Reduced time to suppression among neonates with HIV initiating antiretroviral therapy within 7 days of age
Authors: Domínguez-Rodríguez S, Tagarro A. Palma P, et al.
Published in: JAIDS 2019;82(5):483-490
Authors: Domínguez-Rodríguez S, Tagarro A. Palma P, et al.
Published in: JAIDS 2019;82(5):483-490
Authors: Foster C, Dominguez S, Tagarro A, Nastouli E, Gkouleli R, Heaney J, PalmaP, Rossi P, Giaquinto C, Rojo P
Published: 10th IAS Conference on HIV Science, July 21rd-24th 2019, Mexico City
Background Future strategies aimed at achieving antiretroviral therapy (ART)-free HIV remission are likely to target individuals with a limited size of viral reservoir. We investigated factors associated with a low reservoir measured as total HIV-1 DNA in PBMCs in perinatally infected children (PaHIV) from 5 European centers in the EPIICAL consortium.
Authors: Heaney J, Busby E, Gärtner K, Grant P, Spyer MJ, O’Sullivan DM, Gkouleli T, Marcelin AG, Pillay D, Foster C, Rojo P, Palma P, Muñoz Fernández MA, deRossi A, Huggett JF, Nastouli E
Published: International Workshop on HIV Pediatrics, July 19th-20th, 2019. P_102
Background Despite effective antiretroviral therapy(ART), HIV persists as integrated provirus generating latent viral reservoirs even in the absence of detectable plasma viremia.
Latently infected cells, primarily CD4+ T cells, have the potential to release progeny virus and contribute to viral rebound after treatment interruption or HIV-1 remission.
Robust assays are needed to monitor the viral reservoir, and remission, as emerging therapeutic approaches aimed at achieving ART-free HIV remission, or cure, are likely to target individuals with low levels of total HIV-1 DNA. The current gold standard for measuring specific DNA amounts in clinical diagnostics and research is quantitative PCR (qPCR), whereas digital PCR (dPCR) is a more recent technology that has become commercially available since 2011.
Authors: Chan MK, Goodall R, Judd A, et al.
Published in: Aids. 2019; 33(7):1155-1165
Objective To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy.
Design Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC).
Methods Infants with perinatal HIV starting cART aged <6 months with ≥1 viral load (VL) measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last VL≥400 and first VL<400copies/ml.
Results Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% UK/Ireland, 15% Eastern Europe and 3% Thailand; 46% and 54% started a boosted protease inhibitor- or non-nucleoside reverse transcriptase inhibitor- based regimen, respectively. At cART initiation, the median age, CD4% and VL were 2.9 (IQR:1.4-4.1) months, 34 (IQR:24-45)% and 5.5 (IQR:4.5-6.0) log10copies/ml, respectively. Overall, an estimated 89% (95%CI:86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age (aHR:0.84 per month older; P < 0.001), higher CD4% (aHR:1.11 per 10% higher; P = 0.010) and lower log10 VL (aHR:0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression.
Conclusion We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long term health.
Authors: Cotugno N, Morrocchi E, Pepponi I, et al.
Abstract Early initiation of ART in HIV vertically infected infants influences specific immunity by limiting Ag exposure and reducing the viral reservoir size. Currently these patients represent ideal candidates for testing immune therapeutic strategies towards HIV-remission. However a proportion of these early ART treated children (ET) show an undetectable HIV Ab response. It is still unknown whether such profile is associated with a lower ability of these children to mount HIV specific responses once the Ag is re-encountered.
In the present study, we investigated whether HIV specific B-cells persist in seronegative (SN) patients, and the associated gene signatures after re-encountering the virus in vitro. We enrolled 20 ET (6 SN and 14 seropositive, SP), who initiated ART at a mean age of 4.4±3.6 mo. and under durable viral control (> 2 years). We found that gp140+ B-cells, analyzed by FACS, persist in SN patients with a similar frequency of SP. Further analysis revealed a higher percentage of HIV-specific IgM cells in SN CD27+ IgD+ memory subset compared to SP (P=0.002). In addition we investigated by multiplexed RT-PCR, gene expression dynamics after in vitro stimulation with HIV peptides mix. Our results on sorted HIV specific IgM+ cells showed up-regulation of Blimp1 expression only in SP (fold change=1.9; p=0.03), suggesting an impairment of plasma cell differentiation in IgM+gp140+ B-cells in SN patients. Our results firstly reveal that HIV specific B-cell response persists in SN ET, and predominantly resides in the IgM memory compartment. We hypothesize that such responses could be targeted by novel strategies aiming at HIV remission in HIV early treated children.
Authors: Rinaldi S, Cotugno N, Pallikkuth S, Pahwa R, Palma P, Pahwa S
Abstract Early initiation of antiretroviral therapy (ART) in vertically HIV-infected children provides an opportunity to limit the size of HIV reservoir. However, how the time of ART initiation impacts host HIV-specific immune responses is still poorly understood. In this study, we analyzed HIV-specific CD4 and CD8 T cell functionality in vertically HIV-infected children (age range 2.3–17.5yrs) enrolled at Bambino Gesù Children Hospital under suppressive ART and durable viral control (plasma HIV-RNA<50cp/mL). Children were designated as early treated (ET, n=8, ART initiated at age <6mo) or late treated (LT, n=7, ART initiated at age >1 year) with longer duration of ART in ET (p<0.05). Antigen-specific (CD40L+CD4+/CD107a+CD8+) T cells were evaluated in cryopreserved PBMC by flow cytometry for intracellular cytokines (IL2, IFN g, TNFα, IL21, Perforin, Granzyme B) following 12hr stimulation with GAG PTE peptides. Differences between groups were determined by Mann-Whitney t tests (P≤0.05).
Frequencies of GAG-specific CD8 and CD4 T cells were not different between ET and LT. Boolean analyses revealed that CD8 T cells of LT had a higher frequency of Granzyme B+ cells compared to ET whereas CD4 T cells were qualitatively superior in ET compared to LT and exhibited higher proportions of IL2, IFNg and TNFα producing T cells and enrichment of polyfunctional T cells.
Our results suggest that time of ART initiation in HIV-infected children has a long-term impact on the quality but not the quantity of the host HIV-specific T-cell immune responses. Larger studies are needed to confirm these results and to further evaluate their role in future strategies aiming at functional cure.
Authors: Violari A, Chan M, Otwombe KN, Panchia R, Jean-Philippe P, Gibb D, Cotton M, Babiker A
HIV RNA viral load (VL) from stored samples was assessed 8 weeks after interruption and 12 weekly thereafter. Included were children with VL<400 c/ml at interruption and ≥1 VL measurement within 12 months. Multivariable stepwise Cox regression models (backwards elimination, exit probability p=0.05) were used to identify factors associated with time to viral rebound (confirmed VL≥400 c/ml). Follow-up was censored at ART reinitiation (if VL had not rebounded) or last VL measurement.
Of 183 children virally suppressed (VL<400) at interruption, 54% were from ART-40W and 61% were female. At enrolment, 81% received PMTCT, 81% had CDC stage N; median [IQR] birth weight was 3 [2.7,3.3]Kg. At ART start, median [IQR] age was 1.8 [1.5,2.1] months, CD4% 34 [29,40]%, CD4 count 1982 [1445,2745], CD8% 28 [22,34]% and VL 750000 [376000,750000] copies/ml. Median VL at rebound was 354615 [91040,750000] copies/ml, not significantly different between arms [ART-40W=418760; ART-96W=325000 copies/ml; P=0.19]. 86% of children suppressed within 40 weeks of ART start [88% ART-40W; 83% ART-96W; P=0.38]. Overall estimated cumulative probability of rebound (95% CI) at 2, 4, 6 and 8 months were 70% (63,76)%, 80% (74, 85)%, 94% (90,97)% and 99% (96,100)%, respectively. Median time to rebound was 1.8 (range: 0.9-13.1) months. One child (ART-40W) maintained viral suppression until last VL available. Five children were censored due to ART restart. In univariable analysis, among baseline demographic and clinical factors, CD4% was the strongest predictor of longer time to rebound based on the log likelihood ratio. In multivariable analysis, longer time to rebound was associated with higher birth weight, baseline CD4% and viral suppression within 40 weeks of ART start (Table). There was no evidence of significant effect of gender, baseline VL and CD8%, CDC stage, PMTCT, age at ART initiation (6-12weeks) and length of therapy (arm) or site. Sensitivity analyses produced similar results.
Most children rebounded by 13 months while one remained suppressed until the end of follow up. Age at ART initiation ranging from 6 to 12 weeks and length of therapy were not associated with longer time to rebound. Our findings may inform the design of clinical trials involving analytic treatment interruption in paediatric HIV.
Authors: Cameron M, Rinaldi S, Richardson B, Cotugno N, Williams S, Pallikkuth S, de Armas LR, Cameron C, Pahwa R, Palma P, Pahwa S
Published: 25th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2018 – Boston. P_868
Abstract The study explores the impact of early ART on host immune response looking at HIV-specific CD4 T cell functionality and host transcriptome analysis.
Authors: Chan M, Tagarro A, Zangari P, Ferns B, Foster C, De Rossi A, Nastouli E, Ángeles Muñoz-Fernández M, Gibb D, Rossi P, Giaquinto C, Babiker A , Palma P, Rojo Conejo P
Published: 25th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2018 – Boston. P_ 866
Abstract The study focused on the determinants of low viral reservoir in a large cohort of European early treated HIV-1 infected children. Timing of cArt initiation and timing spent on effective ART are main factors associated with low HIV-DNA
Authors: Rocca S, Zangari P, Cotugno N, et al.
Published in: J Pediatric Infect Dis Soc.2018; 28. doi:10
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.