I I II I I. . .P P PA A AT T TI I IE E EN N NT T TS S S A A AN N ND D D M M ME E ET T TH H HO O OD D DS S S
The study subjects i ncl uded consecuti ve 40 ADV-refractory chroni c hepati ti s B pati ents wi th pri or LAM resi stance.Al l pati ents had LMV resi stance documented by vi rol ogi c breakthrough defi ned as an i ncrease i n thel evelofHBV DNA ofatl east1l og 10 copi es/mL from thel owestpoi nt duri ng therapy , genotypi c anal ysi s of rtM204 sequences,and LAM was swi tched to ADV monotherapy. Pati ents were consi dered to be ADV refractory i f they had al i mi ted vi rol ogi cal response wi th or wi thout documented ADV mutati ons whi l e on ADV.Fourteen pati ents devel oped ADV resi stance and another26 pati ents experi enced subopti malvi rol ogi cal response to ADV monotherapy.These were swi tched to ETV monotherapy from ADV.Pati ents were posi ti ve forHBsAg atl east1 yearbefore LAM therapy. None of the pati ent had co-i nfecti ons(HCV, HIV) or other concomi tantl i verdi seasesuchasal cohol i cl i verdi seaseorautoi mmunel i ver di sease.Al lpati ents had HBV DNA l evel> 5l og 10 copi es/mL before ETV admi ni strati on and recei ved 1. 0mg ETV oncedai l y.Bi ochemi stry and HBV DNA l evel s were tested before and every 3 months duri ng ETV therapy.
Liver biopsy is the gold standard for assessing liver fibrosis and necroinflammatory activity, but the procedure is limited by sampling error, risk of complications, patient discomfort, and inter-observer variation (Poynard et al, 2000; Regev et al, 2002; Bedossa et al, 2003). For these reasons, the usefulness of a liver biopsy as the follow-up method forpatients receiving antiviral therapy is quite limited. Non-invasive assessment of liver fibrosis has become an area of clinical interest in the past decade. A number of serum markers have been evaluated for the assessment of hepatic fibrosis. Some of those markers have been widely validated in patientswith chronic liver disease (Wai et al, 2003; Wai et al, 2006;
definitions in various clinical settings, because pattern of prescribing antiviral agent might be quite different depending on the clinical settings. We investigated two different sized hospitals; one is tertiary hospital and the other is secondary hospital. Although we tried to validate the operational definitions using real world data from two different hospitals, we thought 133 patients were not enough to validate for 7166 decompensatedpatients’ data. Third, the definition of “compensated CHB” is more lenient as it included both CHB and early compensated cirrhosispatients, while “decompensated CHB” is very strict, as it only includes “patientswith large amounts of ascites” but generally “ascites is a feature of decompensation.” Patients with moderate ascites who used diuretics and had mild variceal bleeding with no drug therapy were excluded from the study. Consequently, the decompensated complications defined in the present study may have been underestimated compared to those in actual patientswithdecompensatedcirrhosis.
In cirrhotic patients, the SVR rate of the genotype non-1 group was similar at around 52.6%. The SVRs of genotype 1 group was reported to be very low at 13-14%, 14,15 however, the SVR was relatively high at 20.8% in this study. This was consistent with the results of relatively high SVRs in Korean patients compared to those in Western countries in studies withpatients who did not have liver cirrhosis, but the accurate reason is unknown. 16,17 Furthermore, in this study, even the SVR rate of patientswith portal hypertension who showed splenic enlargement in imaging study, thrombocytopenia, or esophageal or gastric varices in upper gastrointestinal endoscopy was 30.0% (9/30), which was better than the results of other studies. There was no significant difference in SVR, compared to patients who did not have portal hypertension. However, the clinical judgment on portal hypertension may be subjective and the number of patients is small in our study. Therefore, accurate diagnosis methods such as measurement of hepatic venous pressure gradient for the assessment of portal hypertension, and studies with a larger number of patients may be needed.
Methods: Two hundred seven adult hepatectomy patientswith HCV-related HCC were prospectively identified at our institution be- tween July 2005 and May 2019.
Results: One hundred sixteen (56%) hepatectomy patients had HCC in a non-cirrhotic liver. The non-cirrhotic group had better liver function than the cirrhotic group. Consistently, the FIB-4 grade, ALBI grade, and APRI were higher in the cirrhotic group than in the non-cirrhotic group. The cumulative disease-free survival rates and patient survival rates in the non-cirrhotic group were significantly better than in the cirrhotic group. HCC recurrence is related to major liver resection (LR) and alpha-fetoprotein (AFP) > 40 ng/mL, death is related to long hospitalization, and AFP > 40 in multivariate analysis. APRI was the only predisposing factor for HCC recur- rence in non-cirrhotic patients in multivariate analysis. The FIB-4 grade, ALBI grade, and the presence of cirrhosis were not related to HCC recurrence or patient survival in multivariate analyses.
We retrospectively evaluated patients diagnosed with HCV genotype 1b infection who received DCV and ASV combination therapy between August 2015 and March 2017 at five university hospitals in Daegu and Gyeong- sangbuk-do. Exclusion criteria for this study were: pa- tients diagnosed withdecompensatedcirrhosis, those with hepatocellular carcinoma (HCC) requiring treat- ment, those with a history of liver transplantation, and coinfection with other HCV genotypes, hepatitis B vi- rus, or the human immunodeficiency virus. Decompen- sated cirrhosis was defined as cirrhosis categorized as Child-Turcotte-Pugh class B or C based on the results of blood tests and imaging studies such as abdominal ultrasonography and/or computed tomography. The enrolled patients were divided into three groups: the treatment-naïve, treatment failure (including null re- sponse, partial response, virologic breakthrough, re- lapse after previous treatment), and treatment-intoler- ant group (those who discontinued treatment owing to adverse events). The study protocol was approved by the Institutional Review Board (CR-17-021) of each partici- pating hospital. Patients were not required to provide
From January 7, 2007 to December 29, 2015, patientswith HBV who underwent LT (both living-donor LT [LDLT] and deceased-donor LT [DDLT]) at Samsung Medical Center (Seoul, Republic of Korea) were included. Primary diseases for transplantation include HCC, liver cirrhosis, and acute liver failure. Data were collected for 3 years after operation. HBsAg positivity, HBV-DNA positivity, and continuous use of TDF or ETV for HBV prevention were included. HCV infection, HIV infection, HDV infection, autoimmune hepatitis, previous renal disease such as IgA nephropathy, focal segmental glomerulosclerosis or other chronic renal failure, and death or re-transplantation within 2 years after operation were exclusion criteria. We defined ‘chronic renal failure’ as ‘e-GFR < 60 mL/
The number of NK cells in the peripheral blood of HCC patients has been published as significantly pos-
itively correlated with survival rates and the prognosis of liver cancer. 25 Given the fact that previous successful treatment of leukemia was achieved with alloreactive hap- loidentical KIR ligand-mismatched NK cells, it was ex- pected that administration of MG4101 would be safe and exhibit enhanced clinical benefit in HCC patients over other therapies. The function of allogeneic NK cells, dis- tinct from major MHC-restricted cytolytic activity of T cells, may play a role in antitumor surveillance through an MHC-unrestricted manner. Together, NK cells contrib- ute to the induction of adaptive immune responses by se- creting cytokines and chemokines. These concepts of allo- geneic NK cell therapy are currently being evaluated in various phases of clinical trials for the treatment of human cancers.
MATERIALS AND METHODS
Patients and study design
A total of 50 CHB patientswith genotypic ETV resistance, who subsequently received rescue ADV- based combination therapyfor more than 12 mo at 13 medical centers in South Korea between January 2008 and October 2012, were enrolled in this retrospective cohort study. ETV resistance was documented in all patients by genotypic analyses at the time of switching to ADV-based combination therapy. We excluded patients infected with other viruses such as hepatitis C virus, human immunodeficiency virus, or hepatitis D virus and those with other concomitant liver diseases such as alcoholic liver disease, autoimmune liver disease, or HCC. All patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments.
anism of this phenomenon needs to be elucidated.
Our study had several limitations. First, 11.9% of the patients have not been evaluated for the SVR, so the pro- portion of patients achieving SVR may be either over- estimated in the PP analysis or underestimated in the ITT analysis. It was an unavoidable situation in the re- al-world setting, but antiviral efficacy would be favorable because even three of the four patients who withdrew EBR/GRZ therapy within 30 days did not show detect- able HCV RNA level at 12 weeks after antiviral therapy (data not shown). Secondly, the adverse events were not graded owing to retrospective design. Nonetheless, visits to respective physicians on each site confirmed that all treatment withdrawal cases were not related to adverse events: one person withdrew due to unaffordability and three were lost to follow-up.
TDF is a potent nucleotide analog used to treat HBV infec- tion. 10) It exhibited sustained antiviral efficacy in treatment- naïve patientswith CHB and it was effective in patientswith CHB with an altered response to NAs. 11,12) TDF demon- strated a similar efficacy in patientswith LAM failure as that in NA-naïve patientswith CHB, independent of the presence of antiviral resistance conferred by mutations. 13) In addition, TDF exhibited excellent and long-term efficacy, even in patientswith CHB who experienced NA treatment failure. 14) However, TDF had lower efficacy in patientswith CHB and previous ADV exposure than in NA-naïve patientswith CHB. 15) ETV is another potent nucleoside for the treatment of HBV-infected patients. 10) HBV resistance to ETV is not common in NA- naïve patientswith CHB; furthermore, long-term ETV ther- apy in these patients led to the reversal of fibrosis/cirrhosis and sustained histological improvement. 6,10,16) However, ETV resistance during therapy was noted in NA-experienced patientswith CHB and suboptimal viral suppression was also reported in NA-naïve patientswith CHB owing to poor adher- ence and individual genetic variation. 10)
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II. PATIENTS AND METHODS
A. Patients Selection
Between October 2005 and June 2009, 384 consecutive patientswithhepatitis B virus (HBV) infections who underwent liver biopsies in 6 centers (Ajou University Hospital, Hallym University Chuncheon, CHA University Hospital, Inje University Busan Paik Hospital, Pusan National University Hospital and Catholic University St. Vincent’s Hospital) in South Korea were recruited in this study. The inclusion criteria were CHB patients who underwent a liver biopsy and had not received antiviral treatment within 6 months prior this study’s commencement. Patients were not included if there were other causes of liver disease or decompensatedcirrhosis.
Methods: Patients who received allogeneic stem cell transplant were evaluated. Sixty patients, thirty in each group who received LVD or ETV prophylaxis were included in the study. All the baseline and post-transplant data was evaluated which includes anti –CD20 agent exposure, duration of prophylaxis of each drugs and clinical and virological follow up post transplantation. Serum ALT, HBsAg, anti HBs and HBV DNA were the parameters measured.
similar to or lower than previously reported rates, suggesting no correlation between GZR-containing regimens and HCC inci- dence. 24-29
This analysis had several limitations. Most patients in this study were treatment-naive and HCV mono-infected; caution when ex- trapolating these findings to other patients groups, such as those previously treated for HCV infection or those with HCV/HIV coin- fection. Korean patients in this analysis were identified as individ- uals enrolled at Korean study sites: no additional measures were taken to confirm the nationality/race of patients. The comparison of SVR12 rates between Korean, Asian, and non-Asian patients was restricted to individuals with HCV GT1b infection who re- ceived EBR/GZR for 12 weeks; however, these populations may have differed with regard to other characteristics, such as the proportions withcirrhosis, HIV coinfection, high baseline viral load, or other comorbidities such as chronic kidney disease, inher- ited blood disorders, or active injection drug use.
patients (4 patients), these findings should be considered with caution.
Assessing the severity of liver disease solely by measure- ments of plasma transaminase levels is inadequate. Histologi- cal data are also necessary, possibly with an estimated dura- tion of virus infection. However, due to the lack of histo- logical studies of patient tissues in the current study, we were not able to address this issue. In our study, to enhance cost-effectiveness ALT, AST, and ferritin levels were only measured in the control group. Regardless of whether TTV is a cause of liver disease in thalassemic patients, pathogenic mechanisms of the virus need to be rapidly elucidated in order to develop new strategies to prevent transmission and for therapeutic intervention. Targeted longitudinal studies of TTV in the future will be helpful in this regard .
In addition to seroprevalence data, the cost of serologic test- ing, the cost of vaccination, patient compliance, and the like- lihood of the occurrence of a clinically significant fatal HAV superinfection should also be determined to facilitate the iden- tification of the most efficient vaccination strategy. In young or childhood CLD patients, the serum anti-HAV rate is very low and the risk of infection is high, but the symptomatic infection rate and the risk of severe hepatic failure are mini- mal and natural life long immunity is frequently attained after a mild or asymptomatic infection. Therefore, the selec- tive HAV vaccination of middle aged adult CLD patients appears more urgent than the universal vaccination for younger CLD patients (24). Further nationwide large scale studies, including the active evaluation of the clinical significance of acute HAV infection and cost-benefit analyses of different vaccination strategies in different age groups of CLD patients will provide firmer data for designing an optimal vaccination strategy.
ference. They reported that the reason is that patientswith RA are relatively older than patientswith SLE. Our study also showed that the anti-HBc-positivity rate increases with age.
Our study found that the vaccination effectiveness in the patients newly diagnosed with IBD was significantly lesser than that in the controls. Many studies have presented that immunosuppressant use reduces HBV vaccination effi- cacy. 7-10 However, the patients in this study were newly diag- nosed with and not yet treated for IBD, and the vaccination effectiveness results were similar to those in another study. 18 He et al. 22 opposed that HBV infection in patientswith IBD could worsen when treated with immunosuppressants; their finding was concordant with those of this study. We also found that the vaccination effectiveness rate was significant- ly lower in the subgroup of patients newly diagnosed with IBD aged <20 years than in the age-matched controls (IBD, 58.5% vs. control, 75.1%, P=0.045). We did not compare the vaccination rates between the patients and controls; how- ever, we can assume that the vaccination rate of the <20-year subgroup would be higher than that of the other subgroups because of the nationwide vaccination strategy. Therefore, it appears that the lower vaccination effectiveness rate in the patients newly diagnosed with IBD was because of reasons other than the vaccination rate and use of immunosuppres- sants. One possible explanation for this might be a confused immune response. Cellular immune responses initiated by Type 1 helper T cells, cytokines, and regulatory T (Treg) cells effectively protect against and downregulate inflammation in human studies and animal models of CD. 23 HBV infection is also thought to cause an unusual cell-mediated immune response, and it has been proven that Treg cells are an im- portant prognostic factor of HBV infection. 24 However, these hypotheses should be investigated in future research studies;
Many previous studies have shown successful analyses of gene expression profiles for the prognostic prediction of patientswith cancer, but their clinical applications have been overoptimistic and still premature. The lack of consistency and the robustness of expression profiles is thought to be one of major obstacles for its clinical application. In this regard, external validation by comparing totally independent cross- platform and cross-site studies will help to identify robust predictors reducing data set – derived systematic biases. The application of cross-platform comparison of independent studies has its own limitations due to the heterogeneity and unavailability of the data sets to be combined. However, this approach is now at the stage of one of reliable solutions to overcome with the overfitting problem of microarray data.