Pre-cART Immune Parameters in People Living With HIV Might Help Predict CD8+ T-Cell Characteristics, Inflammation Levels, and Reservoir Composition After Effective cART

Background: Combined antiretroviral treatment (cART) for HIV infection is highly effective in controlling viral replication. However, it cannot achieve a sterilizing cure. Several strategies have been proposed to achieve a functional cure, some of them based on immune-mediated clearing of persistently infected cells. Here, we aimed at identifying factors related to CD8TC and CD4TC quality before cART initiation that associate with the persistence of CD8TC antiviral response after cART, inflammation levels, and the size of the viral reservoir. Methods: Samples from 25 persons living with HIV were obtained before and after (15 months) cART initiation. Phenotype and functionality of bulk and HIV-specific T cells were assayed by flow cytometry ex vivo or after expansion in pre-cART or post-cART samples, respectively. Cell-Associated (CA) HIV DNA (total and integrated) and RNA (unspliced [US] and multiple spliced [MS]) were quantitated by real-time PCR on post-cART samples. Post-cART plasma levels of CXCL10 (IP-10), soluble CD14 (sCD14) and soluble CD163 (sCD163) were measured by ELISA. Results: Pre-cART phenotype of CD8TCs and magnitude and phenotype of HIV-specific response correlated with the phenotype and functionality of CD8TCs post-cART. Moreover, the phenotype of the CD8TCs pre-cART correlated with markers of HIV persistence and inflammation post-cART. Finally, exhaustion and differentiation of CD4TCs pre-cART were associated with the composition of the HIV reservoir post-cART and the level of inflammation. Conclusions: Overall, this work provides data to help understand and identify parameters that could be used as markers in the development of immune-based functional HIV cure strategies.

Inflammation and microbial translocation measured prior to combination antiretroviral therapy (cART) and long-term probability of clinical progression in people living with HIV

Background Despite the effectiveness of cART, people living with HIV still experience an increased risk of serious non-AIDS events, as compared to the HIV negative population. Whether pre-cART microbial translocation (MT) and systemic inflammation might predict morbidity/mortality during suppressive cART, independently of other known risk factors, is still unclear. Thus, we aimed to investigate the role of pre-cART inflammation and MT as predictors of clinical progression in HIV+ patients enrolled in the Icona Foundation Study Cohort. Methods We included Icona patients with ≥2 vials of plasma stored within 6 months before cART initiation and at least one CD4 count after therapy available. Circulating biomarker: LPS, sCD14, EndoCab, hs-CRP. Kaplan-Meier curves and Cox regression models were used. We defined the endpoint of clinical progression as the occurrence of a new AIDS-defining condition, severe non-AIDS condition (SNAEs) or death whichever occurred first. Follow-up accrued from the data of starting cART and was censored at the time of last available clinical visit. Biomarkers were evaluated as both binary (above/below median) and continuous variables (logescale). Results We studied 486 patients with 125 clinical events: 39 (31%) AIDS, 66 (53%) SNAEs and 20 (16%) deaths. Among the analyzed MT and pro-inflammatory markers, hs-CRP seemed to be the only biomarker retaining some association with the endpoint of clinical progression (i.e. AIDS/SNAEs/death) after adjustment for confounders, both when the study population was stratified according to the median of the distribution (1.51 mg/L) and when the study population was stratified according to the 33% percentiles of the distribution (low 0.0–1.1 mg/L; intermediate 1.2–5.3 mg/L; high > 5.3 mg/L). In particular, the higher the hs-CRP values, the higher the risk of clinical progression (p = 0.056 for median-based model; p = 0.002 for 33% percentile-based model). Conclusions Our data carries evidence for an association between the risk of disease progression after cART initiation and circulating pre-cART hs-CRP levels but not with levels of MT. These results suggest that pre-therapy HIV-driven pro-inflammatory milieu might overweight MT and its downstream immune-activation.

Virological failure and antiretroviral resistance among HIV-infected children after five years follow-up in the ANRS 12225-PEDIACAM cohort in Cameroon

Objective In the present study, we aimed to evaluate the virological failure (VF) and drug resistance among treated HIV-infected children after five years follow-up in the ANRS-Pediacam cohort in Cameroon. Methods From November 2007 to October 2011, HIV-infected children born to HIV-infected mothers were included in the ANRS-PEDIACAM study and followed-up for more than 5 years. Plasma viral load (VL) was measured at each visit (every three months until month 24 and every 6 months thereafter). VF was the main outcome and HIV drug resistance test was performed using the ANRS procedures and algorithm. Results Data from 155 children were analyzed. The median age at combination antiretroviral therapy (cART) initiation was 4.2 months (interquartile range (IQR): 3.2–5.8), with 103 (66.5%) children taking LPV/r-containing regimen and 51 (32.9%) children taking NVP. After five years follow-up, 63 (40.6%; CI: 32.9–48.8) children experienced VF. The median duration between cART initiation and VF was 22.1 months (IQR: 11.9–37.1) with a median VL of 4.8 log10 (IQR: 4.0–5.5). Among the 57 children with HIV drug resistance results, 40 (70.2%) had at least one drug resistance mutation. The highest resistance rates (30.4–66.1%) were obtained with Lamivudine; Efavirenz; Nevirapine and Rilpivirine. Conclusions These results show high resistance to NNRTI and emphasize the need of VL and resistance tests for optimal follow-up of HIV-infected people especially children.

Pre-cART Inflammation, Microbial Translocation and Long-Term Probability of Clinical Progression in People Living With HIV

Background. We aimed to investigate the role of pre-cART inflammation and microbial translocation (MT) as predictors of clinical progression in HIV+ patients enrolled in the Icona Foundation Study Cohort.Methods. We included Icona patients with plasma stored within 6 months before cART initiation and at least one CD4 count after therapy available. Circulating biomarker: LPS, sCD14, EndoCab, hs-CRP. Kaplan-Meier curves and Cox regression models were used. We defined the endpoint of clinical progression as the occurrence of a new AIDS-defining condition, severe non-AIDS condition (SNAEs) or death whichever occurred first. Follow-up accrued from the data of starting cART and was censored at the time of last available clinical visit. Biomarkers were evaluated as both binary (above/below median) and continuous variables (logescale).Results. We studied 486 patients with 125 clinical events:10.8 (0.77-14.8)/1000 PYFU new AIDS, 18.3 (14.2-23.3)/1000 PYFU SNAEs, and 5.56 (3.40-8.57)/1000 PYFU deaths. Among morbidity events, the incidence of infectious-related events was 19.4 (15.2-24.5)/1000 PYFU. Hs-CRP seemed to be the only biomarker retaining some association with the endpoint of clinical progression (i.e. AIDS/SNAEs/death p=.056).Conclusions. Circulating pre-cART hs-CRP but not MT seems associated with the risk of disease progression after cART initiation, suggesting that pre-therapy HIV-driven pro-inflammatory milieu might overweight MT and its downstream immune-activation. This result should help guiding the design of interventional studies.

Initiating antiretroviral treatment early in infancy has long-term benefits on the HIV reservoir in late childhood and adolescence

Background Early combined antiretroviral therapy (cART) limits the total HIV-DNA load in children. However, data on its impact in older children and adolescents remain scarce. This study aims to compare HIV reservoirs in children (5-12 years) and adolescents (13-17 years) who started cART before 6 months (early (E-)group) or after 2 years old (late (L-)group). Methods The ANRS-EP59-CLEAC study prospectively enrolled 76 HIV-1 perinatally-infected patients who reached HIV-RNA<400 copies/mL less than 24 months after cART initiation, regardless of subsequent viral suppression (E-group: 27 children, 9 adolescents; L-group: 19 children, 21 adolescents). Total and integrated HIV-DNA were quantified in blood and in CD4+ T cell subsets. A substudy assessed HIV reservoir inducibility after ex vivo peripheral blood mononuclear cells (PBMCs) stimulation. Results Total HIV-DNA levels were lower in early- than late-treated patients (Children: 2.14 vs 2.87 log cp/million PBMCs, p<0.0001; Adolescents: 2.25 vs 2.74log, p<0.0001). Low reservoir was independently associated with treatment precocity, protective HLA and low cumulative viremia since cART initiation. The 60 participants with undetectable integrated HIV-DNA started cART earlier than the other patients (4 vs 54 months, p=0.03). In those with sustained virological control, transitional memory and effector memory CD4+T cells were less infected in the E-group than in the L-group (p=0.03 and 0.02, respectively). Viral inducibility of reservoir cells after normalization to HIV-DNA levels was similar between the groups. Conclusions Early cART results in a smaller blood HIV reservoir until adolescence, but all tested participants had an inducible reservoir. This deserves cautious consideration for HIV remission strategies.

Effect of combination antiretroviral therapy on human immunodeficiency virus 1 specific antibody responses in subtype-C infected children

Protective antibody responses to human immunodeficiency virus (HIV)-1 infection evolve only in a fraction of infected individuals by developing broadly neutralizing antibodies (bnAbs) and/or effector functions such as antibody-dependent cellular cytotoxicity (ADCC). HIV-1 chronically infected adults and children on combination antiretroviral therapy (cART) showed a reduction in ADCC activity and improvement in HIV-1 specific neutralizing antibody (nAb) responses. Early initiation of cART in infected adults is found to be beneficial in reducing the viral load and delaying disease progression. Herein, we longitudinally evaluated the effect of cART on HIV-1 specific plasma ADCC and nAb responses in a cohort of 20 perinatally HIV-1 subtype-C infected infants and children ≤2 years of age, pre-cART and up to 1 year post-cART initiation. Significant reductions in HIV-1 specific plasma ADCC responses to subtype-C and subtype-B viruses and improvement in HIV-1 neutralization were observed in HIV-1 infected children 1 year post-cART initiation. A positive correlation between reduction in viral load and the loss of ADCC response was observed. This study provides information aiding the understanding of the effects of early initiation of cART on antibody effector functions and viral neutralization in HIV-1 infected children, which needs to be further evaluated in large cohorts of HIV-1 infected children on cART to plan future intervention strategies.

Substantial gap in primary care: older adults with HIV presenting late to care

Background Late diagnosis of human immunodeficiency virus (HIV) is associated with increased morbidity and mortality, and represents a serious public health concern. Methods A retrospective medical record review was conducted on 188 patients with newly diagnosed HIV at a large academic center’s HIV clinic from 1/2010 to 12/2019. Patient demographic data, HIV staging, and response to combination antiretroviral therapy (cART) as measured by HIV viral suppression at 12 weeks (HIV RNA < 50 copies) were collected. Bivariate analyses were applied to compare patients ≥50 years old to those < 50 years old. Results Over two-thirds of the older patients with a new diagnosis of HIV presented with a CD4 count < 200, or an AIDS-defining illness. Though not statistically significant, this same group also had a delay to viral suppression with only 59% achieving viral suppression after 12-weeks of cART initiation. Conclusions This study suggests that older patients are presenting to care with advanced stages of HIV, and may also have a delay in achieving viral suppression after cART initiation. Future studies should aim to target HIV testing and treatment strategies for this at-risk older adult group.

Shorter Granulocyte Telomeres Among Children and Adolescents With Perinatally Acquired Human Immunodeficiency Virus Infection and Chronic Lung Disease in Zimbabwe

Background Chronic lung disease (CLD) has been reported among African children with perinatally acquired human immunodeficiency virus (HIV) infection (C-PHIV), despite combination antiretroviral therapy (cART). In adults, shorter telomere length (TL) has been reported in association with both CLD and HIV. As little is known in children, our objective was to compare TL in HIV-positive (cART-naive or -treated) and HIV-negative children with and without CLD. Methods Participants included Zimbabwean C-PHIV, aged 6–16, who were either newly diagnosed and cART-naive, or on cART for &gt;6 months, and HIV-negative controls of similar age and sex. Packed blood cell (granulocyte) TLs from 621 children were compared cross-sectionally between groups. For a subset of newly diagnosed C-PHIV, changes in TL following cART initiation were evaluated. Results C-PHIV had shorter granulocyte TL compared with uninfected peers, regardless of cART. Among 255 C-PHIV without CLD, TL was shorter in cART-naive participants. In multivariable analyses adjusted for age, sex, CLD, and HIV/cART status, shorter TL was independently associated with older age, being HIV positive, and having reduced forced vital capacity (FVC). Last, cART initiation increased TL. Conclusions In this cohort, C-PHIV and those with reduced FVC have shorter granulocyte TL, possibly the result of increased immune activation and cellular turnover due to longstanding HIV infection with delayed cART initiation.

Decreased Time to Viral Suppression After Implementation of Targeted Testing and Immediate Initiation of Treatment of Acute Human Immunodeficiency Virus Infection Among Men Who Have Sex With Men in Amsterdam

Background Men who have sex with men (MSM) with acute human immunodeficiency virus (HIV) infection (AHI) are a key source of new infections. To curb transmission, we implemented a strategy for rapid AHI diagnosis and immediate initiation of combination antiretroviral therapy (cART) in Amsterdam MSM. We assessed its effectiveness in diagnosing AHI and decreasing the time to viral suppression. Methods We included 63 278 HIV testing visits in 2008–2017, during which 1013 MSM were diagnosed. Standard of care (SOC) included HIV diagnosis confirmation in &lt; 1 week and cART initiation in &lt; 1 month. The AHI strategy comprised same-visit diagnosis confirmation and immediate cART. Time from diagnosis to viral suppression was assessed for 3 cART initiation periods: (1) 2008–2011: cART initiation if CD4 &lt; 500 cells/μL (SOC); (2) January 2012–July 2015: cART initiation if CD4 &lt; 500 cells/μL, or if AHI or early HIV infection (SOC); and (3a) August 2015–June 2017: universal cART initiation (SOC) or (3b) August 2015–June 2017 (the AHI strategy). Results Before implementation of the AHI strategy, the proportion of AHI among HIV diagnoses was 0.6% (5/876); after implementation this was 11.0% (15/137). Median time (in days) to viral suppression during periods 1, 2, 3a, and 3b was 584 (interquartile range [IQR], 267–1065), 230 (IQR, 132–480), 95 (IQR, 63–136), and 55 (IQR, 31–72), respectively (P &lt; .001). Conclusions Implementing the AHI strategy was successful in diagnosing AHI and significantly decreasing the time between HIV diagnosis and viral suppression.