Hepatitis delta infection among persons living with HIV in Europe

BACKGROUND AND AIMS A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes. METHODS All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti-HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV-positive and HDV-negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver-related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause-specific multivariable Cox regression. RESULTS Of 2793 HBsAg-positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%-17.1%) and 66% (132/200) of HDV-positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%-55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%-5.9%) among other participants. During a median follow-up of 10.8 years (interquartile range 5.6-17.8), 82 (34.6%) HDV-positive and 265 (20.1%) HDV-negative individuals died. 41.5% (34/82) of deaths were liver-related in HDV-positive individuals compared to 17.7% (47/265) in HDV-negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2-2.1), liver-related death (2.9, 1.6-5.0) and HCC (6.3, 2.5-16.0). CONCLUSION We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver-related mortality and HCC incidence

Hepatitis delta infection among persons living with HIV in Europe

Background and aims: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes. Methods: All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti-HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV-positive and HDV-negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver-related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause-specific multivariable Cox regression. Results: Of 2793 HBsAg-positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%-17.1%) and 66% (132/200) of HDV-positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%-55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%-5.9%) among other participants. During a median follow-up of 10.8 years (interquartile range 5.6-17.8), 82 (34.6%) HDV-positive and 265 (20.1%) HDV-negative individuals died. 41.5% (34/82) of deaths were liver-related in HDV-positive individuals compared to 17.7% (47/265) in HDV-negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2-2.1), liver-related death (2.9, 1.6-5.0) and HCC (6.3, 2.5-16.0). Conclusion: We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver-related mortality and HCC incidence

Low Risk of Failing Direct-Acting Antivirals in People With Human Immunodeficiency Virus/Hepatitis C Virus From Sub-Saharan Africa or Southeastern Asia: A European Cross-Sectional Study

Background: Several studies have reported suboptimal efficacy of direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) subtypes endemic to sub-Saharan Africa (SSA) and Southeastern Asia (SEA). The extent of this issue in individuals with human immunodeficiency virus (HIV)/HCV from SSA or SEA residing in Europe is unknown. Methods: We retrospectively analyzed data from several prospective European cohorts of people living with HIV. We included individuals with HIV/HCV who originated from SSA or SEA, were treated with interferon-free DAAs, and had an available HCV RNA result ≥12 weeks after the end of treatment. The primary outcome was sustained virological response at least 12 weeks after the end of treatment (SVR12). Results: Of the 3293 individuals with HIV/HCV treated with DAA and with available SVR12 data, 142 were from SSA (n = 64) and SEA (n = 78). SVR12 was achieved by 60 (94% [95% confidence interval {CI}, 86%-98%]) individuals from SSA and 76 (97% [95% CI, 92%-99%]) from SEA. The genotypes of the 6 individuals failing DAA treatment were 2, 3a, 3h, 4a, 4c, and 6j. For 2 of the 4 unsuccessfully treated individuals with available sequence data at treatment failure, NS5A resistance-associated substitutions were present (30R/93S in an individual with genotype 4c and 31M in an individual with genotype 6j). Conclusions: SVR12 rates were high in individuals with HIV/HCV residing in Europe and originating from regions where intrinsically NS5A-resistant HCV strains are endemic. HCV elimination for this population in Europe is unlikely to be hampered by suboptimal DAA efficacy. Keywords: coinfection; elimination; hepatitis C virus; human immunodeficiency viru

Global prevalence and genotype distribution of hepatitis C virus infection in 2015 : A modelling study

Publisher Copyright: © 2017 Elsevier LtdBackground The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.publishersversionPeer reviewe

HIV-1/HCV co infection : Immunity and viral dynamics

Human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) are the agents behind two viral epidemics causing huge morbidity and mortality worldwide. HCV infection is a leading cause of end-stage liver disease. Co-infection with HIV leads to faster progression to cirrhosis and lower clearance rate of HCV infection following current standard treatment with pegylated interferon alpha (peg-IFNalpha) and ribavirin. The overall aims of the studies described in this thesis were to gain knowledge of how to best manage HIV/HCV co-infection in clinical practice, to study immunological features in co-infected patients, to search for immunological host factors affecting HCV treatment outcome, and to identify possible predictive markers of treatment response. In paper I we investigated the feasibility of treating HIV/HCV co-infected patients with peg-IFNalpha and ribavirin in a Swedish HIV outpatient clinic. We found that only a small fraction of the patients were suitable treatment candidates when following international guidelines. However, in those treated the response was good and correlated to HCV RNA kinetics during initial treatment. One of the patients, who was among those screened for participation in the abovementioned study, spontaneously cleared her chronic HCV infection. Since this is a very rare event we further investigated the immune response of this patient, as described in paper II. She displayed a low level of T cell activation and a high level of T cell function comparedto HIV/HCV co-infected control subjects, thus resembling a healthy individual. In paper III we investigated the impact of chronic HIV/HCV co-infection and the effects of treatment with peg-IFNalpha and ribavirin on NK cells and on NKT cells by flow cytometry. Conventional NK cells were largely unaffected by the co-infection, with only a slight decrease in perforin content in CD56dim cells and an increased CD56bright immunoregulatory population. In contrast, the NKT cells were severely reduced in the co-infected patients and were not restored by HCV therapy. Interestingly, we observed a significant accumulation of unconventional CD56-CD16+ NK cells in these subjects. The expansion of CD56- NK cells was rapidly reverted when HCV replication was suppressed by HCV treatment. In paper IV, we observed that the CD56- NK cells in HCV infected patients were functionally skewed, with poor IFNgamma production but retained MIP-1beta expression. In addition, we found that pretreatment levels of CD56- NK cells in peripheral blood correlated with peg-IFNalpha and ribavirin treatment outcome. Patients with low levels of CD56- NK cells were more likely to clear the HCV infection, and this was not directly linked to other viral and host factors known to influence treatment outcome. In paper V we measured the chemokine IP-10 in plasma from HIV/HCV co-infected patients. We found that lower pretreatment plasma IP-10 levels were associated with faster clearance of the virus. This effect was more pronounced on the first phase viral reduction (day 0-2), than on the second (day 7-28). In summary, this thesis increases our knowledge of the immune system s interaction with HCV and HIV, and identifies an immunological biomarker that correlates with HCV treatment outcome. In addition, it highlights the need for further implementation of HCV treatment in the HIV/HCV co-infected patient group

The dynamic relationship between innate immune biomarkers and interferon-based treatment effects and outcome in hepatitis C virus infection is altered by telaprevir.

Soluble CD14 (sCD14) and IL-18 are markers and mediators of the innate immune response, and their plasma levels candidate biomarkers of HCV treatment effects and outcome. Here, we retrospectively studied sCD14 and IL-18 over the course of interferon-based treatment of HCV genotype 1 infection, with the aim to investigate the impact of direct-acting antivirals (DAAs) on the dynamics and relationships between these biomarkers and treatment effects and outcome. Two cohorts were followed longitudinally; one treated with standard dual therapy of pegylated IFNα and ribavirin, and one cohort receiving triple therapy including Telaprevir. sCD14 and IL-18 were measured before and during treatment and analyzed in relation to treatment effects. The initial analysis confirmed two patterns previously observed in patients with HCV/HIV-1 co-infection: Baseline levels of sCD14 were significantly lower in patients that went on to clear HCV infection in response to IFNα and ribavirin, and sCD14 levels were strongly induced during the course of this treatment. Interestingly, baseline levels of sCD14 and IL-18 in combination predicted treatment outcome in dual therapy better than either marker alone. Notably, these associations were weaker with the addition of Telaprevir to the treatment regimen, suggesting that the relationships between innate immune activation and outcome were altered and diminished by inclusion of a DAA in the treatment. In triple therapy, the dynamic increase of sCD14 in response to treatment was higher in patients clearing the virus, suggesting that the innate response to interferon is still significantly associated with outcome in patients treated with DAA-containing regimens. These results support the notion that levels of innate immune activation before and during treatment are associated with interferon-based treatment outcome. Furthermore, the addition of Telaprevir significantly alters the dynamics and relationships between innate immune biomarkers and treatment effects and outcome

Induced elevation of sCD14 is associated with triple therapy outcome.

<p>(A) Differences in the induction of sCD14 between sustained virological response (SVR) and no sustained response (NSR) patients whom undergo dual therapy (SVR n = 33, NSR n = 19). (B) Differences in the induction of IL-18 between SVR and NSR patients whom undergo dual therapy (SVR n = 33, NSR n = 19). (C) Differences in the induction of sCD14 between SVR and NSR patients whom undergo triple therapy (SVR n = 36, NSR n = 36, unpaired T test with Welch’s correction P = 0.0435). (D) Differences in the induction of IL-18 between SVR and NSR patients whom undergo triple therapy. *P≤0.05. Patients in the triple therapy cohort were ordered with those with the highest levels of sCD14 elevation in quartile 1 (Q1) to the lowest in Q4 and number of patients with a SVR or NSR in each quartile was assessed. (E) Number of SVR and NSR patients in each sCD14 quartile (n = 72). (F) Number of SVR and NSR patients in each IL-18 quartile (n = 72). P values shown represent Chi-squared test for trend.</p

Associations between treatment outcome and levels of sCD14 and IL-18 in plasma: effect of Telaprevir.

<p>Patients were ranked according to their baseline levels of sCD14, IL-18 or a combination of the two, ((x–x)/IQRx)+((y–y)/IQRy), from lowest to highest, with number of patients with a sustained virological response (SVR) or no sustained response (NSR) in each quartile assessed. (A) Number of SVR and NSR patients for increasing levels of baseline sCD14 in patients receiving dual therapy (n = 72). (B) Number of SVR and NSR patients for increasing levels of baseline IL-18 in patients receiving dual therapy (n = 72). (C) Number of SVR and NSR patients for increasing levels of the combination of the two analytes in patients receiving dual therapy (n = 72). (D) Number of SVR and NSR patients for increasing levels of baseline sCD14 in patients receiving triple therapy (n = 82). (E) Number of SVR and NSR patients for increasing levels of baseline IL-18 in patients receiving triple therapy (n = 82). (F) Number of SVR and NSR patients for increasing levels of the combination of the two analytes in patients receiving triple therapy (n = 82). P values shown represent Chi-squared test for trend.</p

Patient data for the dual and triple therapy cohorts.

<p>Abbreviations: SVR, sustained virological response; nd, no data.</p><p>Patient data for the dual and triple therapy cohorts.</p