Incidence of Hepatocellular Carcinoma and Decompensated Liver Cirrhosis and Prognostic Accuracy of the PAGE-B HCC Risk Score in a Low Endemic Hepatitis B Virus Infected Population.

Purpose: We aimed to determine incidence of hepatocellular carcinoma (HCC) and decompensated liver cirrhosis in persons with chronic hepatitis B virus (HBV) infection in Denmark stratified by disease phase, liver cirrhosis, and treatment status at baseline. Additionally, we aimed to assess the prognostic value of the PAGE-B HCC risk score in a mainly non-cirrhotic population. Patients and Methods: In this register-based cohort study, we included all individuals over the age of 18, with chronic HBV infection first registered between 2002 and 2016 in at least one of three nationwide registers. The study population was followed until HCC, decompensated liver cirrhosis, death, emigration, or December 31, 2017, which ever came first. Results: Among 6016 individuals included in the study, 10 individuals with and 23 without baseline liver cirrhosis developed HCC during a median follow up of 7.3 years (range 0.0-15.5). This corresponded to five-year cumulative incidences of 7.1% (95% confidence interval (CI) 2.0-12.3) and 0.2% (95% CI 0.1-0.4) in persons with and without baseline liver cirrhosis. The five-year cumulative incidence of decompensated liver cirrhosis was 0.7% (95% CI 0.5-1.0). Among 2038 evaluated for liver events stratified by disease phase, incidence of HCC was low in all who were non-cirrhotic and untreated for HBV at baseline. PAGE-B score was evaluated in 1529 persons. The 5-year cumulative incidence of HCC was 0, 0.8 (95% CI 0.5-1.8), and 8.7 (95% CI 1.0-16.4) in persons scoring <10, 10-17 and >17, respectively (c-statistic 0.91 (95% CI 0.84-0.98)). Conclusion: We found low incidence of HCC and decompensated liver cirrhosis in persons with chronic HBV infection in Denmark. Moreover, the PAGE-B score showed good accuracy for five-year risk of developing HCC in the population with chronic HBV infection in Denmark.

Mortality and cause of death in persons with chronic hepatitis B virus infection versus healthy persons from the general population in Denmark.

The study aimed to determine adjusted all-cause mortality and cause of death in persons with chronic hepatitis B virus (HBV) infection compared with age- and sex-matched persons from the general population. We used nationwide registers to identify persons aged ≥18 years with chronic HBV infection in 2002-2017 in Denmark and included 10 age- and sex-matched controls for each. Follow-up was from 6 months after diagnosis until death, emigration, or 31 December 2017. Mortality rate ratios (MRRs) adjusted for age, sex, employment, origin and comorbidity were calculated using Poisson regression. Unadjusted cause-specific mortality rate ratios with 95% confidence intervals were calculated assuming a Poisson distribution. A total of 6988 persons with chronic HBV infection and 69,847 controls were included. During a median follow-up of 7.7 years (range 0.0-15.5), 315 (5%) persons with-and 1525 (2%) without-chronic HBV infection died. The adjusted all-cause MRR was 1.5 (95% CI 1.2-2.0). Persons with chronic HBV infection had increased mortality due to liver disease including hepatocellular carcinoma (MRR 12.3 [8.6-17.7]), external causes (MRR 3.3 [2.5-4.7]), endocrine disease (MRR 3.2 [1.8-5.4]), genitourinary disease (MRR 3.2 [1.2-7.6]) and neoplasms (except hepatocellular carcinoma; MRR 1.6 [1.2-2.0]). In conclusion, this study showed an increased all-cause mortality in persons with chronic HBV infection in comparison with age- and sex-matched persons without chronic HBV infection which remained after adjustment for several confounding factors. Excess mortality was mainly associated with liver disease, but also external factors, endocrine disease, genitourinary disease and neoplasms (excluding hepatocellular carcinoma).

Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation.

OBJECTIVES: We describe factors associated with and barriers to initiation of Direct Acting Antiviral (DAA) treatment in patients with chronic hepatitis C, who fulfill national fibrosis treatment guidelines in Denmark. MATERIALS AND METHODS: In this nationwide cohort study, we included patients with chronic hepatitis C from The Danish Database for Hepatitis B and C (DANHEP) who fulfilled fibrosis treatment criteria. Factors associated with treatment initiation and treatment failure were determined by logistic regression analyses. Medical records were reviewed from patients who fulfilled fibrosis treatment criteria, but did not initiate DAA treatment to determine the cause. RESULTS: In 344 (49%) of 700 patients, who fulfilled treatment criteria, factors associated with DAA treatment initiation were transmission by other routes than injecting drug use odds ratio (OR) 2.13 (CI: 1.38-3.28), previous treatment failure OR 2.58 (CI: 1.84-3.61) and ALT above upper limit of normal OR 1.60 (CI: 1.18-2.17). The most frequent reasons for not starting treatment among 356 (51%) patients were non-adherence to medical appointments (n = 107/30%) and ongoing substance use (n = 61/17%). Treatment failure with viral relapse occurred in 19 (5.5%) patients, who were more likely to have failed previous treatment OR 4.53 (CI: 1.59-12.91). CONCLUSIONS: In this nationwide cohort study, we found non-adherence to medical appointments and active substance use to be major obstacles for DAA treatment initiation. Our findings highlight the need for interventions that can overcome these barriers and increase the number of patients who can initiate and benefit from curative DAA treatment.

Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial.

INTRODUCTION: Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy. METHODS: In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms. RESULTS: Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients. CONCLUSION: Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed. TRIAL REGISTRATION: Clinicaltrials.gov NCT00647244.

Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression.

BACKGROUND: The nef gene from HIV-1 has been shown to be an important pathogenic factor when considering development of AIDS. Detection of nef variants with an effect on immune modulation is important to understand HIV-1 pathogenesis and has possible impact on treatment strategies. METHODS: The nef gene of HIV-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. RESULTS: In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337-45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS.

HIV/SIV escape from immune surveillance: focus on Nef.

During a progressive HIV-1 infection, the gradual decrease in functional CD4+ T(helper) cells leads to immunodeficiency and eventually death in the untreated patient. The virulence role of the lentiviral accessory gene nef was first reported from deletion studies in the macaque model, and research during the past decade has revealed a pluripotent protein capable of multiple points of interference with cellular mechanisms. Importantly, Nef has the capacity to modify the plasma membrane signalling by regulation of receptor/ligand endocytosis as well as to modulate cellular regulation such as apoptosis and lymphocyte activation. This effective defence against an apparent vigorous and specific immune response is crucial for the ability of HIV-1 to persist in the host. Here we review the multitude of functions exerted by Nef and discuss the functional domains of the protein in terms of cellular interaction partners and the effect of nef mutations in the course of AIDS disease progression.