Hepatitis B reactivation is the reappearance or rise of hepatitis B virus (HBV) DNA in patients with past or chronic HBV infection, usually occurring in the context of immunosuppression. HBV ...reactivation has been most commonly reported in patients with hematologic disorders, with potentially serious and life-threatening consequences. In this review, we discuss the basis and presentation of HBV reactivation, and risk factors in terms of the host, the virus and the immunosuppression regimen, including newer agents used to manage hematologic malignancies. We overview the management of HBV reactivation, highlighting an up-dated recommendation on the use of newer nucleoside and nucleotide analogs, such as tenofovir and entecavir, for antiviral prophylaxis.
Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free ...combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis.
We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval CI, 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%.
A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events.
In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.).
(1) Background: Hepatocellular carcinoma (HCC) is an important cause of mortality in individuals with chronic hepatitis B infection, with screening of high-risk groups recommended in all major ...international guidelines. Our understanding of the risk factors involved has improved over time, encouraging researchers to develop models that predict future risk of HCC development. (2) Methods: A literature search of the PubMed database was carried out to identify studies that derive or validate models predicting HCC development in patients with chronic hepatitis B. Subsequently, a second literature search was carried out to explore the potential role of novel viral biomarkers in this field. (3) Results: To date, a total of 23 models have been developed predicting future HCC risk, of which 12 have been derived from cohorts of treatment-naïve individuals. Most models have been developed in Asian populations (
= 20), with a smaller number in Caucasian cohorts (n = 3). All of the models demonstrate satisfactory performance in their original derivation cohorts, but many lack external validation. In recent studies, novel viral biomarkers have demonstrated utility in predicting HCC risk in patients with chronic hepatitis B, amongst both treated and treatment-naïve patients. (4) Conclusion: Several models have been developed to predict the risk of HCC development in individuals with chronic hepatitis B infection, but many have not been externally validated outside of the Asian population. Further research is needed to refine these models and facilitate a more tailored HCC surveillance programme in the future.
Introduction of effective combined antiretroviral therapy has made HIV infection a chronic illness. Substantial reductions in the number of AIDS-related deaths have been accompanied by an increase in ...liver-related morbidity and mortality due to co-infection with chronic hepatitis B and C viruses. Increases in non-alcoholic fatty liver disease and drug-induced hepatotoxicity, together with development of hepatocellular carcinoma, also potentiate the burden of liver disease in individuals with HIV infection. We provide an overview of the key causes, disease mechanisms of pathogenesis, and recommendations for treatment options including the evolving role of liver transplantation.
Summary Background Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ...ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. Methods We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600–1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255 ). Findings Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70–96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81–100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66–96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60–91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84–98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93–100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91–100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84–100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78–100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86–100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3–98) of two CTP-C patients (12 weeks treatment); and four (80%, 34–99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55–100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56–92) of 18 patients (12 weeks treatment) and 16 (94%, 75–100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir–sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. Interpretation Ledipasvir–sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. Funding Gilead Sciences.
Tenofovir alafenamide (TAF), a novel prodrug of tenofovir was developed to deliver enhanced antiviral potency and reduced systemic toxicities by more efficient intracellular delivery of the active ...metabolite tenofovir disphosphate than tenofovir disoproxil fumarate (TDF). In two randomized, double-blind, multinational phase III trials in patients with hepatitis B e antigen (HBeAg)-positive or -negative infection, TAF 25 mg was non-inferior to TDF 300 mg in achieving the primary efficacy outcome of a hepatitis B virus (HBV) DNA level < 29 IU/ml at week 48 and was associated with higher rates of alanine aminotransferase (ALT) normalization based on AASLD (American Association for the Study of Liver Diseases) criteria. TAF was well tolerated with low rates of adverse events, comparable to TDF. A significantly lower decline in the estimated glomerular filtration rate (eGFR) was observed in patients receiving TAF compared with patients receiving TDF and loss of bone mineral density at the hip and spine was significantly lower in the TAF groups. These trends continued to week 96. The requirement for long-term therapy in chronic HBV highlights the importance of these efficacy and safety trends, however their true clinical relevance is yet to be established and further studies with long-term follow up and real-world clinical data are needed.
Given the hepatitis C virus (HCV) burden and despite curative treatments, more efforts focused on scaling-up testing and treatment in homeless populations are needed. This project aimed to implement ...education and flexible on-site HCV testing, treatment, and follow-up for a homeless population in south London and to evaluate engagement, therapy initiation, and cure rates.
A mobile unit (van) for on-site HCV education, screening, treatment, and follow-up was placed on the street in a well-known homeless population areas from January 2018 to September 2021. Homeless was defined as living in temporary housing (hostel/hotel-based) or living on the street (street-based). Sociodemographic status, risk factors, comorbidities, concomitant medication, and data related with HCV treatment were recorded. Univariable and multivariable modeling were performed for treatment initiation and sustained virological response (SVR).
Nine hundred forty homeless people were identified and 99.3% participated. 56.2% were street-based, 243 (26%) tested positive for HCV antibody, and 162 (17.4%) were viremic. Those with detectable HCV RNA had significantly more frequent psychiatric disorders, active substance use disorders, were on opioid agonist treatment, had advanced fibrosis, and had lower rates of previous treatment in comparison with undetectable HCV RNA. Overall treatment initiation was 70.4% and SVR was 72.8%. In the multivariable analysis, being screened in temporary housing (odds ratio OR 3.166; P = 0.002) and having opioid agonist treatment (OR 3.137; P = 0.004) were positively associated with treatment initiation. HCV treatment adherence (OR 26.552; P < 0.001) was the only factor associated with achieving SVR.
Promoting education and having flexible and reflex mobile on-site testing and treatment for HCV in the homeless population improve engagement with the health care system, meaning higher rates of treatment initiation and SVR. However, street-based homeless population not linked with harm reduction services are less likely to initiate HCV treatment, highlighting an urgent need for a broad health inclusion system.
End-stage liver disease(ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus(HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus(HCV) ...infection,drug-induced hepatotoxicity related to combined antiretro-viral therapy,alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore,anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However,HIV-HCV coinfection transplant outcomes remain suboptimal due to recurrence. In this article,we review the key challenges faced by this patient cohort in the pre- and posttransplant period.
Background & Aims Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes ...at reduced systemic tenofovir exposures. Methods Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. Results 51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (−2.81, −2.55, −2.19, and −2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (−2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses ⩽25 mg were associated with ⩾92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg. Conclusions Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development.
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