HIV

7

Sep, 2020

The effect of pregnancy on the pharmacokinetics of total and unbound Dolutegravir and its main metabolite in women living with Human Immunodeficiency Virus

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Authors: Bollen P, Freriksen J, Konopnicki D, Weizsäcker K , et al; on behalf of the Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women Network

Published in: Clin infect Dis. 2020;26.ciaa006

Background Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents.

Methods Within the multicenter Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) study, pregnant women living with HIV and using dolutegravir once daily (50 mg, with food) underwent 24-hour pharmacokinetic profiling in their third trimester and postpartum. Dolutegravir exposure in the third trimester was considered adequate if geometric mean unbound, pharmacologically active, minimal plasma concentrations (Cmin, unbound) and ≥90% of individual Cmin, unbound levels were >0.85 µg/L, the proposed 90% inhibitory concentration for unbound dolutegravir. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) for comparison of total and unbound pharmacokinetic parameters in the third trimester and postpartum were calculated, including the metabolic ratio for dolutegravir-glucuronide. Safety and virological data were collected.

Results Seventeen women (76% black) were enrolled (25 evaluable pharmacokinetic profiles; 15 in the third trimester, 10 in postpartum). In the third trimester, geometric mean (coefficient of variation, %) Cmin, unbound was 2.87 (87) µg/L and 93% of individual Cmin, unbound levels were >0.85 µg/L. The GMR (90% CI) in the third trimester vs postpartum was 0.86 (.68-1.10) for area under the curve (AUC0-24h), and for Cmax, 0.93 (.77-1.13). GMR (90% CI) for the trough concentrations was 0.71 (.49-1.02), based on total dolutegravir concentrations. Four serious adverse events were reported, unlikely related to dolutegravir. The HIV polymerase chain reaction test was negative in 14/17 infants (result unknown for 3 infants).

Conclusions Pharmacokinetic changes for dolutegravir in late pregnancy are not clinically relevant and support the use of dolutegravir 50 mg once daily with food in pregnancy.

7

Sep, 2020

Clinically significant lower elvitegravir exposure during third trimester of pregnant patients living with HIV: data from the PANNA study

 

Authors: Bukkems V, Necsoi C, Hidalgo Tenorio C, et al. PANNA Network

Published in: Clin infect Dis. 2020; 24;ciaa488.

Abstract This phase-IV study investigated the influence of pregnancy on the pharmacokinetics of elvitegravir/cobicistat in 14 HIV-1-positive women. The results support the recommendation against elvitegravir/cobicistat use during pregnancy, as the elvitegravir Ctrough was reduced by 77%, with 85% of pregnant women having a Ctrough below the EC90.

6

Aug, 2020

Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial

 

Authors: Bollen P,  Moore CL ,  Mujuru H et al; the ODYSSEY trial team

Published in: LANCET HIV. 2020;8:e533-e544

Background Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV.

Methods We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir’s pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children’s weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses.

Findings Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir.

Interpretation Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg.

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21

Jul, 2020

The CARMA study: early infant antiretroviral therapy—Timing impacts on total HIV-1 DNA quantitation 12 years later

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Authors: Foster C, Domínguez-Rodríguez S, Tagarro A, et al. For the Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life (EPIICAL) Consortium

Published in: J Pediatr Infect Dis Soc. 2020 2020 Jul 17;piaa071

Background Strategies aimed at antiretroviral therapy (ART)–free remission will target individuals with a limited viral reser- voir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV).

Methods Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life (EPIICAL) consortium who commenced ART aged <2 years, and remained suppressed (viral load [VL] <50 copies/mL) for >5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association.

Results Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-1 DNA measured; median 12 (IQR, 7.3– 15.4) years after ART initiation. Eleven had total HIV-1 DNA <10 copies/106 PBMCs. HIV-1 DNA levels were positively associated with age and VL at ART initiation, baseline CD4%, and Western blot antibody score. Age at ART initiation presented a linear associ- ation (coefficient = 0.10 ± 0.001, P ≤ .001), the effect of VL (coefficient = 0.35 ± 0.1, P ≤ .001) noticeable >6 logs. The effect of CD4% (coefficient = 0.03 ± 0.01, P = .049) was not maintained >40%.

Conclusions In this PaHIV cohort, reduced total HIV-1 DNA levels were associated with younger age and lower VL at ART initiation. The impact of early-infant treatment on reservoir size persists after a decade of suppressive therapy.

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13

Jul, 2020

The size of HIV reservoir is associated with telomere shortening and immunosenescence in early ART-treated HIV-infected children

 

Authors: De Rossi A, Dalzini A, Ballin G, Dominguez-Rodriuguez S, Rojo P, Foster C, Palma P, Sessa L, Nastouli E, Pahwa S, Rossi P, Giaquinto C, EPIICAL Consortium

Published in: 23rd International AIDS Conference, July 6th-10th, 2020

Background: HIV infection is linked to premature senescence, with increased risk of aging-associated illnesses. Early ART has been associated with a reduced HIV reservoir in HIV-perinatally infected children (PHIV), but its impact on the senescence process is an open question. Telomeres are critical for cellular replicative potential and their shortening is a marker of cellular senescence and aging process. We investigated the relationship between immunosenescence and HIV reservoir in PHIV enrolled in a multicenter cross-sectional study (CARMA, EPIICAL consortium).

Methods: 37 PHIV, who started ART <2 years of age and had undetectable viremia for at least 5 years, were enrolled in this study. HIV-DNA copies on CD4 cells and relative telomere length and levels of T-cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Senescent and activated CD4 and CD8 cells were estimated by flow cytometry. To explore the associations between cellular parameters, HIV reservoir and age at ART initiation, data were analyzed using a multivariable Poisson regression (adjusted for baseline % CD4, plasmaviremia, age at reservoir measurement, and age at ART initiation as interaction term).

Results: HIV reservoir was significantly (p<0.001) associated with immunosenescence (1.23[1.21-1.26]) and telomere shortening (0.15[0.13-0.17]) in CD4 cells, and immune activation (3.67[3.49-3.85]) and TREC levels (1.08[1.06-1.11]) in CD8 cells. These associations decreased by 1%, 10%, 6% and 6%, respectively, for each month ART was delayed. Early treated PHIV (ART initiation ≤6 months of age) displayed significantly lower HIV-DNA level (89[56-365] vs 552[303-1001] copies/106 cells)  and % CD4 senescent cells (1.0[0.5-2.7] vs 2.9[2.0-6.3]) than late treated ones.

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13

Jul, 2020

Aging B-cells (ABC) and anti-Env humoral responses are associated with T-bet expression in B-cells of perinatally HIV infected children (PHIV) treated within 24 months (m) of life (the CARMA cohort)

 

Authors: Ruggiero A, Cotugno N, Domínguez-Rodríguez S,  Zicari S, Rinaldi S, Zangari P, Tagarro A, Foster C, De Rossi A, Nastouli E, Luzuriaga K, Giaquinto C, Rossi P, Pawha S, Palma P, on behalf of the EPIICAL consortium.

Published in: 23rd Virtual International AIDS Conference, July 6th-10th, 2020

Background The role of T-bet, an immune factor involved in adaptative and innate response, has been poorly explored in B-cells. Previous studies concentrated on HIV+ and HIV- adults and T-bet was found to be associated with ABC. This work characterizes T-bet expression in B-cell (CD19+CD10-) subsets associated with aging (activated memory AM CD21-CD27+, Tissue Like Memory TLM CD21-CD27- and Double Negative DN CD27-IgD-) and with immunological memory (Resting Memory, RM CD27+CD21+IgD-) in PHIV.

Methods We studied 40 PHIV starting ART at median 4m of age (min 0m, max 22m) and ART-suppressed for >5 years (median 14 years (y) (min 5y, max 22y). Flow Cytometry was used to define B-cell phenotype and intracellular T-bet (MFI) in PHIV and in 20 age and gender-matched controls (HC). Anti-HIV serology was measured using Western blot and ELISA. Comparisons were analysed using Mann-Whitney test (MW). Associations were explored using Spearman test (rho, p) and multivariable ridge Poisson Regression model including baseline CD4, gender, and age at ART as confounders.

Results DN were expanded in PHIV compared with HC (p=0.01 MW). T-bet levels were elevated in AM, TLM and marginally DN compared to the others.  The models demonstrated a strong association between T-bet levels and time of ART start: for each month without ART T-bet increased by 3% and 2% in DN and AM, respectively (Fig.1a). Anti-Env responses were positively associated and were identified as predictors of T-bet levels in IgG+ B-cells (rho=0.35, p=0.03, Fig 1b), IgM+ B-cells (rho=0.39, p=0.01), RM IgM+ (rho=0.33, p=0.042).

Conclusions ABC are expanded in PHIV compared with HC, despite suppressive ART. Earlier ART-start preserves from premature aging of B-cell compartment. Furthermore, elevated levels of T-bet in memory B-cells was associated with anti-Env responses. Our findings add onto the previous literature by suggesting a role of T-bet in the anti-HIV B-cell response that warrant further investigation.

 

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12

Jul, 2020

A machine learning approach for predicting probability of death or disease progression in an early-treated pediatric African cohort

 

Authors: Domínguez-Rodríguez S, Tagarro A, Serna Pascual M, Otwombe K, Violari A, Fernández S, Nhampossa T, Lain M,  Vaz P , Behuhuma NO, Danaviah S, Dobbels E, Barnabas S, Cotugno N, Zangari P, Palma P, Oletto A,  Nardone A, Nastouli E, Spyer M, Kuhn L, Rossi P, Giaquinto C, Rojo P on behalf of EPIICAL consortium.

Published in: 23rd international AIDS Conference, July 6th-10th 2020

Background In perinatally HIV infected children, mortality and morbidity are highest in the first months after ART initiation and is linked to advanced disease and late diagnosis. The random forest approach can deal with more predictors than classical models and has no model assumptions such as normality, linearity or hazard proportionality. The aim of this study was to predict the probability of death or clinical progression at a specific time of follow-up.

Methods EARTH (EPIICAL consortium) is an African multi-centre cohort enrolling HIV-infected infants treated within 3 months of life (n=151). A total of 134 infants with >1 follow-up visit were included in this analysis. The primary endpoint was the right-censored time to death or progression to AIDS. To predict the outcome, a log-rank random survival forest with imbalance correction was performed in a training subset (n=95, 70%). The algorithm was validated on the remaining 30% (n=39).

Results A total of 22 infants reached the primary endpoint with 13 (10%) patients dead and 9 (7%) with an AIDS defining condition. A total of 10000 trees were built with an error rate of 20%. The most important predictors of reaching the primary endpoint were baseline HIV viral load, age at diagnosis, weight-for-age, gender, age at ART initiation, and baseline CD4 count. In the validation, the model predicted a higher probability of reaching the primary endpoint among children who did indeed die or progress to AIDS, as compared to the group of children who did well (1-month: 14% vs. 0.01%, p-value=0.045; 6-months: 62% vs. 0.03%, p-value=0.019; 12-months: 76% vs. 16%, p-value=0.012). The AUC for predicting survival or progression was 0.83, 0.84, and 0.72 for 1-month, 6-months, and 1-year respectively.

Conclusions This model helps clinicians individualize the probability of death or progression to AIDS at time of diagnosis and may be useful for the early identification of high-risk patients.

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31

May, 2020

The HIV-1 antibody response: a footprint of the viral reservoir in children vertically infected with HIV

 

Authors: Palma P, McManus M, Cotugno N, Rocca S, Rossi P, Luzuriaga K

Published in: Lancet HIV. 2020;7(5):e359-e365

Abstract Several assays have been developed to measure and characterise the replication-competent HIV-1 reservoir, which constitutes the barrier to cure. To date, the application of these assays to studies in children and in limited-resource settings has been minimal, primarily because of their expense, the large required blood volumes, and labour-intensive technologies. For children vertically infected with HIV-1 who initiated suppressive antiretroviral therapy (ART) regimens in infancy, HIV-1-specific antibody concentrations are associated with viral persistence and could be used to estimate the size of the residual latent reservoir on ART. This strategy could be particularly useful for screening children on suppressive ART for enrolment into therapeutic vaccine trials and other protocols aimed at achieving HIV-1 remission.

12

May, 2020

Differences in inducibility of the latent HIV reservoir in perinatal and adult infection

 

Authors: Dhummakupt A, Rubens JH, Andeson T, et al.

Published in: JCI Insight. 2020;5(4)

Abstract The HIV latent reservoir in resting memory CD4+ T cells precludes cure. Therapeutics to reactivate and eliminate this reservoir are in clinical trials in adults, but not yet in pediatric populations. We determined, ex vivo, the inducibility of the latent reservoir in perinatal infection as compared with adult infections using the Tat/rev induced limiting dilution assay (TILDA), in which a single round (12 hours) of CD4+ T cell stimulation with PMA/ionomycin maximally activates T cells and leads to proviral expression with multiply spliced HIV RNA production. Markers of immune activation and exhaustion were measured to assess interactions with inducibility. Although rates of T cell activation with PMA/ionomycin were similar, the latent reservoir in perinatal infection was slower to reactivate and of lower magnitude compared with adult infection, independent of proviral load. An enhanced TILDA with the addition of phytohemagglutin and a duration of 18 hours augmented proviral expression in perinatal but not adult infection. The baseline HLA-DR+CD4+ T cell level was significantly lower in perinatal compared with adult infections, but not correlated with induced reservoir size. These data support the hypothesis that there are differences in kinetics of latency reversal and baseline immune activation in perinatal compared with adult infections, with implications for latency reversal strategies toward reservoir clearance and remission.

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12

Apr, 2020

Differences in inducibility of the latent HIV reservoir in perinatal and adult infection

 

Authors: Dhummakupt A, Reubens JH, Anderson T, et al.

Published: Poster presented at 27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Abstract The HIV latent reservoir in resting memory CD4+ T cells prevents cure. Novel therapies to reactivate and eliminate the reservoir are in clinical trials in adults, but not yet in pediatric populations.

HIV proviral reservoir size was determined in perinatal (N=11) and adult infections (N=10) by digital droplet PCR (ddPCR) and with the intact proviral DNA assay (IPDA) in perinatal samples. The inducibility of the latent reservoir was determined with the Tat/rev Induced Limiting Dilution Assay (TILDA) that uses single-round (12 hr) T cell stimulation of CD4+ T cells with PMA/ ionomycin to maximally activate cells to induce proviral expression, measured as multiply-spliced HIV RNA Units per 106 CD4 cells (msRUPM). Markers of immune activation (CD69, CD25 and HLA-DR) and exhaustion (PD-1, TIM-3 and TIGIT) were also assessed. An enhanced TILDA with addition of PHA and for 18 hours was performed to enhance proviral expression in perinatal infections. Non-parametric tests were used for differences between paired and unpaired measurements; correlations were quantified by Spearman rank coefficient.

The median age was 15.8 yrs with a median duration of suppression of 6.7 yrs for perinatal infections, and 40.5 yrs with a median duration of suppression of 7.3 yrs for adult infections.  We found that despite a higher proviral reservoir size (median 132.1 vs. 66.7 c/106 PBMCs) and similar rates of T cell activation with PMA/ionomycin (median %CD69 = 96.7% and 93.0%) in perinatal and adult infections, respectively, the size of the induced reservoir was significantly lower in perinatal than in adult infections (median msRUPM of 2.99 vs 11.92, p=0.020). With the enhanced TILDA, the size of the induced reservoir increased significantly in perinatal infections (1.5-fold to a median of 4.5 msRUPM; p=0.034), but not in adult infections. The proportion of induced provirus was significantly lower in perinatal infections at 1.6% compared with 4.0% in adult infections (p=0.030). At baseline, the proportion of HLA-DR+ T cells was significantly lower in perinatal compared with adult infections (median HLA-DR+ cells = 4.56% vs 10.5%, p=0.012), but not correlated with the induced reservoir size.

The inducibility of the latent reservoir is substantially lower in perinatal compared with adult infections, possibly due to differences in baseline states of immune activation, with implications for latency reversal strategies towards ART-free remission.

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