Faculty Bibliography

Background and Aims: TAF provides similar efficacy to tenofovir disoproxil fumarate (TDF) but with an improved safety profile particularly for bone loss and renal injury. However, continued benefit with longer-term TAF has not been sufficiently studied. Here we evaluate virologic suppression rates, eGFR, fibrosis, and ALT at 48+ weeks of TAF therapy in US clinical practice.
Method(s): TRIO has developed a national HBV network consisting of 6 academic and 4 community-based centers serving 17 US States to understand real-world HBV treatment. Of the 1037 patients enrolled from Jan 2017,270 patients initiated TAF and remained on therapy for 48+ weeks as of Jan 2019. Lab measurement data at baseline and at or after (but nearest) 48 weeks of TAF therapy were collected. Elevated ALT was defined as >35 U/L for males and?>25 U/L for females, HBV suppression was assigned for HBV DNA measures <=2000 IU/ml. Comparisons between baseline and 48-week measures were made using McNemar's test (for dichotomous variables), Bowker's test (for multi-level variables) or t-test (for continuous variables). To identify variables associated with elevated ALT, eGFR >0 ml/min, or FIB4 >1.45 at 48 weeks, logistic regressions were conducted with adjustments for multicollinearity of variables.
Result(s): The study population (n = 270) was mostly male (59%), Asian (89%), and under or normal weight (60%) with a mean age of 53 years. Prior to initiating TAF, 81% of the patients received TDF, 8% entecavir, 6% were treatment naive, 2% TDF/emtricitabine, 1% lamivudine, and 1% adefovir dipivoxil. As of Jan 2019, mean (median) TAF duration was 508 (512) days and ranged from 338 to 803 days. In paired analyses (Table), statistically significant changes were reduced mean ALT and increased DNA suppression; changes in FIB4 and eGFR were not significantly different between baseline and 48 weeks. Variables associated with elevated ALT and eGFR >0 ml/min at 48 weeks were baseline elevated ALT (p < 0.001) and baseline eGFR >0 ml/min (p < 0.001), respectively. For FIB4?>1.45 at 48 weeks, significantly associated variables were baseline FIB4 >1.45 (p < 0.001) and Medicare as primary coverage (p = 0.010, collinear with Age >=50).
Conclusion(s): This study of HBV-infected individuals receiving TAF for 48+ weeks found that statistically significant improvements occurred in ALTand HBV DNA suppression. Continued monitoring is ongoing to understand changes in these and other measures with longer term TAF.
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Background and Aims: Noninvasive tests of fibrosis (NITs) are an alternative to liver biopsy for fibrosis staging and monitoring; however, associations between NITs and disease progression are poorly understood. Our aim was to evaluate the risk of liver-related complications according to baseline at enrolment (BL) and changes in the Enhanced Liver Fibrosis (ELF) test and liver stiffness by transient elastography (LS by TE) following sustained virologic response (SVR) in patients with HCV cirrhosis.
Method(s): Patients with pre-treatment HCV cirrhosis who achieved SVR with sofosbuvir (SOF)-based regimens were enrolled in an ongoing, prospective registry (NCT02292706). Patients underwent routine clinical and laboratory assessments, including semi-annual ELF testing and annual LS by TE. At BL, fibrosis stage was defined based on ELF (F0-F2, <9.8; F3, 9.8-11.3; F4, >11.3) and LS by TE (F0-F2, <9.6 kPa; F3, 9.6-12.5 kPa; F4,?>12.5 kPa). Changes at 48 weeks (improved, no change, worse) were defined based on ELF response (>=0.5 unit change from BL) and LS by TE response (>=25% change from BL). Associations between NITs and all-cause mortality, hepatocellular carcinoma (HCC), and total liver-related events (hepatic decompensation, transplantation, HCC, and liver-related death) were evaluated using Cox regression.
Result(s): We included 1,370 subjects with HCV Child-Pugh A cirrhosis (median 60 years of age, 32% female). At BL, median ELF was 9.8 (IQR 9.1, 10.7); 530 (39%) and 158 (12%) patients had ELF scores consistent with F3 and F4 fibrosis, respectively. Median LS by TE was 13.9 kPa (IQR 9.1, 21.3); 210 (15%) and 640 (47%) patients had LS by TE consistent with F3 and F4 fibrosis, respectively. After a median follow-up from BL of 144 weeks (IQR 119, 172), BL ELF and LS by TE class were associated with risks of all-cause mortality, HCC, and liver-related events (Table). Relative to BL F0-F2, significantly increased risks for all outcomes were observed for both F3 and F4 fibrosis defined by ELF, and F4 fibrosis defined by LS by TE. Worsening of ELF at 48 weeks was significantly associated with increased risk of all-cause mortality, while risks of HCC and total liver-related events were numerically, but non-significantly, higher for this group. In contrast, worsening of LS by TE at 48 weeks was not significantly associated with increased risks of the studied outcomes. Improvements in either measure were not associated with the risk of complications.
Conclusion(s): Following successful HCV therapy in patients with HCV-related cirrhosis, BL NITs are prognostic. Changes in NITs over 48 weeks may also be predictive of disease progression; however, further study is necessary following the accrual of additional follow-up time and events. This study is among the first to show an association between changes in liver fibrosis and changes in liver-associated morbidity and mortality in patients with compensated cirrhosis. [Figure presented]
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Background and Aims: Previously we reported increased HBV suppression, ALT normalization, and improved renal function with TAF treatment. However, certain patients that would potentially benefit from switching to TAF, e.g. with impaired renal function, remained on non-TAF therapies. Here we further examined variables associated with TAF adoption from approval (Nov 2016) to Dec 2018.
Method(s): Patients enrolled in the TRIO HBV registry from 6 academic and 4 community centers in the US were included in this study. TAF initiation was assessed using Kaplan-Meier methods with subsequent log-rank tests. Overall TAF initiation rates were compared using z-tests.
Result(s): Study population (n = 1037): predominantly male (599, 58%), Asian (887, 86%), <60 years old (700, 68%), from academic centers (611, 59%), with HBV DNA suppression (951/1035, 92%), and receiving tenofovir disoproxil fumarate (TDF [640, 62%]) at enrollment. A history of HCC (inactive) was present for 2% (25) patients, 4% (44) fatty liver, 10% (103) diabetes, 13% (131) hyperlipidemia, 23% (237) hypertension, and 8% (78) osteopenia/osteoporosis. At enrollment, 5% (48/965) had FIB4 >3.25, 6% (65/1030) had eGFR <60 ml/min, and 29% (304/1035) had elevated ALT (>25 U/L in females or >35 U/L in males). In the study window, 396 (38%) patients initiated TAF. Adoption was significantly higher in patients receiving TDF at enrollment (52% v. 12% non-TDF, p < 0.001), at community practices (56% v. 25% academic, p < 0.001), and without HCC history (39% v. 8%, p = 0.005), fatty liver (39% v. 8%, p < 0.001), or hyperlipidemia (39% v. 28%, p = 0.005). Adoption was not significantly different by age, insurance type, osteopenia/osteoporosis, eGFR, FIB4, or ALT. [Figure] Reasons for initiating TAF were provided for 365/396 patients: 66% (241/365) indicated safety/side effects, 27% (99/365) physician preference, and 6% (21/365) efficacy.
Conclusion(s): Safety/side effects was stated as a primary reason for initiating TAF, yet osteopenia/osteoporosis, suboptimal eGFR, ALT, or FIB4 were not associated with significantly higher TAF adoption. These data suggest that prevention, rather than observation of detrimental clinical measures, accounted for most TAF adoption. Most patients with renal or bone disease were not switched to TAF which may be due to access, an issue which will be further explored.
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Objectives: Here, we describe changes in HBV treatment in the 24 months after TAF approval as observed in a US network of 10 HBV-care centers.
Method(s): Data were retrospectively obtained from patient records through an electronic registry at enrollment (Nov 2016) with further collection at each patient visit. Of 1037 enrolled patients, 725 patients with 24-month follow up were included in this study.
Result(s): 7% (50/725) patients were untreated at enrollment and throughout the observation period (Nov 2016 to Dec 2018). Reasons for non-treatment: 82% (41/50) low HBV DNA, 54% (27/50) normal liver function, 8% (4/50) patient decision, 6% (3/50) HBeAg negative, 2% (1/50) does not meet guidelines, and 2% (1/50) unspecified. In Jan 2017 (end of enrollment), 58% (418/725) patients received tenofovir disoproxil fumarate (TDF), 23% (168/725) entecavir (ETV), and 2% (14/725) TAF. In Dec 2018 (end of the observation period), 30% (218/725) received TDF, 21% (152/725) ETV, and 35% (254/725) TAF. 37% (271/725) patients switched therapies for reasons of safety/side effects (58%, 156/271), physician preference (25%, 69/271), efficacy (8%, 23/271), or insurance/cost (6%, 17/271). Most switches were to TAF (91%, 246/271) from TDF (88%, 217/246). Rate of switching differed by site of care; compared to community practices, academic sites had a lower switch rate (26% [114/441] vs 55% [157/284]). Treatment switches in both academic (81%, 92/114) and community (98%, 154/157) sites were mainly to TAF, but the therapies prior to TAF were more varied in the academic sites.
Conclusion(s): In this study, 7% of patients were untreated while 37% received >1 regimen during the observation window. Reasons for non-treatment were mainly low HBV DNA and normal liver function. For the population receiving treatment, initial regimens were mostly TDF and ETV. Switches away from initial therapy was mainly due to safety/side effects concerns and were predominately to TAF.
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Background and aims: TAF provides similar efficacy to tenofovir disoproxil fumarate (TDF) but with an improved safety profile particularly for renal injury. Here, we assess clinical experience with TAF for patients with HBV in US Clinical Practice.
Method(s): The TRIO HBV Registry, consisting of 1078 enrolled patients from 6 academic and 4 community-based centers serving 17 US States, was created to understand real-world HBV treatment. Data presented here are limited to 250 registry patients who initiated TAF between Nov 2016 and Apr 2018, received >= 6 months of TAF therapy, and were followed up to 18 months. Baseline measures were closest to but between -30 to +60 days from regimen start. Measures in other time periods were those with the maximum date while on TAF. Comparisons to baseline were made using paired 2-tailed T-Tests. eGFR was calculated using the CKD-EPI equation.
Result(s): Characteristics of the study population: median age 52 years, BMI 24.3 kg/m2, male (147/250, 59%), Asian ethnicity (220/250, 88%), HBeAg positive (54/250, 22%), osteopenia/osteoporosis (47/250, 19%), and FIB-4 >3.25 (17/250, 7%). Mean and median TAF duration was 13 months as of data collection. 233/250 (93%) of patients receiving TAF switched from TDF (214/233, 92%), entecavir (16/233, 7%), or other therapies (3/233, 1%). At TAF initiation, 17/250 (7%) patients had baseline HBV DNA >= 2000 IU/ml. Of the 17, 16 patients had controlled HBV (< 2000 IU/ml) after 6 or 12 months of TAF therapy. One patient had a 50% viral reduction to 30, 000 IU/ml after 6 months of therapy but did not achieve suppression. 233/250 (93%) patients had baseline HBV DNA<2000 IU/ml; of these, 226 were assessed after 6 or 12 months of therapy and all had maintained HBV suppression (< 2000 IU/ml). 224/250 (90%) patients had baseline eGFR >= 60 ml/min and 26/250 (10%) < 60 ml/min with minimum 28 ml/min. In paired comparisons, mean eGFR increased 5% from baseline 85.7 to 90.1 ml/min (p < 0.001) after 6 months of TAF therapy (n = 213). Of 158 patients with eGFR measures after 12 months of TAF, the mean eGFR increase was 4% from baseline 86.9 to 90.5 ml/min (p = 0.001). For patients with baseline eGFR < 60 ml/min, mean eGFR increased 16% from 48.4 to 56.0 ml/min after 6 months (n = 24, p < 0.001). In the eGFR < 60 ml/min subset with 12+ months of TAF, the change in eGFR was 14% from baseline 54.0 to 61.4 ml/min though this change did not reach significance (n = 11, p = 0.066).
Conclusion(s): In US, clinical practice experience with TAF indicates effective HBV suppression after switching and improved renal function in real-world application. Continued long-term monitoring is critical to assess potential effects of prolonged treatment with lower dose tenofovir. (HBsAg). Currently approved drugs, nucleos (t)ide analogues, effectively reduce HBV DNA but only rarely result in a functional cure (defined as sustained HBsAg loss). Therefore, a critical need arises for novel therapies that reduce HBsAg levels and restore virus-specific immune responsiveness in patients. We have found that two subregions in 3' untranslated region of 2.1/2.4 kb HBV RNAs, here referred as "region X" and "region Y," regulate HBsAg production (unpublished data). Here, focusing on region X and Y, we aimed to screen host proteins to identify novel therapeutic targets reducing HBsAg.
Method(s): Host proteins binding to region X and Y were determined by following two methods. (1) The lysate of HepG2.2.15 hepatoblastoma cells was incubated with in vitro-transcribed RNA corresponding to above two regions, and binding proteins were pulled-down. The proteins pulled-down were identified by SDS-PAGE and LC-MS/MS. (2) Host proteins binding to region X and Y were presented by searching an RNA-binding protein database. siRNAs specific to the proteins determined by above two methods were transfected into HepG2.2.15 cells, and the effects on the HBsAg production were analyzed.
Result(s): Among those proteins either identified by pull-down assays or presented by database search, knockdown of 7 proteins showed potent anti-HBsAg effects, more than 90% reduction in HBsAg, without affecting cell viability. Interestingly, these were all nuclear-localizing proteins. Some of them were reported to regulate RNA splicing, stability or nuclear export of mRNA while the others were functionally unknown. Then, expression levels of 2.1/2.4 kb HBV RNAs were quantified, and silencing of these proteins showed less than 80% reduction in those RNAs, that was slightly milder reduction compared with that in HBsAg protein. These data suggested that the proteins identified here could regulate HBsAg production by affecting RNA processing or dynamics.
Conclusion(s): Host proteins binding to region X and Y in 2.1/2.4 kb HBV RNAs were shown to be attractive therapeutic targets to reduce HBsAg, suggesting novel insights for better understanding of HBV virology.
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A 57-year-old man with chronic kidney disease stage 5 presented for ambulatory evaluation of his arteriovenous fistula. He underwent rheolytic thrombectomy with tissue plasminogen activator infusion, angioplasty, and brachial artery stenting under local sedation. His immediate postoperative course was complicated by hypotension, cardiac dysrhythmias and hyperkalemia requiring emergent hemodialysis, due to severe intravascular hemolysis. This case illustrates that mechanical thrombectomy can cause clinically significant intravascular hemolysis, thus careful postoperative monitoring is recommended.