Addressing barriers to the prevention, diagnosis and treatment of hepatitis B and C in the face of persisting fiscal constraints in Europe: report from a high level conference.

In the WHO-EURO region, around 28 million people are currently living with chronic viral hepatitis, and 120,000 people die every year because of it. Lack of awareness and understanding combined with the social stigma and discrimination exacerbate barriers related to access to prevention, diagnosis and treatment services for those most in need. In addition, the persisting economic crisis has impacted on public health spending, thus posing challenges on the sustainable investment in promotion, primary and secondary prevention, diagnosis and treatment of viral hepatitis across European countries. The Hepatitis B and C Public Policy Association in cooperation with the Hellenic Center for Disease Prevention and Control together with 10 partner organizations discussed at the Athens High Level Meeting held in June 2014 recent policy developments, persisting and emerging challenges related to the prevention and management of viral hepatitis and the need for a de minimis framework of urgent priorities for action, reflected in a Call to Action (Appendix S1). The discussion confirmed that persisting barriers do not allow the full realisation of the public health potential of diagnosing and preventing hepatitis B and C, treating hepatitis B and curing hepatitis C. Such barriers are related to (a) lack of evidence-based knowledge of hepatitis B and C, (b) limited access to prevention, diagnosis and treatment services with poor patient pathways, (c) declining resources and (d) the presence of social stigma and discrimination. The discussion also confirmed the emerging importance of fiscal constraints on the ability of policymakers to adequately address viral hepatitis challenges, particularly through increasing coverage of newer therapies. In Europe, it is critical that public policy bodies urgently agree on a conceptual framework for addressing the existing and emerging barriers to managing viral hepatitis. Such a framework would ensure all health systems share a common understanding of definitions and indicators and look to integrate their responses to manage policy spillovers in the most cost-effective manner, while forging wide partnerships to sustainably and successfully address viral hepatitis.

Nucleos(t)ide analog(s) prophylaxis after hepatitis B immunoglobulin withdrawal against hepatitis B and D recurrence after liver transplantation.

BACKGROUND/AIMS: Nucleos(t)ide analogs (NAs) have made a hepatitis B immunoglobulin (HBIG)-sparing protocol an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, this approach is considered controversial in patients transplanted for HBV and hepatitis D (HDV) co-infection. MATERIAL/METHODS: All patients transplanted for HBV/HDV cirrhosis were evaluated. After LT, each patient received HBIG + NAs and then continued with NAs prophylaxis. All patients were followed up with HBV serum markers and HBV DNA, while anti-HDV/HDV RNA was performed in those with HBV recurrence. RESULTS: A total of 34 recipients were included (22 men, age: 46.7 ± 16 years). After HBIG discontinuation, NAs were received as monoprophylaxis (lamivudine [LAM]: 2, adefovir [AFV]: 1, entecavir: 9, tenofovir [TDF]: 12) or dual prophylaxis (LAM + AFV [or TDF]: 10 patients). Two (5.8%) of the 34 patients had HBV/HDV recurrence after HBIG withdrawal (median follow-up: 28 [range, 12-58] months). These 2 patients had undetectable HBV DNA at LT. Statistical analysis revealed that those with recurrence had received HBIG for shorter period, compared to those without recurrence (median: 9 vs. 28 months, P = 0.008). CONCLUSIONS: We showed for the first time, to our knowledge, that maintenance therapy with NAs prophylaxis after HBIG discontinuation was effective against HBV/HDV recurrence, but it seems that a longer period of HBIG administration might be needed before it is withdrawn after LT.

Telbivudine is associated with improvement of renal function in patients transplanted for HBV liver disease.

Recent studies showed that telbivudine in patients with hepatitis B virus (HBV) infection improved their glomerular filtration rate (GFR), but data regarding its impact on renal function in liver transplant (LT) recipients are very limited. We evaluated 17 consecutive recipients who received at baseline nucleos(t)ide analogue(s) (NAs) other than telbivudine for 12 months, and then they were switched to telbivudine prophylaxis for another 12 months. In each patient, laboratory data including evaluation of GFR (using MDRD and CKD-EPI) were prospectively recorded. The changes in GFR (ΔGFR) between baseline and after 12 months (1st period) and between telbivudine initiation and 24 months (2nd period) were evaluated. All patients remained serum HBsAg and HBV-DNA negative. GFR-MDRD at baseline, 12 months and 24 months were 72 ± 18, 67.8 ± 16 and 70.3 ± 12 mL/min, respectively, (P = 0.025 for comparison between 12 months and 24 months). ΔGFR at the 1st period was significantly lower, compared with ΔGFR at the 2nd period [mean ΔGFR-MDRD: -4.2 (range: -24-9) vs 2.5 (range: -7-22) mL/min, P = 0.013; mean ΔGFR-CKD-EPI: -4.2 (range: -19-10) vs 4.0 (range: -7-23) mL/min, P = 0.004], although the serum levels of calcineurin inhibitors were similar between the two periods. A second group of recipients (n = 17) who remained under the same nontelbivudine NA(s) for 24 months had a decline in the mean eGFR during the total follow-up period. In conclusion, we showed that telbivudine administration in LT recipients for HBV cirrhosis was effective and it was associated with significant improvement in renal function, but this remains to be confirmed in larger well-designed studies.

Intermediate hepatocellular carcinoma: current treatments and future perspectives.

Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment of Barcelona-Clinic Liver Cancer (BCLC)-B patients. However, the long-term survival outcomes of patients managed with this technique do not appear fully satisfactory; in addition, intermediate-stage hepatocellular carcinoma (HCC) includes a heterogeneous population of patients with varying tumour burdens, liver function and disease aetiology. Therefore, not all patients with intermediate-stage HCC may derive similar benefit from TACE, and some patients may benefit from other treatment options, which are currently approved or being explored. These include different TACE modalities, such as selective TACE or drug-eluting beads TACE and radioembolization. The introduction of sorafenib in the therapeutic armamentarium for HCC has provided a new therapeutic option for the treatment of BCLC-B patients who are unsuitable to TACE or in whom TACE resulted in unacceptable toxicity. In addition, clinical trials aimed at investigating the potential role of this molecule in the treatment of patients with intermediate-stage HCC within combination therapeutic regimens are ongoing. This narrative review will present and discuss the most recent evidence on the locoregional or medical treatment with sorafenib in patients with intermediate-stage HCC.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation.

Newer nucleos(t)ide analogues (NUCs) have better resistance profiles making hepatitis B immunoglobulin (HBIG)-sparing protocol an attractive prophylactic approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). We evaluated the risk of HBV recurrence after withdrawal of HBIG in patients who had been under HBIG plus NUCs after LT. Stable patients without HBV recurrence after LT while receiving combination of HBIG plus NUCs for at least 12 months were eligible for HBIG discontinuation. The patients were at low risk for HBV recurrence (only 4.5% had detectable HBV DNA at the time of LT, and 32% had HBV/hepatitis D virus co-infection). All patients were followed up with HBV serum markers, HBV-DNA, and evaluation of renal function, including glomerular filtration rate. Forty-seven recipients discontinued HBIG and were maintained on newer NUCs. Median follow-up post-HBIG withdrawal was 24 months (range: 6-40 months). Twenty-eight (60%) patients continued on lamivudine in combination with adefovir dipivoxil (n = 23, 82%) or tenofovir (n = 5, 18%); 10 (21%) and 9 (19%) of the 47 patients continued on tenofovir and entecavir monoprophylaxis, respectively. Although 3 (6.3%) patients developed detectable hepatitis B surface antigen, all of them had undetectable HBV DNA and no clinical manifestations of HBV recurrence. Renal function was similar between the different groups of patients. In conclusion, maintenance therapy with newer NUCs after discontinuation of HBIG prophylaxis was effective, but further studies in larger cohorts with longer follow-up are needed.

Severe gastrointestinal cryptosporidiosis three years after multi-visceral transplantation.

BACKGROUND: Cryptosporidia are known to cause opportunistic gastrointestinal tract infections with variable severity. Such infections can be life-threatening in transplant recipients. We report the evolution of cryptosporidiosis in a multi-visceral transplant recipient with repeated endoscopic biopsies until specific therapy was instituted. CASE DESCRIPTION: A 40-year-old woman with a history of multi-visceral (stomach, duodenum, small bowel, liver, and pancreas) transplantation presented with severe acute diarrhea three years after transplantation. Endoscopic biopsies of the stomach, duodenum, and lower small bowel were performed and submitted for histologic examination to assess the possibility of rejection. Microscopic examination of the lower small bowel biopsy specimens revealed mild to moderate inflammation and the presence of microorganisms with features of Cryptosporidia in the intestinal crypts. No evidence of rejection was found. While waiting for the availability of nitazoxanide, the patient was initiated on metronidazole, but her diarrhea worsened. Eleven days later, new biopsies were obtained, revealing abundant Cryptosporidia in the lower small bowel and duodenal specimens and few Cryptosporidia in the gastric biopsy specimen. Nitazoxanide was soon administered, leading to clinical improvement. Six weeks later, new biopsies showed complete resolution of inflammation and the absence of microorganisms. CONCLUSION: Histological examination of biopsy specimens is crucial for the diagnosis of cryptosporidiosis, which can threaten the life of immunocompromised individuals. The importance of specific antiprotozoal treatment must be emphasized. HIPPOKRATIA 2022, 26 (3):121-123.

Tenofovir alafenamide prophylaxis post-liver transplantation: a real-world study in patients with chronic kidney disease.

Background & aims: Tenofovir alafenamide fumarate (TAF) was shown equally efficacious in suppressing hepatitis B virus (HBV) but with less renal toxicity than tenofovir disoproxil fumarate (TDF). The aim of this real-world study was to evaluate renal function in post-liver transplantation (LT) patients that changed TDF with TAF. Methods: The TAF group (n=17) included patients who switched to TAF due to low (<60 ml/min/1.73m2) Glomerular Filtration Rate (GFR). The control group included patients that remained on TDF (n=30), although some (n= 14) had chronic kidney disease (CKD) (TDF-CKD group). GFR was assessed using: i) MDRD-6 variable; ii) CKD-EPI formula; iii) radionuclide technique (rGFR). Results: There were no significant differences between the two groups except for the presence of diabetes and follow-up period, which were more common and shorter, respectively, in the TAF group (35% vs. 10%, p=0.03; 13.7 vs. 35.5 months, p<0.001). At the end of follow-up there were no significant changes in renal function between the TAF and the TDF group or TDF-CKD group, although the numerical change in rGFR in the latter comparison was greater in the TAF group (ΔrGFR 3 vs. -2.14 ml/min, p=0.26). The use of everolimus was associated with improvement in renal function (ΔrGFR 2 vs. -7.75 ml/min, p=0.06 [TAF vs. TDF group]; 2 vs. -12 ml/min, p=0.01 [TAF vs. TDF-CKD group]). There were no TAF- related side effects or cases of HBV recurrence. Conclusion: Conversion to TAF in post-LT patients who develop CKD does not lead to improvement of kidney function after a period of one year.

Decreased diversity of salivary microbiome in patients with stable decompensated cirrhosis.

BACKGROUND: In the setting of the oral-gut-liver axis, microbiome dysbiosis has been associated with decompensated cirrhosis progression. However, little is known on salivary microbiome profiles in stable decompensated patients. METHODS: We studied patients with stable decompensated cirrhosis (n =28) and matched healthy controls (n =26). There were five patients (17.8 %) with hepatocellular carcinoma (HCC). Microbiomes of the 54 salivary samples were profiled through next-generation sequencing of the 16S-rRNA region in bacteria. RESULTS: The two study groups (patients and controls) did not differ significantly concerning their baseline characteristics. The most abundant phyla were Firmicutes, Bacteroidetes, Proteobacteria, and Fusobacteria. Proposed dysbiosis ratio Firmicutes/Bacteroidetes was lower in patients than in controls (range: 0.05-2.54 vs. 0.28-2.18, p =0.4), showing no statistical significance. Phylum Deinococcus-Thermus was detected only in controls, while Phylum Planctomycetes only in patients. A-diversity analysis indicated low diversity of salivary microbiome in decompensated patients and patients with HCC, who presented specific discriminative taxa. On principal coordinate analysis (PCoA), the patients' and controls' salivary microbiomes clustered apart, suggesting differences in community composition (PERMANOVA test, p =0.008). Boruta wrapper algorithm selected the most representative genera to classify controls and patients (area under the curve =0.815). CONCLUSIONS: Patients with stable decompensated cirrhosis of various etiology and history of complications have decreased diversity of their salivary microbiome. PCoA and Boruta algorithm may represent useful tools to discriminate the salivary microbiome in patients with decompensation. Further studies are needed to establish the utility of salivary microbiome analysis, which is easier obtained than fecal, in decompensated cirrhosis. HIPPOKRATIA 2020, 24(4): 157-165.

'Distribution of Hepatitis C Virus genotypes in northern Greece in the last decade: descriptive analysis and clinical correlations'.

Hepatitis C virus (HCV) represents a major public health problem, while the identification of a HCV genotype is clinically very important for therapy prescription. The aim of the present study was to determine the HCV genotype distribution patients from northern Greece with HCV RNA positive viral load and to identify whether there is a shift in this distribution, during 2009-2017. The study was performed on 915 HCV positive patients and according to the results, genotype 3 was the most prevalent genotype (Ν = 395, 43.2%) followed by genotype 1 (Ν = 361, 39.5%). Regarding the gender of the patients, genotype 1 was mostly detected in women. Moreover, genotype 1 was associated with higher viral loads, while genotype 3 was most frequently detected in patients with a history of intravenous drug use. In conclusion, our results show that genotype 3 is the most prevalent genotype in Greece during the last decade as opposed to older epidemiological studies, likely due to intravenous drug use becoming the major source of infection.

Trough Levels of Everolimus Are Associated With Recurrence Rates of Hepatocellular Carcinoma After Liver Transplantation.

PURPOSE: Everolimus, a mammalian target of rapamycin inhibitor, may have a protective role on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT), but data regarding the impact of its trough serum levels on HCC recurrence are missing. METHODS: Fifty-five patients (43 men, age 55 ± 8 years) who underwent LT for HCC were evaluated. Several demographic and clinical variables were recorded, including radiological and histological characteristics of HCC as well as dosages and trough levels of immunosuppressive regimens. RESULTS: HCC recurrence occurred in 11 (20%) patients: 5 (25%) of 20 patients under calcineurin inhibitors and 6 (17%) of the 35 patients under everolimus (P = .48). The patients with HCC recurrence (n = 11, group 1), compared to those without recurrence (n = 44, group 2), had significantly more frequent HCC in the explant: outside Milan criteria (P = .001), microvascular invasion (P < .001), and higher number of nodules (P = .001). In multivariate analysis, microvascular invasion was the only independent factor significantly associated with HCC recurrence (OR: 2.3, 95% CI: 1.4-10.5, P = .03). Among the patients who received everolimus-based immunosuppression, the recipients with HCC recurrence, compared to those without HCC recurrence, had significantly lower mean trough levels of everolimus at 7-12 months post-LT (3.9 vs 5.9 ng/mL, P = .001), while the patients with mean trough levels of everolimus >6 ng/mL had decreased HCC recurrence rates (log rank: 2.3, P = .007). CONCLUSIONS: We found for the first time mean concentrations of everolimus between 7-12 months post-LT as the only modifiable variable related with HCC recurrence in LT recipients. However, larger studies are needed for final conclusions.

The evolution of the role of liver transplantation in treating alcoholic cirrhosis in Greece.

BACKGROUND: Liver transplantation represents the main treatment for alcoholic cirrhosis. The goal of this article is to review the results of liver transplantation for alcoholic cirrhosis in Greece over the last 2 decades. METHODS: Among 247 patients who underwent liver transplantation between 1991 and 2007, 34 (13.7%) experienced alcoholic cirrhosis as the primary diagnosis. We reviewed their demographic data, stage of liver disease, and outcomes regarding survival via a Kaplan-Meier curve. Also we analyzed the causes of death and the postoperative complications. RESULTS: Mean Model for End-Stage Liver Disease (MELD) score was 18.4. Other diagnoses included hepatitis C virus (HCV; 23.5%), hepatitis B virus (HBV; 14.7%), and hepatocellular carcinoma (8.8%). Eleven patients died the most frequent causes being primary graft nonfunction (n = 3), hepatic artery thrombosis (n = 2), sepsis (n = 2), and portal vein thrombosis (n = 2). Complications included rejection (32.4%), infection (26.5%), hepatic graft dysfunction (11.8%), and recurrent HCV, recurrent HBV, and renal failure (8.8% each). Recurrence of alcoholism was observed in 3 patients (8.8%) with mild effects on liver function tests. There has been a significant increase in the number of liver transplantations for alcoholic cirrhosis in the last 6 years, namely 25 patients versus 9 in the previous 10 years. CONCLUSIONS: We observed a significant increase in the frequency of alcoholic cirrhosis leading to liver transplantation in the last several years in Greece.

Tenoxicam-associated hepatic injury: a case report and review.

A 51-year-old woman developed jaundice while taking tenoxicam. A full evaluation, including ultrasound, computed tomography, endoscopic cholangiography and liver biopsy, confirmed the diagnosis of mixed hepatic injury. The patient's jaundice and all other liver function abnormalities normalized 1 month after she discontinued taking tenoxicam. This is the first case report of mixed hepatic injury, confirmed with biopsy, associated with tenoxicam. Tenoxicam should be considered as a potential cause of hepatic injury when other more common aetiologies have been excluded.

Treatment of a patient with classical paroxysmal nocturnal hemoglobinuria and Budd-Chiari syndrome, with complement inhibitor eculizumab: Case Report.

Background. Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired clonal disorder of hematopoietic stem cells involving all blood cells. Erythrocytes have increased susceptibility to complement-mediated haemolysis. Thrombosis is the leading cause of mortality and follows episodes of acute hemolysis. Eculizumab, a monoclonal antibody blocking activation of complement C5 is currently used in the treatment of PNH. Recent results demonstrated that eculizumab effectively reduces thrombosis. Description of case. We present a 30-year-old male patient admitted with abdominal and lumbar pain. Thorough investigation revealed severe hemolytic anemia requiring transfusions and hepatosplenomegaly. Imaging findings were compatible with a Budd-Chiari syndrome. Flow cytometry confirmed the PNH diagnosis. Due to refractory ascites he underwent a transjugular intrahepatic portal-systemic shunt (TIPS) and eculizumab administration was started. Results. He has already completed three years of eculizumab treatment and he is transfusion independent. There is also a significant reduction in fatigue with improvement in his quality of life. Doppler scans of his TIPS persistently show it to be patent. Conclusions. Classical PNH patients with thrombosis and severe intravascular hemolysis are particularly challenging to manage. For these patients, eculizumab is a reasonable therapeutic option, expecting that by decreasing the risk for thrombosis, life expectancy may be increased.

Hepatitis C and liver transplantation.

Cirrhosis due to chronic hepatitis C is the leading indication for liver transplantation in Europe, United States and Japan. Reinfection after liver transplantation is universal and chronic liver disease develops in at least 70% of patients at 3 years, with an accelerated course compared to the nontransplant setting. These facts underscore the need for a better understanding of hepatitis C infection and the various treatment modalities. This paper attempts a brief review of the scope of the disease, as well as the different treatment modalities, with special emphasis given to orthotopic liver transplantation.

Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study.

BACKGROUND: Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes. AIM: To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR. METHODS: We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5-6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006). CONCLUSIONS: IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.