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Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART.

Long-acting insulin analogues are the standard of care for Type 1 diabetes (T1D) in high-income countries but remain inaccessible in many low-resource settings. Cost-effectiveness is a key consideration for their adoption. This analysis evaluated the cost-effectiveness of biosimilar insulin glargine (IGlar) versus neutral protamine Hagedorn (NPH) insulin in youth with T1D in Tanzania and Bangladesh. Data from the HumAn-1 trial informed a short-term economic model comparing NPH and IGlar over 12 months. The analysis, conducted from a health systems perspective, incorporated micro-costing data for insulin, injection supplies, blood glucose monitoring, and estimated hospitalization costs for complications. Effectiveness was based on a reduction in nocturnal hypoglycemia. In both countries, we calculated incremental cost-effectiveness ratios per quality-adjusted life year (QALY) gained in scenarios that compared IGlar against NPH across delivery devices (i.e., vials, cartridges, single-use pens). IGlar was cost-effective compared to NPH when provided in cartridges in Bangladesh at a threshold of three times gross domestic product per capita. Other delivery devices in Bangladesh and all options in Tanzania were not cost-effective at current prices. If offered, IGlar vials would be cost-effective in Tanzania and Bangladesh if the price introduced was no more than 32% or 134% higher, respectively, than the current prices of NPH vials. Annual per patient costs and other cost-effectiveness thresholds were explored. In low-resource settings, IGlar can be a cost-effective alternative to NPH, largely due to reduced nocturnal hypoglycemia, but the delivery device for the insulin has a major impact on the costs and cost-effectiveness comparisons.

Background. The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain. Methods. To determine the effect of pre-existing minority nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure, we reanalyzed a case-cohort substudy of efavirenz recipients in AIDS Clinical Trials Group protocol A5095. Minority K103N or Y181C populations were determined by allele-specific polymerase chain reaction in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent treatment adherence estimated the relative risk of virologic failure in the presence of NNRTI-resistant minority variants. Results. The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with virologic failure, 144 without virologic failure), plus 127 of the remaining subjects who experienced virologic failure. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%), and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of virologic failure in the setting of recent treatment adherence (hazard ratio, 3.45 [95% confidence interval, 1.90–6.26]) but not in nonadherent subjects (hazard ratio, 1.39 [95% confidence interval, 0.58–3.29]). Of note, 70% of subjects with minority Y181C variants achieved long-term viral suppression. Conclusions. In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of virologic failure of first-line efavirenz-based antiretroviral therapy. Clinical trials registration. NCT00013520.

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.

A case-cohort study was used to determine the effect of baseline nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance, as assessed by viral genotyping, on the response to efavirenz-containing regimens in AIDS Clinical Trials Group A5095. The sample included a random cohort of efavirenz-treated subjects plus unselected subjects who experienced virologic failure. Of 220 subjects in the random cohort, 57 (26%) had virologic failure. The prevalence of baseline NNRTI resistance was 5%. The risk of virologic failure for subjects with baseline NNRTI resistance was higher than that for subjects without such resistance (hazard ratio 2.27 [95% confidence interval], 1.15–4.49; P = .018). These results support resistance testing before starting antiretroviral therapy

Identifying pre-ART factors associated with the emergence of HIV-1 drug resistance is critical for optimizing strategies to prevent virologic failure. A previous study reported that lower pre-ART HIV-1 pol diversity was associated with higher risk of virologic failure in HIV-1-infected children. To investigate this association in adults, we measured HIV-1 diversity with deep sequencing in pre-ART samples from adults with well-characterized virologic outcomes in a study (A5142) of initial ART conducted by the AIDS Clinical Trials Group (ACTG). We identified 22 cases in ACTG A5142 who experienced virologic failure with drug resistance mutations in RT and 44 matched controls who did not experience virologic failure. cDNA was synthesized from plasma HIV-1 RNA. Each cDNA molecule was tagged with a unique primer ID and RT codons 41-103 were amplified and deep sequenced. Sequences with the same tag were aligned and a consensus was generated to reduce PCR and sequencing errors. Diversity was calculated by measuring average pairwise distance (APD) of the consensus sequences. An exact conditional logistic regression model with percent APD as the risk factor estimated the odds ratio for VF and the corresponding 95% confidence interval. Consensus single-genome sequences and diversity estimates of pol were obtained for pre-ART samples from 21 cases and 42 controls. The median (IQR) pre-ART percent APD was 0.71 (0.31-1.13) in cases and 0.58 (0.32-0.94) in controls. A possible trend was found for higher diversity being associated with greater risk of virologic failure in adults (OR = 2.2 per one percent APD increase, 95% CI = [0.8, 7.2]; p = 0.15). This study in adults suggests there is a positive association between higher pre-ART pol diversity and the risk of virologic failure in adults rather than an inverse relationship reported in children.

BACKGROUNDPersistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART.METHODSParticipants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay.RESULTSSixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm3, plasma HIV RNA <100 copies/mL) were assessed after a median 8.6 years of ART. In CSF, cell-free RNA was detected in 4%, CA-RNA in 9%, and CA-DNA in 48% of participants (median level 2.1 copies/103 cells). Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = 0.007). CSF inflammatory biomarkers did not correlate with HIV persistence measures. Detection of CSF CA-DNA HIV was associated with worse neurocognitive outcomes including global deficit score (P = 0.005), even after adjusting for age and nadir CD4 count.CONCLUSIONHIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance.FUNDINGThis observational study, AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321), was supported by the National Institutes of Health (NIAID and NIMH).

Background. Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined. Methods. Blood mononuclear cells obtained during 7–12 years of effective ART were assayed for total HIV-1 DNA and 2-long terminal repeat (LTR) circles by quantitative polymerase chain reaction (qPCR). Slopes of HIV-1 DNA were estimated by participant-specific linear regressions. Plasma was assayed for residual viremia (HIV-1 RNA) by qPCR. Results. Thirty participants were studied. HIV-1 DNA decreased significantly from years 0–1 and 1–4 of ART with median decay slopes of -0.86 (interquartile range, -1.05, -0.59) and -0.11 (-0.17, -0.06) log 10 (copies/10 6 CD4+ T-cells)/year, respectively (P < .001). Decay was not significant for years 4–7 (-0.02 [-0.06, 0.02]; P = .09) or after year 7 of ART (-0.006 [-0.030, 0.015]; P = .17). All participants had detectable HIV-1 DNA after 10 years (median 439 copies/10 6 CD4+ T-cells; range: 7–2074). Pre-ART HIV-1 DNA levels were positively associated with pre-ART HIV-1 RNA levels (Spearman = 0.71, P < .001) and with HIV-1 DNA at years 4, 7, and 10 on ART (Spearman ≥ 0.75, P < .001). No associations were found (P ≥ .25) between HIV-1 DNA slopes or levels and % activated CD8+ T-cells (average during years 1–4) or residual viremia (n = 18). 2-LTR circles were detected pre-ART in 20/29 and in 8/30 participants at last follow-up. Conclusions. Decay of HIV-1 DNA in blood is rapid in the first year after ART initiation (86% decline), slows during years 1–4 (23% decline/year), and subsequently plateaus. HIV-1 DNA decay is not associated with the levels of CD8+ T-cell activation or persistent viremia. The determinants of stable HIV-1 DNA persistence require further elucidation. Clinical Trials Registration. NCT00001137.

•Atrial fibrillation (AF) is a common, morbid disease.•We conducted a trial (n = 243) of a 4-month intervention to improve OAC adherence.•We combined a novel mobile health intervention with a heart rate and rhythm monitor.•The intervention did not improve objective or self-reported OAC adherence.•The intervention arm had 2-fold lower health care utilization rates than control. Atrial fibrillation (AF) requires long-term adherence to oral anticoagulation and self-care. We conducted a randomized controlled trial of a smartphone-based relational agent and heart rhythm monitor with the primary outcome of anticoagulation adherence and secondary outcomes of quality of life (QOL) and health care utilization. The trial enrolled individuals with Atrial fibrillation (AF) taking anticoagulation. Intervention participants received a smartphone-based relational agent for disease education, adherence monitoring, and self-care, and a heart rate and rhythm monitor. Attention control participants received a smartphone health education application and the same heart monitor. Participants had baseline and 4-, 8-, and 12-month visits. The primary outcome was 12-month proportion of days covered (PDC) ascertained with pharmacy claims. From January, 2020 to April, 2022, the trial enrolled 243 participants (age 70.8 ± 9.8 years; 64.2% female; 30.5% Black race). The adjusted mean PDC at 12 months in the intervention arm was 0.88 (95% Confidence Interval [CI], 0.84-0.93) and in the attention control 0.85 (95% CI, 0.81-0.90) with no difference in odds of PDC ≥ 0.80 in intervention compared to the control (Odds Ratio, 1.26 [95% CI, 0.66-2.38]). Self-reported nonadherence and QOL did not differ by study arm. The event rates for health care utilization were significantly less for intervention than attention control participants as measured by emergency room visits and hospitalizations (P < .001) and number of days hospitalized (P = .004). The smartphone-based relational agent intervention did not achieve its primary endpoint of increased anticoagulation adherence but did yield decreased health care utilization. ClinicalTrials.gov Identifier: NCT04075994