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.

Effectiveness and Safety of Interferon-Free Direct-Acting Antiviral Hepatitis C Virus Therapy in HIV/Hepatitis C Virus Coinfected Individuals: Results From a Pan-European Study.

OBJECTIVES: To investigate the effectiveness, safety, and reasons for premature discontinuation of direct-acting antivirals (DAAs) in a diverse population of HIV/hepatitis C virus (HCV) coinfected individuals in Europe. METHODS: All HIV/HCV coinfected individuals in the EuroSIDA study that started interferon free DAA treatment between January 6, 2014, and January 3, 2018, with ≥12 weeks of follow-up after treatment stop were included in this analysis. Sustained virological response (SVR) was defined as a negative HCV-RNA result ≥12 weeks after stopping treatment (SVR12). Logistic regression was used to explore factors associated with SVR12. RESULTS: 1042 individuals started interferon-free DAA treatment after 1/6/2014 and were included, 862 (82.2%) had a known response to treatment, and 789 [91.5%, 95% confidence interval (CI): 89.7 to 93.4] of which achieved SVR12. There were no differences in SVR12 across regions of Europe (P = 0.84). After adjustment, the odds of achieving SVR12 was lower in individuals that received sofosbuvir/simeprevir ± ribavirin (RBV) [adjusted odds ratio 0.21 (95% CI: 0.08 to 0.53)] or ombitasvir/paritaprevir/dasabuvir ± RBV [adjusted odds ratio 0.46 (95% CI: 0.22 to 1.00)] compared with sofosbuvir/ledipasvir ± RBV. Forty-three (4.6%) individuals had one or more components of their HCV regimen stopped early, most commonly because of toxicity (n = 14); of these 14, 11 were treated with ribavirin. Increased bilirubin was the most common grade 3 or 4 laboratory adverse event (n = 15.3%) and was related to treatment with atazanavir and ribavirin. CONCLUSIONS: Our findings from real-world data on HIV/HCV coinfected individuals across Europe show DAA treatment is well tolerated and that high rates of SVR12 can be achieved in all regions of Europe.

Long-Term Study of Hepatitis Delta Virus Infection at Secondary Care Centers: The Impact of Viremia on Liver-Related Outcomes.

BACKGROUND AND AIMS: Hepatitis delta virus (HDV) infection is associated with fast progression to liver cirrhosis and liver complications. Previous studies have, however, been mainly from tertiary care centers, with risk for referral bias toward patients with worse outcomes. Furthermore, the impact of HDV viremia per se on liver-related outcomes is not really known outside the human immunodeficiency virus co-infection setting. We have therefore evaluated the long-term impact of HDV viremia on liver-related outcomes in a nationwide cohort of patients with hepatitis B and D co-infection, cared for at secondary care centers in Sweden. APPROACH AND RESULTS: In total, 337 patients with anti-HDV positivity, including 233 patients with HDV RNA viremia and 91 without HDV viremia at baseline, were retrospectively studied, with a mean follow-up of 6.5 years (range, 0.5-33.1). The long-term risks for liver-related events (i.e., hepatocellular carcinoma [HCC], hepatic decompensation, or liver-related death/transplantation) were assessed, using Cox regression analysis. The risk for liver-related events and HCC was 3.8-fold and 2.6-fold higher, respectively, in patients with HDV viremia compared with those without viremia, although the latter was not statistically significant. Among patients with HDV viremia with no baseline cirrhosis, the cumulative risk of being free of liver cirrhosis or liver-related events was 81.9% and 64.0% after 5 and 10 years of follow-up, respectively. This corresponds to an incidence rate of 0.04 cases per person-year. CONCLUSIONS: HDV RNA viremia is associated with a 3.8-fold higher risk for liver-related outcomes. The prognosis was rather poor for patients with HDV viremia without cirrhosis at baseline, but it was nevertheless more benign than previous estimates from tertiary centers. Our findings may be of importance when making decisions about treatment and evaluating potential outcomes of upcoming antivirals against HDV.

Plasma FABP4 is associated with liver disease recovery during treatment-induced clearance of chronic HCV infection.

Direct-acting antivirals (DAAs) have dramatically improved the management of chronic hepatitis C (CHC). In this study, we investigated the effects of hepatitis C virus clearance on markers of systemic inflammation measured in plasma samples from CHC patients before, during and after DAA therapy. We identified a plasma soluble protein profile associated with CHC. Successful DAA therapy rapidly normalised the plasma inflammatory milieu, with the notable exception of soluble (s)CD163, a marker of macrophage activation, which remained elevated after viral clearance and segregated patients with high and low levels of cirrhosis. Patients who received DAA in combination with Ribavirin maintained elevated levels of CXCL10, consistent with an immune-stimulatory role of Ribavirin. As anticipated, DAA-treated patients experienced durable improvement in liver fibrosis measurements. Interestingly, pre-treatment levels of fatty acid-binding protein 4 (FABP4) were inversely associated with reduction of APRI and FIB-4 scores during treatment. Together, these results support the notion of a rapid restoration of many aspects of the inflammatory state in CHC patients in response to DAA therapy. Furthermore, the associations with sCD163 and FABP4 warrant further investigation into the role of macrophages in residual liver disease and fibrosis resolution after viral clearance.

Clinical Outcomes in Persons Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus: Impact of Hepatitis C Virus Treatment.

BACKGROUND: A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear. METHODS: People living with HIV from EuroSIDA with a known HCV status after January 2001 were classified into strata based on time-updated HCV RNA measurements and HCV treatment, as either HCV antibody-negative; spontaneously resolved HCV; chronic, untreated HCV; cured HCV (HCV RNA-negative); or HCV treatment failures (HCV RNA-positive). Poisson regression was used to compare incidence rates between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non-acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD). RESULTS: There were 16 618 persons included (median follow-up 8.3 years, interquartile range 3.1-13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0-6.9) for CVD, 6.5 (95% CI 6.1-6.9) for NADM, and 3.1 (95% CI 2.8-3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14-0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36-1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02-2.13) or treatment failure (aIRR 1.80, 95% CI 1.22-2.66) had significantly raised rates of ESLD, compared to those who were cured. CONCLUSIONS: Incidences of NADM or CVD were independent of HCV group, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD.

Uptake of hepatitis C virus treatment in HIV/hepatitis C virus-coinfected patients across Europe in the era of direct-acting antivirals.

BACKGROUND AND AIMS: To investigate the uptake of hepatitis C virus (HCV) therapy among HIV/HCV-coinfected patients in the pan-European EuroSIDA study between 2011 and 2016. METHODS: All HCV-RNA+ patients were included. Baseline was defined as latest of anti-HCV+, January 2011 or enrolment in EuroSIDA. The incidence of starting first interferon-free direct-acting antiviral (DAA) therapy was calculated. Factors associated with starting interferon-free DAA were determined by Poisson regression. RESULTS: Among 4308 HCV-RNA+ patients (1255, 970, 663, 633, 787 from South, West, North, Central East and East Europe, respectively) with 11 863 person-years of follow-up, 1113 (25.8%) started any HCV therapy. Among patients with at least F3 fibrosis, more than 50% in all regions remained untreated. The incidence (per 1000 person-years of follow-up, 95% confidence interval) of starting DAA increased from 7.8 (5.9-9.8) in 2014 to 135.2 (122.0-148.5) in 2015 and 128.9 (113.5-144.3) in 2016. The increase was highest in North and West and intermediate in South, but remained modest in Central East and Eastern Europe. After adjustment, women, individuals from Central East or East, genotype 3, antiretroviral therapy naïve and those with detectable HIV-RNA were less likely to start DAA. Older persons, those with HCV-RNA more than 500 000 IU/ml and those with more advanced liver fibrosis were more likely to start DAA. CONCLUSION: Uptake of DAA therapy among HIV/HCV-coinfected patients increased considerably in Western Europe between 2014 and 2016, but was modest in Central East and East. In all regions more than 50% with at least F3 fibrosis remained untreated. Women were less likely to start DAA.

IL13Rα2 expression identifies tissue-resident IL-22-producing PLZF+ innate T cells in the human liver.

Innate lymphocytes are selectively enriched in the liver where they have important roles in liver immunology. Murine studies have shown that type I NKT cells can promote liver inflammation, whereas type II NKT cells have an anti-inflammatory role. In humans, type II NKT cells were found to accumulate in the gut during inflammation and IL13Rα2 was proposed as a marker for these cells. In the human liver, less is known about type I and II NKT cells. Here, we studied the phenotype and function of human liver T cells expressing IL13Rα2. We found that IL13Rα2 was expressed by around 1% of liver-resident memory T cells but not on circulating T cells. In support of their innate-like T-cell character, the IL13Rα2+ T cells had higher expression of promyelocytic leukaemia zinc finger (PLZF) compared to IL13Rα2- T cells and possessed the capacity to produce IL-22. However, only a minority of human liver sulfatide-reactive type II NKT cells expressed IL13Rα2. Collectively, these findings suggest that IL13Rα2 identifies tissue-resident intrahepatic T cells with innate characteristics and the capacity to produce IL-22.

The association between detected drug resistance mutations and CD4+ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen.

BACKGROUND: To analyse the effect of drug resistance mutations (DRM) on CD4+ T-cell (CD4) trends in HIV-positive people maintained on virologically failing antiretroviral therapy (ART). METHODS: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with ≥1 CD4 count and ≥1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline. RESULTS: 5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline. CONCLUSIONS: Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

Long-term effectiveness of unboosted atazanavir plus abacavir/lamivudine in subjects with virological suppression: A prospective cohort study.

Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant.We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR <50 copies/mL) and a snapshot analysis at 48, 96, and 144 weeks. Virological failure (VF) was defined as confirmed pVL >50 copies/mL.We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL ≤50 copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42-0.93] per 100 cells higher), time with pVL ≤50 copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28-6.04]). Resistance selection at failure was uncommon.A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure.

The Human NK Cell Response to Yellow Fever Virus 17D Is Primarily Governed by NK Cell Differentiation Independently of NK Cell Education.

NK cells play an important role in the defense against viral infections. However, little is known about the regulation of NK cell responses during the first days of acute viral infections in humans. In this study, we used the live attenuated yellow fever virus (YFV) vaccine 17D as a human in vivo model to study the temporal dynamics and regulation of NK cell responses in an acute viral infection. YFV induced a robust NK cell response in vivo, with an early activation and peak in NK cell function at day 6, followed by a delayed peak in Ki67 expression, which was indicative of proliferation, at day 10. The in vivo NK cell response correlated positively with plasma type I/III IFN levels at day 6, as well as with the viral load. YFV induced an increased functional responsiveness to IL-12 and IL-18, as well as to K562 cells, indicating that the NK cells were primed in vivo. The NK cell responses were associated primarily with the stage of differentiation, because the magnitude of induced Ki67 and CD69 expression was distinctly higher in CD57(-) NK cells. In contrast, NK cells expressing self- and nonself-HLA class I-binding inhibitory killer cell Ig-like receptors contributed, to a similar degree, to the response. Taken together, our results indicate that NK cells are primed by type I/III IFN in vivo early after YFV infection and that their response is governed primarily by the differentiation stage, independently of killer cell Ig-like receptor/HLA class I-mediated inhibition or education.

The future disease burden of hepatitis C virus infection in Sweden and the impact of different treatment strategies.

UNLABELLED: OBJECTIVE. Recently, new highly effective direct-acting antivirals (DAAs) against hepatitis C virus (HCV) were introduced. Whether these will alleviate the anticipated increase of liver disease burden in Sweden is unknown, partly because high costs may restrict the use. The objectives were to model the HCV epidemic in Sweden, the burden of disease, and the potential impact of different treatment strategies. MATERIAL AND METHODS: HCV disease progression was modeled to 2030. Scenarios were simulated using new DAAs with sustained annual treatment rate (n = 1130), reduced treatment rate (n = 380) to maintain budget, and increased treatment rates (n = 1430 or 2260) to reduce HCV infections. RESULTS: With today's triple therapies, the estimated number of serious liver complications and death are expected to peak in 2021. Using new DAAs among F0-F4 patients, an unchanged annual treatment rate can reduce the number of HCV infections by 10% by 2030; however, hepatocellular carcinoma (HCC) and mortality will remain unchanged. By reducing to 380 treatments annually and focusing on patients with advanced fibrosis (F3-F4), serious complications will remain constant but the total number of HCV infections will increase. By doubling the number of DAA treatments, HCC-incidence and liver-related deaths would decrease by 65-70% by 2030. CONCLUSION: Mortality and HCC can be reduced with new DAAs and sustained treatment uptake when restricted to F2-F4 patients, or with increased uptake in F0-F4 patients. Treatment restrictions to limit cost may reduce the positive effects and increase the burden of HCV infection. These results may be important for the future strategies of HCV management.

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.

High HCV treatment uptake in the Swedish HIV/HCV co-infected cohort.

BACKGROUND: HCV co-infection is a leading cause of death in HIV-positive patients. Despite a strong indication for the treatment of HCV, treatment uptake is generally lower than in HCV mono-infected patients. The aim of this study was to determine the HCV treatment uptake and to define factors associated with initiation or deferral of HCV treatment in Swedish HIV/HCV co-infected patients. METHODS: All 5315 adult HIV-positive patients in Sweden are included in the InfCare HIV database. Demographic, virologic, and treatment data for 652 HIV/HCV co-infected patients were extracted from this database in September 2010. Factors associated with initiation of interferon-based HCV treatment were analysed. Patient- and physician-reported reasons for deferring HCV treatment were investigated in a subgroup. RESULTS: The anti-HCV prevalence was 14% and the chronic HCV infection rate 11%. In total, 25% of HIV/HCV co-infected patients had initiated HCV treatment. HCV genotype 2 or 3, HIV transmission route other than intravenous drug use, and ongoing HIV treatment were factors associated with a higher HCV treatment rate. The main reason for not having initiated HCV treatment was intravenous drug use or alcohol abuse. CONCLUSIONS: The 14% prevalence of anti-HCV noted in Swedish HIV-infected patients was low by international comparisons. The 25% HCV treatment rate noted in our HIV/HCV co-infected patients was high and of the same magnitude as that published for HCV mono-infected patients in Sweden. People who inject drugs had the lowest HCV treatment uptake.

Occasional spontaneous clearance of chronic hepatitis C virus in HIV-infected individuals.

The IL28B genotype has been found to have a strong influence on spontaneous clearance of acute HCV both in HCV mono- and HIV/ the HCV co-infected patients. Spontaneous clearance of chronic HCV without HCV treatment is rare. Here, we report on three chronic HCV cases co-infected with HIV with spontaneous clearance of their HCV infection, all with the IL28B CC genotype. These cases were derived from a surveillance of the total HIV/HCV co-infected cohort in Sweden (n =4 66). The estimated frequency of spontaneous clearance of chronic HCV infection in our cohort was calculated to be 0.6-4.7%. Our cases lend some support to the initiation of ART prior to HCV treatment in HIV/HCV co-infected patients. Furthermore, HCV-RNA testing should be recommended immediately before initiation of HCV treatment, to find the subset of HIV/HCV co-infected patients with IL28B CC that may have cleared their chronic infection spontaneously.

Clinical significance of residual viremia detected by two real-time PCR assays for response-guided therapy of HCV genotype 1 infection.

BACKGROUND & AIMS: The duration of current standard dual and protease inhibitor-based triple therapies for chronic hepatitis C is determined by assessment of early viral kinetics. Little is known about differences between HCV RNA assays for the use in response guided therapy. METHODS: HCV RNA was assessed by two widely used real-time PCR-based assays, Cobas Ampliprep/Cobas TaqMan (CAP), and Real-Time HCV (ART) in 903 samples of hepatitis C genotype 1 patients treated with dual (n=169) or telaprevir-based triple therapy (n=164) in three European countries. RESULTS: Overall, CAP and ART were in excellent agreement for the determination of HCV-RNA concentrations (mean difference 0.21 log10 IU/ml). For treatment-naïve patients treated with peginterferon-alfa and ribavirin a lower rate of undetectable HCV-RNA at week 4 (RVR) was observed for ART (9%) vs. CAP (16%). Although 11/27 (41%) of patients with shortened treatment (24weeks) had detectable HCV-RNA <12IU/ml by ART at week 4 none of these patients experienced virologic relapse after treatment cessation. In patients who received triple therapy, 67% and 37% had undetectable HCV-RNA at week 4 by CAP and ART, respectively. However, 18/31 (58%) eligible patients for shortened treatment based on CAP had detectable HCV-RNA by ART at week 4. Again, relapse was not observed in these patients. CONCLUSIONS: Lower rates of undetectable HCV-RNA at week 4 were observed with ART compared to CAP in patients treated with dual and triple therapies. For ART, detectable <12IU/ml HCV-RNA levels at week 4 may be sufficient as part of the criteria used for selecting patients who receive a shortened treatment regimen.

Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response.

The live attenuated yellow fever virus (YFV) 17D vaccine provides a good model to study immune responses to an acute viral infection in humans. We studied the temporal dynamics, composition, and character of the primary human T cell response to YFV. The acute YFV-specific effector CD8 T cell response was broad and complex; it was composed of dominant responses that persisted into the memory population, as well as of transient subdominant responses that were not detected at the memory stage. Furthermore, HLA-A2- and HLA-B7-restricted YFV epitope-specific effector cells predominantly displayed a CD45RA(-)CCR7(-)PD-1(+)CD27(high) phenotype, which transitioned into a CD45RA(+)CCR7(-)PD-1(-)CD27(low) memory population phenotype. The functional profile of the YFV-specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and it tended to become less polyfunctional during the course of this transition. Interestingly, activation of CD4 T cells, as well as FOXP3(+) T regulatory cells, in response to YFV vaccination preceded the kinetics of the CD8 T cell response. The present results contribute to our understanding of how immunodominance patterns develop, as well as the phenotypic and functional characteristics of the primary human T cell response to a viral infection as it evolves and matures into memory.

Chronic immune activation in the T cell compartment of HCV/HIV-1 co-infected patients.

Activation of innate and adaptive immune mechanisms in response to infection is necessary to control and clear infections. However, chronic immune activation in human immunodeficiency virus 1 (HIV-1) infection has a series of detrimental effects and is a major driving force in HIV-1 disease progression. We recently found that patients with chronic hepatitis C virus (HCV)/HIV-1 co-infection display sharply elevated immune activation as determined by expression of CD38 in T cells. High immune activation was observed despite that these patients were on effective antiretroviral therapy (ART), which usually brings down activation levels in HIV-infected people. HCV treatment with pegylated interferon-α (IFNα) and ribavirin reduced activation, and this was at first glance unexpected as IFNα is believed to be involved in driving activation. Here, we briefly summarize these findings and discuss them in context of the emerging roles of the gut barrier and the liver in chronic immune activation and viral disease progression.

IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV.

The aim of this study was to investigate the utility of baseline plasma interferon-gamma inducible protein-10 (IP-10) levels in human immunodeficiency virus (HIV)-hepatitis C virus (HCV) co-infected patients. Baseline IP-10 was monitored during HCV combination therapy in 21 HIV-HCV co-infected patients (HCV genotype 1 (n = 16), 2 (n = 2), and 3 (n = 3)). Lower baseline IP-10 was significantly associated with a rapid decline in HCV RNA, in particular with the first phase reduction, and similar cut-off levels (< 150 and > 600 pg/ml) as in HCV mono-infected patients apply. In conclusion, baseline IP-10 < 150 pg/ml is predictive of a favourable viral response to HCV therapy in HIV-HCV co-infected patients, and may thus be useful in encouraging such difficult-to-treat patients to initiate therapy.

HCV/HIV co-infection at a large HIV outpatient clinic in Sweden: feasibility and results of hepatitis C treatment.

We investigated the prevalence of hepatitis C virus (HCV) co-infection in HIV-infected patients at a large Swedish outpatient clinic. We also evaluated the feasibility of treating this patient group with pegylated-interferon alpha-2a and ribavirin (RBV) and found that only a small fraction of the HCV/HIV co-infected patients met the criteria for HCV treatment when following international guidelines. Thus, 11 patients were treated, and HCV kinetics were measured during early treatment. The overall treatment response rate was surprisingly high (73%) and correlated to early virological response.