Five-year follow-up of children with perinatal HIV-1 infection receiving early highly active antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>Early highly active antiretroviral therapy (HAART), started within the first months of age, has been proven to be the optimal strategy to prevent immunological and clinical deterioration in perinatally HIV-infected children. Nevertheless, data about long-term follow-up of early treated children are lacking.</p> <p>Methods</p> <p>We report data from 40 perinatally HIV-infected-children receiving early HAART, with a median follow-up period of 5.96 years (interquartile range [IQR]:4.21–7.62). Children were enrolled at birth in the Italian Register for HIV Infection in Children. Comparison with 91 infected children born in the same period, followed-up from birth, and receiving deferred treatment was also provided.</p> <p>Results</p> <p>Nineteen children (47.5%) were still receiving their first HAART regimen at last follow-up. In the remaining children the first regimen was discontinued, after a median period of 3.77 years (IQR: 1.71–5.71) because of viral failure (8 cases), liver toxicity (1 case), structured therapy interruption (3 cases), or simplification/switch to a PI-sparing regimen (9 cases). Thirty-nine (97.5%) children showed CD4⁺T-lymphocyte values>25%, and undetectable viral load was reached in 31 (77.5%) children at last visit. Early treated children displayed significantly lower viral load than not-early treated children, until 6 years of age, and higher median CD4⁺T-lymphocyte percentages until 4 years of age. Twenty-seven (29.7%) not-early treated vs. 0/40 early treated children were in clinical category C at last follow-up (P < 0.0001).</p> <p>Conclusion</p> <p>Our findings suggest that clinical, virologic and immunological advantages from early-HAART are long-lasting. Recommendations indicating the long-term management of early treated children are needed.</p

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development

Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand

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

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand

Objective: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. Design: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. Methods: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. Results: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. Conclusion: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Search for Ultra-high-energy Photons from Gravitational Wave Sources with the Pierre Auger Observatory

A search for time-directional coincidences of ultra-high-energy (UHE) photons above 10 EeV with gravitational wave (GW) events from the LIGO/Virgo runs O1 to O3 is conducted with the Pierre Auger Observatory. Due to the distinctive properties of photon interactions and to the background expected from hadronic showers, a subset of the most interesting GW events is selected based on their localization quality and distance. Time periods of 1000 s around and 1 day after the GW events are analyzed. No coincidences are observed. Upper limits on the UHE photon fluence from a GW event are derived that are typically at &amp; SIM;7 MeV cm(-2) (time period 1000 s) and &amp; SIM;35 MeV cm(-2) (time period 1 day). Due to the proximity of the binary neutron star merger GW170817, the energy of the source transferred into UHE photons above 40 EeV is constrained to be less than 20% of its total GW energy. These are the first limits on UHE photons from GW sources

Arrival Directions of Cosmic Rays above 32 EeV from Phase One of the Pierre Auger Observatory

A promising energy range to look for angular correlations between cosmic rays of extragalactic origin and their sources is at the highest energies, above a few tens of EeV (1 EeV equivalent to 10^(18) eV). Despite the flux of these particles being extremely low, the area of similar to 3000 km^(2) covered at the Pierre Auger Observatory, and the 17 yr data-taking period of the Phase 1 of its operations, have enabled us to measure the arrival directions of more than 2600 ultra-high-energy cosmic rays above 32 EeV. We publish this data set, the largest available at such energies from an integrated exposure of 122,000 km^(2) sr yr, and search it for anisotropies over the 3.4 pi steradians covered with the Observatory. Evidence for a deviation in excess of isotropy at intermediate angular scales, with similar to 15 degrees Gaussian spread or similar to 25 degrees top-hat radius, is obtained at the 4 sigma significance level for cosmic-ray energies above similar to 40 EeV

Searches for Ultra-High-Energy Photons at the Pierre Auger Observatory

The Pierre Auger Observatory, which is the largest air-shower experiment in the world, offers unprecedented exposure to neutral particles at the highest energies. Since the start of data collection more than 18 years ago, various searches for ultra-high-energy (UHE, E greater than or similar to 10^(17) eV) photons have been performed, either for a diffuse flux of UHE photons, for point sources of UHE photons or for UHE photons associated with transient events such as gravitational wave events. In the present paper, we summarize these searches and review the current results obtained using the wealth of data collected by the Pierre Auger Observatory

Results of a self-triggered prototype system for radio-detection of extensive air showers at the Pierre Auger Observatory

We describe the experimental setup and the results of RAuger, a small radio-antenna array, consisting of three fully autonomous and self-triggered radio-detection stations, installed close to the center of the Surface Detector (SD) of the Pierre Auger Observatory in Argentina. The setup has been designed for the detection of the electric field strength of air showers initiated by ultra-high energy cosmic rays, without using an auxiliary trigger from another detection system. Installed in December 2006, RAuger was terminated in May 2010 after 65 registered coincidences with the SD. The sky map in local angular coordinates (i.e., zenith and azimuth angles) of these events reveals a strong azimuthal asymmetry which is in agreement with a mechanism dominated by a geomagnetic emission process. The correlation between the electric field and the energy of the primary cosmic ray is presented for the first time, in an energy range covering two orders of magnitude between 0.1 EeV and 10 EeV. It is demonstrated that this setup is relatively more sensitive to inclined showers, with respect to the SD. In addition to these results, which underline the potential of the radio-detection technique, important information about the general behavior of self-triggering radio-detection systems has been obtained. In particular, we will discuss radio self-triggering under varying local electric-field conditions

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

CD4 recovery following antiretroviral treatment interruptions in children and adolescents with HIV infection in Europe and Thailand

Objectives The aim of the study was to explore factors associated with CD4 percentage (CD4%) reconstitution following treatment interruptions (TIs) of antiretroviral therapy (ART). Methods Data from paediatric HIV-infected cohorts across 17 countries in Europe and Thailand were pooled. Children on combination ART (cART; at least three drugs from at least two classes) for &gt; 6 months before TI of &gt;= 30 days while aged CD4% at restart of ART (r-ART) and in the long term (up to 24 months after r-ART) following the first TI was modelled using asymptotic regression. Results In 779 children with at least one TI, the median age at first TI was 10.1 [interquartile range (IQR) 6.4, 13.6] years and the mean CD4% was 27.3% [standard deviation (SD) 11.0%]; the median TI duration was 9.0 (IQR 3.5, 22.5) months. In regression analysis, the mean CD4% was 19.2% [95% confidence interval (CI) 18.3, 20.1%] at r-ART, and 27.1% (26.2, 27.9%) in the long term, with half this increase in the first 6 months. r-ART and long-term CD4% values were highest in female patients and in children aged TI. Long-term CD4% was highest in those with a TI lasting 1 to &lt;3 months, those with r-ART after year 2000 and those with a CD4% nadir &gt;= 25% (all P &lt; 0.001). The effect of CD4% nadir during the TI differed significantly (P = 0.038) by viral suppression at the start of the TI; in children with CD4% nadir TI, recovery was better in those virally suppressed prior to the TI; viral suppression was not associated with recovery in children with CD4% nadir &gt;= 25%. Conclusions After restart of ART following TI, most children reconstituted well immunologically. Nevertheless, several factors predicted better immunological reconstitution, including younger age and higher nadir CD4% during TI