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Current recommendations concerning hepatitis C virus (HBV) reactivation are limited, with nearly all guidelines focused on its occurrence in patients with hematological malignancies or some solid tumors, who are treated with immunosuppressive therapies. Few of the guidelines address reactivation in patients receiving immunosuppression with organ transplants or treatment with any of the many immunosuppressive agents in use today for the treatment of multiple different diseases, or in patients receiving the direct-acting antivirals used in the treatment of hepatitis C virus (HCV). This article covers the immunology of HBV reactivation, mechanisms of viral clearance, and recommendations for screening and prophylaxis.

Introduction Understanding the economic impact of managing allogeneic hematopoietic stem cell transplant (HCT) recipients with cytomegalovirus (CMV) is important for future planning within institutional transplant programs. CMV remains the most frequent viral infection following HCT but less is known about the impact of CMV on health resource utilization. Objectives We aimed to evaluate the economic burden of CMV infection in a large HCT centre operating under a universal health care system. Methods A retrospective single centre study at the Royal Melbourne Hospital, Australia was performed on all allogeneic HCT recipients between Jan2015 to Dec2017. CMV pre-emptive monitoring using quantitative CMV viral load was performed from time of transplant to 100 days or longer if GVHD. Clinically significant CMV (csCMV) was defined as viremia requiring anti-CMV treatment. First line anti-CMV therapy was (val)ganciclovir and second-line therapy was foscarnet. Hospital costing data for all admissions in the first 12 months were obtained. Financial year costing was available for FY2015/2016 to FY2017/2018. Ethics was approved by the Melbourne Health Human Ethics Review Committee (HREC 2017.368). Results A total of 255 patients underwent alloHCT with a median age of 51 years (IQR 40-59). The most common underlying diagnosis was AML (41%) and 54% had unrelated donor transplants. Pre-transplant recipient CMV seropositivity was 62% (n=158), of whom 139 had detectable CMV viremia and 105 (41.2%) experienced clinically significant CMV (csCMV). The median duration of CMV treatment was 33 days (IQR 21-63). Re-admission to hospital within the first 12 months of HCT occurred in 78.4%. There was a greater number of admissions observed in csCMV patients compared to no csCMV (median 3 vs 2, p=0.001) with the duration of admitted days within the first 12 months being significantly greater in csCMV patients compared to no csCMV (median 65 vs 36 days, p Conclusion The health care cost and resource utilization of treating CMV infection following an allogeneic HSCT is substantial and places a heavy burden on limited health resources. In this study, patients experiencing csCMV had an increased number and longer total duration of admissions days compared to patients who did not require CMV treatment. Interventions aimed at reducing the burden of CMV in alloHCT recipients are required.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people living with HIV (PLWH), without proven pharmacologic treatments in this population. We assessed the effects of tesamorelin on liver fat and histology in PLWH with NAFLD. METHODS: 61 men and women with HIV-infection and hepatic fat fraction (HFF) ≥5% by proton magnetic resonance spectroscopy were randomized to receive tesamorelin 2mg daily vs. identical placebo for 12 months at two academic centers. The primary endpoint was change in HFF. The primary safety endpoint was glucose. The study was randomized and double-blind, with identical placebo as a comparator. A random treatment sequence was generated by the statistician and provided to the research pharmacies. Analysis was by intention to treat using all available data. FINDINGS: Tesamorelin (N=26) reduced HFF compared to placebo (N=28), with an absolute effect size of −4.1% (95% CI −7.6, −0.7, P=0.02), corresponding to a −37% (CI −67, −7, P=0.02) relative reduction from baseline. After 12 months, 35% of individuals receiving tesamorelin vs. 4% receiving placebo had a reduction in HFF to

Background & AimsTelaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV.MethodsTreatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12–36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.ResultsThree hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0–1% and 8–11%, respectively, p

Genetic variations in host immunity may influence susceptibility to novel infections like the recently emergent pandemic influenza virus. Prior studies demonstrated that mannose-binding lectin (MBL) inactivates influenza. Furthermore, MBL deficiency is common and appears to predispose to respiratory virus infections. Therefore, we studied whether MBL deficiency played a role in infection with the novel H1N1 2009 influenza strain in exposed health care workers. In a nested case–control study, we observed no association between phenotypic MBL deficiency, variously defined, and predisposition to H1N1 2009 influenza in 63 pairs of seropositive and seronegative participants. MBL appears to currently have little impact on innate immune responses to H1N1 2009 influenza.

HIV infection has a significant impact on the natural progression of hepatitis B virus (HBV) related liver disease. In HIV-HBV co-infected patients, little is known about mutations in the HBV genome, which can influence severity of liver disease. The aim of this study was to characterize and to determine the frequency of known clinically significant mutations in the HBV genomes from HIV-HBV co-infected patients and from HBV mono-infected patients. To accomplish this, genomic length HBV sequencing was performed in highly-active anti-retroviral therapy (HAART)-naïve HIV-HBV co-infected patients (n=74) and in anti-HBV therapy-naïve HBV mono-infected patients (n=55).The frequency of HBV mutations differed between the co-infected and mono-infected patients when comparing patients with the same genotype. BCP mutations A1762T and G1764A were significantly more frequent in HBV genotype C mono-infection and the -1G frameshift was significantly more frequent in co-infection and was only observed in HBV genotype A co-infection. PreS2 deletions were observed more frequently in the setting of co-infection. Further work is needed to determine if these mutational patterns influence the differences in liver disease progression in HIV-HBV co-infected and HBV mono-infected patients.

Summary Background Catheter-related blood stream infections (CRBSI) cause significant morbidity and mortality in patients with hematological malignancies. Previous studies have identified a predominance of gram-positive organisms causing CRBSI but they included both neutropenic and non-neutropenic patients with solid organ and hematological malignancies. The aim of our study was to evaluate the incidence and microbiological profile of CRBSIs in a specific cohort of patients with hematological malignancies in their non-neutropenic phase of illness. Methods A detailed retrospective review was done from January 2003 to December 2005 on all patients with hematological malignancies who had double-lumen non-antibiotic impregnated tunneled CVCs (Hickman catheters) inserted in our hospital to identify those fulfilling our criteria for CRBSI episodes. Results Amongst 273 evaluable patients, 61 developed CRBSI on 70 occasions. In contrast to previous studies, there was a predominance of gram-negative infections (68%). The majority (73%) of initial CRBSI episodes required catheter removal within 7days of onset. Vancomycin and cefepime was the most common initial antibiotic regimen used. Conclusions This study highlights the predominance of gram-negative infections in our cohort of non-neutropenic patients with underlying hematological malignancies who had Hickman catheters whose lines were not salvageable in the majority of cases. Empiric monotherapy with an antimicrobial agent with broad spectrum gram-negative cover needs to be given upfront pending results of the nature and sensitivity of organisms identified.

We characterised the antiviral phenotype and genotype of 41 herpes simplex virus (HSV) strains from patients clinically resistant to acyclovir (ACV). Our results confirm recognised mutational sites as being major determinants of thymidine kinase (tk)-associated ACV resistance, in particular insertions and/or deletions at homopolymer stretches of Gs and Cs (59% of all isolates). Previously described amino acid substitutions in functional sites of the tk were also identified (7% of all isolates). In addition, we identified several stop codons in novel locations on the amino acid sequence (7% of all isolates) and amino acid substitutions (15% of all isolates) likely to be directly responsible for conferring resistance to ACV. When there were no mutations detected in the tk gene (12% of all isolates), mutations in the DNA polymerase gene likely to be important in the generation of resistant virus were identified.

The HBV drug entecavir – effects on HIV-1 replication and resistance. McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hegarty R, Chong CR, Liu JO, Siliciano RF, Thio CL. Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1−log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens. [Abstract reproduced by permission of N Engl J Med 2007;356:2614–2621]

Over the last few years we have seen the advent of effective antiviral drug therapy, the major ramifications being in the area of herpes infections. Acyclovir has become an established part of clinical practice, and other compounds are being increasingly used in the immunocompromised host. An effective vaccine is available for chickenpox, but herpes simplex and cytomegalovirus vaccines are still in early development. Thus, antiviral agents will continue to play a major role in the management of all herpesvirus infections for the foreseeable future. Current work includes the development of increased bioavailability prodrugs (BW 256, famciclovir), which are converted to active drug once absorbed, enabling rapid high serum levels, and hence may turn out to have increased efficacy in HSV- and VZV-induced diseases, for which oral acyclovir currently is the treatment of choice. Markedly increased efficacy against VZV in vitro has been demonstrated by two current agents under study (BVaraU, BW 882). HPMPC is now entering clinical trials with a markedly improved efficacy profile against CMV and HSV in animal models. Finally, drug combinations that are being investigated in AIDS may offer a means to avoid resistance in herpes infections in immunocompromised patients.

462 PREDICTION OF LIVER CIRRHOSIS RISK BY LONG-TERM CHANGES IN SERUM LEVELS OF HBV DNA AND ALANINE AMINOTRANSFERASE C.-F. Chen, H.-I. Yang, H.-C. Chang, C.-L. Jen, U.H. Iloeje, J. Su, C.K. Hsiao, L.-Y. Wang, S.-L. You, S.-N. Lu, W.-C. Lee, C.-J. Chen, The R.E.V.E.A.L.-HBV Study Group. Genomics Research Center, Academia Sinica, Taipei, Department of Health-Business Administration, Hungkuang University, Molecular and Genomic Epidemiology Research Center, China Medical University Hospital, Taichung, Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan R.O.C.; Research and Development, Bristol-Myers Squibb Co., Wallingford, CT, USA; Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Department of Medicine, Mackay Medical College, New Taipei City, Department of Gastroenterology, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan R.O.C. E-mail: d90842003@ntu.edu.tw

Background: Adult patients with haemophilia are frequently coinfected with HIV and HCV, usually due to blood and plasma factor transfusion prior to effective screening programs. The current standard therapy for HCV is pegylated interferon and ribavirin (PEG+RBV), which has been investigated in HCVmonoinfection and HIV/HCV coinfection. Little data exists regarding the effectiveness of HCV therapy in coinfected patients with haemophilia. We reviewed HCV treatment outcomes in our cohort of patients with haemophilia and HIV/HCV coinfection. Methods: We performed a retrospective review of all patients with haemophilia and HIV/HCV co-infection treated with PEG+RBV at the Alfred Hospital between 2001—2007 (n = 13). Patient histories and medical records were reviewed for demographics, adverse events and effectiveness, including early, end of treatment and sustained virological response (EVR, EOTR and SVR, defined as undetectable HCV viral load/PCR at 12, 48 and 72 weeks respectively) of HCV Results: All patients were male with haemophilia A, and a median age of 43 (range 27—62) at initiation of HCV therapy. Nine of thirteen (69%) patients had genotype (gt1) 1 HCV (gt3 = 3, gt4 = 1). Due to bleeding tendencies, only 1/13 patients underwent liver biopsy prior to HCV therapy. Twelve of 13 (92%) were receiving ART, with a mean CD4 count of 428 cells/uL (range 175—928 cells/ L) at initiation of HCV therapy. Six of 11 (55%) patients achieved EVR (3× gt1, 2× gt3) at 12 weeks, 4/13 (31%) had EOTR (2× gt1, 2× gt3) and 1/13 (8%) achieved SVR (gt1). 7/11 (64%) patients normalised ALT during therapy wherein mean ALT fell from 101 to 76U/L. Only 1/13 (8%) patients prematurely stopped therapy prematurely due to side effects. CD4 cell counts and HIV viral load remained stable during HCV treatment, with a mean 437 cells/uL and