Feb, 2021

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

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Authors: Cecilia L. Moore, Anna Turkova , Hilda Mujuru , Adeodata Kekitiinwa, Abbas Lugemwa, Cissy M. Kityo, Linda N. Barlow-Mosha, et al, ODYSSEY trial team

Published in: BMC Infectious Diseases


Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development.

Methods: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks.

Results: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ARTnaïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls.

Conclusions: By employing a basket design, to include ART-naïve and -experienced children, and nested PK substudies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children.



Dec, 2020

A population pharmacokinetics analysis assessing the exposure of raltegravir once‐daily 1200mg in pregnant women living with HIV


Authors: Vera E. Bukkems, Teun M. Post, Angela P. Colbers, David M. Burger, Elin M. Svensson

Published in: American Society for Clinical Pharmacology and Therapeutics


Abstract: Once‐daily two 600mg tablets (1200mg QD) raltegravir offers an easier treatment option compared to the twice‐daily regimen of one 400mg tablet. No pharmacokinetic, efficacy or safety data of the 1200mg QD regimen have been reported in pregnant women to date as it is challenging to collect these clinical data.

This study aimed to develop a population pharmacokinetic (popPK) model to predict the pharmacokinetic profile of raltegravir 1200mg QD in pregnant women and to discuss the expected pharmacodynamic properties of raltegravir 1200mg QD during pregnancy based on previously reported concentration‐effect relationships. Data from 11 pharmacokinetic studies were pooled (n=221).

A two‐compartment model with first‐order elimination and absorption through three sequential transit compartments best described the data. We assessed that the bio‐availability of the 600mg tablets was 21% higher as the 400mg tablets, and the bio‐availability in pregnant women was 49% lower. Monte‐Carlo simulations were performed to predict the pharmacokinetic profile of 1200mg QD in pregnant and non‐pregnant women.

The primary criteria for efficacy was that the lower bound of the 90% confidence interval (CI) of the concentration before next dose administration (Ctrough) geometric mean ratio (GMR) of simulated pregnant/non‐pregnant women had to be >0.75. The simulated raltegravir Ctrough GMR (90%CI) was 0.51 (0.41‐0.63), hence not meeting the primary target for efficacy. Clinical data from two pregnant women using 1200mg QD raltegravir showed a similar Ctrough ratio pregnant/non‐pregnant.

Our pharmacokinetic results support the current recommendation of not using the raltegravir 1200mg QD regimen during pregnancy until more data on the exposure‐response relationship becomes available.

View the full article here.



Dec, 2020

Cascade of care in children and adolescents with HIV in Russian Federation

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Author: Anna Turkova, Evgeny Voronin, Yulia Plotnikova, Anna Samarina, Edith Milanzi, Vladimir Rozenberg, Liubov Okhonskaia, Inga Latysheva, Aleksey Plynsky, Elena Fertikh, Siobhan Crichton, Charlotte Jackson, Ali Judd, Intira J Collins, on behalf of the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC)

Published in: 12th International Workshop on HIV Pediatrics

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The cascade of care summarises the 90-90-90 UNAIDS targets, of 90% of HIV+ people knowing their status, of whom 90% receive antiretroviral treatment (ART), of whom 90% are virally suppressed

By 2019, there were 1,068,839 people diagnosed with HIV in Russia, of whom 50% were on ART, and of those 76% were virally suppressed1.

However, there is less data on the HIV care continuum in children and adolescents with HIV in Russia



To summarise the cascade of care in children and adolescents living with HIV in three Russian clinics.



We included data on children/adolescents aged <18 years at HIV diagnosis from three Russian clinics within the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC).

Follow-up data from first presentation to HIV care until death, loss to follow-up, transfer to adult care or last visit (data cut-off 1/10/2016) were included.

As all patients were already diagnosed with HIV, we adapted the cascade of care as follows: (a) initiated ART, (b) virally suppressed (VS) ≤1000 copies/ml and (c) having good WHO immune status* at last visit.  The analysis was restricted to patients in active paediatric follow-up (FU) in 2015-2016 and had ≥12 months of FU.

Characteristics of patients and cascade results were stratified by age of HIV diagnosis:

i.Diagnosed during “childhood” (age <10) and

ii.Diagnosed during “adolescence” (age ≥10)

The proportion with VS and good immune status* at 12(±3) months after ART start was also summarized overall and by calendar year of ART start.



  • Of 922 patients followed in the 3 centres, 703 had ≥12 months FU and were in care in 2015/16 and included in this analysis. Of these:
  • 655 (93%) were diagnosed in childhood, of whom 94% had perinatally acquired HIV (Table 1)
  • 48 (7%) were diagnosed in adolescence, of whom 27% had perinatally acquired HIV, 25% sexually-acquired, and 48% had other or unknown mode of transmission
  • 94% (618/655) in the childhood group initiated ART compared to 81% (39/48) in the adolescent group.
  • At ART initiation, the median age was 2.2 years and 16.1 years in the childhood and adolescence group, respectively. 52% and 58% had advanced or severe WHO immunosuppression at ART start, respectively (Table 1).


Dec, 2020

Pediatric dolutegravir (DTG) dosing recommendations derived from combined P1093 and ODYSSEY Population Pharmacokinetic analysis

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Authors: Singh R, Baker M, Thapar M, Gibb D, Turkova A, Ford D, Ruel T, Wiznia A, Farhad M, Alvero C, Green J, Bollen P, Colbers A, Burger D, Acosta E

Published in: 12th International Workshop on HIV Pediatrics

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Background: HIV treatment options remain limited in children. The recent Tivicay (dolutegravir, DTG) pediatric regulatory submissions propose WHO weight-band based recommendations for once-daily dosing in children ≥4 weeks of age using combined datasets from two pediatric studies: IMPAACT P1093 and ODYSSEY (PENTA20). These doses were informed by the Population PK (PopPK) analysis described below.

Methods: P1093 is a Phase I/II, non-comparative pharmacokinetic (PK) and safety study in HIV-1 infected children (≥4 weeks to <18 years of age). ODYSSEY is a non-inferiority, phase II/III study comparing the efficacy and toxicity of DTG plus 2 NRTIs vs. standard of care in infants and children. Intensive and sparse PK samples following dosing with film coated tablets (FCT), granules and dispersible tablet (DT) formulations in the fasted state and without regard to food were collected in P1093; intensive PK samples using FCTs and DTs in fasted state were collected in ODYSSEY. A PopPK model was developed with data from P1093 (1711 concentrations from n=151 participants) and ODYSSEY (939 concentrations from n=88 participants) to characterize PK, covariates, and associated variability. The final PopPK model simulated exposures across weight bands, doses, and formulations which were compared with established adult reference data.

Results: Of N=239 participants included, baseline age ranged from 0.17-17.5 years and weight from 3.9-91 kg, 50% were male and 80% were black. The model described study data and associated variability well with estimated mean (interindividual variability) CL/F=1.03L/h (29%) and V/F=13.6 L (107%). Based on observed and simulated data, dose stratification by age (<6 months and ≥6 months) in the 6 to <10 kg weight band (10 and 15 mg DTG DT, respectively) was proposed to account for metabolic enzyme maturation. The proposed doses are 5mg DT in 3 to <6kg; 10 mg DT in 6 to<10kg and <6 months, 15mg DT in 6 to <10kg and ≥6months, 20mg DT in 10 to <14kg, 25mg DT in 14 to <20kg and 30mg DT or 50 mg FCT in >20kg. At these doses, the simulated 24- hour concentration (C24h) was consistent across weight bands, similar to observed data, and met the minimum target concentrations of 0.697μg/mL. Similarly, simulated 24-hour area-under-the-curve (AUC24h) met the minimum target (46 h*μg/mL) across weight bands. Simulated maximum concentration (Cmax) results were 0.96 to 1.79- fold those observed historically in adults at the approved dose of DTG 50 mg BID (4.15 μg/mL). The safety exposure-response analysis demonstrated no relationships between PK parameters and adverse events.

Conclusions: Using FCT and DT formulations, DTG dosing in children ≥4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed PK variability was higher in this pediatric population and no additional safety concerns were observed.



Oct, 2020

COVID and HIV: Psychological impact and awareness of COVID-19 in young people with HIV

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Authors: S. Bernardi1, E. Mozzo, M. Di Pastena, F. Leone, C. Novello, A. Oletto, N. Cotugno, P. Zangari, P. Palma, V. Santilli, P. Palma, O. Rampon, C. Giaquinto

Published in: 12th National Congress of Italian Conference on AIDS and Antiviral Research

Background: Public health emergencies may affect the health, safety, and well-being of both individuals and communities. These effects may translate into a range of emotional reactions and unhealthy behaviours. Some people may be more vulnerable than others to the psychosocial effects of pandemics. Young people living with HIV can experience solitude, depression and anxiety as a consequence of the stigma that continues to surround HIV and the daily challenge of living with a chronic infection. We investigated the psychological impact of the current COVID-19 pandemic among a group of HIV-infected young people and assessed their knowledge on HIV and COVID-19 infections.



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


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 Dis2020;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.


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 Dis2020; 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.


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.



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.



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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