in HBsAg-positive lung cancer patients during chemotherapy. The primary outcome was the incidence of HBV reactivation, the secondary outcomes were the incidence of hepatitis, chemotherapy disruption and mortality.Eleven studies involving 794 patients were analyzed. The incidences of HBV reactivation in control group and antiviral prophylaxis group ranged from 0% to 38% (median, 21%, 95% CI: 0.17-0.25) and 0% to 7% (median, 4%, 95% CI: 0.02-0.06), respectively. Antiviral prophylaxis had significantly reduced the risk for HBV reactivation (RR, 0.22 [95% CI: 0.13-0.37], p< 0.0001), hepatitis (RR, 0.35 [95% CI: 0.22-0.56], p<0.0001) and chemotherapy disruption (RR: 0.29 [95% CI, 0.15-0.55], p<0.0002) compared to those without antiviral prophylaxis. There was no significant heterogeneity in the comparisons, and a fixed-model was used.The risks of HBV reactivation and relevant complications are high in HBsAg-positive lung cancer patients receiving chemotherapy, and available evidences support HBV screening for antiviral prophylaxis before initiation of chemotherapy for lung cancer patients.
Project description:Hepatitis B virus (HBV) produces large (L), middle (M), and small (S) envelope proteins, alternatively referred to as hepatitis B surface antigen (HBsAg). Currently, yeast-derived S protein serves as the preventive vaccine, while hepatitis B immune globulin (HBIG) concentrated from pooled plasma of vaccine recipients is employed for post-exposure prophylaxis. However, only a small proportion of the antibodies in HBIG are HBV specific. In the present study, a human monoclonal anti-S antibody (G12) was developed, produced under GLP conditions, and subjected to a panel of functional assays. In vitro results demonstrated high affinity of G12 for the S protein (KD = 7.56 nM). It reacted with envelope proteins of all 7 HBV genotypes tested (A-F, H) by immunofluorescent staining, and more than 97% of HBsAg-positive patient serum samples by enzyme-linked immunosorbent assay. G12 recognized a conformational epitope, although the exact sequence remains unknown. Strikingly, G12 was at least 1,000-fold more potent than HBIG in neutralizing HBV infectivity in both HepaRG cell line and HepG2 cells reconstituted with the HBV receptor. In a transgenic mouse model of HBV persistence, a single peritoneal injection of G12 markedly diminished serum HBsAg titers in all 7 mice, which was sustained for the observation period of 144 d in mice with low pre-treatment levels. While the therapeutic potential of G12 warrants further investigation using a large number of animals, G12 is a potent neutralizing human monoclonal antibody and a promising candidate to replace or supplement HBIG in the prevention of HBV infection.
Project description:BACKGROUND:Data on the cost effectiveness of hepatitis B virus (HBV) screening and vaccination strategies for prevention of vertical transmission of HBV in resource limited settings is sparse. METHODS:A decision tree model of HBV prevention strategies utilised data from a cohort of 7071 pregnant women on the Thailand-Myanmar border using a provider perspective. All options included universal HBV vaccination for newborns in three strategies: (1) universal vaccination alone; (2) universal vaccination with screening of women during antenatal visits with rapid diagnostic test (RDT) plus HBV immune globulin (HBIG) administration to newborns of HBV surface antigen positive women; and (3) universal vaccination with screening of women during antenatal visits plus HBIG administration to newborns of women testing HBV e antigen positive by confirmatory test. At the time of the study, the HBIG after confirmatory test strategy was used. The costs in United States Dollars (US$), infections averted and incremental cost effectiveness ratios (ICERs) were calculated and sensitivity analyses were conducted. A willingness to pay threshold of US$1200 was used. RESULTS:The universal HBV vaccination was the least costly option at US$4.33 per woman attending the clinic. The HBIG after (RDT) strategy had an ICER of US$716.78 per infection averted. The HBIG after confirmatory test strategy was not cost-effective due to extended dominance. The one-way sensitivity analysis showed that while the transmission parameters and cost of HBIG had the biggest impact on outcomes, the HBIG after confirmatory test only became a cost-effective option when a low test cost was used or a high HBIG cost was used. The probabilistic sensitivity analysis showed that HBIG after RDT had an 87% likelihood of being cost-effective as compared to vaccination only at a willingness to pay threshold of US$1200. CONCLUSIONS:HBIG following confirmatory test is not a cost-effective strategy for preventing vertical transmission of HBV in the Thailand-Myanmar border population. By switching to HBIG following rapid diagnostic test, perinatal infections will be reduced by nearly one third. This strategy may be applicable to similar settings for marginalized populations where the confirmatory test is not logistically possible.
Project description:OBJECTIVE:The purpose of this study was to evaluate the efficacy of different nucleos(t)ide analogues in the prognosis of HBV-related hepatocellular carcinoma (HCC) patients after curative treatment by network meta-analysis. METHODS:Literature retrieval was conducted in globally recognized databases, namely, PubMed, EMBASE, Cochrane Library databases, and Science Citation Index Expanded, to address relative studies investigating nucleot(s)ide analogues for HBV-related HCC patients after curative resection. Relative parametric data, including 1-, 3-, and 5-year overall survival rate and 1-, 3-, and 5-year recurrence-free survival rate were quantitatively pooled and estimated. The inconsistency factor, the cumulative ranking curve, and the publication bias were evaluated. RESULTS:Fourteen observational studies of 2481 adults performed between 2000 and 2019 were eligible. In terms of overall survival, ADV (Adefovir dipivoxil) (Odds ratio (OR): 2.35, 95% confidence interval (CI): 1.17-4.73), Lamivudine (OR: 2.08, 95% CI: 1.78-5.58), and Entecavir (OR: 2.14, 95% CI: 1.59-2.88) were found to be more beneficial than control group while ADV has the highest probability of having the most efficacious treatment (SCURA values 66.3) for 5-year overall survival. In late recurrence-free survival, ADV (OR?=?1.88, 95% CI: 1.77-4.60), Entecavir (OR?=?1.96, 95% CI: 1.36-2.55), and Lamivudine (OR?=?1.73, 95% CI: 1.06-2.82) all had better significant prognosis than patients without antiviral therapy postoperatively and patients with ADV as postoperative antiviral therapy has significantly recurrence-free survival benefit at 5-year follow-up compared to those undertaking Entecavir (OR?=?1.96, 95% CI: 1.52-7.38) and Lamivudine (OR?=?1.39, 95% CI: 1.09-3.01). Moreover, the application of ADV possessed the highest possibility of having the best clinical effects on 1- (surface under the cumulative ranking probabilities (SUCRA), 64.7), 3- (SUCRA, 64.7), and 5-year (SUCRA, 70.4) recurrence survival rate for HBV-related HCC patients. CONCLUSIONS:Patients with postoperative nucleos(t)ide analogues antiviral therapy had better survival benefit than those without antiviral therapy for HBV-related HCC patients after curative treatment. Additionally, nucleotide analogues like ADV and Tenofovir disoproxil fumarate has better impact on early and late recurrence-free survival of patients after curative treatment than those undertaking nucleoside analogues.
Project description:Currently, no consensus exists regarding the optimal oral prophylactic regimens for hepatitis B surface antigen seropositive patients undergoing chemotherapy. We aimed to compare the efficacy of oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of chemotherapy-induced hepatitis B virus (HBV) reactivation and its related morbidity and mortality in patients with chronic HBV (CHB) infection.Fifty-two eligible articles consisting of 3892 participants were included. For HBV reactivation, prophylactic treatment with NAs were all significantly superior to no prophylaxis, with odds ratio (OR) from 0.00 (95% confidence interval [CI] 0.00~0.04) for the most effective intervention (tenofovir) to 0.10 (95% CI 0.06~0.14) for the least effective intervention (lamivudine). For secondary outcomes, prophylaxis with NAs also significantly outperformed observation. The results suggested that entecavir reduced the risk of HBV related hepatitis (predicted probability, 83%), HBV related death (68%) and all causes of hepatitis (97%) most efficaciously. It ranked second in decreasing all causes of death (34%).PubMed, Embase and Cochrane Library database were searched for controlled trials up to March 31, 2015. Primary outcome was the incidence of HBV reactivation. Secondary outcomes included the incidence of HBV-related hepatitis and death, all causes of hepatitis and death. Network meta-analysis combined direct and indirect evidence to estimate ORs for the clinical outcomes. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment based on clinical outcomes.Available evidence suggests that prophylatic therapy with tenofovir and entecavir may be the most potent interventions in prevention of HBV reactivation and HBV-related morbidity and mortality for CHB infection patients undergoing chemotherapy.
Project description:Although routine immunoprophylaxis has been known to reduce hepatitis B virus (HBV) transmission, immunoprophylaxis failure still occurs. The study aimed to investigate the protective efficacy of an improved immunoprophylaxis protocol to prevent mother-to-infant transmission of HBV and to explore the potential risk factors associated with immunoprophylaxis failure and low antibody response.A prospective observational cohort study was conducted from July 2012 to April 2015. A total of 863 HBsAg-positive mothers and their 871 infants (8 pairs of twins) were included in the study. Two different hepatitis B vaccine doses (20 or 10??g) were administered to the infants based on the hepatitis B e-antigen (HBeAg) status of their mothers. Simultaneously, hepatitis B immunoglobulin (HBIG) was administered to the infants. Initial injections of HBIG and the hepatitis vaccine were given within 2?hours after birth. Rates of HBV infections among the infants were evaluated at 7 months of age. Factors associated with immunoprophylaxis failure and low responses to vaccination were analyzed by unconditional logistic regression..At 7 months of age, no immunoprophylaxis failure was observed in the 565 infants born to HBeAg-negative mothers. Among the 306 infants born to HBeAg-positive mothers, immunoprophylaxis failed in 16 infants (5.2%) of the infants and they were found to be HBsAg-positive. Further analysis showed that HBV DNA levels ?10?IU/mL [odds ratio (OR)?=?4.53, 95% confidence interval (95% CI): 1.19-17.34], delayed vaccination (OR?=?4.14, 95% CI: 1.00-17.18), and inadequate initial injections (OR?=?7.69, 95% CI: 1.71-34.59) were independently associated with immunoprophylaxis failure. Adequate titers of antibody to HBsAg (anti-HBs, ?100?mIU/mL) were present in 96.5% of immunoprophylaxis-successful infants. For full-term infants, birth weights <3000?g were correlated with low immune responses to vaccination.This improved immunoprophylaxis protocol is effective in preventing perinatal transmission of HBV. Among infants with HBeAg-positive mothers, high HBV viral loads and inadequate and delayed initial injections were associated with immunoprophylaxis failure. The majority of the infants in our study produced adequate levels of protective anti-HBs titers after immunoprophylaxis. Additional efforts to further reduce perinatal transmission should be considered, especially for HBeAg-positive mothers.