J Schulze zur Wiesch

High efficacy of sofosbuvir/velpatasvir and impact of baseline resistance-associated substitutions in hepatitis C genotype 3 infection

Twelve weeks of the pangenotypic direct‐acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL‐3 approval study. However, presence of resistance‐associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response.

O119 : Stopping tenofovir disoproxil fumarate (TDF) treatment after long term virologic suppression in HBeAg-negative CHB: Week 48 interim results from an ongoing randomized, controlled trial (“finite CHB”)

O119 STOPPING TENOFOVIR DISOPROXIL FUMARATE (TDF) TREATMENT AFTER LONG TERM VIROLOGIC SUPPRESSION IN HBeAg-NEGATIVE CHB: WEEK 48 INTERIM RESULTS FROM AN ONGOING RANDOMIZED, CONTROLLED TRIAL (“FINITE CHB”) T. Berg, K.-G. Simon, S. Mauss, E. Schott, R. Heyne, D. Klass, C. Eisenbach, T.M. Welzel, R. Zachoval, G. Felten, J. Schulze zur Wiesch, M. Cornberg, E.B. Martins, L. Gallo, T. Warger, J. Petersen. Innere Medizin, Sektion Hepatologie, Universitatsklinikum, Leipzig, Gastroenterologische Gemeinschaftspraxis, Leverkusen, Zentrum HIV and Hepatogastroenterologie, Dusseldorf, Charite, Leberzentrum Checkpoint, Berlin, Innere Medizin I, Universitatsklinikum, Ulm, Universitatsklinikum, Heidelberg, J.W.-Goethe Universitat, Frankfurt a. Main, Klinikum der LMU, Munchen, Gastroenterologische Gemeinschaftspraxis, Herne, University Hamburg Eppendorf, Hamburg, Medizinische Hochschule, Hannover, Germany; Gilead Sciences, Foster City, United States; IFI Institut, Hamburg, Germany E-mail: lothar.gallo@gilead.com

Successful treatment of chronic hepatitis C with ground ledipasvir / sofosbuvir in a patient with Crohn's disease and short bowel syndrome

To the Editor: We read the comprehensive review by Gitto et al.1 entitled “NS5A inhibitors for the treatment of hepatitis C infection” (CHC) with great interest. Indeed, the development of direct acting antivirals (DAAs) now enables successful treatment of formerly difficulttotreat patient populations (eg, cirrhosis or chronic kidney disease). However, little is known about the use of DAAs in patients with short bowel syndrome, for example following inflammatory bowel disease (IBD), because these patients are yet excluded from clinical trials.2 In the following, we describe herewith the first report of successful treatment with ground Harvoni® (LDV/SOF) tablets in a treatmentnaïve 47yearold male patient with CHC and concomitant short bowel syndrome following complicated Crohn’s disease (CD). Crohn’s disease was diagnosed in 1984 with consecutive complete colectomy, and multiple resections of the small intestine, resulting in endjejunostomy with severe short bowel syndrome and necessity of a venous port system to support parenteral nutrition for the past 15 years. CHC, genotype 1b was diagnosed in 1985. In 2016, transient elastography suggested earlystage fibrosis (7.5 kPa) and antiviral treatment was initiated with a combination of LDV/SOF for 12 weeks. Each pill was mechanically ground because the patient previously engaged in placing intact tablets into the stoma. Preceding CHC treatment, CD was restaged by endoscopy, histology and MRI without any further complications or necessity of medical treatment (stomach 25 cm; remaining small intestine 84 cm, blind ending rectum 18 cm). Blood count, renal and liver function tests were normal, despite an elevated GPT (1.08 of ULN). HCVRNA (taqMan® PCR, Roche) rapidly decreased from 880 000 to 27 IU/mL 2 weeks after start of treatment and was undetectable from week 4 throughout posttreatment week 24, demonstrating cure (Figure 1). No adverse events or exacerbation of CD occurred. While treatment of CHC with Interferonbased regimens in IBD patients was regarded challenging,3 knowledge about therapy with DAAs in these patients is very limited. Physiologically, concentrations of LDV and SOF’s metabolite GS331007 peak ~44.5 hours postdose.4 Yet, in how far crushing the tablet enhanced the extent of absorption is unclear, but would likely serve to hasten drug dissolution and maximize the potential for drug absorption. While the LDV/SOF tablet is not recommended to be crushed due to poor taste, consideration may be warranted in instances such as for this or similar patients. The current case is promising for patients with CHC and malabsorption, although more data and guidance are needed to optimally treat this underserved population with the different DAA regimen available.

Breadth of the HCV-specific CD4+ T-cell response in spontaneous resolvers is independent of the IL-28 haplotype.

Dear Sir We read with great interest the recent article by Bes et al. about ‘IL28 genetic variation and the HCV CD4+ Tcell response in antiHCVpositive blood donors’.1 Overall, our results do not differ greatly from the reported results. However, our conclusions partially differ from Bes et al.1 who conclude that there may be stronger ELISPOT responses towards HCV antigens in patients with IL28 nonCC haplotype than in patients with CC haplotype. We also analysed the breadth and strength of the HCV CD4+ Tcell response of 66 patients with spontaneously resolved HCV with a highly sensitive assay and stratified the patients according to the abovementioned IL28 polymorphism.2 HCVspecific polyclonal CD4+ Tcell cultures were generated as previously described.3 PBMC were then tested for individual responses against any of the 24 most frequently detected HCV1 20 mer peptides located in the region of the nonstructural proteins by single peptide ELISPOT as previously described.3 Positive responses in the ELISPOT assay were additionally confirmed in a single peptide intracellular cytokine staining (ICS) assay for specific IFNγ production of CD3+CD8CD4+ cells for each positive peptide response. On the whole, we did not find any difference in the breadth of the HCVspecific CD4+ response with regard to the IL28B haplotype (Fig. 1a). Furthermore, we did not find differences in the magnitude of these responses as determined by the mean of the strength of the individual ICS response in the HCVspecific CD4+ Tcell ICS assay after individual HCV peptide stimulation (Fig. 1b). It has to be remarked that in the study by Bes et al., statistically, there was also no difference in the strength of the Tcell response in the groups of spontaneous resolvers as stratified by the IL28 haplotype. The comparison of the response of chronic patients with the response of resolvers according to the IL28 haplotype is not fully clear to us as to our mind, only patients with the same clinical course can be directly compared.1 In summary, our data provide further evidence that the HCVspecific CD4+ Tcell response in subjects with spontaneously resolved infection is primed at similar breadth regardless of the IL28B genotype, and these two factors more likely independently tilt the balance in favour of resolution of the HCV infection. The results of two recent large genetic studies of HCV patients with different disease outcome support this hypothesis.4,5

Lack of evidence for human serum albumin as major source of HEV infections: Letter to the Editor

Dear Sir, We read with interest the recent article by Juhl et al., regarding transmission of the hepatitis E virus (HEV) by coagulation factor concentrates (Juhl et al., 2017). Based on seroprevalence data, the authors interpret their results as evidence that HEV is efficiently inactivated during the manufacturing process of coagulation factor concentrates. In our region, HEV genotype 3 infections can be acquired autochthonously (Hoofnagle et al., 2012). The most relevant sources of transmission are swine contact and consumption of undercooked swine meat. Individuals in contact with swine have a two-fold increased risk for anti-HEV positivity compared to healthy controls (blood donors without swine contact) (Krumbholz et al., 2012). Within the last few years, blood products have been identified as a relevant source of HEV transmission. Transmission via blood products is assumed to be less frequent compared to transmission via swine consumption. However, detailed epidemiological data are still lacking. Recently, we demonstrated, in a large cohort of almost 19·000 blood donations, that approximately 1/1000 blood donations in Germany tested positive for positive by polymerase chain reaction (PCR) (Westholter et al., 2018). Therefore, in our opinion, it is crucial to further investigate other products derived from blood donations as potential source of infection: Human serum albumin (HSA) is a product manufactured from mixed pools of plasma donations (1000 to 1660 L) of several thousands of donors (Horowitz et al., 2004). Human albumin is usually administered to patients with liver cirrhosis and refractory ascites (8 g L−1 of removed ascites) (EASL, 2010). Some of these patients develop acute-on-chronic liver failure, with potentially fatal outcomes. It still needs to be determined if HEV infection transmitted by HSA infusions can play a role in this context, perhaps as a trigger or additional hit. In 2015, in a British/French study of 343 patients with decompensated chronic liver disease demonstrated, it was found that 11 patients (3·2%) had acute hepatitis E, and 3 of these 11 died (Blasco-Perrin et al., 2015). How many of these patients received albumin, and whether this could have been their source of infection, is unknown. As HSA is a product derived from pooled human plasma, it represents a potential source of HEV transmission.

Editorial: genotype 3 HCV-who still needs ribavirin in a pan-genotypic era? Authors’ reply

We read with interest the editorial provided by Dr. Sadler on our manuscript reporting real-world experience with sofosbuvir and velpatasvir (SOF/VEL) and the impact of baseline resistance associated substitutions in the nonstructural protein 5A (NS5A RASs) on treatment outcome in patients with chronic hepatitis C (HCV) genotype 3 infection (GT3). Dr. Sadler assessed the prevalence of high level NS5A RASs in our study as too low to draw meaningful conclusions regarding their impact on treatment outcome. However, we would like to emphasise that the prevalence of NS5A RASs in our study was effectively comparable to that reported in clinical trials of SOF/ VEL for HCV GT3. In a pooled analysis of the ASTRAL studies, 12% of GT3 patients (57 of 476 patients) had any baseline NS5A RASs and 4.6% had a Y93H RAS (22 of 476 patients), compared to 11.2% and 4.6%, respectively, in our study. This surely might be explained by the fact that most patients had not received an NS5A inhibitor before. Moreover, our data are complemented by a recent real-world study from several European countries, including Germany, Switzerland and Austria, that showed a 9% NS5A RASs prevalence in 375 DAA-na€ıve GT3 patients. Therefore, we believe that our study population adequately mirrors the prevalence of NS5A RASs in the Western GT3 population. More importantly, our results suggest that their impact on treatment outcome may be less striking than previously reported, particularly in patients without cirrhosis. Regarding the use of ribavirin in patients with compensated cirrhosis, we agree with Dr. Sadler on the limited conclusions that can be drawn from our study. A definite answer to this question would require a controlled, randomised trial, which is unlikely to be conducted given the overall high SVR rates with modern DAA regimens. We also agree that the use of ribavirin is required in patients with decompensated cirrhosis; a recommendation based on the ASTRAL-4 clinical trial and now further underscored by our results with notably even higher SVR rates. Concerning the importance of ribavirin in patients without cirrhosis but baseline NS5A RAS probably studies in larger patient cohorts may be required to draw definite conclusions. Currently, our findings do not support the general use of ribavirin in GT3 patients without cirrhosis, irrespective of the presence of baseline NS5A RAS. Further our results suggest that ribavirin may not be necessary in most DAA-na€ıve patients with compensated cirrhosis considering the high SVR rates in this subgroup treated without ribavirin. However, the role of SOF/VEL plus ribavirin after DAA failure as a possible treatment alternative to, for example, SOF/VEL plus voxilaprevir certainly requires further investigation in the real-world setting. ACKNOWLEDGEMENTS

P0831 : Safety and efficacy of Sofosbuvir-based treatment regimens for chronic hepatitis C virus infection: A “Real-Life”, single-center experience in 117 patients

polymorphism in NS3 or NS5A, while two patients with the polymorphism experienced viral breakthrough. Except for the two patients, patients with NS5A Y93H/N or L31M showed similar viral response until 4 weeks of the therapy. The frequently reported adverse events were mild headache, fever, or elevations of ALT, g-GTP or ALP and one patient stopped the therapy because of the onset of brain infarction. There were no further serious adverse events during early course of the treatment. Conclusions: The response of HCV-RNA was favorable enough during the DCV+ASV therapy, even for women, aged patients, patients with liver cirrhosis or patients with intractable IL-28B polymorphism. However, resistance-associated polymorphism of HCV could affect treatment response, and further examination for absolute quantity of the resistance-associated polymorphism is desired to evaluate the effectiveness for the DCV+ASV treatment.

Alterations in function and distribution of regulatory T Cells (Tregs) may blunt vaccine induced immune responses in HIV infection

Methods Peripheral blood and individual lymph nodes of a large cohort of HIV+ patients (n=131) at different disease stages, including 15 long-term nonprogressors and 21 elite controllers , was analyzed to determine the frequency, phenotype and function of Tregs. Results A significantly increased relative frequency of Tregs within the CD4+ compartment of HIV+ patients in comparison with healthy controls (p 0.05). Loss of absolute Treg numbers was associated with increased markers of immune activation (HLA-DR, CD38 Ki-67)(p<0.0006). Initiation of antiviral therapy significantly increased absolute Treg numbers (p<0.0031). Moreover, we find that the expression of CD39 and CD73, newly defined ectonucleotidases involved in ATP degradation, correlated with progressive HIV disease, VL and immune activation. Of note, the capacity to suppress T cell proliferation in vitro was limited to the CD4+CD25highCD39+ T cell subset. Depletion of this distinct Treg subset in vitro resulted in a restoration of HIV specific T cell responses. Tregs of elite controllers exhibited the highest expression of CCR5, CTLA-4 and ICOS and the lowest level of CD39 indicating the functional importance of this ATP modulating enzymatic reaction. Conclusion These data reconcile the seemingly contradictory results of previous studies on Tregs in HIV and highlight the complexity of Treg mediated immunoregulation. Blocking of ATP modulating molecules which are highly expressed on Tregs may restore HIV specific immune responses.

Downregulation of the 5’-ectonucleotidase CD73 of CD8+ CTL of HIV infected patients correlates with immune activation and diminished IL-2 production

Background Chronic untreated HIV infection is immunologically characterized by irreversible loss of CD4+ T cells, general immune activation and CD4+ and CD8+ T cell dysfunction with diminished proliferative capacity. CD73 is an ectoenzyme (5’-ectonucleotidase) expressed on T cells converting 5’-AMP to adenosine, but there is additional evidence of ectonucleotidase-independent CD73 function. Altogether CD73 seems to play a role as a co-stimulatory molecule for T cell differentiation.

[92] VIRAL SEQUENCE EVOLUTION IN ACUTE HCV INFECTION

1 Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 2 Department of Virology, University Hospital Essen, Germany 3 Departamento de Virologia, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Brazil 4 Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA