Alcohol Consumption Among Persons Living with HIV: Perceptions, Messages and Interventions-A Qualitative Study at an HIV Treatment Clinic in South Western Uganda.

In Sub-Saharan Africa, efficacy trials of brief interventions to reduce unhealthy drinking among persons living with HIV (PLWH) have yielded mixed results. A better understanding of the perceptions of drinking, especially by PLWH, and how drinking is talked about at HIV treatment clinics in this setting, may guide more optimal designs for future trials. We conducted a qualitative study at an HIV treatment clinic in South Western Uganda to better understand perceptions of drinking, how drinking is talked about, and perceptions of interventions, especially a protocolled screening and brief intervention (SBI) for unhealthy drinking among PLWH. We conducted in-depth interviews with 17 PLWH who engaged in unhealthy drinking and 6 health workers, and one focus group discussion with 3 community advisory-board members. We performed manual preliminary data analysis and computer-assisted detailed thematic analysis to identify emergent themes. Four themes emerged: perceptions of alcohol use in the general population; perceptions of alcohol use in PLWH; interaction between PLWH and health workers about alcohol use; perceptions of interventions for unhealthy drinking including SBI. Unhealthy drinking was seen as a problem in the general population and among those with HIV, where it was negatively perceived. Communication about drinking was done by counselors, but doctors participated in screening for unhealthy alcohol use. Messages about drinking covered reduction and abstinence. Participants expressed positive attitudes towards SBI and preference for person-delivered SBI over technological alternatives. A protocolled SBI for unhealthy alcohol use among PLWH would be well-received but successful implementation may depend on mode of delivery.

Social networks and HIV treatment adherence among people with HIV initiating treatment in rural Uganda and peri-urban South Africa.

Timely initiation of and adherence to antiretroviral therapy (ART) is critical for improving HIV outcomes and reducing HIV transmissibility. Social networks, or the social relationships individuals have with each other, have been linked with positive health outcomes, but less is known about the extent to which social network composition and structure are associated with improved ART adherence among people living with HIV (PLWH). We conducted an ego-centric network study among 828 previously ART-naïve PLWH presenting for ART initiation at 11 clinics in Mbarara, Uganda (rural population) and Gugulethu, South Africa (peri-urban population). We collected social network data using name generator and name interpreter questions. ART adherence was monitored over 12 months using wireless monitors (Wisepill). Our primary outcome of interest was ART adherence during the 12-month follow-up period. We used generalized linear models to estimate the associations between network measures and ART adherence. PLWH at the Uganda site (compared with the South Africa site) were less isolated, had larger social networks, and had more social ties providing sufficient social support; they were also more likely to bridge different social groups whereby not all social ties were connected to each other. In Uganda, social isolation was associated with a 5.5 percentage point reduction in ART adherence (95% confidence interval [CI] -9.95 to -1.13; p = 0.014), while having more same gender social ties was associated with higher ART adherence (b = 0.13, 95% CI 0.02-0.25, p = 0.025). In South Africa, there was no association between social isolation and ART adherence, and having more friendship ties (vs. family ties) was associated with lower ART adherence (b = -2.20, 95% CI -3.56 to -0.84; p = 0.002). Identifying and supporting PLWH who are isolated may facilitate optimal adherence, but understanding how networks differentially affect ART adherence by country context is important.

HIV, Social Networks, and Loneliness among Older Adults in Uganda.

Loneliness among older adults has been identified as a major public health problem. Yet little is known about loneliness, or the potential role of social networks in explaining loneliness, among older people with HIV (PWH) in sub-Saharan Africa, where 70% of PWH reside. To explore this issue, we analyzed data from 599 participants enrolled in the Quality of Life and Ageing with HIV in Rural Uganda study, including older adults with HIV in ambulatory care and a comparator group of people without HIV of similar age and gender. The 3-item UCLA Loneliness Scale was used to measure loneliness, and HIV status was the primary explanatory variable. The study found no statistically significant correlation between loneliness and HIV status. However, individuals with HIV had smaller households, less physical and financial support, and were less socially integrated compared to those without HIV. In multivariable logistic regressions, loneliness was more likely among individuals who lived alone (aOR:3.38, 95% CI:1.47-7.76) and less likely among those who were married (aOR:0.34, 95% CI:0.22-0.53) and had a higher level of social integration (aOR:0.86, 95% CI: 0.79-0.92). Despite having smaller social networks and less support, older adults with HIV had similar levels of loneliness as those without HIV, which may be attributed to resiliency and access to HIV-related health services among individuals with HIV. Nonetheless, further research is necessary to better understand the mechanisms involved.

Electronic Antiretroviral Therapy Adherence Monitors and Associated Interventions Improve Adolescent-Caregiver Relationships and Self-Efficacy Among Adolescents and Young Adults with HIV in Uganda.

Many adolescents and young adults with HIV (AYWH) struggle with antiretroviral therapy (ART) adherence and experience poorer outcomes than adults. Relevant factors include forgetfulness and poor self-efficacy related to their evolving neurobiology. We qualitatively explored experiences of AYWH-caregivers dyads using real-time ART adherence monitors and associated reminder functions in the home setting. As part of an implementation science-oriented study, AYWH used the Wisepill adherence monitor for 3 months. AYWH could also opt for short message service (SMS) self-reminders, a self-selected social supporter for delayed or missed doses, or an alarm reminder. We conducted in-depth interviews with randomly selected AYWH-caregiver dyads regarding their experience using the monitor. Qualitative data were analyzed using inductive content analysis. We completed 15 AYWH-caregiver dyad interviews. Of the AYWH, 67% were female, mean age was 16 years, 56% lived with their biological mother, and 86% were virologically suppressed. AYWH and their caregivers generally found the adherence monitors acceptable, though some had privacy concerns. AYWH felt the monitors helped them take charge of their medication, largely through the real-time alarm and SMS reminders; this took the burden of adherence reminders away from the caregivers, improving strained AYWH-caregiver relationships. Two adolescents reported rebound poor adherence after monitor withdrawal. ART adherence monitors and associated tools were largely acceptable to AYWH and their caregivers in home settings. The intervention helped improve AYWH self-efficacy and alleviated burden from some AYWH-caregiver relationships. Rebound poor adherence suggests the need for on-going support and/or other means to achieve intrinsic mechanisms for sustained adherence. Clinical Trial Registration number: NCT03825952.

Population health impact, cost-effectiveness, and affordability of community-based HIV treatment and monitoring in South Africa: A health economics modelling study.

Community-based delivery and monitoring of antiretroviral therapy (ART) for HIV has the potential to increase viral suppression for individual- and population-level health benefits. However, the cost-effectiveness and budget impact are needed for public health policy. We used a mathematical model of HIV transmission in KwaZulu-Natal, South Africa, to estimate population prevalence, incidence, mortality, and disability-adjusted life-years (DALYs) from 2020 to 2060 for two scenarios: 1) standard clinic-based HIV care and 2) five-yearly home testing campaigns with community ART for people not reached by clinic-based care. We parameterised model scenarios using observed community-based ART efficacy. Using a health system perspective, we evaluated incremental cost-effectiveness and net health benefits using a threshold of $750/DALY averted. In a sensitivity analysis, we varied the discount rate; time horizon; costs for clinic and community ART, hospitalisation, and testing; and the proportion of the population receiving community ART. Uncertainty ranges (URs) were estimated across 25 best-fitting parameter sets. By 2060, community ART following home testing averted 27.9% (UR: 24.3-31.5) of incident HIV infections, 27.8% (26.8-28.8) of HIV-related deaths, and 18.7% (17.9-19.7) of DALYs compared to standard of care. Adolescent girls and young women aged 15-24 years experienced the greatest reduction in incident HIV (30.7%, 27.1-34.7). In the first five years (2020-2024), community ART required an additional $44.9 million (35.8-50.1) annually, representing 14.3% (11.4-16.0) of the annual HIV budget. The cost per DALY averted was $102 (85-117) for community ART compared with standard of care. Providing six-monthly refills instead of quarterly refills further increased cost-effectiveness to $78.5 per DALY averted (62.9-92.8). Cost-effectiveness was robust to sensitivity analyses. In a high-prevalence setting, scale-up of decentralised ART dispensing and monitoring can provide large population health benefits and is cost-effective in preventing death and disability due to HIV.

Association between cancer and dementia risk in the UK Biobank: evidence of diagnostic bias.

Epidemiological studies have identified an inverse association between cancer and dementia. Underlying methodological biases have been postulated, yet no studies have systematically investigated the potential for each source of bias within a single dataset. We used the UK Biobank to compare estimates for the cancer-dementia association using different analytical specifications designed to sequentially address multiple sources of bias, including competing risk of death, selective survival, confounding bias, and diagnostic bias. We included 140,959 UK Biobank participants aged ≥ 55 without dementia before enrollment and with linked primary care data. We used cancer registry data to identify cancer cases prevalent before UK Biobank enrollment and incident cancer diagnosed after enrollment. We used Cox models to evaluate associations of prevalent and incident cancer with all-cause dementia, Alzheimer's disease (AD), and vascular dementia. We used time-varying models to evaluate diagnostic bias. Over a median follow-up of 12.3 years, 3,310 dementia cases were diagnosed. All-site incident cancer was positively associated with all-cause dementia incidence (hazard ratio [HR] = 1.14, 95% CI: 1.02-1.29), but prevalent cancer was not (HR = 1.04, 95% CI: 0.92-1.17). Results were similar for vascular dementia. AD was not associated with prevalent or incident cancer. Dementia diagnosis was substantially elevated in the first year after cancer diagnosis (HR = 1.83, 95% CI: 1.42-2.36), after which the association attenuated to null, suggesting diagnostic bias. Following a cancer diagnosis, health care utilization or cognitive consequences of diagnosis or treatment may increase chance of receiving a dementia diagnosis, creating potential diagnostic bias in electronic health records-based studies.

Sexually Transmitted Infection Point-of-Care Testing in Resource-Limited Settings: A Narrative Review Guided by an Implementation Framework.

ABSTRACT: Most sexually transmitted infections (STIs) are acquired in resource-limited settings (RLSs) where laboratory diagnostic access is limited. Advancements in point-of-care testing (POC) technology have the potential to bring STI testing to many RLSs. We define POC as performed near the patient and with results readily available to inform clinical practice. The World Health Organization Special Programme for Research and Training in Tropical Diseases further outlines desirable POC characteristics with the REASSURED criteria.Despite advantages related to immediate test-and-treat care, integrating POC into RLS health care systems can present challenges that preclude reliance on these tests. In 2018, we incorporated molecular near-POC for chlamydia, gonorrhea, and trichomoniasis and SDBioline treponemal immunochromatographic testing confirmed by rapid plasma reagin for syphilis diagnosis at the Mbarara University of Science and Technology Research Laboratory in rural southwestern Uganda. We describe our experiences with STI POC as a case example to guide a narrative review of the field using the Consolidated Framework for Implementation Research as a conceptual framework.Although POC and near-POC are described as easy to use, the challenges of limited person-power, health care processes, limited infrastructure/resources, high costs, and quality control obstacles can impede the impact of these tests. Increased investment in operators, training, and infrastructure, restructuring health care systems to accommodate increased POC access, and optimizing costs are all crucial to the successful implementation of STI POC in RLS. Expanded STI POC in RLS will increase access to accurate diagnoses, appropriate treatment, and engagement in partner notification, treatment, and prevention efforts.

Factors Associated With Changes in Alcohol Use During Pregnancy and the Postpartum Transition Among People With HIV in South Africa and Uganda.

Identifying factors associated with alcohol use changes during pregnancy is important for developing interventions for people with HIV (PWH). Pregnant PWH (n = 202) initiating antiretroviral therapy in Uganda and South Africa completed two assessments, 6 months apart (T1, T2). Categories were derived based on AUDIT-C scores: "no use" (AUDIT-C = 0 at T1 and T2), "new use" (AUDIT-C = 0 at T1, >0 at T2), "quit" (AUDIT-C > 0 at T1, =0 at T2), and "continued use" (AUDIT-C > 0, T1 and T2). Factors associated with these categories were assessed. Most participants had "no use" (68%), followed by "continued use" (12%), "quit" (11%), and "new use" (9%). Cohabitating with a partner was associated with lower relative risk of "continued use." Borderline significant associations between food insecurity and higher risk of "new use" and between stigma and reduced likelihood of "quitting" also emerged. Alcohol use interventions that address partnership, food security, and stigma could benefit pregnant and postpartum PWH.

Associations of the COVID-19 pandemic with quality of life: A cross-sectional study of older-age people with and without HIV in rural Uganda.

Background: COVID-19-related lockdowns and other public health measures may have differentially affected the quality of life (QOL) of older people with and without human immunodeficiency virus (HIV) in rural Uganda. Methods: The Quality of Life and Aging with HIV in Rural Uganda study enrolled people with and without HIV aged over 49 from October 2020 to October 2021. We collected data on COVID-19-related stressors (behavior changes, concerns, interruptions in health care, income, and food) and the participants' QOL. We used linear regression to estimate the associations between COVID-19-related stressors and QOL, adjusting for demographic characteristics, mental and physical health, and time before vs after the lockdown during the second COVID-19 wave in Uganda. Interaction between HIV and COVID-19-related stressors evaluated effect modification. Results: We analyzed complete data from 562 participants. Mean age was 58 (standard deviation (SD) = 7); 265 (47%) participants were female, 386 (69%) were married, 279 (50%) had HIV, and 400 (71%) were farmers. Those making ≥5 COVID-19-related behavior changes compared to those making ≤2 had worse general QOL (estimated linear regression coefficient (b) = - 4.77; 95% confidence interval (CI) = -6.61, -2.94) and health-related QOL (b = -4.60; 95% CI = -8.69, -0.51). Having access to sufficient food after the start of the COVID-19 pandemic (b = 3.10, 95% CI = 1.54, 4.66) and being interviewed after the start of the second lockdown (b = 2.79, 95% CI = 1.30, 4.28) were associated with better general QOL. Having HIV was associated with better health-related QOL (b = 5.67, 95% CI = 2.91,8.42). HIV was not associated with, nor did it modify the association of COVID-19-related stressors with general QOL. Conclusions: In the context of the COVID-19 pandemic in an HIV-endemic, low-resource setting, there was reduced QOL among older Ugandans making multiple COVID-19 related behavioral changes. Nonetheless, good QOL during the second COVID-19 wave may suggest resilience among older Ugandans.

The benefits of care: treated HIV infection and health-related quality of life among older-aged people in Uganda.

OBJECTIVES: The objective of this study is to explore how HIV care affects health-related quality of life (HRQoL) among older people in Uganda. METHODS: We enrolled older-aged (≥49 years) people with HIV receiving HIV care and treatment, along with age- and sex-similar people without HIV. We measured health-related quality of life using the EQ-5D-3L scale. RESULTS: People with HIV (n = 298) and people without HIV (n = 302) were similar in median age (58.4 vs. 58.5 years), gender, and number of comorbidities. People with HIV had higher self-reported health status (b = 7.0; 95% confidence interval [CI], 4.2-9.7), higher EQ-5D utility index (b = 0.05; 95% CI, 0.02-0.07), and were more likely to report no problems with self-care (adjusted odds ratio [AOR], 2.0; 95% CI, 1.2-3.3) or pain/discomfort (AOR = 1.8, 95% CI, 1.3-2.8). Relationships between HIV serostatus and health-related quality of life differed by gender, but not age. CONCLUSIONS: Older people with HIV receiving care and treatment reported higher health-related quality of life than people without HIV in Uganda. Access to primary care through HIV programs and/or social network mobilization may explain this difference, but further research is needed to elucidate the mechanisms.

Factors Associated with 30-Day in-Hospital Mortality Among Patients Admitted with Severe Covid-19 in Mbarara Regional Referral Hospital.

Background: COVID-19 has created a burden on the healthcare system globally. Severe COVID-19 is linked with high hospital mortality. Data regarding 30-day in-hospital mortality and its factors has not been explored in southwestern Uganda. Methods: We carried out a retrospective, single-center cohort study, and included all in-patients with laboratory-confirmed, radiological, or clinical severe COVID-19 admitted between April 2020 and September 2021 at Mbarara Regional Referral Hospital (MRRH). Demographic, laboratory, treatment, and clinical outcome data were extracted from patients' files. These data were described comparing survivors and non-survivors. We used logistic regression to explore the factors associated with 30-day in-hospital mortality. Results: Of the 283 patients with severe COVID-19 admitted at MRRH COVID-19 unit, 58.1% were male. The mean age ± standard deviation (SD) was 61±17.4 years; there were no differences in mean age between survivors and non-survivors (59 ± 17.2 versus 64.4 ±17.3, respectively, p=0.24) The median length of hospital stay was 7 (IQR 3-10) days (non-survivors had a shorter median length of stay 5 (IQR 2-9) days compared to the survivors; 8 (IQR 5-11) days, p<0.001. The most frequent comorbidities were hypertension (30.5%) and diabetes mellitus (30%). The overall 30-day in-hospital mortality was 134 of 279 (48%) mortality rate of 47,350×105 with a standard error of 2.99%. The factors associated with 30-day in-hospital mortality were age: 65 years and above (aOR, 3.88; 95% CI, 1.24-11.70; P =0.020) a neutrophil to lymphocyte ratio above 5 (aOR, 4.83; 95% CI, 1.53-15.28; P =0.007) and oxygen requirement ≥15L/min (aOR, 15.80; 95% CI, 5.17-48.25; P <0.001). Conclusion: We found a high 30-day in-hospital mortality among patients with severe forms of COVID-19. The identified factors could help clinicians to identify patients with poor prognosis at an early stage of admission.

Antiretroviral therapy adherence patterns, virological suppression, and emergence of drug resistance: A nested case-control study from Uganda and South Africa.

BACKGROUND: Relationships between distinct antiretroviral therapy (ART) adherence patterns and risk of drug resistance are not well understood. METHODS: We conducted a nested case-control analysis within a longitudinal cohort study of individuals initiating efavirenz-based ART. Primary outcomes of interest, measured at 6 and 12 months after treatment initiation, were: 1) virologic suppression, 2) virologic failure with resistance, and 3) virologic failure without resistance. Our primary exposure of interest was ART adherence, measured over the 6 months before each visit with electronic pill monitors, and categorized in three ways: 1) 6 months average adherence; 2) running adherence, defined as the proportion of days with average adherence over 9 days of less than or equal to 10%, 20%, and 30%; and 3) number of 3-, 7-, and 28-day treatment gaps in the prior 6 months. RESULTS: We analyzed data from 166 individuals (107 had virologic failure during observation and 59 had virologic suppression at 6 and 12 months). Average adherence was higher among those with virologic suppression (median 83%, IQR 58-96%) versus those with virologic failure with resistance (median 35%, IQR 20-77%, pairwise P < 0.01) and those with virologic failure without resistance (median 21%, IQR 2-54%, pairwise P < 0.01). Although treatment gaps generally predicted virologic failure (P < 0.01), they did not differentiate failure with and without drug resistance (P > 0.6). CONCLUSIONS: Average adherence patterns, but not the assessed frequency of treatment gaps, differentiated failure with versus without drug resistance among individuals initiating efavirenz-based ART. Future work should explore adherence-resistance relationships for integrase inhibitor-based regimens.

Priorities for health and wellbeing for older people with and without HIV in Uganda: a qualitative methods study.

INTRODUCTION: With improved HIV treatment availability in sub-Saharan Africa, the population of older people with HIV (PWH) is growing. In this qualitative study, we intended to understand (1) the lived experiences of ageing people in rural Uganda, with and without HIV, (2) their fears and health priorities as they grow older. METHODS: We conducted 36 semi-structured interviews with individuals with and without HIV in Mbarara, Uganda from October 2019 to February 2020. Interview guide topics included priorities in older age, physical functioning in daily activities, social functioning, HIV-related stigma and the impact of multimorbidity on health and independence. Interviews were conducted in Runyankole, transcribed, translated and inductively coded thematically by two researchers with tests for inter-coder reliability. RESULTS: The respondents were purposively sampled to be evenly divided by sex and HIV serostatus. The median age of respondents was 57 (49-73). Two-thirds were married or cohabitating, 94% had biological children and 75% cited farming as their primary livelihood. Overall, PWH considered themselves as healthy or healthier than people without HIV (PWOH). PWH rarely considered their HIV status a barrier to a healthy life, but some reported a constant sense of anxiety as it relates to their long-term health. Irrespective of HIV status, nearly all respondents noted concerns about memory loss, physical pain, reductions in energy and the effect of these changes on their ability to complete physical tasks like small-scale farming, and activities of daily living important to the quality of life, such as participating in community groups. Increasing reliance on others for social, physical and financial support was also a common theme. The most prevalent health concern among participants involved the threat of non-communicable diseases and perceptions that physical functioning may diminish. CONCLUSIONS: In rural Uganda, we found that PWH consider themselves to be healthy and do not anticipate a different ageing experience from PWOH. Common priorities shared by both groups included the desire for physical and financial independence, health maintenance and social support for daily functioning and social needs. Entities supporting geriatric care in Uganda would benefit from attention to concerns about functional limitations and reported needs as people age with and without HIV.

Implementation of Electronic Adherence Monitors and Associated Interventions for Routine HIV Antiretroviral Therapy in Uganda: Promising Findings.

Background: High, sustained adherence is critical for achieving the individual and public health benefits of HIV antiretroviral therapy (ART). Electronic monitors provide detailed adherence information and can enable real-time interventions; however, their use to date has largely been confined to research. This pilot study (NCT03825952) sought to understand feasibility and acceptability a relatively low-cost version of this technology and associated interventions for routine ART delivery in sub-Saharan Africa. Methods: We provided two ART clinics in rural, southwestern Uganda with electronic adherence monitors for data-informed counseling as well as optional SMS messages to clients and/or social supporters (daily or triggered by missed or delayed doses) and/or an alarm. Clinic and ART client experiences were observed for 3 months per client, including time and motion studies. Qualitative interviews among clients, clinicians, and healthcare administrators were informed by the Consolidated Framework for Implementation Research. Results: Fifty-one ART clients were enrolled; 57% were male and the median age was 34 years. Choice of associated intervention varied among participants. The median number of visits during follow-up was two per client. Counselors reviewed the adherence data with 90% of clients at least once; 67% reviewed data at all visits. Average adherence was 94%; four clients had adherence gaps >1 week. Acceptability was high; all but one client found the monitor "very useful" and all found SMS "very useful." Clinic visits among clients with the intervention lasted 4 min longer on average than those in standard care. The monitors and daily SMS generally functioned well, although excess SMS were triggered, primarily due to cellular network delays. Overall, participants felt the technology improved adherence, clinic experiences, and clinician-client relationships. Few worried about stigma and privacy. Cost was a concern for implementation, particularly at scale. Conclusion: We successfully implemented a relatively low-cost electronic ART adherence monitor and associated interventions for routine care in rural Uganda. Feasibility and acceptability were generally high, and individuals were identified who could benefit from adherence support. Future work should involve longitudinal follow-up of diverse populations, clinical outcomes, and detailed cost-effectiveness analysis to help drive policy decisions around the uptake of this technology for routine clinical care. Clinical Trial Registration: identifier: NCT03825952.

Association of Genetic Variants Linked to Late-Onset Alzheimer Disease With Cognitive Test Performance by Midlife.

Importance: Identifying the youngest age when Alzheimer disease (AD) influences cognition and the earliest affected cognitive domains will improve understanding of the natural history of AD and approaches to early diagnosis. Objective: To evaluate the age at which cognitive differences between individuals with higher compared with lower genetic risk of AD are first apparent and which cognitive assessments show the earliest difference. Design, Setting, and Participants: This cross-sectional study used data from UK Biobank participants of European genetic ancestry, aged 40 years or older, who contributed genotypic and cognitive test data from January 1, 2006, to December 31, 2015. Data analysis was performed from March 10, 2020, to January 4, 2022. Exposure: The AD genetic risk score (GRS), which is a weighted sum of 23 single-nucleotide variations. Main Outcomes and Measures: Seven cognitive tests were administered via touchscreen at in-person visits or online. Cognitive domains assessed included fluid intelligence, episodic memory, processing speed, executive functioning, and prospective memory. Multiple cognitive measures were derived from some tests, yielding 32 separate measures. Interactions between age and AD-GRS for each of the 32 cognitive measures were tested with linear regression using a Bonferroni-corrected P value threshold. For cognitive measures with significant evidence of age by AD-GRS interaction, the youngest age of interaction was assessed with new regression models, with nonlinear specification of age terms. Models with youngest age of interaction from 40 to 70 years, in 1-year increments, were compared, and the best-fitting model for each cognitive measure was chosen. Results across cognitive measures were compared to determine which cognitive indicators showed earliest AD-related change. Results: A total of 405 050 participants (mean [SD] age, 57.1 [7.9] years; 54.1% female) were included. Sample sizes differed across cognitive tests (from 12 455 to 404 682 participants). The AD-GRS significantly modified the association with age on 13 measures derived from the pairs matching (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.5%-11.5%), symbol digit substitution (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.0%-5.8%), and numeric memory tests (difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 8.8%) (P = 1.56 × 10-3). Best-fitting models suggested that cognitive scores of individuals with a high vs low AD-GRS began to diverge by 56 years of age for all 13 measures and by 47 years of age for 9 measures. Conclusions and Relevance: In this cross-sectional study, by early midlife, subtle differences in memory and attention were detectable among individuals with higher genetic risk of AD.

Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). METHODS: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. CONCLUSIONS: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03334747).

High residual inflammation despite HIV viral suppression: Lessons learned from real-time adherence monitoring among people with HIV in Africa.

BACKGROUND: Lower antiretroviral therapy (ART) adherence is associated with higher systemic inflammation in virally suppressed people with HIV (PWH); however, previous studies have mostly relied on subjective adherence measures and have not assessed this association by disease stage upon ART initiation. METHODS: In the Monitoring Early Treatment Adherence study, adherence was monitored electronically in real time among adult, treatment-naïve PWH in Uganda and South Africa who initiated tenofovir disoproxil fumarate/emtricitabine/efavirenz during early-stage (CD4 > 350 cells/µL) or late-stage (CD4 < 200 cells/µL) disease. Participants who achieved viral suppression (< 400 copies/mL) at 6 months and remained suppressed after 12 months were analysed. The association between average ART adherence and plasma concentrations of interleukin 6 (IL-6), soluble CD14 (sCD14) and D-dimer was evaluated using adjusted multivariable linear regression, stratified by disease stage. RESULTS: In all, 488 PWH (61% women, mean age 35 years) were included in the analysis. Median ART adherence overall was 87%. In adjusted models, every 10% increase in average adherence was associated with a 3.0% decrease in IL-6 [95% confidence interval (CI): -5.9 to -0.01, p = 0.05] at 12 months. This relationship was observed in PWH with both early-stage (5.9%, 95% CI: -10.1 to -1.6, p = 0.009) and late-stage disease (3.7%, 95% CI: -7.2 to -0.2, p = 0.039). No significant associations were found with sCD14 or D-dimer. CONCLUSIONS: Objective ART adherence measurement was inversely associated with systemic inflammation in PWH who achieved viral suppression after ART initiation in sub-Saharan Africa, with a greater association in those with early-stage HIV. This finding underscores the importance of ART adherence beyond establishing viral suppression.

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa.

BACKGROUND: The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether-lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. METHODS: This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether-lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. RESULTS: Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether-lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether-lumefantrine. Cipargamin was well tolerated with no safety concerns. CONCLUSIONS: This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin. Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202.