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When an HIV-infected mother gives birth, the virus may be passed on to the child. Fortunately, an HIV infection is not a death sentence anymore. Since international guidelines changed in 2008 to always start treatment immediately after birth, many children nowadays survive into adolescence. They, however, depend lifelong on antiretroviral drugs to control the virus. As part of the EPIICAL project, concerned with the improvement of the life of children with HIV, the research presented in this thesis has aimed to quantitatively assess the response to early initiation of treatment and to describe differences among children. To do so, we have developed mathematical models describing viral load (VL) and CD4+ T-cell dynamics for every child individually. The models were fitted to data taken from previous observational cohort studies and focuses on those children who successfully suppress HIV after initiating treatment within 6 months of age. By characterising the VL decay patterns in these children, we can mathematically express the time to viral suppression (TTS). In children without treatment complications, we can predict TTS based on the baseline VL and the percentage of CD4+ T-cells at the start of treatment. Next, we have aimed to quantify CD4+ T-cell reconstitution in response to the treatment. To this end, we have developed novel normalisation functions for T-lymphocyte counts and percentages, especially capturing the dynamic immunological changes during the first year of life. We have shown that children typically have the potential to recover their deteriorated CD4+ T-cell levels “fully” once the HIV VL is under control. Lastly, we have shifted our attention to disease progression in untreated children, who tend to progress towards AIDS fast and have high VLs. We have shown that their immature immune response most parsimoniously explains the observed small contractions in VLs. Thus, perinatally HIV-infected children rely on very early treatment initiation to survive. Our quantification of many time courses of the VL and CD4+ T-cell counts in early treated children with HIV broadens our knowledge on paediatric HIV infections and provides a first step towards informing clinicians about the timing and selection of alternative treatment strategies, hopefully paving the way for an HIV cure in the future.

When an HIV-infected mother gives birth, the virus may be passed on to the child. Fortunately, an HIV infection is not a death sentence anymore. Since international guidelines changed in 2008 to always start treatment immediately after birth, many children nowadays survive into adolescence. They, however, depend lifelong on antiretroviral drugs to control the virus. As part of the EPIICAL project, concerned with the improvement of the life of children with HIV, the research presented in this thesis has aimed to quantitatively assess the response to early initiation of treatment and to describe differences among children. To do so, we have developed mathematical models describing viral load (VL) and CD4+ T-cell dynamics for every child individually. The models were fitted to data taken from previous observational cohort studies and focuses on those children who successfully suppress HIV after initiating treatment within 6 months of age. By characterising the VL decay patterns in these children, we can mathematically express the time to viral suppression (TTS). In children without treatment complications, we can predict TTS based on the baseline VL and the percentage of CD4+ T-cells at the start of treatment. Next, we have aimed to quantify CD4+ T-cell reconstitution in response to the treatment. To this end, we have developed novel normalisation functions for T-lymphocyte counts and percentages, especially capturing the dynamic immunological changes during the first year of life. We have shown that children typically have the potential to recover their deteriorated CD4+ T-cell levels “fully” once the HIV VL is under control. Lastly, we have shifted our attention to disease progression in untreated children, who tend to progress towards AIDS fast and have high VLs. We have shown that their immature immune response most parsimoniously explains the observed small contractions in VLs. Thus, perinatally HIV-infected children rely on very early treatment initiation to survive. Our quantification of many time courses of the VL and CD4+ T-cell counts in early treated children with HIV broadens our knowledge on paediatric HIV infections and provides a first step towards informing clinicians about the timing and selection of alternative treatment strategies, hopefully paving the way for an HIV cure in the future.

Background Early antiretroviral therapy (ART) restricts the size of the human immunodeficiency virus (HIV) reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown. Methods We measured total and integrated HIV DNA, as well as the frequency of CD4 T cells producing multiply spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically infected Thai infants. Eighty-five infants were followed longitudinally for up to 3 years. We compared the size of the reservoir in children who received continuous ARV prophylaxis since birth vs those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings. Results Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous ARV prophylaxis since birth compared to those in whom ARV prophylaxis was discontinued or never initiated (P < .020 and P < .001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (P Conclusions Neonatal ARV prophylaxis with direct transition to ART durably limits the size of the HIV reservoir.

BACKGROUND: Perinatally HIV-acquired infants benefit from an early antiretroviral treatment initiation. Thanks to a short viral exposure time, their immune system can be maintained or reconstituted, allowing a "normal" immune development. METHODS: In this study, we mathematically modeled and quantified individual CD4+ T-cell reconstitution of a subset of 276 children who started treatment within 6 months of age and achieved sustained viral suppression. Considering natural age differences in CD4+ T-cell dynamics, we fitted distances to age-matched healthy reference values with a linear model approaching an asymptote. RESULTS: Depleted CD4+ percentages (CD4%) and CD4+ counts (CD4ct) restored healthy levels during treatment. CD4ct recovered with a median rate of 4 cells/µL/d, and individual recovery rates were correlated negatively with their initial CD4ct. CD4 values at onset of treatment decrease with age, whereas recovery times and levels seem to be age-independent. CD4 recovery correlates positively with viral suppression, and the stabilization of CD4 levels usually occurs after viral suppression. CD4 levels stabilize within 3-13 months after treatment initiation. The recovery dynamics of the CD4% is comparable with those of the CD4ct. CONCLUSIONS: In early-treated children with successful viral suppression, the CD4 depletion is typically mild and CD4+ T cells tend to "fully" recover in numbers.

Early initiation of antiretroviral therapy and adherence to achieve viral load suppression (VLS) are crucial for reducing morbidity and mortality of perinatally HIV-infected infants. In this descriptive cohort study of 39 HIV perinatally infected infants, who started treatment at one month of life in Mozambique, we aimed to describe the viral response over 2 years of follow up. VLS ≤ 400 copies/mL, sustained VLS and viral rebound were described using a Kaplan–Meier estimator. Antiretroviral drug transmitted resistance was assessed for a sub-group of non-VLS infants. In total, 61% of infants reached VLS, and 50% had a rebound. Cumulative probability of VLS was 36%, 51%, and 69% at 6, 12 and 24 months of treatment, respectively. The median duration of VLS was 7.4 months (IQR 12.6) and the cumulative probability of rebound at 6 months was 30%. Two infants had resistance biomarkers to drugs included in their treatment regimen. Our findings point to a low rate of VLS and high rate of viral rebound. More frequent viral response monitoring is advisable to identify infants with rebound and offer timely adherence support. It is urgent to tailor the psychosocial support model of care to this specific age group and offer differentiated service delivery to mother–baby pairs.

BackgroundReduction of the reservoir of latent HIV-infected cells might increase the possibility of long-term remission in individuals living with HIV. We investigated factors associated with HIV-1 proviral DNA levels in children receiving different antiretroviral therapy (ART) strategies in the children with HIV early antiretroviral therapy (CHER) trial.MethodsInfants with HIV < 12 weeks old with CD4% ≥ 25% were randomized in the CHER trial to early limited ART for 40 or 96 weeks (ART-40 W, ART-96 W), or deferred ART (ART-Def). For ART-Def infants or following ART interruption in ART-40 W/ART-96 W, ART was started/re-started for clinical progression or CD4% FindingsLonger duration of ART was significantly associated with lower HIV-1 proviral DNA at both 96 (p = 0.0003) and 248 weeks (p = 0.0011). Higher total CD8 count at ART initiation was associated with lower HIV-1 proviral DNA at both 96 (p = 0.0225) and 248 weeks (p = 0.0398). Week 248 HIV-1 proviral DNA was significantly higher in those with positive HIV-1 serology at week 84 than those with negative serology (p = 0.0042).IntepretationLonger ART duration is key to HIV-1 proviral DNA reduction. Further understanding is needed of the effects of “immune-attenuation” through early HIV-1 exposure.FundingWellcome Trust, National Institutes of Health, Medical Research Council.

Introduction: Infant HIV-1-infection is associated with high morbidity and mortality if antiretroviral treatment (ART) is not initiated promptly. We characterized development of circulating T follicular helper cells (cTfh) and their relationship to naïve/memory B cell subsets in a cohort of neonates initiating ART within the first week of life.Methods: Infants were diagnosed within 48 hours of birth and started ART as soon as possible. The frequency and phenotype of cTfh and B cells were analyzed at enrollment (birth −19 days) and at 4, 12, and 72 weeks of age in blood of 27 HIV-1-intrauterine-infected and 25 HIV-1 exposed uninfected (HEU) infants as part of a study in Johannesburg, South Africa. cTfh cells were divided into Tfh1, Tfh2, and Tfh17 subsets. B cell phenotypes were defined as naïve, resting memory, activated memory and tissue-like memory cells.Results: HIV-1-infected infants had higher frequencies of cTfh cells than HEU infants up to 12 weeks of age and these cTfh cells were polarized toward the Tfh1 subset. Higher frequencies of Tfh1 and lower frequencies of Tfh2 and Tfh17 correlated with lower CD4+ T cell percentages. Lower frequencies of resting memory, with corresponding higher frequencies of activated memory B cells, were observed with HIV-1 infection. Importantly, dysregulations in B cell, but not cTfh cell, subsets were normalized by 72 weeks.Conclusion: Very early ART initiation in HIV-1-infected infants normalizes B cell subsets but does not fully normalize perturbations in cTfh cell subsets which remain Tfh1 polarized at 72 weeks. It remains to be determined if very early ART improves vaccine antibody responses despite the cTfh and B cell perturbations observed over the time course of this study.

HIV-related inflammation is associated with poor outcomes. We describe inflammatory biomarkers in 17 participants in a pre-exposure prophylaxis trial who seroconverted with very early initiation of antiretroviral therapy. Inflammation peaked at the time of HIV infection and returned to baseline within 6–12 months. Starting antiretroviral therapy very early could help mitigate long-lasting HIV-related inflammation., In seventeen HIV-seroconverters in a PrEP trial who were treated very early on, inflammation peaked at the time of HIV-infection and returned to pre-HIV-infection levels within twelve months. Starting antiretroviral therapy very early could help mitigate long-lasting HIV-related inflammation.

A seguito del Piano Globale per l'eliminazione dell'HIV pediatrico e del Start Free Stay Free AIDS Free framework, sono stati fatti notevoli progressi nella prevenzione della trasmissione verticale dell’HIV (PMTCT), nell’accesso al trattamento antiretrovirale (ART) e nella riduzione dei decessi dovuti all'AIDS pediatrico. Tuttavia nel 2018, 160.000 nuove infezioni pediatriche si sono verificate a livello globale, il 52% dei bambini ha avuto accesso ad un test per la diagnosi precoce e solo la metà dei 1,7 milioni di bambini infetti ha ricevuto il trattamento. Dati recenti della valutazione dell'impatto dell'HIV nella popolazione hanno riportato una soppressione virale (SV) del 37% tra i bambini. Nell'attuale sforzo globale per ottenere l'eliminazione di nuove infezioni pediatriche, garantire l'accesso universale precoce all'ART e ottenere una SV sostenuta tra i bambini, è necessaria una migliore comprensione del continuum di cure del PMTCT fino alla diagnosi finale, all’accesso ai servizi di cura e il pattern della risposta virologica nei bambini, per disegnare una risposta su misura ed efficace. In Mozambico, la prevalenza dell'HIV tra le donne in età fertile è del 15,4% e nonostante più del 95% delle donne in gravidanza che accedono alle cure prenatali abbiano fatto il test dell’HIV e ricevuto il trattamento antiretrovirale, il tasso di trasmissione verticale è del 10%, si sono verificate 16.000 nuove infezioni pediatriche nel 2018; la soppressione virale tra i bambini è del 46%. Ci sono pochi dati sulle lacune del programma PMTCT e sulla risposta virale all'ART nei bambini che iniziano il trattamento ad 1 mese di vita. L'obiettivo principale di questo progetto È migliorare le attuali conoscenze sulle lacune nel continuum di assistenza alle mamme e ai bambini esposti all'HIV fino alla diagnosi, al trattamento precoce e alla soppressione virale nel Mozambico meridionale, dove la prevalenza dell'HIV È del 22,8%. In primo luogo, è stato condotto uno studio analitico trasversale utilizzando i dati dell'indagine nazionale sull'HIV 2015 per studiare i fattori associati allo stato di esposizione all'HIV in bambini di età inferiore ai 2 anni. Lo studio ha rilevato il 32% di bambini con stato di esposizione all’HIV sconosciuto; i fattori associati erano: residenza nella regione settentrionale e centrale del Mozambico, nelle zone rurali, madre senza istruzione e avere come capofamiglia l’uomo. In secondo luogo, uno studio di coorte retrospettivo ha analizzato la proporzione dei bambini esposti all'HIV che non hanno completato il follow-up (LTFU) fino alla diagnosi definitiva e i fattori correlati. È stato trovato un tasso del 16% di LTFU. I fattori associati erano l'età inferiore ai 2 mesi all'entrata nel servizio postnatale, l'allattamento al seno non exclusivo, la scarsa aderenza alla profilaxia con cotrimoxazolo. In terzo luogo, uno studio di coorte ha descritto la risposta virale durante 18 mesi di follow-up dei bambini che hanno iniziato il trattamento a 1 mese di età. La soppressione virale (SV) (

Despite major advances in HIV testing, early detection of infection at the point of care (PoC) remains a key challenge. Although rapid antibody PoC and laboratory-based nucleic acid amplification tests dominate the diagnostics market, the viral capsid protein p24 is recognized as an alternative early virological biomarker of infection. However, the detection of ultra-low levels of p24 at the PoC has proven challenging. Here we review the landscape of p24 diagnostics to identify knowledge gaps and barriers and help shape future research agendas. Five hundred and seventy-four research articles to May 2018 that propose or evaluate diagnostic assays for p24 were identified and reviewed. We give a brief history of diagnostic development, and the utility of p24 as a biomarker in different populations such as infants, the newly infected, those on preexposure prophylaxis and self-testers. We review the performance of commercial p24 assays and consider elements such as immune complex disruption, resource-poor settings, prevalence, and assay antibodies. Emerging and ultrasensitive assays are reviewed and show a number of promising approaches but further translation has been limited. We summarize studies on the health economic benefits of using antigen testing. Finally, we speculate on the future uses of high-performance p24 assays, particularly, if available in self-test format.

BACKGROUND: Assays to estimate human immunodeficiency virus (HIV) reservoir size require large amounts of blood, which represents a drawback especially in pediatric settings. We investigated whether HIV-antibody repertoire could estimate the viral reservoir size. Moreover, we assessed the magnitude of HIV-antibody response as a predictor of time of antiretroviral therapy (ART) initiation. METHODS: Human immunodeficiency virus-antibody responses to 10 different viral proteins were evaluated by HIV Western blot (WB) kit and a WB score was assigned to each patient. Patients were classified in 2 subgroups based on the timing of ART initiation (early treated [ET], 0–24 weeks and late treated [LT], >24 weeks). Human immunodeficiency virus-deoxyribonucleic acid (DNA) was quantified using real-time quantitative polymerase chain reaction on total peripheral blood mononuclear cells. Logistic regression and principal component analysis were built on these data to test the ability of WB score to predict the expected value of HIV-DNA and the timing of ART initiation. RESULTS: Sixty-nine perinatally HIV-infected children were evaluated. Reduced HIV-specific antibody responses and lower size of HIV-DNA were observed in ET compared with LT patients (P < .001 and P = .02, respectively). We found that WB score correlates with HIV-DNA (P = .032) and timing of ART initiation (P < .001). Based on the logistic regression analysis, we found that WB score can predict the HIV-DNA size and the timing of ART initiation with an Akaike information criterion of −118.13 and −151.51, respectively. CONCLUSIONS: Western blot score can estimate HIV-DNA size and timing of ART initiation in long-term virally suppressed children. This rapid, inexpensive, and easily reproducible tool can provide useful information to identify potential candidates for HIV remission studies.

Tregs contribute to SIV/HIV disease progression by inhibition of antiviral specific responses and effector T-cell proliferation. Tregs also cause tissue fibrosis via transforming growth factor β1 production and collagen deposition, which are associated with microbial translocation and generalized immune activation. Early ARV initiation upon viral exposure is recommended globally and results in improved immune function recovery and reduced viral persistence. Here, using an acute SIV infection model of rhesus macaques, we demonstrated for the first time that despite clear improvements in mucosal CD4 T cells, in contrast to blood, Treg frequencies in MLNs remained elevated following early ARV initiation. The particular Th17/Treg balance observed in MLNs can contribute, in part, to the maintenance of mucosal fibrosis during suppressive ARV treatment. Our results provide a better understanding of gut mucosal immune dynamics following early ARV initiation. These findings suggest that Treg-based treatments could serve as a novel immunotherapeutic approach to decrease gut mucosal damage during SIV/HIV infections., Increased frequencies of immunosuppressive regulatory T cells (Tregs) are associated with gut lymphoid tissue fibrosis and dysfunction which, in turn, contribute to disease progression in chronic simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection. Mesenteric lymph nodes (MLNs), which drain the large and small intestine, are critical sites for the induction and maintenance of gut mucosal immunity. However, the dynamics of Tregs in MLNs are not well understood due to the lack of accessibility to these tissues in HIV-infected individuals. Here, the dynamics of Tregs in blood and MLNs were assessed in SIV-infected rhesus macaques (RMs) following early antiretroviral drug (ARV) initiation. Early ARV initiation reduced T-cell immune activation, as assessed by HLA-DR/CD39 expression, and prevented the depletion of memory CCR6+ Th17 cells in both blood and MLNs. Untreated animals showed higher frequencies of Tregs, CD39+ Tregs, thymic Tregs, and new memory CD4 populations sharing similarity with Tregs as CTLA4+ PD1– and CTLA4+ PD1– FoxP3+ T cells. Despite early ARV treatment, the frequencies of these Treg subsets remained unchanged within the MLNs and, in contrast to blood normalization, the Th17/Treg ratio remained distorted in MLNs. Furthermore, our results highlighted that the expressions of IDO-1, TGFβ1 and collagen-1 mRNA remained unchanged in MLN of ARV-treated RMs. ARV interruption did not affect T-cell immune activation and Th17/Treg ratios in MLN. Altogether, our data demonstrated that early ARV initiation within the first few days of SIV infection is unable to reduce the frequencies and homing of various subsets of Tregs within the MLNs which, in turn, may result in tissue fibrosis, impairment in MLN function, and HIV persistence. IMPORTANCE Tregs contribute to SIV/HIV disease progression by inhibition of antiviral specific responses and effector T-cell proliferation. Tregs also cause tissue fibrosis via transforming growth factor β1 production and collagen deposition, which are associated with microbial translocation and generalized immune activation. Early ARV initiation upon viral exposure is recommended globally and results in improved immune function recovery and reduced viral persistence. Here, using an acute SIV infection model of rhesus macaques, we demonstrated for the first time that despite clear improvements in mucosal CD4 T cells, in contrast to blood, Treg frequencies in MLNs remained elevated following early ARV initiation. The particular Th17/Treg balance observed in MLNs can contribute, in part, to the maintenance of mucosal fibrosis during suppressive ARV treatment. Our results provide a better understanding of gut mucosal immune dynamics following early ARV initiation. These findings suggest that Treg-based treatments could serve as a novel immunotherapeutic approach to decrease gut mucosal damage during SIV/HIV infections.

Purpose of review Understanding the characteristics of transmission during acute HIV infection (AHI) may inform targets for vaccine-induced immune interdiction. Individuals treated in AHI with a small HIV reservoir size may be ideal candidates for therapeutic HIV vaccines aiming for HIV remission (i.e. viremic control after treatment interruption). Recent findings The AHI period is brief and peak viremia predicts a viral set point that occurs 4–5 weeks following infection. Robust HIV-specific CD8+ T-cell responses lower viral set points. Phylogenetic analyses of founder viruses demonstrated unique bottleneck selections and specific genetic signatures to optimize for high-fitness variants and successful transmission events. HIV clades, route of transmission and the presence of minor variants may affect vaccine protection. Antiretroviral treatment in AHI results in smaller HIV reservoir size, better CD4+ T-cell recovery and fewer virus escapes. Summary The knowledge of untreated and treated AHI informs the development of vaccines, in that preventive vaccines will require broad coverage for multiple clades and antigenic variants associated with unique bottleneck selections. Vaccines that help the host to control viremia could minimize onward transmission. Therapeutic HIV vaccines aimed at HIV remission should be studied in early-treated individuals who have few or no viral escape mutants and a more preserved immune system.

Supplemental Digital Content is Available in the Text., Background: Total CD4+ T-cell counts predict HIV disease progression but do not necessarily reflect normalization of immune function. CD4/CD8 ratio is a marker of immune dysfunction, a prognostic indicator for non-AIDS mortality, and reflects viral reservoir size. Despite antiretroviral therapy (ART), recovery of CD4/CD8 ratio in chronic HIV infection is incomplete; we hypothesize enhanced CD4/CD8 ratio recovery with earlier treatment initiation in recently infected individuals. Methods: CD4+ count and CD4/CD8 ratio were analyzed using data from 2 cohorts: SPARTAC trial and the UK HIV Seroconverters Cohort where primary HIV infection (PHI) was defined as within 6 months from estimated date of infection. Using time-to-event methods and Cox proportional hazard models, we examined the effect of CD4/CD8 ratio at seroconversion on disease progression (CD4 1.0). Findings: Of 573 seroconverters, 482 (84%) had abnormal CD4/CD8 ratios at HIV seroconversion. Individuals with higher CD4/CD8 ratio at seroconversion were significantly less likely to reach the disease progression endpoint [adjusted hazard ratio (aHR) (95% CI) = 0.52 (0.32 to 0.82), P = 0.005]. The longer the interval between seroconversion and ART initiation [HR (95% CI) = 0.98 per month increase (0.97, 0.99), P < 0.001], the less likely the CD4/CD8 ratio normalization. ART initiation within 6 months from seroconversion was significantly more likely to normalize [HR (95% CI) = 2.47 (1.67 to 3.67), P < 0.001] than those initiating later. Interpretation: Most individuals presenting in PHI have abnormal CD4/CD8 ratios. The sooner the ART is initiated in PHI, the greater the probability of achieving normal CD4/CD8 ratio.

INTRODUCTION: In sub-Saharan Africa, HIV prevalence remains high, especially among key populations. In such situations, combination prevention including clinical, behavioural, structural and biological components, as well as adequate treatment are important. We conducted a demonstration project at the Dispensaire IST, a clinic dedicated to female sex workers (FSWs) in Cotonou, on early antiretroviral therapy (E-ART, or immediate "test-and-treat") and pre-exposure prophylaxis (PrEP). We present key indicators such as uptake, retention and adherence.METHODS: In this prospective observational study, we recruited FSWs from October 4th 2014 to December 31st 2015 and followed them until December 31st 2016. FSWs were provided with daily tenofovir disoproxil fumarate/emtricitabine (Truvada® ) for PrEP or received a first-line antiretroviral regimen as per Benin guidelines. We used generalized estimating equations to assess trends in adherence and sexual behaviour.RESULTS: Among FSWs in the catchment area, HIV testing coverage within the study framework was 95.5% (422/442). At baseline, HIV prevalence was 26.3% (111/422). Among eligible FSWs, 95.5% (105/110) were recruited for E-ART and 88.3% (256/290) for PrEP. Overall retention at the end of the study was 59.0% (62/105) for E-ART and 47.3% (121/256) for PrEP. Mean (±SD) duration of follow-up was 13.4 (±7.9) months for E-ART and 11.8 (±7.9) months for PrEP. Self-reported adherence was over 90% among most E-ART participants. For PrEP, adherence was lower and the proportion with 100% adherence decreased over time from 78.4% to 56.7% (p-trend < 0.0001). During the 250.1 person-years of follow-up among PrEP initiators, two seroconversions occurred (incidence 0.8/100 person-years (95% confidence interval: 0.3 to 1.9/100 person-years)). The two seroconverters had stopped using PrEP for at least six months before being found HIV-infected. In both groups, there was no evidence of reduced condom use.CONCLUSIONS: This study provides data on key indicators for the integration of E-ART and PrEP into the HIV prevention combination package already offered to FSWs in Benin. PrEP may be more useful as an individual intervention for adherent FSWs rather than a specific public health intervention. E-ART was a more successful intervention in terms of retention and adherence and is now offered to all key populations in Benin.STUDY REGISTRATION: ClinicalTrials.gov NCT02237.

The WHO 2010 guidelines recommended to treat all HIV-infected children < 2 years of age, and for those < three years, a lopinavir/ritonavir (LPV/r) based antiretroviraltherapy (ART) is recommended. But, less is known about its field implementation and effectiveness in West Africa (WA) settings. Our objective was to document the midterm (25 months) outcomes of the early ART (EART) initiation in West-African HIVinfected infants before the age of two years and its correlates. We assessed thefeasibility of EART; to assess its clinical, immunological, virological outcomes and its tolerance; to assess its simplification by switching to a protease inhibitor-sparingtherapy based on efavirenz (EFV) in virologically suppressed infants; and to describe the HIV drug resistance profile in those with virological failure. Our findings show thatin WA settings, EART is feasible, but access to early infant HIV diagnosis and EART remains too late with a high rate of competing mortality before and after ART initiation.Despite this delay, LPV/r-based EART is well tolerate and effective in mid-term with viral suppression reaching 78% 12-month and 74% at-24-months. In virologically suppressed children, LPV/r-based ART could be simplify with EFV-based ART, but this simplification strategy needs implementation in adherent infants with a closely viralload monitoring. In children with virological failure, resistance analyses highlighted a high frequency of nucleoside and non-nucleoside reverse transcriptase inhibitorsresistance mutations. It is urgent to develop innovative interventions to improve early HIV-infected infant diagnosis and EART and to strengthen lifelong treatment adherence in WA.; Depuis 2010, l’OMS recommande de traiter tous les enfants infectés par le VIH avant deux ans, et pour ceux ≤ trois ans avec traitement antirétroviral précoce (TAP) à base de lopinavir/ritonanir (LPV/r). En Afrique de l’Ouest (AO), peu de données existent sur l’accès à un TAP et sur la réponse à ce traitement. L’objectif de ce travail était de documenter le devenir à moyen terme (25 mois) et ses facteurs associés des enfants recevant un TAP avant l’âge de deux ans dans le contexte du projet MONOD ANRS 12206 en AO. Mon travail a consisté à évaluer la faisabilité du TAP basé sur le LPV/r, d’évaluer sa réponse clinique, immunologique, virologique et sa tolérance, d’évaluer la possibilité d’une simplification en remplaçant le LPV/r par de l’Efavirenz (EFV) chez des enfants en succès virologique, et de décrire le profil de résistance aux antirétroviraux. Nos résultats montrent que le TAP à base de LPV/r chez les enfants est faisable en AO, mais l’accès au traitement reste encore trop tardif avec une mortalité pré et post initiation du TAP élevée. Malgré cet accès tardif, le traitement est bien toléré et est efficace avec un taux de succès virologique après 12 mois de 78 %, et de 74 % à 25 mois. Chez les enfants en succès virologique à M12, le LPV/r peut être remplacé par EFV à condition de disposer d’une charge virale en routine et demaintenir une bonne observance. Cependant, chez les enfants en échec virologique, la fréquence des mutations de résistances aux inhibiteurs nucléosidiques et non nucléosiques de la transcriptase inverse était préoccupante. Il demeure urgent de développer des interventions innovantes pour accroitre l’accès au diagnostic, au TAP, et faciliter l’observance.

INTRODUCTION: The unchanged global HIV incidence may be related to ignoring acute HIV infection (AHI). This scoping review examines diagnostic, clinical, and public health implications of identifying and treating persons with AHI. METHODS: We searched PubMed, in addition to hand-review of key journals identifying research pertaining to AHI detection and treatment. We focused on the relative contribution of AHI to transmission and the diagnostic, clinical, and public health implications. We prioritized research from low- and middle-income countries (LMICs) published in the last fifteen years. RESULTS AND DISCUSSION: Extensive AHI research and limited routine AHI detection and treatment have begun in LMIC. Diagnostic challenges include ease-of-use, suitability for application and distribution in LMIC, and throughput for high-volume testing. Risk score algorithms have been used in LMIC to screen for AHI among individuals with behavioural and clinical characteristics more often associated with AHI. However, algorithms have not been implemented outside research settings. From a clinical perspective, there are substantial immunological and virological benefits to identifying and treating persons with AHI - evading the irreversible damage to host immune systems and seeding of viral reservoirs that occurs during untreated acute infection. The therapeutic benefits require rapid initiation of antiretrovirals, a logistical challenge in the absence of point-of-care testing. From a public health perspective, AHI diagnosis and treatment is critical to: decrease transmission via viral load reduction and behavioural interventions; improve pre-exposure prophylaxis outcomes by avoiding treatment initiation for HIV-seronegative persons with AHI; and, enhance partner services via notification for persons recently exposed or likely transmitting. CONCLUSIONS: There are undeniable clinical and public health benefits to AHI detection and treatment, but also substantial diagnostic and logistical barriers to implementation and scale-up. Effective early ART initiation may be critical for HIV eradication efforts, but widespread use in LMIC requires simple and accurate diagnostic tools. Implementation research is critical to facilitate sustainable integration of AHI detection and treatment into existing health systems and will be essential for prospective evaluation of testing algorithms, point-of-care diagnostics, and efficacious and effective first-line regimens.

La majorité des infections par le VIH de l’enfant sont acquises par transmission de la mère à l’enfant en période périnatale. Le fait que le système immunitaire des nourrissons soit « immature » par certains aspects et le fait que le virus transmis ait déjà échappé au contrôle de l’environnement immunitaire maternel, génétiquement proche de celui de l’enfant, sont probablement responsables du risque important que l’évolution naturelle soit extrêmement rapide lorsque l’infection est acquise en tout début de vie. En l’absence d’un traitement antirétroviral, la réplication virale va en effet se maintenir à un niveau très élevé pendant les premières années de vie chez tous les enfants et jusque 25% d’entre eux vont évoluer jusqu’au stade SIDA ou le décès durant leur 1ère année de vie. L'utilisation des traitements antirétroviraux puissants actuellement disponibles permet de réduire drastiquement la réplication virale et a profondément modifié le pronostic de l’infection par le VIH. D’une infection inéluctablement fatale, elle est devenue une affection chronique peu ou pas évolutive pour autant que le traitement antirétroviral soit pris de façon ininterrompue. Dans ce travail, nous présentons les résultats d’une étude prospective qui incluait les patients chez qui un traitement antirétroviral efficace était débuté pour la première fois. Nous avons pu démontrer que le nombre de lymphocytes CD4+ naïfs était d’autant plus rapidement reconstitué après l’initiation d’un traitement antiviral que celui-ci avait été débuté jeune. Non seulement les patients restauraient leurs nombres de cellules CD4+, et leurs cellules CD4+ naïves en particulier, mais des tests plus fonctionnels des lymphocytes (réponses lymphoprolifératives aux mitogènes) montraient également une nette amélioration sous traitement antirétroviral. Malgré cela, certaines anomalies, et en particulier l’activation des lymphocytes CD8+ persistaient après un an de traitement.Dans une étude cross-sectionnelle ayant inclus 46 patients, nous avons ensuite démontré qu’un traitement antirétroviral de longue durée débuté lorsque l’immunodépression est déjà sévère permet de récupérer des réponses lymphoprolifératives semblable à celles des progresseurs lents, y compris contre un antigène spécifique du VIH ce qui n’est généralement pas le cas chez les adultes. Toutefois, des altérations dans la sécrétion des cytokines en réponse à un mitogène (la phytohémagglutinine) persistent, et la sécrétion de cytokines après stimulation par un antigène spécifique du VIH est biaisée vers une réponse de type Th2, montrant encore une fois que si les capacités d’immunorestauration des enfants sont très importantes, des anomalies immunitaires persistent même après un traitement de longue durée lorsque le traitement est débuté à un stade avancé dans l’évolution de la maladie.Dans le contexte de l’absence d'espoir d'atteindre l'éradication du virus par la seule utilisation des drogues antirétrovirales, la caractérisation du phénotype des patients « non progresseurs » prend tout son sens. Nous avons donc axé notre travail suivant sur la caractérisation des patients chez qui la maladie progresse lentement et qui gardent une réplication virale basse sans prendre de traitement antirétroviral. Ces patients ont une faible activation et une faible différentiation de leurs lymphocytes CD4+ et un profil particulier de réponses CD4 vis-à-vis de la protéine Gag du VIH.Enfin, la dernière partie du travail décrit les bénéfices de ces traitements lorsqu’ils sont administrés très précocement (dans les 2 mois après la naissance) et le devenir à long terme de ces enfants en se basant sur la cohorte suivie au sein du CHU Saint-Pierre. L’histoire naturelle de l’infection par le VIH de l’enfant contaminé par sa mère est en effet caractérisée par une évolution bi-modale. Trois quarts des enfants infectés vont avoir une évolution comparable aux patients infectés à l’âge adultes, mais le dernier quart aura une évolution beaucoup plus rapide menant au développement d’une affection classant l’enfant au stade SIDA ou au décès dans la première année de vie. De plus, à cet âge, il y a un large recouvrement entre les valeurs des taux de lymphocytes CD4+ des enfants qui vont évoluer rapidement ou plus lentement. Nous avons participé activement à la démonstration qu’un traitement antirétroviral très précoce est très bien supporté par les nourrissons, est capable d’empêcher la réplication virale de façon durable et réduit la quantité de DNA proviral intracellulaire prévenant de ce fait les manifestations cliniques ou biologiques de l’infection. Alors que les adultes infectés par le VIH expriment quasi toujours des anticorps contre le VIH, même lorsqu’ils sont traités très précocement par une trithérapie, les enfants traités précocement deviennent souvent séronégatifs. Ils perdent les anticorps spécifiques contre le VIH transmis durant la grossesse mais n’en sécrètent pas par la suite, alors qu’ils peuvent les synthétiser dès que le traitement antirétroviral est interrompu. Ces patients traités très précocement ont un profil particulier caractérisé par un système immunitaire non altéré par l’infection par le VIH mais aussi par l’absence de défenses spécifiques contre ce virus et un réservoir viral très faible., Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

Introduction: The World Health Organization (WHO) 2010 guidelines recommended to treat all HIV-infected children less than two years of age. We described the inclusion process and its correlates of HIV-infected children initiated on early antiretroviral therapy (EART) at less than two years of age in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso. Methods: All children with HIV-1 infection confirmed with a DNA PCR test of a blood sample, aged less than two years, living at a distance less than two hours from the centres and whose parents (or mother if she was the only legal guardian or the legal caregiver if parents were not alive) agreed to participate in the MONOD ANRS 12206 project were included in a cohort to receive EART based on lopinavir/r. We used logistic regression to identify correlates of inclusion. Results: Among the 217 children screened and referred to the MONOD centres, 161 (74%) were included and initiated on EART. The main reasons of non-inclusion were fear of father's refusal (48%), mortality (24%), false-positive HIV infection test (16%) and other ineligibility reasons (12%). Having previously disclosed the child's and mother's HIV status to the father (adjusted odds ratio (aOR):3.20; 95% confidence interval (95% CI):1.55 to 6.69) and being older than 12 months (aOR: 2.05; 95% CI: 1.02 to 4.12) were correlates of EART initiation. At EART initiation, the median age was 13.5 months, 70% had reached WHO Stage 3/4 and 57% had a severe immune deficiency. Conclusions: Fear of stigmatization by the father and early competing mortality were the major reasons for missed opportunities of EART initiation. There is an urgent need to involve fathers in the care of their HIV-exposed children and to promote early infant diagnosis to improve their future access to EART and survival. Copyright: - 2016 Dahourou DL et al;., SCOPUS: ar.j, info:eu-repo/semantics/published

BackgroundThere is intense interest in the role of programmed death 1 (PD-1) in causing persistent T-cell dysfunction in HIV infection. However, the impact of HIV infection and antiretroviral treatment (ART) on the expression of PD-1 on T cells is still poorly defined.MethodsPD-1 was measured longitudinally in a cohort of recently HIV-infected individuals (n = 121) who started ART early (

(See the editorial commentary by Li and Gandhi on pages 1519–22.) Mother-to-child transmission (MTCT) remains the primary mode of pediatric human immunodeficiency virus type 1 (HIV-1) infection. Antiretroviral prophylaxis and maternal antiretroviral therapy (ART) have decreased MTCT, but >260 000 new pediatric infections occur globally each year [1]. Perinatally infected children experience more-rapid disease progression than adults [2, 3]. In limited-resource settings, one half of perinatally infected children die by their second birthday, while 75% die by their third birthday [4]. The initiation of combination antiretroviral therapy (cART) within the first several months of life effectively controls HIV-1 replication, preserves immune function [5–8], and markedly reduces HIV-1–related mortality [9]. Early diagnosis of HIV-1 infection with prompt initiation of cART in HIV-1–infected infants is thus recommended globally [10, 11]. Available data suggest that early therapy limits replication-competent HIV-1 reservoirs [12] and HIV-1 quasispecies diversity [13]. However, latently infected, resting CD4+ T cells carrying replication-competent HIV-1 remain detectable in most children (80%) studied up to 5 years following early initiation of therapy [13]. As a result, lifelong therapy, which is expensive and potentially toxic, is currently recommended. Because larger numbers of children access early cART and highly sensitive techniques to characterize and measure HIV-1 reservoirs have evolved, we have begun to use these techniques to characterize HIV-1 reservoirs in children undergoing durable suppression of virus replication following early cART. Here, we report long-term follow-up of a small cohort of perinatally infected youth aged 14–18 years who initiated cART between 2 and 11 weeks of age and who have maintained suppression of plasma HIV-1 RNA to below the limits of detection of clinical assays for up to 18 years following cART initiation.

OBJECTIVES\ud \ud The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onward transmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIV infection (CHI).\ud \ud DESIGN\ud \ud Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450) trials.\ud \ud METHODS\ud \ud Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences in pVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression. Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimated through a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop.\ud \ud RESULTS\ud \ud Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48-51) weeks after stopping ART. Four weeks after stopping treatment, although the proportion with pVL ≥ 400 copies/ml was similar (78% PHI versus 79% CHI), levels were 0.45 (95% CI 0.26-0.64) log(10) copies/ml lower for PHI versus CHI, and remained lower up to 48 weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir >500 cells/mm(3) was comparable to that experienced by PHI participants.\ud \ud CONCLUSIONS\ud \ud Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increased transmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.