HIV

14

Nov, 2019

Analysing small groups within clinical trials, while borrowing information from larger groups

 

Authors: Turner B, Ford D, Moore C, Gibb D, Turkova A,  White I, and ODYSSEY trial team

Published in: Oral Presentation atInternational Society for Clinical Biostatics; July 16th 2019

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14

Nov, 2019

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

Abstract There are limited data on infants with HIV starting antiretroviral therapy (ART) in the neonatal period. We investigated the association between the timing of ART initiation and time-to-suppression among infants who tested HIV-positive and initiated ART within the first 28 days of life. The effect was estimated using cumulative probability flexible parametric spline models and a multivariable generalized additive mixed model was performed to test nonlinear associations. Forty-four neonates were included. Nineteen (43.2%) initiated ART within 7 days of life and 25 (56.8%) from 8 to 28 days. Infants treated within 7 days were 4-fold more likely to suppress earlier than those treated after 7 days [Hazard ratio (HR) 4.01 (1.7–9.5)]. For each week the ART initiation was delayed, the probability of suppression decreased by 35% (HR 0.65 [0.46–0.92]). Age at ART start was linearly associated with time-to-suppression. However, a linear association with normally distributed residuals was not found between baseline viral load and time-to-suppression, with no association found when baseline viral loads were ≤5 log(10) copies/mL, but with exponential increase in time-to-suppression with > log5 copies/mL at baseline. Starting ART within 7 days of life led to 4-fold faster time to viral suppression, in comparison to initiation from 8 to 28 days.

14

Sep, 2019

Pharmacokinetics of dolutegravir 5mg dispersible tablets in children weighing 6 to <20kg dosed using WHO weight bands

 

Authors: Waalewijn H, Bollen PDJ, Moore C, Kekitiinwa A, et al. The ODYSSEY Trail Team

Published in: Oral Presentation at 10th IAS Conference, July, 21-24th 2019

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2

Sep, 2019

The CARMA Study: Children on early suppressive ART Total HIV-1 DNA quantitation 12 years post ART initiation

 

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.

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2

Sep, 2019

Comparison of qPCR and dPCR methods to investigate the latent HIV reservoir in a paediatric population with long viral suppression on therapy

 

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.

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30

Aug, 2019

Dolutegravir pharmacokinetics during pregnancy and postpartum

 

Authors: Colbers A, Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alejandre I,  van Crevel R, Burger D; on behalf of the PANNA network

Published: 26th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2019– Seattle. P_758.

 

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30

Aug, 2019

Dolutegravir pharmacokinetics during pregnancy and postpartum

 

Authors: Colbers A, Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alejandre I,  van Crevel R, Burger D.

Published: Oral presentation at 9th edition of the International Workshop on HIV & Women, March 2nd-3rd 2019, Seattle

 

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30

Aug, 2019

Efavirenz pharmacokinetics during pregnancy and infant washout

 

Authors: Kreitchmann R, Schalkwijk S, Best B, et al.

Published in: Antivir Ther. 2019;24(2):95-103

Background Limited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout.

Methods HIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-h pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6-12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration-time curve (AUC) in non-pregnant historical controls (40.0 μg•h/ml) and a trough concentration (C24 h) of 1 μg/ml. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe).

Results Among 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7-43.5) years, weight 74 (50-132) kg and gestational age 33.4 (28.4-37.9 weeks). Efavirenz AUC during the 3T (60 μg•h/ml) was similar to that reported in non-pregnant adults (58 μg•h/ml). Exposure in the 2T was lower, but within the 0.80-1.25 range. C24concentrations during pregnancy were lower compared to historical controls on 600 mg efavirenz, however, they were similar to the C24concentrations after equally potent dose of 400 mg efavirenz. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36-0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 h (40.6-129). HIV RNA viral loads at delivery were <400 and <50 copies/ml for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8/41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C24 below target.

Conclusions Efavirenz exposure was similar during pregnancy compared with PP, C24 was in line with C24 after 400 mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants.

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30

Aug, 2019

Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling

 

Authors: Schalkwijk S, Ter Heine R, Colbers A, et al.

Published in: J Antimicrob Chemother. 2019;30 [Epub ahead of print]

Background Darunavir 800 mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available.

Objectives To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women.

Patients and Methods A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC0-τ and Ctrough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure.

Results Simulations predicted that total darunavir exposure (AUC0-τ) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC0-τ was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%).

Conclusion The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.

29

Apr, 2019

Incidence of switching to second-line antiretroviral therapy and associated factors in children with HIV: an international cohort collaboration

 

Authors: Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration.

Published in: Lancet HIV. 2019;6(2):e105-e115.

Background Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration.

Methods In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks.

Findings At the data cutoff of Sept 16, 2015, 182 747 children with HIV were included in the CIPHER dataset, of whom 93 351 were eligible, with 83 984 (90·0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3·9 years (IQR 1·6–6·9) and 82 885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9–52). 3883 (4·2%) patients switched to second-line ART after a median of 35 months (IQR 20–57) of ART. The cumulative incidence of switching at 3 years was 3·1% (95% CI 3·0–3·2), but this estimate varied widely depending on the cohort monitoring strategy, from 6·8% (6·5–7·2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0·8% (0·6–1·0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p<0·0001). Cohort-level factors that increased the likelihood of switching were higher-income country (p=0·0017) and routine or targeted monitoring of CD4 and viral load (p<0·0001), which was associated with a 166% increase in likelihood of switching compared with CD4 only monitoring (subdistributional hazard ratio 2·66, 95% CI 2·22–3·19).

Interpretation Our global paediatric analysis found wide variations in the incidence of switching to second-line ART across monitoring strategies. These findings suggest the scale-up of viral load monitoring would probably increase demand for paediatric second-line ART formulations.