Adults with Perinatally Acquired HIV; Emerging Clinical Outcomes and Data Gaps.

In resourced settings, adults living with perinatally acquired HIV are approaching the 5th decade of life. Their clinical and psychological outcomes highlight potential future issues for the much larger number of adolescents growing up with HIV in sub-Saharan Africa, and will inform the development of appropriate healthcare services. Lifelong exposure to HIV, and increasingly to antiretroviral therapy throughout growth and development, contrasts with adults acquiring HIV in later life. This review describes the clinical outcomes for adults living with perinatally acquired HIV including post transition mortality, morbidity and retention in care. Rates of viral suppression, drug resistance and immunological function are explored. Co-morbidities focus on metabolic, cardiovascular, respiratory and bone health with quality-of-life data including neurocognitive functioning and mental health. Sexual and reproductive health including vaccine-preventable disease and the prevention of onward transmission to partners and infants are considered. The data gaps and future research questions to optimise outcomes for this emerging adult cohort are highlighted.

Hospitalisation rates for youth living with perinatally acquired HIV in England.

INTRODUCTION: Complex challenges amongst ageing cohorts of adolescents and adults living with perinatally acquired HIV (PaHIV) may impact on hospitalisation. We report hospitalisation rates and explored predictive factors for hospitalisation in adolescents and adults (10-35 years) living with PaHIV in England. METHOD: Retrospective observational cohort study over a three-year period 2016-2019. Data collected included cause and duration of hospitalisation, HIV viral load and CD4 lymphocyte count. The primary outcome was overnight hospitalisation. Patients exited at study end/ transfer of care (TOC)/ loss to follow up (LTFU) or death. Maternity/hospital admissions at other centres were excluded. Admission rates per 100 person-years (95% CI) were calculated by age group. Negative binomial regression with generalized estimating equations was performed. RESULTS: 255 patients contributed 689 person-years of follow up. 56% were female and 83% were of a Black, Black British, Caribbean or African ethnicity. At baseline, the median age was 19 years (IQR 16-22). 36 individuals experienced a total of 62 admissions which resulted in 558 overnight stays (median stay was 5 nights). One person died (lymphoma), six had TOC and one was LTFU by the end of the three-year study period. Crude incidence of admission for the whole cohort was 9.0 per 100 PY (6.9-11.6). The respective crude incidence rates were 1.5 PY (0.0-8.2) in those aged 10-14 years and 3.5 PY (1.5-7.0) in the 15-19-year-olds. In those aged 20-24 years it was 14.5 PY (10.1-20.2) and in those >25 years the crude incidence rate was 11.7 PY (6.9-18.5). Factors significantly associated with admission were a CD4 lymphocyte count <200 cells/uL, adjusted IRR 4.0 (1.8-8.8) and a history of a CDC-C diagnosis, adjusted IRR 2.9 (1.6-5.3). 89% admissions were HIV-related: 45% new/current CDC-C diagnoses, 76% due to infection. CONCLUSIONS: Hospitalisation rates were four-fold higher in adults (>20 years of age) compared to adolescents (10-19-year-olds). The continuing challenges experienced by PaHIV youth require enhanced multidisciplinary support throughout adulthood.

The HIV Empowering Adults' Decisions to Share: UK/Uganda (HEADS-UP) Study-A Randomised Feasibility Trial of an HIV Disclosure Intervention for Young Adults with Perinatally Acquired HIV.

Young adults with perinatally acquired HIV (PAH) face numerous challenges, including antiretroviral therapy (ART) adherence, managing onward HIV transmission risks and maintaining wellbeing. Sharing one's HIV status with others (onward HIV disclosure) may assist with these challenges but this is difficult. We developed and tested the feasibility of an intervention to help HIV status sharing decision-making for young adults with PAH. The study used a randomised parallel group feasibility design with 18-25-year-olds in Uganda and 18-29 year-olds in the UK. Participants were randomly assigned to intervention or standard of care (SOC) condition. The intervention consisted of four sessions (3 group, 1 individual) with follow-up support, delivered in person in Uganda and remotely in the UK. Assessments were carried out at: Pre-intervention /baseline; Post-intervention (intervention group only); Six-month follow-up. 142 participants were recruited (94 Uganda, 48 UK; 89 female, 53 male). At six-month follow-up, 92/94 (98%) participants were retained in Uganda, 25/48 (52%) in the UK. Multivariate analysis of combined data from both countries, showed a non-significant effect of intervention condition on HIV disclosure cognitions and affect (p = 0.08) and HIV disclosure intention (p = 0.09). There was a significant intervention effect on well-being (p = 0.005). This study addressed important gaps in understanding acceptable and feasible ways of delivering HIV status sharing support for young people living with PAH across two very different settings. The intervention was acceptable in both countries and feasible in Uganda. In the UK, retention may have been affected by its remote delivery.Trial registration: ISRCTN Registry, ISRCTN31852047, Registered on 21 January 2019.

Low unspliced cell-associated HIV RNA in early treated adolescents living with HIV on long suppressive ART.

Introduction: Initiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population. Methods: Forty adolescents perinatally infected with HIV on suppressive ART for >5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested. Results: CA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-α was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study. Conclusions: Low CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation.

Standardizing Extracted Data Using Automated Application of Controlled Vocabularies.

BACKGROUND: Extraction of toxicological end points from primary sources is a central component of systematic reviews and human health risk assessments. To ensure optimal use of these data, consistent language should be used for end point descriptions. However, primary source language describing treatment-related end points can vary greatly, resulting in large labor efforts to manually standardize extractions before data are fit for use. OBJECTIVES: To minimize these labor efforts, we applied an augmented intelligence approach and developed automated tools to support standardization of extracted information via application of preexisting controlled vocabularies. METHODS: We created and applied a harmonized controlled vocabulary crosswalk, consisting of Unified Medical Language System (UMLS) codes, German Federal Institute for Risk Assessment (BfR) DevTox harmonized terms, and The Organization for Economic Co-operation and Development (OECD) end point vocabularies, to roughly 34,000 extractions from prenatal developmental toxicology studies conducted by the National Toxicology Program (NTP) and 6,400 extractions from European Chemicals Agency (ECHA) prenatal developmental toxicology studies, all recorded based on the original study report language. RESULTS: We automatically applied standardized controlled vocabulary terms to 75% of the NTP extracted end points and 57% of the ECHA extracted end points. Of all the standardized extracted end points, about half (51%) required manual review for potential extraneous matches or inaccuracies. Extracted end points that were not mapped to standardized terms tended to be too general or required human logic to find a good match. We estimate that this augmented intelligence approach saved >350 hours of manual effort and yielded valuable resources including a controlled vocabulary crosswalk, organized related terms lists, code for implementing an automated mapping workflow, and a computationally accessible dataset. DISCUSSION: Augmenting manual efforts with automation tools increased the efficiency of producing a findable, accessible, interoperable, and reusable (FAIR) dataset of regulatory guideline studies. This open-source approach can be readily applied to other legacy developmental toxicology datasets, and the code design is customizable for other study types. https://doi.org/10.1289/EHP13215.

Disseminating the research findings from the adolescents and adults living with Perinatal HIV (AALPHI) study: an approach from young people living with HIV.

BACKGROUND: The Adolescents and Adults Living with Perinatal HIV (AALPHI) study is one of only three cohort studies worldwide evaluating the impact of HIV on young people living with perinatal HIV (PLHIV) relative to a comparable group of HIV negative young people in close relationship with an HIV positive individual, for example, their mother, sibling or partner. This project aimed to engage young people with the AALPHI study findings, help them take ownership, and decide how they would disseminate the key messages to both study participants and to the wider community. METHODS: In brief, 318 PLHIV and 100 HIV negative adolescents participated in AALPHI, where they each were interviewed twice, around two years apart. They were asked a wide range of psychosocial and risk behaviour questions and their cognitive function was assessed. We invited three AALPHI participants and seven members of the Youth Trials Board at the Children's HIV Association (CHIVA) to attend up to four workshops. They were provided with the key AALPHI research findings and asked to develop them into a format that was accessible and understandable for young people. Some who had not participated before formed a group in the fourth dissemination workshop that confirmed the most important concepts and results. RESULTS: The young people decided to develop a film and a leaflet about the AALPHI findings and co-produced them with a film maker and graphic designer. Challenges included working with the film maker and the venue for the first three dissemination workshops was an office space which was not ideal. CONCLUSION: Engaging young people in the dissemination of the AALPHI findings ensured the results were communicated in a way that was more likely to be relevant, accessible and useful to those affected by the study. This project demonstrates how young people in potentially stigmatised areas of care, such as HIV, can be involved in research dissemination.

Informing young people of the results of a study in which they participated, in a manner they can understand, is an ethical minimum. Increasingly, young people themselves may be involved in this dissemination activity, to ensure that study results are communicated in a way which is more likely to be relevant, accessible and useful to those directly affected by the study. The Adolescents and Adults Living with Perinatal HIV (AALPHI) study is a cohort study evaluating the impact of HIV on young people living with perinatal HIV (PLHIV) relative to HIV negative young people affected by HIV. This project aimed to engage PLHIV with the AALPHI findings, and help them take ownership of their dissemination, deciding how to communicate key messages to study participants and the wider community. We invited three AALPHI participants and seven members of a Youth Trials Board at the Children's HIV Association, (CHIVA), to attend four workshops. We provided them with key AALPHI findings and asked them to develop them into an understandable format for young people. They co-produced the content for a film and a leaflet about the results, working with a film maker and graphic designer. The 4th comprised of three workshop participants and seven new participants from CHIVA. This work shows that young PLHIV can be part of the process of evaluating study results and guiding dissemination by creating outputs that align with young people's priorities. This area of work could be further developed in the future through direct evaluation of participant involvement.

Cultural Adaption, Translation, Preliminary Reliability and Validity of Key Psychological and Behavioural Measures for 18 to 25 Year-Olds Living with HIV in Uganda: A Multi-Stage Approach.

HIV remains a significant public health issue among young adults living in Uganda. There is a need for reliable and valid measures of key psychological and behavioural constructs that are related to important outcomes for this population. We translated, adapted and tested the psychometric properties of questionnaires measuring HIV stigma, HIV disclosure cognitions and affect, antiretroviral therapy (ART) adherence, social support, personal values, and hope, using a multi-step process. This included: translation, back-translation, expert review, cognitive interviewing, readability and assessments of internal consistency with 93 young adults (18-25 years) living with perinatally acquired HIV in Uganda. Preliminary criterion validity was assessed by examining relationships between the adapted measures and wellbeing, HIV disclosure behaviour, HIV disclosure intention and viral load suppression. The measures all showed acceptable reliability and every questionnaire apart from the Agentic and Communal Value Scale was easy to read. Those scales measuring HIV disclosure affect and cognitions, social support, HIV stigma and hope showed relationships with other constructs suggestive of validity. There is preliminary evidence to support the use of these measures in research and clinical contexts for young adults living with perinatally acquired HIV in Uganda.

Infant feeding: emerging concepts to prevent HIV transmission.

PURPOSE OF REVIEW: HIV screening in pregnancy, universal suppressive antiretroviral therapy (ART) and breastfeeding avoidance can almost completely prevent vertical transmission of HIV. Breastfeeding is associated with an additional risk of transmission, although this risk is extremely low with suppressive maternal ART. This minimal risk must be balanced with the benefits of breastfeeding for women living with HIV (WLHIV) and their infants. Guidance in high-income countries has evolved, moving towards supported breast feeding for women on suppressive ART. RECENT FINDINGS: Breastmilk transmission accounts for an increasing proportion of new infant infections globally. The majority of transmission data comes from studies including women not on suppressive ART. Breastmilk transmissions in the context of undetectable viral load have rarely occurred, although risk factors remain unclear. Outcome data on supported breastfeeding are accumulating, providing evidence for guidelines and informing infant feeding decisions. Long-acting ART for maternal preexposure prophylaxis or treatment, and infant postnatal prophylaxis are promising future options. SUMMARY: Breastfeeding on suppressive ART has a very low risk of vertical transmission and can have multiple benefits for WLHIV and their infants. However, caution is advised with relaxation of breastfeeding guidance so as not to jeopardise the global goal of elimination of vertical transmission by 2030.

Evolution of CD4 T-Cell Count With Age in a Cohort of Young People Growing Up With Perinatally Acquired Human Immunodeficiency Virus.

BACKGROUND: Recent studies have shown a decrease in CD4 count during adolescence in young people with perinatally acquired human immunodeficiency virus (HIV, PHIV). METHODS: Young people with PHIV in the United Kingdom, followed in the Collaborative HIV Paediatric Study who started antiretroviral therapy (ART) from 2000 onward were included. Changes in CD4 count over time from age 10 to 20 years were analyzed using mixed-effects models, and were compared to published CD4 data for the gerneral population. Potential predictors were examined and included demographics, age at ART start, nadir CD4 z score (age-adjusted) in childhood, and time-updated viral load. RESULTS: Of 1258 young people with PHIV included, 669 (53%) were female, median age at ART initiation was 8.3 years, and the median nadir CD4 z score was -4.0. Mean CD4 count was higher in young people with PHIV who started ART before age 10 years and had a nadir CD4 z score ≥-4; these young people with PHIV had a decline in CD4 count after age 10 that was comparable to that of the general population. Mean CD4 count was lower in young people with PHIV who had started ART before age 10 and had a nadir CD4 z score <-4; for this group, the decline in CD4 count after age 10 was steeper over time. CONCLUSIONS: In children, in addition to starting ART at an early age, optimizing ART to maintain a higher CD4 z score during childhood may be important to maximizing immune reconstitution later in life.

An adapted algorithm for patient engagement in care for young people living with perinatal HIV in England.

BACKGROUND: Evidence suggests that engagement in care (EIC) may be worse in young people living with perinatal HIV (YPLPHIV) compared to adults or children living with HIV. We took a published EIC algorithm for adults with HIV, which takes patients' clinical scenarios into account, and adapted it for use in YPLPHIV in England, to measure their EIC. METHODS: The adult algorithm predicts when in the next 6 months the next clinic visit should be scheduled, based on routinely collected clinical indicators at the current visit. We updated the algorithm based on the latest adult guidelines at the time, and modified it for young people in paediatric care using the latest European paediatric guidelines. Paediatric/adolescent HIV consultants from the UK reviewed and adapted the resulting flowcharts. The adapted algorithm was applied to the Adolescent and Adults Living with Perinatal HIV (AALPHI) cohort in England. Data for 12 months following entry into AALPHI were used to predicted visits which were then compared to appointment attendances, to measure whether young people were in care in each month. Proxy markers (e.g. dates of CD4 counts, viral loads (VL)) were used to indicate appointment attendance. RESULTS: Three hundred sixteen patients were in AALPHI, of whom 41% were male, 82% of black African ethnicity and 58% born abroad. At baseline (time of AALPHI interview) median [IQR] age was 17 [15-18] years, median CD4 was 597 [427, 791] cells/µL and 69% had VL ≤50c/mL. 10 patients were dropped due to missing data. 306 YPLPHIV contributed 3,585 person months of follow up across the 12 month study in which a clinic visit was recorded for 1,204 months (38/1204 dropped due to missing data). The remaining 1,166 months were classified into 3 groups: Group-A: on ART, VL ≤ 50c/mL-63%(734/1,166) visit months, Group-B: on ART, VL > 50c/mL-27%(320/1,166) Group-C: not on ART-10%(112/1,166). Most patients were engaged in care with 87% (3,126/3,585) of months fulfilling the definition of engaged in care. CONCLUSIONS: The adapted algorithm allowed the varying clinical scenarios of YPLPHIV to be taken into account when measuring EIC. However availability of good quality surveillance data is crucial to ensure that EIC can be measured well.

The alarms should no longer be ignored: survey of the demand, capacity and provision of adult community eating disorder services in England and Scotland before COVID-19.

AIMS/METHOD: This national pre-pandemic survey compared demand and capacity of adult community eating disorder services (ACEDS) with NHS England (NHSE) commissioning guidance. RESULTS: Thirteen services in England and Scotland responded (covering 10.7 million population). Between 2016-2017 and 2019-2020 mean referral rates increased by 18.8%, from 378 to 449/million population. Only 3.7% of referrals were from child and adolescent eating disorder services (CEDS-CYP), but 46% of patients were aged 18-25 and 54% were aged >25. Most ACEDS had waiting lists and rationed access. Many could not provide full medical monitoring, adapt treatment for comorbidities, offer assertive outreach or provide seamless transitions. For patient volume, the ACEDS workforce budget was 15%, compared with the NHSE workforce calculator recommendations for CEDS-CYP. Parity required £7 million investment/million population for the ACEDS. CLINICAL IMPLICATIONS: This study highlights the severe pressure in ACEDS, which has increased since the COVID-19 pandemic. Substantial investment is required to ensure NHS ACEDS meet national guidance, offer evidence-based treatment, reduce risk and preventable deaths, and achieve parity with CEDS-CYP.

Effective early antiretroviral therapy in perinatal-HIV infection reduces subsequent plasma inflammatory profile.

BACKGROUND: The long-term immunologic effects of antiretroviral therapy (ART) in children with perinatally-acquired HIV (PHIV) have not been fully elucidated. Here, we investigated how the timing of ART initiation affects the long-term immune profile of children living with PHIV by measuring immunomodulatory plasma cytokines, chemokines, and adenosine deaminases (ADAs). METHODS: 40 PHIV participants initiated ART during infancy. 39 participant samples were available; 30 initiated ART ≤6 months (early-ART treatment); 9 initiated ART >6 months and <2 years (late-ART treatment). We compared plasma cytokine and chemokine concentrations and ADA enzymatic activities between early-ART and late-ART treatment 12.5 years later and measured correlation with clinical covariates. RESULTS: Plasma concentrations of 10 cytokines and chemokines (IFNγ, IL-12p70, IL-13, IL-17A, IL-IRA, IL-5, IL-6, and IL-9 as well as CCL7, CXCL10), ADA1, and ADA total were significantly higher in late-ART compared to early-ART treatment. Furthermore, ADA1 was significantly positively correlated with IFNγ, IL-17A, and IL-12p70. Meanwhile, total ADA was positively correlated with IFNγ, IL-13, IL-17A, IL-1RA, IL-6, and IL-12p70 as well as CCL7. CONCLUSIONS: Elevation of several pro-inflammatory plasma analytes in late-ART despite 12.5 years of virologic suppression compared to early-ART treatment suggests that early treatment dampens the long-term plasma inflammatory profile in PHIV participants. IMPACT: This study examines differences in the plasma cytokine, chemokine, and ADA profiles 12.5 years after treatment between early (≤6months) and late (>6 months and <2 years) antiretroviral therapy (ART) treatment initiation in a cohort of European and UK study participants living with PHIV. Several cytokines and chemokines (e.g., IFNγ, IL-12p70, IL-6, and CXCL10) as well as ADA-1 are elevated in late-ART treatment in comparison to early-ART treatment. Our results suggest that effective ART treatment initiated within 6 months of life in PHIV participants dampens a long-term inflammatory plasma profile as compared to late-ART treatment.

Sexual and reproductive health needs of young women living with perinatally acquired HIV.

BACKGROUND: Increasingly, young women living with perinatally acquired HIV (YWLPaHIV) have transitioned from paediatric to adult services. There remains a paucity of data on the sexual and reproductive health (SRH) needs of YWLPaHIV and their access to youth-friendly care. Amidst healthcare changes due to COVID-19 pandemic restrictions, we explored SRH needs of a cohort of YWLPaHIV. METHODS: Evaluation of SRH needs of YWLPaHIV attending a UK NHS-youth HIV service with data collected from patient records and self-reported questionnaires amongst women attending between July and November 2020 following easing of the first lockdown and reintroduction of in-person appointments. RESULTS: 71 of 112 YWLPaHIV registered at the clinic completed questionnaires during the study period and were included in the analysis. Median age was 23 y (IQR 21-27, range 18-36). 51/71(72%) reported coitarche, average age 17.6 y (IQR 16-18, range 14-24). 24 women reported 47 pregnancies resulting in 16 (34%) HIV-negative live-births, 19 (40%) terminations, 9(19%) miscarriages, with 3 pregnancies ongoing. 31/48(65%) sexually active women reported current contraception: 10 (32%) condoms, 19 (62%) long-acting, and 3(10%) oral contraceptive pill. 18/51(35%) reported a previous sexually transmitted infection; human papillomavirus (HPV) (11), Chlamydia trachomatis (9) and herpes simplex (2). 27/71(38%) women had undergone cervical cytology including 20/28(71%) women aged ≥25 y with abnormalities documented in 29%. HPV vaccination was reported in 83%, with protective hepatitis B titres in 71%. CONCLUSION: High rates of unplanned pregnancy, STIs and cervical abnormalities highlight the continuing SRH needs of YWLPaHIV and requirement for open access to integrated HIV/SRH services despite pandemic restrictions.

Compassionate use of long-acting cabotegravir plus rilpivirine for people living with HIV-1 in need of parenteral antiretroviral therapy.

OBJECTIVES: Physicians could request compassionate use of oral and long-acting (LA) cabotegravir + rilpivirine for people living with HIV-1 under a single-patient request programme supported by ViiV Healthcare and Janssen. Outcomes are reported. METHODS: Eligibility criteria included need for parenteral therapy, no primary resistance mutations to cabotegravir or rilpivirine, and established retention in care. Demographic, efficacy, and safety data were obtained from standardized programme applications and quarterly clinical updates. Individuals received a loading dose of LA cabotegravir 600 mg + rilpivirine 900 mg, followed by LA maintenance doses of 400 mg/600 mg every 4 weeks; some received lead-in oral cabotegravir and rilpivirine. RESULTS: Through July 2020, 35 people living with HIV-1 had data available. The most frequent reason for compassionate use request was chronic non-adherence due to psychological conditions (n = 15). Of 35 people living with HIV-1, 28 had detectable viremia (median viral load 60 300 copies/mL) and seven were virologically suppressed at programme entry; 16/28 and 6/7 achieved or maintained virological suppression at data cutoff, respectively. Seven people living with HIV-1 discontinued for incomplete virological response, six with detectable viremia at initiation; six and four had new reverse transcriptase and integrase mutations at discontinuation, respectively. Six non-fatal serious adverse events were reported, two considered possibly treatment related. Four deaths were reported; none were treatment related. One individual reported two pregnancies and continued LA dosing. CONCLUSIONS: Most people living with HIV-1 had advanced disease and achieved (16/28) or maintained (6/7) virological suppression with LA therapy. Cabotegravir LA + rilpivirine LA as compassionate use provided a valuable treatment option for individuals with adherence issues with oral therapy and advanced disease.

Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy.

Antiestrogen therapy (AET) is an alternative to cytotoxic chemotherapy for recurrent ovarian cancer, yet the often short duration of response suggests mechanisms of resistance. We previously demonstrated that tumor microenvironment interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokines induce tumor cell JAK-STAT signaling to promote cancer growth. Crosstalk between estrogen signaling and cytokine signaling has been reported. Therefore, we sought to characterize the impact of IL6/LIF signaling on estrogen signaling in epithelial ovarian cancer and investigate the efficacy of combination therapy. We first assessed patient tumors for cytokine expression and compared it with response to AET to determine clinical relevance. In vitro, we determined the effect of IL6/LIF on estrogen receptor expression and signaling. Cell viability assays were used to determine the efficacy and potential synergy of cytokine blockade and AET. We then extended studies to animal models, incorporating patient-derived stromal cells. Our results demonstrated shorter progression-free interval on AET in patients with stromal IL6/LIF expression. In vitro, IL6/LIF increased tumor cell estrogen receptor expression and signaling, and combination cytokine blockade and AET resulted in synergistic inhibition of tumor cell growth. The anticancer effect was verified in a mouse model. In conclusion, due to crosstalk between IL6/LIF cytokine signaling and estrogen signaling, dual blockade is a potential new treatment approach for ovarian cancer.

Learning and memory function in young people with and without perinatal HIV in England.

Learning and memory are important for successful education and career progression. We assess these functions in young people (YP) with perinatal HIV (PHIV) (with or without a previous AIDS-defining illness) and a comparable group of HIV-negative YP. 234 PHIV and 68 HIV-negative YP completed 9 tests; 5 National Institutes of Health (NIH) Toolbox tests (2 executive function, 1 speed of information processing, 2 memory); 2 Hopkins Verbal Learning Test Revised (HVLT-R) (learning (L), delayed recall (R)), and 2 verbal application measures. Z-scores for each test were calculated using normative data and averaged by domain where appropriate. The effect of predictors on test scores in the three domains with the lowest z-scores were analysed using linear regression. 139(59%) and 48(71%) PHIV and HIV-negative YP were female, 202(86%) and 52(76%) Black, and median age was 19 [17, 21] and 18 [16, 21] years respectively. 55(24%) PHIV had a previous Center for Disease Control and Prevention (CDC) class C AIDS-defining diagnosis (PHIV/C). For HVLT-R, there was a trend towards PHIV/C YP having the lowest mean z-scores (L -1.5 (95% CI -1.8,-1.2), R -1.7 (-2.0,-1.4)) followed by PHIV without a CDC C diagnosis (L -1.3 (-1.4,-1.1), R -1.4 (-1.5,-1.2)) and then the HIV-negative group (L -1.0 (-1.3,-0.7), R -1.1 (-1.3,-0.8)); all were greater than 1 SD below the reference mean. The same trend was seen for verbal application measures; however, z-scores were within 1 SD below the reference mean. NIH Toolbox tests were similar for all groups. In multivariable analyses PHIV/C and Black ethnicity predicted lower HVLT-R scores. Black ethnicity also predicted lower executive function scores, however each year increase in age predicted higher scores. In conclusion, cognitive performance in verbal learning and recall fell below population normative scores, and was more pronounced in PHIV/C, supporting wider findings that earlier antiretroviral therapy initiation, before the occurrence of AIDS-defining conditions, may protect aspects of cognitive development.