Faculty Bibliography

Background and Aims: In 2 identically-designed double-blind, randomized (2:1), Phase 3 studies, the safety and efficacy of TAF vs TDF was evaluated in subjects treated for 3 years.
Method(s): 1298 HBeAg-negative and HBeAg-positive CHB patients were randomized and treated with TAF 25 mg or TDF 300 mg QD. Included in this analysis, were 1118 patients (759 HBeAg-positive and 359 HBeAg-negative); 866 of whom received TAF and 252 who received TDF for 3 years. Efficacy analyses included virologic, biochemical, and serologic responses, and pooled safety assessments included changes in bone mineral density (BMD), serum creatinine, and estimated GFR by Cockcroft- Gault method (eGFRCG).
Result(s): Baseline characteristics were similar between groups; mean age 39 years, 63% males, 78% Asian, mostly genotypes C (48%) and D (26%); mean HBV DNA was 7.0 log10 IU/mL (34% had HBV DNA >= 8 log10 IU/mL), and 25% previously treated with nucleos(- t)ides. At Week 144, high rates of virologic control were maintained in TAF vs. TDF subjects; a greater proportion of TAF vs TDF patients achieved ALT normalization (Table). Overall, adverse events (AEs) and serious AEs were similar between groups. At Week 144, greater median declines in eGFRCG were observed with TDF treatment; similarly, hip and spine BMD declines in the TDF group were larger than in the TAF group (Table).
Conclusion(s): After three years of treatment, high and similar rates of virologic suppression were achieved and maintained, and continued improvements in renal and bone safety were observed in patients receiving TAF compared to TDF

BACKGROUND:Data on tenofovir disoproxil fumarate (TDF) therapy for preventing vertical transmission of hepatitis B virus (HBV) in the real-world setting are limited. AIMS/OBJECTIVE:To investigate TDF for preventing vertical transmission of HBV in real-world practice. METHODS:IU/mL to receive TDF between gestational weeks 24-33 and delivery were prospectively enrolled and followed until post-partum week 28. All infants received immunoprophylaxis. Primary endpoints were safety of TDF use and mother-to-child transmission rates. Secondary outcomes were maternal HBV-DNA level suppression (<200 000 IU/mL) at delivery and HBeAg and hepatitis B surface antigen (HBsAg) serologic changes during the study. RESULTS:Among 147 mothers enrolled, 143 started TDF and 143/144 infants completed the study. At delivery, 93.7% (134/143) of the mothers achieved HBV-DNA<200 000 IU/L. On-treatment, alanine aminotransferase (ALT) flares were observed in 8.4% (12/143) of mothers. After TDF cessation, ALT increased in 7.7% (11/143) of the mothers and 2.8% (4/143) achieved HBeAg negativity, but none had HBsAg loss. At birth, HBsAg was detected in 13.9% (20/144) of newborns and none at post-partum week 28. Vertical transmission rates among infants were 0.7% (1/144, intention-to-treat) and 0% (per-protocol). No infants had birth defects. No serious adverse effects were reported in either mothers or infants. Breastfeeding did not increase the HBV infection rate among infants although mothers had viral rebound after TDF cessation. CONCLUSIONS:TDF for highly viraemic mothers was well tolerated and reduced vertical transmission of HBV in a real-world setting. There were no safety concerns during the postpartum 28-week follow-up. Registry number: Chinese Clinical Trial Registration No. ChiCTR-OIC-17010869.

Although gut dysbiosis appears in 20%-75% of cirrhotic patients, there are limited data on microbiota profiles in viral hepatitis cirrhotics and its role in progression to cirrhosis. Further understanding on the relationship between gut dysbiosis and cirrhosis presents a unique opportunity in not only predicting the development of cirrhosis but also discovering new therapies. Recent advances have been made on identifying unique microbiota in viral hepatitis cirrhotics and adopting the microbiota index to predict cirrhosis. Therapeutic intervention with microbiome-modulating has been explored. Cirrhosis from viral infection has unique bacterial or fungal profiles, which include increased numbers of Prevotella, Streptococcus, Staphylococcaceae, and Enterococcus, as well as decreased Ruminococcus and Clostridium. In addition, the gut microbiota can stimulate liver immunity, effectively helping hepatitis virus clearance. In clinical settings, CDR, GDI, Basidiomycota/Ascomycota, specific POD, and so forth are efficient microbiota indexes to diagnose or prognosticate cirrhosis from viral hepatitis. FMT, probiotics, and prebiotics can restore microbial diversity in cirrhotic patients with viral hepatitis, decrease ammonia serum or endotoxemia levels, prevent complications, reduce rehospitalization rate, and improve prognosis. Cirrhotics from viral hepatitis had unique bacterial or fungal profiles, associated with specific metabolic, immune, and endocrinological statuses. Such profiles are modifiable with medical treatment. The role of gut archaea and virome, implementation of FMT, microbiota metabolites as adjuvant immunotherapy, and microbiota indexes for prognostication deserve attention.

Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In 2 clinical trials, 1298 HBeAg-positive and HBeAg-negative patients with CHB were randomized 2:1 and treated with TAF (n=866) or TDF (n=432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (pol/RT) were assessed using INNO-LiPA Multi DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥69IU/mL) by HBV pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to study drug. At baseline, the majority of patients harbored virus with wild type pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF 11.1%, TDF 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF: 2.8%, TDF: 3.2%) that was often associated with drug nonadherence (TAF: 30%, TDF: 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96 with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro. After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA <69 IU/mL) was similar across treatment groups and no substitutions associated with resistance to TAF or TDF were detected.