a survey of healthcare providers across the WHO European region

FundingThis work was supported by European AIDS Clinical Society.Women living with HIV are reaching older age and experiencing menopause and age-related comorbidities. Data suggest that women living with HIV experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. However, there are no guidelines on the screening for and management of age-related comorbidities and events in women living with HIV. Moreover, little is known about provision of care to this population across Europe. We surveyed 121 HIV healthcare providers in 25 World Health Organization European countries to ascertain screening practices for, and management of, menopause, psychosocial and sexual well-being and age-related comorbidities in women with HIV. Most respondents screened for diabetes, cardiovascular disease (CVD) risk factors and poor mental health at least annually. Low bone mineral density (BMD) was regularly checked but less than once a year. Fewer regularly screened for sexual well-being and intimate partner violence. Menstrual pattern and menopausal symptoms in women aged 45–54 were assessed by 67% and 59% of respondents. 44% stated that they were not confident assessing menopausal status and/or symptoms. CVD, diabetes, low BMD and poor mental health were managed mainly within HIV clinics, whereas menopause care was mainly provided by gynaecology or primary care. Most respondents stated a need for HIV and menopause guidelines. In conclusion, we found that whilst metabolic risk factors and poor mental health are regularly screened for, psychosocial and sexual well-being and menopausal symptoms could be improved. This highlights the need for international recommendations and clinician training to ensure the health of this population.publishersversionepub_ahead_of_prin

Psychological and Behavioural Within-participant Predictors of Adherence to Oral HIV Pre-Exposure Prophylaxis (PrEP)

Oral PrEP's effectiveness relies on adequate adherence during periods of substantial HIV risk. Since most PrEP users will miss doses, understanding predictors within participants can help to explain adherence. We used a cross-sectional, within-participant design with 67 gay, bisexual, and other men who have sex with men taking PrEP daily. Using a questionnaire, informed by the Information Motivation Behavioral Skills Model, participants were asked about an adherent and a non-adherent episode. PrEP non-adherence was associated with non-normality of the day (p < .001), being out of the home (p < .001), weekend days (p = .01), having company (p = .02), using substances (p = .2), not using reminders (p = .03), lower PrEP information (p = .04), lower behavioural skills (p < .001) and less positive affect (p = .002). PrEP adherence assessment could focus on situational variations, supporting the construction of alternative strategies to facilitate adherence in these situations

Pharmacokinetics (PK) of ethinylestradiol/levonorgestrel co-administered with atazanavir/cobicistat.

Background and objectives: Access to safe and reliable contraception in the context of ARVs is essential. This study aimed to investigate the steady-state pharmacokinetics (PK) of ethinylestradiol/levonorgestrel (EE/LNG) 30/150 μg (Microgynon®) and atazanavir/cobicistat (ATV/COBI) 300/150 mg (Evotaz®), co-administered in HIV negative female volunteers, and assess its safety and tolerability. Methods: This phase 1, open label, 57-day, cross over, PK study randomized participants to one of two groups: (i) group 1 received EE/LNG alone on days 1-21, EE/LNG (21 days) + ATV/COBI (14 days) in the co-administration phase (days 22-42) and ATV/COBI alone on days 43-56; (ii) group 2 followed the same sequence but started with ATV/COBI and concluding with EE/LNG. Each group underwent intensive PK sampling on days 14, 35, and 56. EE/LNG and ATV/COBI concentrations were measured using validated LC-MS/MS methods. Results: Of 14 healthy female volunteers screened, 11 attended baseline and six completed all PK phases (five withdrew secondary to side effects). Paired data were available for analysis in six subjects for EE/LNG and eight for ATV/COBI. Geometric mean ratios (GMR, with versus without ATV/COBI) and 90% confidence intervals (CI) for LNG Cmax, AUC0-24, C24 were 0.83 (0.68-1.02), 0.92 (0.71-1.18), 1.01 (0.73-1.38). GMR and 90% CI for EE Cmax, AUC0-24, C24 were 1.05 (0.92-1.19), 1.01 (0.83-1.22), 0.75 (0.60-0.93). No grade 3 or 4 adverse events or laboratory abnormalities were observed in the women who completed the study. Conclusions: Our findings showed no significant changes in LNG concentrations and a 25% decrease in EE C24 when EE/LNG was co-administered with ATV/COBI

A qualitative study exploring the social and environmental context of recently acquired HIV infection among men who have sex with men in South-East England.

OBJECTIVES: A key UK public health priority is to reduce HIV incidence among gay and other men who have sex with men (MSM). This study aimed to explore the social and environmental context in which new HIV infections occurred among MSM in London and Brighton in 2015. DESIGN: A qualitative descriptive study, comprising in-depth interviews, was carried out as a substudy to the UK Register of HIV Seroconverters cohort: an observational cohort of individuals whose date of HIV seroconversion was well estimated. An inductive thematic analysis was conducted in NVivo, guided by a socio-ecological framework. SETTING: Participants were recruited from six HIV clinics in London and Brighton. Fieldwork was conducted between January and April 2015. PARTICIPANTS: All MSM eligible for the UK Register Seroconverter cohort (an HIV-positive antibody test result within 12 months of their last documented HIV-negative test or other laboratory evidence of HIV seroconversion) diagnosed within the past 12 months and aged ≥18 were eligible for the qualitative substudy. 21 MSM participated, aged 22-61 years and predominantly white. RESULTS: A complex interplay of factors, operating at different levels, influenced risk behaviours and HIV acquisition. Participants saw risk as multi-factorial, but the relative importance of factors varied for each person. Individual psycho-social factors, including personal history, recent life stressors and mental health, enhanced vulnerability towards higher risk situations, while features of the social environment, such as chemsex and social media, and prevalent community beliefs regarding treatment and HIV normalisation, encouraged risk taking. CONCLUSIONS: Recently acquired HIV infection among MSM reflects a complex web of factors operating at different levels. These findings point to the need for multi-level interventions to reduce the risk of HIV acquisition among high-risk MSM in the UK and similar settings

Comorbidities and menopause assessment in women living with HIV: a survey of healthcare providers across the WHO European region

Women living with HIV are reaching older age and experiencing menopause and age-related comorbidities. Data suggest that women living with HIV experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. However, there are no guidelines on the screening for and management of age-related comorbidities and events in women living with HIV. Moreover, little is known about provision of care to this population across Europe. We surveyed 121 HIV healthcare providers in 25 World Health Organization European countries to ascertain screening practices for, and management of, menopause, psychosocial and sexual well-being and age-related comorbidities in women with HIV. Most respondents screened for diabetes, cardiovascular disease (CVD) risk factors and poor mental health at least annually. Low bone mineral density (BMD) was regularly checked but less than once a year. Fewer regularly screened for sexual well-being and intimate partner violence. Menstrual pattern and menopausal symptoms in women aged 45-54 were assessed by 67% and 59% of respondents. 44% stated that they were not confident assessing menopausal status and/or symptoms. CVD, diabetes, low BMD and poor mental health were managed mainly within HIV clinics, whereas menopause care was mainly provided by gynaecology or primary care. Most respondents stated a need for HIV and menopause guidelines. In conclusion, we found that whilst metabolic risk factors and poor mental health are regularly screened for, psychosocial and sexual well-being and menopausal symptoms could be improved. This highlights the need for international recommendations and clinician training to ensure the health of this population

Predictors of starting and stopping chemsex in men who have sex with men in England: findings from the AURAH2 prospective study

BACKGROUND: Chemsex (the use of psychoactive drugs in sexual contexts) has been associated with HIV acquisition and other STIs, so there is benefit in identifying those most likely to start chemsex to offer risk reduction interventions such as pre-exposure prophylaxis (PrEP). To date, there have been no data from a longitudinal study analysing factors most associated with starting and stopping chemsex. METHODS: The prospective cohort study, Attitudes to and Understanding Risk of Acquisition of HIV over Time (AURAH2), collected 4 monthly and annual online questionnaire data from men who have sex with men (MSM) from 2015 to 2018. We investigate the association of sociodemographic factors, sexual behaviours and drug use with starting and stopping chemsex among 622 men who completed at least one follow-up questionnaire. Poisson models with generalised estimating equations were used to produce risk ratios (RRs) accounting for multiple starting or stopping episodes from the same individual. Multivariable analysis was adjusted for age group, ethnicity, sexual identity and university education. FINDINGS: In the multivariable analysis, the under 40 age group was significantly more likely to start chemsex by the next assessment (RR 1.79, 95% CI 1.12 to 2.86). Other factors which showed significant association with starting chemsex were unemployment (RR 2.10, 95% CI 1.02 to 4.35), smoking (RR 2.49, 95% CI 1.63 to 3.79), recent condomless sex (CLS), recent STI and postexposure prophylaxis (PEP) use in the past year (RR 2.10, 95% CI 1.33 to 3.30). Age over 40 (RR 0.71, 95% CI 0.51 to 0.99), CLS, and use of PEP (RR 0.64, 95% CI 0.47 to 0.86) and PrEP (RR 0.47, 95% CI 0.29 to 0.78) were associated with lower likelihood of stopping chemsex by the next assessment. INTERPRETATION: Knowledge of these results allows us to identify men most likely to start chemsex, thus providing an opportunity for sexual health services to intervene with a package of risk mitigation measures, especially PrEP use

Impact of antiretroviral therapy in primary HIV infection on natural killer cell function and the association with viral rebound and HIV DNA following treatment interruption

Natural Killer (NK) cells play a key role in controlling HIV replication, with potential downstream impact on the size of the HIV reservoir and likelihood of viral rebound after antiretroviral therapy (ART) cessation. It is therefore important to understand how primary HIV infection (PHI) disrupts NK cell function, and how these functions are restored by early ART. We examined the impact of commencing ART during PHI on phenotypic and functional NK cell markers at treatment initiation (baseline), 3 months, 1 year, and 2 years in seven well-characterised participants in comparison to HIV seronegative volunteers. We then examined how those NK cell properties differentially impacted by ART related to time to viral rebound and HIV DNA levels in 44 individuals from the SPARTAC trial who stopped ART after 48 weeks treatment, started during PHI. NK cell markers that were significantly different between the seven people with HIV (PWH) treated for 2 years and HIV uninfected individuals included NKG2C levels in CD56dim NK cells, Tim-3 expression in CD56bright NK cells, IFN-γ expressed by CD56dim NK cells after IL-12/IL-18 stimulation and the fraction of Eomes-/T-bet+ in CD56dim and CD56bright NK cells. When exploring time to viral rebound after stopping ART among the 44 SPARTAC participants, no single NK phenotypic marker correlated with control. Higher levels of IL-12/IL-18 mediated NK cell degranulation at baseline were associated with longer times to viral rebound after treatment interruption (P=0.028). Additionally, we found higher fractions of CD56dim NK cells in individuals with lower levels of HIV DNA (P=0.048). NKG2A and NKp30 levels in CD56neg NK cells were higher in patients with lower HIV DNA levels (p=0.00174, r=-0.49 and p=0.03, r= -0.327, respectively) while CD27 levels were higher in those with higher levels of HIV DNA (p=0.026). These data show NK cell functions are heterogeneously impacted by HIV infection with a mixed picture of resolution on ART, and that while NK cells may affect HIV DNA levels and time to viral rebound, no single NK cell marker defined delayed viral rebound

No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach

Objective HIV-remission strategies including kick-and-kill could induce viral transcription and immune-activation in the central nervous system, potentially causing neuronal injury. We investigated the impact of kick-and-kill on plasma neurofilament light (NfL), a marker of neuro-axonal injury, in RIVER trial participants commencing antiretroviral treatment (ART) during primary infection and randomly allocated to ART-alone or kick-and-kill (ART + vaccination + vorinostat (ART + V + V)). Design Sub-study measuring serial plasma NfL concentrations. Methods Plasma NfL (using Simoa digital immunoassay), plasma HIV-1 RNA (using single-copy assay) and total HIV-1 DNA (using quantitative polymerase chain reaction in peripheral CD4+ T-cells) were measured at randomisation (following ≥22 weeks ART), week 12 (on final intervention day in ART + V + V) and week 18 post-randomisation. HIV-specific T-cells were quantified by intracellular cytokine staining at randomisation and week 12. Differences in plasma NfL longitudinally and by study arm were analysed using mixed models and Student's t-test. Associations with plasma NfL were assessed using linear regression and rank statistics. Results At randomisation, 58 male participants had median age 32 years and CD4+ count 696 cells/μL. No significant difference in plasma NfL was seen longitudinally and by study arm, with median plasma NfL (pg/mL) in ART-only vs ART + V + V: 7.4 vs 6.4, p = 0.16 (randomisation), 8.0 vs 6.9, p = 0.22 (week 12) and 7.1 vs 6.8, p = 0.74 (week 18). Plasma NfL did not significantly correlate with plasma HIV-1 RNA and total HIV-1 DNA concentration in peripheral CD4+ T-cells at any timepoint. While higher HIV-specific T-cell responses were seen at week 12 in ART + V + V, there were no significant correlations with plasma NfL. In multivariate analysis, higher plasma NfL was associated with older age, higher CD8+ count and lower body mass index. Conclusions Despite evidence of vaccine-induced HIV-specific T-cell responses, we observed no evidence of increased neuro-axonal injury using plasma NfL as a biomarker up to 18 weeks following kick-and-kill, compared with ART-only

CD32-Expressing CD4 T Cells Are Phenotypically Diverse and Can Contain Proviral HIV DNA.

Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low, CD32+CD14+, and CD32high). Of note, CD4 negative enrichment kits remove the majority of CD4+CD32+ T cells, potentially skewing subsequent analyses if used. CD32high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαβ, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3+CD4+CD32+ phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32+ T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations

CD32-Expressing CD4 T Cells Are Phenotypically Diverse and Can Contain Proviral HIV DNA.

Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low, CD32+CD14+, and CD32high). Of note, CD4 negative enrichment kits remove the majority of CD4+CD32+ T cells, potentially skewing subsequent analyses if used. CD32high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαβ, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3+CD4+CD32+ phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32+ T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations