Integration of a recent infection testing algorithm into HIV surveillance in Ireland: improving HIV knowledge to target prevention.

Recent infection testing algorithms (RITA) for HIV combine serological assays with epidemiological data to determine likely recent infections, indicators of ongoing transmission. In 2016, we integrated RITA into national HIV surveillance in Ireland to better inform HIV prevention interventions. We determined the avidity index (AI) of new HIV diagnoses and linked the results with data captured in the national infectious disease reporting system. RITA classified a diagnosis as recent based on an AI < 1.5, unless epidemiological criteria (CD4 count <200 cells/mm3; viral load <400 copies/ml; the presence of AIDS-defining illness; prior antiretroviral therapy use) indicated a potential false-recent result. Of 508 diagnoses in 2016, we linked 448 (88.1%) to an avidity test result. RITA classified 12.5% of diagnoses as recent, with the highest proportion (26.3%) amongst people who inject drugs. On multivariable logistic regression recent infection was more likely with a concurrent sexually transmitted infection (aOR 2.59; 95% CI 1.04-6.45). Data were incomplete for at least one RITA criterion in 48% of cases. The study demonstrated the feasibility of integrating RITA into routine surveillance and showed some ongoing HIV transmission. To improve the interpretation of RITA, further efforts are required to improve completeness of the required epidemiological data.

Inequalities in HIV testing uptake and needs among men who have sex with men living in Ireland: findings from an internet survey.

OBJECTIVES: HIV disproportionately affects men who have sex with men (MSM) in Ireland. The aim of this study was to improve understanding of HIV testing among MSM living in Ireland to inform prevention and testing initiatives. METHODS: We used data from the MSM Internet Survey Ireland 2015 (MISI 2015), a cross-sectional survey of MSM living in Ireland. We identified factors associated with never having tested for HIV using univariable and multivariable logistic regression. We identified preferred sites for future tests and examined the relationships between unmet HIV testing needs and socio-demographic groups. RESULTS: More than one-third (n = 1006; 36%) of MSM had never tested for HIV. Multivariable logistic regression showed that untested men were more likely to be aged 18-24 years, live outside Dublin, have a lower level of education, be born in Ireland, identify as bisexual, be out to fewer people, and not have had sex with a man in the previous 12 months. The same groups of men also had the least knowledge about HIV and were least confident in accessing an HIV test. Men who had never tested for HIV were more likely to prefer testing by their general practitioner (GP) or using home sampling HIV kits and less likely to prefer testing in a sexual health clinic. CONCLUSIONS: HIV prevention and testing programmes for MSM should be targeted towards younger men, those living outside Dublin and those with lower levels of education. We recommend increased promotion and availability of free HIV testing services in a range of clinical and nonclinical settings (including self-sampling and home testing).

Smoking Behaviour Among People Living with HIV and AIDS: A Sub-Group Comparison.

Recent advancements in the treatment of HIV have significantly improved long-term health outcomes and life expectancy among people living with HIV/AIDS. As such, healthcare professionals have begun to focus more seriously on health protective behaviour changes that could further reduce mortality including smoking and tobacco dependence. A cross-sectional survey was conducted with 438 people living with HIV/AIDS (PLWHA) attending a clinic in an urban area to measure current smoking behaviours. After removing missing data, the final sample was 402 service users. Among those surveyed 141 (35.0%) were current smokers with 35 (8.2%) ex-smokers. Rates among key sub-groups were higher. Comparatively, smoking prevalence was very low among African migrants (8, 7.2%), particularly African born women (1, 1.3%). In line with international studies, smoking prevalence among PLWHA was nearly double that of the general population. These findings come at a time when smoking in the general population in Ireland is at an all-time low, making the need to address tobacco dependence among PLWHA all the more vital.

Immunological efficacy of pneumococcal vaccine strategies in HIV-infected adults: a randomized clinical trial.

The aim of this study was to compare the immunologic response to a prime-boost immunization strategy combining the 13-valent conjugate pneumococcal vaccine (PCV13) with the 23-valent polysaccharide pneumococcal vaccine (PPSV23) versus the PPSV23 alone in HIV-infected adults. HIV-infected adults were randomized to receive PCV13 at week 0 followed by PPSV23 at week 4 (n = 31, prime-boost group) or PPSV23 alone at week 4 (n = 33, PPSV23-alone group). Serotype specific IgG geometric mean concentration (GMC) and functional oposonophagocytic (OPA) geometric mean titer (GMT) were compared for 12 pneumococcal serotypes shared by both vaccines at week 8 and week 28. The prime-boost vaccine group were more likely to achieve a ≥2-fold increase in IgG GMC and a GMC >1 ug/ml at week 8 (odds ratio (OR) 2.00, 95% confidence interval (CI) 1.46-2.74, p < 0.01) and week 28 (OR 1.95, 95% CI 1.40-2.70, p < 0.01). Similarly, the prime-boost vaccine group were more likely to achieve a ≥4-fold increase in GMT at week 8 (OR 1.71, 95% CI 1.22-2.39, p < 0.01) and week 28 (OR 1.6, 95% CI 1.15-2.3, p < 0.01). This study adds to evidence supporting current pneumococcal vaccination recommendations combining the conjugate and polysaccharide pneumococcal vaccines in the United States and Europe for HIV-infected individuals.

HPV vaccine acceptability in HIV-infected and HIV negative men who have sex with men (MSM) in Ireland.

Background Men who have sex with men (MSM), particularly HIV-infected MSM are disproportionately affected by HPV infection and associated disease. The HPV vaccine has potential to greatly reduce the burden of HPV-associated disease including anal cancer in MSM. The efficacy of the HPV vaccine is dependent on high levels of vaccine uptake. The aim of this study was to examine HPV vaccine acceptability and factors influencing vaccine acceptability in MSM in Ireland. Methods A self-administered survey was distributed to HIV-infected and HIV negative MSM examining HPV vaccine acceptability and factors associated with vaccine acceptability. Logistic regression was used to identify key variables and predictors of HPV vaccine acceptability. Results 302 MSM participated in the study. Acceptability of HPV vaccine was 31% (unconditional), 51% (conditional on stated efficacy and a cost of €300), 65% (conditional on stated efficacy and a cost of €100) and 78% (conditional on stated efficacy and no cost). Cost was negatively associated with HPV vaccine acceptability (p<0.01) while knowledge of HPV vaccine efficacy was significantly associated with vaccine acceptability, even in the context of associated cost (p<0.01). Conclusions Acceptability of HPV vaccine in MSM in Ireland is high based on no cost vaccine and on stated vaccine efficacy (78%). Cost is negatively associated with vaccine acceptability. Understanding levels of knowledge of HPV infection, HPV associated disease and attitudes toward HPV vaccination are important as they will contribute to HPV vaccine acceptability among MSM and will help guide effective preventive programs.

Clinical and epidemiological characteristics of patients with early syphilis from three academic centres in Poland, Germany and Ireland: initial findings from the POETS study.

OBJECTIVES: Syphilis recognition in HIV-positive patients has important implications. Initial data from this study, established in June 2012 to better understand the natural history of syphilis and treatment response, examine the characteristics of patients including sexual behaviour, rates of concurrent sexually transmitted infections (STI) and type of treatment given. METHODS: Patients were recruited from Ireland, Poland and Germany. Data gathered included demographics, method of syphilis acquisition, stage of syphilis infection, HIV status, nadir and current CD4 counts and HIV viral suppression rates. Data were then subanalysed into HIV-positive and HIV-negative groups. RESULTS: Of 175 patients recruited, 68% were HIV-positive and 86.3% were men who have sex with men. Most HIV-positive patients presented with secondary syphilis (55.7% vs 13.2%) (p=0.0001) while the majority of HIV-negative patients had primary syphilis noted at the time of recruitment (47.2% vs18.9%, p=0.0002). Approximately half of all patients had a HIV RNA viral load <40 copies/mL (55%). Previous syphilis infection occurred more frequently in HIV-positive than HIV-negative patients (p=0.0001). Concurrent STIs at the time of syphilis diagnosis were found in 26.8%, of whom 31 (25.4%) were HIV-positive (p=0.64). HIV-positive patients received doxycycline more frequently than their HIV-negative counterparts (33.6% vs 1.9%, p=0.0001) while HIV-negative patients were treated with long-acting penicillin in 88.7% of cases vs 58% of HIV-positive patients (p=0.0002). CONCLUSIONS: A 40% rate of unsuppressed viraemia, high levels of STIs and varying treatment regimens represent a public health risk for Europe, suggesting the model of sexual healthcare delivery in HIV-positive patients requires further evaluation.

Circulating CD56dim natural killer cells and CD56+ T cells that produce interferon-γ or interleukin-10 are expanded in asymptomatic, E antigen-negative patients with persistent hepatitis B virus infection.

Infection with hepatitis B virus (HBV) can result in spontaneous resolution or chronic infection, which can remain asymptomatic or can progress to cirrhosis and/or hepatocellular carcinoma. The host immune response is thought to be a major determinant of the outcome of HBV infection and virus-specific cytotoxic T lymphocytes (CTL) can mediate immunity against the virus and cause liver pathology. Antigen-nonspecific innate lymphocytes may also contribute to HBV infection and liver disease, therefore, we examined the frequencies, phenotypes, cytolytic activities and cytokine profiles of circulating natural killer (NK) cells, CD1d-restricted invariant natural killer T (iNKT) cells and CD56(+) T cells in 102 asymptomatic HBV-infected patients and compared them with those in 66 uninfected control subjects. NK cells expressing low levels of CD56 (CD56(dim)) and CD56(+) T cells were significantly expanded in the circulation of HBV-infected patients compared with control subjects. CD1d expression and iNKT cell frequencies were similar in both groups. Despite these expansions, we did not detect augmented natural or cytokine-induced cytotoxicity in the HBV-infected subjects. All lymphocyte populations studied produced interferon-γ (IFN-γ) significantly more frequently when taken from HBV-infected patients compared with when taken from healthy controls. Additionally, NK cells from the patients more frequently produced interleukin-10. As our HBV-infected cohort consisted of asymptomatic patients with low viral loads, we propose that CD56(dim) NK cells and CD56(+) T cells control HBV infection by noncytolytic mechanisms.

Clinically significant extra-cardiac findings in asymptomatic HIV-positive men undergoing cardiac magnetic resonance imaging.

Increased research-based imaging has led to an increase in clinically significant extra-cardiac findings. HIV patients are at increased risk of having polypathology at a younger age; therefore, it may be hypothesised that they would have more incidental findings on imaging. We reviewed the magnetic resonance imaging results of 169 HIV-positive and 40 HIV-negative, clinically well volunteers undergoing cardiac magnetic resonance imaging scanning to assess the prevalence of subclinical cardiac pathology. This sub-study assessed the prevalence of clinically significant extra-cardiac findings. Associated risk factors were assessed and clinical follow-up and outcome were ascertained. Of the HIV-positive study group, 12/169 (7.1%) vs. 1/40 (2.5%) control patients had a clinically significant extra-cardiac finding which warranted further radiological or clinical intervention (p = 0.28). A total of three out of 169 (1.1%) were highly clinically significant findings. On logistic regression analysis, age was the only significant contributing factor (p = 0.049); no HIV-associated factors were found to be significant. The prevalence of clinically significant extra-cardiac findings of 7.1% in this HIV-positive cohort is comparable to the prevalence found in previous studies carried out on an older, sicker general population. This highlights the need for planning for unexpected outcomes and also the high rate of clinically significant findings in a seemingly well HIV-positive population.

Prevalence of human papillomavirus in men who have sex with men in the era of an effective vaccine; a call to act.

OBJECTIVES: The incidence of human papillomavirus (HPV)-associated anal cancer is increasing. Men who have sex with men (MSM), particularly those coinfected with HIV, are disproportionately affected. Documenting the molecular epidemiology of HPV infection is important in guiding policy makers in formulating universal and/or targeted vaccine guidelines. METHODS: A prospective cohort study was conducted. HIV-positive and HIV-negative MSM > 18 years old were invited to participate. Provider-performed anal swabs were collected and anal HPV infection was detected using consensus primer solution phase polymerase chain reaction (PCR) followed by type-specific PCR for high-risk (HR)-HPV types 16, 18 and 31. Between-group differences were analysed using χ(2) tests and Wilcoxon rank tests. RESULTS: One hundred and ninety-four MSM [mean (standard deviation (SD)) age 36 (10) years; 51% HIV-positive) were recruited. The median number of sexual contacts in the preceding 12 months was 4 (interquartile range 2-10). HIV-positive subjects had a mean (SD) CD4 count of 557 (217) cells/µL, and 84% were on highly active antiretroviral therapy (HAART). Thirty-one samples were B-globin negative and thus excluded from further analysis. A total of 113 subjects (69%) had detectable HPV DNA. Sixty-eight subjects (42%) had an HR-HPV type detected. HR HPV type 16 was detected in 44 samples (27%), HR-HPV type 18 in 26 samples (16%) and HR-HPV type 31 in 14 samples (23%). Twenty-eight subjects (17%) had more than one type of HR-HPV type detected. When HPV and HR-HPV were stratified by age, those > 35 years had a higher prevalence (P = 0.001 and P = 0.028, respectively). HIV-positive subjects were more likely than HIV-negative subjects to have any detectable HPV (77% vs. 61%, respectively; P = 0.04), to have HR-HPV type 18 or 31 (P = 0.05 and P = 0.006, respectively) and to be infected with more than one HR-HPV type (31% vs. 3%, respectively; P < 0.001). Within the HIV-positive group, the prevalence of HPV was higher in those not on HAART (P = 0.041), although it did not differ when stratified by CD4 count. CONCLUSIONS: The identified prevalence of anal HPV infection was high. Emerging patterns of HPV-related disease strengthen the call for universal vaccination of boys and girls with consideration of catch-up and targeted vaccination of high-risk groups such as MSM and those with HIV infection.

High prevalence of asymptomatic sexually transmitted infections in HIV-infected men who have sex with men: a stimulus to improve screening.

In Ireland the incidence of sexually transmitted infections (STIs) is steadily increasing while the number of new HIV-diagnoses in men who have sex with men has more than doubled in the past decade. This study investigated the prevalence of STIs in asymptomatic HIV-infected men who have sex with men (MSM) attending a clinic for routine HIV care in the largest HIV-centre in Ireland. Fifty HIV-infected MSM were included in the study (mean age [SD] 38years [9], 66% Irish). Sixteen per cent of HIV-infected MSM screened were diagnosed with a STI. Thirty-eight per cent reported always using condoms while 4% reported never using condoms, 46% used condoms inconsistently and 10% reported no sexual contacts in the preceding 12 months. Recognising the need to optimise STI screening, a pilot self-screening programme was subsequently introduced to our HIV clinic as a quality improvement initiative. Asymptomatic MSM attending for routine HIV care were invited to have an opportunistic STI screen either provider performed or by self-screening. Seventy-one patients were included in the pilot. Sixty-five (92%) opted for self-collected rectal swabs. Ten STIs were detected in eight patients. This study supports guidelines recommending routine screening for STIs in the care of HIV-infected patients and highlights opportunities to provide relevant screening and education interventions targeting unsafe sexual behaviours.

Use of the Alcohol Use Disorders Identification Test (AUDIT) to determine the prevalence of alcohol misuse among HIV-infected individuals.

The aim of the paper is to evaluate alcohol misuse among an inner city adult HIV clinic population with AUDIT (Alcohol Use Disorders Identification Test). A cross-sectional HIV outpatient clinic analysis between 28 February 2011 and 11 March 2011 was carried out. AUDIT, demographic and clinical data were collected. Univariate analysis was performed to look for the associations between variables. Backward stepwise multivariate analyses were performed on significant variables from the univariate analysis to assess for predictors of alcohol dependence. In total, 111 patients were included (60% uptake of clinic attendees); 66% were men and 26% were hepatitis C virus (HCV) co-infected. The median AUDIT score was 5 (within normal range). Thirty-four 'AUDIT positive' cases were identified: five (4.5%) indicated consumption of hazardous levels of alcohol; 21 (19%) indicated harmful levels of alcohol; and eight (7%) were likely alcohol dependent. Younger age (<40 years old) was significantly associated with AUDIT positivity (P = 0.006). On multivariate analysis younger age (P = 0.045, odds ratio 13.8) and lower level of education (P = 0.006, odds ratio 6.7) were predictive of scores indicative of alcohol dependence (AUDIT ≥20). In conclusion, younger age and lower educational levels were associated with scores consistent with alcohol dependence. AUDIT was well tolerated and easy to administer in this outpatient HIV clinic population.

Long-term neurological follow-up of HIV-positive patients diagnosed with syphilis.

No cerebrospinal fluid (CSF) abnormalities are found in HIV-positive patients in long-term follow-up after standard syphilis treatment. Syphilis has been reported to have immunological effects on HIV infection and HIV is known to modulate both the manifestations of syphilis and the serological response to therapy. HIV-positive patients who had been diagnosed with and treated for syphilis prior to 2007 were identified. Patients were consented for lumbar puncture. Serum HIV viral load, CD4 count and CSF were recorded. Thirty-five patients with previously diagnosed and treated syphilis underwent lumbar puncture. Thirty-four patients had a normal neurological exam. Only one patient had an abnormal mean white cell count (10.7 cells per high-power field). The finding that those with previously diagnosed syphilis had normal CSF and clinical findings is reassuring and supports the practice of using standard syphilis therapy in HIV-positive patients.

Soluble signals from mechanically disrupted lung tissue induce lung-related gene expression in bone marrow-derived cells in vitro.

Differentiation of bone marrow (BM)-derived cells into lung epithelial cells has been reported in vivo in animal models of lung injury. Most studies have used cytokeratin or surfactant protein expression as markers of BM-to-lung cell differentiation. However, concerns as to whether fusion rather than differentiation is the mechanism involved, verification of BM-derived lung cells, and inconsistent findings with different injury models mean that the differentiation potential of BM-derived cells remains unclear. We used a co-culture system, in which BM cell-lung cell fusion is prevented, to examine the ability of 'damage' signals released from mechanically disrupted lung tissue to induce expression of lung-related genes in BM-derived cells in vitro. BM-derived hematopoietic progenitor cells (BM-HPCs) were co-cultured with mechanically disrupted lung tissue. Liver tissue and medium-only co-cultures were also studied as controls. BM-HPCs differentiated into myeloid cells in culture. BM-HPCs proliferated in response to soluble lung damage signals and differentiated into suspension and adherent populations with dendritic cell and Langerhans cell-like characteristics, respectively. Cytokeratins 7 and 18 and surfactant protein B mRNA expression was either induced or upregulated in the dendritic cell (DC)-like population in lung co-cultures. In contrast, these genes were not induced or up-regulated in medium only or liver co-cultures. Up-regulation of E-cadherin mRNA and protein expression also occurred in response to lung damage signals. These results confirm that signals released from damaged lung tissue can induce lung-related gene expression in BM-derived DC-like cells in the absence of cell fusion.

CFTR gene transfer to lung epithelium--on the trail of a target cell.

Cystic fibrosis (CF) is a lethal inherited disease that afflicts up to 1 in 2,500 people in the western world. Since 1989, when mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were identified as responsible for the disease, intense effort has been applied to the development of replacement gene therapy strategies to cure CF. Problems with basic gene delivery techniques along with limited knowledge of the pathogenesis of CF have hindered progress so far. However, recent insights into the expression patterns and functions of CFTR in developing and adult lungs are now advancing our understanding of this disease. It is becoming apparent that progress in gene delivery to cure CF may be best served by identification of a target cell(s) around which gene transfer strategies can be specifically tailored to most closely reproduce the effects of normal CFTR expression. In fact, accurate restoration of endogenous expression patterns may be crucial, not only for disease reversal, but also to avoid potentially deleterious effects of inappropriate expression. This approach is in turn confounded however, by ill-defined stem and progenitor cell pathways within the lung epithelium. Nonetheless, studies to date suggest that these pathways are relatively plastic and may respond differently during homeostasis compared with repair following injury. It may therefore be feasible to target the lung epithelium in a non-cell specific manner and allow endogenous differentiation pathways to subsequently establish correct CFTR distribution patterns. In this review, emerging information on CFTR expression and function in developing and adult lungs is discussed in the context of putative stem cell populations and their potential for current gene delivery approaches.

Immunologic assessment of a cluster of asymptomatic HTLV-I-infected individuals in New Orleans.

PURPOSE: Although clusters of individuals infected with the human T-cell lymphotrophic virus type I (HTLV-I) have been identified in the United States, no systematic evaluation of the immunologic status of these persons has been reported. We therefore studied a group of 11 HTLV-I-infected former intravenous drug abusers who were long-term participants in a methadone maintenance program in New Orleans, Louisiana, to determine the effects of HTLV-I and chronic opiate use on immunity. PATIENTS AND METHODS: Mitogenic responses and results of serologic studies, cell phenotype analysis, and cytotoxicity assays were compared to those in two other HTLV-I seronegative groups: a similar group of 17 methadone users and 15 healthy age-, sex-, and race-matched control subjects. All study participants were seronegative for human immunodeficiency virus type 1. RESULTS: Percentages and numbers of total T lymphocytes (CD2+,CD3+), T-suppressor/cytotoxic lymphocytes (CD8+), cytotoxic lymphocytes (Leu7+, Leu11+, NKH-1+) and B lymphocytes (B4+) were similar among the study groups. Although percentages and numbers of total T-helper lymphocytes (CD4+) were also similar among the groups, HTLV-I-infected subjects had higher percentages and proportions of helper/inducer cells (CD4:4B4+) than did HTLV-I seronegative methadone users. Both methadone using groups had decreased percentages and numbers of suppressor/inducer T lymphocytes (CD4:2H4+). Major histocompatibility complex unrestricted T-cell cytotoxicity (lectin-dependent cellular cytotoxicity), natural killer cell function, and mitogenic responses to the T-cell mitogen phytohemagglutin were similar among the three study groups. Pokeweed mitogen responses were severely depressed in the HTLV-I-infected population. CONCLUSIONS: We conclude that HTLV-I infection is associated with abnormalities in T-cell-dependent B-cell proliferative responses. Furthermore, both long-term methadone use and HTLV-I infection are associated with abnormalities in the distribution of CD4+ cell subpopulations. The increase in the helper/inducer and T-cell cell populations and decrease in the pokeweed mitogenic response noted in HTLV-I-infected subjects appear to be markers for infection with this retrovirus.

A mitochondrial chemiluminescence evoked by a novel mixed copper(II)-cyanide complex/acetaldehyde cyanohydrin chelate: a kinetic analysis suggesting a role for membrane-bound vicinal sulfhydryls.

Cyanide added to mitochondria in the presence of copper and acetaldehyde evokes a chemiluminescence which follows series pseudo-first-order kinetics: (formula; see text) An evaluation of the effects of protein (mitochondria), copper, cyanide, acetaldehyde, and oxygen on the kinetic parameters shows that k1 is influenced by protein, cyanide (at low concentrations), and oxygen while k2 is influenced by cyanide, acetaldehyde (at low, less than 11.9 mM, and high, greater than 35.6 mM, concentrations), and oxygen. The integral light increases linearly with the square root of total copper(II) and with the square of the total acetaldehyde. The sustained emissions appear to reflect an initial oxidative event mediated by a novel mixed copper(II)-cyanide complex/acetaldehyde cyanohydrin chelate. Cu(I) formed by the reduction of Cu(II), probably by mitochondrial vicinal sulfhydryls, reacts with dioxygen to form an O2-copper complex which reacts with acetaldehyde to form the acetyl-1-hydroxyhydroperoxyl radical. This radical disproportionates by the Russell mechanism to generate electronically excited singlet and triplet carbonyl functions and singlet oxygen species whose emissive relaxations to the ground state display as the observed chemiluminescence. The kinetic evidence indicates that there are two Cu(I)-oxygen cyanide complexes transferring O2- to acetaldehyde. This evidence addresses the mechanisms of autoxidation of low-molecular-weight Cu(I) complexes with dioxygen. A suggested role for the involvement of vicinal sulfhydryl groups in the reactions is shown, kinetically, by the influence of copper and acetaldehyde on the integral light.

Nucleotide modification, a radical mechanism of oxidative toxicity.

Reduced nicotinamide adenine dinucleotide (NADH) reacts rapidly with hypochlorite to form five major products separable by reversed-phase high-pressure liquid chromatography (HPLC). The involvement of a free radical mechanism is indicated by an electron spin resonance (ESR) signal as well as unusual pH changes and the uptake of oxygen. The present work suggests that hypochlorite may contribute to the cytotoxic activity of phagocytic cells through its ability to modify important cellular components by means of radicals generated by its reaction with reduced pyridine nucleotides.