- Email: [email protected]
Efficacy of Prolonged Tenofovir Monotherapy for Partial Virologic Response to Tenofovir in Treatment-Naïve Chronic Hepatitis B Patients
POSTER PRESENTATIONS inflammasome NLRP3 is essential for initiating caspase-1 activity to drive innate immune response. However, little is known the functional role of Notch signal in the regulation of inflammasome NLRP3 activation during liver ischemia and reperfusion injury (IRI). This study was designed to dissect the innate immune network regulated by Notch signal in IR-triggered liver inflammation. Methods: Myeloid specific Notch1 knockout (Notch1M-KO), β-catenin knockout (β-cateninM-KO), floxed Notch1 (Notch1flox/flox) or β-catenin (β-cateninflox/flox) mice (n = 6/group) were subjected to 90 min partial liver warm ischemia followed by 6 h of reperfusion. In parallel in vitro study, Bone marrow-derived macrophages (BMMs) from these conditional mutant mice were transfected with CRISPR/Cas9expressing Notch1 ( p-Notch1) or JSAP1 knockout vectors ( p-JSAP1 KO) followed by LPS (100 ng/mL) stimulation. Results: Myeloid-specific Notch1 knockout (Notch1M-KO) exacerbated liver damage, as evidenced by increased sALT levels and hepatocellular necrosis/apoptosis. Unlike in Notch1flox/flox controls, Notch1M-KO reduced β-catenin yet increased TXNIP, NLRP3, caspase-1, and IL-1β levels in ischemic livers. Transfection of pNotch1 in Notch1-deficient BMMs enhanced HES1, β-catenin, HIF-1α, and Cyclin D1 but inhibited TXNIP and NLRP3 activation after LPS stimulation, as compared with controls. However, ablation of myeloid β-catenin increased liver injury and macrophage/neutrophil trafficking with reduced HIF-1α, CyclinD1, and augmented JSAP1, MKK4, JNK, TXNIP and NLRP3 expression in ischemic livers. Moreover, knockdown of JSAP1 with p-JSAP1 KO transfection reduced the phosphorylation of MKK4 and JNK, inhibited TXNIP/ NLRP3 activation, and diminished IL-1β levels in β-catenin-deficient BMMs after LPS stimulation. Conclusions: This study demonstrates that activation of Notch1 signaling regulates inflammasome NLRP3-mediated innate immunity by activating β-catenin, HIF-1α, and depressing JNK scaffold protein activity, which in turn inhibits TXNIP/NLRP3 activation in IR-triggered liver inflammation. Our novel findings underscore the crucial role of Notch1 signaling in the modulation of NLRP3 function within the innate immune system. Establishing macrophage Notch1 as a key regulator of innate immunity-mediated inflammation implies novel therapeutic potential for the management of liver IRI in transplant recipients. FRI-216 DO MUCOSAL-ASSOCIATED INVARIANT T (MAIT) CELLS IMPACT FIBROSIS IN HCV AND HIV/HCV CO-INFECTED PATIENTS? B. Beudeker1, G. Van Oord1, M. Van der Heide1, R. De Knegt1, A. Verbon2, A. Boonstra1, M. Claassen2. 1Department of Gastroenterology and Hepatology; 2Department of Internal Medicine, Infectious Diseases Section, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands E-mail: [email protected] Background and Aims: Among HIV-infected patients, HCV-related end-stage liver disease is presently an important cause of morbidity and the second-most important cause of death. Much is unknown on the mechanism of accelerated fibrosis in HIV/HCV co-infected patients. Continuous translocation of gut microbial products into the circulation, caused by failing immunological control during HIV infection, may contribute to increased inflammation and liver fibrosis. Several reports suggest that loss of MAIT cells, innate T cells important for antimicrobial defense, is implicated in this process. However, little is known on intrahepatic MAIT cell frequencies and phenotype during HCV and HIV/HCV co-infections. We aim to assess this frequency and phenotype and to correlate this with liver fibrosis. Methods: Blood samples and liver aspirate biopsies were collected from 20 males with either chronic HIV/HCV co-infection, all with cART induced suppression of HIV-infection, or chronic HCV monoinfection. Using flowcytometry we identified MAIT cells by the
expression of CD3, CD8, CD161 and TCR Vα7.2. For immune phenotyping we used markers like PD1, CD69 and 2B4. Results: In line with previous data on HIV mono-infected patients, MAIT frequencies in blood of HCV and HIV/HCV co-infected patients were dramatically decreased in comparison to healthy controls. Furthermore, intrahepatic MAIT cells were not completely depleted in these HIV and HIV/HCV patients. Moreover, also patients with advanced liver fibrosis showed higher MAIT cell proportions of CD8+ T cells than in peripheral blood. Liver MAIT cells in both HCV-infected groups displayed an exhausted phenotype as they expressed PD1, CD69 and 2B4. In these patients, intrahepatic natural killer (NK) cells did not express PD1 and showed lower CD69 expression, however, all NK cells did show very high 2B4 expression. We found a trend that intrahepatic MAIT cell frequencies were lower in patients with advanced fibrosis regardless of age. Conclusions: To our knowledge, this is the first report on frequency and phenotype of intrahepatic MAIT cells in HCV mono- and HIV/HCV co-infected patients. Frequencies and exhaustion of MAIT cells may impact fibrogenesis during HIV and HIV/HCV infection. However, future research is needed to examine whether HIV infection affects the function of MAIT cells and their migration. This may help us understand ongoing inflammation and subsequent morbidity during HIV, HCV and HIV/HCV infections. FRI-217 EFFICACY OF PROLONGED TENOFOVIR MONOTHERAPY FOR PARTIAL VIROLOGIC RESPONSE TO TENOFOVIR IN TREATMENTNAÏVE CHRONIC HEPATITIS B PATIENTS B.S. Kim1, M.K. Kim1, S.M. Kang1, S.H. Kim1, J.E. Song1, G.Y. Kim1, S.A. Baek1, C.H. Lee1. 1Catholic University of Daegu School of Medicine, Daegu, South Korea E-mail: [email protected] Background and Aims: The optimal management of chronic hepatitis B (CHB) patients exhibiting a partial virologic response (PVR) to tenofovir disoproxil fumarate (TDF) is currently not established. The aim of this study was to evaluate the efficacy of prolonged TDF monotherapy in treatment-naïve CHB patients exhibiting a PVR to TDF therapy. Methods: This study included 117 treatment-naïve CHB patients treated with TDF for ≥48 weeks and who received continuous TDF monotherapy for ≥24 weeks. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA of more than 2 log10 IU/mL from baseline but detectable HBV DNA by real-time PCR assay at week 48. All patients were monitored at baseline and every 3 months during treatment. Results: Twenty-three of 117 patients (19.7%) showed PVR. The mean follow-up duration in PVR group was 79.0 ± 9.2 weeks. The mean age was 49.2 ± 14.5 years, and 15 patients (63.2%) were men. Sixteen patients (69.6%) were HBeAg-positive, and 10 patients (43.5%) had cirrhosis. Nine of 23 patients (39.1%) achieved a virologic response (VR, HBV DNA <20 IU/mL) during prolonged TDF monotherapy for ≥24 weeks (mean duration, 27.4 ± 5.9 weeks). VR rate in HBeAgpositive patients was 38.4% (5/13). Among 14 patients who did not achieve a VR during continuous TDF therapy, 10 patients had poor drug compliance. The cumulative probabilities of a VR at week 60 and 72 from treatment initiation in patients with PVR were 22.2% and 31.6%, respectively. The PVR was associated with HBV DNA levels at baseline, week 4, 12, and 24, and also with virologic breakthrough. Conclusions: Long-term continuous TDF monotherapy with good medication compliance may be effective for achieving VR in treatment-naïve CHB patients exhibiting a PVR to TDF therapy.
Journal of Hepatology 2016 vol. 64 | S425–S630
S509
expression of CD3, CD8, CD161 and TCR Vα7.2. For immune phenotyping we used markers like PD1, CD69 and 2B4. Results: In line with previous data on HIV mono-infected patients, MAIT frequencies in blood of HCV and HIV/HCV co-infected patients were dramatically decreased in comparison to healthy controls. Furthermore, intrahepatic MAIT cells were not completely depleted in these HIV and HIV/HCV patients. Moreover, also patients with advanced liver fibrosis showed higher MAIT cell proportions of CD8+ T cells than in peripheral blood. Liver MAIT cells in both HCV-infected groups displayed an exhausted phenotype as they expressed PD1, CD69 and 2B4. In these patients, intrahepatic natural killer (NK) cells did not express PD1 and showed lower CD69 expression, however, all NK cells did show very high 2B4 expression. We found a trend that intrahepatic MAIT cell frequencies were lower in patients with advanced fibrosis regardless of age. Conclusions: To our knowledge, this is the first report on frequency and phenotype of intrahepatic MAIT cells in HCV mono- and HIV/HCV co-infected patients. Frequencies and exhaustion of MAIT cells may impact fibrogenesis during HIV and HIV/HCV infection. However, future research is needed to examine whether HIV infection affects the function of MAIT cells and their migration. This may help us understand ongoing inflammation and subsequent morbidity during HIV, HCV and HIV/HCV infections. FRI-217 EFFICACY OF PROLONGED TENOFOVIR MONOTHERAPY FOR PARTIAL VIROLOGIC RESPONSE TO TENOFOVIR IN TREATMENTNAÏVE CHRONIC HEPATITIS B PATIENTS B.S. Kim1, M.K. Kim1, S.M. Kang1, S.H. Kim1, J.E. Song1, G.Y. Kim1, S.A. Baek1, C.H. Lee1. 1Catholic University of Daegu School of Medicine, Daegu, South Korea E-mail: [email protected] Background and Aims: The optimal management of chronic hepatitis B (CHB) patients exhibiting a partial virologic response (PVR) to tenofovir disoproxil fumarate (TDF) is currently not established. The aim of this study was to evaluate the efficacy of prolonged TDF monotherapy in treatment-naïve CHB patients exhibiting a PVR to TDF therapy. Methods: This study included 117 treatment-naïve CHB patients treated with TDF for ≥48 weeks and who received continuous TDF monotherapy for ≥24 weeks. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA of more than 2 log10 IU/mL from baseline but detectable HBV DNA by real-time PCR assay at week 48. All patients were monitored at baseline and every 3 months during treatment. Results: Twenty-three of 117 patients (19.7%) showed PVR. The mean follow-up duration in PVR group was 79.0 ± 9.2 weeks. The mean age was 49.2 ± 14.5 years, and 15 patients (63.2%) were men. Sixteen patients (69.6%) were HBeAg-positive, and 10 patients (43.5%) had cirrhosis. Nine of 23 patients (39.1%) achieved a virologic response (VR, HBV DNA <20 IU/mL) during prolonged TDF monotherapy for ≥24 weeks (mean duration, 27.4 ± 5.9 weeks). VR rate in HBeAgpositive patients was 38.4% (5/13). Among 14 patients who did not achieve a VR during continuous TDF therapy, 10 patients had poor drug compliance. The cumulative probabilities of a VR at week 60 and 72 from treatment initiation in patients with PVR were 22.2% and 31.6%, respectively. The PVR was associated with HBV DNA levels at baseline, week 4, 12, and 24, and also with virologic breakthrough. Conclusions: Long-term continuous TDF monotherapy with good medication compliance may be effective for achieving VR in treatment-naïve CHB patients exhibiting a PVR to TDF therapy.
Journal of Hepatology 2016 vol. 64 | S425–S630
S509