Incidence of hepatocellular carcinoma in patients with chronic liver disease due to hepatitis B or C and coinfected with the human immunodeficiency virus:a retrospective cohort study

AIM To assess the incidence of hepatocellular carcinoma(HCC) in chronic liver disease due to hepatitis B virus(HBV) or hepatitis C virus(HCV) coinfected with human immunodeficiency virus(HIV).METHODS A retrospective cohort study was performed, including patients with chronic liver disease due to HBV or HCV, with and without HIV coinfection. Patients were selected in the largest tertiary public hospital complex in southern Brazil between January 2007 and June 2014. We assessed demographic and clinical data, including lifestyle habits such as illicit drug use or alcohol abuse, in addition to frequency and reasons for hospital admissions via medical records review.RESULTS Of 804 patients were included(399 with HIV coinfection and 405 monoinfected with HBV or HCV). Coinfected patients were younger(36.7 ± 10 vs 46.3 ± 12.5, P < 0.001). Liver cirrhosis was observed in 31.3% of HIV-negative patients and in 16.5% of coinfected(P < 0.001). HCC was diagnosed in 36 patients(10 HIV coinfected and 26 monoinfected). The incidence density of HCC in coinfected and monoinfected patients was 0.25 and 0.72 cases per 100 patient-years(95%CI: 0.12-0.46 vs 0.47-1.05)(long-rank P = 0.002), respectively. The ratio for the HCC incidence rate was 2.98 for HIV-negative. However, when adjusting for age or when only cirrhotic are analyzed, the absence of HIV lost statistical significance for the development of HCC. CONCLUSION In this study, the presence of HIV coinfection in chronic liver disease due to HBV or HCV showed no relation to the increase of HCC incidence.

Incidence of hepatocellular carcinoma in outpatients with cirrhosis in Brazil: A 10-year retrospective cohort study

AIM To determine the incidence of hepatocellular carcinoma(HCC) and the impact of HCC surveillance on early diagnosis and survival of cirrhotic outpatients. METHODS In this retrospective cohort study, cirrhotic outpatients undergoing HCC surveillance between March 2005 and March 2014 were analyzed. Exclusion criteria were HIV coinfection; previous organ transplantation; diagnosis of HCC at first consultation; missing data in the medical chart; and less than 1 year of follow-up. Surveillance was carried out every six months using ultrasound and serum alpha-fetoprotein determination. Ten-year cumulative incidence and survival were estimated through Kaplan-Meier analysis. RESULTS Four hundred and fifty-three patients were enrolled, of which 57.6% were male. Mean age was 55 years. Hepatitis C virus and heavy use of alcohol were the main etiologic agents of cirrhosis. HCC was diagnosed in 75 patients(16.6%), with an estimated cumulative incidence of 2.6% in the 1st year, 15.4% in the 5th year, and 28.8% in the 10 th year. Median survival was estimated at 17.6 mo in HCC patients compared to 234 mo in non-HCC patients(P < 0.001). Early-stage HCC was more often detected in patients who underwent surveillance every 6 mo or less(P = 0.05). However, survival was not different between patients with early stage vs non-early stage tumors [HR = 0.54(0.15-1.89), P = 0.33].CONCLUSION HCC is a frequent complication in patients with cirrhosis and adherence to surveillance programs favors early diagnosis.

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma(HCC)worldwide,and this association is likely to remain during the next decade.Moreover,viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years.In order to reduce such a burden,some major challenges must be faced.Universal vaccination against hepatitis B virus,especially in the neonatal period,is probably the most relevant primary preventive measure against the development of HCC.Moreover,considering the large adult population already infected with hepatitis B and C viruses,it is also imperative to identify these individuals to ensure their access to treatment.Both hepatitis B and C currently have highly effective therapies,which are able to diminish the risk of development of liver cancer.Finally,it is essential for individuals at high-risk of HCC to be included in surveillance programs,so that tumors are detected at an early stage.Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program.As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis,other high-risk groups of patients with hepatitis B are also candidates for surveillance.Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.

Interleukin 28B-related polymorphisms: A pathway for understanding hepatitis C virus infection?

AIM:To analyze the role of rs12979860 and rs8099917polymorphisms in hepatitis C virus(HCV)genotype 1infection of Brazilians.METHODS:A total of 145 adult patients diagnosed with genotype 1 chronic hepatitis C(CHC)who had completed a 48-wk regimen of pegylated-interferonα-2a or-2b plus ribavirin combination therapy were recruited from six large urban healthcare centers and199 healthy blood donors(controls)from a single site between January 2010 and January 2012.Data on the patients’response to treatment was collected.Polymerase chain reaction-restriction fragment length polymorphism genotyping of the interleukin(IL)28B gene fragment encompassing the single nucleotide polymorphisms(SNPs)rs12979860(C/T)and rs8099917(T/G)was carried out for 79 of the CHC patients and 199 of the controls.Bi-directional amplicon sequencing of the two SNPs was carried out for the remaining 66 CHC patients.RESULTS:SNP rs12979860 genotyping was successful in 99.5%of the controls and 97.2%of the CHC patients,whereas the SNP rs8099917 genotyping was successful in 95.5%of the controls and 100%of the CHC patients.The genotype and allele distributions for both rs12979860 and rs8099917 were significantly different between the control and CHC patient groups,with significantly higher genotype frequencies of CC and TT in the controls(P=0.037 and 0.046,respectively)and of TT and GG in the CHC patients(P=0.0009and 0.0001,respectively).Analysis of the CHC patients who achieved sustained virological response(SVR)to treatment(n=55)indicated that the rs12979860 C allele and CC genotype were predictors of SVR(P=0.02).No significant correlation was found between rs8099917 genotypes and treatment response,but carriers of the T allele showed significantly higher rates of SVR(P=0.02).Linkage disequilibrium analysis of the group that achieved SVR showed a significant association between rs12979860 and rs8099917(P=0.07).CONCLUSION:The higher allele frequency of rs12979860 C and rs8099917 T observed in non-HCVinfected individuals may indicate a potential protective role for these IL28B-related polymorphisms.

Multi-resistant bacteria in spontaneous bacterial peritonitis: A new step in management?

Spontaneous bacterial peritonitis(SBP) is the most typical infection observed in cirrhosis patients. SBP is responsible for an in-hospital mortality rate of approximately 32%. Recently, pattern changes in the bacterial flora of cirrhosis patients have been observed, and an increase in the prevalence of infections caused by multi-resistant bacteria has been noted. The wide-scale use of quinolones in the prophylaxis of SBP has promoted flora modifications and resulted in the development of bacterial resistance. The efficacy of traditionally recommended therapy has been low in nosocomial infections(up to 40%), and multi-resistance has been observed in up to 22% of isolated germs in nosocomial SBP. For this reason, the use of a broad empirical spectrum antibiotic has been suggested in these situations. The distinction between community-acquired infectious episodes, healthcare-associated infections, or nosocomial infections, and the identification of risk factors for multi-resistant germs can aid in the decision-making process regarding the empirical choice of antibiotic therapy. Broad-spectrum antimicrobial agents, such as carbapenems with or without glycopeptides or piperacillin-tazobactam, should be considered for the initial treatment not only of nosocomial infections but also of healthcare-associated infections when the risk factors or severity signs for multi-resistant bacteria are apparent. The use of cephalosporins should be restricted to community-acquired infections.

Noninvasive imaging assessment of non-alcoholic fatty liver disease:focus on liver scintigraphy

Noninvasive diagnoses of nonalcoholic fatty-liver disease(NAFLD) involve the use of serologic markers and imaging methods, such as conventional ultrasonography(US),computed tomography, and magnetic resonance imaging. Although these methods are reliable for the noninvasive detection of moderate to severe fatty changes in the liver, they are not reliable for detecting nonalcoholic steatohepatitis(NASH) and fibrosis. New imaging technologies, such as US-based transient elastography, acoustic radiation force impulse and magnetic resonancebased elastography, can reportedly be used to determine the severity of liver fibrosis associated with NASH. In this context, the field of nuclear medicine through liver scintigraphy has recently been proposed, and is being explored for use in the diagnosis of NASH. More importantly, nuclear medicine may contribute to the distinction between simple steatosis and NASH. For example, the enhanced release of cytokines and the decrease in the phagocytic activity of Kupffer cells play important roles in the pathogenesis of NASH. Removal of technetium-99 m colloid from circulation by Kupffer cell phagocytosis therefore provides a valuable imaging technique. Thus, nuclear medicine is poised to provide useful tools for the evaluation of patients with NAFLD. However, the evidence is still scarce, and more studies with larger samples are needed to identify their role before they are used in clinical practice.

Nutritional evaluation in cirrhosis: Emphasis on the phase angle

Protein-calorie malnutrition(PCM) is a common condition in cirrhotic patients, leading to a worse prognosis, complications, poor quality of life and lower survival rates. Among ways of assessing nutritional status, there are anthropometric methods such as the evaluation of the triceps skinfold, the arm circumference, the arm muscle circumference and the body mass index, and nonanthropometric methods such as the subjective global assessment, the handgrip strength of non-dominant hand, and the bioelectrical impedance analysis(BIA). PCM is frequently under-diagnosed in clinical settings in patients with cirrhosis due to the limitations of nutritional evaluation methods in this population. BIA is a useful method, but cannot be indicated in patients with abnormal body composition. In these situations, the phase angle(PA) has been used, and can become an important tool in assessing nutritional status in any situation. The PA is superior to anthropometric methods and might be considered as a nutritional indicator in cirrhosis. The early characterization of the nutritional status in patients with cirrhosis means an early nutritional intervention, with a positive impact on patients' overall prognosis. Among the usually accepted methods for nutritional diagnosis, the PA provides information in a quick and objective manner.

Chronic hepatitis C genotype 1 virus:Who should wait for treatment?

Elucidation of the natural history of chronic hepatitis C(CHC)and the identification of risk factors for its progression to advanced liver disease have allowed many physicians to recommend deferral treatment(triple therapy)in favour of waiting for new drug availability for patients who are at low risk of progression to significant liver disease.Newer generation drugs are currently under development,and are expected to feature improved efficacy and safety profiles,as well as less complex and shorter duration delivery regimens,compared to the current standards of care.In addition,patients with cirrhosis and prior null responders have a low rate(around 15%)of achieving sustained virological response(SVR)with triple therapy,and physicians must also consider the decision to wait for new treatments in the future for these patients as well.Naive patients are the most likely to achieve a close to 100%SVR rate;therefore,it may be advisable to recommend that patients with mild to moderate CHC should wait for the newer therapy options.In contrast,patients with advanced fibrosis and cirrhosis will be those with the greatest need for expedited therapeutic intervention.There remains a need,however,for establishing definitive clinical management guidelines to maximize the benefit of waiting for new drugs and minimize risk of side effects and non-response to the current triple therapy.

Polymorphisms and resistance mutations of hepatitis C virus on sequences in the European hepatitis C virus database

AIM To evaluate the occurrence of resistant mutations in treatment-na?ve hepatitis C virus(HCV) sequences deposited in the European hepatitis C virus database(euH CVdb). METHODS The sequences were downloaded from the eu HCVdb(https://euhcvdb.ibcp.fr/eu HCVdb/). The search was performed for full-length NS3 protease, NS5 A and NS5 B polymerase sequences of HCV, separated by genotypes 1a, 1b, 2a, 2b and 3a, and resulted in 798 NS3, 708 NS5 A and 535 NS5 B sequences from HCV genotypes1a, 1b, 2a, 2b and 3a, after the exclusion of sequences containing errors and/or gaps or incomplete sequences, and sequences from patients previously treated with direct antiviral agents(DAA). The sequence alignment was performed with MEGA 6.06 MAC and the resulting protein sequences were then analyzed using the BioE dit 7.2.5. for mutations associated with resistance. Only positions that have been described as being associated with failure in treatment in in vivo studies, and/or as conferring a more than 2-fold change in replication in comparison to the wildtype reference strain in in vitro phenotypic assays were included in the analysis.RESULTS The Q80 K variant in the NS3 gene was the most prevalent mutation, being found in 44.66% of subtype 1a and 0.25% of subtype 1b. Other frequent mutations observed in more than 2% of the NS3 sequences were: I170V(3.21%) in genotype 1a, and Y56F(15.93%), V132I(23.28%) and I170V(65.20%) in genotype 1b. For the NS5 A, 2.21% of the genotype 1a sequences have the P58 S mutation, 5.95% of genotype 1b sequences have the R30 Q mutation, 15.79% of subtypes 2a sequences have the Q30 R mutation, 23.08% of subtype 2b sequences have a L31 M mutation, and in subtype 3a sequences, 23.08% have the M31 L resistant variants. For the NS5 B, the V321 L RAV was identified in 0.60% of genotype 1a and in 0.32% of genotype 1b sequences, and the N142 T variant was observed in 0.32% of subtype 1b sequences. The C316 Y, S556 G, D559 N RAV were identified in 0.33%, 7.82% and 0.32% of genotype 1b sequences, respectively, and were not observed in other genotypes.CONCLUSION HCV mutants resistant to DAAs are found in low frequency, nevertheless they could be selected and therapy could fail due resistance substitutions in HCV genome.

Albumin administration in patients with cirrhosis: Current role and novel perspectives

Mortality in cirrhosis is mostly associated with the development of clinical decompensation,characterized by ascites,hepatic encephalopathy,variceal bleeding,or jaundice.Therefore,it is important to prevent and manage such complications.Traditionally,the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis,but it is currently understood that decompensation might also be driven by a systemic inflammatory state(the systemic inflammation hypothesis).Considering its oncotic and nononcotic properties,albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events.There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis,patients with spontaneous bacterial peritonitis,those with acute kidney injury(even before the etiological diagnosis),and those with hepatorenal syndrome.Moreover,there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites(long-term albumin administration),individuals with hepatic encephalopathy,and those with acute-on-chronic liver failure undergoing modest-volume paracentesis.Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications,such as individuals with extraperitoneal infections,those hospitalized with decompensated cirrhosis and hypoalbuminemia,and patients with hyponatremia.