Lack of evidence of acute HEV infections as a sexually transmitted disease: Data from a German cohort of PrEP users

Abstract Background While the sexual transmissibility of HAV in MSM has been extensively described, the potential for sexual transmission of HEV has not been definitively established. Although HEV has been detected in the ejaculate of chronically infected men, studies among MSM PrEP users in France did not observe an elevated anti-HEV seroprevalence as an indicator of increased exposure risk by sexual intercourse. Patients and methods A total of 111 unselected PrEP users and 111 age- and sex-matched blood donors were tested for anti-HEV IgG, IgM and HEV (PCR). Of the participants 79/111 (71 %) responded to a questionnaire covering topics as sexual preferences, previous sexually transmitted diseases, profession, food consumption, and pet ownership. Results The anti-HEV IgG seroprevalence in PrEP users (22 %) did not differ significantly from the rate in controls (17 %). While one PrEP user and three controls tested positive for anti-HEV IgM, all PrEP users and controls tested PCR negative. Conclusion In immunocompetent individuals with frequent changes of sexual partners, the epidemiology of Hepatitis E Virus does not significantly involve the sexual transmission route.

[HIV First Diagnoses in Germany in 2014 - A Regional Analysis]. / HIV-Erstdiagnosen in Deutschland im Jahr 2014 ­ eine regionale Analyse.

BACKGROUND: Information on testing units in health care is scarce, particularly the group of late-presenters among the HIV-first diagnoses is still a challenge in Germany. AIM: Analysis of the impact of testing units on and reasons for the prevalence of HIV-first diagnoses and late presentation, taking 2014 for illustrative purposes. MATERIAL AND METHODS: Cross-sectional analysis of all individuals, treated in the Network HIV-Regional who were first diagnosed with HIV in 2014; patient characteristics, demographic and clinical data, including information on HIV testing were collected retrospectively and in a decentralised manner, pseudonymized and statistically evaluated. RESULTS: A total of 971 individuals with HIV-first diagnosis from 31 specialised care centres throughout Germany (15 hospitals, 16 private practices) represented 27.5% of all National HIV-first diagnoses -registrations from Robert Koch Institute for 2014, with similar results for CD4-cell count and HIV-transmission risk. The most common test site was a hospital (34.8%), followed by the office of a family doctor (19.6%) and medical specialist (16.1%). If the first diagnosis was established in hospital, then the patients were on average older than those tested on an ambulant care basis (42 vs. 37 years, p=0.001); moreover, the HI-viral load was higher (585 vs. 270 thousand copies/mL, p<0.001) and the CD4-cell count lower (265 vs. 414/µL, p<0.001). In 208/971 individuals with first diagnosis, at least one AIDS-defining disease was found, most frequently pneumocystis-pneumonia (43.8%), candidiasis (36.5%) and Kaposi sarcoma (10.6%). A regional comparison revealed that in eastern Germany, for first diagnosed HIV-patients were younger, had a higher HIV-RNA viral load and also more often clinical AIDS. CONCLUSION: This analysis of HIV-Regional for 2014 enables a deeper insight into HIV first diagnoses, on the eve of the introduction of important prevention tools in Germany, e. g., HIV home testing and pre-exposure prophylaxis. This cross-sectional analysis was representative for Germany and underscores the importance of specialised hospitals, in particular for eastern Germany, and furthermore the involvement of late-presenters into HIV health care.

The association between hepatitis B virus infection and nonliver malignancies in persons living with HIV: results from the EuroSIDA study.

OBJECTIVES: The aim of this study was to assess the impact of hepatitis B virus (HBV) infection on non-liver malignancies in people living with HIV (PLWH). METHODS: All persons aged ≥ 18 years with known hepatitis B virus (HBV) surface antigen (HBsAg) status after the latest of 1 January 2001 and enrolment in the EuroSIDA cohort (baseline) were included in the study; persons were categorized as HBV positive or negative using the latest HBsAg test and followed to their first diagnosis of nonliver malignancy or their last visit. RESULTS: Of 17 485 PLWH included in the study, 1269 (7.2%) were HBV positive at baseline. During 151 766 person-years of follow-up (PYFU), there were 1298 nonliver malignancies, 1199 in those currently HBV negative [incidence rate (IR) 8.42/1000 PYFU; 95% confidence interval (CI) 7.94-8.90/1000 PYFU] and 99 in those HBV positive (IR 10.54/1000 PYFU; 95% CI 8.47-12.62/1000 PYFU). After adjustment for baseline confounders, there was a significantly increased incidence of nonliver malignancies in HBV-positive versus HBV-negative individuals [adjusted incidence rate ratio (aIRR) 1.23; 95% CI 1.00-1.51]. Compared to HBV-negative individuals, HBsAg-positive/HBV-DNA-positive individuals had significantly increased incidences of nonliver malignancies (aIRR 1.37; 95% CI 1.00-1.89) and NHL (aIRR 2.57; 95% CI 1.16-5.68). There was no significant association between HBV and lung or anal cancer. CONCLUSIONS: We found increased rates of nonliver malignancies in HBsAg-positive participants, the increases being most pronounced in those who were HBV DNA positive and for NHL. If confirmed, these results may have implications for increased cancer screening in HIV-positive subjects with chronic HBV infection.

Clinical setting-based smoking cessation programme and the quality of life in people living with HIV in Austria and Germany.

PURPOSE: To report on the global quality of life (QOL) in people living with HIV (PLWHIV) and how a smoking cessation intervention influences the changes in QOL. METHODS: Participants were asked to fill out a questionnaire during visits to their HIV outpatient clinic consisting of sociodemographic information, general health data and the WHOQOL HIV-Bref. Exhaled carbon monoxide measurements were used to confirm the smoking status, based on which participants classified as smokers received a short 5 min structured intervention and were offered participation in a full smoking cessation programme consisting of five sessions. Follow-up was done 8 months after the baseline. RESULTS: Overall 447 (mean age = 45.5) participants took part with 221 being classified as smokers. A total of 165 (74.6%) participants received a short intervention and 63 (29.4%) agreed to participate in the full program. At baseline, differences in QoL were observed, where smokers had lower QoL in domains of physical (M = 16.1 vs. 15.3, p = 0.009) and psychological (M = 15.3 vs. 14.6, p = 0.021) well-being, independency level (M = 16.1 vs. 15.2, p = 0.003) and environment (M = 16.5 vs. 16.0, p = 0.036). At study end, 27 (12.2%) participants quit smoking; 12 (19.0%) participants of the full programme and 15 (14.7%) that received the short intervention. There were no significant differences in QoL between those that continued to smoke and quitters at follow-up. CONCLUSION: Quality of life results may be used to better understand the underlying motivation of PLWHIV who start cessation programs. In order to reduce the high prevalence and health burden that smoking causes in PLWHIV, it is necessary to introduce effective interventions that can be used in the clinical settings.

Brief Report: Increased Frequency of CD39+ CD56bright Natural Killer Cells in HIV-1 Infection Correlates With Immune Activation and Disease Progression.

The expression pattern of the ectonucleotidases CD39 and CD73 on natural killer (NK) cells was examined in peripheral blood mononuclear cell of 61 HIV-1-infected patients. Increased frequencies of CD39CD56 NK cells were detectable in untreated HIV patients, which was associated with high viral load, low CD4 T-cell count, and CD8 T-cell activation. Additionally, levels of CD39 on NK cells were inducible by in vitro stimulation of NK cells, correlating with aryl hydrocarbon receptor and interleukin 10 expression. Here, we provide the first evidence of increased CD39CD56 NK cell frequencies during HIV infection, which might have consequences for NK cell function and HIV pathogenesis.

High proportion of HIV late presenters at an academic tertiary care center in northern Germany confirms the results of several cohorts in Germany: time to put better HIV screening efforts on the national agenda?

165 treatment-naive patients who first presented at the infectious disease clinic of the University Medical Center Hamburg-Eppendorf from 2009 to 2011 were retrospectively analyzed with emphasis on patients with late presentation (LP). In line with other recent German reports, there was a large proportion of 105 of the 165 treatment-naïve patients (63.6 %) who presented late. Old age, heterosexual transmission risk and migrant background were associated risk factors for late presentation. Thus, further intensified national efforts like the HIV in Europe initiative are needed to identify such patients at high risk for HIV infection.

Prevalence and Correlates of Smoking and Readiness to Quit Smoking in People Living with HIV in Austria and Germany.

We aimed to investigate the prevalence and correlates of smoking in people living with HIV (PLWHIV) in Germany and Austria and their readiness to quit. A total of 447 consecutive patients with confirmed positive HIV status who were treated in different outpatient HIV centres in Austria and Germany were included. Nicotine dependence and stages of change were assessed by standardized questionnaires, and this was confirmed by measuring exhaled carbon monoxide. Prevalence of smoking was 49.4%. According to a multivariate logistic regression analysis, higher age (for each year of life OR = 0.96; 95% CI 0.92-1.00) and tertiary education level (OR = 0.43; 95% CI 0.15-0.79) were associated with a lower chance, and occasional (OR = 3.75; 95% CI 1.74-8.07) and daily smoking of the partner (OR 8.78; 95% CI 4.49-17.17) were significantly associated with a higher chance of smoking. Moderate (OR = 3.41; 95% CI = 1.30-9.05) and higher nicotine dependency level (OR = 3.40; 95% CI 1.46-7.94), were significantly associated with higher chance, and older age (for each year of life OR = 0.95; 95% CI = 0.91-0.99), with lower chance for readiness to quit smoking. Those results may be used to address preventive measures to quit smoking aimed at PLWHIV and the importance of addressing smoking habits.

Smoking prevalence, readiness to quit and smoking cessation in HIV+ patients in Germany and Austria.

INTRODUCTION: Due to the interaction between smoking and the virus and the antiretroviral therapy, the excess health hazard due to smoking is higher in HIV+ patients than in the general population. International studies suggest a higher prevalence of smoking in HIV+ subjects compared to the general population. It was the aim of the study to assess prevalence of smoking, to analyze determinants of smoking, and to evaluate readiness to quit in HIV+ patients in Germany and Austria. MATERIAL AND METHODS: Consecutive patients with positive tested HIV status, smokers and non-smokers, who are treated in seven different HIV care centres in Austria and Germany were included. Nicotine dependence was assessed with the Fagerström Test for Nicotine Dependency (FTND), and stages of change by a standardized readiness to quit questionnaire. Self-reported smoking status was objectified by measuring exhaled carbon monoxide levels. Smokers who wanted to quit were offered a structured smoking cessation programme, and those who did not want to quit received a 1-minute consultation. After six months, the smoking status of all included subjects was reassessed. RESULTS: A total of 447 patients were included; the response rate was 92%. Prevalence of smoking was 49.4%. According to a multivariate logistic regression analysis, lower age, male sex, lower educational level, and smoking of the partner were significantly associated with the smoking status. According to the FTND, 25.3% showed a low (0-2 points), 27.6 a moderate (3-4 points) and 47.1% a high (5-10 points) dependency. Regarding stages of change, 15.4% of the smokers were in the stadium precontemplation, 48.4 in contemplation, 15.4 in preparation and 10.0 in the stadium action. 11.0% were not assignable in any stadium. Higher education level and lower grade of dependency were significantly associated with the wish to quit smoking. Six months after the baseline examination, smoking cessation visits (at least one session) was performed in 28.5% of the smokers. 13% of the smokers have quit smoking, 23% have reduced smoking and 63% did not change smoking habits positively 6 months after the first visit. CONCLUSIONS: Prevalence rates for smoking in HIV+ subjects are higher than in the general population. Readiness to quit is, however, high, and 13% of smokers who have quit smoking after six months is a remarkable short-term success. This observation underlines the importance and feasibility of addressing smoking habits in HIV care.

Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion.

Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5'-NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (∼10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8(+) T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8(+) T cells, a positive correlation between CD73 expression and CD4 counts (P=0.0003) was detected. CD73 expression on CD8(+) T cells negatively correlated with HLA-DR (<0.0001) and PD1 (P=0.0457) expression. The lower CD73 expression on CD8(+) T cells was partially reversible after initiation of ART (P=0.0016). Functionally, we observed that CD8(+)CD73(+) T cells produce more IL-2 upon HIV-specific and unspecific stimulation than their CD73(-) counterparts and show a higher proliferative capacity. These data indicate that down-regulation of CD73 on CD8(+) T cells correlates with immune activation and leads to functional deficits in HIV infection.

Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease.

There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection. Peripheral blood of a large cohort of HIV-infected patients (n = 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine the frequency and phenotype of Tregs, defined as CD4(+), CD25(high), CD127(low), FoxP3(high) cells. A significantly increased relative frequency of Tregs within the CD4(+) compartment of HIV(+) patients compared to that of healthy controls (P < 0.0001) was observed. Additionally, the relative frequency of Tregs directly correlated with HIV viral load and inversely with CD4(+) counts. However, the absolute Treg number was reduced in HIV-infected patients versus healthy controls (P < 0.0001), with the exception of elite controllers (P > 0.05). The loss of absolute Treg numbers coincided with rising markers of immune activation (P < 0.0006). The initiation of antiviral therapy significantly increased absolute Treg numbers (P < 0.0031). We find that the expression of CD39, a newly defined ectonucleotidase with immunomodulatory functions on Tregs, correlated with progressive HIV disease, HIV viral load, and immune activation. Of note, when tested in peripheral blood mononuclear cells of healthy volunteers, the in vitro capacity to suppress T-cell proliferation was limited to CD4(+), CD25(high), CD39(+) T cells. Interestingly, Tregs of elite controllers exhibited not only the highest expression of CCR5, CTLA-4, and ICOS but also the lowest level of CD39. The data presented here reconcile the seemingly contradictory results of previous studies looking at Tregs in HIV and highlight the complexity of Treg-mediated immunoregulation during human viral infections.

Adoptive transfer of syngeneic T cells in HIV-1 discordant twins indicates rapid regulation of T-cell homeostasis.

The safety and efficacy of adoptive T-cell transfer (ATT) was tested in the context of viral suppression in syngeneic twins discordant for human immunodeficiency virus type 1 (HIV-1) infection. Human leucocyte antigen-matched T cells of seven HIV-negative twins were obtained by lymphapheresis and immediately transfused into the HIV-infected sibling. Four twins received 12 ATTs each, with a mean of 2.10 +/- 0.97 x 10(9) CD4(+) T cells and 1.74 +/- 0.81 x 10(9) CD8(+) T cells. Additional transfers were performed in three more twin pairs to study the short-term kinetics of transfused syngeneic T cells. Mean CD4(+) T-cell counts increased significantly, by 0.133 +/- 0.136 x 10(9) cells/l at 1 h and 0.144 +/- 0.12 x 10(9) cells/l at 3 h post-transfusion (P < 0.0001). Short-term kinetic studies suggested a rapid clearance of transferred T cells from the peripheral blood within minutes due to a distribution to marginal pools. After a mean follow up of 39 months, however, a sustained increase of the mean CD4(+) T-cell count was observed (from 0.232 x 10(9) to 0.523 x 10(9) cells/l) without changes of plasma viraemia. We conclude that ATT combined with highly active antiretroviral therapy is safe and leads to a considerable increase in CD4(+) T-cell numbers. The clearance kinetics of the transfused cells from peripheral blood indicates a very rapid regulation of T-cell homeostasis in HIV infection.

Substrate specificity of nickel/cobalt permeases: insights from mutants altered in transmembrane domains I and II.

HoxN, a high-affinity, nickel-specific permease of Ralstonia eutropha H16, and NhlF, a nickel/cobalt permease of Rhodococcus rhodochrous J1, are structurally related members of the nickel/cobalt transporter (NiCoT) family. These transporters have an eight-helix structure and are characterized by highly conserved segments with polar or charged amino acid residues in transmembrane domains (TMDs) II, III, V, and VI. Two histidine residues in a Ni2+ binding motif, the signature sequence of NiCoTs, in TMD II of HoxN have been shown to be crucial for activity. Replacement of the corresponding His residues in NhlF affected both Co2+ and Ni2+ uptake, demonstrating that NhlF employs a HoxN-like mechanism for transport of the two cations. Multiple alignments of bacterial NiCoT sequences identified a striking correlation between a hydrophobic residue (Val or Phe) in TMD II and a position in the center of TMD I occupied by either an Asn (as in HoxN) or a His (as in NhlF). Introducing an isoleucine residue at the latter position strongly reduced HoxN activity and abolished NhlF activity, suggesting that a Lewis base N-donor moiety is important. The Asn-to-His exchange had no effect on HoxN, whereas the converse replacement reduced NhlF-mediated Ni2+ uptake significantly. Replacement of the entire TMD I of HoxN by the respective NhlF segment resulted in a chimera that transported Ni2+ and Co2+ with low capacity. The Val-to-Phe exchange in TMD II of HoxN led to a considerable rise in Ni2+ uptake capacity and conferred to the variant the ability to transport Co2+. NhlF activity dropped in response to the converse mutation. Our data predict that TMDs I and II in NiCoTs spatially interact to form a critical part of the selectivity filter. As seen for the V64F variant of HoxN, modification of this site can increase the velocity of transport and concomitantly reduce the specificity.