"A fog that impacts everything": a qualitative study of health-related quality of life in people living with HIV who have cognitive impairment.

BACKGROUND: Cognitive impairment (CI) in people living with HIV (PLWH) is an important health concern in the context of an ageing HIV population. Impacting 14-28% of PLWH, CI is associated with lower health-related quality of life (HRQoL), however, evaluation of the illness-specific factors comprising HRQoL in PLWH with CI have not been assessed. OBJECTIVE: We sought to contribute evidence toward an understanding of HRQoL and identify domains of HRQoL in PLWH with CI. METHODS: Qualitative interviews with 25 PLWH with objective CI related to HIV disease were conducted with participants attending HIV clinics in the UK. Clinically significant CI was defined based on The European AIDS Clinical Society guidelines, requiring: (i) subjective reporting of cognitive symptoms; (ii) symptoms to be related to HIV (e.g. potentially confounding non-HIV related conditions have been excluded or are being optimally managed) and; (iii) formal neuropsychological assessment confirming CI. Median age was 56 years (range 35-80); 18 participants were men (72%); 11 (44%) were white British and 8 (32%) were Black African; 14 (56%) were men that have sex with men and 10 (40%) were heterosexual; median number of years living with HIV was 17 (range 1-34); and all participants were on combination antiretroviral therapy. Analyses employed techniques from grounded theory, underpinned by an inductive, collaborative team-based approach. RESULTS: Findings revealed seven interrelated domains comprising HRQoL experiences were identified: Physical function, Cognition, Social connectedness, Physical and mental health, Stigma, Self-concept, and Control and acceptance, and each was defined by specific descriptive components. CONCLUSION: This study provides valuable insights on the factors that drive HRQoL in PLWH with CI and contribute to a body of evidence which provides targets for the development of targeted interventions to maintain or improve quality of life.

Impact of interrupting antiretroviral therapy started during primary HIV-1 infection on plasma neurofilament light chain protein, a marker of neuronal injury: The SPARTAC trial.

Objective: Antiretroviral therapy (ART)-conferred suppression of HIV replication limits neuronal injury and inflammation. ART interruption tests efficacy in HIV cure trials and viral rebound after ART interruption may induce neuronal injury. We investigated the impact of protocol-defined ART interruption, commenced during primary HIV-1 infection (PHI) on a biomarker of neuro-axonal injury (neurofilament light protein (NfL)), and its associations with inflammation (D-dimer and interleukin-6 (IL-6)) and HIV-1 reservoir size (total HIV-1 DNA). Design: Retrospective study measuring plasma NfL in 83 participants enrolled in SPARTAC randomised to receive 48-weeks ART initiated during PHI, followed by ART interruption. Methods: NfL (Simoa immunoassay, Quanterix™) was measured before ART, after 48 weeks on ART, and 12 weeks after stopping ART. Plasma D-dimer and IL-6, and total HIV-1 DNA in peripheral CD4+ T-cells results were available in a subset of participants. Longitudinal NfL changes were assessed using mixed models, and associations with clinical and laboratory parameters using linear regression. Results: NfL decreased following 48-weeks ART (geometric mean 6.9 to 5.8 pg/mL, p = 0.006) with no further significant change up to 12-weeks post-stopping ART despite viral rebound in the majority of participants (median 1.7 to 3.9 plasma HIV-1 RNA log10 copies/mL). Higher baseline NfL was independently associated with higher plasma HIV-1 RNA (p = 0.020) and older age (p = 0.002). While NfL was positively associated with D-dimer (n = 48; p = 0.002), there was no significant association with IL-6 (n = 48) or total HIV-1 DNA (n = 51). Conclusions: Using plasma NfL as a surrogate marker, a decrease in neuro-axonal injury was observed in a cohort of participants following ART initiation during PHI, with no evidence of neuro-axonal injury rebound following ART interruption for up to 12 weeks, despite viral rebound in the majority of participants.

Health-Related Quality of Life in People Living With HIV With Cognitive Symptoms: Assessing Relevant Domains and Associations.

This study aimed to validate and assess a comprehensive set of illness-specific health-related quality of life (HRQL) domains in people living with HIV (PLWH) with cognitive symptoms. One hundred and three HIV patients with cognitive symptoms (n = 93 male, 90.3%) were identified from two UK HIV clinics and complete a series of validated scales measuring seven HRQL domains identified as important to HRQL by PLWH with cognitive impairment. These included: physical functioning, cognition, social connectedness, self-concept, HIV stigma, acceptance of and perceived control over cognitive health, and physical and mental health and wellbeing. Exploratory factor analysis confirmed that domain total scores loaded onto one main factor, representing HRQL. Scale cut-off scores revealed a significant proportion of patients scored outside the normal range on single domains (between 26.2% and 79.6%), and many patients on multiple domains (40.8% on 4 or more domains). We found evidence of poor HRQL across domains in the majority of PLWH with cognitive symptoms and identified domains driving these experiences. This provides targets for intervention development and clinical action to maintain or improve HRQL in PLWH with cognitive symptoms or impairment.

Sexual and reproductive health in HIV-positive adolescents.

PURPOSE OF REVIEW: This review aims to summarize data in the last 18 months on the sexual and reproductive health of perinatally and horizontally infected adolescents and young people living with HIV (age 13-25 years) and to highlight some key issues faced by this group of adolescents as they reach puberty and sexual debut. RECENT FINDINGS: Adolescents and young people living with HIV are a growing cohort worldwide and a significant proportion engage in high-risk sexual activity, pose risk of onward HIV transmission, yet have poor access to sexual and reproductive health (SRH) services and lack the knowledge and support to advocate for their needs. SUMMARY: Providing adolescents living with HIV with access to SRH services is essential. Integrated HIV and SRH services and peer support models work well. HIV healthcare providers should educate all young people around disclosure, treatment as prevention and adherence, options for preexposure and postexposure prophylaxis and contraception, and support them to advocate for their own sexual health.

Implementation and outcomes of a new safeguarding pathway for vulnerable adults presenting to sexual health services.

Adult safeguarding is the process of protecting vulnerable adults from harm or exploitation. In 2014, our sexual health clinic implemented a new adult safeguarding pathway, including an adult safeguarding proforma, an electronic database and a monthly adult safeguarding meeting. We conducted a retrospective case note review of patients entered onto the safeguarding database and found that greater numbers of adults were identified as vulnerable following the introduction of this pathway. Many required referral for onward support, highlighting the importance of robust safeguarding procedures in a sexual health setting.

Identification and characteristics of vulnerable adults attending an inner city sexual health service.

Adult safeguarding is the function of protecting vulnerable adults from abuse or neglect. The 2012 Department of Health Draft Care and Support Bill highlighted adult safeguarding as a key government priority and stated that a clear framework is required for organisations dealing with 'adults at risk'. Adults at risk present to sexual health services but no formal guidance currently exists to aid their identification and management in this setting. We conducted a retrospective case note review which identified that vulnerable adults attend our service. They may display recognised risk factors, awareness of which is likely to facilitate identification and assessment of this group and aid appropriate onward referral.

The effect of short-course antiretroviral therapy initiated in primary HIV-1 infection on interleukin-6 and D-dimer levels.

OBJECTIVE: Interruption of antiretroviral therapy (ART) in chronic HIV disease is associated with increased mortality, predicted by elevations in interleukin-6 (IL-6) and D-dimer. The effect of ART interruption in primary HIV-1 infection on these biomarkers is unknown. METHODS: Plasma samples from 200 HIV seroconverters enrolled in the Short Pulse Anti-Retroviral Therapy At HIV Seroconversion trial of deferred ART (standard of care) - 12 or 48 week ART (ART12 or ART48, respectively) - were analysed for IL-6 and D-dimer at weeks 0, 12, 16, 48, 52, 60 and 108 after randomization. Changes in log10 levels from weeks 0 to 12 were analysed using linear regression, as were changes from baseline to 4 weeks after stopping ART. Areas under the biomarker-time curves (AUC) to week 108 were adjusted for baseline values, and compared across all arms. RESULTS: Median (inter-quartile range) baseline IL-6 and D-dimer were 1.45 (0.88, 2.41) pg/ml and 0.34 (0.20, 0.50) mg/l, respectively. At week 12, D-dimer levels were significantly lower among treated compared to untreated individuals (P < 0.001), whereas IL-6 levels were similar (P = 0.23). Within 4 weeks from stopping ART, IL-6 and D-dimer levels rose by 22 and 18%, reaching pre-ART levels. Over 108-week follow-up, there was no difference between arms in IL-6 AUC (P = 0.53), but D-dimer AUC was significantly lower for ART12 and ART48 compared to standard of care (overall P = 0.008). CONCLUSION: Stopping ART in primary HIV-1 infection leads to inflammatory biomarker rebound to pre-treatment levels. However, over 108-week follow-up, we found no evidence that biomarker levels were higher for those interrupting ART, compared to those remaining ART-naïve, and D-dimer levels were significantly lower.

Immunological biomarkers predict HIV-1 viral rebound after treatment interruption.

Treatment of HIV-1 infection with antiretroviral therapy (ART) in the weeks following transmission may induce a state of 'post-treatment control' (PTC) in some patients, in whom viraemia remains undetectable when ART is stopped. Explaining PTC could help our understanding of the processes that maintain viral persistence. Here we show that immunological biomarkers can predict time to viral rebound after stopping ART by analysing data from a randomized study of primary HIV-1 infection incorporating a treatment interruption (TI) after 48 weeks of ART (the SPARTAC trial). T-cell exhaustion markers PD-1, Tim-3 and Lag-3 measured prior to ART strongly predict time to the return of viraemia. These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription. Our results may open new avenues for understanding the mechanisms underlying PTC, and eventually HIV-1 eradication.

Sexual health for travellers.

BACKGROUND: Sexually transmitted infections (STIs) are prevalent worldwide, yet a high proportion of international travellers engage in unprotected sex while overseas and may be at risk. OBJECTIVE: This article discusses some of the STIs that may be acquired abroad, and suggests key points of pretravel advice for the general practitioner to give the traveller before departure. DISCUSSION: Many travellers will visit their GP for pretravel vaccinations and advice. This presents an ideal opportunity for pretravel sexual health education and discussion on the risks and prevention of HIV and other STIs.

Interleukin-6 and D-dimer levels at seroconversion as predictors of HIV-1 disease progression.

OBJECTIVE: Inflammation and coagulation biomarkers interleukin (IL)-6 and D-dimer are predictive of all-cause mortality in chronic HIV-1 infection; however, their predictive value in individuals with recent infection has not been described. METHODS: SPARTAC was a randomized controlled trial comparing three strategies of intervention in primary HIV-1 infection [no therapy, 12-week or 48-week antiretroviral therapy (ART)]. Plasma IL-6 and D-dimer were measured in 200 participants from sites in Australia, Brazil, UK and Italy. We evaluated age, sex/HIV risk group, time since HIV-1 seroconversion, baseline HIV-RNA, CD4 cell count and BMI as possible predictors of IL-6 and D-dimer levels at seroconversion using multivariable linear regression. For participants remaining ART-naive, we evaluated whether baseline IL-6 and D-dimer levels independently predicted time to reaching CD4 cell count less than 350 cells/µl or initiating ART using multivariable Cox proportional hazards models. RESULTS: Median (interquartile range, IQR) baseline IL-6 and D-dimer levels were 1.45 (0.88-2.41) pg/ml and 0.34 (0.20-0.50) µg/l, respectively. Higher levels were associated with older age (P=0.008 and 0.004, respectively). Higher D-dimer levels were associated with higher HIV-RNA (P<0.001). For the 73 participants not initiating ART (median follow-up 225 weeks), of whom 48 reached the primary endpoint, higher baseline IL-6, but not D-dimer, was independently associated with a shorter time to primary endpoint [hazard ratio=1.38 per additional pg/ml, 95% confidence interval (CI) 1.09-1.75; P=0.007]. Other baseline predictors were older age (P=0.030), higher RNA (P=0.033) and lower CD4 cell count (P<0.001). CONCLUSION: IL-6 levels at time of HIV-1 seroconversion independently predict HIV-1 disease progression in patients with primary HIV-1 infection.

Increased levels of CD4 T-cell activation in individuals with CXCR4 using viruses in primary HIV-1 infection.

CXCR4-tropic (X4) HIV-1 variants are associated with faster disease progression compared with CCR5-tropic variants; however, the mechanism for this is unclear. We measured T-cell activation in 120 individuals with primary HIV-1 infection. X4-utilizing variants, determined genotypically, were present in 8.3% of the participants and were associated with higher levels of CD4 T-cell activation, even after adjusting for other prognostic factors. Increased CD4 T-cell activation may influence the more rapid immunological decline associated with X4 virus.

Plasma HIV viral rebound following protocol-indicated cessation of ART commenced in primary and chronic HIV infection.

OBJECTIVES: The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onward transmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIV infection (CHI). DESIGN: Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450) trials. METHODS: Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences in pVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression. Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimated through a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop. RESULTS: Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48-51) weeks after stopping ART. Four weeks after stopping treatment, although the proportion with pVL ≥ 400 copies/ml was similar (78% PHI versus 79% CHI), levels were 0.45 (95% CI 0.26-0.64) log(10) copies/ml lower for PHI versus CHI, and remained lower up to 48 weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir >500 cells/mm(3) was comparable to that experienced by PHI participants. CONCLUSIONS: Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increased transmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.