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Journal articleSun W, Gao C, Gladkov GT, et al., 2024,
Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection
, Journal of Experimental Medicine, Vol: 221, ISSN: 0022-1007Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.
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Journal articleWinston A, Henderson M, 2024,
Our evolving understanding of the impact of primary HIV infection on brain health.
, Brain, Vol: 147, Pages: 3643-3644 -
Journal articleCockbain B, Fidler S, Lyall H, 2024,
Preventing perinatal HIV acquisition; current gaps and future perspectives.
, Curr Opin HIV AIDS, Vol: 19, Pages: 293-304PURPOSE OF REVIEW: Although current treatment could eradicate vertical transmission, in 2022, 130 000 infants acquired HIV globally. HIV suppression with antiretroviral therapy (ART) transforms survival for people living with HIV (PLWH), and prevents transmission, including vertical. International guidelines recommend lifelong ART for PLWH, consequently perinatal HIV acquisition reflects implementation gaps in the HIV care cascade. We summarize these gaps, exploring potential novel approaches and therapeutic innovations towards eliminating vertical HIV transmission. RECENT FINDINGS: Multifactorial challenges continue to underpin gaps in the HIV care cascade, including accessibility, availability and sustainability of HIV testing, prevention and treatment, alongside stigma, gender-based violence and poverty. Long-acting ART may be important in preventing perinatal HIV acquisition, with early data demonstrating tolerability and efficacy of injectable ART throughout pregnancy, both as HIV treatment and prevention. Carefully selected long-acting broadly neutralizing antibodies (bNAbs) matching circulating, exposing viral envelope sequences have demonstrated safety, clinical trials are ongoing to demonstrate efficacy. SUMMARY: Emerging clinical studies should prioritize pregnant/lactating people and infants to ensure such therapies are well tolerated and efficacious. Alongside therapeutic innovation, programmatic strategies must address social and economic challenges, ensuring sustainable HIV treatment/prevention programmes and facilitating global elimination of blood-borne viruses.
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Journal articleTipoe T, Ogbe A, Lee M, et al., 2024,
Impact of antiretroviral therapy during primary HIV infection on T-cell immunity after treatment interruption.
, Eur J Immunol, Vol: 54This study aims to understand the impact of early antiretroviral therapy (ART) on HIV-specific T-cell responses measured after treatment interruption, which may inform strategies to deliver ART-free immune-mediated viral suppression. HIV-specific T-cell immunity was analysed using gamma interferon enzyme-linked immunospot assays in two studies. SPARTAC included individuals with primary HIV infection randomised to 48 weeks of ART (n = 24) or no immediate therapy (n = 37). The PITCH (n = 7) cohort started antiretroviral therapy in primary infection for at least one year, followed by TI. In SPARTAC, participants treated in PHI for 48 weeks followed by TI for 12 weeks, and those who remained untreated for 60 weeks made similar HIV Gag-directed responses (both magnitude and breadth) at week 60. However, the treated group made a greater proportion of novel HIV Gag-directed responses by Week 60, suggestive of a greater reserve to produce new potentially protective responses. In the more intensively followed PITCH study, 6/7 participants showed dominant Gag and/or Pol-specific responses post-TI compared with pre-TI. Although early ART in PHI was not associated with major differences in HIV-specific immunity following TI compared with untreated participants, the potential to make more new Gag-directed responses warrants further investigation as this may inform strategies to achieve ART-free control.
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Journal articleLazzarino R, Borek AJ, Honeyford K, et al., 2024,
Views and Uses of Sepsis Digital Alerts in National Health Service Trusts in England: Qualitative Study With Health Care Professionals.
, JMIR Hum Factors, Vol: 11BACKGROUND: Sepsis is a common cause of serious illness and death. Sepsis management remains challenging and suboptimal. To support rapid sepsis diagnosis and treatment, screening tools have been embedded into hospital digital systems to appear as digital alerts. The implementation of digital alerts to improve the management of sepsis and deterioration is a complex intervention that has to fit with team workflow and the views and practices of hospital staff. Despite the importance of human decision-making and behavior in optimal implementation, there are limited qualitative studies that explore the views and experiences of health care professionals regarding digital alerts as sepsis or deterioration computerized clinician decision support systems (CCDSSs). OBJECTIVE: This study aims to explore the views and experiences of health care professionals on the use of sepsis or deterioration CCDSSs and to identify barriers and facilitators to their implementation and use in National Health Service (NHS) hospitals. METHODS: We conducted a qualitative, multisite study with unstructured observations and semistructured interviews with health care professionals from emergency departments, outreach teams, and intensive or acute units in 3 NHS hospital trusts in England. Data from both interviews and observations were analyzed together inductively using thematic analysis. RESULTS: A total of 22 health care professionals were interviewed, and 12 observation sessions were undertaken. A total of four themes regarding digital alerts were identified: (1) support decision-making as nested in electronic health records, but never substitute professionals' knowledge and experience; (2) remind to take action according to the context, such as the hospital unit and the job role; (3) improve the alerts and their introduction, by making them more accessible, easy to use, not intrusive, more accurate, as well as integrated across the whole health care system; and (4) contextual factors affectin
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Journal articleMahdifar M, Boostani R, Taylor GP, et al., 2024,
Comprehensive insight into the functional roles of NK and NKT cells in HTLV-1-associated diseases and asymptomatic carriers
, Molecular Neurobiology, Vol: 61, Pages: 7877-7889, ISSN: 0893-7648Human T cell leukemia virus type 1 (HTLV-1) is the first human oncogenic retrovirus to be discovered and causes two major diseases: a progressive neuro-inflammatory disease, termed HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and an aggressive malignancy of T lymphocytes known as adult T cell leukemia (ATL). Innate and acquired immune responses play pivotal roles in controlling the status of HTLV-1-infected cells and such, the outcome of HTLV-1 infection. Natural killer cells (NKCs) are the effector cells of the innate immune system and are involved in controlling viral infections and several types of cancers. The ability of NKCs to trigger cytotoxicity to provide surveillance against viruses and cancer depends on the balance between the inhibitory and activating signals. In this review, we will discuss NKC function and the alterations in the frequency of these cells in HTLV-1 infection.
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Journal articleWhitlock G, Fidler S, Clarke A, et al., 2024,
A randomised control trial of BIC/F/TAF vs DRV/c/F/TAF in context of HIV test-and-treat, BicTnT
, HIV Research & Clinical Practice, Vol: 25, ISSN: 2578-7489Background:Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test‐and‐treat setting.Setting:BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV‐1 diagnosis before baseline laboratory.Methods:The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test.Results:36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events.Conclusion:In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.
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Journal articleThao MNL, Quoc GN, An MDT, et al., 2024,
Impact of a community-based participatory research project with underserved communities at risk for hepatitis C virus in Ho Chi Minh City, Vietnam: an evaluation study.
, Res Involv Engagem, Vol: 10BACKGROUND: Participatory approaches have become a widely applied research approach. Despite their popularity, there are many challenges associated with the evaluation of participatory projects. Here we describe an evaluation of a community-based participatory research study of underserved communities in Ho Chi Minh City (HCMC), Vietnam at risk for hepatitis C virus. The goals of our evaluation were to explore the main benefits and challenges of implementing and participating in a participatory study and to describe study impacts. METHODS: We conducted two meetings with leaders and members of the participating groups followed by in-depth interviews with 10 participants. We then held a dissemination meeting with over 70 participants, including the representatives of each group, researchers from non-governmental organizations (community-based, national and international), and govenrment officials from the Vietnam Ministry of Health and the Department of Health of HCMC. RESULTS: Results include four categories where we describe first the participatory impacts, followed by the collaborative impacts. Then we describe the benefits and challenges of creating and belonging to one of the groups, from members' and leaders' points of view. Finally, we describe the key suggestions that participants provided for future research. CONCLUSION: In conclusion, the evaluation approach led to both a research reflection on the 'success' of the project and enabled participants themselves to reflect on the outcomes and benefits of the study from their point of view.
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Journal articleLee MJ, Eason M, Castagna A, et al., 2024,
The impact of analytical treatment interruptions and trial interventions on time to viral re-suppression in people living with HIV restarting ART in cure-related clinical studies: a systematic review and meta-analysis.
, J Int AIDS Soc, Vol: 27INTRODUCTION: To assess the effectiveness of novel HIV curative strategies, "cure" trials require periods of closely monitored antiretroviral therapy (ART) analytical treatment interruptions (ATIs). We performed a systematic review and meta-analysis to identify the impact of ATI with or without novel therapeutics in cure-related studies on the time to viral re-suppression following ART restart. METHODS: Medline, Embase and Web of Science databases were searched for human studies involving ATIs from 1 January 2015 till 22 April 2024. The primary outcome was time to first viral re-suppression (plasma HIV viral load [VL] <50 copies/ml) stratified by receipt of interventional drug with ATI (IA) or ATI-only groups. Random-effects proportional meta-analysis and multivariable Cox proportional hazards analysis were performed using R. RESULTS: Of 1073 studies screened, 13 were included that met the inclusion criteria with VL data available after restarting ART (n = 213 participants). There was no difference between time to viral suppression in IA or ATI-only cohorts (p = 0.22). For 87% of participants, viral suppression within 12 weeks of ART restart was achieved, and all eventually had at least one VL <50 copies/ml during follow-up. After adjusting for covariables, while participants in the IA cohort were associated with less rapid suppression (adjusted hazard ratio [aHR] 0.61, 95% CI 0.40-0.94, p = 0.026), other factors include greater log VL at ART restart (aHR 0.56, 95% CI 0.46-0.68, p<0.001), duration since HIV diagnosis (aHR 0.93, 95% CI 0.89-0.96) and longer intervals between HIV VL monitoring (aHR 0.66, 95% CI 0.59-0.74, p<0.001). However, the use of integrase inhibitors was associated with more rapid viral suppression (aHR 1.74, 95% CI 1.16-2.59). DISCUSSION: When designing studies involving ATIs, information on time to viral re-suppression after restarting ART is important to share with participants, and should be regularly monitored and repor
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Journal articleSteinhaus MC, Nicholson TJ, Pliakas T, et al., 2024,
Prevalence and risk of burnout among HIV service providers in South Africa and Zambia: findings from the HPTN 071 (PopART) trial.
, Hum Resour Health, Vol: 22BACKGROUND: In the high disease burden and resource-constrained contexts of sub-Saharan Africa (SSA), health workers experience a range of psychosocial stressors that leave them vulnerable to developing burnout, which can reduce service quality and negatively impact their own health and wellbeing. As universal testing and treatment (UTT) for HIV scales up across SSA, we sought to understand the implications of this human resource-intensive approach to HIV prevention to inform decision-making about health workforce staffing and support needs. METHODS: Using the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), we assessed the prevalence of three domains of burnout-emotional exhaustion, depersonalization, and personal accomplishment-among three cadres of health workers delivering health services in areas receiving a UTT intervention in Zambia and South Africa. These cadres included health facility workers (n = 478), community health workers (n = 159), and a study-specific cadre of community HIV care providers (n = 529). We used linear regression to assess risk factors associated with emotional exhaustion, the only domain with sufficient variation in our sample. RESULTS: The MBI-HSS was completed by 1499/2153 eligible participants (69.6% response rate). Less than 1% of health workers met Maslach's definition for burnout. All groups of health workers reported lower levels of emotional exhaustion than found in previous studies of this type (mean score scores ranged from 10.7 to 15.4 out of 54 across health cadres). Higher emotional exhaustion was associated with higher educational attainment (βadj = 2.24, 95% CI 0.76 to 3.72), greater years providing HIV services (βadj = 0.20, 95% CI 0.03 to 0.36), and testing negative for HIV at last HIV test (βadj = - 3.88 - 95% CI 5.69 to - 2.07). Working as a CHW was significantly associated with lower emot
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