[특집]Biosolids Disposal in 2006 and Beyond: An Overview

John Flaherty 유기성자원학회 2007 유기물자원화 Vol.15 No.1

A cont inuing problem faced by governments worldwide is the safe and cost effective disposal of human waste sludge or biosolids. This document will focus on t he United States, although its findings and conclusions have applicability in other countries. The central premise is that the wastewater treatment field is facing growing difficulties with current approaches to the processing and disposal of sludge. As a result, it is beginning to move away from widely used methods such as incineration, land fill ng, land application, and composting. Increasingly these will be replaced or augmented by a heavier emphasis on volume reduction through heat drying .

HBV : Clinical Characteristics of Patients who Developed HCC While Receiving Tenofovir Disoproxil Fumarate (TDF) Up to 288 Weeks of Therapy

( W Ray Kim ),( Rohit Loomba ),( Selim Gurel ),( John Flaherty ),( Eduardo B Martins ),( Leland J Yee ),( Phillip Dinh ),( Maria Buti ),( Patrick Marcellin ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: Patients with chronic hepatitis B Virus (HBV) infection are at increased risk for hepatocellular carcinoma (HCC). Population-based studies have suggested an increased risk of hepatocellular carcinoma (HCC) in patients with higher levels of HBV-DNA. Therefore, it is possible that anti-viral therapy that reduces HBV-DNA levels may reduce the occurrence of HCC. We examined the clinical and demographic characteristics of HCC cases in patients receiving tenofovir disoproxil fumarate (TDF). Methods: We studied the clinical and demographic characteristics of the 641 patients enrolled in pivotal studies GSUS- 174-0102 and GS-US-174-0103. Results: During the first 288 weeks of studies 102/103, there were 13 cases of HCC. Three cases occurred during the first 48 weeks. 9/13 cases were HBeAg-negative and 3 of these were cirrhotic. 4/13 cases were HBeAg-positive at baseline and 3 of these were cirrhotic. 11/13 cases were male. 2/13 patients had regression of histological cirrhosis on repeat liver biopsies. Among the 13 HCC cases, 5 were genotype (gt)-D, 4 gt-C, 1 gt- B, 1 gt-E, 1 gt-F and 1 unable to genotype. Conclusions: In 288 weeks of TDF therapy, there were only 13 cases of HCC. 3 of the HCC cases were reported within the first 48 weeks of therapy. Despite the small number of cases, HCC surveillance needs to be done in patients on long-time oral antivirals.

Viral Kinetics in Women of Child Bearing Potential with Chronic HBV Following Treatment with Tenofovir Alafenamide or Tenofovir Disoproxil Fumarate

( Brunetto ),( Carla Coffin ),( Audrey Lau ),( Shuyuan Mo ),( John F. Flaherty ),( Anuj Gaggar ),( G Mani Subramanian ),( Mindie H. Nguyen ),( Selim Gurel ),( Alexander Thompson ),( Edward J. Gane ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Suppression of the HBV in women of childbearing potential (WOCBP) has important implications in preventing transmission of HBV from mother to infant. Antiviral therapy that reduces HBV DNA to < 2x105 IU/mL at delivery in mothers can substantially reduce the risk of perinatal transmission. We evaluated the viral kinetics of TAF and TDF in WOCBP. Methods: : In two Phase 3 studies (HBeAg positive and negative patients), 1301 patients (37% female) were randomized (2:1) to receive TAF 25 mg QD or TDF 300 mg QD. All patients were required to have HBV DNA >2x104 IU/mL at screening and serum ALT >2 times AASLD criteria.WOCBP were defined as nonmenopausal females 18 years or older without history of hysterectomy, bilateral oophorectomy, or ovarian failure. For this subanalysis, patients were stratified by baseline HBV DNA levelsand the endpoints were virologic suppression to HBV DNA <29 IU/mL or < 2x105 IU/mL. Results: 365(76%) female were identified as WOCBP with 118 (32%) having HBV DNA >1x108 IU/mL at baseline. Suppression rates were generally similar between TAF and TDF groups and within viral load strata for HBeAg positive and negative patients. After 12 weeks of treatment with TAF or TDF, 77% of WOCBP with baseline HBV DNA <2x105 IU/mL had full suppression to <29 IU/mL compared to 1% of those at the highest baseline viral load (Figure A). By Week 24, 54% of all WOCBP had achieved complete viral suppression. Of WOCBP with baseline viral load ≥2x105 IU/mL (n=305), 76%, 89%, and 93% achieved viral load reduction to <2x105 IU/mL by Weeks 4, 8, and 12, respectively (Figure B). Conclusions: After 12 weeks of treatment the majority of WOCBP had HBV DNA to <2x105 IU/mL. In women with higher baseline viral loads, longer treatment duration may be necessary to achieve viral suppression below recommended thresholds.

Evaluation of Renal and Bone and Safety in Patients with CHB and CKD Treated with TAF in Post Liver Transplantation

( Anuj Gaggar ),( Bibin George ),( Stephen Munn ),( Hongyuan Wang ),( Vithika Suri ),( John Flaherty ),( Ed Gane ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Chronic Hepatitis B(CHB) remains a leading indication for orthotopic liver transplantation(OLT) worldwide. Common complications following OLT include renal dysfunction secondary to perioperative renal injury and post-operative nephrotoxicity from calcineurin inhibitors; osteoporosis is also observed secondary to preoperative malnutrition and post-operative corticosteroids. In this setting, antiviral prophylaxis to prevent recurrent HBV infection with TAF may have advantages over TDF due to its improved renal and bone safety profile. Methods: In this Phase 2 study (NCT02862548), LT recipients with stage 2 or greater CKD and receiving antiviral prophylaxis with TDF were randomized 1:1 to either receive TAF 25 mg or continue TDF . The primary efficacy analysis was the percent of patients who maintained viral suppression at Week 24. Key pre-specified secondary safety endpoints were changes in hip and spine BMD, changes in sCr, estimated GFR and direct GFR assessment over 48 weeks. Results: 51 patients were randomized and treated at a single site in New Zealand. Baseline characteristics included: mean age 60 years, 75% males, 53% Pacific Islander and mean baseline eGFRCKD-EPI 52mL/min/1.73m2 with 53% of patients with <50mL/min/1.73m2. The median baseline surface area corrected GFRCr-EDTA was 58 mL/min/1.73m2. The median interval since transplantation was approximately 9 years. Of the 47 patients that have reached Week 12, all patients maintained viral suppression. There were no treatment discontinuations and serious adverse events were numerically lower in TAF arm compared to the TDF arm. Switching to TAF treatment resulted in a trend toward improved sCr levels (median change: -0.07 for TAF vs. -0.02 for TDF; P=0.09) and improved eGFRCKD-EPI (median change: 2.7 for TAF vs. 0.8 for TDF; P=0.14) as early as week 12 (Figure 1). Conclusions: Early after switching from TDF to TAF in LT recipients, viral suppression is maintained while smaller changes in renal function were observed.

HBV : No Detectable Tenofovir Resistance with Tenofovir Disoproxil Fumarate (TDF) or Emtricitabine+TDF (FTC/TDF) through 96 Weeks in Lamivudine Resistance CHB Patients

( Edward Gane ),( Amoreena C Corsa ),( Yang Liu ),( Ben C Mitchell2 ),( John F Flaherty ),( Michael D Miller ),( Kathryn M Kitrinos ),( Scott Fung ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background/Aim: To evaluate amino acid changes within HBV pol/RT after 96 weeks of treatment with TDF or FTC/ TDF and determine their potential association with TDF resistance. Methods: In Study GS-US-174-0121, 280 patients receiving lamivudine (LAM) with detectable LAM-resistance mutations in HBV pol/RT (LAM-R: rtM204V/I±rtL180M) were randomized 1:1 to receive blinded treatment with TDF or FTC/TDF for 96 weeks. Virologic breakthrough (VB) was defined as confirmed HBV DNA >1 log10 increase from nadir or HBV DNA ≥400 copies/mL (69 IU/mL) after <400 copies/mL. Resistance genotyping by HBV pol/RT sequencing was attempted for all patients at baseline and if viremic (HBV DNA ≥400 copies/ mL) at Week 96/study discontinuation. Results: Overall, 18 patients (9 TDF, 9 FTC/TDF) were viremic viremic at Week 96/last visit. The mean baseline HBV DNA was significantly higher for viremic patients (8.04 log10 copies/mL) compared to patients who did not qualify for genotyping (6.39 log10 copies/mL). In the TDF arm, 3 patients had conserved site changes/reversions (1 with VB), 1 had unique polymorphic site changes, 2 had no change, and 3 were unable to be genotyped. In the FTC/TDF arm, 2 patients had conserved site changes/reversions, 1 had unique polymorphic site changes, 4 had no change, and 2 were unable to be genotyped. No phenotypic resistance to TDF was observed. Four of eight (50%) patients had LAM-R reversions (rtV/I204M±rtM180L) on TDF while 1/8 (12.5%) patients on FTC/TDF had LAM-R reversions. Thirteen patients (4.6%) with prior entecavir (ETV) exposure and 25 patients (8.9%) with baseline ETV-R were enrolled; neither had an impact on viral kinetics. Conclusions: No TDF resistance has been detected through 96 weeks of treatment with either TDF or FTC/TDF in LAM-R patients. The presence of ETV-R or ETV exposure did not impact viral kinetics through 96 weeks. Resistance surveillance in this population will continue through Year 5.

Improvement in Renal Parameters in CHB Patients Treated with Tenofovir Alfenamide (TAF) versus Tenofovir Disoproxil Fumarate (TDF) over 96 Weeks

( Hyung Joon Kim ),( Wan Long Chuang ),( Kosh Agarwal ),( Jae Seok Hwang ),( Florin Caruntu ),( Florence Wong ),( Hie Won Hann ),( John Flaherty ),( Audrey Lau ),( Anuj Gaggar ),( Vithika Suri ),( Shu 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: In Phase 3 studies in CHB patients the efficacy of TAF was found smaller changes in renal parameters compared with TDF treatment. This benefit was particularly evident in patients with risk factors for renal impairment.Here, we present renal safety results after 96 weeks of treatment. Methods: In Phase 3 studies (HBeAg positive patients [N=873] and HBeAg negative patients [N=425]), patients were randomized 2:1 to TAF 25 mg QD or TDF 300 mg QD, and treated for 144 weeks. Renal parameters including estimated glomerular filtration rate (eGFR) calculated by the Cockcroft-Gault method were evaluated. Chronic kidney disease (CKD) staging was categorized by the National Kidney Foundation KDOQI guidelines. Evaluated risk factors for kidney disease included older age (age ≥ 50), female gender, renal impairment (eGFR <90mL/min) and presence of comorbidities (hypertension, cardiovascular disease and diabetes). Urine markers of renal glomerular dysfunction (urine protein and albumin to creatinine ratio) and tubular dysfunction (retinol binding protein (RBP) and beta-2 microglobulin [B2M] to creatinine ratio) were serially assessed. Results: Patients treated with TAF continued to show smaller changes in serum creatinine (p=0.001) and eGFRCG (p<0.001) at 96 weeks. Similarly, median percentage changes in renal tubular markers, were also smaller in TAF-treated patients compared with TDF patients at Week 96; RBP/Cr (p<0.0001) and B2M/Cr (p<0.0001). A lower percentage of patients experienced ≥1 stage worsening in NKF CKD stage when treated with TAF compared with TDF at Week 96 overall and when evaluated by risk factors for kidney disease.Furthermore, CKD stage progression increased disproportionately in the TDF group in patients with ≥2 risk factors (Table). Conclusions: Treatment with TAF for 96 weeks continued to be associated with smaller changes in renal parameters compared with TDF treatment. The benefits of TAF are particularly evident in patients with risk factors for kidney disease.

Improved Bone and Renal Safety of Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) in CHB Patients

( Young Suk Lim ),( Henry L. Chan ),( Scott Fung ),( Wai Kay Seto ),( Ed Gane ),( John F. Flaherty ),( Vithika Suri ),( Lanjia Lin ),( Anuj Gaggar ),( G Mani Subramanian ),( Wan Long Chuang ),( Kosh A 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: TAF has shown less bone and renal effects with similar efficacy rates compared to TDF in two Phase 3 studies after 48 weeks treatment. Here, we evaluate patients completed 96 weeks of double blind(DB) treatment with TAF or TDF and have switched to open label(OL) treatment with TAF to determine changes in bone mineral density(BMD), creatinine clearance(CrCl), and the maintenance of viral suppression. Methods: Immune active CHB patients who were HBeAg negative (Study 0108; N=425) or HBeAg positive (Study 0110; N=873) were randomized to and treated with TAF 25 mg QD or TDF 300 mg QD. A subset of patients (N=200 in Study 0108 and N=340 in Study 0110) in these ongoing 8 year studies had completed 96 weeks of DB treatment with TAF or TDF and switched to OLTAF at Week 96 analysis. Dual energy X-ray absorptiometry (DXA) scans were evaluated every 24 weeks as were serial assessments of CrCl and viral suppression. Results: CrCl improved significantly in patients switched from DB TDF to OL TAF at Week 120 compared to Week 96 (N=117, mean (SD) change=+2.43 (12.81) ml/min, p=0.04); and remained stable in those previously receiving TAF (Figure A). BMD also showed improvement at Week 120 from Week 96 among patients switched from DB TDF to OL TAF (hip: N=58, mean (SD) % change=+0.71% (1.43), p=0.0004; spine: N=60, mean (SD) % change=+1.41% (2.30), p<.0001). BMD changes in hip and spine for DB TAF patients entering the OL TAF period were relatively stable (Figure B). Compared to results at Week 96, high rates of virologic control were maintained across subjects in both studies during the OL period. Conclusions: Patients who switched from TDF to TAF treatment demonstrated rapid improvements in BMD and CrCl within the first 24 weeks of treatment, and virologic control was maintained.

48-Week Safety and Efficacy of Switching to Tenofovir Alafenamide (TAF) from Tenofovir Disoproxil Fumarate (TDF) in Asian Patients with TDF Risk Factors (RF)

( Won Young Tak ),( Sang Hoon Ahn ),( Seung Woon Paik ),( Jia-Horng Kao ),( Hie-won Hann ),( Fung Scott ),( Trinh Huy ),( Nguyen Tuan Trong ),( Gaggar Anuj ),( Flaherty John ),( Yee Leland J ),( Jump 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: In a recent Phase 3 study (Study 4018) in HBV patients suppressed on TDF treatment, switching to TAF demonstrated noninferior efficacy to continued TDF with superior bone and renal safety at Week 48. This study aims assess the safety and efficacy of switching to TAF from TDF in patients of Asian descent with risk factors for TDF toxicity as per current EASL and AASLD guidelines. Methods: Virally suppressed patients (HBV DNA <20 IU/mL at screening) on TDF were randomized (1:1) to switch to TAF or continue TDF for 48 weeks in a double-blind fashion. Viral suppression and changes in bone (BMD by DXA) and renal (creatinine clearance [eGFR_CG]) parameters were assessed over 48 weeks. Results: Among the 400 Asian patients enrolled, 288 (72%) had at least 1 TDF RF. At Week 48, similar proportions with ≥1 RF had HBV-DNA <20IU/mL (TAF 97%; TDF 97%) and normal ALT by 2018 AASLD criteria (TAF 76%; TDF 73%). TAF subjects with ≥1 RF had increases in eGFR_CG compared to decreases on TDF [median (Q1, Q3) change; TAF: +2.6 (-2.01, 7.34); TDF: -2.7 (-7.56, +15.79); P<0.0001)]. Among patients with ≥1 RF, improvements were seen in BMD for TAF vs. continued declines in TDF patients at both spine (P<0.0001) and hip (P<0.0001). Conclusions: Virally suppressed Asian patients with CHB and risk factors for TDF who switched to TAF showed improved bone and renal safety while efficacy was well-maintained.

Bone and Renal Parameters Following Switch to Tenofovir Alafenamide after 96- or 144-Weeks of Tenofovir Disoproxil Fumarate Treatment in East Asians with Chronic HBV

( Ki Tae Yoon ),( Seto Wai-kay ),( Kao Jia-horng ),( Lim Seng-gee ),( Peng Cheng-yuan ),( Kwan Soo Byun ),( Inokuma Tetsuro ),( June Sung Lee ),( Flaherty John ),( Yee Leland J ),( Jump Belinda ),( Se 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Background: Tenofovir alafenamide (TAF) has shown similar efficacy to tenofovir disoproxil fumarate (TDF) with better bone and renal safety in 2 Phase 3 trials through 96 weeks. After a protocol amendment, some TDF patients received 96 weeks while others received 144 weeks of TDF treatment before rolling over to open-label (OL) TAF. Aim: To examine whether duration of prior TDF treatment impacted changes in bone and renal parameters after 48 weeks of OL TAF treatment in the subset of East Asian (EA) patients with chronic HBV. Methods: Among 190 EAs randomized to TDF, changes in bone mineral density (BMD) by DXA scans and renal parameters were assessed from OL baseline to Week 48 following switch to OL TAF. Results: At Week 48, mean (SD) percent changes from OL baseline in hip-BMD were +0.92 (2.32) and +0.79 (2.47) and in spine-BMD were +1.52 (2.68) and +2.27 (3.51) for DB-TDF-144wks and DB-TDF-96wks, respectively. Similarly, median (Q1, Q3) changes from OL baseline in creatinine clearance (eGFR_CG) were +2.4 (-4.2, +10.8) and +3.0 (-3.0, +8.4) mL/min for DB-TDF-144wks and DBTDF-96wks, respectively. Similar trends in BMD and eGFR_CG changes were seen in non-EAs. Following switching to OL TAF, improvements in bone and renal biomarkers were also observed. Conclusions: In EA patients who switched to TAF from TDF, improvements were seen in bone and renal parameters.

Efficacy and Safety of Tenofovir DF (TDF) in Chronic Hepatitis B Patients (CHB) with Lamivudine Resistance (LAM-R): 5-year Results

( Florence Wong ),( Scott Fung ),( Hie-won Hann ),( Magdy Elkhashab ),( Thomas Berg ),( Milotka J. Fabri ),( Andrzej Horban ),( Mijomir Pelemis ),( Ioan Sporea ),( John F. Flaherty ),( Benedetta Masse 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: In CHB patients with LAM-R, TDF has shown efficacy comparableto FTC/TDF and no detectable TDF resistance at 2 years. The final5 year efficacy and safety results from this trial are presented.Methods: CHB patients on LAM with HBV DNA >3 log10 IU/mL andwith documented LAM-R were randomized (1:1) to TDF or FTC/TDFand followed for 5 years.Results: Two hundred eighty patients were randomized; 232 (83%)completed 5 years of treatment. At baseline, mean age was 47 years,most were male (75%) and non-Asian (66%); 53% were HBeAgnegative. Mean HBV DNA was 5.7 log10 IU/mL and 42% had ALT≤ULN at baseline. At Year 5, virologic, serologic, and biochemicalresponses were similar among groups, and remained stable. Ninepatients (4-TDF, 5-FTC/TDF) discontinued due to an adverse event,including increased serum creatinine in 1 patient. For both groupscombined, confirmed renal safety endpoints over 5 years were: CrCL<50 mL/min in 19 (6.8%) patients (12 requiring dose modification),increases in serum creatinine of ≥0.3 and ≥0.5 mg/dL from baselinein 21 (7.5%) and 2 (0.7%) patients, respectively, and serum phosphorus<2 mg/dL in 3 (1.1%) patients. Mean declines in BMD (g/cm2)from baseline for hip and spine BMD, respectively, were 1.7% and1.5% at Year 2, and 2.5%, and 1% at Year 5. Seven patientsexperienced fracture (all except 1 were trauma-related). No TDF resistancewas detected through 5 years by population sequencing.Conclusions: In LAM R patients with CHB treated for 5 years withTDF, a high rate of HBV DNA suppression was achieved and maintainedwith no detectable TDF resistance. There is no apparent ad advantageof combination FTC/TDF in this population. Renal eventsassociated with TDF occurred in up to 7.5% of patients, and averagelosses in bone mineral density of 1 2.5% were observed.