Antiretroviral Research Articles

Real-World Effectiveness and Tolerability of Dolutegravir and Lamivudine 2-Drug Regimen in People Living with HIV: Systematic Literature Review and Meta-Analysis.

Dolutegravir (DTG) + lamivudine (3TC) demonstrated high rates of virologic suppression (VS) and low rates of virologic failure (VF), discontinuation, and drug resistance in randomized trials. Real-world evidence can support treatment effectiveness, safety, and tolerability in clinical practice and aid in treatment decisions. A systematic literature review (SLR) was conducted to identify studies using DTG + 3TC (January 2013-March 2024). Studies were screened to include observational studies reporting 48- or 96-week on-treatment VS, VF, or discontinuation outcomes; proportions of individuals with each outcome at each time point were estimated using random- and common-effects models. Of 249 SLR-identified publications, 43 reported consistently defined outcomes of interest at comparable time points, representing 1480 individuals naive to antiretroviral therapy (ART) and 12,234 individuals with prior ART experience. At weeks48 and 96, respectively, estimated proportions (95%CIs; random-effects model) with on-treatment VS were high (naive to ART, 0.964 [0.945-0.979] and 0.902 [0.816-0.966]; prior ART, 0.966 [0.950-0.980] and 0.971 [0.946-0.990]), with low estimated proportions experiencing VF (naive to ART, 0.001 [0.000-0.013] and 0.001 [0.000-0.008]; prior ART, 0.009 [0.005-0.015] and 0.015 [0.007-0.024]) and discontinuations for any reason (naive to ART, 0.052 [0.019-0.097] and 0.130 [0.084-0.183]; prior ART, 0.067 [0.042-0.098] and 0.084 [0.047-0.130]). Across identified studies (> 44,000 unique individuals), those reporting resistance outcomes at VF/blip (regardless of emergence) detected integrase strand transfer inhibitor (INSTI) mutations in 0 of 2346 individuals naive to ART and 0.02% (4/20,060) of individuals with prior ART experience (S147G, R263K, G118R + E138K, T66A + G118R + E138K); additionally, N155H was reported in an individual using DTG + 3TC with unknown baseline ART status. Overall treatment outcomes in real-world settings confirm the efficacy, tolerability, and high barrier to resistance seen in phase3 trials across diverse populations, including those naive to ART or with prior ART experience.

Transcriptomic Profiling and Tumor Microenvironment Classification Reveal Unique and Dynamic Immune Biology in HIV-Associated Kaposi Sarcoma

Kaposi Sarcoma (KS) is a vascular tumor originating from endothelial cells and is associated with human herpesvirus 8 (KSHV) infection. It disproportionately affects populations facing health disparities. Although antiretroviral therapy (ART) has improved KS control in people with HIV (PWH), treatment options for advanced KS remain limited. This study investigates the tumor microenvironment (TME) of KS through whole-transcriptomic profiling, analyzing changes over time and differences based on HIV status. The TME was categorized into four subtypes: immune-enriched (IE), non-fibrotic, immune-enriched/fibrotic (IE/F), fibrotic (F) and immune-depleted (D). Nine KS patients (four HIV-negative and five HIV-positive) were enrolled in the study. Longitudinally collected KS samples from three patients (one HIV-negative and two HIV-positive) allowed for the investigation of dynamic TME changes within individual patients. The immune cellular composition was determined using deconvolution and compared to a cohort of non-KS patients. Our findings revealed that all KS samples, regardless of HIV status, were enriched in endothelial cells. Compared to non-KS tissues, the KS samples contained a higher percentage of NK and CD8+ T cells. HIV-negative KS samples displayed the IE and IE/F TME subtypes, while HIV-positive samples exhibited IE, IE/F, and F subtypes. Over the course of the disease, a decrease in angiogenic signatures was observed in two HIV-positive KS patients. Notably, HIV-negative KS samples showed alterations in NK cell-mediated immunity and cytotoxic response pathways, whereas HIV-positive samples exhibited changes in growth regulation and protein kinase activity pathways at the time of initial diagnosis. The gene expression of immune checkpoints, including CD274 (PD-L1) and PDCD1LC2 (PD-L2), was comparable between HIV-positive and HIV-negative KS samples at diagnosis. Furthermore, sequencing identified a shared TCRβ chain in all patients analyzed, indicating a T-cell immune response to a common antigen. This study demonstrates unique transcriptomic features and TME subtypes in KS that differ based on HIV status. Additionally, it illustrates longitudinal dynamic changes in the gene signatures and TME subtypes in individual patients. The identification of a shared TCRβ chain suggests that immune T cells in KS patients may target a common antigen. Future studies should further explore the immune microenvironment and unique T cell clonotypes, which could pave the way for the development of novel therapeutic strategies for KS patients.

Evaluation of preventive medicine amongst people living with human immunodeficiency virus attending a hospital-based care setting.

With improved outcomes in human immunodeficiency virus (HIV) due to the use of anti-retroviral therapy, ensuring adequate preventative healthcare and management of HIV-related comorbidities is essential. To evaluate adherence with recommended guidelines for comorbidity and immunisation status screening amongst people living with HIV within a hospital-based setting across two timepoints. A single-centre retrospective case series was conducted at a hospital between 2011 and 2021. Inclusion criteria were ≥18 years, confirmed diagnosis of HIV and commencement of care within study period. Medical data were reviewed over two 12-month periods to capture comorbidity screening and vaccination adherence using established guidelines (Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine, Alfred Screening tool and Australian Technical Advisory Group recommendations). Descriptive statistics were obtained with IBM spss (version 29.0). Of 102 patients, 82 (80.4%) were male and 55 (53.9%) born overseas. Nineteen (18.6%) patients entered in 2011, with a median of 36.5 months from service entry to exit. Within 12 months of entry 56 (55.4%) participants had influenza vaccination recorded. Within the last 12 months, 94.8% had recorded COVID-19 vaccination, with improvements in pneumococcal (72.3%) and hepatitis B (82.8%) since service entry. Recording of comorbidity screening was >90% for blood pressure, weight and renal function at both timepoints, however, suboptimal (<10%) for substance misuse, cognitive and osteoporosis screening. There is a disparity amongst comorbidity screening and documentation of vaccination status. Further measures are required to target improvements in immunisation, bone health, substance misuse and cognitive impairment screening.

Safety, Tolerability, and Pharmacokinetics of Long-Acting Broadly Neutralizing HIV-1 Monoclonal Antibody VRC07523LS in Newborn Infants Exposed to HIV-1.

Vertical HIV-1 transmission despite antiretroviral therapy may be mitigated by use of long-acting, broadly neutralizing, monoclonal antibodies (bNAb) such as VRC07523LS. The present study was designed to determine the safety and pharmacokinetics of VRC07523LS. VRC07523LS, 80mg/dose, was administered subcutaneously after birth to non-breastfed (Cohort 1; N=11, enrolled in USA) and breastfed (Cohort 2; N=11, enrolled in South Africa and Zimbabwe) infants exposed to HIV-1. Breastfed infants (Cohort 2) received a second 100-mg dose at 12 weeks if still receiving breastmilk. All infants received antiretroviral prophylaxis in addition to VRC07523LS. VRC07523LS levels were compared to VRC01 levels, as determined previously in this study. Local reactions (all Grade ≤2) occurred after Dose 1 in 18% of infants in Cohort 1 and after Doses 1 and 2 in 100% of infants in Cohort 2. The VRC07523LS dose at birth (mean 26mg/kg) achieved a mean±SD plasma level of 222.3±71.6 mcg/mL by 24 hours and 18.4±7.2 mcg/mL at Week 12, prior to Dose 2. The pre-established target of ≥10 mcg/mL at Week 12 was met in 94% of infants. The terminal half-life of VRC07523LS was observed to be 39.2±5.0 days. At Week 4 and Week 8, bNAb levels were significantly higher (p≤0.002) after one dose of VRC07523LS, compared to one dose of VRC01 (20mg/kg). No infant included in the study acquired HIV-1. VRC07523LS was well tolerated with pharmacokinetics that support further studies of potent long-acting bNAbs together with antiretrovirals to prevent HIV-1 acquisition in infants.

MicroRNA in neuroexosome as a potential biomarker for HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorder (HAND) is a complication of chronic inflammation caused by HIV infection that impairs cognitive and motor functions. HAND can occur at any age, regardless of the duration of infection, even in people living with HIV (PLWH) whose blood viral load is controlled by antiretroviral therapy. The diagnosis of HAND requires a battery of neuropsychological tests, which is time-consuming and burdensome, limiting its effectiveness for screening PLWH. Here, we aimed to identify biomarkers for quantitatively diagnosing and screening for HAND using minimally invasive blood tests. Neuronal-derived exosomes (neuroexosomes) were isolated from the peripheral blood of PLWH, and the transcriptomes of their microRNAs (miRNAs) were analyzed. We identified five upregulated miRNAs (hsa-miR-16-5p, hsa-miR-26a-3p, hsa-92a-3p, hsa-miR-103a-3p, and hsa-miR-185-5p), and two downregulated miRNA (hsa-miR-3613-3p and hsa-miR-4668-5p) in PLWH diagnosed with HAND (HAND PLWH). Functional analysis of five miRNAs whose expression levels increased in HAND PLWH using the database showed that these miRNAs are involved in motor proteins and endocytosis, which are associated with nerve function. The expression levels of hsa-miR-16-5p, hsa-miR-103a-3p, and hsa-miR-185-5p were significantly higher than those in the non-HIV controls and non-HAND PLWH, suggesting that these miRNAs are potential biomarkers for HAND. Since there were no changes in known dementia miRNA biomarkers in HAND PLWH, the miRNAs identified in this study will allow for early differentiation of HAND.

Loneliness and social isolation in people with HIV.

Antiretroviral therapy (ART) has significantly extended the life expectancy of people with HIV (PWH). However, as this population ages, they face increased risk of social isolation and loneliness (SIL), driven by stigma, discrimination, and shrinking social networks. SIL is a major public health issue, closely linked to mental health conditions, reduced adherence to treatment, and lower health-related quality of life (HRQoL). This review examines the prevalence, risk factors, health impacts, and interventions related to SIL, highlighting its critical importance for improving HRQoL in PWH. SIL is common among PWH and strongly associated with HIV-related stigma, depression, anxiety, and systemic inflammation. These factors accelerate aging and contribute to chronic conditions while undermining ART outcomes. Recent research supports the effectiveness of interventions like psychological therapies and social prescribing in reducing SIL and improving HRQoL. However, progress is limited by the lack of standardized tools to assessment SIL, which hampers consistent research and the development of targeted solutions. Addressing SIL is essential to advancing holistic and person-centered HIV care. Integrating SIL evaluation into routine clinical practice, creating standardized assessment tools, and implementing targeted interventions can improve HRQoL and reduce health burdens, particularly as the aging PWH population grows.

Assessment, Decision, Adaptation, Production, Topical Experts-Integration, Training, and Testing (ADAPT-ITT) Framework to Tailor Evidence-Based Posttraumatic Stress Disorder Treatment for People With HIV to Enhance Engagement and Adherence: Qualitative Results from a Feasibility Randomized Controlled Trial.

Individuals with co-occurring posttraumatic stress disorder (PTSD) and HIV are at high-risk for negative HIV-related outcomes, including low adherence to antiretroviral therapy, faster disease progression, more hospitalizations, and almost twice the rate of death. Despite high rates of PTSD in persons with HIV (PWH) and poor HIV-related health outcomes associated with PTSD, an effective evidence-based treatment for PTSD symptoms in PWH does not exist. This study aimed to describe the adaptation and theater testing of an evidence-based intervention designed for people with co-occurring PTSD and HIV. The Assessment, Decision, Adaptation, Production, Topical experts-integration, Training, and Testing (ADAPT-ITT) framework guided the formative process used to modify an evidence-based PTSD treatment (cognitive processing therapy; CPT) to meet the unique needs of PWH experiencing PTSD. With the integration of Life-Steps for Medication Adherence (Life-Steps), the adapted protocol (CPT-Life-Steps for integration of adherence; CPT-L) targeted HIV-related stigma and HIV medication adherence within a trauma-informed framework. Theater testing was completed with 7 participants to evaluate acceptability of CPT-L for PWH. The qualitative data (N=54 recordings) used to evaluate and adapt CPT-L emerged from individual interviews conducted with participants after each therapy session as well as exit interviews conducted at posttreatment data collection. After challenging stigma-related appraisals, participants expressed feeling less constrained by maladaptive thoughts. These shifts translated to increased self-efficacy with both HIV-related care and mental health. These results indicate that trauma-informed work with PWH should consider the impact of HIV on trauma-related stuck points, intersecting identities (including living with HIV), and challenging internalized stigma. Findings provide evidence that CPT-L is acceptable and effective in addressing internalized HIV stigma that impacts PTSD symptom maintenance and HIV treatment engagement. ClinicalTrials.gov; NCT05275842; https://clinicaltrials.gov/study/NCT05275842?id=NCT05275842&rank=1. RR2-10.1016/j.conctc.2023.101150.

Effect of antiretroviral therapy on the mortality of HIV-1 infection long-term non-progressors: a cohort study

BackgroundThe study aims to investigate the demographic characteristics, the variations in their immune status, and mortality risk among HIV-1 infection long-term non-progressors (LTNP).MethodsEligible LTNP and typical progressors (TP) were recruited in Guangxi by December 2018. Participants were followed up until December 2022, monitoring ART status, CD4+ T cell counts, and survival/death outcomes. Multivariate logistic, Cox regression, and Kaplan-Meier method were employed to scrutinize associated factors and mortality risk of LTNP.ResultsA total of 212 LTNP and 390 TP were included. LTNP cohort predominantly comprised males (84.43%), those diagnosed with HIV at age ≤ 40 years (93.87%), and those infected through injection drug use (59.91%). The mortality rate of LTNP were lower than TP (12.74% vs. 27.18%). TP had a higher mortality risk compared to LTNP (adjusted hazard ratio [aHR] = 4.051, 95% CI: 2.284–7.186, P < 0.001). The mortality risk was also elevated in the ART-naïve group versus the ART-experienced ones (aHR = 3.943, 95%CI: 2.658–5.850, P < 0.001). Notably, the CD4/CD8 ratio in the LTNP group did not fully recover (< 1.0) despite ART. However, LTNP with ART-experienced had a significantly lower mortality risk compared to ART-naïve LTNP group (Log-rank: P = 0.003).ConclusionsART effectively restores and maintains normal CD4+ T cell levels among LTNP, thereby decreasing mortality risk. Nonetheless, the CD4/CD8 ratio in LTNP exhibits incompletely recovered post-ART. These findings provide a scientific foundation for promoting ART in LTNP population.

Exploring survival rates in HIV-infected Ethiopian children receiving HAART: a retrospective cohort study

BackgroundStudies have shown a high rate of mortality among adults despite the introduction of highly active antiretroviral therapy (HAART). However, long-term outcomes of HAART among children remain poorly documented in...

Barriers to clinician reporting to the Antiretroviral Pregnancy Registry from within and outside the United States

Abstract Background Excluding pregnant women with HIV from clinical trials results in inadequate pregnancy safety data for new antiretroviral therapies (ART). More rapid accumulation of ART pregnancy safety data is required. The Antiretroviral Pregnancy Registry (APR) collects teratogenicity data on ART exposures during conception and pregnancy, yet reporting to the registry is suboptimal, impacting ART choices for women with HIV globally. This research assesses awareness of the APR and barriers to reporting among HIV providers in the United States (US) and Australia. Method Anonymous, online surveys were conceived independently by researchers in the US and Australia. The surveys were distributed through national email distribution lists to healthcare providers for pregnant women with HIV, their newborns or women of reproductive potential with HIV, to assess their awareness of the APR and barriers to reporting. Results In total, 146 healthcare providers (66 US, 80 Australia) completed the survey. Respondents from the US had greater awareness of the registry and more reporting experience, describing the process as complex and laborious. Providers from Australia were largely unaware that the APR accepts reports from outside the US. Key barriers to reporting were uncertainty about how to report and incomplete access to all relevant maternal and paediatric data. Conclusions Barriers to reporting to the APR are context specific. There is scope to raise the global profile of the APR to expedite data collection, reducing time between antiretroviral licensure and accumulation of sufficient pregnancy safety data.

HIV-1 DNA Genotypic Drug Resistance Testing Guides Antiretroviral Therapy in Patients with Low-Level Viremia.

In 2023, we published a case study involving a 10-year-old HIV-1-infected child with low-level viremia (LLV). We showed that this child patient achieved successful viral suppression by modifying the antiretroviral therapy (ART) regimen according to the HIV-1 DNA genotypic drug resistance testing. In this study, we aimed to address whether HIV-1 DNA genotypic drug resistance testing could direct successfully virological suppression in HIV-1-infected patients experiencing persistent LLV based on evidence from a cohort study. The subjects of this study were all people living with HIV-1 who received ART and followed in the Yuexi County (Liangshan, China) from December 2010 to February 2024. From June 2021 to February 2024, a total of 10 mL of peripheral blood was collected from each subject at each follow-up and separated. HIV-1 RNA and HIV-1 DNA were quantified, followed by HIV-1 genotypic drug resistance testing. ART regimens were accordingly adjusted, while follow-up tests were performed in terms of HIV-1 RNA and DNA measurements. The prevalent HIV-1 DNA drug resistance mutations (DRMs) included M184V, K103N, K101E/P, and V108I. The primary resistance mutations observed for nucleoside reverse transcriptase inhibitor (NRTI) were against abacavir, lamivudine, and emtricitabine. For non-NRTI, the primary DRMs were associated with efavirenz and nevirapine. Five out of the six patients were subjected to regimen adjustments according to HIV-1 DNA DRMs, while one patient was continuously treated with unchanged regimen. Viral suppression was achieved in all five ART-changed cases, with observation of remarkable of HIV-1 DNA decline. The ART-unchanged case showed progressive treatment failure with drastic increase of plasma HIV-1 RNA and whole blood HIV-1 DNA. For patients with LLV, HIV-1 DNA genotypic drug resistance testing directed ART regimen considerations are highly recommended for achieving viral suppression.

Pervasive Games for Sexual Health Promotion: Scoping Literature Review.

Serious games play a fundamental role in promoting safe sexual behaviors. This medium has great potential for promoting healthy behaviors that prevent potential risk factors, such as sexually transmitted infections, and promote adherence to sexual health treatments, such as antiretroviral therapy. The ubiquity of mobile devices enhances access to such tools, increasing the effectiveness of video games as agents of change. In this scoping review, we aimed to (1) identify the extent to which pervasive games have been used in the field of sexual health, (2) determine the theories used in the design and evaluation of pervasive games for sexual health, (3) identify the methods used to evaluate pervasive games for sexual health, and (4) explore the reported benefits of using pervasive games for sexual health. Following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) methodology, we conducted a comprehensive literature search in the Web of Science, Scopus, IEEE Xplore, and ACM databases for articles published between January 1, 2000, and August 4, 2024. Included articles were published in English between 2000 and 2024 and involved the design, implementation, or evaluation of a ubiquitous video game focused on promoting safe sexual behaviors, with qualitative and/or quantitative results based on theory-based techniques and ubiquitous technologies. Review articles, conference papers, or books without available data or quantitative or qualitative results were excluded. We screened 521 of 612 articles (85.1%) after removing duplicates. After the title and abstract review, 51 (9.8%) articles were assessed for eligibility, and 30 (5.8%) articles meeting the criteria were studied and evaluated in depth. The results suggested that the use of pervasive video games has a positive impact on promoting safe sexual behaviors. This is enhanced by the effectiveness of theory-based techniques and the use of mobile technologies as developmental factors that drive the gaming experience. The results indicated that this domain is a growing field that should not be ignored. The literature showed that pervasive video games have been effective in promoting safe sexual behaviors. Substantial growth has been seen in scientific community interest in researching this domain; nevertheless, there is still much to work on. In this context, we advocate for the standardization of design, implementation, and experimentation as essential phases in creating video game experiences. These 3 fundamental aspects are critical in the development of video game-based studies to ensure the reproducibility of experiments.

Plasma Proteomic Signature as a Predictor of Age Advancement in People Living With HIV.

Due to the increased burden of non-AIDS-related comorbidities in people living with HIV (PLHIV), identifying biomarkers and mechanisms underlying premature aging and the risk of developing age-related comorbidities is a priority. Evidence suggests that the plasma proteome is an accurate source for measuring biological age and predicting age-related clinical outcomes. To investigate whether PLHIV on antiretroviral therapy (ART) exhibit a premature aging phenotype, we profiled the plasma proteome of two independent cohorts of virally suppressed PLHIV (200HIV and 2000HIV) and one cohort of people without HIV (200FG) using O-link technology. Next, we built a biological age-prediction model and correlated age advancement (the deviation of the predicted age from the chronological age) with HIV-related factors, comorbidities, and cytokines secreted by immune cells. We identified a common signature of 77 proteins associated with chronological age across all cohorts, most of which were involved in inflammatory and senescence-related processes. PLHIV showed increased age advancement compared to people without HIV. In addition, age advancement in the 2000HIV cohort was positively associated with prior hepatitis C and cytomegalovirus (CMV) infections, non-AIDS-related comorbidities, ART duration, cumulative exposure to the protease inhibitor Ritonavir, as well as higher production of monocyte-derived proinflammatory cytokines and chemokines and lower secretion of T-cell derived cytokines. Our proteome-based predictive model is a promising approach for calculating the age advancement in PLHIV. This will potentially allow for further characterization of the pathophysiological mechanisms linked to accelerated aging and enable monitoring the effectiveness of novel therapies aimed at reducing age-related diseases in PLHIV.

Effects of Tesamorelin on Neurocognitive Impairment in Abdominally Obese Persons with HIV.

In people with HIV (PWH) who are virally suppressed (VS) on antiretroviral therapy (ART), abdominal obesity (AO) is linked to neurocognitive impairment (NCI), potentially due to visceral adiposity, inflammation, and reduced insulin-like growth factor 1 (IGF-1). Tesamorelin, a growth hormone-releasing hormone, reduces AO and increases IGF-1, suggesting it might mitigate NCI in VS PWH. This 6-month, Phase II randomized, open-label clinical trial compared Tesamorelin versus standard-of-care (SOC) for NCI in abdominally obese PWH. Participants had VS, NCI, and AO (elevated waist circumference [WC]). Exclusions included conditions other than HIV causing NCI, active substance use disorder, and malignancy. Seventy-three participants were randomized 3:2 to Tesamorelin or SOC (2mg subcutaneously daily). The primary outcome was the change in neurocognitive performance at 6 months, with secondary outcomes including WC, mood, and daily functioning. The groups were well-matched at baseline. The Tesamorelin group showed a trend toward improved neurocognitive performance after 6 months (mean change: 0.146, 95% CI: -0.002 to 0.294, p=0.060), while the SOC group did not (0.103, 95% CI: -0.095 to 0.301, p=0.295), but the between-group difference was not significant (p=0.673). IGF-1 levels increased, but changes did not correlate with sRCS or WC. The Tesamorelin group had a greater reduction in WC than the SOC group (median difference -2.7 cm, p=0.015). While tesamorelin reduced WC, the cognitive benefits did not significantly differ between groups. Recognizing the limitations of insufficient power and no placebo arm, this study suggests no clear benefit of short-term AO reduction with tesamorelin on NCI.

The Lived Experiences of Mothers Living with HIV in West Papua, Indonesia: A Qualitative Study.

Mothers living with human immunodeficiency virus (HIV) may experience adjustment issues due to their illness progression and the risk of intergenerational transmission of the disease. Existing research on women living with HIV has focused on how psychological transitions such as child care and breastfeeding influence maternal life, and how socioeconomic status, stigma, and social support impact psychological transitions. Little is known about the experiences of mothers living with HIV in Indonesia. This study employed interpretive phenomenological methods to learn about the experiences of mothers living with HIV in West Papua, Indonesia. Twenty mothers with HIV were invited to participate in a study at a public health center. Themes identified were emotional reaction to HIV diagnosis, destruction of relationships, treatment burden, emotional coping, motherhood, and uncertainty about their child's future status. Formal and informal peer-led support groups may be practical tools for increasing partner communication and antiretroviral therapy uptake and decreasing HIV vertical transmission, especially in low-resource contexts.

An Immunocytochemistry Method to Investigate the Translationally Active HIV Reservoir

Despite the success of combination antiretroviral therapy (cART) to suppress HIV replication, HIV persists in a long-lived reservoir that can give rise to rebounding viremia upon cART cessation. The translationally active reservoir consists of HIV-infected cells that continue to produce viral proteins even in the presence of cART. These active reservoir cells are implicated in the resultant viremia upon cART cessation and likely contribute to chronic immune activation in people living with HIV (PLWH) on cART. Methodologies to quantify the active reservoir are needed. Here, an automated immunocytochemistry (ICC) assay coupled with computational image analysis to detect and quantify intracellular Gag capsid protein (CA) is described (CA-ICC). For this purpose, fixed cells were deposited on microscopy slides by the cytospin technique and stained with antibodies against CA by an automated stainer, followed by slide digitization. Nuclear staining was used to count the number of cells in the specimen, and the chromogenic signal was quantified to determine the percentage of CA-positive cells. In comparative analyses, digital ELISA, qPCR, and flow cytometry were used to validate CA-ICC. The specificity and sensitivity of CA-ICC were assessed by staining a cell line that expresses CA (MOLT IIIB) alongside a control cell line (Jurkat) devoid of this marker, as well as peripheral blood mononuclear cells (PBMCs) from HIV seronegative donors before or after ex vivo infection with an HIV laboratory strain. The sensitivity of CA-ICC was further assayed by spiking MOLT IIIB cells into uninfected Jurkat cells in limiting dilutions. In those analyses, CA-ICC could detect down to 10 CA-positive cells per million with a sensitivity superior to flow cytometry. To demonstrate the application of CA-ICC in pre-clinical research, bulk PBMCs obtained from mouse and non-human primate animal models were stained to detect HIV CA and SIV p27, respectively. The level of intracellular CA quantified by CA-ICC in PBMCs obtained from animal models was associated with plasma viral loads and cell-associated CA measured by qPCR and ELISA, respectively. The application of CA-ICC to evaluate the activity of small-molecule targeted activator of cell-kill (TACK) in clinical specimens is presented. Overall, CA-ICC offers a simple imaging method for specific and sensitive detection of CA-positive cells in bulk cell preparations.

Effect of Kinases in Extracellular Vesicles from HIV-1-Infected Cells on Bystander Cells

As of 2023, there were 39.9 million people living with Human Immunodeficiency Virus type 1 (HIV-1). Although great strides have been made in treatment options for HIV-1, and our understanding of the HIV-1 life cycle has vastly improved since the start of this global health crisis, a functional cure remains elusive. One of the main barriers to a cure is latency, which allows the virus to persist despite combined antiretroviral therapy (cART). Recently, we have found that exosomes, which are small, membrane-enclosed particles released by virtually all cell types and known to mediate intercellular communication, caused an increase in RNA Polymerase II loading onto the HIV-1 promoter. This resulted in the production of both short- and long-length viral transcripts in infected cells under cART. This current study examines the effects of exosome-associated kinases on bystander cells. The phospho-kinase profiling of exosomes revealed differences in the kinase payload of exosomes derived from uninfected and HIV-1-infected cells, with CDK10, GSK3β, and MAPK8 having the largest concentration differences. These kinases were shown to be biologically active and capable of phosphorylating substrates, and they modulated changes in the cell cycle dynamics of exposed cells. Given the relevance of such effects for the immune response, our results implicate exosome-associated kinases as new possible key contributors to HIV-1 pathogenesis that affect bystander cells. These findings may guide new therapeutic avenues to improve the current antiretroviral treatment regimens.

Enhancing Antiretroviral Therapy Initiation for Hospitalized and Recently Discharged People Living With HIV in Johannesburg, South Africa.

Despite increased antiretroviral therapy (ART) access in South Africa, HIV testing and ART initiation are suboptimal in hospital settings. Key gaps include in-hospital case finding, ART initiation support, and primary health care (PHC) facility linkage after discharge. We identified weaknesses in hospital processes by comparing them with PHC HIV services and developed a quality improvement model for implementation in 5 Johannesburg hospitals. We introduced dedicated teams of HIV testing counselors for structured case finding and ART-trained nurses and linkage officers to provide in-hospital or post-discharge ART initiation and support to strengthen PHC facility linkage. Monitoring data (May 2020-March 2021) was used to measure initiation rates. Over 11 months, despite COVID-19 pandemic-related disruptions, our model achieved 74% (5,201/7,025) ART linkage within 28 days post-discharge and 87% (6,087/7,025) overall, including all initiations (i.e., all newly diagnosed, known not on ART and reinitiating individuals). The 2 highest-performing hospitals achieved 97% (2,096/2,170) linkage overall, demonstrating the potential of implementing this quality improvement model with fidelity. Over half (58%, 4,092/7,025) of patients initiated ART within 7 days, with 39% (2,748) initiating on the same day. Women and men achieved similar initiation rates (3,010/4,015, 75%; 2,186/3,003, 73%, respectively). Combining rapid (<7 days) in-hospital ART initiation with 28-day post-discharge follow-up supported high ART initiation rates. Using the model mitigated initiation gaps for men and older people, engaging stakeholders supported implementation, and using a team-based approach founded on clear roles and responsibilities improved service delivery. This model achieved above-average ART linkage rates in a large hospitalized population. We recommend considering introducing this model or adaptations of it to hospitals across South Africa and similar settings where hospital-to-PHC ART service gaps are identified to optimize case finding, ART initiation, and post-discharge linkage support.

Low Bone Mineral Density and Associated Factors Among People Living With HIV in Kerman, Iran: A Cross-Sectional Study in 2021-2022.

Chronic diseases such as osteoporosis and low bone mineral density (BMD) are significant public health concerns for people living with HIV (PLWH), especially with the increased life expectancy because of antiretroviral therapy (ART). This study evaluated the prevalence and associated factors of low BMD among 94 PLWH in Kerman, Iran, from September 2021 to February 2022. Using dual-energy X-ray absorptiometry, BMD was measured, with low BMD defined by specific T-scores and Z-scores. Predictors were assessed through interviews, medical records, and blood tests. Bivariable and multivariable logistic regression models identified associations between low BMD and various factors. The study found a 51.1% prevalence of low BMD, with significant associations with hypogonadism (adjusted odds ratio [aOR]: 3.19), longer ART duration (aOR per month: 1.02), and lower body mass index (aOR per unit: 0.83). The findings highlight the need for regular screening and timely intervention for low BMD among PLWH, particularly with prolonged ART use.

95-95-95 HIV indicators among children younger than 15 years in South Africa: results from the 2017 national HIV prevalence, incidence, behaviour, and communication survey

BackgroundEarly detection and initiation of care is crucial to the survival and long-term well-being of children living with HIV (CLHIV). However, there remain challenges regarding early testing and linking of CLHIV for early treatment. This study examines the progress made towards achieving the 95-95-95 HIV indicators and associated factors among CLHIV < 15 years in South Africa.MethodsThe data was collected as part of the 2017 cross-sectional, multistage cluster randomized population-based household National HIV survey. Age-appropriate structured questionnaires were utilized to gather sociodemographic data, HIV-related knowledge, risk behaviours, and health-related information. Blood samples were collected to test for HIV serology, viral load suppression, and antiretroviral usage. Backward stepwise multivariable generalized linear regression models were fitted to identify factors associated with the 95-95-95 HIV indicators. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) are shown, and p < 0.05 indicates statistical significance.ResultsA total of 12,237 CLHIV < 15 years were included (median 8 years, interquartile range 4–11 years). HIV prevalence was 2.8% (95% CI: 2.4–3.3). Overall, 40.0% of the CLHIV were tested and knew their status (first 95%), and among these, 72.6% (95% CI: 61.7–81.3) were on antiretroviral therapy (ART) (second 95%), and 95.0% (95% CI: 88.4–97.9) of these were virally suppressed (third 95%). Among CLHIV, the odds of testing and knowing the HIV-positive status were significantly higher among children whose health was rated as fair/poor than excellent/good [AOR = 1.32 (95%CI: 1.05–1.67), p = 0.022], and were significantly lower among females than males [AOR = 0.82 (95% CI: 0.71–0.95), p = 0.009], and were significantly lower among those attending private healthcare facilities than public health facilities [AOR = 0.64 (95% CI:0.57–0.74), p < 0.001]. Among those who knew their HIV-positive status, the odds of being on ART were significantly higher among children residing in farm areas than urban areas [AOR = 1.40 (95% CI:1.05–1.86), p = 0.017], and were significantly lower among children attending private healthcare facilities [AOR = 0.44 (95% CI:0.36–0.54), p < 0.001].ConclusionsAwareness of HIV status and initiation of treatment in children was low. The findings highlight the need to improve HIV status awareness and disclosure to children. The findings underscore the need for targeted interventions and programs tailored for CLHIV in urban areas.