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Antimicrobial Agents and Chemotherapy Jul 2024Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in...
Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.
PubMed: 38953364
DOI: 10.1128/aac.00464-24 -
MedRxiv : the Preprint Server For... May 2024HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which...
INTRODUCTION
HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the World Health Organization in 2019 for first-, second-, and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance.
METHODS AND ANALYSIS
DTG RESIST is a multicentre longitudinal study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virologic failure on dolutegravir-based ART. At the time of virologic failure whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (i) individuals who experienced virologic failure on dolutegravir, and (ii) on those who started or switched to such a regimen and were at risk of virologic failure. For population (i), the outcome will be any InSTI drug resistance mutations, and for population (ii) virologic failure defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virologic failure and limited power for analysing factors associated with individual InSTI drug resistance mutations.
ETHICS AND DISSEMINATION
The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa, and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in IeDEA and have obtained ethics approval from their local ethics committee to conduct the additional data collection.
REGISTRATION
NCT06285110.
STRENGTHS AND LIMITATIONS OF THIS STUDY
- DTG RESIST is a large international study to prospectively examine emergent dolutegravir resistance in diverse settings characterised by different HIV-1 subtypes, provision of ART, and guidelines on resistance testing. - Embedded within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST will benefit from harmonized clinical data across participating sites and expertise in clinical, epidemiological, biological, and computational fields. - Procedures for sequencing and assembling genomes from different HIV-1 strains will be developed at the heart of the HIV epidemic, by the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), in Durban, South Africa. Phenotypic testing, Genome Wide Association Study (GWAS) methods and Bayesian evolutionary models will explore and predict treatment failure genotypes. - A significant limitation is the absence of genotypic resistance data from participants before they started dolutegravir treatment, as collecting and bio-banking pre-treatment samples was not feasible at most IeDEA sites. Consistent and harmonized data on adherence to treatment are also lacking. - The distribution of HIV-1 subtypes across different sites is uncertain, which may limit the statistical power of the study in analysing patterns and risk factors for dolutegravir resistance. The results from GWAS and Bayesian modelling analyses will be preliminary and hypothesis-generating.
PubMed: 38952780
DOI: 10.1101/2024.05.23.24307850 -
BMC Public Health Jun 2024Nitrite inhalants (poppers) are associated with HIV transmission and commonly used among young men who have sex with men (YMSM), a group at increased risk for HIV....
Nitrite inhalants (poppers) are associated with HIV transmission and commonly used among young men who have sex with men (YMSM), a group at increased risk for HIV. Significant research gaps exist in understanding the context in which YMSM use poppers. Qualitative interviews were conducted with 15 YMSM (22-31 years) with HIV to better understand the context in which poppers are used and their impacts on HIV care outcomes, such as care retention and antiretroviral adherence. The Social Ecological Model was applied to understand intrapersonal, interpersonal, community, and system level influences on popper use. Factors influencing popper use included: ubiquity of popper use in sexual settings, introduction to poppers by casual sexual partners, patient-HIV provider communication surrounding poppers, neighborhood, substance use and HIV care systems, and the legal status of poppers. Implications for clinical care, public health, policy, and future research are discussed.
Topics: Humans; Male; HIV Infections; Adult; Homosexuality, Male; Qualitative Research; Young Adult; Nitrites; Interviews as Topic
PubMed: 38951768
DOI: 10.1186/s12889-024-19284-1 -
PloS One 2024Toxoplasma gondii can cause symptomatic toxoplasmosis in immunodeficient hosts, including in people living with human immunodeficiency virus (PLWH), mainly because of...
INTRODUCTION
Toxoplasma gondii can cause symptomatic toxoplasmosis in immunodeficient hosts, including in people living with human immunodeficiency virus (PLWH), mainly because of the reactivation of latent infection. We assessed the prevalence of toxoplasmosis and its associated risk factors in PLWH in the Asia-Pacific region using data from the TREAT Asia Human Immunodeficiency Virus (HIV) Observational Database (TAHOD) of the International Epidemiology Databases to Evaluate AIDS (IeDEA) Asia-Pacific.
METHODS
This study included both retrospective and prospective cases of toxoplasmosis reported between 1997 and 2020. A matched case-control method was employed, where PLWH diagnosed with toxoplasmosis (cases) were each matched to two PLWH without a toxoplasmosis diagnosis (controls) from the same site. Sites without toxoplasmosis were excluded. Risk factors for toxoplasmosis were analyzed using conditional logistic regression.
RESULTS
A total of 269/9576 (2.8%) PLWH were diagnosed with toxoplasmosis in 19 TAHOD sites. Of these, 227 (84%) were reported retrospectively and 42 (16%) were prospective diagnoses after cohort enrollment. At the time of toxoplasmosis diagnosis, the median age was 33 years (interquartile range 28-38), and 80% participants were male, 75% were not on antiretroviral therapy (ART). Excluding 63 out of 269 people without CD4 values, 192 (93.2%) had CD4 ≤200 cells/μL and 162 (78.6%) had CD4 ≤100 cells/μL. By employing 538 matched controls, we found that factors associated with toxoplasmosis included abstaining from ART (odds ratio [OR] 3.62, 95% CI 1.81-7.24), in comparison to receiving nucleoside reverse transcriptase inhibitors plus non-nucleoside reverse transcriptase inhibitors, HIV exposure through injection drug use (OR 2.27, 95% CI 1.15-4.47) as opposed to engaging in heterosexual intercourse and testing positive for hepatitis B virus surface antigen (OR 3.19, 95% CI 1.41-7.21). Toxoplasmosis was less likely with increasing CD4 counts (51-100 cells/μL: OR 0.41, 95% CI 0.18-0.96; 101-200 cells/μL: OR 0.14, 95% CI 0.06-0.34; >200 cells/μL: OR 0.02, 95% CI 0.01-0.06), when compared to CD4 ≤50 cells/μL. Moreover, the use of prophylactic cotrimoxazole was not associated with toxoplasmosis.
CONCLUSIONS
Symptomatic toxoplasmosis is rare but still occurs in PLWH in the Asia-Pacific region, especially in the context of delayed diagnosis, causing advanced HIV disease. Immune reconstitution through early diagnosis and ART administration remains a priority in Asian PLWH.
Topics: Humans; Male; Risk Factors; Adult; Female; Toxoplasmosis; HIV Infections; Asia; Retrospective Studies; Case-Control Studies; Middle Aged; Prevalence; Prospective Studies; Toxoplasma
PubMed: 38950027
DOI: 10.1371/journal.pone.0306245 -
The Journal of the Association of...
Topics: Humans; Female; Black or African American; HIV Infections; Pre-Exposure Prophylaxis; Adult; Community-Based Participatory Research; Anti-HIV Agents; United States; Patient Acceptance of Health Care; Middle Aged
PubMed: 38949909
DOI: 10.1097/JNC.0000000000000456 -
The Journal of the Association of...In the U.S. South, over half of new HIV diagnoses occur among Black Americans with research lagging for women who face increased HIV rates and low PrEP uptake, among...
In the U.S. South, over half of new HIV diagnoses occur among Black Americans with research lagging for women who face increased HIV rates and low PrEP uptake, among other health inequities. Community engaged research is a promising method for reversing these trends with established best practices for building infrastructure, implementing research, and translating evidence-based interventions into clinical and community settings. Using the 5Ws of Racial Equity in Research Framework (5Ws) as a racial equity lens, the following paper models a review of a salon-based intervention to improve PrEP awareness and uptake among Black women that was co-developed with beauty salons, stylists, and Black women through an established community advisory council. In this paper we demonstrate how the 5Ws framework was applied to review processes, practices, and outcomes from a community-engaged research approach. The benefits of and challenges to successful collaboration are discussed with insights for future research and community impact.
Topics: Humans; Female; HIV Infections; Black or African American; Pre-Exposure Prophylaxis; Community-Based Participatory Research; Anti-HIV Agents; Adult; Healthcare Disparities; Health Knowledge, Attitudes, Practice; Patient Acceptance of Health Care; United States; Health Equity
PubMed: 38949908
DOI: 10.1097/JNC.0000000000000453 -
The Journal of the Association of...Black women are essential to ending the HIV epidemic in the United States; yet prevention, access, testing, and structural racism affect how HIV disproportionately...
Black women are essential to ending the HIV epidemic in the United States; yet prevention, access, testing, and structural racism affect how HIV disproportionately affects them. Limited public health research focuses on Black women attending Historically Black Colleges and Universities (HBCUs) and the ability to address HIV prevention, such as pre-exposure prophylaxis (PrEP) uptake. PrEP is a once-daily oral pill used to prevent HIV transmission and has suboptimal uptake within the Black community. This generic qualitative descriptive analysis identifies the barriers and facilitators of PrEP uptake among Black women attending an HBCU using the health belief model. Overall, 22 Black college women participated in a 60-minute focus group. Emergent categories were as follows: (a) Barriers-stigma, cost, and side effects; (b) Facilitators-PrEP's effectiveness, exposure to HIV, and unprotected sex. Our findings can inform future efforts to increase PrEP uptake among Black women attending an HBCU.
Topics: Humans; Female; Pre-Exposure Prophylaxis; HIV Infections; Qualitative Research; Universities; Black or African American; Adult; Anti-HIV Agents; Focus Groups; Young Adult; Social Stigma; Health Services Accessibility; Health Knowledge, Attitudes, Practice; Patient Acceptance of Health Care; Students; Racism; Adolescent
PubMed: 38949902
DOI: 10.1097/JNC.0000000000000470 -
Journal of Neurovirology Jun 2024HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be...
BACKGROUND
HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be initiated in the periphery, but the contribution of peripheral T cells in HAND pathogenesis remains poorly understood.
METHODS
We assessed markers of T cell activation (HLA-DR + CD38+), immunosenescence (CD57 + CD28-), and immune-exhaustion (TIM-3, PD-1 and TIGIT) as well as monocyte subsets (classical, intermediate, and non-classical) by flow cytometry in peripheral blood derived from individuals with HIV on long-term stable anti-retroviral therapy (ART). Additionally, normalized neuropsychological (NP) composite test z-scores were obtained and regional brain volumes were assessed by magnetic resonance imaging (MRI). Relationships between proportions of immune phenotypes (of T-cells and monocytes), NP z-scores, and brain volumes were analyzed using Pearson correlations and multiple linear regression models.
RESULTS
Of N = 51 participants, 84.3% were male, 86.3% had undetectable HIV RNA < 50 copies/ml, median age was 52 [47, 57] years and median CD4 T cell count was 479 [376, 717] cells/uL. Higher CD4 T cells expressing PD-1 + and/or TIM-3 + were associated with lower executive function and working memory and higher CD8 T cells expressing PD-1 and/or TIM-3 were associated with reduced brain volumes in multiple regions (putamen, nucleus accumbens, cerebellar cortex, and subcortical gray matter). Furthermore, higher single or dual frequencies of PD-1 + and TIM-3 + expressing CD4 and CD8 T-cells correlated with higher CD16 + monocyte numbers.
CONCLUSIONS
This study reinforces evidence that T cells, particularly those with immune exhaustion phenotypes, are associated with neurocognitive impairment and brain atrophy in people living with HIV on ART. Relationships revealed between T-cell immune exhaustion and inflammatory in CD16 monocytes uncover interrelated cellular processes likely involved in the immunopathogenesis of HAND.
PubMed: 38949728
DOI: 10.1007/s13365-024-01223-w -
BioRxiv : the Preprint Server For... Jun 2024HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a...
HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of HIV infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption and CVD pathogenesis. Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for biomarkers of intestinal epithelial barrier disruption (IEBD), inflammasome activation (IL-1β and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). Higher plasma levels of IL-1β and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding protein (LBP), during the chronic phase of treated SIV infection. Further, significant correlations of plasma IFABP levels with IL-1β and IL-18 were observed between 10-12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV+ART phase along with a trend of increase in frequencies of activated CD14 CD16 intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1β following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could accelerate CVD pathogenesis. Further research is needed to understand mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated CVD and metabolic complications, enabling targeted interventions in people with HIV.
PubMed: 38948748
DOI: 10.1101/2024.06.14.599106 -
Open Forum Infectious Diseases Jul 2024Dolutegravir resistance is emerging in routine clinical contexts in southern Africa, primarily in patients with prior treatment experience failing dolutegravir-based...
Dolutegravir resistance is emerging in routine clinical contexts in southern Africa, primarily in patients with prior treatment experience failing dolutegravir-based antiretroviral therapy (ART). This potential issue was raised by The Nucleosides and Darunavir/Dolutegravir in Africa trial that compared dolutegravir and boosted protease inhibitor-based therapy as second-line ART, in which new dolutegravir resistance was observed at failure. However, recent data suggest that also at risk are patients who were transitioned to dolutegravir from non-nucleoside reverse transcriptase inhibitor-based ART while viremic. Identifying patients experiencing failure of dolutegravir with resistance will be difficult given current gaps in viral load monitoring and limited capacity for genotypic resistance testing. As a result, in the short term, most patients affected will go unrecognized, with particularly important implications for patients affected who have advanced HIV or who are pregnant/breastfeeding. Prospective research is needed to understand the scope of the problem, identify additional risk factors, and determine best management. In the short term, for most patients with dolutegravir resistance and prior non-nucleoside reverse transcriptase inhibitor exposure, the best option will be a timely switch to a regimen anchored by a boosted protease inhibitor, with a high genetic barrier to resistance.
PubMed: 38947737
DOI: 10.1093/ofid/ofae321