Interferon alpha is the only treatment option for hepatitis delta virus (HDV). Trials investigating the efficacy of pegylated interferon alpha (PEG‐IFNa) showed HDV RNA negativity rates of 25‐30% 24 ...weeks after therapy. However, the clinical and virological long‐term outcome of HDV‐infected patients treated with PEG‐IFNa is unknown. We performed a retrospective‐prospective follow‐up of 77 patients treated for 48 weeks with either PEG‐alfa‐2a and adefovir (ADV) or either drug alone in the Hep‐Net‐International‐Delta‐Hepatitis‐Intervention‐Study 1 (HIDIT‐1) trial. Long‐term follow‐up data were available for 58 out of 77 patients (75%) with a median time of follow‐up of 4.5 (0.5‐5.5) years and a median 3 visits per patient. Patients treated with ADV alone received retreatment with PEG‐IFNa (48% versus 19%; P = 0.02) more often. Hepatitis B virus surface antigen (HBsAg) became negative in six PEG‐IFNa‐treated patients until the end of long‐term follow‐up (10%). Sixteen patients tested HDV RNA‐negative 6 months after PEG‐IFNa treatment who were entered in the long‐term follow‐up study. Out of these, nine individuals tested HDV RNA‐positive at least once during further long‐term follow‐up, with seven patients being HDV RNA‐positive at the most recent visit. Clinical endpoints (liver‐related death, liver transplantation, hepatic decompensation, hepatocellular carcinoma) were observed in three PEG‐IFNa‐treated (8%) and three ADV‐treated (14%) patients during posttreatment long‐term follow‐up with an overall annual event rate of 2.5% (4.9% in cirrhosis). Sequencing confirmed the reappearance of pretreatment virus strains in all cases. Conclusion: Late HDV RNA relapses may occur after PEG‐IFNa therapy of hepatitis delta and thus the term sustained virological response should be avoided in HDV infection. The annual posttreatment rate of clinical events in hepatitis delta patients eligible for PEG‐IFNa therapy is about 2.5% and 4.9% in patients with cirrhosis. (Hepatology 2014;60:87‐97)
Hepatitis D virus (HDV) infection is considered to cause more severe hepatitis than hepatitis B virus (HBV) monoinfection. With more than 9.5 million HBV-infected people, Vietnam will face an ...enormous health burden. The prevalence of HDV in Vietnamese HBsAg-positive patients is speculative. Therefore, we assessed the prevalence of HDV in Vietnamese patients, determined the HDV-genotype distribution and compared the findings with the clinical outcome.
266 sera of well-characterized HBsAg-positive patients in Northern Vietnam were analysed for the presence of HDV using newly developed HDV-specific RT-PCRs. Sequencing and phylogenetic analysis were performed for HDV-genotyping.
The HDV-genome prevalence observed in the Vietnamese HBsAg-positive patients was high with 15.4% while patients with acute hepatitis showed 43.3%. Phylogenetic analysis demonstrated a predominance of HDV-genotype 1 clustering in an Asian clade while HDV-genotype 2 could be also detected. The serum aminotransferase levels (AST, ALT) as well as total and direct bilirubin were significantly elevated in HDV-positive individuals (p<0.05). HDV loads were mainly low (<300 to 4.108 HDV-copies/ml). Of note, higher HDV loads were mainly found in HBV-genotype mix samples in contrast to single HBV-infections. In HBV/HDV-coinfections, HBV loads were significantly higher in HBV-genotype C in comparison to HBV-genotype A samples (p<0.05).
HDV prevalence is high in Vietnamese individuals, especially in patients with acute hepatitis B. HDV replication activity showed a HBV-genotype dependency and could be associated with elevated liver parameters. Besides serological assays molecular tests are recommended for diagnosis of HDV. Finally, the high prevalence of HBV and HDV prompts the urgent need for HBV-vaccination coverage.
The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-κB ...pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-κB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-κB pathway inhibition and were mediated by induction of G₁-phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities.
Objectives
Emerging treatments for relapsed or refractory multiple myeloma (rrMM) have led to increasing options for many patients. This study aimed to assess changes in utilization of these options ...in Germany with a focus on modern triplet regimens including new agents, such as carfilzomib, ixazomib, elotuzumab and daratumumab, and to evaluate whether this had an impact on rrMM‐related outcomes over time.
Methods
The study population consisted of 1255 rrMM patients who were assigned to one of the following 6 treatment groups: immunomodulatory drug (IMiD)‐based doublets, proteasome inhibitor (PI)‐based doublets, daratumumab monotherapy, PI‐IMiD‐based triplets, monoclonal antibodies (mAbs)‐based triplets, or other treatment.
Results
Use of triplet‐based therapy regimens increased from 5.9% in 2014 to 31.4% in 2017. In parallel, use of IMiD‐based doublets decreased from 74.3% in 2014 to 37.6% in 2017. Over the same time period, the risk of death decreased by 32% and the risk of hospitalization which was reduced by 30%. The risk for serious adverse events remained unchanged.
Conclusions
Between 2014 and 2017, the use of triplet‐based therapy regimens for rrMM in Germany has significantly increased and this was associated with a significant decline in deaths and hospitalizations without an increased incidence of serious adverse events.
Hepatitis B virus (HBV) infection is a major global health burden with distinct geographic public health significance. Oman is a country with intermediate HBV carrier prevalence; however, little is ...known about the incidence of HBV variants in circulation. We investigated the HBV genotype distribution, the occurrence of antiviral resistance, and HBV surface antigen (HBsAg) escape mutations in HBsAg-positive patients in Oman.
Serum samples were collected from 179 chronically HBV-infected patients enrolled in various gastroenterology clinics in Oman. HBV genotypes were determined by sequencing and phylogenetic analysis. Mutations in the HBV polymerase and the HBsAg gene were characterized by mutational analysis.
HBV genotypes D (130/170; 76.47%) and A (32/170; 18.28%) are predominant in Oman. The HBV genotypes C and E were less frequent (each 1.18%), while the HBV genotypes B, G, F, and H were not detected. Four patients revealed HBV genotype mixtures (HBV-A/D and D/C). The analyses of vaccine escape mutations yield that 148/170 (87.06%) HBV sequences were wild type. 22/170 (12.94%) HBV sequences showed mutations in the "a" determinant of the HBsAg domain. Two patients showed the described HBV vaccine escape mutation sP120T. 8/146 (5.48%) HBV isolates harbored mutations in the HBV polymerase known to confer resistance against antiviral therapy. Especially the lamivudine resistance mutations rtL180M/rtM204V and rtM204I were detected.
This study shows the distribution of HBV genotypes, therapy resistance, and vaccine escape mutations in HBV-infected patients in Oman. Our findings will have a major impact on therapy management and diagnostics of chronic HBV infections in Oman to control HBV infection in this intermediate HBV-endemic country.
This study aimed to describe biologic treatment of German inflammatory bowel disease (IBD) patients, including biologics' dosage, health care resource use, and treatment-associated cost.
In this ...retrospective claims data analysis, all continuously insured adult IBD patients (Crohn's disease CD or ulcerative colitis UC) who started a new therapy with an anti-tumor necrosis factor alpha (anti-TNF-α) or vedolizumab (VDZ) were included. Observation started with the date of the first prescription of index biologic therapy and lasted 12 months.
In the database, 1248 out of 57 296 IBD patients started a biologic treatment of interest (1020 anti-TNF-α, 228 VDZ), and 837 patients were bio-naïve (773 anti-TNF-α, 64 VDZ). The mean age of bio-naïve/bio-experienced anti-TNF-α patients was 39.2/38.1 years (54.9 %/56.7 % female) and 42.6/37.8 years for VDZ patients (56.3 %/54.9 % female). The proportion of patients receiving a maintenance dosage > 150 % compared to SmPC was 15.1 % for Adalimumab, 5.2-39.0 % for Golimumab, 14.7-34.5 % for Infliximab, and 19.7 % for VDZ patients. During the maintenance phase, up to 58.8 % of patients received at least 1 prescription of any CS, and 41.7 %/47.1 % (anti-TNF-α/VDZ) were treated in a hospital due to IBD. The mean IBD-related direct health care cost per patient year was € 30 246 (anti-TNF-α)/ € 28 227 (VDZ) for bio-naïve patients (p = 0.288) and € 34 136 (anti-TNF-α)/ € 32 112 (VDZ) for bio-experienced patients (p = 0.011).
A substantial percentage of patients receive a high biologic dosage in the maintenance phase. Despite biologic therapy, 30-40 % receive a CS therapy and/or experience at least 1 IBD-associated hospitalization within a year, possibly indicating a remaining disease activity.
Background In Germany, several triplet therapies for treating relapsed or refractory multiple myeloma (rrMM) patients have recently been approved. While most of them are administered intravenously, ...ixazomib-based combination is the only orally bioavailable regimen. Objective To conduct a 1-year and 3-year budget impact analysis (BIA) of different novel triplets to treat patients with rrMM in second or subsequent therapy lines accounting for costs covered by German statutory health insurance (SHI). Methods A 3-state partitioned survival model (PSM) was developed to evaluate the budget impact of the following regimens: carfilzomib plus lenalidomide plus dexamethasone (KRd), elotuzumab plus lenalidomide plus dexamethasone (ERd), daratumumab plus lenalidomide plus dexamethasone (DRd), and ixazomib plus lenalidomide plus dexamethasone (IRd). The analysis included direct medical costs such as drug acquisition, comedication and preparation for parenteral solutions, drug administration and other 1-time costs, adverse event management costs and direct non-medical costs, such as transportation costs. Results Based on current drug market shares in German healthcare market, the estimated costs after 1 year of treatment was €551 million (KRd),€163 million (ERd), €584 million (DRd), and €95 million (IRd). The total budget impact of €1393 million is mainly driven by drug acquisition and subsequent therapy costs. Conclusion Among the regimens of interest, the oral-based therapy regimens offered cost advantages over intravenous-based therapy regimens. The higher overall costs of intravenous therapy regimens were attributed primarily to higher drug acquisition costs.
This study describes preferences of German relapsed refractory multiple myeloma (RRMM) patients with novel proteasome inhibitor-based combination treatments.
Patients with a minimum age of 18 years ...and a diagnosis of RRMM were included. Their preferences were assessed using a discrete choice experiment design, which was developed based on a literature review and two patient focus group discussions. The final discrete choice experiment design consisted of four attributes, namely "therapy application regimen," "time without progression of disease," "possibility of grade ≥3 adverse events (AEs) affecting the blood," and "possibility of grade ≥3 AE heart failure."
Analysis was based on 84 patients (36.9% females, mean age 62.7 years, mean multiple myeloma disease duration 5.5 years). Among the tested attributes, "therapy application regimen" was assigned the highest importance for treatment decisions (38.8%), the second important attribute was "time without progression of disease" (38.7%), followed by "possibility of AE heart failure" (13.9%) and "possibility of AEs affecting the blood" (8.6%). Patients preferred oral intake once a day and once a week over other application modes such as oral intake once a day and once a week plus twice-weekly infusions. Furthermore, they preferred longer disease progression-free time and lower risk of grade ≥3 AEs. The highest overall utility was derived for ixazomib + lenalidomide + dexamethasone (utility: 3.218), compared with lenalidomide + dexamethasone (2.769), and carfilzomib + lenalidomide + dexamethasone (1.928).
RRMM patients prefer treatments with an all-oral application, a longer disease-progression-free time, and a lower probability of AEs. If patients face tradeoffs, they accept a lower progression-free time and/or higher AE rates to get an all-oral therapy.
E- and P-selectin ligands (E- and P-ligs) guide effector memory T cells into skin and inflamed regions, mediate the inflammatory recruitment of leukocytes, and contribute to the localization of ...hematopoietic precursor cells. A better understanding of their molecular regulation is therefore of significant interest with regard to therapeutic approaches targeting these pathways. In this study, we examined the transcriptional regulation of fucosyltransferase 7 (FUT7), an enzyme crucial for generation of the glycosylated E- and P-ligs. We found that high expression of the coding gene fut7 in murine CD4
T cells correlates with DNA demethylation within a minimal promoter in skin/inflammation-seeking effector memory T cells. Retinoic acid, a known inducer of the gut-homing phenotype, abrogated the activation-induced demethylation of this region, which contains a cAMP responsive element. Methylation of the promoter or mutation of the cAMP responsive element abolished promoter activity and the binding of CREB, confirming the importance of this region and of its demethylation for fut7 transcription in T cells. Furthermore, studies on human CD4
effector memory T cells confirmed demethylation within FUT7 corresponding to high FUT7 expression. Monocytes showed an even more extensive demethylation of the FUT7 gene whereas hepatocytes, which lack selectin ligand expression, exhibited extensive methylation. In conclusion, we show that DNA demethylation within the fut7 gene controls selectin ligand expression in mice and humans, including the inducible topographic commitment of T cells for skin and inflamed sites.
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