Hepatic steatosis in people older and younger than fifty who are living with HIV and HIV-negative controls: A cross-sectional study nested within the POPPY cohort.

BACKGROUND: Hepatic steatosis is a major cause of chronic liver disease associated with several negative health outcomes. We compared the prevalence of and factors associated with steatosis in people living with and without HIV. METHODS: Older (>50 years) and younger (<50 years) people with HIV and older HIV-negative controls (>50 years) underwent liver transient elastography examination with controlled attenuation parameter (steatosis ≥238 dB/m, moderate/severe steatosis ≥280 dB/m, liver fibrosis ≥7.1 kPa). We compared groups using logistic regression/Chi-squared/Fisher's exact/Kruskal-Wallis tests. RESULTS: In total, 317 participants (109 older people with HIV; 101 younger people with HIV; 107 HIV-negative controls) were predominantly white (86%) and male (76%), and 21% were living with obesity (body mass index ≥30 kg/m2 ). Most (97%) people with HIV had undetectable HIV RNA. The prevalence of fibrosis was 8.4%, 3.0%, and 6.5% in the three groups, respectively (p = 0.26). Fibrosis was predominately (>65%) mild. The prevalence of steatosis was the same in older people with HIV (66.4%) and controls (66.4%) but lower in younger people with HIV (37.4%; p < 0.001). After adjustment, younger people with HIV were less likely to have steatosis (odds ratio [OR] 0.26; 95% confidence interval [CI] 0.14-0.52) than controls, but male sex (OR 2.45; 95% CI 1.20-4.50) and high waist-to-hip ratio (OR 3.04; 95% CI 1.74-5.33) were associated with an increased odds of steatosis. We found no association between steatosis and HIV-related variables. CONCLUSIONS: The prevalence of hepatic steatosis and fibrosis was similar between older participants regardless of HIV status. Age, sex, and abdominal obesity, but not HIV-related variables, were associated with steatosis. Interventions for controlling obesity should be integrated into routine HIV care.

HIV outcomes during the COVID-19 pandemic in people of Black ethnicities living with HIV in England.

OBJECTIVES: To describe HIV care outcomes in people of Black ethnicities living in England during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]) pandemic. METHODS: This was an observational cohort study of people of self-reported Black ethnicities attending for HIV care at nine HIV clinics across England. The primary outcome was a composite of antiretroviral therapy (ART) interruption and HIV viraemia (HIV RNA ≥200 copies/mL) ascertained via self-completed questionnaires and review of medical records. We used multivariable logistic regression to explore associations between ART interruption/HIV viraemia and demographic factors, pre-pandemic HIV immunovirological control, comorbidity status, and COVID-19 disease and vaccination status. RESULTS: We included 2290 people (median age 49.3 years; 56% female; median CD4 cell count 555 cells/mm3; 92% pre-pandemic HIV RNA <200 copies/mL), of whom 302 (13%) reported one or more ART interruption, 312 (14%) had documented HIV viraemia ≥200 copies/mL, and 401 (18%) experienced the composite endpoint of ART interruption/HIV viraemia. In multivariable analysis, a pre-pandemic HIV RNA <200 copies/mL (odds ratio [OR] 0.21; 95% confidence interval [CI] 0.15-0.30) and being vaccinated against SARS-CoV-2 (OR 0.41; 95% CI 0.30-0.55) were associated with reduced odds of ART interruption/HIV viraemia; pandemic-related disruptions to HIV care were common self-reported additional factors. CONCLUSIONS: During the COVID-19 pandemic, one in six people of Black ethnicities in this HIV cohort experienced an ART interruption/HIV viraemia. Some of these episodes resulted from pandemic-related healthcare disruptions. Associations with suboptimal engagement in HIV care pre-pandemic and not being vaccinated against SARS-CoV-2 suggest that wider health beliefs and/or poor healthcare access may have been contributory factors.

Cardiovascular disease risk in people of African ancestry with HIV in the United Kingdom.

OBJECTIVES: Our objective was to describe the prevalence of cardiovascular disease (CVD) risk factors in people of African ancestry with HIV in the UK. METHODS: We conducted a cross-sectional analysis of CVD risk factors in Black people with HIV aged ≥40 years and estimated the 10-year CVD risk using QRISK®3-2018. Correlations between body mass index (BMI) and CVD risk factors were described using Pearson correlation coefficients, and factors associated with 10-year CVD risk ≥5% were described using logistic regression. RESULTS: We included 833 Black people with HIV and a median age of 54 years; 54% were female, 50% were living with obesity (BMI ≥30 kg/m2), 61% had hypertension, and 19% had diabetes mellitus. CVD risk >5% ranged from 2% in female participants aged 40-49 years to 99% in men aged ≥60 years, and use of statins ranged from 7% in those with CVD risk <2.5% to 64% in those with CVD risk ≥20%. BMI was correlated (R2 0.1-0.2) with triglycerides and diastolic blood pressure in women and with glycated haemoglobin, systolic and diastolic blood pressure, and total:high-density lipoprotein (HDL) cholesterol ratio in men. In both female and male participants, older age, blood pressure, diabetes mellitus, and kidney disease were strongly associated with CVD risk ≥5%, whereas obesity, total:HDL cholesterol, triglycerides, and smoking status were variably associated with CVD risk ≥5%. CONCLUSIONS: We report a high burden of CVD risk factors, including obesity, hypertension, and diabetes mellitus, in people of African ancestry with HIV in the UK. BMI-focused interventions in these populations may improve CVD risk while also addressing other important health issues.

Clinical epidemiology of COVID-19 in people of black ethnicity living with HIV in the UK.

OBJECTIVES: To describe the clinical epidemiology of COVID-19 in people of black ethnicity living with HIV in the UK. METHODS: We investigated the incidence and factors associated with COVID-19 in a previously established and well-characterized cohort of black people with HIV. Primary outcomes were COVID-19 acquisition and severe COVID-19 disease (requiring hospitalization and/or resulting in death). Cumulative incidence was analysed using Nelson-Aalen methods, and associations between demographic, pre-pandemic immune-virological parameters, comorbidity status and (severe) COVID-19 were identified using Cox regression analysis. RESULTS: COVID-19 status was available for 1847 (74%) of 2495 COVID-AFRICA participants (median age 49.6 years; 56% female; median CD4 cell count = 555 cells/µL; 93% HIV RNA <200 copies/mL), 573 (31%) of whom reported at least one episode of COVID-19. The cumulative incidence rates of COVID-19 and severe COVID-19 were 31.0% and 3.4%, respectively. Region of ancestry (East/Southern/Central vs. West Africa), nadir CD4 count and kidney disease were associated with COVID-19 acquisition. Diabetes mellitus [adjusted hazard ratio (aHR) = 2.39, 95% confidence interval (CI): 1.26-4.53] and kidney disease (aHR = 2.53, 95% CI: 1.26-4.53) were associated with an increased risk, and recent CD4 count >500 cells/µL (aHR = 0.49, 95% CI: 0.25-0.93) with a lower risk of severe COVID-19. CONCLUSIONS: Region of ancestry was associated with COVID-19 acquisition, and immune and comorbidity statuses were associated with COVID-19 disease severity in people of black ethnicity living with HIV in the UK.

Epigenetic associations with kidney disease in individuals of African ancestry with APOL1 high-risk genotypes and Human Immunodeficiency Virus.

BACKGROUND: Apolipoprotein L1 (APOL1) high-risk variants are major determinants of chronic kidney disease (CKD) in people of African ancestry. Previous studies have identified epigenetic changes in relation to kidney function and CKD, but not in individuals with APOL1 high-risk genotypes. We conducted an epigenome-wide analysis of CKD and estimated glomerular filtration rate (eGFR) in in people of African ancestry and APOL1 high-risk genotypes with HIV. METHODS: DNA methylation profiles from peripheral blood mononuclear cells of 119 individuals with APOL1 high-risk genotypes (mean age 48 years, 49% female, median CD4 count 515 cells/mm3, 90% HIV-1 RNA <200 copies/mL, 23% with CKD) were obtained by Illumina MethylationEPIC BeadChip. Differential methylation analysis of CKD considered technical and biological covariates. We also assessed associations with eGFR. Replication was pursued in three independent multi-ancestry cohorts with and without HIV. RESULTS: DNA methylation levels at 14 regions were associated with CKD. The strongest signals were located in SCARB1, DNAJC5B and C4orf50. Seven of the 14 signals also associated with eGFR, and most showed evidence for a genetic basis. Four signals (in SCARB1, FRMD4A, CSRNP1 and RAB38) replicated in other cohorts, and 11 previously reported epigenetic signals for kidney function or CKD replicated in our cohort. We found no significant DNA methylation signals in, or near, the APOL1 promoter region. CONCLUSIONS: We report several novel as well as previously reported epigenetic associations with CKD and eGFR in individuals with HIV having APOL1 high-risk genotypes. Further investigation of pathways linking DNA methylation to APOL1 nephropathies is warranted.

Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa.

AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.

Social determinants of health and long-term conditions in people of Black African and Black Caribbean ethnicity living with HIV in London: A qualitative study.

BACKGROUND: People living with human immunodeficiency virus (HIV) are disproportionately impacted by socioeconomic deprivation and are at increased risk of developing other long-term conditions (LTCs). These illnesses require transformative action to tackle the adverse effects on their health. Data on lived experiences of LTCs among people living with HIV of Black African and Black Caribbean ethnicities are sparse, and how people with LTCs are impacted by social determinants of health (SDoH). METHODS: Through a phenomenological study design this qualitative study, conducted in 2022, comprised four focus group discussions (FGDs) with 20 people of Black ethnicities living with HIV were purposively invited from a community organisation (CO) in London, including four semistructured interviews with CO staff. Following transcription, qualitative data were analysed thematically and measures to validate the findings were implemented. RESULTS: The findings are presented in terms of the following four levels of SDoH: (1) individual determinants (such as the impact of SDoH on lifestyle modification and self-management); (2) interpersonal determinants (such as positive experiences of accessing healthcare for LTCs); (3) clinical determinants (such as care pathway barriers) and (4) systemic determinants (such as systemic barriers related to race/ethnicity). CONCLUSIONS: It is necessary to provide ongoing and interactive education to community members who live with HIV, focusing on risks and management of LTCs. Additionally, individuals would benefit from support to navigate increasingly complex and fragmented health services. Health Service staff require cultural competence when caring for patients of Black African and Black Caribbean ethnicities with complex health and psychosocial needs. PATIENT OR PUBLIC CONTRIBUTION: The research team collaborated with an HIV CO in South London from the very start of the project to agree the study design and learn about the realities of their daily lived experiences. Community collaborators helped to develop the semistructured interview and FGD topic guides, and were directly involved in the data gathering, analysis and validation.

Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans.

OBJECTIVE: Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans. METHODS: Genetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine ß2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations. RESULTS: 336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 ( P  = 0.022), ABCC10 rs2125739 ( P  = 0.07), and ABCC4 rs1059751 ( P  = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 ( P  = 0.0013), rs691857 ( P  = 0.00039), and PKD2 rs72659631 ( P  = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 ( P  = 3.4 × 10 -9 ), CDH4 rs66494466 ( P  = 5.6 × 10 -8 ), and ITGA4 rs3770126 ( P  = 6.1 × 10 -7 ). CONCLUSION: Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.

Obesity and diabetes in people of African ancestry with HIV.

Obesity is a chronic disease with multiple adverse effects on health. The prevalence of obesity is increasing worldwide, and people of African ancestry are disproportionally affected. Several widely used antiretrovirals have been associated with weight gain and contribute to the rising burden of obesity in people with HIV. Obesity and weight gain on antiretroviral therapy are risk factors for the development of type 2 diabetes mellitus, a condition which also disproportionally affects black populations. In this review, we discuss recent data on weight gain in relation to initiating or switching antiretroviral therapy and advances in the management of obesity. Availability of highly effective treatments for obesity have the potential to address, and potentially reverse, the epidemics of obesity and diabetes mellitus in people with HIV.

Anticholinergic medications associated with falls and frailty in people with HIV.

BACKGROUND: Anticholinergic medications (ACMs) are associated with poorer age-related outcomes, including falls and frailty. We investigate associations between ACM use and recurrent falls and frailty among older (aged ≥50 years) people with HIV in the POPPY study. METHODS: Anticholinergic potential of co-medications at study entry was coded using the anticholinergic burden score, anticholinergic risk score, and Scottish Intercollegiate Guidelines Network score; drugs scoring ≥1 on any scale were defined as ACM. Associations with recurrent falls (two or more falls in the previous 28 days) and frailty (modified Fried's) were assessed using logistic regression adjusting for (1) possible demographic/lifestyle confounders and (2) clinical factors and depressive symptoms (Patient Health Questionnaire-9). RESULTS: ACM use was reported by 193 (28%) of 699 participants, with 64 (9%) receiving two or more ACM; commonly prescribed ACMs were codeine (12%), citalopram (12%), loperamide (9%), and amitriptyline (7%). Falls were reported in 63/673 (9%), and 126/609 (21%) met the frailty criteria. Both recurrent falls and frailty were more common in ACM users than in non-users (recurrent falls: 17% in users vs. 6% in non-users, p < 0.001; frailty: 32% vs. 17%, respectively, p < 0.001). Use of two or more ACMs was associated with increased odds of falls after adjustment for demographic/lifestyle factors (odds ratio [OR] 4.53; 95% confidence interval [CI] 2.06-9.98) and for clinical factors (OR 3.58; 95% CI 1.37-9.38). Similar albeit weaker associations were seen with frailty (OR 2.26; 95% CI 1.09-4.70 and OR 2.12; 95% CI 0.89-5.0, respectively). CONCLUSIONS: ACM are commonly prescribed for people living with HIV, and evidence exists for an association with recurrent falls and frailty. Clinicians should be alert to this and reduce ACM exposure where possible.

CD4+ T-Cell Count at Antiretroviral Therapy Initiation in the "Treat-All" Era in Rural South Africa: An Interrupted Time Series Analysis.

BACKGROUND: South Africa implemented universal test and treat (UTT) in September 2016 in an effort to encourage earlier initiation of antiretroviral therapy (ART). METHODS: We therefore conducted an interrupted time series (ITS) analysis to assess the impact of UTT on mean CD4 count at ART initiation among adults aged ≥16 years attending 17 public sector primary care clinics in rural South Africa, between July 2014 and March 2019. RESULTS: Among 20 599 individuals (69% women), CD4 counts were available for 74%. Mean CD4 at ART initiation increased from 317.1 cells/µL (95% confidence interval [CI], 308.6 to 325.6) 1 to 8 months prior to UTT to 421.0 cells/µL (95% CI, 413.0 to 429.0) 1 to 12 months after UTT, including an immediate increase of 124.2 cells/µL (95% CI, 102.2 to 146.1). However, mean CD4 count subsequently fell to 389.5 cells/µL (95% CI, 381.8 to 397.1) 13 to 30 months after UTT but remained above pre-UTT levels. Men initiated ART at lower CD4 counts than women (-118.2 cells/µL, 95% CI, -125.5 to -111.0) throughout the study. CONCLUSIONS: Although UTT led to an immediate increase in CD4 count at ART initiation in this rural community, the long-term effects were modest. More efforts are needed to increase initiation of ART early in those living with human immunodeficiency virus, particularly men.

Bone mineral density, kidney function and participant-reported outcome measures in women who switch from tenofovir disoproxil emtricitabine and a nonnucleoside reverse transcriptase inhibitor to abacavir, lamivudine and dolutegravir.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG). METHODS: We conducted a randomized controlled trial in which women aged ≥ 40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy. RESULTS: Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively]. CONCLUSIONS: Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.

Follicle-stimulating hormone in postmenopausal women living with HIV: a prevalence study.

OBJECTIVES: We examined follicle-stimulating hormone (FSH) levels in women living with HIV aged > 45 reporting ≥ 12 months' amenorrhoea, and investigated correlation with menopausal symptoms. METHODS: A cross-sectional substudy of 85 women from the Positive Transitions through the Menopause (PRIME) Study who reported irregular periods at entry into the PRIME Study and ≥ 12 months' amenorrhoea at recruitment into this substudy. Serum FSH was supplemented with clinical data and menopausal symptom assessment. Serum FSH > 30 mIU/mL was defined as consistent with postmenopausal status. Associations between FSH and menopausal symptom severity were assessed using Pearson's correlation and the Kruskal-Wallis test. RESULTS: Median age was 53 years [interquartile range (IQR): 51-55]; all were on antiretroviral therapy, three-quarters (n = 65) had a CD4 T-cell count > 500 cells/µL and 91.8% (n = 78) had an HIV viral load (VL) < 50 copies/mL. Median FSH was 65.9 mIU/mL (IQR: 49.1-78.6). Only four women (4.7%) had FSH ≤ 30 mIU/mL; none reported smoking or drug use, all had CD4 T-cell count ≥ 200 cells/µL, and one had viral load (VL) ≥ 50 copies/mL. Median body mass index (BMI) was elevated compared with women with FSH > 30 mIU/mL (40.8 vs. 30.5 kg/m2 ). Over a quarter (28.2%) reported severe menopausal symptoms, with no correlation between FSH and severity of menopausal symptoms (p = 0.21), or hot flushes (p = 0.37). CONCLUSIONS: Four women in this small substudy had low FSH despite being amenorrhoeic; all had BMI ≥ 35 kg/m2 . We found that 95% of women with HIV aged > 45 years reporting ≥ 12 months' amenorrhoea had elevated FSH, suggesting that menopausal status can be ascertained from menstrual history alone in this group.

COVID-19 mortality among people with diagnosed HIV compared to those without during the first wave of the COVID-19 pandemic in England.

OBJECTIVES: We describe COVID-19 mortality among people with and without HIV during the first wave of the pandemic in England. METHODS: National surveillance data on adults (aged ≥ 15 years) with diagnosed HIV resident in England were linked to national COVID-19 mortality surveillance data (2 March 2020-16 June 2020); HIV clinicians verified linked cases and provided information on the circumstances of death. We present COVID-19 mortality rates by HIV status, using negative binomial regression to assess the association between HIV and mortality, adjusting for gender, age and ethnicity. RESULTS: Overall, 99 people with HIV, including 61 of black ethnicity, died of/with COVID-19 (107/100 000) compared with 49 483 people without HIV (109/100 000). Compared to people without HIV, higher COVID-19 mortality rates were observed in people with HIV of black (188 vs. 122/100 000) and Asian (131 vs. 77.0/100 000) ethnicity, and in both younger (15-59 years: 58.3 vs. 10.2/100 000) and older (≥ 60 years: 434 vs. 355/100 000) people. After adjustment for demographic factors, people with HIV had a higher COVID-19 mortality risk than those without (2.18; 95% CI: 1.76-2.70). Most people with HIV who died of/with COVID-19 had suppressed HIV viraemia (91%) and at least one comorbidity reported to be associated with poor COVID-19 outcomes (87%). CONCLUSIONS: In the first wave of the pandemic in England, COVID-19 mortality among people with HIV was low, but was higher than in those without HIV, after controlling for demographic factors. This supports the strategy of prioritizing COVID-19 vaccination for people with HIV and strongly encouraging its uptake, especially in those of black and Asian ethnicity.

Weight Change Following Antiretroviral Therapy Switch in People With Viral Suppression: Pooled Data from Randomized Clinical Trials.

BACKGROUND: We sought to identify factors associated with weight gain in randomized clinical trials of antiretroviral therapy (ART) switch. METHODS: We explored the effects of demographic factors, clinical characteristics, and ART on weight gain in a pooled analysis of 12 prospective clinical trials, wherein virologically suppressed people living with human immunodeficiency virus (PWH) were randomized to switch or remain on a stable baseline regimen (SBR). RESULTS: Both PWH randomized to switch ART (n = 4166) and those remaining on SBR (n = 3150) gained weight. Median weight gain was greater in those who switched (1.6 kg, interquartile range [IQR], -.05 to 4.0 vs 0.4 kg, [IQR], -1.8 to 2.4 at 48 weeks, P < .0001), with most weight gain occurring in the first 24 weeks after switch. Among baseline demographic and clinical characteristics, only younger age and lower baseline body mass index were associated with any or ≥10% weight gain. By week 48, 4.6% gained ≥10% weight (6.4% of switch and 2.2% of SBR), the greatest risk was with switch from efavirenz (EFV) to rilpivirine (RPV) or elvitegravir/cobicistat and switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). Switch from abacavir to TAF was associated with less weight gain than switch from TDF to TAF and was not associated with increased risk for ≥10% weight gain. CONCLUSIONS: Moderate weight gain after ART switch was common and usually plateaued by 48 weeks. Baseline ART was a predictor of post-switch weight gain; participants who switched off of EFV and TDF had the greatest weight gain. The biological mechanisms that underlie the differential effects of switching ART agents on weight and associated clinical implications require further study.

Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.

BACKGROUND: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. INTERPRETATION: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. FUNDING: Gilead Sciences.

Correlation between computerised and standard cognitive testing in people with HIV and HIV-negative individuals.

We investigated the correlations and agreement between cognitive assessments made using a computerised (CogState™, six domains) and a standard pen-and-paper battery (five domains) in PWH and lifestyle-similar HIV-negative individuals. Demographically adjusted domain and global T-scores were obtained and used to define cognitive impairment according to the multivariate normative comparison (MNC) criteria. Correlations between T-scores and the agreement between the classifications of cognitive impairment obtained from the two batteries were assessed using the Spearman's rank correlation and Cohen's κ, respectively. The correlation between global T-scores from the two batteries was 0.52 (95% CI 0.44-0.60) in PWH and 0.45 (0.29-0.59) in controls (p = 0.38 for their difference). Correlations were generally stronger between domains within the same battery than between those from different batteries. The agreement between the two batteries in classifying individuals as cognitively impaired or not impaired was fair in PWH (κ = 0.24) and poor in HIV-negative individuals (κ = -0.02). The moderate correlation between overall cognitive function and the modest agreement between binary classifications of cognitive impairment obtained from two different batteries indicate the two batteries may assess slightly different components of cognition.

Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials.

BACKGROUND: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. METHODS: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. RESULTS: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. CONCLUSIONS: Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

Cervical cancer risk in women living with HIV across four continents: A multicohort study.

We compared invasive cervical cancer (ICC) incidence rates in Europe, South Africa, Latin and North America among women living with HIV who initiated antiretroviral therapy (ART) between 1996 and 2014. We analyzed cohort data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. We used flexible parametric survival models to determine regional ICC rates and risk factors for incident ICC. We included 64,231 women from 45 countries. During 320,141 person-years (pys), 356 incident ICC cases were diagnosed (Europe 164, South Africa 156, North America 19 and Latin America 17). Raw ICC incidence rates per 100,000 pys were 447 in South Africa (95% confidence interval [CI]: 382-523), 136 in Latin America (95% CI: 85-219), 76 in North America (95% CI: 48-119) and 66 in Europe (95% CI: 57-77). Compared to European women ICC rates at 5 years after ART initiation were more than double in Latin America (adjusted hazard ratio [aHR]: 2.43, 95% CI: 1.27-4.68) and 11 times higher in South Africa (aHR: 10.66, 95% CI: 6.73-16.88), but similar in North America (aHR: 0.79, 95% CI: 0.37-1.71). Overall, ICC rates increased with age (>50 years vs. 16-30 years, aHR: 1.57, 95% CI: 1.03-2.40) and lower CD4 cell counts at ART initiation (per 100 cell/µl decrease, aHR: 1.25, 95% CI: 1.15-1.36). Improving access to early ART initiation and effective cervical cancer screening in women living with HIV should be key parts of global efforts to reduce cancer-related health inequities.

The impact of continuous quality improvement on coverage of antenatal HIV care tests in rural South Africa: Results of a stepped-wedge cluster-randomised controlled implementation trial.

BACKGROUND: Evidence for the effectiveness of continuous quality improvement (CQI) in resource-poor settings is very limited. We aimed to establish the effects of CQI on quality of antenatal HIV care in primary care clinics in rural South Africa. METHODS AND FINDINGS: We conducted a stepped-wedge cluster-randomised controlled trial (RCT) comparing CQI to usual standard of antenatal care (ANC) in 7 nurse-led, public-sector primary care clinics-combined into 6 clusters-over 8 steps and 19 months. Clusters randomly switched from comparator to intervention on pre-specified dates until all had rolled over to the CQI intervention. Investigators and clusters were blinded to randomisation until 2 weeks prior to each step. The intervention was delivered by trained CQI mentors and included standard CQI tools (process maps, fishbone diagrams, run charts, Plan-Do-Study-Act [PDSA] cycles, and action learning sessions). CQI mentors worked with health workers, including nurses and HIV lay counsellors. The mentors used the standard CQI tools flexibly, tailored to local clinic needs. Health workers were the direct recipients of the intervention, whereas the ultimate beneficiaries were pregnant women attending ANC. Our 2 registered primary endpoints were viral load (VL) monitoring (which is critical for elimination of mother-to-child transmission of HIV [eMTCT] and the health of pregnant women living with HIV) and repeat HIV testing (which is necessary to identify and treat women who seroconvert during pregnancy). All pregnant women who attended their first antenatal visit at one of the 7 study clinics and were ≥18 years old at delivery were eligible for endpoint assessment. We performed intention-to-treat (ITT) analyses using modified Poisson generalised linear mixed effects models. We estimated effect sizes with time-step fixed effects and clinic random effects (Model 1). In separate models, we added a nested random clinic-time step interaction term (Model 2) or individual random effects (Model 3). Between 15 July 2015 and 30 January 2017, 2,160 participants with 13,212 ANC visits (intervention n = 6,877, control n = 6,335) were eligible for ITT analysis. No adverse events were reported. Median age at first booking was 25 years (interquartile range [IQR] 21 to 30), and median parity was 1 (IQR 0 to 2). HIV prevalence was 47% (95% CI 42% to 53%). In Model 1, CQI significantly increased VL monitoring (relative risk [RR] 1.38, 95% CI 1.21 to 1.57, p < 0.001) but did not improve repeat HIV testing (RR 1.00, 95% CI 0.88 to 1.13, p = 0.958). These results remained essentially the same in both Model 2 and Model 3. Limitations of our study include that we did not establish impact beyond the duration of the relatively short study period of 19 months, and that transition steps may have been too short to achieve the full potential impact of the CQI intervention. CONCLUSIONS: We found that CQI can be effective at increasing quality of primary care in rural Africa. Policy makers should consider CQI as a routine intervention to boost quality of primary care in rural African communities. Implementation research should accompany future CQI use to elucidate mechanisms of action and to identify factors supporting long-term success. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov under registration number NCT02626351.