Timing Of Antiretroviral Therapy Initiation Research Articles

Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques

While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.

No evidence for ongoing replication on ART in SIV-infected macaques

The capacity of HIV-1 to replicate during optimal antiretroviral therapy (ART) is challenging to assess directly. To gain greater sensitivity to detect evolution on ART, we used a nonhuman primate (NHP) model providing precise control over the level of pre-ART evolution and more comprehensive analyses than are possible with clinical samples. We infected 21 rhesus macaques (RMs) with the barcoded virus SIVmac239M and initiated ART early to minimize baseline genetic diversity. RMs were treated for 285–1200 days. We used several tests of molecular evolution to compare 1352 near-full-length (nFL) SIV DNA single genome sequences from PBMCs, lymph nodes, and spleen obtained near the time of ART initiation and those present after long-term ART, none of which showed significant changes to the SIV DNA population during ART in any animal. To investigate the possibility of ongoing replication in unsampled putative tissue sanctuaries during ART, we discontinued treatment in four animals and confirmed that none of the 336 nFL SIV RNA sequences obtained from rebound plasma viremia showed evidence of evolution. The rigorous nature of our analyses reinforced the emerging consensus of a lack of appreciable ongoing replication on effective ART and validates the relevance of this NHP model for cure studies.

Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation.

Despite effective antiretroviral therapy (ART), persons living with HIV harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute ART initiators would be integrated into antiviral genes, whereas integration sites (ISs) in chronic ART initiators would favor genes associated with cell proliferation and exhaustion. We found that the HIV DNA distribution across HIV-specific versus herpesvirus-specific CD4+ T cells was as hypothesized. HIV ISs in acute ART initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1α-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. ISs in chronic ART initiators were enriched in a gene set controlling EZH2 histone methylation, and methylation has been associated with diminished long terminal repeat transcription. These differences that we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.

Advances in Antiretroviral Therapy for Patients with Human Immunodeficiency Virus-Associated Tuberculosis.

Tuberculosis is one of the most common opportunistic infections and a prominent cause of death in patients with human immunodeficiency virus (HIV) infection, in spite of near-universal access to antiretroviral therapy (ART) and tuberculosis preventive therapy. For patients with active tuberculosis but not yet receiving ART, starting ART after anti-tuberculosis treatment can complicate clinical management due to drug toxicities, drug-drug interactions and immune reconstitution inflammatory syndrome (IRIS) events. The timing of ART initiation has a crucial impact on treatment outcomes, especially for patients with tuberculous meningitis. The principles of ART in patients with HIV-associated tuberculosis are specific and relatively complex in comparison to patients with other opportunistic infections or cancers. In this review, we summarize the current progress in the timing of ART initiation, ART regimens, drug-drug interactions between anti-tuberculosis and antiretroviral agents, and IRIS.

The timing of HIV-1 infection of cells that persist on therapy is not strongly influenced by replication competency or cellular tropism of the provirus.

People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction (~10%) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60%) did not differ from the average percent of replication competent inducible viruses that formed late (69%), and this was also true for proviral DNA that was hypermutated (57%). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.

Predictors of HIV rebound differ by timing of antiretroviral therapy initiation.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Optimal Timing of Antiretroviral Therapy Initiation in Acquired Immunodeficiency Syndrome–Associated Toxoplasmic Encephalitis: A Prospective Observational Multicenter Study in China

Abstract Background Toxoplasmic encephalitis (TE) is the most frequent cause of expansive brain lesions among patients with acquired immunodeficiency syndrome (AIDS). However, the optimal timing of antiretroviral therapy (ART) initiation in these patients remains controversial. This study aims to investigate the differences in outcomes of ART initiation at different times, in order to help clarify the treatment timing of AIDS-associated TE. Methods This multicenter prospective observational study included 87 patients recruited from 11 research centers in China (from March 2019 to December 2022). Of the patients, 38 were assigned to the early ART group (initiating ART within 2 weeks after anti-Toxoplasma treatment initiation), and the remaining 49 patients received deferred ART (initiating ART at least 2 weeks after anti-Toxoplasma treatment initiation). The main outcomes included mortality and emergence of immune reconstitution inflammatory syndrome (IRIS). Human immunodeficiency virus (HIV)-1 viral load and CD4+ T-cell counts at weeks 24 and 48 were observed. Results The number of deaths (1 vs. 5, P = 0.225) and incidence of IRIS (2.6% vs. 0, P = 0.437) were not significantly different between the early and deferred ART groups at week 48. Early ART initiation did not contribute significantly to HIV-1 viral load control (<50 copies/mL, n = 8 vs. n = 3 at week 24, P = 0.142; n = 7 vs. n = 7 at week 48, P = 1.000). The median CD4+ T-cell counts between the two groups were not significantly different, either at week 24 (155 vs. 91 cells/mm3, P = 0.837) or at week 48 (181 vs. 146 cells/mm3, P = 0.219). Conclusion In patients with AIDS-associated TE, early ART initiation was not significantly different from deferred ART initiation in terms of incidence of mortality, IRIS, and HIV virological and immunological outcomes. Trial registration: This study was registered (registration number: ChiCTR1900021195) as one of 12 clinical trials under the title of a general project at the Chinese Clinical Trial Registry (chictr.gov) on February 1, 2019. Enrollment for this study began in March 2019.

Immunologic and Virologic Parameters Associated With Human Immunodeficiency Virus (HIV) DNA Reservoir Size in People With HIV Receiving Antiretroviral Therapy.

A better understanding of the dynamics of human immunodeficiency virus (HIV) reservoirs in CD4+ T cells of people with HIV (PWH) receiving antiretroviral therapy (ART) is crucial for developing therapies to eradicate the virus. We conducted a study involving 28 aviremic PWH receiving ART with high and low levels of HIV DNA. We analyzed immunologic and virologic parameters and their association with the HIV reservoir size. The frequency of CD4+ T cells carrying HIV DNA was associated with higher pre-ART plasma viremia, lower pre-ART CD4+ T-cell counts, and lower pre-ART CD4/CD8 ratios. During ART, the High group maintained elevated levels of intact HIV proviral DNA, cell-associated HIV RNA, and inducible virion-associated HIV RNA. HIV sequence analysis showed no evidence for preferential accumulation of defective proviruses nor higher frequencies of clonal expansion in the High versus Low group. Phenotypic and functional T-cell analyses did not show enhanced immune-mediated virologic control in the Low versus High group. Of considerable interest, pre-ART innate immunity was significantly higher in the Low versus High group. Our data suggest that innate immunity at the time of ART initiation may play an important role in modulating the dynamics and persistence of viral reservoirs in PWH.

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size.

The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date.

1583. Optimal timing of antiretroviral therapy initiation in AIDS-associated Toxoplasma encephalitis: a prospective observational multicenter study in China

Abstract Background Toxoplasma encephalitis (TE) is the most frequent cause of expansive brain lesions among acquired immunodeficiency syndrome (AIDS) patients; however, the optimal timing of antiretroviral therapy (ART) initiation in these patients remains controversial. Methods This was a multicenter prospective observational study, and eligible patients were recruited from eleven treatment centers in China. Results In total, 87 patients were included, and 38 of them were assigned to the Early ART group (initiating ART within 2 weeks after anti-Toxoplasma treatment initiation), while the remaining 49 patients were allocated to receive deferred ART (initiating ART at least 2 weeks after anti-Toxoplasma treatment initiation). Our results indicated that the incidence of immune reconstitution inflammatory syndrome (IRIS) (2.6% vs. 0, p=0.437) and the number of death events (1 vs. 5, p=0.225) were not significantly different between the two groups at Week 48. The timing of ART initiation was also found to not significantly contribute to human immunodeficiency virus (HIV) viral load control. The difference in the number of patients who maintained an undetectable HIV viral load of &amp;lt;50 copies/mL in each of the two groups of patients was calculated to not be statistically significant at Week 24 (8 vs. 3, p=0.142) and Week 48 (7 vs. 7, p=1.000). Meanwhile, median CD4+ T-cell counts were also observed not to reach statistical significance between the two groups, both at Week 24 (155 vs. 91, p=0.837) and Week 48 (181 vs. 96, p=0.219). Conclusion In our study, early ART initiation was observed to not confer statistically significant differences in the incidence of IRIS, mortality, and HIV virological and immunological outcomes, when compared to deferred ART initiation. Disclosures All Authors: No reported disclosures

Identifying longitudinal patterns of HIV treatment (dis)engagement and re-engagement from oral histories of virologically unsuppressed persons in Uganda: A thematic trajectory analysis

BackgroundThere is limited study of persons deemed “harder to reach” by HIV treatment services, including those discontinuing or never initiating antiretroviral therapy (ART). We conducted narrative research in southern Uganda with virologically unsuppressed persons identified through population-based sampling to discern longitudinal patterns in HIV service engagement and identify factors shaping treatment persistence. MethodsIn mid-2022, we sampled adult participants with high-level HIV viremia (≥1000 RNA copies/mL) from the prospective, population-based Rakai Community Cohort Study. Using life history calendars, we conducted initial and follow-up in-depth interviews to elicit oral histories of participants’ journeys in HIV care, from diagnosis to the present. We then used thematic trajectory analysis to identify discrete archetypes of HIV treatment engagement by “re-storying” participant narratives and visualizing HIV treatment timelines derived from interviews and abstracted clinical data. ResultsThirty-eight participants (median age: 34 years, 68% men) completed 75 interviews. We identified six HIV care engagement archetypes from narrative timelines: (1) delayed ART initiation, (2) early treatment discontinuation, (3) treatment cycling, (4) prolonged treatment interruption, (5) transfer-related care disruption, and (6) episodic viremia. Patterns of service (dis)engagement were highly gendered, occurred in the presence and absence of optimal ART adherence, and were shaped by various factors emerging at different time points, including: denial of HIV serostatus and disclosure concerns; worsening HIV-related symptoms; psychological distress and depression; social support; intimate partner violence; ART side effects; accessibility constraints during periods of mobility; incarceration; and inflexible ART dispensing regulations. ConclusionsIdentified trajectories uncovered heterogeneities in both the timing and drivers of ART (re-)initiation and (dis)continuity, demonstrating the distinct characteristics and needs of people with different patterns of HIV treatment engagement throughout the life course. Enhanced mental health service provision, expanded eligibility for differentiated service delivery models, and streamlined facility switching processes may facilitate timely (re-)engagement in HIV services.

Impact of Latent M. tuberculosis Infection Treatment on Time to CD4/CD8 Recovery in Acute, Recent, and Chronic HIV Infection.

In people living with HIV, active and latent tuberculosis (TB) coinfections are associated with immune activation that correlate with HIV progression and mortality. We investigated the effect of initiating antiretroviral therapy (ART) during acute (AHI), recent (RHI), or chronic HIV infection (CHI) on CD4/CD8 ratio normalization and associated factors, the impact of latent TB infection treatment, and prior/concomitant TB diagnosis at the time of ART initiation. We included sex with men and transgender women individuals initiating ART with AHI, RHI and CHI between 2013 and 2019, from a prospective cohort in Brazil. We compared time from ART initiation to the first normal CD4/CD8 ratio (CD4/CD8 ≥1) using Kaplan-Meier curves and multivariable Cox proportional hazards models. Sociodemographic and clinical variables were explored. Variables with P -values <0.20 in univariable analyses were included in multivariable analyses. Five hundred fifty participants were included, 11.8% classified as AHI and 6.4% as RHI, 46.7% with CHI-CD4 cell counts ≥350 cells/mm 3 and 35.1% with CHI-CD4 cell counts <350 cells/mm 3 . Time to normalization was shortest among AHI patients, followed by RHI and CHI individuals with higher baseline CD4. In the multivariable model, AHI was associated with a six-fold increased likelihood of achieving a CD4/CD8 ratio ≥1 (hazard ratio [HR]: 6.03; 95% confidence interval [CI]: 3.70 to 9.82; P < 0.001), RHI with HR: 4.47 (95% CI: 2.57 to 7.76; P < 0.001), and CHI CD4 ≥350 cells/mm 3 with HR: 1.87 (95% CI: 1.24 to 2.84; P = 0.003). Latent TB infection treatment was significantly associated with a higher likelihood of the outcome (HR: 1.79; 95% CI: 1.22 to 2.62; P = 0.003). Previous history or concomitant active TB at ART initiation was associated with a lower likelihood of the outcome (HR: 0.41; 95% CI: 0.16 to 1.02; P = 0.054). Initiating ART early during AHI may offer an opportunity to mitigate immune damage. Efforts to implement HIV diagnosis and ART initiation during AHI are critical to amplify ART benefits.

Early Initiation of Antiretroviral Therapy Preserves the Metabolic Function of CD4+ T Cells in Subtype C Human Immunodeficiency Virus 1 Infection.

Immune dysfunction often persists in people living with human immunodeficiency virus (HIV) who are on antiretroviral therapy (ART), clinically manifesting as HIV-1-associated comorbid conditions. Early ART initiation may reduce incidence of HIV-1-associated immune dysfunction and comorbid conditions. Immunometabolism is a critical determinant of functional immunity. We investigated the effect of HIV-1 infection and timing of ART initiation on CD4+ T cell metabolism and function. Longitudinal blood samples from people living with HIV who initiated ART during hyperacute HIV-1 infection (HHI; before peak viremia) or chronic HIV-1 infection (CHI) were assessed for the metabolic and immune functions of CD4+ T cells. Metabolite uptake and mitochondrial mass were measured using fluorescent analogues and MitoTracker Green accumulation, respectively, and were correlated with CD4+ T cell effector functions. Initiation of ART during HHI prevented dysregulation of glucose uptake by CD4+ T cells, but glucose uptake was reduced before and after ART initiation in CHI. Glucose uptake positively correlated with interleukin-2 and tumor necrosis factor-α production by CD4+ T cells. CHI was associated with elevated mitochondrial mass in effector memory CD4+ T cells that persisted after ART and correlated with PD-1 expression. ART initiation in HHI largely prevented metabolic impairment of CD4+ T cells. ART initiation in CHI was associated with persistently dysregulated immunometabolism of CD4+ T cells, which was associated with impaired cellular functions and exhaustion.

A cross-sectional survey on mother-to-child transmission of HIV among the migrant population in Dongguan, China.

The migrant population, consisting of individuals who relocate from rural to urban areas, faces unique challenges that heighten their vulnerability to HIV infection. These challenges stem from a combination of sociodemographic factors and limited access to healthcare services. Understanding the dynamics of HIV transmission within this population is crucial for the development of effective prevention strategies. To investigate the factors contributing to HIV vulnerability among migrants, we conducted a cross-sectional study at Dongguan People's Hospital from January 1, 2018, to December 31, 2021. Our study focused on pregnant women living with HIV and their infants, with a particular emphasis on sociodemographic characteristics, HIV testing and treatment profiles, and neonatal clinical data. Data were systematically collected using standardized forms. Analysis of data from 98 participants revealed noteworthy findings. No significant associations were observed between age, marital status, and educational background regarding HIV vulnerability. Similarly, factors such as the status of sexual partners, spousal therapy, and the number of children had no significant impact. However, our analysis highlighted the critical role of treatment strategies for HIV-positive women and the timing of antiretroviral therapy initiation for women with HIV, both of which were associated with HIV transmission (P < 0.05). Additionally, factors such as feeding type, neonatal antiretroviral prophylaxis, and preventive treatment strategies showed significant associations, while the preventive treatment program for neonates demonstrated no significant impact. These findings provide valuable insights into the specific risk factors and barriers to HIV prevention faced by the migrant population in Dongguan. They underscore the importance of targeted interventions and policies aimed at curtailing mother-to-child HIV transmission. By addressing the unique challenges experienced by migrant mothers and their infants, this study contributes significantly to broader efforts in controlling the spread of HIV, ultimately enhancing the health outcomes and well-being of Dongguan's migrant population. Furthermore, our research introduces a distinctive perspective within the extensively examined domain of Prevention of Mother-to-Child Transmission (PMTCT) programs, focusing on the internally migrant Chinese population, an understudied demographic group in this context. This study, conducted in Dongguan, China, represents one of the pioneering investigations into pregnant women with HIV and their infants within this migrant community.

Assessing the Impact of Universal Test and Treat Implementation Strategy on Retention to Antiretroviral Therapy in HIV Care: A Retrospective Cohort Review

Namibia has an adult HIV prevalence of 12.6% according to the Namibia population-based HIV impact assessment survey of 2017 making it one of the highest in the world. Early initiation of antiretroviral therapy (ART) has excellent outcomes for both morbidity and mortality. The National Strategic Framework for HIV and the Namibia Ministry of Health and Social Services (MoHSS) rolled out the WHO 2015 UTTS guidelines making Namibia one of the first African countries to implement UTTS. With UTTS guidelines, rolled out in October 2016, clients who test HIV positive are initiated on ART immediately preferably the same day or within seven days regardless of their HIV clinical stage or CD4 count. Retention in care is required for optimal clinical outcomes in patients with HIV infection. However, after two years of adopting the strategy, it is not well understood whether UTTS affects the retention to care. We therefore sought to establish any emerging differences in retention of ART care after the implementation of UTTS. We used a retrospective cohort review study design that employed both quantitative and qualitative methods. 879 client records were reviewed, 678 clients were initiated on treatment two years prior to the UTTS and 201 were initiated after January 2017 when the UTTS was fully rolled out and had been on treatment for at least 12 months. Data analysis was done using Excel and Statistical Package for Social Sciences (SPSS) version 23.0 software. The overall retention after 12 months of follow-up was (822/879) 93.5% (95% CI: 91.3% to 95.7%). The retention rate at 12 months among clients in the UTTS cohort was 95.5% (95% CI: 93.5% to 97.5%) and somewhat higher than that in the pre-UTTS cohort 92.9% (95% CI: 90.6% to 95.2%). At the end of the review period, attrition was higher in the pre-UTTS cohort 251/678 (37.0%; 95% CI 34.8 to 39.2) versus 42/201 (21.0%; 95% CI 19.0 to 23) during UTTS. Retention on ART was nearly 5% higher after UTTS implementation but young adults and men between 31 and 40 years of age had higher chances of attrition at the time of ART initiation. We recommend that all facilities in Namibia and other parts of sub-Saharan Africa should embrace the UTTS strategy to benefit their clients. Keywords: Antiretroviral therapy, Retention, Retrospective cohort review, Universal test &amp; treat.

Predicting the Risk of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients with Central Nervous System Tuberculosis

Objective — to identify risk factors associated with the development of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) in HIV-infected patients with central nervous system tuberculosis. The analysis assessed the relationship between the risk of develo­ping TB-IRIS with neurological manifestations and the following factors: 1) viral load before antiretroviral therapy (ART) initiation; 2) CD4+ lymphocyte of blood before ART initiation; 3) duration of antituberculosis therapy before starting ART; 4) presence of active tuberculosis at the time of ART initiation. Materials and methods. 112 cases of neurological TB-IRIS were analyzed. These patients were treated and observed during the 1 year in anti-tuberculosis facilities in Kyiv and Kyiv region in 2017—2021. All patients received ART in accordance with the HIV treatment protocols adopted in Ukraine. Treatment according to the standard of tuberculosis treatment adopted in Ukraine. The logistic regression model construction method was used to analyze. Statistical processing of the obtained data was carried out using free software — the EZR package (version 1.61; https://www.jichi.ac.jp/).The study was carried out as part of the applied research work 0121U107800 «Predicting the development of the incidence of tuberculosis in Ukraine in connection with the COVID-19 pandemic», funded by the Ministry of Health of Ukraine. Results and discussion. After calculations, two factor signs were identified, associated with the of deve­loping TB-IRIS with neurological manifestations: the baseline level of CD4+ lymphocytes in 1 μl of blood at the beginning of treatment and the presence of active tuberculosis at the time of ART initiation. Conclusions. It was found that the risk of developing TB-IRIS with neurological manifestations is significantly associated (p &lt; 0.05) with the following factors: 1) the level of CD4+ lymphocytes in 1 μl at the beginning of treatment; 2) presence of active tuberculosis at the time of ART initiation.

An active HIV reservoir during ART is associated with maintenance of HIV-specific CD8+ T cell magnitude and short-lived differentiation status

Before initiation of antiretroviral therapy (ART), HIV-specific CD8+ Tcells are dysfunctional and short lived. To better understand the relationship between the HIV reservoir in CD4+ Tcells and the magnitude and differentiation status of HIV-specific CD8+ Tcells, we investigated these cells from acute and chronic HIV-infected individuals after 2 years of ART. Although both the HIV reservoir and the CD8+ Tcell responses declined significantly after 2 years of ART, sustained HIV-specific CD8+ Tcell responses correlated with a greater reduction of integrated HIV provirus. However, the magnitude of CD8+ Tcells specific for HIV Gag, Pol, Nef, and Vif proteins positively associated with the active reservoir size during ART, measured as cell-associated RNA. Importantly, high HIV DNA levels strongly associate with maintenance of short-lived HIV-specific CD8+ Tcells, regardless of ART initiation time. Our data suggest that the active reservoir maintains HIV-specific CD8+ Tcell magnitude but prevents their differentiation into functional cells.

New Concepts in Therapeutic Manipulation of HIV-1 Transcription and Latency: Latency Reversal versus Latency Prevention.

Antiretroviral therapy (ART) has dramatically improved the prognosis for people living with HIV-1, but a cure remains elusive. The largest barrier to a cure is the presence of a long-lived latent reservoir that persists within a heterogenous mix of cell types and anatomical compartments. Efforts to eradicate the latent reservoir have primarily focused on latency reversal strategies. However, new work has demonstrated that the majority of the long-lived latent reservoir is established near the time of ART initiation, suggesting that it may be possible to pair an intervention with ART initiation to prevent the formation of a sizable fraction of the latent reservoir. Subsequent treatment with latency reversal agents, in combination with immune clearance agents, may then be a more tractable strategy for fully clearing the latent reservoir in people newly initiating ART. Here, we summarize molecular mechanisms of latency establishment and maintenance, ongoing efforts to develop effective latency reversal agents, and newer efforts to design latency prevention agents. An improved understanding of the molecular mechanisms involved in both the establishment and maintenance of latency will aid in the development of new latency prevention and reversal approaches to ultimately eradicate the latent reservoir.

Perspectives of people living with HIV on barriers to timely ART initiation following referral for antiretroviral therapy: A qualitative study at an urban HIV clinic in Kampala, Uganda.

Early initiation of antiretroviral therapy (ART) after HIV diagnosis prevents HIV transmission, progression of HIV to AIDS and improves quality of life. However, little is known about the barriers to timely ART initiation among patients who test HIV positive in settings different from where they will receive HIV treatment, hence are referred in the routine setting. Therefore, we explored the perspectives of people living with HIV on barriers faced to initiate ART following HIV testing and referral for treatment. In this qualitative study, we purposively sampled and enrolled 17 patients attending the Mulago ISS clinic. We selected patients (≥18 years) who previously were received as referrals for HIV treatment and had delayed ART initiation, as ascertained from their records. We conducted in-depth interviews, which were audio recorded, transcribed and translated. We used Atlas.ti version 9 software for data management. Data analysis followed thematic and framework analysis techniques and we adopted the socio-ecological model to categorize final themes. Key themes were found at organizational level including; negative experiences at the place of HIV diagnosis attributed to inadequate counselling and support, unclear communication of HIV-positive results and ambiguous referral procedures; and, long waiting time when patients reached the HIV clinic. At individual level, the themes identified were; immediate denial with late acceptance of HIV-positive results attributed to severe emotional and psychological distress at receiving results, fear of perceived side effects and long duration on ART. At interpersonal level, we found that anticipated and enacted stigma after HIV diagnosis resulted in non-disclosure, discrimination and lack of social support. We found that challenges at entry (during HIV test) and navigation of the HIV care system in addition to individual and interpersonal factors contributed to delayed ART initiation. Interventions during HIV testing would facilitate early ART initiation among patients referred for HIV care.

Hypertension and traditional risk factors for cardiovascular diseases among treatment naïve HIV- infected adults initiating antiretroviral therapy in Urban Tanzania

BackgroundCardiovascular diseases (CVDs) have become an important cause of ill health and death among people living with HIV and/or AIDS (PLHIV) in the antiretroviral therapy (ART) era. There is scarce data on the burden of hypertension (HTN) and risk factors for CVDs among PLHIV in developing countries, including Tanzania during the ART era.Objective(s)To determine the prevalence of HTN and risk factors for CVDs among ART naïve PLHIV initiating ART.MethodsWe analysed baseline data of 430 clinical trial participants on the effect of low-dose aspirin on HIV disease progression among HIV-infected individuals initiating ART. HTN was the outcome CVD. Traditional risk factors for CVDs studied were age, alcohol consumption, cigarette smoking, individual and family history of CVDs, diabetes mellitus (DM), obesity/overweight, and dyslipidaemia. A generalized linear model (robust Poisson regression) was used to determine the predictors for HTN.ResultsThe median (IQR) age was 37 (28, 45) years. Females were the majority contributing 64.9% of all participants. The prevalence of HTN was 24.8%. The most prevalent risk factors for CVDs were dyslipidaemia (88.3%), alcohol consumption (49.3%), and overweight or obesity (29.1%). Being overweight or obese predicted the occurrence of HTN, aPR 1.60 (95% CI 1.16–2.21) while WHO HIV clinical stage 3 was protective against HTN, aPR 0.42(95% CI 0.18–0.97).ConclusionThe prevalence of HTN and traditional risk factors for CVDs in the treatment naïve PLHIV initiating ART are significant. Identifying these risk factors and managing them at the time of ART initiation may lower future CVDs among PLHIV.