Concerns related to CCR5 gene delta 32 mutation role in hepatitis B virus infection

STUDY OBJECTIVE: A literature review to analyze potential evidence regarding the influence of Δ32 CCR5 gene mutation on resistance to/clinical recovery from HBV infection METHODS: Literature search, covering the period 1996-2017, was performed using Medline. Comparative between-studies analysis was conducted with regard to reliability as well as statistical and clinical significance of results RESULTS: Data on the influence of Δ32 CCR5 mutation on the course of HBV infection are sparse and results obtained in various scientific studies are not consistent. As the example, heterozygosity for CCR5/CCR5Δ32 in healthy Iranian blood donors was greater than in cases with chronic HBV infection; in the American study on Caucasian subjects who had been infected with HBV CCR5 Δ32 reduced the risk of developing a persistent HBV infection by nearly half. Conversely, the Indian study revealed that heterozygosity for CCR5/CCR5Δ32 was more often present in patients with chronic hepatitis B than in healthy controls. However, there were some methodological errors found in previously published studies such as limited sample size and/or incorrect selection of controls; this could influence the fact that results were not heterogeneous CONCLUSIONS: The evidence for potential association of CCR5 gene Δ32 mutation on HBV infection in regard to the resistance to HBV infection or recovery from an HBV infection are insufficient. Previously conducted studies presented the lack of results' consistency, possibly due to between-population differences in the context of genetic determinants, ethnic and geographical origin, as well as methodological errors. There is an urgent need to conduct further, methodologically correct studies on larger populations from different regions, including Polish subjects

Five-Year Follow-Up of Cured HCV Patients under Real-World Interferon-Free Therapy.

(1) Background: Treatment of hepatitis C virus (HCV) infections with direct-acting antivirals (DAA) has demonstrated high efficacy and an excellent safety profile. The cured patients showed a sustained virological response and improved liver function, but also a continued risk of hepatocellular carcinoma (HCC) during the 2-3 years of follow-up after treatment; (2) Methods: A total of 192 patients out of 209 of the primary AMBER study were analyzed five years after treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin. Results: We confirmed that HCV clearance after DAA treatment is stable regardless of baseline liver fibrosis. We found that sustained virologic response is associated with a gradual but significant reduction in liver stiffness over 5 years. Liver function improved during the first 2 years of follow-up and remained stable thereafter. The risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful DAA treatment. However, in non-cirrhotic patients, it appears to clear up 3 years after treatment; (3) Conclusions: Monitoring for more than 5 years after curing HCV infection is necessary to assess the long-term risk of possible development of HCC, especially in patients with cirrhosis of the liver.

Hepatotropic Properties of SARS-CoV-2-Preliminary Results of Cross-Sectional Observational Study from the First Wave COVID-19 Pandemic.

Liver injury-expressed as elevated liver enzymes-is common in patients with COVID-19. Little is known about the potential mechanisms of liver damage by SARS-CoV-2. A direct cytopathic effect on hepatocytes as well as injury related to hypoxia or hepatotoxicity are being considered. The aim of the study was to compare the clinical characteristic of COVID-19 disease in patients with normal and abnormal liver enzymes activity. A group of 150 patients with COVID-19, hospitalized in our center, was analyzed. Patients with the known liver comorbidities were excluded (n = 15). Clinical features and laboratory parameters were compared between patients with normal and abnormal aminotransferase values. Liver injury expressed as any alanine aminotransferase (ALT) elevation was noted in 45.6% of patients hospitalized due to COVID-19. The frequencies of aspartate aminotransferase (AST) elevation were lower. It was noted that elevated ALT/AST unfavorably affected other parameters related to liver function such as albumin level; gamma-glutamyl transpeptidase (GGTP); and partly, ALP activity and influenced inflammation-related parameters. The most probable cause of mild hepatitis during COVID-19 was anoxia and immune-mediated damage due to the inflammatory response following SARS-CoV-2 infection. A direct cytopathic effect of SARS-CoV-2 on hepatocytes, albeit less probable, can be considered as well. The use of potentially hepatotoxic drugs may contribute to liver damage.

Nosocomial COVID-19 Infection and Severe COVID-19 Pneumonia in Patients Hospitalized for Alcoholic Liver Disease: A Case Report.

BACKGROUND COVID-19 is an infectious disease caused by SARS-CoV-2. It has spread rapidly through the world, endangering human life. The main target of COVID-19 is the lungs; however, it can involve other organs, including the liver. Patients with severe COVID-19 have an increased incidence of abnormal liver function, and patients with liver disorders are considered to be at a higher risk of severe COVID-19 infection. The mechanism of liver injury reported in 14% to 53% of COVID-19 patients is poorly recognized and several possibilities need to be considered (cytokine storm, direct viral action, hypoxia). The incidence of underlying liver comorbidities in patients with a COVID-19 infection ranges from 1% to 11%. CASE REPORT This is a report of 2 nosocomial COVID-19 infections and severe COVID-19 pneumonia in 2 patients who were hospitalized during treatment for alcoholic liver disease (ALD). Case 1 and case 2 were a 31-year-old woman and a 40-year-old woman, respectively, with decompensated ALD and symptoms of the COVID-19 infection. Both patients were transferred from another hospital to our hospital after confirmation of COVID-19 during their hospitalization. The course of the infection progressed rapidly in both patients with the development of multiple-organ failure and death over a short period. CONCLUSIONS There are no clear recommendations on the management of ALD in the COVID-19 pandemic. Alcoholic hepatitis may be a risk factor for severe COVID-19 and a poor outcome. A high percentage of nosocomial COVID-19 infections are observed; therefore, special precautions should be taken to minimize the risk of COVID-19 exposure.

Recurrence of Hepatocellular Carcinoma After Liver Transplantation: A Single-Center Experience.

BACKGROUND There is a worldwide increase in use of liver transplantation (LT) for treatment of hepatocellular carcinoma (HCC). We analyzed our experience with LT for HCC to determine long-term and recurrence-free survival, accuracy of imaging diagnosis of HCC compared to the explant pathology, recurrence rate of HCC, and predictors of recurrence. MATERIAL AND METHODS The whole explant was examined by the same pathologist and compared with the baseline diagnosis established according to clinical, laboratory, and radiological data. A group of patients with pathologically confirmed HCC was characterized, with special attention to etiology, survival, recurrence, and diagnostic accuracy of imaging techniques. RESULTS Among 718 patients transplanted from 2000 to 2018 in our center, HCC was found in 166 explanted livers. In 42 cases the clinical diagnosis of HCC was not accurate, being either false positive or negative; however, the specificity and sensitivity of CT/MRI in HCC recognition was 97.87% and 88.24%, respectively. Five- and 10-year survival was 81.27% and 66.57%, respectively, and it was inferior to the overall survival. The recurrence rate was 9.6% with a median time to recurrence of 14 months and a median survival time of 9 months. Poor differentiation of HCC and HCV etiology of the baseline disease, but not previous DAA treatment, were the risk factors of HCC recurrence. CONCLUSIONS Adherence to strictly defined selection criteria for LT in HCC patients guarantees the success of LT in HCC treatment.

Effect of comedication on ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin therapy in chronic hepatitis C - a real-world study.

AIM OF THE STUDY: This multicentre study aimed to examine the actual risk for drug-drug interactions in a cohort of Polish patients, and their impact on antiviral therapy. MATERIAL AND METHODS: Concomitant medications were analyzed in hepatitis C virus (HCV)-infected patients treated with still valuable therapy with OBV/PTV/r ± DSV ± RBV. An established online tool (http://www.hep-druginteractions.org/) was used to assess potential drug interactions. To assess the impact of comedications on virologic outcomes, HCV RNA levels were measured at given time points during and after the treatment. The results were compared between subgroups depending on the number of drugs used. RESULTS: Among the 209 patients included in this multicentre study, concomitant medications were taken by 140 (67.0%) patients. Modification of treatment due to expected interactions was required in 33 (15.8%) patients, of whom nine (4.3%) had at least one comedication replaced or discontinued. Sustained virologic response rates ranged from 95.1% to 100.0%, and were lowest in patients taking one to five comedications who were null-responders to pegylated interferon or cirrhotic. CONCLUSIONS: Although most HCV-infected patients received concomitant medications, only some required treatment modification. OBV/PTV/r ± DSV ± RBV was effective in all subgroups, irrespective of the number of comedications taken. Multimorbidity and polypharmacy in patients with chronic hepatitis C should not discourage the decision to initiate antiviral therapy, although caution should be exercised for potential drug-drug interactions.

State of the iron metabolism in patients with chronic hepatitis C type C does not influence antiviral treatment with interferon and ribavirin.

BACKGROUND/AIMS: Comparison of the iron status in patients who responded and did not respond to combination treatment with interferon alpha and ribavirin in chronic hepatitis C. METHODOLOGY: The study group comprised of 61 patients with chronic hepatitis C (genotype 1) treated with alpha 2b interferon and ribavirin. The iron metabolism was evaluated based on serum iron level, total iron binding capacity, transferrin saturation, serum ferritin concentration and hepatic iron concentration. In the evaluation of antiviral treatment efficacy biochemical and virological responses were taken into account. RESULTS: End of treatment response was observed in 38 patients (62%). Significant differences in iron parameters were not observed between responders and non-responders. Also, sustained viral response, 6 months after treatment completion, was reached in 32 patients (52.5%). Iron metabolism parameters did not differ significantly in the group of sustained responders versus non- responders. Finally, ALT normalization was observed in 42 patients (68.9%). Again, no significant differences in iron status were observed between patients with and without biochemical response excluding significantly higher serum ferritin concentration in non-responders. CONCLUSIONS: Results of this study show that iron status does not significantly influence the efficacy of treatment with interferon and ribavirin in patients with chronic hepatitis C.

Hepatitis C coinfection adversely affects the life expectancy of people living with HIV in northwestern Poland.

INTRODUCTION: Hepatitis C (HCV) infection adversely affects survival among people living with HIV, increasing mortality risk due to liver-related causes. In Poland HCV is found among ~30% of HIV infected individuals, with only a small percentage successfully treated for this coinfection. This study aimed to analyze the HCV-associated influence on the life expectancy among HIV/HCV coinfected patients from northwestern Poland. MATERIAL AND METHODS: Longitudinal data of 701 (368 HIV monoinfected and 368 HIV/HCV coinfected) patients were investigated to assess the life expectancy and survival after HIV diagnosis. Kaplan-Meier and Cox analyses were used to assess the mortality risk in both unadjusted and multivariate models. Effect plots indicate the adjusted hazard ratio for HCV-associated survival. RESULTS: Overall mortality was significantly higher among HCV coinfected (22.52%) compared to HIV monoinfected (10.32%) cases (p < 0.001, OR = 2.52 (95% CI: 1.65-3.85)), with shorter life expectancy among HIV/HCV infected patients (median: 55.4 (IQR: 42.8-59.1) years) compared to HIV monoinfection (median 72.7 (IQR: 60.4-76.8) years, univariate HR = 4.15 (95% CI: 2.7-6.38), p < 0.0001, adjusted HR = 2.32 (95% CI: 1.47-3.65), p < 0.0001). After HIV diagnosis, HCV adversely influenced the survival after 15 years of follow-up, with a strengthened impact in the subsequent 5 years (univariate HR = 1.57 (95% CI: 1.05-2.34) p = 0.026 for the 20-year survival time point, adjusted HR = 2.21 (95% CI: 1.18-4.13), p = 0.013). CONCLUSIONS: Among patients living with HIV, HCV coinfection is associated with a median life expectancy decrease of 17.3 years and low probability of surviving until the age of 65 years. In the era of directly acting anti-HCV drugs, treatment scale-up and immediacy of treatment are advisable in this cohort.

Real-World Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir/+Dasabuvir±Ribavirin (OBV/PTV/r/+DSV±RBV) Therapy in Recurrent Hepatitis C Virus (HCV) Genotype 1 Infection Post-Liver Transplant: AMBER-CEE Study.

BACKGROUND The introduction of direct-acting antivirals (DAAs) has considerably improved therapeutic outcomes for patients with chronic hepatitis C virus (HCV) infections. The AMBER-CEE study aimed to assess real-world efficacy and safety of ombitasvir/paritaprevir/ritonavir/+ dasabuvir ±ribavirin (OBV/PTV/r/ +DSV±RBV) in the treatment of post-transplant recurrence of HCV infection. MATERIAL AND METHODS Liver transplant recipients with recurrent HCV genotype 1 infection, scheduled for OBV/PTV/r/+DSV±RBV according to therapeutic guidelines, were eligible. The primary efficacy endpoint was sustained virologic response (SVR) 12 weeks after the end of treatment (FU12). Clinical and laboratory adverse events (AEs) were recorded from baseline to FU12. RESULTS A total of 35 patients were included: 91.4% genotype 1b-infected, 94.3% treatment-experienced, and 77.1% at fibrosis stage ≥F2. SVR12 was achieved by all patients (35/35, 100%) including one patient with genotype 1a, one patient with detectable HCV RNA at the end of treatment, two patients with a history of first-generation DAA therapy, and two patients who prematurely discontinued the regimen. AEs were experienced by 22 patients (62.9%) and were mostly mild. No death, graft loss, or acute graft rejections were reported during the therapy. On-treatment hepatic decompensation occurred in three patients (8.6%). Anemia was observed in 29 patients (83.9%), with 21 (60%) requiring RBV dose reduction or discontinuation. CONCLUSIONS OBV/PTV/r/+DSV±RBV has excellent efficacy in post-transplant recurrence of HCV genotype 1-infection treated under real-world conditions. Excellent virologic outcomes were observed irrespective of prior treatment history or the degree of fibrosis, and AEs were mostly mild and transient.

[Efficacy of combination therapy with interferon-alpha and ribavirin for chronic hepatitis C in relation to liver fibrosis and serum aminotransferase activity]. / Skutecznosc skojarzonego leczenia interferonem z rybawiryna przewleklego wirusowego zapalenia watroby typu C zaleznie od stopnia wloknienia oraz aktywnosci enzymów watrobowych.

The aim of the study was to evaluate the efficacy of interferon alpha (IFNalpha)-2b in combination with oral ribavirin for treatment of chronic hepatitis C in relation to age, sex, liver enzymes activity as well as to grading and staging of liver disease in histologic examination. There were 154 adult patients assigned for the retrospective analysis including 69 females and 85 males of 16 to 70 years of age (mean age 43.3 +/- 12 years) treated with IFNalpha and ribavirin for 24 or 48 weeks. Sustained virological response was achieved in 66 patients (42.9%) and sustained biochemical response rate was 44%. Sustained response correlated with younger age, lower baseline AST, GT and ALP activities as well as with lower staging of liver disease. Combination treatment with interferon and ribavirin was significantly more effective in patient under 40 years of age and in patients without cirrhosis. Sex, baseline ALT activity and histological grading of liver disease did not differ between sustained responders and non-responders. Sustained virological response on combination therapy was achieved in 5 out of 7 previous monotherapy relapsers (71.4%) whereas only 5 patients out of 22 monotherapy non-responders benefited from combination therapy (22.7%). In conclusion, efficacy of combination therapy with IFNalpha and ribavirin in patients with liver cirrhosis is less effective and should be considered in chosen situations, especially in younger patients. Normal ALT activity should not be an exclusion criterion to therapy. Combination retherapy in previous monotherapy non-responders seems to be ineffective whereas in monotherapy relapsers good sustained response can be achieved.

Hepatitis B core antigen in liver tissue from HBs-positive, HBe-negative patients.

BACKGROUND/AIMS: We aimed to study the relationship between HBcAg in liver tissue, histological and biochemical activity and serum HBV-DNA levels among HBeAg-negative patients. METHODOLOGY: 49 biopsy specimens taken from 16 females and 29 males were studied. Immunostaining for HBcAg was performed with commercially available kits (Dako). Serum HBV-DNA was detected by the hybridization method, in case of negative hybridization, repeated by PCR. RESULTS: HBcAg was found in 16 biopsy specimens (32.6%) (group I)--in 10 cases in hepatocytes nuclei and cytoplasm, in 5 in the nuclei and in one case in cytoplasm only. 15 out of 16 patients were serum HBV-DNA positive. Seven patients showed chronic liver disease of moderate or severe activity with HBcAg expression both in the nuclei and cytoplasm. Group II consisted of 33 patients who were HBcAg-negative. In 7 patients HBV-DNA was not found by hybridization or by PCR. In eleven patients ALT and AST activity exceeded 1.5x the ULN. ALT and AST differed significantly between group II and I. CONCLUSIONS: In our opinion immunohistochemical examination is an essential part of classification to antiviral treatment. HBcAg immunostaining should be performed in every HBeAg-negative patient to exclude reasons for aminotransferase elevation other than HBV infection.

[Increased incidence of hepatocellular carcinoma]. / Wzrost zachorowan na raka pierwotnego watroby.

Increased incidence of hepatocellular carcinoma related to hepatitis C virus (HCV) infection has been noted recently. Only in year 2000 seven new cases of HCC in HCV-positive patients were diagnosed. In all cases liver tumors were found in cirrhotic patients and they were at advanced stage (multiple or large in size) precluding successful therapy. More than half of HCC cases related to HCV infection were connected with blood transfusion(s) in the past. Patients transfused a few decades ago should be screened for HCV infection and those with liver cirrhosis require careful and regular monitoring including ultrasound and a-fetoprotein examinations in order to detect focal lesions at less advanced stage making medical intervention possible.

[Relationship of serum alanine aminotransferase (ALT) to body weight, age and sex in blood donors population]. / Aktywnosc aminotransferazy alaninowej (ALT) a masa ciala, wiek i plec w populacji krwiodawców.

The activity of alanine aminotransferase (ALT) is the most popular parameter in hepatology. Increase of ALT usually suggests the damage of hepatocytes. The aim of the study was to assess the range of value of serum alanine aminotransferase in healthy population and to assess the relationship between ALT level and body mass index (BMI), age and gender. We have analyzed a large population of healthy blood donors--all of them were screened for ALT, weight and height. Patients were divided into four groups: I--patients with underweight, II--patients with normal weight, III--patients with overweight, IV--obese patients. In the studied population 862 persons were taken into account (820 men and 42 women), 19-62 years of age. The ALT level varied from 6 to 77 U/L, mean 27.39 U/L. Inadequate BMI was found in 12 persons, normal BMI in 497 persons, overweight in 270 persons and obesity in 83 persons. ALT and BMI are statistically significantly higher in men than in women. In general population and in men group we found correlations between ALT and BMI (p = 0.0000), between ALT and age (p = 0.0000). In women we did not find those dependences. ALT level was statistically significantly higher in groups with higher BMI: ALT level in group II was higher than in group I (p < 0.024), ALT level in group III was higher than in group III (p = 0.0000). We did not find any differences in ALT level between group III and IV. ALT level strongly correlates with body mass, age and gender. We suggest the necessity of taking into consideration those parameters in a clinical interpretation of ALT level.

Rescue therapy with intravenous silibinin in liver transplant recipients with recurrent HCV hepatitis - two case reports.

BACKGROUND: Recurrence of hepatitis C virus (HCV) infection after liver transplantation is inevitable and decreases survival. Graft loss due to recurrent HCV occurs in 25% to 30% of patients. The recommended AASLD treatment is PEG-IFN, with or without ribavirin, but some patients might be not eligible for this treatment. An alternative antiviral agent is silibinin (SIL). In vitro silibinin stops replication, probably by inhibiting HCV RNA polymerase. CASE REPORT: We present the cases of 2 patients with severe recurrent HCV infection who received intravenous silibinin (IV SIL) as a "rescue therapy". In the first patient with cholestatic fibrosing hepatitis, HCV RNA became undetectable. We also noted significant viremia reduction, and improvement in laboratory results and clinical presentation in the second patient. CONCLUSIONS: Administration of IV SIL resulted in a rapid decrease of HCV viremia. In post-transplant patients with HCV recurrence who are not eligible for standard antiviral treatment, IV SIL can be considered as an alternative, but further investigations are necessary to establish treatment protocols.

Impact of antiviral treatment on survival in HCV-positive liver recipients.

BACKGROUND: Sequels of chronic HCV infection are currently one of the most common indications for liver transplantation (LTx). Because HCV reinfection and allograft injury are inevitable, it may influence survival. Earlier studies have not reported higher mortality among HCV-infected patients, but cumulative data seem to contradict these findings. The aim of the study was to analyze post-LTx survival in HCV-positive patients in comparison with non-HCV-positive recipients and impact of antiviral treatment on survival in patients with recurrent HCV hepatitis. MATERIAL AND METHODS: Using data from the Polish national transplant registry, a retrospective cohort study of 327 patients who underwent LTx between 2000 and 2012 was performed. Cumulative 5-year mortality for HCV-positive patients vs. HCV-negative recipients and HCV-positive recipients treated with pegylated interferon/ribavirin vs. non-treated subjects was calculated using Kaplan-Meyer methodology. Mortality hazard rates were estimated using univariate proportional Cox models. RESULTS: Liver transplantation in HCV-positive vs. HCV-negative recipients was associated with significantly lower survival rate (cumulative 5-year survival 89.8 vs. 80.26%, respectively, p=0.04276) with a 5-year mortality HR of 1.99. Antiviral treatment improved survival irrespective of virological response (84.06% treated vs. 51.22% non-treated, p=0.00003). Univariate Cox HR for HCV treated vs. untreated patients is 0.18. Further improvement of survival was significantly associated with sustained virological response (100% vs. 77.67%, p=0.042). CONCLUSIONS: Our study confirms higher mortality risk among HCV-infected transplant recipients, improved survival related to the HCV treatment following graft reinfection, and positive association between the HCV treatment success and better survival.

Risk factors and dynamics of weight gain in patients after liver transplantation.

BACKGROUND: Weight gain is commonly observed after OLTx. It is still debatable whether increasing weight is due to the regain of weight lost before transplantation or it is a complex metabolic disorder. MATERIAL/METHODS: Body mass index and weight gain were sought at 6 months, one, two and four years after liver transplantation (OLTx) in relation to sex, weight at the time of transplantation, aetiology of liver disease, type of immunosuppression, glucose metabolism and lipid parameters as well as cardiovascular episodes. A group of 75 patients has been studied. RESULTS: Mean weight gain and BMI change were the highest within the first six months after OLTx (6.1 kg and 2.0 kg/m(2), respectively); since than gaining weight decreased. Men gained more weight than women, especially in the first half-year after OLTx. The only clear predictive factor of overweight and obesity was the baseline weight (the higher the baseline weight the most dynamic the weight gain after OLTx). CONCLUSIONS: Dietary mistakes and lack of physical activity may play a major role in the weight increase after OLTx. Despite striking proportion of overweight and obese patients in the studied group, the number of cardiovascular episodes seem to match the general population.