Suzanne Lunding

Predictors of antiviral treatment initiation in hepatitis C virus‐infected patients: a Danish cohort study

Summary.  Predictive factors for initiation of antiviral therapy in chronically infected hepatitis C virus (HCV) patients are not fully elucidated. The aim of this study was to determine predictive factors for initiation of treatment with standard or pegylated interferon either alone or combined with ribavirin. A Danish cohort of individuals chronically infected with HCV was used and observation time was calculated from the date of inclusion in the cohort to date of death, last clinical observation, 1 January 2007, or start of HCV antiviral treatment in treatment‐naïve patients. Kaplan–Meier survival analysis was used to construct time to event curves. Cox regression was used to determine the incidence rate ratios as estimates of relative risk (RR) and 95% confidence intervals (CI). A total of 1780 patients were enrolled in the study. The cumulative chance of treatment initiation over 5 years was 33.0%. We found several strong predictors of treatment initiation: elevated alanine aminotransferase [>2 times upper limit (RR = 2.17, 95% CI 1.64–2.87), >3 times upper limit (RR = 3.64, 95% CI 2.75–4.81)], genotype 2 or 3 (RR = 1.86, 95% CI 1.49–2.31) and HIV co‐infection (RR = 0.28, 95% CI 0.15–0.53). To our knowledge, this study is the first to estimate factors predicting initiation of antiviral treatment in patients with chronic HCV infection on a nationwide scale. We found that several of the factors predicting initiation of antiviral treatment correlate with factors known to predict a better response to treatment and factors known to increase the progression of liver disease.

Nationwide Experience of Treatment with Protease Inhibitors in Chronic Hepatitis C Patients in Denmark: Identification of Viral Resistance Mutations

Background and Aims The first standard of care in treatment of chronic HCV genotype 1 infection involving directly acting antivirals was protease inhibitors telaprevir or boceprevir combined with pegylated-interferon and ribavirin (triple therapy). Phase III studies include highly selected patients. Thus, treatment response and development of viral resistance during triple therapy in a routine clinical setting needs to be determined. The aims of this study were to investigate treatment outcome and identify sequence variations after triple therapy in patients with chronic HCV genotype 1 infection in a routine clinical setting. Methods 80 patients, who initiated and completed triple therapy in Denmark between May 2011 and November 2012, were included. Demographic data and treatment response were obtained from the Danish Database for Hepatitis B and C. Direct sequencing and clonal analysis of the RT-PCR amplified NS3 protease were performed in patients without cure following triple therapy. Results 38 (47%) of the patients achieved cure, 15 (19%) discontinued treatment due to adverse events and remained infected, and 27 (34%) experienced relapse or treatment failure of whom 15 of 21 analyzed patients had well-described protease inhibitor resistance variants detected. Most frequently detected protease variants were V36M and/or R155K, and V36M, in patients with genotype 1a and 1b infection, respectively. Conclusions The cure rate after triple therapy in a routine clinical setting was 47%, which is substantially lower than in clinical trials. Resistance variants towards protease inhibitors were seen in 71% of patients failing therapy indicating that resistance could have an important role in treatment response.

Perception of sexuality and fertility in women living with HIV: a questionnaire study from two Nordic countries

As the human immunodeficiency virus (HIV)‐positive population ages, issues concerning sexuality and fertility, among others, are becoming relevant. HIV is still surrounded by stigma and taboos, and there have been few studies conducted in industrialized settings concerning these questions. We therefore wanted to investigate the perception of sexuality and fertility in women living with HIV (WLWH) in an industrialized setting, using a questionnaire.

Vertical transmission of hepatitis B virus during pregnancy and delivery in Denmark

Abstract Objective: In Denmark, pregnant women have been screened for hepatitis B virus (HBV) since 2005, and children born to HBV-infected mothers offered hepatitis B immunoglobulin at birth, vaccination against HBV at birth and after 1, 2 and 12 months. The purpose of this study was to determine the risk of vertical HBV transmission in children born to mothers with chronic HBV infection, to investigate the antibody response in the children and to investigate possible maternal predictive risk factors for HBV transmission. Materials and methods: Through the Danish Database for Hepatitis B and C, we identified 589 HBV-infected women who had given birth to 686 children, of whom 370 children were born to 322 women referred to hospital. 132 (36%) children, born to 109 mothers, were included in the study; 128 children had blood samples tested for HBsAg, anti-HBc (total), anti-HBs and HBV-DNA and four children had saliva samples tested for anti-HBc. Results: We found vertical HBV transmission in Denmark to be 2.3% [95% CI: 0.5, 6.5], a high proportion of HBsAg-negative children with low levels of anti-HBs (18.4%) and a high proportion (15.2%) with resolved HBV infection. No maternal risk factor was statistically significantly associated with HBV vertical transmission. Conclusion: In a HBV low prevalence setting as Denmark, despite a national vaccination program, vertical HBV transmission occurred in 2.3% of children born to HBV-infected mothers. In addition, a high proportion of the children had insufficient anti-HBs levels and a high proportion had serological signs of resolved HBV infection.

Influence of referral pathway on ebola virus disease case-fatality rate and effect of survival selection bias

Case-fatality rates in Ebola treatment centers (ETCs) varied widely during the Ebola virus disease (EVD) outbreak in West Africa. We assessed the influence of referral pathway on ETC case-fatality rates with a retrospective cohort of 126 patients treated at the Mathaska ETC in Port Loko, Sierra Leone. The patients consisted of persons who had confirmed EVD when transferred to the ETC or who had been diagnosed onsite. The case-fatality rate for transferred patients was 46% versus 67% for patients diagnosed onsite (p = 0.02). The difference was mediated by Ebola viral load at diagnosis, suggesting a survival selection bias. Comparisons of case-fatality rates across ETCs and clinical management strategies should account for potential survival selection bias.

Mortality in patients with Chronic Hepatitis C and cirrhosis compared to the general population: a Danish cohort study

Background Knowledge of mortality in patients with Chronic Hepatitis C (CHC) with cirrhosis is limited. This study aimed to estimate all-cause mortality among CHC patients with and without cirrhosis in Denmark compared to the general population. Methods Patients registered in The Danish Database for Hepatitis B and C with CHC and a liver fibrosis assessment were eligible for inclusion. Liver fibrosis was based on liver biopsy, transient elastography, and clinical cirrhosis. Up to 20 sex- and age-matched individuals per patient were identified in the general population. Data were extracted from nationwide registries. Results 3,410 CHC patients (1,014 with cirrhosis), and 67,315 matched individuals were included. Adjusted mortality rate ratios (MRR) between patients with and without cirrhosis and their comparison cohorts were 5.64 [CI95% 4.76; 6.67] and 1.94 [1.55; 2.42], respectively. Cirrhosis among patients was associated with a MRR of 4.03 [3.43; 4.72]. A cure for CHC was associated with a MRR of 0.64 [0.40; 1.01] among cirrhotic patients and 2.33 [1.47; 3.67] compared to the general population. Conclusions Mortality was high among CHC patients with and without cirrhosis compared to the general population. Curing CHC was associated with reduced mortality among cirrhotic patients but remained higher than the general population.

The Danish PEP Registry: Experience with the use of post-exposure prophylaxis following blood exposure to HIV from 1999-2012.

Abstract Background: The risk of occupational exposures to blood cannot be eliminated completely and access to post-exposure prophylaxis (PEP) to prevent HIV transmission is important. However, PEP administration has been associated with frequent adverse effects, low compliance and difficulties to ensure a proper risk assessment. This nationwide study describes 14 years of experience with the use of PEP following blood exposure in Denmark. Methods: A descriptive study of all PEP cases following non-sexual exposure to HIV in Denmark from 1999–2012. Results: A total of 411 cases of PEP were described. There was a mean of 29.4 cases/year, increasing from 23 cases in 1999 to 49 cases in 2005 and then decreasing to 16 cases in 2012. Overall 67.2% of source patients were known to be HIV-positive at the time of PEP initiation, with no significant change over time. The median time to initiation of PEP was 2.5 h (0.15–28.5) following occupational exposure. Adverse effects were reported by 50.9% with no significant difference according to PEP regimen. In 85.1% of cases with available data, either a full course of PEP was completed or PEP was stopped because the source was tested HIV-negative. Only 6.6% stopped PEP early due to adverse effects. Conclusions: PEP in Denmark is generally prescribed according to the guidelines and the annual number of cases has declined since 2005. Adverse effects were common regardless of PEP regimens used and new drug regimens should be considered.

Hospital admission among Hiv-exposed uninfected children compared with Hiv-unexposed children

Objective: :The main objective of this study was, on a national level, to investigate the risk of in-hospital admissions and use of antibiotics during the first 4 years of life among HIV-exposed uninfected (HEU) children compared with a matched control group of HIV-unexposed children. Design:A nationwide register-based cohort study. Methods:All HEU children born in Denmark from 2000 to 2012 were individually matched to five HIV-unexposed controls. Outcomes were risk of hospital admission (any, because of an infectious disease, observation/nonspecific diagnosis) and use of antibiotics during the first 4 years of life. Incidence rate ratios (IRRs) were estimated using Poisson regression analysis. Results:In total, 317 HEU children and 1581 matched controls were included. HEU children had a three-fold increased risk of overall admissions {incidence rate ratio (IRR) 3.49 [95% confidence interval (CI) 2.98–4.08]}. There was no difference in risk of admission because of infectious diseases [IRR 1.11 (95% CI 0.73–1.70)] and no difference in use of antibiotics [IRR 0.88 (95% CI 0.73–1.04)]. The excess risk per 100 person-years of admission was primarily caused by an increased risk of admission because of observation/nonspecific diagnosis [excess incidence rate 22.6 (95% CI 18.2–27.0), IRR 6.06 (95% CI 4.84–7.61)]. Conclusion:HEU children had an increased risk of overall hospital admission mainly due to an increased risk of admission because of observation/nonspecific diagnosis. There was no increased risk of admission due to infectious disease. The excess risk of admission among HEU may be related to prophylactic treatment and/or HIV testing rather than somatic disease related to HIV or exposure to antiretroviral therapy.

Genetic Variants in the Apoptosis Gene BCL2L1 Improve Response to Interferon-Based Treatment of Hepatitis C Virus Genotype 3 Infection

Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV) infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on sustained virological response (SVR) to pegylated interferon-α and ribavirin (pegIFN/RBV) treatment of HCV genotypes 1 and 3 infections. We conducted a candidate gene association study in a prospective cohort of 201 chronic HCV-infected individuals undergoing treatment with pegIFN/RBV. Differences between groups were compared in logistic regression adjusted for age, HCV viral load and interleukin 28B genotypes. Four single nucleotide polymorphisms (SNPs) located in the B-cell lymphoma 2-like 1 (BCL2L1) gene were significantly associated with SVR. SVR rates were significantly higher for carriers of the beneficial rs1484994 CC genotypes. In multivariate logistic regression, the rs1484994 SNP combined CC + TC genotypes were associated with a 3.4 higher odds ratio (OR) in SVR for the HCV genotype 3 (p = 0.02). The effect estimate was similar for genotype 1, but the association did not reach statistical significance. In conclusion, anti-apoptotic SNPs in the BCL2L1 gene were predictive of SVR to pegIFN/RBV treatment in HCV genotypes 1 and 3 infected individuals. These SNPs may be used in prediction of SVR, but further studies are needed.