Final results from the ribavirin pregnancy registry, 2004-2020.

INTRODUCTION: Significant teratogenic effects have been demonstrated for ribavirin in animal studies. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in pregnant women and their male sexual partners. Both are advised to avoid pregnancy for 6 months after exposure. The registry monitored pregnancy exposures to oral formulations of ribavirin for hepatitis C for signals of possible human teratogenicity from 2004 to 2020. METHODS: Pregnant women were voluntarily enrolled following direct exposure (ribavirin use during pregnancy or the 6 months prior) or indirect exposure (through sexual contact during pregnancy or 6 months prior, with a man who has taken ribavirin within 6 months). Women were followed until the end of pregnancy. Infants were followed until 1 year of age. Birth defect rates were compared with the published rate of 2.67 per 100 live births from the Metropolitan Atlanta Congenital Defects Program (MACDP). RESULTS: The registry enrolled 280 pregnancies resulting in 186 live births: eight birth defect cases among 88 directly exposed [9.09% (8/88, 95% CI: 4.01, 17.13)], and six birth defect cases among 98 indirectly exposed [6.12% (6/98, 95% CI: 2.28, 12.85)]. The 95% CI around the birth defect rate among directly exposed pregnancies exceeds the MACDP rate; however, no patterns suggestive of a teratogenic mechanism or safety signal were detected. CONCLUSION: Based on the patterns of birth defects reported, the final results from this registry do not suggest a clear signal of human teratogenicity for ribavirin. The registry did not meet sample size requirements; therefore, caution should be exercised when interpreting the results.

Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo-a Meta-analysis of Individual Data From Controlled Trials.

BACKGROUND & AIMS: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. METHODS: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. RESULTS: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48-0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43-0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P = .04) but not in multiple-imputation analysis (HR 0.71; P = .08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10-1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20-1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. CONCLUSIONS: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.

The Ribavirin Pregnancy Registry: An Interim Analysis of Potential Teratogenicity at the Mid-Point of Enrollment.

INTRODUCTION: Significant teratogenic effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in women who are pregnant and in the male sexual partners of women who are pregnant. Both sexes are advised to avoid pregnancy for 6 months after exposure. The Ribavirin Pregnancy Registry was established in 2003 to monitor pregnancy exposures to ribavirin for signals of possible human teratogenicity. METHODS: This voluntary registry enrolls pregnant women with prenatal exposure to ribavirin. Exposure is classified as direct-women taking ribavirin during pregnancy or the 6 months prior to conception-or indirect-women exposed through sexual contact, 6 months prior to or during pregnancy, with a man who is taking or has taken ribavirin in the past 6 months. Women are followed until delivery and infants for 1 year. When enrollment is complete, birth defect rates will be compared with the Metropolitan Atlanta Congenital Defects Program's published rate of 2.67. Using data collected since inception in 2003 through February 2016, preliminary rates were calculated. RESULTS: The registry has enrolled 272 pregnant women, with 180 live births: there were seven birth defect cases among 85 directly exposed women [7/85 (8.2%) (95% confidence interval (CI) 3.4-16.2)] and four birth defect cases among 95 indirectly exposed women [4/95 (4.2%) (95% CI 1.2-10.4)]. Of the 11 infants, nine had structural defects and two had chromosomal anomalies. Patterns suggesting a common etiology or relationship with ribavirin exposure are not seen. CONCLUSION: Based on the patterns of birth defects reported, preliminary findings do not suggest a clear signal of human teratogenicity for ribavirin. However, the current sample size is insufficient for definitive conclusions, and ribavirin exposure should be avoided during pregnancy and during the 6 months prior to pregnancy, in accordance with prescribing information. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00114712.

Chronic Hepatitis B Virus Infection: Disease Revisit and Management Recommendations.

Chronic hepatitis B virus (HBV) infection evolves from immune-tolerance phase, through immune clearance phase to a quiescent phase or reactivation as hepatitis B e antigen-negative hepatitis. Persistent infection may result in the development of cirrhosis and hepatocellular carcinoma (HCC). Host factors including gender, age, family history, HLA-DP, and viral factors including HBV DNA, genotypes, precore mutations, pre-S deletions, and hepatitis B surface antigen (HBsAg) level are associated with the development of these complications. Risk scores for the development of HCC have been derived. Patients with persistently elevated alanine aminotransferase levels (>30 for males; >19 U/L for females) and HBV DNA levels >2000 IU/mL should be treated. Patients with established cirrhosis with detectable HBV DNA should also be treated. The recommended first-line agents include pegylated interferon and 2 nucleos(t)ide analogs, entecavir and tenofovir. NAs require long-term treatment to maintain suppression of HBV DNA. They have been shown to decrease hepatic fibrosis, or reverse cirrhosis and to reduce the development of HCC. They have very low rates (0% to 1.2%) of resistance. HBsAg seroclearance, although the ideal endpoint, is only achievable in 10% to 12% of patients by multicenter trials usually studying relatively young patients. Patients on long-term treatment should be monitored for viral breakthrough that may be due to noncompliance or the development of resistance. Newer agents are under trials to enhance the rate of HBsAg seroclearance. However, even with the current NAs, long-term treatment of >6 years can markedly reduce the covalently closed circular DNA, the viral component responsible for initiation of viral replication.

Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension.

INTRODUCTION: Macitentan is a novel dual endothelin receptor antagonist (ERA) showing sustained receptor occupancy. In vitro and in vivo animal studies have demonstrated its potency in antagonizing endothelin-induced disorders. A large morbidity/mortality study in patients with pulmonary arterial hypertension (PAH) taking macitentan has been completed recently. AREAS COVERED: This drug evaluation reviews the efficacy, safety and clinical pharmacology of macitentan in the treatment of PAH. EXPERT OPINION: The large Phase III study (SERAPHIN) tested macitentan in more than 700 PAH patients and has provided unique long-term outcome data for this ERA, not available for other members of this class. The effect on a composite clinically relevant morbidity/mortality end point was highly significant at a 10 mg/day dose. The safety profile of macitentan appears to be superior with respect to hepatic safety and edema/fluid retention than bosentan and ambrisentan, respectively, and is similar when considering decrease in hemoglobin concentration. The drug has a low propensity for drug-drug interactions and has one circulating pharmacologically active metabolite. The pharmacokinetics of macitentan in patients with renal or hepatic impairment does not require dose adjustments. Based on its characteristics, macitentan is an important addition to the therapeutic armamentarium in the long-term treatment of PAH. Its potential use in other disorders is under investigation.

Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.

INTRODUCTION: A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) ≥ 32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. AIMS: To compare 28-day survival between corticosteroid- and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. METHODS: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n=3), enteral nutrition (n=1) or an antioxidant cocktail (n=1). RESULTS: 221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroid-treated patients than in non-corticosteroid-treated patients (79.97±2.8% vs 65.7±3.4%, p=0.0005). In multivariate analysis, corticosteroids (p=0.005), DF (p=0.006), leucocytes (p=0.004), Lille score (p<0.00001) and encephalopathy (p=0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score ≤ 0.16; ≤ 35th percentile), partial responders (Lille score 0.16-0.56; 35th-70th percentile) and null responders (Lille ≥ 0.56; ≥ 70th percentile). 28-day survival was strongly associated with these groupings (91.1±2.7% vs 79.4±3.8% vs 53.3±5.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p=0.006) and in partial responders (HR 0.38, p=0.04) but not in null responders. CONCLUSION: Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

The Ribavirin Pregnancy Registry: Findings after 5 years of enrollment, 2003-2009.

INTRODUCTION: Ribavirin, with interferons or pegylated interferons, is used to treat chronic hepatitis C. Ribavirin is contraindicated in pregnancy (FDA Pregnancy Category X) and in men whose partners may become pregnant. In 2003, the Ribavirin Pregnancy Registry was established to monitor pregnancy exposures to ribavirin and to evaluate the potential human teratogenicity of prenatal exposure. METHODS: This voluntary registry enrolls pregnant women who have been exposed to ribavirin during pregnancy or during the six months prior to conception either directly, by taking ribavirin, or indirectly through sexual contact with a man taking ribavirin. Women are followed until delivery; live born infants are followed for one year. The Registry aims to enroll 131 live births following direct (maternal) exposure to ribavirin and 131 live births following indirect (male) exposures. RESULTS: After more than five years of operation, the Registry has enrolled 49 live births with direct exposure and 69 live births following indirect exposure. Six outcomes with birth defects have been reported. All were among live born infants: torticollis (2), hypospadias (1), polydactyly and a neonatal tooth (1), glucose-6-phosphate dehydrogenase deficiency (1), ventricular septal defect and cyst of 4th ventricle of the brain (1). Three received direct exposures ([6.1% (95% CI: 1.2, 16.9)], three were exposed indirectly [4.3% (95% CI: 0.9, 12.2)]. CONCLUSIONS: Although current enrollment is far short of the required sample size, preliminary findings have not detected a signal indicating human teratogenicity for ribavirin. However, findings must be interpreted with caution concerning direct or indirect prenatal ribavirin exposures.

Hepatitis B virus infection in 6,130 unvaccinated Korean-Americans surveyed between 1988 and 1990.

OBJECTIVES: During the past decades, the influx of immigrants from hepatitis B virus (HBV) endemic regions has brought significant changes in the prevalence of HBV-associated liver diseases and hepatocellular carcinoma (HCC) in the United States. Our program, which was intended to identify those in need of hepatitis B vaccination, helped us to learn of the natural history of HBV infection in Korean Americans. METHODS: Between November of 1988 and May 1990, we screened 6,130 Korean Americans in the eastern United States for HBV infection. RESULTS: The overall hepatitis B surface antigen (HBsAg) (+) rate was 6.1%, with 8.0% for males and 4.4% for females. The carrier rate peaked in subjects between the ages of 21 and 40 yr. The HBsAg (+) rate for 452 U.S.-born children was lower (2.7%) than that of 623 Korean-born (5.5%). None received hepatitis B immune-globulin or HBV vaccination. The vertical transmission rate was 30.3% in children born to HBsAg (+) mothers and 100% in those born to hepatitis B e antigen (HBeAg) positive mothers. In contrast, the paternal transmission rate was low; 10.3% in children with HBsAg (+) fathers and 19.2% in those with HBeAg (+) fathers. Another significant observation was the unexpected finding of ongoing liver diseases in incidentally identified carriers. Evaluation of 139 asymptomatic adult carriers revealed that 42% had elevated liver enzymes and 11% had already developed liver cirrhosis. CONCLUSION: These findings strongly suggest the need for active HBV screening of immigrants from endemic regions and, most importantly, the need for careful monitoring of the carriers.

Role of antibiotics in the management of hepatic encephalopathy.

This article explores the rationale for use of antibiotics in the treatment of hepatic encephalopathy, discusses the role of antibiotics relative to other therapeutic approaches, and considers the reasons that limit the use of the antibiotics most commonly prescribed for the management of hepatic encephalopathy in the United States. Although the scientific rationale for the use of antibiotics in hepatic encephalopathy is well founded, the clinical evidence for their benefits is rather limited. There is no doubt that many antibiotics cause a decrease in intraluminal production of ammonia. However, the commonly prescribed antibiotics are also associated with a variety of adverse effects. None of the antibiotics typically used for hepatic encephalopathy is adequately tolerated in the target patient population. The clinical evidence to date does not support the first-line use of currently available antibiotics in the treatment of hepatic encephalopathy. To improve upon current antibiotic offerings for hepatic encephalopathy, an antibiotic should provide broad-spectrum coverage against both aerobic and anaerobic bacteria, effectively control neuropsychiatric signs and symptoms, and be extremely well tolerated in the target population. An antibiotic fulfilling these criteria would constitute an advance in therapy for hepatic encephalopathy.

Drug-induced hepatotoxicity: 2005.

The removal from the marketplace of several widely prescribed drugs due to hepatotoxicity has attracted considerable attention. Now under extensive review are means by which we can better identify hepatic risk prior to federal approval. Assessment of risk-to-benefit ratios regarding a novel agent with hepatotoxicity issues (especially one for a life-threatening condition) requires considerable judgment and education on the part of prescribers and patients. The spectrum of drug-induced liver injury is broad with simulation of almost all unknown liver disorders. Drug-induced liver injuries often have a somewhat characteristic signature, as regards type of injury (hepatocellular vs cholestatic) and time of onset. The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. Factors affecting susceptibility to drug-induced injury include age, sex, concomitant use of other drugs, and genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs. Drug-drug interactions present particular problems in patients, often elderly, who are receiving several drugs simultaneously. Mechanisms of drug-induced liver injury are many and varied. With many drugs, intermediary products produced during metabolism are highly reactive and toxic. In these situations, the balance between the rate of production of the metabolite and the effectiveness of the drug may determine whether or not hepatic injury occurs.

Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH.

BACKGROUND/AIMS: Controversy surrounding the efficacy of corticosteroids in severe alcoholic hepatitis (AH) persists. THE AIMS OF OUR STUDY WERE: (a) to analyze individual data of patients with severe AH discriminant function (DF)> or =32 from the last three randomized controlled trials; and (b) to identify the independent prognostic factors associated with short-term survival. METHODS: Individual data were collected from the three principal investigators. Survival analysis was performed at 28 days using the Kaplan-Meier method and log-rank test. The independent prognostic values were assessed by the proportional hazards regression model. RESULTS: About 102 placebo and 113 corticosteroid patients with DF > or =32 were analyzed. At 28 days, corticosteroid patients had significantly higher survival: 84.6+/-3.4% vs. 65.1+/-4.8%, P=0.001. In univariate analysis, corticosteroid treatment, age, DF, albumin, creatinine and encephalopathy were prognostic factors. In multivariate analysis, age (P=0.0001), serum creatinine (P<0.002) and corticosteroid treatment (P=0.002) were independent prognostic variables. A more dramatic decrease of median serum bilirubin values (micromol/l) was observed at 7 and 14 days in corticosteroid patients (P<0.05) : -76.5 vs. -35 and -105 vs. -45. CONCLUSIONS: Corticosteroids improved short-term survival of patients with severe AH. Age and serum creatinine are independent prognostic factors. Corticosteroids are recommended for patients with severe AH.