HIV-1 RNA Research Articles

Efficacy of bictegravir/emtricitabine/tenofovir alafenamide versus dolutegravir-based three-drug regimens in people with HIV with varying adherence to antiretroviral therapy

Abstract Objective Five Phase 3 bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) clinical studies demonstrated that the efficacy of B/F/TAF was non-inferior to dolutegravir (DTG) + 2 NRTIs. We retrospectively assessed drug adherence and effect on virologic outcomes. Methods Studies (NCT02607930, NCT02607956, NCT03547908, NCT02603120 and NCT03110380) were double-blind, placebo-controlled and enrolled treatment-naïve or virologically suppressed adults. Adherence was calculated by pill count from returned pill bottles; virologic outcome was assessed by last on-treatment HIV-1 RNA. Results Altogether, 2622 participants (B/F/TAF: n = 1306; DTG + 2 NRTIs: n = 1316) were categorized as having high (≥95%), intermediate (≥85% to <95%) or low (<85%) adherence. Through Week 48, low adherence was observed in 46 (3.5%) participants in the B/F/TAF group (78% median adherence) and 69 (5.2%) in the DTG + 2 NRTI group (80% median adherence). Overall, 1287 (98.5%) participants in the B/F/TAF group and 1292 (98.2%) in the DTG + 2 NRTI group had virologic suppression (VS; HIV-1 RNA < 50 copies/mL) through Week 48. VS in participants with low adherence versus high or intermediate adherence was similar in the B/F/TAF group, but lower in the DTG + 2 NRTI group (P ≤ 0.002). Similar results were observed at Weeks 96 and 144. Two participants (<95% adherence) in the DTG + 2 NRTI group receiving DTG and abacavir/lamivudine developed M184V; there was no treatment-emergent resistance to B/F/TAF. Conclusions Participants with suboptimal (<85%) adherence to B/F/TAF maintained high levels of VS, whereas suboptimal DTG + 2 NRTI adherence was associated with lower VS.

Asymptomatic Cerebrospinal Fluid HIV-1 Escape: Incidence and Consequences.

The incidence and clinical relevance of asymptomatic cerebrospinal fluid escape (CSF-E) during antiretroviral therapy (ART) is uncertain. We examined the impact and incidence of asymptomatic CSF-E in a Swedish HIV cohort. Neuroasymptomatic people living with HIV (PLWH) who have been on ART for at least six months with suppressed plasma viral load were followed longitudinally. CSF-E was defined as either increased CSF HIV-1 RNA with concurrent plasma suppression or as CSF HIV-1 RNA exceeding that in plasma when both were quantifiable. Paired CSF and plasma were analyzed for HIV-1 RNA, neopterin, neurofilament light protein (NfL), white blood cell (WBC) count, and albumin ratio. Asymptomatic CSF-E (cut-off 50 copies/mL) was found in 4/173 PLWH (2%) and 5/449 samples (1%). The corresponding proportions were 8% of PLWH and 4% for samples using a 20 copies/mL cut-off for CSF HIV-1 RNA. CSF-E samples (cut-off 20 copies/mL) had a 25% higher geometric mean of CSF neopterin (P = .01) and 8% higher albumin ratio (P = .04) compared to samples without CSF-E. No differences were observed in CSF NfL levels (P = .8). The odds ratio for increased CSF WBC (≥ 3 cells/μL) in samples with CSF-E was 3.9 (P = .004), compared to samples without elevated CSF viral load. Asymptomatic CSF-E was identified in only four (2%) PLWH, with no cases of continuous CSF-E observed. Increased CSF HIV-1 RNA was associated with biomarkers of CNS immune activation and blood-brain-barrier impairment, but not with biomarkers of neuronal injury.

Changes to inflammatory markers during 5 years of viral suppression and during viral blips in people with HIV initiating different integrase inhibitor based regimens

BackgroundHeightened levels of inflammatory markers are linked to increased morbidity/mortality in people with HIV (PWH) and often remain elevated after virologic suppression by antiretroviral therapy (ART). As new combinations of ART become available, an evaluation of their effects on immune activation and inflammation is warranted. Additionally, it remains unknown whether transient increases in viral load (“blips”) during ART are associated with increases in inflammation.MethodsWe utilized cryopreserved samples from treatment-naïve PWH enrolled in two Phase 3 clinical trials investigating the efficacy and safety of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) or dolutegravir, abacavir, and lamivudine (DTG/ABC/3TC) or DTG + F/TAF over a 5-year window (GS-US-380-1489/1490). At week 144, participants were offered the option to switch to open label B/F/TAF for an additional 96 weeks. We measured levels of interleukin-6 (IL-6), C-reactive protein (hsCRP), D-dimer, soluble CD14 (sCD14), and tumor necrosis factor-α receptor 1 (TNFR1) from available baseline, week 24, 48, 144, and 240 samples (B/F/TAF, N=123; DTG/ABC/3TC, N=62; DTG+F/TAF, N=58). Additional samples from PWH who experienced a viral blip (n=44, defined as a single HIV-1 RNA >50c/mL) were also analyzed and paired with the most recent available suppressed sample before the blip. Longitudinal biomarker changes were assessed using a constrained mixed effects linear regression model adjusting for covariates.ResultsBaseline demographics and selected laboratory characteristics were similar across groups. Levels of D-dimer, sCD14, and TNFR1 decreased significantly from baseline in all treatment arms, with no significant differences between arms at any timepoint. Biomarker levels also remained stable following ART-switch at week 144. No significant changes in hsCRP or IL-6 were observed versus baseline in any arm at any timepoint. A significant association was observed between sCD14 and increasing viral load (p=0.022) in viral blips; D-dimer also increased with blips in the B/F/TAF arm.ConclusionsViral suppression was associated with reductions in most inflammatory markers in PWH, with no significant differences among the three ART regimens during the 144-week randomized period. These decreases were sustained after the open label switch to B/F/TAF. Viral blips were associated with increases in monocyte activation (sCD14). Further analysis is needed to confirm these findings and determine the potential impact on clinical outcomes.

A simple phylogenetic approach to analyze hypermutated HIV proviruses reveals insights into their dynamics and persistence during antiretroviral therapy

Abstract Hypermutated proviruses, which arise in a single HIV replication cycle when host antiviral APOBEC3 proteins introduce extensive G-to-A mutations throughout the viral genome, persist in all people living with HIV receiving antiretroviral therapy (ART). But, hypermutated sequences are routinely excluded from phylogenetic trees because their extensive mutations complicate phylogenetic inference, and as a result we know relatively little about their within-host evolutionary origins and dynamics. Using >1400 longitudinal single-genome-amplified HIV env-gp120 sequences isolated from six women over a median 18 years of follow-up − including plasma HIV RNA sequences collected over a median 9 years between seroconversion and ART initiation, and >500 proviruses isolated over a median 9 years on ART − we evaluated three approaches for masking hypermutation in nucleotide alignments. Our goals were to 1) reconstruct phylogenies that can be used for molecular dating and 2) phylogenetically infer the integration dates of hypermutated proviruses persisting during ART. Two of the approaches (stripping all positions containing putative APOBEC3 mutations from the alignment, or replacing individual putative APOBEC3 mutations in hypermutated sequences with the ambiguous base R) consistently normalized tree topologies, eliminated erroneous clustering of hypermutated proviruses, and brought env-intact and hypermutated proviruses into comparable ranges with respect to multiple tree-based metrics. Importantly, these corrected trees produced integration date estimates for env-intact proviruses that were highly concordant with those from benchmark trees that excluded hypermutated sequences, supporting the use of these corrected trees for molecular dating. Subsequent molecular dating of hypermutated proviruses revealed that these sequences spanned a wide age range, with the oldest ones dating to shortly after infection. This indicates that hypermutated proviruses, like other provirus types, begin to be seeded into the proviral pool immediately following infection, and can persist for decades. In two of the six participants, hypermutated proviruses differed from env-intact ones in terms of their age distributions, suggesting that different provirus types decay at heterogeneous rates in some hosts. These simple approaches to reconstruct hypermutated provirus’ evolutionary histories reveal insights into their in vivo origins and longevity, towards a more comprehensive understanding of HIV persistence during ART.

Study on the correlation between viral load and activation and exhaustion levels of CD8+T cells in HIV/AIDS patients

Objective: To investigate and analyze the correlation between the expression levels of CD38, HLA-DR and programmed cell death-1 (PD-1) on peripheral blood CD8+T cells and HIV-1 RNA viral load, immune activation and exhaustion in patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Methods: A total of 81 HIV/AIDS patients (64 without antiretroviral therapy and 17 with therapy) and 40 healthy donors in the same period were enrolled as the control group. Flow cytometry was used to analyze the CD4+T lymphocyte count and the expression levels of activation markers CD38 and HLA-DR and apoptosis marker PD-1 on CD8+T cells. HIV-1 RNA in the plasma of HIV-1 infected patients was quantitatively detected by real-time fluorescence quantitative polymerase chain reaction. Variance analysis was used to compare the expression levels of CD38, HLA-DR and PD-1 on CD8+T cells between HIV/AIDS patients and healthy controls. Spearman correlation analysis was used to analyze the correlation between different T lymphocyte counts and HIV RNA viral load, and the correlation between HIV RNA viral load and peripheral blood CD8+T cell CD38, HLA-DR and PD-1. Results: Among the 81 HIV/AIDS patients, 69 (85.19%) were males and 12 (14.81%) were females, with an age M (Q1, Q3) of 58 (36.5, 65.0) years. There were 60 HIV/AIDS patients over 55 years old (74.07%) and 21 HIV/AIDS patients between 18 and 55 years old (25.93%). The results of variance analysis showed that compared with the healthy control group, the expression levels of CD38, HLA-DR and PD-1 on CD8+T cells in HIV/AIDS patients increased, and the differences were statistically significant (all P<0.05). In addition, the expression of CD38, HLA-DR and PD-1 increased significantly in patients with CD4+T cell count less than 350 cells/μl, and the differences were statistically significant (all P<0.05). Spearman correlation analysis showed that CD4+and CD4+/CD8+were negatively correlated with viral load in HIV/AIDS patients (r=-0.407 and -0.378, respectively, both P<0.05), and CD8+was positively correlated with viral load (r=0.356, P<0.05). When the HIV RNA level was≤105 CPs/ml, there was no correlation between the HIV RNA level and the expression levels of CD38, HLA-DR and PD-1 on CD8+T cells (all P>0.05). However, when the level of HIV RNA was>105 CPs/ml, the level of HIV RNA was positively correlated with the expression levels of CD38, HLA-DR and PD-1 on CD8+T cells (r=0.412, 0.387, 0.395, respectively, all P<0.05). Conclusions: The activation levels of CD38 and HLA-DR and the expression of PD-1 on CD8+T cells in the peripheral blood of HIV/AIDS patients are increased. When the viral load is high, the HIV RNA viral load is positively correlated with the activation and exhaustion levels of CD8+T cells.

Rapid viral suppression using integrase inhibitors during acute HIV-1 infection.

Antiretroviral therapy (ART) is recommended for all individuals with HIV infection, including those with acute HIV-1 infection (AHI). While recommendations are similar to those for chronic infection, efficacy data regarding treatment of acute HIV is limited. This was a single arm, 96-week study of a once-daily integrase inhibitor (INSTI)-based regimen using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) in AHI. Primary endpoint was proportion of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL by treatment weeks 24 and 48, respectively. We also examined time to viral suppression and weight gain after treatment initiation. Outcomes and characteristics were compared with a historical AHI cohort using a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). Thirty-three participants with AHI were enrolled with 31 available for analyses. Most were African American (61%) and men who have sex with men (73%). Median age was 26 (IQR 22-42). Demographics were similar between the two AHI cohorts. By Week 24, 100% in the INSTI and 99% in the NNRTI cohort were <200 copies/mL; by Week 48, 100% in both cohorts were <50 copies/mL. Time to viral suppression was shorter in the INSTI cohort (median 54 versus 99 days). Mean weight change was similar with a 3.6 kg increase in the INSTI cohort and 2.4 kg in the NNRTI cohort at 96 weeks. INSTI-based ART during AHI resulted in rapid and sustained viral suppression. Over 96 weeks, weight increased in the INSTI-based cohort but was similar to weight increase in a historical NNRTI-based AHI cohort.

Cystatin C provides substantially higher glomerular filtration rate estimates than creatinine in a subset of Black people with HIV on current antiretroviral regimens

Background In African populations, estimated glomerular filtration rate by cystatin C (eGFRcys) is better aligned with gold-standard GFR measurements than eGFR by creatinine (eGFRcr). Moreover, eGFRcys is unaffected by the effects of antiretroviral therapy (ART) on tubular secretion and may thus provide better estimates of GFR in people with HIV on ART. Setting Observational cohort study of people of African ancestry living with suppressed HIV RNA on ART in London, United Kingdom. Methods Cross sectional analysis of 360 paired serum creatinine and cystatin C measurements. Participants whose eGFRcys substantially (&gt;10%) exceeded eGFRcr were identified, and factors associated with this outcome identified in logistic regression analysis. Results The median age was 52 years, 56% were female, and 82% born in Africa or the Caribbean. The eGFRcys substantially exceeded eGFRcr in 42% of participants in the overall cohort, and in 68% of those with eGFRcr 45-75 mL/min/1.73m2. In multivariable analysis, a higher eGFRcr was associated with lower odds (0.59 [0.50, 0.68] per 10 mL/min/1.73m2 increase) of eGFRcys substantially exceeding eGFRcr; a higher BMI was also associated with this outcome while ART regimens inhibiting tubular secretion of creatinine were not predictive. Of the 22 participants with eGFRcr 45-60 mL/min/1.73m2, 16 (73%) had eGFRcys &gt;60 mL/min/1.73m2. Conclusion: We report substantially higher eGFRcys than eGFRcr in a subset of people of African ancestry with suppressed HIV, particularly among those with eGFRcr 45-75 mL/min/1.73m2. In this population, eGFRcys provides clinically useful information irrespective of ART regimen.

The Contribution of Socioeconomic Factors to HIV RNA Suppression in Persons With HIV Engaged in Care in the NA-ACCORD.

Socioeconomic status (SES) influences well-being among people living with HIV (people with HIV [PWH]); when individual-level SES information is not available, area-level SES indicators may be a suitable alternative. We hypothesized that (1) select ZIP code-level SES indicators would be associated with viral suppression and (2) accounting for ZIP code-level SES would attenuate racial disparities in viral suppression among PWH. The NA-ACCORD, a collaboration of clinical and interval cohorts of PWH, was used. Participants with ≥1 viral load measurement and ≥1 US residential 5-digit ZIP code(s) between 2010 and 2018 were included. In this serial cross-sectional analysis, multivariable logistic regression models were used to quantify the annual association of race and ethnicity with viral suppression, in the presence of SES indicators and sex, hepatitis C status, and age. We observed a dose-response relationship between SES factors and viral suppression. Lower income and education were associated with 0.5-0.7-fold annual decreases in odds of viral suppression. We observed racial disparities of approximately 40% decreased odds of viral suppression among non-Hispanic Black compared with non-Hispanic White participants. The disparity persisted but narrowed by 3%-4% when including SES in the models. ZIP code-based SES was associated with viral suppression, and accounting for SES narrowed racial disparities in viral suppression among PWH in the NA-ACCORD. Inclusion of ZIP code-level indicators of SES as surrogates for individual-level SES should be considered to improve our understanding of the impact of social determinants of health and racial disparities on key outcomes among PWH in North America.

Transmission of highly virulent CXCR4 tropic HIV-1 through the mucosal route in an individual with a wild-type CCR5 genotype

BackgroundNearly all transmitted/founder (T/F) HIV-1 are CCR5 (R5)-tropic. While previous evidence suggested that CXCR4 (X4)-tropic HIV-1 are transmissible, virus detection and characterization were not at the earliest stages of acute infection. MethodsWe identified an X4-tropic T/F HIV-1 in a participant (40700) in the RV217 acute infection cohort. Coreceptor usage was determined in TZM-bl cell line, NP-2 cell lines, and primary CD4+ T cells using pseudovirus and infectious molecular clones. CD4 subset dynamics were analyzed using flow cytometry. Viral load in each CD4 subset was quantified using cell-associated HIV RNA assay and total and integrated HIV DNA assay. FindingsParticipant 40700 was infected by an X4 tropic HIV-1 without CCR5 using ability. This participant experienced significantly faster CD4 depletion compared to R5 virus infected individuals in the same cohort. Naïve and central memory (CM) CD4 subsets declined faster than effector memory (EM) and transitional memory (TM) subsets. All CD4 subsets, including the naïve, were productively infected. Increased CD4+ T cell activation was observed over time. This X4-tropic T/F virus is resistant to broadly neutralizing antibodies (bNAbs) targeting V1/V2 and V3 regions, while most of the R5 T/F viruses in the same cohort are sensitive to the same panel of bNAbs. InterpretationsX4-tropic HIV-1 is transmissible through mucosal route in people with wild-type CCR5 genotype. The CD4 subset tropism of HIV-1 may be an important determinant for transmissibility and virulence. FundingInstitute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.

A prospective study to evaluate the clinical specificity of the cobas® MPX Test kit for screening for HIV RNA, HCV RNA, and HBV DNA in blood donation samples using the cobas® 6800 System in HBV endemic areas

A prospective study to evaluate the clinical specificity of the cobas® MPX Test kit for screening for HIV RNA, HCV RNA, and HBV DNA in blood donation samples using the cobas® 6800 System in HBV endemic areas

Effectiveness, safety, and patient-reported outcomes of emtricitabine/tenofovir alafenamide-based regimens for the treatment of HIV-1 infection: Final 24-month results from the prospective German TAFNES cohort study.

Tenofovir alafenamide (TAF) was introduced in the European Union in 2015 as a novel prodrug of tenofovir showing similar efficacy in clinical trials and a more favorable safety profile than tenofovir disoproxil fumarate (TDF). The German TAFNES cohort study (2016-2019) was conducted to generate real-world evidence. Treatment-naïve (TN) and treatment-experienced (TE) people with HIV (PWH) receiving elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF), rilpivirine/F/TAF (R/F/TAF) or F/TAF + 3rd agent were included. Month (M) 24 outcomes included virologic effectiveness (HIV RNA <50 copies/mL), treatment persistence, adverse drug reactions (ADRs) and patient-reported outcomes, using the HIV Symptom Index (HIV-SI), 36-Item Short Form Health Survey (SF-36) and HIV Treatment Satisfaction (HIVTSQ) questionnaires. The study included 767 PWH (92% men, median age 46 years; 301 TN, 466 TE; E/C/F/TAF [n = 318], R/F/TAF [n = 192], F/TAF + 3rd agent [n = 257]). Among TN, 35% had late HIV diagnosis (CD4 < 350/μL and/or AIDS). Of TE, 95% were on suppressive antiretroviral therapy (ART) before switching. D:A:D (Data Collection on Adverse Effects of Anti-HIV Drugs) 5-year risks for chronic kidney disease were high for about 1 in 10 TN and 4 in 10 TE. Overall treatment persistence at M24 was 81% (E/C/F/TAF: 88%; R/F/TAF: 86%; F/TAF + 3rd agent: 70%, with ART simplification of multiple-tablet regimens in 13%). M24 viral suppression (missing = excluded) was 96% (479/501). Discontinuations due to virologic failure or ADRs were rare, 2% (12/767) and 4% (30/767), respectively. HIV-SI and SF-36 summary scores improved in TN; HIVTSQ change scores showed an improvement in treatment satisfaction in TE. Real-world data confirmed a favorable safety profile and high virologic effectiveness with high treatment satisfaction on F/TAF-based ART.

Archived HIV-1 Drug Resistance Mutations: Role of Proviral HIV-1 DNA Genotype for the Management of Virological Responder People Living with HIV

Despite its effectiveness in controlling plasma viremia, antiretroviral therapy (ART) cannot target proviral DNA, which remains an obstacle to HIV-1 eradication. When treatment is interrupted, the reservoirs can act as a source of viral rebound, highlighting the value of proviral DNA as an additional source of information on an individual’s overall resistance burden. In cases where the viral load is too low for successful HIV-1 RNA genotyping, HIV-1 DNA can help identify resistance mutations in treated individuals. The absence of treatment history, the need to adjust ART despite undetectable viremia, or the presence of LLV further support the use of genotypic resistance tests (GRTs) on HIV-1 DNA. Conventionally, GRTs have been achieved through Sanger sequencing, but the advances in NGS are leading to an increase in its use, allowing the detection of minority variants present in less than 20% of the viral population. The clinical significance of these mutations remains under debate, with interpretations varying based on context. Additionally, proviral DNA is subject to APOBEC3-induced hypermutation, which can lead to defective, nonviable viral genomes, a factor that must be considered when performing GRTs on HIV-1 DNA.

Comparison of the Performance of Commercially Available Quantitative Viral Load Assays Using Clinical Samples from Patients from Regions Where Distinct HIV-1 Subtypes Co-Circulate: Potential Implications for Patient Management.

HIV RNA plasma viral load (VL) is the standard surrogate marker to monitor response to antiretroviral treatment (ART). We compared the linearity, repeatability, and concordance of six commercially available HIV RNA VL platforms using clinical samples from patients from Brazilian sites where different HIV-1 subtypes co-circulate. A total of 150 plasma samples from each city were collected in Curitiba, Southern Brazil (subtype C), São Paulo (subtype B), and Santos (BF recombinants), Southeast Brazil. Platforms were VERSANT® Siemens HIV RNA 1.0 (kPCR); VERSANT® Siemens HIV-1 RNA 3.0 (bDNA); Abbott Real-Time HIV-1; NucliSens EasyQ® HIV-1 v2.0 Biomerieux; COBAS® TaqMan®, Roche; and artus HIV Virus-1 RT-PCR, QIAGEN. OptiQuant HIV-1 RNA quantification panel was used to compare VL linearity, using samples containing 50, 500,5,000, 50,000, 500,000, and 5,000,000 HIV copies/mL. HIV RNA panels with subtypes A, B, C, D, F, G, H, circulating recombinant form (CRF)1, and CRF2 were utilized. A high degree of linearity and repeatability was demonstrated for all platforms. When compared with a subtype B reference sample, 17 of 54 (31.48%) samples diverged by more than 0.5 log10 copies/mL. Except for the Roche platform, all platforms underestimated subtype C VLs. A total of 743 (82.6%) valid results were obtained with samples from São Paulo, 707 (78.6%) from Santos, and 673 (74.8%) from Curitiba (São Paulo vs. Santos, p = .03; São Paulo vs. Curitiba, p = .00006; Santos vs. Curitiba, p = .06). The number of discordant samples between different methodologies when VL was undetectable in one method and detectable in the other ranged from 1.25% (Abbot vs. Siemens) to 44.8% (Abbott vs. Biomerieux). Finding samples with undetectable VL in one method and a high VL in another might have important individual and public health consequences. Standardization of VL measurements, particularly for non-B subtypes infections, especially subtype C, is necessary to maximize the individual and public health benefits of ART globally.

Association between lipoprotein particle concentration and size and progression of coronary plaque: the MACS Longitudinal Coronary CT angiography study

Abstract Background People living with HIV have greater risk of cardiovascular diseases (CVD) than people without HIV and tend to have different risk profiles, including higher serum triglycerides and lower LDL cholesterol levels. Nuclear magnetic resonance (NMR) provides a detailed phenotype of lipoproteins. Purpose To examine the associations between lipoprotein particle concentrations and size and progression of coronary artery plaque among people living with and without HIV, and whether these associations differ by HIV serostatus. Methods Men with no clinical CVD in the Multicenter AIDS Cohort Study (MACS) who underwent a coronary CT angiography at baseline (2010-13) and follow-up (2015-17) were included. NMR spectroscopy was completed on fasting serum samples at baseline. Logistic regression models for the change in total coronary plaque volume (in tertiles) were estimated with NMR-derived lipoproteins as predictors. Levels were log-transformed and standardized to make results comparable. Models were adjusted for demographics, statin use and HIV serostatus (model 1) with addition of CVD risk factors (model 2). Interactions by HIV serostatus were also tested. Results A total of 549 men (314 with HIV; 235 without HIV) were included. Mean age was 53 ±7 years; 58% were White, 30% Black, and 12% Hispanic. Coronary plaque was present in 70% and plaque volume progressed in 79% of the cohort. Among men with HIV, 81% had undetectable HIV RNA and 12% had a diagnosis of AIDS at baseline. Men with HIV had significantly higher levels of small LDL-P, and total, medium and large VLDL-P levels compared to men without HIV, and lower levels of total, small and large HDL-P (Table 1). Men with HIV had significantly greater progression of plaque volume (37 mm3) compared to men without HIV (31 mm3, p&amp;lt;0.05). Levels of total and small LDL-P concentrations were directly associated with plaque progression, whereas large HDL-P was inversely associated with plaque progression in the combined sample (Model 2). Associations between total and small LDL-P with plaque progression were stronger in men with HIV than in men without HIV in models 1 and 2 (interaction p&amp;lt;0.01). While associations in fully adjusted models for total VLDL-P and small VLDL-P were significant in men without HIV, there were no significant associations between these particle concentrations with coronary plaque progression among men without HIV (interaction p&amp;lt; 0.01) (Model 2, Table 2). Conclusion Associations between lipid particle concentrations and coronary plaque progression differed between men with and without HIV, with stronger associations seen in men without HIV for total and small LDL-P. Despite having higher VLDL and lower HDL particle concentrations at baseline, these particle concentrations were only associated with plaque progression in men without HIV. Further research is needed to elucidate HIV specific factors for plaque progression to tailor risk reduction strategies.

Correction: Gene expression and chromatin conformation of microglia in virally suppressed people with HIV.

"Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%)" should be corrected to: "Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.5%)."

Sex as a biological variable in HIV-1 and schistosome co-infection.

The sex of people living with HIV-1 infection, schistosome infection, or both, is a fundamental determinant of their clinical outcomes and of how these two infections interact in the host. Data from longitudinal and cross-sectional human studies and animal models indicate that males with HIV-1 and schistosome co-infection excrete fewer schistosome eggs and might have higher HIV-1 RNA viral loads and greater liver damage. Females with schistosome infection appear to have higher risk of HIV-1 acquisition than females without, particularly in Schistosoma haematobium infection, and a greater risk of death in HIV-1 and schistosome co-infection. Greater transmission of HIV-1 to partners has been shown in both sexes in those with schistosome infection. Biological sex is a consequential factor affecting pathophysiological and clinical responses in HIV-1 and schistosome co-infection. Designing future analyses to incorporate sex is vital to optimise research and care for people living with HIV-1, schistosomes, and HIV-1 and schistosome co-infection.

Epigenetic associations with kidney disease in individuals of African ancestry with APOL1 high-risk genotypes and Human Immunodeficiency Virus.

Apolipoprotein L1 (APOL1) high-risk variants are major determinants of chronic kidney disease (CKD) in people of African ancestry. Previous studies have identified epigenetic changes in relation to kidney function and CKD, but not in individuals with APOL1 high-risk genotypes. We conducted an epigenome-wide analysis of CKD and estimated glomerular filtration rate (eGFR) in in people of African ancestry and APOL1 high-risk genotypes with HIV. DNA methylation profiles from peripheral blood mononuclear cells of 119 individuals with APOL1 high-risk genotypes (mean age 48 years, 49% female, median CD4 count 515 cells/mm3, 90% HIV-1 RNA <200 copies/mL, 23% with CKD) were obtained by Illumina MethylationEPIC BeadChip. Differential methylation analysis of CKD considered technical and biological covariates. We also assessed associations with eGFR. Replication was pursued in three independent multi-ancestry cohorts with and without HIV. DNA methylation levels at 14 regions were associated with CKD. The strongest signals were located in SCARB1, DNAJC5B and C4orf50. Seven of the 14 signals also associated with eGFR, and most showed evidence for a genetic basis. Four signals (in SCARB1, FRMD4A, CSRNP1 and RAB38) replicated in other cohorts, and 11 previously reported epigenetic signals for kidney function or CKD replicated in our cohort. We found no significant DNA methylation signals in, or near, the APOL1 promoter region. We report several novel as well as previously reported epigenetic associations with CKD and eGFR in individuals with HIV having APOL1 high-risk genotypes. Further investigation of pathways linking DNA methylation to APOL1 nephropathies is warranted.

Translation of HIV-1 unspliced RNA is regulated by 5' untranslated region structure.

HIV-1 must generate infectious virions to spread to new hosts and HIV-1 unspliced RNA (HIV-1 RNA) plays two central roles in this process. HIV-1 RNA serves as an mRNA that is translated to generate proteins essential for particle production and replication, and it is packaged into particles as the viral genome. HIV-1 uses several transcription start sites to generate multiple RNAs that differ by a few nucleotides at the 5' end, including those with one (1G) or three (3G) 5' guanosines. The virus relies on host machinery to translate its RNAs in a cap-dependent manner. Here, we demonstrate that the 5' context of HIV-1 RNA affects the efficiency of translation both in vitro and in cells. Although both RNAs are competent for translation, 3G RNA is translated more efficiently than 1G RNA. The 5' untranslated region (UTR) of 1G and 3G RNAs has previously been shown to fold into distinct structural ensembles. We show that HIV-1 mutants in which the 5' UTR of 1G and 3G RNAs fold into similar structures were translated at similar efficiencies. Thus, the host machinery translates two 99.9% identical HIV-1 RNAs with different efficiencies, and the translation efficiency is regulated by the 5' UTR structure.IMPORTANCEHIV-1 unspliced RNA contains all the viral genetic information and encodes virion structural proteins and enzymes. Thus, the unspliced RNA serves distinct roles as viral genome and translation template, both critical for viral replication. HIV-1 generates two major unspliced RNAs with a 2-nt difference at the 5' end (3G RNA and 1G RNA). The 1G transcript is known to be preferentially packaged over the 3G transcript. Here, we showed that 3G RNA is favorably translated over 1G RNA based on its 5' untranslated region (UTR) RNA structure. In HIV-1 mutants in which the two major transcripts have similar 5' UTR structures, 1G and 3G RNAs are translated similarly. Therefore, HIV-1 generates two 9-kb RNAs with a 2-nt difference, each serving a distinct role dictated by differential 5' UTR structures.

A Stepped-Wedge, Cluster-Randomized, Multisite Study of Text Messaging Plus Peer Navigation to Improve Adherence and Viral Suppression Among Youth on Antiretroviral Therapy.

To address the need for improved virologic suppression among youth living with HIV (YLH) on antiretroviral treatment (ART), we evaluated peer navigation plus TXTXT daily text message ART reminders. YLH aged 15-24 on ART for at least 3 months at six research sites in four Nigerian cities. Using a stepped-wedge design, Cluster 1 was non-randomized, while Clusters 2 and 3 were randomized to sequences of routine care (control period) and 48 weeks of the combination intervention (intervention period). The primary endpoint was viral suppression (HIV-1 RNA <200 copies/mL) at week 48 of the intervention. Secondary endpoints included adherence measured by self-report (90% considered adherent). Post-hoc analysis assessed virologic control at <50 copies/mL and <1000 copies/mL. Generalized estimating equations determined the difference between intervention and control periods in the intention-to-treat population. We enrolled 558 YLH and followed 541 over time, mean age 18 years, 53.8% female, 71.7% perinatally infected, and 38.6% virologically non-suppressed at enrollment. For the primary endpoint, the intervention periods displayed a small, non-significant increase in viral suppression < 200 copies/mL (OR = 1.16 [0.88, 1.54], p = 0.297). There was a significant effect of the combination intervention on virologic control <1000 copies/mL (OR = 1.42 [1.03, 1.94], p = 0.030). Self-reported adherence also improved (OR = 2.07 [1.46, 2.95], p < 0.001). Peer navigation plus daily text message ART reminders demonstrated limited benefit among ART-experienced, predominantly perinatally-infected YLH, with no significant effect on viral suppression below 200 copies/mL despite improvement in self-reported adherence.

Management of low-level HIV viremia during antiretroviral therapy: Delphi consensus statement and appraisal of the evidence

ObjectiveWhile antiretroviral therapy (ART) is highly effective, detection of low levels of HIV-1 RNA in plasma is common in treated individuals. Given the uncertainties on the topic, we convened a...