Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial

Journal of the International AIDS SocietyVolume 19, Issue 6S5 21264 Abstract SupplementOpen Access Oral abstracts of the 21st International AIDS Conference 18–22 July 2016, Durban, South Africa First published: 22 July 2016 https://doi.org/10.7448/IAS.19.6.21264Citations: 9AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Oral Abstracts Abstract Introduction Within the first weeks of human immunodeficiency virus (HIV) infection, virus replication reaches systemic circulation. Despite the critical, causal role of virus replication in determining transmissibility and kinetics of disease progression, there is limited understanding of the conditions required to transform a small localized transmitted founder population into a large and heterogeneous systemic infection. Methods Cynomolgus and rhesus macaques were infected with simian immunodeficiency virus (SIV) and followed longitudinally. Plasma levels of SIV were monitored using qRT-PCR. Bacterial genomic DNA in plasma was characterized and quantified longitudinally using 16S ribosomal deep sequencing and qPCR. ELISA-based assays were used to monitor intestinal permeability (IFABP) and perturbation of bacteria-specific host factors (sCD14 and EndoCab). Flow cytometry was used to track peripheral blood lymphocyte populations. In vitro assays were performed by exposing freshly isolated peripheral blood mononuclear cells to bacterial lysate prepared from major translocators. Effects of bacterial lysate on CD4+ T cell activation and CD8+ T cell cytotoxicity were measured using flow cytometry. Statistical significance was calculated using ANOVA or Wilcoxon signed-rank testing. Results Prior to the peak of viremia, we observed a transient high-level influx of microbial genomic DNA into peripheral blood. This microbial translocation was accompanied by perturbation of bacteria-specific host factors in plasma, as well as expansion of the CD4+CCR5+ T cell compartment. Exposure of freshly isolated peripheral blood mononuclear cells to lysate prepared from major translocating taxa revealed differential taxa-specific effects on the CD4+CCR5+ T cell compartment and cytotoxic granule expression within CD8+ T cells. Conclusions Altogether, our data identify the influx of microbial products into blood during hyperacute SIV infection as a candidate modifier of early interactions between the antiviral host response and nascent HIV infection. Over the next few months, we will explore the effect of inducing microbial translocation during SIV infection, with particular interest on microbial reactivity within the CD4+CCR5+ target cell compartment. Oral Abstracts Citing Literature Abstract Introduction High dietary fats were reported to induce intestinal dysbiosis, drive gut inflammation and breakdown the intestinal epithelial barrier, granting intestinal flora access to the bloodstream. As microbial translocation is a major determinant of the chronic immune activation and HIV/SIV disease progression, we investigated whether fat diet impacts HIV/SIV pathogenesis. Methods The non-progressive African green monkey (AGM) model of SIV is an ideal system to assess the role of fat diet on disease progression, because they do not develop SIV-related intestinal dysfunction. We included four AGMs that received a fat diet prior and after SIVsab infection, and five controls in which the impact on key parameters of SIV infection such as: viral loads, CD4+ T cell counts, microbial translocation, immune activation and inflammation were compared and contrasted. Results LPS levels increased in the AGMs receiving fat diet prior and after SIV infection. Fat-rich diet also resulted in increases of immune activation (HLA-DR CD38, CD69 and Ki-67) and inflammation (inflammatory cytokines-IL-6, IL-17 and C reactive protein), leading to a prolonged depletion of CD4+ T cells compared to controls. However, these significant alterations of key parameters that are associated with the lack of disease progression in natural hosts of SIVs did not reach the levels described during progressive HIV/SIV infection. Furthermore, these changes did not result in significant increases in the levels of viral replication in the AGMs receiving a fat diet. Conclusions Administration of fat-rich diet resulted in alterations of markers of pathogenicity in the non-progressive SIV infection of AGMs. Although not major, these changes were significant, suggesting that a diet very rich in fats may negatively impact HIV pathogenesis, especially if combined with other behavioural risk factors reported to impact gut integrity or systemic inflammation, such as alcohol consumption, drug usage and smoking. Detailed studies on the correlations between fat diet, alterations in the intestinal microbiota, metabolic markers, liver function and SIV progression to AIDS are in progress. Oral Abstracts Citing Literature Abstract Introduction Tuberculosis remains the leading cause of death in HIV-positive people. A better understanding of the impact of HIV on lung immunity may lead to novel immunotherapeutic interventions. MAIT cells are tissue-homing donor-unrestricted T cells with broad anti-microbial activity. HIV infection causes early and irreversible depletion of MAIT cells in the peripheral circulation, but the effect of HIV on MAIT cells in the lungs is unknown. Methods We FACS-sorted MAIT cells from bronchoalveolar lavage (BAL) fluid and peripheral blood of HIV-infected and HIV-negative patients from Durban, South Africa. MR1-5OPRU tetramer staining was used to identify and phenotype MAIT cells based on expression of CD3, CD4, CD8, TRAV1-2, CD161 and CD26. High throughput bias-controlled TCR sequencing (ImmunoSEQ) of sorted populations enabled detailed analysis of TCRA CDR3a usage. Results HIV infection was associated with depletion of MAIT cells in the peripheral circulation (median %5OPRU+of CD3+CD4- lymphocytes was 1.09% in HIV-negatives, 0.34% in HIV-positives, p=0.027). In contrast, MAIT cells were not depleted in the BAL compartment during HIV infection (0.68% in HIV-negatives, 0.89% in HIV-positives, p=non-significant). In HIV-negative individuals, 77.1% of circulating MAIT cells expressed the expected CD161++CD26++ phenotype, but only 43.8% of BAL MAITs expressed this phenotype (p≤0.0001). In HIV infected lungs, the frequency of MAITs with the CD161++CD26++ phenotype was significantly higher (57.6%) than in HIV-negative lungs (p=0.021). MAIT cells with canonical MAIT TCRA CDR3a rearrangements were highly shared between donors and clonally expanded in the BALs. MAIT cells with non-canonical TCRs were unique to individuals and more frequent in HIV-infection. Conclusions We report for the first time that MAIT cells in the lungs are numerically preserved but phenotypically and clonotypically altered by HIV infection. We confirm previous reports that circulating MAIT cells are depleted in HIV. Our results suggest that peripheral MAIT cell depletions observed in HIV infection may be due to compartment-specific microbial alterations and/or tissue redistribution. Further study is needed to determine the mechanisms underlying the altered phenotypes of lung-resident MAITs and whether these can be targeted to improve anti-microbial lung immunity in people living with HIV. Oral Abstracts Citing Literature Abstract Introduction For the improved design of strategies towards HIV-1 functional cure, it is important to identify biomarkers that could predict the duration of post-treatment virological control. Methods We studied 46 patients that received 24 or 60 weeks of temporary ART initiated at primary HIV infection (PHI). Patients were treated with a quadruple triple-class ART regimen. Cell-associated HIV-1 nucleic acids were quantified by seminested real-time PCR. Results All patients achieved virological suppression (VS) (plasma HIV-1 viremia <50 copies/ml) with a median of 21 weeks. We first assessed the predictive power of plasma viremia, total HIV-1 DNA, unspliced (US) cell-associated HIV-1 RNA, CD4+ T-cell count, and CD4:CD8 ratio, measured at PHI, for the time to VS. In the univariate analysis, both plasma viremia and US RNA were predictive for time to VS (p=0.016 and p=0.0033, respectively, log-rank test). In the multivariate Cox regression, US RNA at PHI was the only significant predictor of the time to VS (HR=0.65 per 1 log10 increase in US RNA, 95% confidence interval (CI): 0.48–0.87, p=0.0043). Subsequently, the same biomarkers were longitudinally quantified every 12 weeks during ART. All 45 patients who discontinued ART experienced virological rebound (VR) (plasma viremia >50 copies/ml) within 9 months after therapy interruption. We assessed the predictive power of the last measurements of the biomarkers on ART before the therapy interruption, as well as of the duration of temporary ART, for the time to VR (the duration of post-treatment virological control). Again, US RNA was the only significant predictor of the time to VR (HR=0.29 for patients with US RNA levels below vs. above the median, 95% CI: 0.10–0.83, p=0.021, log-rank test). Conclusions In summary, in this cohort of patients treated at PHI, cell-associated HIV-1 US RNA level was the sole independent predictor of both virological suppression on ART and post-treatment virological control after ART discontinuation. Further exploration of the potential of this biomarker as a predictor of post-treatment control in large-scale clinical trials aimed at HIV functional cure is warranted. Oral Abstracts Citing Literature Abstract Introduction Clinical outcome of HIV infected patients relies on the recovery of CD4+ T cells after HAART. However, this immune recovery is variable and difficult to predict. Here, we present a cohort of patients with undetectable viral load and a follow up of 48 months of HAART who reached CD4+ T cell counts >1000 cells/mm3 (Hypers) and compare them to those who reached between 350 and 999 CD4+ T cells/mm3 (concordants). Their demographic data, immune recovery kinetics and T CD4+ subsets phenotype as well as their integrated HIV DNA were analyzed. Methods Retrospective data were obtained from the charts of 447 undetectable patients on their first ARV regimen and a follow up of 48 months at the INCMSZ HIV cohort. For immune phenotype and reservoir analysis, 20 Hypers and 19 Concordants matched by sex, age and T CD4+ nadir were available. The following subsets were analyzed by Flow cytometry on whole blood: naïve T-cells, central memory T-cells, effector memory and terminally differentiated. A two-step quantitative real-time PCR (qPCR) method to detect HIV-1 integrated DNA was used, with a DNA pre-amplification using Alu and LTR-specific primers. Proviral DNA levels were determined by a second round SYBR Green-based qPCR assay in reference to a standard curve. Results In total, 28 Hypers (6%) and 354 concordants (79%) were identified. Hypers had a higher proportion of CD4+ naïve T-cells (37.6 vs. 24.8, p<0.05), and a low proportion of CD4+ EM T Cells (27.9 vs. 39.4, p<0.05), with similar results found in CD8+ T Cells. Hypers presented a higher percentage of CD4+CD45RA+CD31neg cells. There was no difference in total integrated HIV DNA copies per 106 PBMC (1729 vs. 3062, p=0.19), however the DNA/CD4 ratio of Hypers was significantly lower (1.2 vs. 2.89, p<0.05). Conclusions T cell recovery of Hypers occurs very early suggesting cell redistribution, however on the long term, their T CD4+ level is driven by non-thymic-central-naïve cells that are less likely to be HIV infected, thus diluting HIV reservoir. Understanding better immune recovery after HAART and its impact on viral reservoir could contribute to design more effective therapeutic strategies. Oral Abstracts Citing Literature Abstract Introduction Neutrophils infiltrate the gastrointestinal (GI) tract during HIV infection, yet their contribution to the pathology of mucosal dysfunction is unknown. In chronic HIV, blood neutrophils expressing high levels of PD-L1 suppress T cell function and correlate with T cell expression of PD-1, an exhaustion marker predictive of HIV disease progression. Methods Our study aimed to investigate whether suppressive neutrophils are also present in the colon in HIV and examined whether bacterial dysbiosis contributed to their induction. Whole blood and isolated colon biopsy leukocytes from 10 HIV-infected individuals were phenotyped by flow cytometry. To examine the effects of bacterial dysbiosis, whole blood was stimulated for 20 hours with HIV-altered mucosal bacteria prior to phenotyping, including Prevotella copri, Prevotella stercorea, Ruminicoccus bromii and Lactobacillus plantarum. Results We found a higher frequency of PD-L1 high neutrophils in the colon compared to blood in HIV-infected individuals (p=0.0028). In addition, colon PD-L1 high neutrophils correlated with colon PD-1+ CD4+ T cells (p=0.0207). Incubation of cells with GI bacteria increased in HIV (Prevotella spp.), induced this PD-L1 high phenotype in neutrophils. Conversely, the beneficial GI bacteria decreased in HIV, R. bromii and Lactobacillus did not affect PD-L1 expression. Neutrophil PD-L1 expression correlated with PD-1 expression on CD4+ T cells after bacterial stimulation (p=0.0065). Finally, stimulation with Prevotella species reduced neutrophil apoptosis compared to the media control. Conclusions These data suggest a role for dysbiotic bacteria in reducing neutrophil homeostatic cell death and clearance and contributing to gut neutrophil infiltration in HIV. Together, these suggests that suppressive colon neutrophils may play a role in T cell exhaustion and mucosal dysfunction associated with bacterial dysbiosis and translocation in HIV, and the continual presence of neutrophils in GI tissues may be a consequence of reduced homeostatic apoptosis upon interaction with these bacteria. Oral Abstracts Citing Literature Abstract Introduction Globally, paediatric HIV is increasingly an adolescent and young adult (AYA) epidemic. Research with perinatally HIV-infected (PHIV+) AYA has prioritized identification of poor health and behavioural risk outcomes, but understanding positive outcomes in spite of adversity is critical to informing evidence-based programmes. Using data from a New York City longitudinal cohort study (CASAH) of PHIV+ and perinatally HIV-exposed, uninfected (PHIV−) youth, we examined psychosocial and health outcomes pertinent to understanding resilience. Methods Data are from the most recent CASAH follow-up interview (2014–2015) with 135 PHIV+ and 86 PHIV− AYA to date. Participants were recruited when aged 9–16 years (2003–2008). Psychosocial batteries are administered every 12–18 months; PHIV+ youth viral load (VL) and CD4 are abstracted from medical records. Data on psychiatric disorders, sexual behaviour, substance use disorders (SUD) and young adult milestones were compared across HIV status and age groups. Descriptive statistics, and chi-square and t-tests for comparing groups were used. Results Most participants were female (55%), African-American (67%), living in impoverished communities (100%); mean age was 22 years (range 15–28). There were no HIV-status differences in rates of psychiatric disorder (28%), SUD (27%), or past 3-month condomless sex (36%). At this wave, only 29% of PHIV+AYA had a psychiatric disorder and 25% SUD. Most PHIV+ AYA aged ≥19 years had achieved young adult milestones: 78% had graduated high school, 29% taken college classes; 53% were currently working or in school; 86% had ever had sex; and 41% were in romantic relationships. Achieving milestones did not differ by HIV status. Among all PHIV+ AYA, most had positive health outcomes: CD4≥250 cells/mm3 (79%); CD4≥500 cells/mm3 (44%) and VL≤1000 copies/ml (70%); 46% had VL<50 copies/ml. Older age was associated with CD4 <250 cells/mm3 (X 2=7.01, df=2, p=0.030) and having a psychiatric disorder was associated with VL>1000 copies/ml (X 2=4.29, df=1, p=0.038). Conclusions In one of the few ongoing US-based studies with this population, we found, despite significant biopsychosocial risks, many PHIV+ AYA have positive health and mental health outcomes and achieve AYA milestones comparable to PHIV- and other vulnerable AYA. Identification of protective factors conferring resilience can inform evidence-based practice for millions of PHIV+ youth world-wide. Oral Abstracts Citing Literature Abstract Introduction Children perinatally infected with HIV surviving due to paediatric ART are now ageing into adolescence. Yet monitoring adolescent treatment programmes remains difficult as large, well-defined cohorts are rare. We quantify the size adolescent ART population and proportion virologic suppressed using a national patient cohort developed from South Africa's National Health Laboratory Service (NHLS) database. Methods Using NHLS data on all public sector viral load tests nationally since 2004, we analyzed information on all patients aged <20 years at test date. We estimated the total number of patients accessing ART care in a given year as the number of individual patients with viral load results. Data were stratified by age and year (2004–2014) to assess shifts in age distribution on ART over time. We also assessed proportions virally suppressed in 2014, by age. Results A total of 929,274 person-years were analyzed. There was a steady increase in number of children on ART under 5 years from 2004 to 2011, after which numbers stabilized, likely due to prevention of mother-to-child transmission (PMTCT) successes. There were large increases in numbers of adolescents on ART, rising 10- to 20-fold from 2004–2007 to 2012–2014 (Table 1). Further increases are expected in 15- to 19-year-olds for the next decade, after which the younger cohort ageing into adolescence will decline. In 2014, the proportion virally suppressed was 71% among 5–9 years (95% confidence interval (CI): 71–72%), 65% among 10–14 years (95% CI: 65–66%) and 61% among 15–19 years (95% CI: 60–61%). Conclusions The rollout of PMTCT and paediatric ART led to a demographic bulge of HIV-infected adolescents and subsequently large numbers of adolescents receiving ART. Declining viral suppression among older adolescence suggests an urgent need to improve care for this vulnerable and growing population. Laboratory datasets represent an important tool for national and local resource planning and allocation. Figure 1Open in figure viewerPowerPoint Distribution of individual viral load test results by age and period. Abstract TUAB0102–Table 1. Distribution of viral load test results by age category and calendar year 0–1 years 1–4 years 5–9 years 10–14 years 15–19 years 2004–2007 11,593 (15%) 27,157 (35%) 24,921 (32%) 8854 (11%) 5904 (8%) 2008–2011 29,983 (9%) 88,391 (26%) 110,737 (33%) 72,774 (22%) 34,981 (10%) 2012–2014 31,299 (6%) 89,530 (17%) 155,163 (30%) 141,945 (28%) 96,042 (19%) Oral Abstracts Citing Literature Abstract Introduction There are limited data on the prognostic effects of time-updated covariates on long-term mortality rates of perinatally HIV-infected children after starting ART. We analyzed individual patient data from 19 cohorts in 16 European countries and Thailand in EPPICC. Methods Perinatally HIV-infected children aged <18 starting cART were followed until death, loss to follow-up (LTFU), transfer to adult care, their 21st birthday or last visit to 31/12/2013. Crude rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for death ≤/>6 months of cART and progression to AIDS were assessed using inverse-probability-censoring-weighted Cox models to account for informative censoring of LTFU. Results Of 3527 children, 32, 20, 18 and 30% were from the UK/Ireland, Thailand, Russia/Ukraine and the rest of Europe, respectively. At cART initiation, median (IQR) age was 5.2 (1.4–9.3) years, and 42% had severe WHO immunological stage. Median follow-up was 5.6 (2.9–8.7) years. There were 94 deaths and 174 first AIDS-defining events, of which 43 (46%) and 79 (45%) occurred within 6 months of cART initiation. The crude mortality rate was 2.50 (95% confidence interval (CI): 1.86–3.38)/100 person-years (PY) in the ≤6 month period, and 0.27 (0.21–0.36) thereafter. In total, 59 (63%) {31 ≤6 months} deaths were from HIV-related infections, 19 (20%) {9} were HIV-related non-infectious conditions, 12 (13%) {1} were HIV-unrelated and 4 (4%) {2} were unknown. The rate of first AIDS-defining event was 0.88 (0.76–1.02)/100PY, including 31 (18%) HIV encephalopathy, 29 (17%) tuberculosis and 25 (14%) HIV wasting syndrome. The Table shows multivariable predictors of increased risk of death >6 months of cART. Predictors for death ≤6 months (baseline only) and progression to AIDS (baseline and time-updated) were broadly similar. Conclusions Almost half of deaths occurred ≤6 months of cART, after which current severe WHO immune stage, low BMI-for-age z-score and fewer VL copy-years suppressed were the strongest predictors for mortality. The raised mortality risk in those aged ≥14 and in middle-income countries raises concern. Abstract TUAB0103–Table 1. Predictors of death >6 months of cART Variable Adjusted HR (95% CI) P Country type Middle-income (Russia, Ukraine, Thailand) ref 0.028 High-income 0.5 (0.2–0.9) Calendar year at cART start 1997–<2004 ref 0.035 2004–<2008 0.4 (0.2–0.8) ≥2008 0.5 (0.1–1.5) BMI-for-age z-score at cART start >0 0.2 (0.1–0.6) 0.045 −3 to 0 ref 0 1.1 (0.4–2.8) <0.001 −3 to 0 ref 500 cells/µl and 89% had HIV-RNA <400 copies/ml (Table 1). After adjusting for site, PHA with the following characteristics were more likely to transfer: longer ART duration at 10 years (adjusted hazard ratio (aHR): 1.29, 95% confidence interval (CI): 1.22–1.35), not severely immunodeficient at ART start (aHR: 1.25; 95% CI: 1.03–1.52), CD4 >500 cells/µl at age 10 (aHR: 1.30; 95% CI: 1.01–1.6) and HIV-RNA <400 copies/ml at age 10 (aHR: 1.38; 95% CI: 1.05–1.82). Conclusions Transfer patterns differ considerably between cohorts with many children transferring during early adolescence. PHA were relatively well at transfer; more than 80% had CD4 >500 cells/µl and virologic control. Understanding transfer patterns and tracking outcomes after transfer are important to comprehensively evaluate PHA outcomes. Abstract TUAB0104–Table 1. Characteristics of children with presumed perinatal HIV infection who remain in care at the original site (RIC) or are transferred out (TFO) RIC (n=2650) (excludes 253 children deceased or LTFU) TFO (n=917) p Female (n/N; %) 1260/2650; 48% 439/917; 48% 0.865 Median (IQR) age in years at ART start 7.2 (5.6–8.4) 7.1 (5.4–8.3) 0.195 WHO-defined severe immunosuppression at ART start (n/N; %) 993/1461; 68% 433/627; 69% 0.623 Median (IQR) age (years) at TFO or last visit if RIC 12.1 (10.9–13.8) 11.4 (10.6–12.7) <0.001 Median (IQR) CD4 (cells/µl) at TFO or last visit if RIC 725 (518–950) 779 (569–1032) <0.001 CD4 >500 cells/µl at TFO or last visit if RIC (n/N; %) 1566/2036; 77% 656/801; 82% 0.004 Height-for-age z-score