People who inject drugs (PWID) living with HIV are less likely to receive care at early disease stages and have low rates of viral suppression. This study examined the feasibility and acceptability of rapid antiretroviral therapy (ART) initiation among PWID with HIV at a syringe services program (SSP) and assessed retention in care after transition to a traditional HIV clinic.

A mixed-methods single-arm pilot study was conducted at an SSP in Miami, Florida. Participants with HIV viral load >200 copies/mL were immediately connected with an HIV care provider and received HIV care and peer navigation at the SSP for 6 months, then were transitioned to a traditional HIV clinic. Demographic data were abstracted from the SSP's administrative records. Laboratory assessments and qualitative interviews were conducted at 1, 3, 6, 9, and 12 months.

Sixty-nine percent, 70%, and 69% of participants were virally suppressed (<200 copies/mL) at 1, 3, and 6 months, respectively. Following transition to a traditional HIV clinic, viral suppression remained high at 74% and 79% at 9 and 12 months, respectively. Themes were identified on: 1) barriers to care in traditional HIV clinics, 2) the SSP as a 'safe haven', 3) benefits of the rapid ART initiation program, 4) acceptability of telehealth, and 5) persistent barriers to engaging in HIV care.

Rapid ART initiation for PWID at an SSP was acceptable and feasible and showed preliminary effectiveness in achieving HIV viral suppression and sustaining it after transition to a traditional HIV clinic.

Widespread access to antiretroviral therapy (ART) has led to near-normal life expectancies for people living with HIV (PLHIV), shifting the leading cause of death (COD) from AIDS-related to non-AIDS-related mortality. We assessed trends in COD among PLHIV who initiated ART in Thai National AIDS Program (NAP).

We analysed NAP data from PLHIV aged ≥15 at ART initiation, who started ART under Thailand's universal health coverage from 2008 to 2021. Individual data was linked with the National Death Registration system, and a rule-based algorithm applied text mining to classify COD as AIDS-related, non-AIDS-related and uncertain. Competing risk models examined associations between demographic and clinical characteristics and COD. Standardized mortality ratios (SMR) were calculated using mortality rate from the general Thai population.

Among 398,182 PLHIV (37.1% females) enrolled, the median (IQR) age was 35 (28-43) years, 43.6% commenced ART with CD4 counts <200 cells/mm3. Over 2,631,435 person years of follow-up, 73,768 (18.5%) deaths occurred: 56% AIDS-related, 40% non-AIDS-related and 4% uncertain. The cumulative incidence of AIDS-related mortality at 14 years was 14.74%, non-AIDS-related 12.04% and all-cause mortality 27.93%. AIDS-related deaths declined from 60% to 50% over the study period. Low CD4 counts, permanently loss to care and treatment at non-capital city were significantly associated with higher AIDS-related mortality. The SMR was higher in females [9.08 (95% CI 8.97-9.20] compared to males [5.83 (95% CI 5.78-5.88).

AIDS-related mortality decreased over time, but continued efforts are needed to improve earlier diagnosis, and equitable outcomes for women and those residing outside major cities.

Supported by National Institute of Health (IeDEA:U01AI069907).

To inform cure in children living with HIV (CWH), we elucidated the dynamics and mechanisms underlying HIV persistence during antiretroviral therapy (ART). In 120 Kenyan CWH who initiated ART between 1-12 months of age, 55 had durable viral load suppression, and 65 experienced ART interruptions. We measured plasma HIV RNA levels, CD4+ T cell count, and levels of intact and defective HIV DNA proviruses via the cross-subtype intact proviral DNA assay (CS-IPDA). By modeling data from the durably suppressed subset, we found that during early ART (year 0-1 on ART), plasma RNA levels decayed rapidly and biphasically and intact and defective HIV DNA decayed with mean 3 and 9 month half-lives, respectively. After viral suppression was achieved (years 1-8 on ART), intact HIV DNA decay slowed to a mean 22 month half-life, whilst defective HIV DNA no longer decayed. In five CWH, we found individual CD4+ TCRβ clones wax and wane, but average kinetics resembled those of defective DNA and CD4 count, suggesting that differential decay of intact HIV DNA arises from selective pressures overlaying normal CD4+ T cell kinetics. Finally, by modeling HIV RNA and DNA in CWH with treatment interruptions, we linked temporary viremia to transient rises in HIV DNA, but long-term intact reservoirs were not strongly influenced, suggesting brief treatment interruptions may not significantly increase HIV reservoirs in children.

Even in antiretroviral therapy (ART)-suppressed human immunodeficiency virus (HIV)-infected individuals, there are heterogeneous populations of HIV-expressing cells exhibiting variable degrees of progression through blocks to HIV transcriptional initiation, elongation, completion, and splicing. These HIV-transcribing cells likely contribute to HIV-associated immune activation and inflammation as well as the viral rebound that occurs after stopping ART. However, it is unclear whether the blocks to HIV transcription are present before ART and how the timing and duration of ART may affect the clearance of cells expressing HIV transcripts that differ in their processivity and/or presence of mutations. To investigate these questions, we quantified different types of HIV transcripts and the corresponding HIV DNA regions/proviruses in longitudinal blood samples obtained before ART initiation (T1) and after 6 months (T2) and 1 year (T3) of ART in 16 individuals who initiated ART during acute HIV infection. Before ART, the pattern of HIV transcripts suggested blocks to elongation and splicing, and only ~10% of intact proviruses were transcribing intact HIV RNA. During the first 6 months of ART, we detected progressively greater reductions in initiated, 5'-elongated, mid-transcribed, completed, and multiply spliced HIV transcripts. Completed HIV RNA decayed faster than initiated or 5'-elongated HIV RNA, and intact HIV RNA tended to decay faster than defective HIV RNA. HIV DNA and RNA levels at T1-T3 correlated inversely with baseline CD4+ T-cell counts. Our findings suggest the existence of immune responses that act selectively to reduce HIV transcriptional completion and/or preferentially kill cells making completed or intact HIV RNA.IMPORTANCEEven in virologically suppressed HIV-infected individuals, expression of viral products from both intact and defective proviruses may contribute to HIV-associated immune activation and inflammation, which are thought to underlie the organ damage that persists despite suppressive ART. We investigated how the timing of ART initiation and the duration of ART affect the heterogeneous populations of HIV-transcribing cells, including a detailed characterization of the different HIV transcripts produced before ART and the rate at which they decay after ART initiation during acute HIV infection. Even during untreated infection, most cells (~90%) have blocks at some stage of transcription. Furthermore, different HIV transcripts decline at different rates on ART, with the fastest decay of cells making completed and intact HIV RNA. Our results suggest that intrinsic or extrinsic immune responses act selectively to either reduce particular stages of HIV transcription or cause selective killing of cells making particular HIV transcripts.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with a 5-year relative survival rate of approximately 18%. The similarity between incidence and mortality (830000 deaths per year) underscores the bleak prognosis associated with the disease. HCC is the fourth most common malignancy and the second leading cause of cancer death in China. Most patients with HCC have a history of chronic liver disease such as chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholism or alcoholic steatohepatitis, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis. Early diagnosis and effective treatment are the keys to improving the prognosis of patients with HCC. Although the total number of human immunodeficiency virus (HIV)-infected patients is declining globally the incidence of HCC is increasing in HIV-infected patients, especially those who are coinfected with HBV or HCV. As a result, people infected with HIV still face unique challenges in terms of their risk of developing HCC.

To investigate the survival prognosis and clinical efficacy of surgical resection in patients with HCC complicated with HIV infection.

The clinical data of 56 patients with HCC complicated with HIV admitted to the Third Affiliated Hospital of Nantong University from January 2013 to December 2023 were retrospectively analyzed. Among these, 27 patients underwent hepatectomy (operation group) and 29 patients received conservative treatment (nonoperation group). All patients signed informed consents in line with the provisions of medical ethics. The general data, clinicopathological features and prognoses for the patients in the two groups were analyzed and the risk factors related to the prognoses of the patients in the operation group were identified.

The median disease-free survival (DFS) and overall survival (OS) of HIV-HCC patients in the surgical group were 13 months and 17 months, respectively, and the median OS of patients in the nonsurgical group was 12 months. The OS of the surgical group was significantly longer than that of the control group (17 months vs 12 months, respectively; P < 0.05). The risk factors associated with DFS and OS in the surgical group were initial HIV diagnosis, postoperative microvascular invasion (MVI), a CD4+ T-cell count < 200/μL, Barcelona stage C-D, and men who have sex with men (MSM; P < 0.05).

Hepatectomy can effectively prolong the survival of patients with HIV-HCC but MVI identified during postoperative pathological examination, late tumor detection, late BCLC stage, CD4+ T < 200/μL and MSM are risk factors affecting the survival and prognosis of patients undergoing hepatectomy. In addition, there were significant differences between the surgical group and the nonsurgical group in terms of the initial diagnosis of HIV, Child-Pugh score, alpha-fetoprotein measurement value, and HART-efficient antiretroviral therapy after the diagnosis of HIV (P < 0.05). Therefore, these factors may also affect the survival and prognosis of patients.

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells ("the reservoir") which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people with HIV (PWH) treated during acute infection, we developed a novel mathematical model to predict reservoir decay from peripheral CD4+ T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t1/2~2.83 weeks; week 5-24: t1/2~15.4 weeks) that extended out to 1 year. These estimates were ~5-fold faster than prior decay estimates among chronic treated PWH. Defective DNA had a similar biphasic pattern, but data were more variable. Predicted intact and defective decay rates were faster for PWH with earlier timing of ART initiation, higher initial CD4+ T cell count, and lower pre-ART viral load. These data add to our limited understanding of HIV reservoir decay at the time of ART initiation, informing future curative strategies targeting this critical time.

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.

BACKGROUNDEarly antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAbs) after acute/early ARTi is relevant but is poorly understood.METHODSWe characterized antibody responses in a cohort of 23 participants following ARTi in acute HIV (<60 days after acquisition) and early HIV (60-128 days after acquisition).RESULTSPlasma virus sequences at the time of ARTi revealed evidence of escape from anAbs after early, but not acute, ARTi. HIV-1 envelopes representing the transmitted/founder virus(es) (acute ARTi) or escape variants (early ARTi) were tested for sensitivity to longitudinal plasma IgG. After acute ARTi, no anAb responses developed over months to years of suppressive ART. In 2 of the 3 acute ARTi participants who experienced viremia after ARTi, however, anAbs arose shortly thereafter. After early ARTi, anAbs targeting those early variants developed between 12 and 42 weeks of ART and continued to increase in breadth and potency thereafter.CONCLUSIONResults indicate a threshold of virus replication (~60 days) required to induce anAbs, after which they continue to expand on suppressive ART to better target the range of reservoir variants.TRIAL REGISTRATIONClinicalTrials.gov NCT02656511.FUNDINGNIH grants U01AI169767, R01AI162646, UM1AI164570, UM1AI164560, U19AI096109, K23GM112526, T32AI118684, P30AI045008, P30AI027763, R24AI067039; Gilead Sciences grant INUS2361354; Viiv Healthcare grant A126326.

To conduct a comprehensive, systematic review of the profile of HIV-1 reservoirs in children and adolescents with perinatally acquired HIV infection.

Randomized and nonrandomized trials, cohort studies, and cross-sectional studies on HIV reservoirs in pediatric populations, published between 2002 and 2022, were included. Archived-drug resistance mutations (ADRMs) and the size of reservoirs were evaluated. Subgroup analyses were performed to characterize further the data, and the meta-analysis was done through random effect models.

Overall, 49 studies from 17 countries worldwide were included, encompassing 2356 perinatally infected participants (48.83% females). There are limited data on the quantitative characterization of viral reservoirs in sub-Saharan Africa, with sensitive methodologies such as droplet digital polymerase chain reaction rarely employed. The overall prevalence of ADRMs was 37.80% (95% CI 13.89-65.17), with 48.79% (95% CI 0-100) in Africa, 42.08% (95% CI 6.68-82.71) in America, 23.88% (95% CI 14.34-34.90) in Asia, and 20.00% (95% CI 10.72-31.17) in Europe, without any difference between infants and adolescents (P = .656). Starting antiretroviral therapy (ART) before 2 months of age limited the levels of HIV-1 DNA (P = .054). Participants with long-suppressed viremia (>5 years) had lower levels of HIV-1 DNA (P = .027). Pre- and post-ART CD4 ≤29% and pre-ART viremia ≥5Log were all found associated with greater levels of HIV-1 DNA (P = .038, P = .047, and P = .041, respectively).

The pooled prevalence of ADRMs is high in perinatally infected pediatric population, with larger proviral reservoir size driven by delayed ART initiation, a shorter period of viral suppression, and immunovirological failures. Thus, strategies for pediatric HIV functional cure should target children and adolescents with very early ART initiation, immunocompetence, and long-term viral suppression.

Clonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290.

Cytopenias serve as common indicators and crucial predictive tools for evaluating disease progression and therapeutic outcomes in individuals with human immunodeficiency virus (HIV) infection. This study aimed to assess the prevalence of cytopenias and their correlation with the level of immunosuppression in treatment-naive HIV-infected participants after initiating highly active combined antiretroviral drug therapy (cART24).

This prospective study focused on evaluating cytopenia in 44 treatment-naive HIV-infected patients who consented to initiate cART and were consecutively enrolled. The research was conducted at the Nasara HIV Treatment & Care Centre of Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, Nigeria, spanning from December 2016 to January 2018. Cytopenias, including anemia, leucopenia, lymphocytopenia, and thrombocytopenia, were defined and assessed according to World Health Organization guidelines. A combination of cross-sectional and longitudinal mixed-design two-step analysis was employed to validate our findings.

The median time from enrollment to cART initiation was 7 days, following the universal test and treat protocol. The prevalence of cytopenia was 75% at the baseline before treatment and increased to 84% after cART24 administration. There were no statistically significant differences in the median values of immuno-hematological parameters between baseline and after cART24 initiation (P >0.05). In terms of longitudinal assessment, the prevalence of anemia, leucopenia, lymphopenia, and thrombocytopenia at baseline were 66%, 23%, 0%, and 11%, respectively, and after cART24, the rates were 66%, 29%, 5%, and 20%. Notably, the prevalence of cytopenia correlated with declining CD4+ T cell counts. Among instances of unicytopenia, 58% exhibited isolated anemia, 6% had lone leucopenia, and 6% had solitary thrombocytopenia. Additionally, 27% demonstrated bi-cytopenia, and 3% exhibited pancytopenia. Interestingly, none of the study participants presented with lymphopenia. The most common combination was anemia and thrombocytopenia. Both longitudinal and cross-sectional analytical findings were consistent.

In treatment-naive HIV-infected individuals, the prevalence of cytopenias, particularly anemia and thrombocytopenia, was substantial and correlated with the degree of immunosuppression as indicated by CD4+ T cell counts. These cytopenias persisted despite initiation of cART24, highlighting the complexity of hematological manifestations in HIV infection. Our study underscores the significant hematopathological impact of HIV and antiretroviral therapy, highlighting the necessity for preventive strategies to mitigate these adverse effects.

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.

'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill). In the Research in Viral Eradication of HIV Reservoirs trial (NCT02336074), people diagnosed with primary HIV infection received immediate antiretroviral therapy (ART) and were randomised 24 weeks later to either a latency-reversing agent, vorinostat, together with ChAdV63.HIVconsv and MVA.HIVconsv vaccines, or ART alone. This intervention conferred no reduction in HIV-1 reservoir size over ART alone, despite boosting virus-specific CD4+ and CD8+ T cells. The effects of the intervention were examined at the cellular level in the two trial arms using unbiased computational analysis of polyfunctional scores. This showed that the frequency and polyfunctionality of virus-specific CD4+ and CD8+ T cell populations were significantly increased over 12 weeks post-vaccination, compared to the ART-only arm. HIV-specific IL-2-secreting CD8+ T cells also expanded significantly in the intervention arm and were correlated with antiviral activity against heterologous HIV in vitro. Therapeutic vaccination during ART commenced in primary infection can induce functional T cell responses that are phenotypically similar to those of HIV controllers. Analytical therapy interruption may help determine their ability to control HIV in vivo.

Human immunodeficiency virus type 1 (HIV-1) infection is treated with antiretroviral therapy (ART), usually consisting of 2-3 different drugs, referred to as combination ART (cART). Our recent randomized clinical trial comparing a switch to dolutegravir monotherapy with continuation of cART in early-treated individuals demonstrated sustained virological suppression over 48 weeks. Here, we characterize the longitudinal landscape of the HIV-1 reservoir in these participants, with particular attention to potential differences between treatment groups regarding evidence of evolution as a proxy for low-level replication. Near full-length HIV-1 proviral polymerase chain reaction and next-generation sequencing was applied to longitudinal peripheral blood mononuclear cell samples to assess proviral evolution and the potential emergence of drug resistance mutations (DRMs). Neither an increase in genetic distance nor diversity over time was detected in participants of both treatment groups. Single proviral analysis showed high proportions of defective proviruses and low DRM numbers. No evidence for evolution during dolutegravir monotherapy was found in these early-treated individuals.

The AIDS epidemic has been a global public health issue for more than 40 years and has resulted in ~40 million deaths. AIDS is caused by the retrovirus, HIV-1, which is transmitted via body fluids and secretions. After infection, the virus invades host cells by attaching to CD4 receptors and thereafter one of two major chemokine coreceptors, CCR5 or CXCR4, destroying the host cell, most often a T lymphocyte, as it replicates. If unchecked this can lead to an immune-deficient state and demise over a period of ~2-10 years. The discovery and global roll-out of rapid diagnostics and effective antiretroviral therapy led to a large reduction in mortality and morbidity and to an expanding group of individuals requiring lifelong viral suppressive therapy. Viral suppression eliminates sexual transmission of the virus and greatly improves health outcomes. HIV infection, although still stigmatized, is now a chronic and manageable condition. Ultimate epidemic control will require prevention and treatment to be made available, affordable and accessible for all. Furthermore, the focus should be heavily oriented towards long-term well-being, care for multimorbidity and good quality of life. Intense research efforts continue for therapeutic and/or preventive vaccines, novel immunotherapies and a cure.

Offering antiretroviral therapy (ART) to patients directly following an HIV diagnosis ("Rapid ART") improves clinical outcomes and is feasible and acceptable for patients and providers. Despite this, implementation of Rapid ART is not yet standard practice in the USA. Structural-level implementation guidance is available, but research at the individual provider level that explores the patient-provider interaction itself remains scarce. The Consolidated Framework for Implementation Research (CFIR) provides a nuanced guide to investigating the less visible, more social elements of implementation like the knowledge and feelings of people, and the influences of culture and resources on individual approaches.

We conducted a multi-site qualitative study, exploring intervention commonalities across three HIV clinic environments: an HIV primary care clinic; an HIV/STI testing, treatment, and prevention clinic; and a large federally qualified health center (FQHC). Qualitative data were gathered from 27 provider informants-Rapid ART program staff and clinicians-using an interview guide developed using the CFIR. An experienced qualitative team conducted a comprehensive thematic analysis and identified cross-cutting themes in how providers approach and engage in the Rapid interaction, as well as longer-form narratives from providers that describe more fully what this interaction looks like for them.

Three main themes represent the range and content of individual provider approaches to the Rapid interaction: (1) patient-centeredness; (2) emotional support and partnership; and (3) correcting misperceptions about HIV. Each theme encompassed both conceptual approaches to offering Rapid ART and concrete examples of messaging to the patient that providers used in the Rapid interaction. We describe and show examples of these themes, offer key take-aways for implementation, and provide expanded narratives of providers' personal approaches to the Rapid interaction.

Exploration of provider-level approaches to Rapid ART implementation, as carried out in the patient-provider Rapid interaction, contributes a critical layer of evidence for wider implementation. It is our hope that, together with existing research showing positive outcomes and core components of systems-level implementation, these findings add to an instructive body of findings that facilitates the implementation of Rapid ART as an enhanced model of HIV care.

CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.

Resistance to multiple antiretroviral drugs among people living with HIV (PLWH) can result in a high pill burden, causing toxicity and drug interactions. Thus, the goal is to simplify treatment regimens while maintaining effectiveness. However, former resistance analysis data may not be current or complete. The use of proviral DNA genotyping may assist in selecting appropriate treatment options. A retrospective study was carried out on individuals belonging to the Cologne HIV cohort with a resistance history to two or more antiretroviral (ARV) classes and on non-standard antiretroviral therapy (ART). Patients required former viral RNA and a recent proviral DNA resistance test to be available prior to the switch to ART. Potential discrepancies between resistance test results obtained through RNA and proviral DNA methods and the consequent virological and clinical outcomes following ART adjustments were analyzed. Out of 1250 patients, 35 were eligible for inclusion in this study. The median length of known HIV infection was 27 years, and the median duration of ART was 22 years. Of the 35 participants, 16 had received all five ARV classes. Based on proviral DNA genotyping results, ART was simplified in 17 patients. At the last follow-up examination after changing therapy, 15 patients had HIV RNA <50 copies/mL (median 202 days, range 21-636). The mean number of pills per day decreased from eight to three, and the median intake frequency decreased from two to one time/day (ranges 1-2). Our study supports the use of proviral DNA genotyping as a safe strategy for switching to simplified ART regimens. However, the lack of extensive research on the advantages of proviral DNA genotyping makes it challenging to fully assess its benefits in terms of treatment selection.

Over the past decade there have been technical advances in human immunodeficiency virus (HIV) assays and updates to testing regulations that have substantially changed the landscape of laboratory testing for HIV. In addition, there have been significant changes in the epidemiology of HIV in Australia in the context of highly effective contemporary biomedical treatment and prevention strategies. Here, we provide an update on contemporary issues for the laboratory detection and confirmation of HIV in Australia. These include (1) the impact of early treatment and biological prevention strategies on the serological and virological detection of HIV; (2) the updated national HIV laboratory case definition and its interaction with testing regulations, public health and clinical guidelines; and (3) novel strategies for the laboratory detection of HIV, including the incorporation of HIV nucleic acid amplification tests (NAATs) into testing algorithms. These developments present an opportunity to develop a nationally consistent contemporary HIV testing algorithm that would result in optimisation and standardisation of HIV testing in Australia.

Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 env from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.

Chronic inflammation and immune activation are a hallmark of HIV-1 infection. In this study, we assessed inflammation biomarkers in a cohort of people living with HIV-1 (PLWH) before and after long-term suppressive combined antiretroviral therapy (cART). A single-center prospective cohort study was conducted to assess inflammatory biomarkers in 86 cART-naive PLWH and after receiving suppressive cART and 50 uninfected controls. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and soluble CD14 (sCD14) were measured using enzyme-linked immunosorbent assay (ELISA). No significant difference was found in IL-6 levels between cART-naïve PLWH and controls (p = 0.753). In contrast, TNF-α level showed a significant difference between cART naïve-PLWH and controls (p = 0.019). Interestingly, IL-6 and TNF-α levels were significantly decreased in PLWH after cART (p < 0.0001). The sCD14 showed no significant difference between cART-naïve patients and controls (p = 0.839) and similar levels were observed in pre- and post-treatment (p = 0.719). Our results highlight the critical importance of early treatment to reduce inflammation and its consequences during HIV infection.

This review describes how advances in CyTOF and high-dimensional analysis methods have furthered our understanding of HIV transmission, pathogenesis, persistence, and immunity.

CyTOF has generated important insight on several aspects of HIV biology: (1) the differences between cells permissive to productive vs. latent HIV infection, and the HIV-induced remodeling of infected cells; (2) factors that contribute to the persistence of the long-term HIV reservoir, in both blood and tissues; and (3) the impact of HIV on the immune system, in the context of both uncontrolled and controlled infection. CyTOF and high-dimensional analysis tools have enabled in-depth assessment of specific host antigens remodeled by HIV, and have revealed insights into the features of HIV-infected cells enabling them to survive and persist, and of the immune cells that can respond to and potentially control HIV replication. CyTOF and other related high-dimensional phenotyping approaches remain powerful tools for translational research, and applied HIV to cohort studies can inform on mechanisms of HIV pathogenesis and persistence, and potentially identify biomarkers for viral eradication or control.

Prior genomewide association studies have identified variation in major histocompatibility complex (MHC) class I alleles and C-C chemokine receptor type 5 gene (CCR5Δ32) as genetic predictors of viral control, especially in 'elite' controllers, individuals who remain virally suppressed in the absence of therapy.

Cross-sectional genomewide association study.

We analyzed custom whole exome sequencing and direct human leukocyte antigen (HLA) typing from 202 antiretroviral therapy (ART)-suppressed HIV+ noncontrollers in relation to four measures of the peripheral CD4+ T-cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T-cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression.

Previously reported 'protective' host genetic mutations related to viral setpoint (e.g. among elite controllers) were found to predict smaller HIV reservoir size. The HLA 'protective' B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3 × 10-3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (P = 4.3 × 10-3) and usRNA (P = 8.7 × 10-3). In addition, genomewide analysis identified several single nucleotide polymorphisms in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression.

We observed a significant association between previously reported 'protective' MHC class I alleles and CCR5Δ32 with the HIV reservoir size in noncontrollers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.

Chronic immune activation has a significant role in HIV-1 disease pathogenesis and CD4+ T-cell depletion. The causes of chronic inflammation and immune activation are incompletely understood, but they are likely multifactorial in nature, involving both direct and indirect stimuli. Possible explanations include microbial translocation, coinfection, and continued presence of competent replicating virus. In fact, long-term viral suppression treatments are unable to normalize elevated markers of systemic immune activation. Furthermore, high levels of pro-inflammatory cytokines increase susceptibility to premature aging of the immune system. The phenomenon of "inflammaging" has begun to be evident in the last decades, as a consequence of increased life expectancy due to the introduction of cART. Quality of life and survival have improved substantially; however, PLWH are predisposed to chronic inflammatory conditions leading to age-associated diseases, such as inflammatory bowel disease, neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities, and non-HIV-associated cancers. Several approaches have been studied in numerous uncontrolled and/or randomized clinical trials with the aim of reducing immune activation/inflammatory status in PLWH, none of which have achieved consistent results.

Highly active antiretroviral therapy (ART) can effectively inhibit virus replication and restore immune function in most people living with human immunodeficiency virus (HIV). However, an important proportion of patients fail to achieve a satisfactory increase in CD4⁺ T cell counts. This state is called incomplete immune reconstitution or immunological nonresponse (INR). Patients with INR have an increased risk of clinical progression and higher rates of mortality. Despite widespread attention to INR, the precise mechanisms remain unclear. In this review, we will discuss the alterations in the quantity and quality of CD4⁺ T as well as multiple immunocytes, changes in soluble molecules and cytokines, and their relationship with INR, aimed to provide cellular and molecular insights into incomplete immune reconstitution.

This study aimed to examine the real prevalence of late presentation of HIV infection and to identify factors associated with late HIV presentation among patients with newly diagnosed HIV/AIDS in Suzhou, China.

Patients with newly diagnosed HIV/AIDS who registered in national AIDS surveillance system from 2017 to 2020 were included in this study. Late presentation (LP) of HIV infection was defined as HIV diagnosis with a CD4 count < 350 cells/μL or an AIDS-defining event. Multivariable logistic regression analyses were used to identify factors associated with LP.

A total of 2,300 patients were enrolled. 1,325 were classified as late presenters, showing a high percentage of 57.6% (95% CI: 54.5-60.7%) and a rise (P = 0.004) over the four-year period. Patients with newly diagnosed HIV/AIDS who were older than 24 years of age (aOR = 1.549, P = 0.001 for 25-39 years; aOR = 2.389, P < 0.001 for 40 years and older), were Suzhou registered residents (aOR = 1.259, P = 0.026), and were from inpatient and outpatient (aOR = 1.935, P < 0.001) were more likely to be late presentation.

This study showed a high percentage and a rise of late presentation of HIV infection among patients with newly diagnosed HIV/AIDS in Suzhou, China, which is a challenge for future prevention and control of AIDS. Targeted measures should be urgently implemented to reduce late HIV diagnosis.

HIV-1 DNA exists in nonintegrated linear and circular episomal forms and as integrated proviruses. In patients with plasma viremia, most peripheral blood mononuclear cell (PBMC) HIV-1 DNA consists of recently produced nonintegrated virus DNA while in patients with prolonged virological suppression (VS) on antiretroviral therapy (ART), most PBMC HIV-1 DNA consists of proviral DNA produced months to years earlier. Drug-resistance mutations (DRMs) in PBMCs are more likely to coexist with ancestral wild-type virus populations than they are in plasma, explaining why next-generation sequencing is particularly useful for the detection of PBMC-associated DRMs. In patients with ongoing high levels of active virus replication, the DRMs detected in PBMCs and in plasma are usually highly concordant. However, in patients with lower levels of virus replication, it may take several months for plasma virus DRMs to reach detectable levels in PBMCs. This time lag explains why, in patients with VS, PBMC genotypic resistance testing (GRT) is less sensitive than historical plasma virus GRT, if previous episodes of virological failure and emergent DRMs were either not prolonged or not associated with high levels of plasma viremia. Despite the increasing use of PBMC GRT in patients with VS, few studies have examined the predictive value of DRMs on the response to a simplified ART regimen. In this review, we summarize what is known about PBMC HIV-1 DNA dynamics, particularly in patients with suppressed plasma viremia, the methods used for PBMC HIV-1 GRT, and the scenarios in which PBMC GRT has been used clinically.

Vaccine strategies aimed at eliciting human immunodeficiency virus (HIV)-specific CD8+ T cells are one major target of interest in HIV functional cure strategies. We hypothesized that CD8+ T cells elicited by therapeutic vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with the interleukin 15 (IL-15) superagonist N-803 after ART discontinuation. We intravenously immunized four simian immunodeficiency virus-positive (SIV+) Mauritian cynomolgus macaques receiving ART with vesicular stomatitis virus (VSV), modified vaccinia virus Ankara strain (MVA), and recombinant adenovirus serotype 5 (rAd-5) vectors all expressing SIVmac239 Gag. Immediately after ART cessation, these animals received three doses of N-803. Four control animals received no vaccines or N-803. The vaccine regimen generated a high-magnitude response involving Gag-specific CD8+ T cells that were proliferative and biased toward an effector memory phenotype. We then compared cells elicited by vaccination (Gag specific) to cells elicited by SIV infection and unaffected by vaccination (Nef specific). We found that N-803 treatment enhanced the frequencies of both bulk and proliferating antigen-specific CD8+ T cells elicited by vaccination and the antigen-specific CD8+ T cells elicited by SIV infection. In sum, we demonstrate that a therapeutic heterologous prime-boost-boost (HPBB) vaccine can elicit antigen-specific effector memory CD8+ T cells that are boosted by N-803. IMPORTANCE While antiretroviral therapy (ART) can suppress HIV replication, it is not a cure. It is therefore essential to develop therapeutic strategies to enhance the immune system to better become activated and recognize virus-infected cells. Here, we evaluated a novel therapeutic vaccination strategy delivered to SIV+ Mauritian cynomolgus macaques receiving ART. ART was then discontinued and we delivered an immunotherapeutic agent (N-803) after ART withdrawal with the goal of eliciting and boosting anti-SIV cellular immunity. Immunologic and virologic analysis of peripheral blood and lymph nodes collected from these animals revealed transient boosts in the frequency, activation, proliferation, and memory phenotype of CD4+ and CD8+ T cells following each intervention. Overall, these results are important in educating the field of the transient nature of the immunological responses to this particular therapeutic regimen and the similar effects of N-803 on boosting T cells elicited by vaccination or elicited naturally by infection.

Significant advances in the field of HIV-1 therapeutics to achieve antiretroviral treatment (ART)-free remission and cure for persons living with HIV-1 are being made with the advent of broadly neutralizing antibodies and very early ART in perinatal infection. The need for HIV-1 remission and cure arises due to the inability of ART to eradicate the major reservoir for HIV-1 in resting memory CD4+ T cells (the latent reservoir), and the strict adherence to lifelong treatment. To measure the efficacy of these cure interventions on reservoir size and to dissect reservoir dynamics, assays that are sensitive and specific to intact proviruses are critical. In this review, we provided a broad overview of some of the key interventions underway to purge the reservoir in adults living with HIV-1 and ones under study in pediatric populations to reduce and control the latent reservoir, primarily focusing on very early treatment in combination with broadly neutralizing antibodies. We also summarized assays currently in use to measure HIV-1 reservoirs and their feasibility and considerations for studies in children.

Early diagnosis of HIV-1 infection and immediate initiation of combination antiretroviral therapy (cART) are important for achieving better virological suppression and quicker immune reconstitution. However, no serological HIV-1 recency testing assay has been approved for clinical use, and the real-world clinical outcomes remain to be explored for the subjects with HIV-1 recent infection (RI) or long-term infection (LI) when antiretroviral therapy is initiated. In this study, a HIV-1 rapid recent-infection testing strip (RRITS) was developed and incorporated into the recent infection testing algorithms (RITAs) to distinguish HIV-1 RI and LI and to assess their clinical outcomes including virological response, the recovery of CD4+ T-cell count and CD4/CD8 ratio and the probability of survival. We found that the concordance between our RRITS and the commercially available LAg-Avidity EIA was 97.13% and 90.63% when detecting the longitudinal and cross-sectional HIV-1 positive samples, respectively. Among the 200 HIV-1 patients analyzed, 22.5% (45/200) of them were RI patients and 77.5% (155/200) were chronically infected and 30% (60/200) of them were AIDS patients. After cART, 4.1% (5/155) of the LI patients showed virological rebound, but none in the RI group. The proportion of CD4+ T-cell count >500 cells/mm3 was significantly higher in RI patients than in LI after 2 years of cART with a hazard ratio (HR) of 2.6 (95% CI: 1.9, 3.6, p < 0.0001) while the probability of CD4/CD8 = 1 was higher in RI than in LI group with a HR of 3.6 (95% CI: 2.2, 5.7, p < 0.0001). Furthermore, the immunological recovery speed was 16 cells/mm3/month for CD4+ T-cell and 0.043/month for the ratio of CD4/CD8 in the RI group, and was bigger in the RI group than in the LI patients (p < 0.05) during the 1st year of cART. The survival probability for LI patients was significantly lower than that for RI patients (p < 0.001). Our results indicated that RRITS combined with RITAs could successfully distinguish HIV-1 RI and LI patients whose clinical outcomes were significantly different after cART. The rapid HIV-1 recency test provides a feasible assay for diagnosing HIV-1 recent infection and a useful tool for predicting the outcomes of HIV-1 patients.