Maternal knowledge of the risk of vertical transmission and offspring acquisition of hepatitis B.

INTRODUCTION AND OBJECTIVES: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. MATERIALS AND METHODS: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. RESULTS: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p=0.02) or diagnosis of HBV (p=0.02). CONCLUSIONS: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5-15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.

Total Alanine Aminotransferase (ALT) Flares in Pregnant North American Women With Chronic Hepatitis B Infection: Results From a Prospective Observational Study.

INTRODUCTION: Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV. METHODS: Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy. RESULTS: Among the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation. DISCUSSION: Spontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.

Nonalcoholic steatohepatitis: the new frontier for liver transplantation.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease globally and nonalcoholic steatohepatitis is projected to become the most common indication for liver transplantation. The purpose of this review is to highlight key issues surrounding NAFLD as an indication for liver transplantation, including its increasing prevalence, outcomes related to liver transplantation, development of post liver transplant NAFLD and NAFLD in the liver donor pool. RECENT FINDINGS: With the advent of direct-acting antiviral therapies, the proportion of patients on the liver transplant list or undergoing liver transplant for chronic hepatitis C infection is steadily decreasing. In contrast, the number transplants performed for NAFLD is increasing. By 2030, it is estimated that the incidence of decompensated cirrhosis and hepatocellular carcinoma will increase by 168 and 137%, respectively, and the number of deaths will increase by 178%. SUMMARY: Liver transplantation cures cirrhosis but does not treat the underlying metabolic disease associated with NAFLD. Thus, strategies to control comorbidities in patients with NAFLD prior to transplant are needed to decrease waitlist mortality and the recurrence of NAFLD after liver transplant. NAFLD in the donor pool is also a growing concern. Strategies to minimize steatosis and expand the number of donors are critical to meet the growing demand for liver transplantation.

Sustained virologic response rates with telaprevir-based therapy in treatment-naive patients evaluated by race or ethnicity.

BACKGROUND: The phase 3 studies of telaprevir (T) in combination with peginterferon α-2a and ribavirin (PR) in treatment-naive genotype 1 chronic hepatitis C virus-infected patients (ADVANCE/ILLUMINATE) were not designed a priori to assess the effect of race and ethnicity on treatment response. However, these factors are important given the lower sustained virologic response (SVR) rates observed in black and Hispanic/Latino patients treated with PR. GOALS: This retrospective pooled analysis evaluated the effect of race or ethnicity on treatment-naive patient response to telaprevir-based therapy and assessed resistant variant profiles. MATERIALS AND METHODS: This analysis comprised patients enrolled in ADVANCE (N=363) and ILLUMINATE (N=540) who received 12 weeks of telaprevir in combination with PR followed by 12 or 36 weeks of PR alone and patients in ADVANCE (N=361) who received 48 weeks of PR alone. Race and ethnicity were self-reported and not mutually exclusive. RESULTS: Higher SVR rates were observed with telaprevir-based therapy compared with PR in blacks [n=99 (62%) vs. n=28 (29%), respectively] and in Hispanics/Latinos [n=89 (72%) vs. n=38 (39%)]. The SVR was lower in telaprevir-treated blacks [n=99 (62%)] compared with nonblacks [n=791 (78%)] and in Hispanic/Latinos compared with non-Hispanics/Latinos [n=89 (72%) vs. n=801 (76%)]. Low discontinuation rates due to adverse events, including rash and anemia, were observed across subgroups. Resistance profiles were similar among the subgroups. CONCLUSIONS: Treatment-naive black and Hispanic/Latino patients with genotype 1 chronic hepatitis C virus infection may benefit from telaprevir-based therapy, an important finding given the lower SVR rates observed in these patients when they are treated with PR alone.

Telaprevir for previously untreated chronic hepatitis C virus infection.

BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).

Acute liver failure caused by herpes simplex virus in a pregnant patient: is there a potential role for therapeutic plasma exchange?

A young woman presented with a febrile illness in the third trimester of pregnancy. Laboratory investigation revealed severe acute hepatitis with thrombocytopenia and coagulopathy. Liver injury progressed despite emergent caesarian section and delivery of a healthy infant. Therefore, therapeutic plasma exchange (TPE) was performed on three consecutive days post-partum for a presumed diagnosis of acute liver failure (ALF) associated with pregnancy due to hemolysis, elevated liver enzymes, and low platelets (HELLP) or acute fatty liver of pregnancy (AFLP). Treatment with TPE was followed by biochemical and clinical improvement but during her recovery herpes simplex virus type 2 (HSV-2) infection was diagnosed serologically and confirmed histologically. Changes in the immune system during pregnancy make pregnant patients more susceptible to acute HSV hepatitis, HSV-related ALF, and death. The disease is characterized by massive hepatic inflammation with hepatocyte necrosis, mediated by both direct viral cytotoxicity and the innate humoral immune response. TPE may have a therapeutic role in acute inflammatory disorders such as HSV hepatitis by reducing viral load and attenuating systemic inflammation and liver cell injury. Further investigation is needed to clarify this potential effect. The roles of vigilance, clinical suspicion, and currently accepted therapies are emphasized.

Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy.

BACKGROUND & AIMS: The immunosuppressive treatment for autoimmune hepatitis (AIH) patients is prednisone and azathioprine. Ten percent to 20% of patients do not respond or are intolerant of standard treatment. The aim of this study was to assess the biochemical, histologic, and hematologic parameters during mycophenolate mofetil (MMF) treatment in AIH patients who did not respond to or were intolerant of prednisone and/or azathioprine. METHODS: A retrospective study was performed of 15 AIH patients who received MMF either as monotherapy or in combination with prednisone after failure or intolerance of the initial regimen. Records were reviewed as to initial therapy, reasons why MMF was initiated, liver enzyme levels, histology on MMF, and complications. RESULTS: The mean age was 60 +/- 15 years. All patients were started on MMF at 1 gram twice a day, 3 on MMF monotherapy, and 12 on prednisone and MMF. The average MMF treatment duration was 41 months. Alanine aminotransferase levels decreased significantly from 91.73 +/- 88.69 to 60.87 +/- 71.2 (P = .03) on MMF treatment. Inflammatory scores (2.59 +/- 0.97 to 1.14 +/- 1.21, P = .02) and Ishak fibrosis scores (4.10 +/- 1.37 to 2.5 +/- 1.51, P = .02) also decreased. No significant hematologic complications were noted during MMF treatment. CONCLUSIONS: Administration of MMF, either as monotherapy or in combination with prednisone, results in biochemical and histologic improvement in AIH patients who are prednisone and/or azathioprine intolerant or resistant without the development of significant complications. MMF should be studied prospectively as an alternative agent in the treatment of autoimmune liver disease.

Outcomes of patients with hepatitis B who developed antiviral resistance while on the liver transplant waiting list.

BACKGROUND & AIMS: Lamivudine has been shown to improve liver disease and survival of hepatitis B virus patients on the orthotopic liver transplantation (OLT) waiting list, but liver failure might worsen in patients with drug resistance. Use of antiviral salvage therapy might decrease this risk. METHODS: We analyzed data from patients enrolled in the NIH HBV OLT cohort to study the effects of pretransplant antiviral therapy on transplant-free survival and survival without transplant. We also compared the clinical outcomes of those who did or did not develop antiviral failure (virologic breakthrough or genotypic resistance) while awaiting transplant. RESULTS: One hundred twenty-two eligible patients received antiviral therapy before OLT and were followed for a median of 40.5 months (range, 0.4-123.0 months) after initiation of antiviral therapy. Forty-four (36.1%) patients developed antiviral failure; all had lamivudine monotherapy as initial treatment. Forty-two patients started salvage therapy a median of 5 months after lamivudine failure; the median Model for End-Stage Liver Disease (MELD) score was 12. Twenty-one (50%) patients had a full response to salvage therapy. Eleven (26.2%) patients had a suboptimal virologic response but remained clinically compensated. Antiviral failure was not a significant predictor of transplant or death (P = .09) or death without transplant (P = .39). Multivariate predictors of transplant or death were high MELD score, hepatocellular carcinoma, and low albumin. High MELD score and low albumin were predictors of death without transplant. CONCLUSIONS: Antiviral failure in patients with HBV on the OLT waiting list did not impair clinical outcome if recognized early and if salvage therapy is promptly initiated.

Liver transplantation at the ochsner clinic: quality and outcomes improvement.

BACKGROUND: In 2005, the results published by the Scientific Registry of Transplant Recipients showed that Ochsner Clinic Foundation's patient and graft survival rates were statistically lower than expected, and the United Network for Organ Sharing Membership and Professional Standards Committee placed our center under peer review. METHODS: In response, patient outcomes prior to August 2005 were carefully reviewed in a transparent fashion and protocols were written to standardize treatments. We renewed the focus on patient-related outcomes and regulatory adherence and empowered frontline staff to express their views, allowing for real teamwork to develop. Multiple changes were implemented in the everyday running of the program. A quality assurance and performance improvement plan (QAPI) was initiated to improve outcomes. RESULTS: In 2012, the Ochsner liver transplant program became the largest liver transplant program in the United States by volume and in 2013 was awarded the prestigious CareChex award, acknowledging it as the number one program in terms of quality of care and outcomes for liver transplantation. CONCLUSION: The methodical application of this QAPI program achieved a remarkable transformation of the Ochsner liver transplant program and exemplifies what is possible with strong teamwork from dedicated and talented staff.

Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.

BACKGROUND: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. METHODS: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 µg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. FINDINGS: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. INTERPRETATION: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. FUNDING: Gilead Sciences.

Optimal Management of the Hepatitis B Patient Who Desires Pregnancy or Is Pregnant.

Women of childbearing age with recognized hepatitis B infection should have their liver disease assessed before pregnancy occurs since the management of hepatitis B virus (HBV) infection in this setting is complex. Initiation of treatment in a woman of child-bearing age will depend on when she intends on conceiving, as well as the severity of her liver disease. During pregnancy, all decisions about initiating, continuing or stopping HBV therapy must include an analysis of the risks and benefits for both mother and fetus. The trimester of the pregnancy and the stage of the mother's liver disease are important factors. Treatment in the third trimester may be considered to aid in prevention of perinatal transmission, which appears to be most pronounced in mothers with high viral loads. Consideration of initiation of third trimester treatment should occur after a high viral load is documented in the latter part of the second trimester, to allow adequate time for initiation of antiviral therapy with significant viral suppression before delivery. This discussion should include the topic of breastfeeding, since it is generally not recommended while on antiviral therapy. Until recently lamivudine and tenofovir appeared to be the therapeutic options with the most reasonable safety data in pregnancy. There are emerging data that telbivudine may also be considered in this setting.

Hepatitis B Therapy in Pregnancy.

All decisions about initiating, continuing, or stopping therapy of the hepatitis B virus (HBV) during pregnancy must include an analysis of the risks and benefits for mother and fetus. The trimester of the pregnancy and the stage of the mother's liver disease are important factors. Treatment in the third trimester may be initiated to aid in preventing perinatal transmission, which appears to be most pronounced in mothers with high viral loads. Consideration of initiating treatment in the third trimester should occur after a high viral load is documented in the latter part of the second trimester, to allow adequate time for initiation of antiviral therapy with significant viral suppression before delivery. This discussion should include the topic of breastfeeding, because it is generally not recommended while receiving antiviral therapy. Currently, lamivudine and tenofovir appear to be the therapeutic options with the most reasonable safety data in pregnancy.