Will we need novel combinations to cure HBV infection?
Journal: Liver international : official journal of the International Association for the Study of the Liver
Feb/20/2020
Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Currently numerous investigational agents being developed to either interfere with specific steps in HBV replication or as host cellular targeting agents, that inhibit viral replication, and deplete or inactivate cccDNA, or as immune modulators. Synergistic mechanisms will be needed to incorporate a decrease in HBV transcription, impairment of transcription from HBV genomes, loss of cccDNA or altered epigenetic regulation of cccDNA transcription, and immune modulation or immunologically stimulated hepatocyte cell turnover. Nucleoside analogue suppressed patients are being included in many current trials. Trials are progressing to combination therapy as additive or synergistic effects are sought. These trials will provide important insights into the biology of HBV and perturbations of the immune response, required to effect HBsAg loss at different stages of the disease. The prospect of cures of hepatitis B would ensure that a wide range of patients could be deemed candidates for treatment with new compounds if these were highly effective, finite and safe. Withdrawal of therapy in short-term trials is challenging because short-term therapies may risk severe hepatitis flares, and hepatic decompensation. The limited clinical trial data to date suggest that combination therapy is inevitable.
Geoffrey Dusheiko
The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis.
Journal: Antiviral therapy
Februar/20/2020
We conducted a systematic review and meta-analysis (CRD#42017070552) to quantify the impact of oral TDF/FTC on bone mineral density (BMD), and the risk of osteoporosis, low bone mass, and fractures, among people taking it as PrEP, HIV treatment and hepatitis B (HBV) treatment.We searched MEDLINE and EMBASE for randomized controlled trials published 1997-2018 reporting BMD, osteoporosis, low bone mass, and/or fractures in treatment-naïve patients taking compared to not taking TDF for 48±4 weeks. We pooled outcomes using DerSimonian random-effects models.
RESULTS
Our search yielded 5178 abstracts, representing 3865 articles, with 25 meeting the inclusion criteria. TDF was associated with greater BMD decline when taken as PrEP (lumbar spine: mean difference, MD=-0.82%, 95%CI=-1.28,-0.37%, I2=38%; total hip: MD=-0.81%, 95%CI=-1.22,-0.40%, I2=48%) and HIV treatment (lumbar spine: MD=-1.62%, 95%CI=-2.30,-0.95%, I2=93%; total hip: MD=-1.75%, 95%CI=-2.08,-1.42%, I2=83%; femoral neck: MD=-1.26%, 95%CI=-2.15,-0.38%, I2=43%) in comparison to those not taking TDF. Eight studies reported on incident osteoporosis or low bone mass, with variable results. Pooled results from five PrEP studies showed that TDF was not associated with increased fractures compared to no PrEP (RR=1.12, 95%CI=0.752,1.74, I2=26%).
TDF caused greater decreases in BMD than did comparators when used for all three indications, and the magnitude of this decrease was larger for HIV treatment compared to PrEP. Fractures were not increased among PrEP patients. The clinically-significant BMD decline caused by TDF and current expansion of PrEP use suggest attention to the adverse bone effects of TDF will increase in importance.
Benjamin Baranek; Shaoyuan Wang; Angela Cheung; Sharmistha Mishra; Darrell Tan
Immune Therapies
Journal: Humana Press
Februar/20/2020
Hepatocellular carcinoma (HCC) is considered an inflammation-induced cancer as it often develops in the setting of chronic hepatitis. Therefore, the application of immune-based therapies may provide an ideal approach to treatment. As a matter of fact, hepatitis B vaccination can be seen as the first preventive cancer vaccine for HCC. The recent approval of nivolumab as second-line therapy for patients with advanced HCC has been the pinnacle of years of research and clinical trials in the application of immunotherapies to patients with HCC. The liver, unlike most organs, has an immune-tolerant microenvironment due to its high antigen exposure from the gut which is often coupled with chronic immune stimulation from confounding liver disease. As a result, efforts to understand HCC antigens as well as the tumor microenvironment has enabled advances in the application of immunotherapies to HCC. Immune-based therapies can be categorized as checkpoint inhibitors, adoptive cell transfer, cytokine-based therapy, and vaccines. In this chapter, we discuss the application of different immunotherapies to HCC.
Zachary Brown; Tim Greten