Publications

Authors: Turkova A, Chappell E, Chalermpantmetagul S, et al.

Published in: Int J Tuberc Lung Dis 2016;20(11):1448-1456.

Setting Centres participating in the Paediatric European Network for Treatment of AIDS (PENTA), including Thailand and Brazil.

Objective To describe the incidence, presentation, treatment and treatment outcomes of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children.

Design Observational study of TB diagnosed in HIV-infected children in 2011–2013.

Results Of 4265 children aged <16 years, 127 (3%) were diagnosed with TB: 6 (5%) in Western Europe, 80 (63%) in Eastern Europe, 27 (21%) in Thailand and 14 (11%) in Brazil, with estimated TB incidence rates of respectively 239, 982, 1633 and 2551 per 100 000 person-years (py). The majority (94%) had acquired HIV perinatally. The median age at TB diagnosis was 6.8 years (interquartile range 3.0–11.5). Over half (52%) had advanced/severe World Health Organization stage immunodeficiency; 67 (53%) were not on antiretroviral therapy (ART) at TB diagnosis. Preventive anti-tuberculosis treatment was given to 23% (n = 23) of 102 children diagnosed with HIV before TB. Eleven children had unfavourable TB outcomes: 4 died, 5 did not complete treatment, 1 had recurrent TB and 1 had an unknown outcome. In univariable analysis, previous diagnosis of acquired immune-deficiency syndrome, not being virologically suppressed on ART at TB diagnosis and region (Brazil) were significantly associated with unfavourable TB outcomes.

Conclusion Most TB cases were from countries with high TB prevalence. The majority (91%) had favourable outcomes. Universal ART and TB prophylaxis may reduce missed opportunities for TB prevention.

Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord.

Published in: Antivir Ther. 2016; 21(4): 353-8

Authors: Judd A, Sohn A, Collins J.

Published in: Curr Opin HIV AIDS 2016;11(5):477-486.

Purpose of review There is an increasing number of deaths among adult survivors of perinatal HIV. Multiple and complex factors drive this mortality, including problems with retention in care and adherence during adolescence, coupled with the critical period of transition from paediatric to adult care, increasing their risk of treatment failure and severe immunosuppression. We reviewed studies that evaluated the impact of service delivery interventions to improve the health of perinatally infected adolescents living with HIV (P-ALHIV) to gain insight into what might help them survive the vulnerable period of adolescence.

Recent findings Youth-focused health services and individual-level interventions may improve P-ALHIV adherence and retention in care. However, there have been few studies, many with small sample sizes and with short durations of follow-up that end before the transition period. Studies from other childhood-onset chronic diseases are similarly limited.

Summary Further studies are urgently needed to identify optimal intervention strategies to reduce mortality and poor outcomes as the adolescent population expands and ages into adult care. Until we have a more robust evidence base, programmes can develop transition plans based on best practice recommendations to optimize the health and longevity of ALHIV in adulthood.

Authors: Ngo-Giang-Huong N, Wittkop L, Judd A, et al. For EuroCoord-CHAIN-EPPICC joint project study group.

Published in: BMC Infect Dis. 2016;16(1):654.

Authors: Kramer LD, Long MT

Published in: Curr Opin Virol. 2016 Dec;21:v-vi

Authors: Schalkwijk S, ter Heine R, Colbers A,  Huitema A, Denti P, Dooley K, Capparelli E, Best B, Cressey T, Greupink R, Russel F, Mirochnick M, Burger D.

Published: 17th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, June 8th-10th 2016, Washington DC.  P_26

Authors: Colbers A, Schalkwijk S, Konopnicki D, Hawkins D, Hidalgo Tenorio C, Moltò J, Taylor G, Weizsacker K, van der Ende M, Burger D

Published: Oral presentation at 17th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, June 8th-10th 2016, Washington DC

Authors: Schalkwijk S, Best B, Colbers A, SteK A, Wang  J, Hawkins D, Mirochnick M, Burger D; for the The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1026s Protocol Team, and the Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-infected Pregnant Women (PANNA) Study Network

Published: 23rd Conference on Retroviruses and Opportunistic Infections, February 22nd-25th 2016, Boston

Authors: Blonk MI, Colbers AP, HidalgoTenorio C, et al.

Published in: Front Pharmacol. 2016 Aug 4;7:239.

Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women.

Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL).

Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC_0–12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19–4.25) and no perinatal transmission occurred.

Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available.

Authors: Schalkwijk S, Feiterna-Sperling C, Weizsacker K, et al.

Published in: AIDS. 2016; 30(12):1999-2001.

No Abstract available

Author: Butler K, Inshaw J, Ford D, et al.

Published in:  Health Technol Assess. 2016;20(49):1-108.

Background For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings.

Objectives To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy.

Design Open, randomised, non-inferiority trial.

Setting Europe, Thailand, Uganda, Argentina and the USA.

Participants Young people (aged 8–24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months.

Interventions Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART).

Main outcome measures Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan–Meier method (12% non-inferiority margin) adjusted for region and age.

Results In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm³, respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap^™ Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference –1.2%, 90% confidence interval (CI) –7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference –2.1%, 90% CI –6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial.

Conclusions Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned.

Author: The BREATHER (PENTA 16) Trial Group

Published in: Lancet HIV. 2016;3(9):e421-430

Background For HIV-1-infected young people facing lifelong antiretroviral therapy (ART), short cycle therapy with long-acting drugs offers potential for drug-free weekends, less toxicity, and better quality-of-life. We aimed to compare short cycle therapy (5 days on, 2 days off ART) versus continuous therapy (continuous ART).

Methods In this open-label, non-inferiority trial (BREATHER), eligible participants were aged 8–24 years, were stable on first-line efavirenz with two nucleoside reverse transcriptase inhibitors, and had HIV-1 RNA viral load less than 50 copies per mL for 12 months or longer. Patients were randomly assigned (1:1) to remain on continuous therapy or change to short cycle therapy according to a computer-generated randomisation list, with permuted blocks of varying size, stratified by age and African versus non-African sites; the list was prepared by the trial statistician and randomisation was done via a web service accessed by site clinician or one of the three coordinating trials units. The primary outcome was the proportion of participants with confirmed viral load 50 copies per mL or higher at any time up to the 48 week assessment, estimated with the Kaplan-Meier method. The trial was powered to exclude a non-inferiority margin of 12%. Analyses were intention to treat. The trial was registered with EudraCT, number 2009-012947-40, ISRCTN, number 97755073, and CTA, number 27505/0005/001-0001.

Findings Between April 1, 2011, and June 28, 2013, 199 participants from 11 countries worldwide were randomly assigned, 99 to the short cycle therapy and 100 to continuous therapy, and were followed up until the last patient reached 48 weeks. 105 (53%) were men, median age was 14 years (IQR 12–18), and median CD4 cell count was 735 cells per μL (IQR 576–968). Six (6%) patients assigned to the short cycle therapy versus seven (7%) assigned to continuous therapy had confirmed viral load 50 copies per mL or higher (difference −1·2%, 90% CI −7·3 to 4·9, non-inferiority shown). 13 grade 3 or 4 events occurred in the short cycle therapy group and 14 in the continuous therapy group (p=0·89). Two ART-related adverse events (one gynaecomastia and one spontaneous abortion) occurred in the short cycle therapy group compared with 14 (p=0·02) in the continuous therapy group (five lipodystrophy, two gynaecomastia, one suicidal ideation, one dizziness, one headache and syncope, one spontaneous abortion, one neutropenia, and two raised transaminases).

Interpretation Non-inferiority of maintaining virological suppression in children, adolescents, and young adults was shown for short cycle therapy versus continous therapy at 48 weeks, with similar resistance and a better safety profile. This short cycle therapy strategy is a viable option for adherent HIV-infected young people who are stable on efavirenz-based ART.

Authors: Schalkwijk S, Colbers A, Konopnicki D, et al. For PANNA network

Published in: AIDS. 2016;30(8):1239-44.

Objective To describe the pharmacokinetics of abacavir 600 mg once daily (q.d.) in HIV-1-positive women during pregnancy and postpartum.

Design A nonrandomized, open-label, multicentre, phase-IV study.

Methods HIV-positive pregnant women receiving abacavir 600 mg q.d. as part of clinical care were included. Intensive 24-h pharmacokinetic sampling was performed during the third trimester and at least 2 weeks after delivery. Pharmacokinetic parameters were calculated by noncompartmental analysis. Paired cord blood and maternal blood samples were taken at delivery when feasible.

Results A total of 14 women were included in the analysis. Geometric mean ratios (90% confidence intervals) of third trimester versus postpartum were 1.05 (0.92–1.19) for AUC0–24h and 1.00 (0.83–1.21) for Cmax. The median (range) ratio of abacavir cord plasma to maternal plasma was 1.0 (0.7–1.0, n = 3). Viral load at the third trimester visit was less than 50 copies/ml in 13 participants (93%; one unknown). In total, 13 (93%; one unknown) children were tested HIV-negative.

Conclusion The pharmacokinetics of abacavir 600 mg q.d. during pregnancy are equivalent to postpartum. No dose adjustments are required during pregnancy and similar antiviral activity is expected.

Authors: Aebi-Popp K, Bailey H, Malyuta R, Volokha A, Thorne C. Ukraine European Collaborative Study in EuroCoord.

Published in: BMC Pregnancy Childbirth. 2016;27;16:94

Authors: Ananworanich J, Melvin D, Ramos Amador JT, et al; on behalf of the PENTA 11 study group.

Published in: AIDS. 2016;30(7):1075-81.

Objective Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research.

Design Children previously randomized to continuous (continuous ART, n = 41) vs. planned treatment interruption (PTI, n = 47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6–16 years old) or Wechsler Adult Intelligence Scale (≥17 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann–Whitney U test, respectively. Scores indicating clinical concern were compared (<7 for neurocognition and <70 for QoL tests).

Results Characteristics were similar between arms with a median age of 12.6 years, CD4+ of 830 cells/μl and HIV RNA of 1.7 log10copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P = 0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern.

Conclusion No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial.

Authors: Schalkwijk S, Colbers A, Konopnicki D, Greupink R, Russel FG, Burger D; PANNA network.

Published in: AIDS. 2016;30(5):807-8.

Abstract not available

Authors: Writing group for the Kids to Adults Working Group and Data Management and Harmonisation Group in EuroCoord.

Published in: Euro Surveill.2016;21(10): 30162

Abstract Accurate ascertainment of the number of children living with human immunodeficiency virus (HIV) is important to plan paediatric and adolescent health services. In Europe, the first generation of perinatally HIV-infected survivors are transferring to adult care and their health needs are unknown. We undertook an online survey of HIV cohort studies participating in the EuroCoord Network of Excellence to ascertain the number of perinatally HIV-infected (pHIV) patients included, to compare it with those published by the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) and to assess the ability of countries to follow up pHIV patients after transfer to adult care. At the end of 2013, 16 countries in EuroCoord reported 8,229 pHIV patients in follow-up in cohorts, compared with 5,160 cumulative diagnoses reported by the ECDC in the same area. Follow-up of pHIV patients after transfer to adult care varied. It is likely that the number of diagnoses of perinatal HIV reported to ECDC is an underestimate, although this varies by country. Further work is needed to refine estimates and encourage follow-up in adult HIV cohorts to investigate long-term outcomes and improve the care of the next generation of children with HIV.

Author: Warris A; European Paediatric Mycology Network (EPMyN)*.

Published in: Curr Fungal Infect Rep. 2016;10:7-9.

Abstract: The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. The EPMyN aims to address the lack of paediatric specific evidence and knowledge needed to (1) improve the management and outcome of invasive fungal infections in children and neonates and to (2) enhance and develop paediatric anti-fungal stewardship programmes.

Authors: S. Bernays, S. Paparini, D. Gibb & J. Seeley

Published in: Vulnerable Child Youth Stud. 2016;11(1):60-68

Abstract Despite mounting evidence recommending disclosure of human immunodeficiency virus (HIV) status to young people with perinatally acquired HIV as a central motivating factor for adherence to antiretroviral therapy, many young people continue to experience disclosure as a partial event, rather than a process. Drawing from two longitudinal, interview-based qualitative studies with young people living with HIV (aged 10-24) in five different countries in low and high income settings, we present data regarding disclosure and information about HIV in the clinic. The article highlights the limits of discussions framing disclosure and patient literacy, and young people’s reluctance to voice their adherence difficulties in the context of their relationships with clinical care teams. We suggest that a clinician-initiated, explicit acknowledgment of the social and practical hurdles of daily adherence for young people would aid a more transparent conversation and encourage young people to disclose missed doses and other problems they may be facing with their treatment. This may help to reduce health harms and poor adherence in the longer-term.

Authors: Moltò J, Valle M, Colbers A, Clotet V, Burger D.

Published: 16th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, May 26th – 28th 2015, Westin Alexandria

Authors: Harrison L, Melvin A, Fiscus S, et al. For PENPACT-1 (PENTA 9PACTG 390) Study Team.

Authors: Bernays S, Seeley J, Paparini S, Rhodes T

Published: BSA Medical Sociology Conference, York, 9-11 September 2015 (Paper ID No: W0012148)

Authors: Blonk MI, Colbers AP, Hidalgo-Tenorio C, et al. Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women PANNA Network; PANNA Network.

Published in: Clin Infect Dis. 2015; 61(5):809-816. 

BackgroundThe use of raltegravir in human immunodeficiency virus (HIV)–infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women.

Methods An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated.

Results Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C_12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53–.96) for AUC_0–12h and 0.64 (.34–1.22) for C_12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02–2.17; n = 9).

Conclusions Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women.

Authors: Colbers A, Clotet V, Burger D.

Published: 16th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, May 26th – 28th 2015, Westin Alexandria

Authors: Best B, Colbers A, Wang J, Taylor G, Stek A, van Kasteren M, Mirochnick M, Burger D.

Published: 24th Conference on Retroviruses and Opportunistic Infections, March 23rd-26th 2015, Seattle. P_892

Authors: Colbers A, Best B, Schalkwijk S, et al. PANNA Network and the IMPAACT 1026 Study Team.

Published in: Clin Infect Dis. 2015; 61(10):1582-1589.

Objective To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)–infected women during pregnancy and post partum.

Methods HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated.

Results Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60–.88) for the area under the curve over a dosing interval (AUC_tau) and 0.70 (0.58–0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (C_trough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03–0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing.

Conclusions Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUC_tau and maximum concentration of about 30%. C_troughwas reduced by 15% but exceeded the minimum C_trough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy.

Authors:  Bernays S, Seeley J, Paparini S, Rhodes T and the ARROW and BREATHER trial teams.

Published in: accepted for presentation at AIDS Impact, Amsterdam 28-31 July, 2015 (abstract 3435)

Authors:  Paparini S on behalf of Bernays S, Seeley S,  Rhodes T,  Namukwaya Kihika S,Kawuma-Kigawa R, Nakyambadde H, Kabajaasi O and the BREATHER Trial Team.

Published in: 3^rd International ASSHH Conference, Stellenbosch, South Africa, 6-9 July 2015.

Authors:  Seeley J on behalf of the Bernays S, Paparini S, Namukwaya Kihika S,  Rhodes T and the BREATHER Trial Team.

Published in: 3^rd International ASSHH Conference, Stellenbosch, South Africa, 6-9 July 2015.

Authors: Klein N, Palma P, Luzuriaga K, et al.

Published in: Lancet Infect Dis. 2015;15(9):1108-1114

Abstract From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection.

Authors: Seeley J on behalf of the Bernays S, Paparini S, Namukwaya Kihika S,  Rhodes T and the BREATHER Trial Team.

Published in: 3rd International ASSHH Conference, Stellenbosch, South Africa, 6-9 July 2015.

Author: Paparini S on behalf of Bernays S, Seeley S, Rhodes T, Namukwaya Kihika S,Kawuma-Kigawa R, Nakyambadde H, Kabajaasi O and the BREATHER Trial Team.

Published in: 3^rd International ASSHH Conference, Stellenbosch, South Africa, 6-9 July 2015.

Authors: Bernays S, Seeley J, Paparini S, Rhodes T and the ARROW and BREATHER trial teams

Published in: AIDS Impact, Amsterdam 28-31 July, 2015 (abstract 3435)

Authors: Palma P, Foster C, Rojo P, et al.

Published in: J Virus Erad. 2015;1(3):134-139.

Abstract The EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children’s Actual Life with Novel Immunotherapeutic Strategies) project arises from the firm belief that perinatally infected children treated with suppressive antiretroviral therapy (ART) from early infancy represent the optimal population model in which to study novel immunotherapeutic strategies aimed at achieving ART-free remission. This is because HIV-infected infants treated within 2–3 months of life have a much reduced viral reservoir size, and rarely show HIV-specific immunity but preserve normal immune development. The goal of EPIICAL is the establishment of an international collaboration to develop a predictive platform using this model to select promising HIV therapeutic vaccine candidates, leading to prioritisation or deprioritisation of novel immunotherapeutic strategies. To establish this platform, the EPIICAL Consortium aims to: develop predictive models of virological and immunological dynamics associated with response to early ART and to treatment interruption using available data from existing cohorts/studies of early-treated perinatally HIV-infected children; optimise methodologies to better characterise immunological, virological and genomic correlates/profiles associated with viral control; test novel immunotherapeutic strategies using in vivoproof-of-concept (PoC) studies with the aim of inducing virological, immunological and transcriptomic correlates/profiles equivalent to those defined by the predictive model. This approach will strengthen the capacity for discovery, development and initial testing of new therapeutic vaccine strategies through the integrated efforts of leading international scientific groups, with the aim of improving the health of HIV-infected individuals.

Authors: Antinori A., Marcotullio S., Andreoni M., Ammassari A., d’Arminio Monforte A., Galli M., Girardi E., Mazzotta F., Mussini C., Puoti M., Lazzarin A.; Italian HIV Guidelines Working Group.

Published in: New Microbiol. 2015, 38: 299-328

Abstract: This short version complies with the intention expressed in the introduction to the full text Italian Guidelines for the use of antiretroviral drugs and the diagnostic-clinical management of people with HIV-1 infection. By definition, this version should not be considered completely exhaustive with respect to the full text version of the Guidelines (HIV/AIDS Italian Expert Panel, 2014)

Authors:  De Bie S., Ferrajolo C., Straus S.M., Verhamme K.M., Bonhoeffer J., Wong I.C., Sturkenboom M.C., GRiP network

Published in: PLoS One. 2015, 10: 0130399.

Abstract: Individual case safety reports (ICSRs) are a cornerstone in drug safety surveillance. The knowledge on using these data specifically for children is limited. We studied characteristics of pediatric ICSRs reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Public available ICSRs reported in children (0–18 years) to FAERS were downloaded from the FDA-website for the period Jan 2004-Dec 2011. Characteristics of these ICSRs, including the reported drugs and events, were described and stratified by age-groups. We included 106,122 pediatric ICSRs (55% boys and 58% from United States) with a median of 1 drug [range 1–3] and 1 event [1–2] per ICSR. Mean age was 9.1 years. 90% was submitted through expedited (15-days) (65%) or periodic reporting (25%) and 10% by non-manufacturers. The proportion and type of pediatric ICSRs reported were relatively stable over time. Most commonly reported drug classes by decreasing frequency were ‘nervous system drugs’ (58%), ‘antineoplastics’ (32%) and ‘anti-infectives’ (25%). Most commonly reported system organ classes were ‘general’ (13%), ‘nervous system’ (12%) and ‘psychiatric’ (11%) disorders. Duration of use could be calculated for 19.7% of the reported drugs, of which 14.5% concerned drugs being used long-term (>6 months). Knowledge on the distribution of the drug classes and events within FAERS is a key first step in developing pediatric specific methods for drug safety surveillance. Because of several differences in terms of drugs and events among age-categories, drug safety signal detection analysis in children needs to be stratified by each age group.

Authors: Thorne C, Indolfi G, Turkova A, Giaquinto C, Nastouli E.

Published in: J Virus Erad. 2015 Jul 1;1(3):203-5.

Authors: Turkova A, Giacomet V, Goetghebuer T, et al.

Published in: J Virus Erad. 2015;1(3):179-184

Methods HCV treatment data on children and young people aged <25 years with HIV/HCV co-infection were collected in a cohort collaboration of 11 European paediatric HIV cohorts. Factors associated with receipt of HCV treatment and with sustained virological response 24 weeks after treatment completion (SVR24) were explored.

Results Of 229 HIV/HCV co-infected patients, 22% had a history of AIDS and of 55 who were treated for HCV, 47 (85%) were receiving combined antiretroviral therapy. The overall HCV treatment rate was 24% (n=55) but it varied substantially between countries, with the highest rate being in Russia at 61% (30/49). Other factors associated with treatment receipt were older age [adjusted odds ratio (AOR) 5.24, 95% confidence interval (CI) 1.9–14.4, for 18–24-year-olds vs 11–17-year-olds, P=0.001] and advanced fibrosis (AOR 5.5, 95% CI 1.3–23.7; for ≥9.6 vs ≤7.2 kPa, P=0.02). Of 50 patients with known treatment outcomes, 50% attained SVR24. Of these, 16 (80%) had genotype (GT) 2,3 and 8 (29%) had GT 1,4 (P<0.001). After adjusting for genotype (GT 1,4 vs GT 2,3), females (P=0.003), patients with non-vertical HCV acquisition (P=0.002) and those with shorter duration of HCV (P=0.009) were more likely to have successful treatment outcomes.

Authors: Paediatric European Network for Treatment of AIDS (PENTA).

Published in: AIDS 2015. 29(18):2447-2457

Objective To evaluate whether once daily (q.d.) lopinavir/ritonavir is noninferior to twice daily (b.i.d.) dosing in children.

Design International, multicentre, phase II/III, randomized, open-label, noninferiority trial (KONCERT/PENTA18/ANRS150).

Setting Clinical centres participating in the PENTA, HIV-NAT and PHPT networks.

Participants Children/adolescents with HIV-1 RNA viral load less than 50 copies/ml for at least 24 weeks on lopinavir/ritonavir-containing antiretroviral therapy.

Intervention Children were randomized to continue lopinavir/ritonavir b.i.d. or change to q.d.

Main Outcome Measure Confirmed viral load ≥50 copies/ml by 48 weeks (12% noninferiority margin).

Results One hundred seventy-three children were randomized in the KONCERT trial (86 q.d., 87 b.i.d.); 46% men, median (IQR) age 11 (9-14) years, CD4% 33 (27-38)%. By week 48, 97 and 98% of time was spent on q.d. and b.i.d., respectively (one q.d. child lost at week 4). Twelve q.d. vs. seven b.i.d. children had confirmed viral load ≥50 copies/ml within 48 weeks; estimated difference in percentage with viral load rebound 6% [90% CI (-2, 14)]. Numbers of children with grade 3/4 adverse events (11 vs. 7) or major resistance mutations (3 vs. 2) were similar, q.d. vs. b.i.d. (both P > 0.3). Among 26 children in an intrasubject lopinavir/ritonavir pharmacokinetic substudy, lower daily exposure (AUC0-24 161 h.mg/l vs. 224 h.mg/l) and lower Clast (1.03 mg/l vs. 5.69 mg/l) were observed with q.d. vs. b.i.d. dosing.

Conclusion Noninferiority for viral load suppression on q.d. vs. b.i.d. lopinavir/ritonavir was not demonstrated. Although results, therefore, do not support routine use of q.d. lopinavir/ritonavir, lack of safety concerns or resistance suggest that q.d. dosing remains an option in selected, adherent children, with close viral load monitoring.

Authors:

Published in: AIDS 2015, 29:2447-2457

Objective To evaluate whether once daily (q.d.) lopinavir/ritonavir is noninferior to twice daily (b.i.d.) dosing in children.

Design International, multicentre, phase II/III, randomized, open-label, noninferiority trial (KONCERT/PENTA18/ANRS150).

Setting Clinical centres participating in the PENTA, HIV-NAT and PHPT networks.

Participants Children/adolescents with HIV-1 RNA viral load less than 50 copies/ml for at least 24 weeks on lopinavir/ritonavir-containing antiretroviral therapy.

Intervention Children were randomized to continue lopinavir/ritonavir b.i.d. or change to q.d.

Main outcome measure Confirmed viral load ≥50 copies/ml by 48 weeks (12% noninferiority margin).

Results One hundred seventy-three children were randomized in the KONCERT trial (86 q.d., 87 b.i.d.); 46% men, median (IQR) age 11 (9-14) years, CD4% 33 (27-38)%. By week 48, 97 and 98% of time was spent on q.d. and b.i.d., respectively (one q.d. child lost at week 4). Twelve q.d. vs. seven b.i.d. children had confirmed viral load ≥50 copies/ml within 48 weeks; estimated difference in percentage with viral load rebound 6% [90% CI (-2, 14)]. Numbers of children with grade 3/4 adverse events (11 vs. 7) or major resistance mutations (3 vs. 2) were similar, q.d. vs. b.i.d. (both P > 0.3). Among 26 children in an intrasubject lopinavir/ritonavir pharmacokinetic substudy, lower daily exposure (AUC0-24 161 h.mg/l vs. 224 h.mg/l) and lower Clast (1.03 mg/l vs. 5.69 mg/l) were observed with q.d. vs. b.i.d. dosing.

Conclusion Noninferiority for viral load suppression on q.d. vs. b.i.d. lopinavir/ritonavir was not demonstrated. Although results, therefore, do not support routine use of q.d. lopinavir/ritonavir, lack of safety concerns or resistance suggest that q.d. dosing remains an option in selected, adherent children, with close viral load monitoring.

Authors: Karina M. Butler on behalf of the BREATHER trial team

Published in: CROI 2015, Seattle, USA, Feb 23 -26 2015.

Abstract For HIV-1 infected young people (YP) facing lifelong ART, short cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity and better adherence, as well as cost savings.

Authors: Freguja R, De Rossi A, Paulson H, Klein N, Del Bianco P, Compagnucci A, Saidi Y, Giaquinto C, Harper L, Gibb D, on behalf of the PENTA Steering Committee

Published in: CROI 2015, Seattle, USA, Feb 23 -26 2015. Poster presentation abstract 919

Authors: Colbers A, Molto J, Ivanovic J, et al. PANNA Network

Published in: J Antimicrob Chemother. 2015; 70(2):534-542

Objectives To describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum.

Patients and Methods This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929.

Results Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported.

Conclusions Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy.

Authors: Harrison L, Melvin A, Fiscus S, et al; PENPACT-1 (PENTA 9PACTG 390) Study Team.

Authors: Colbers A, Hawkins D, HidalgoTenorio C, et al.

Published in: Antivir Ther. 2015; 20(1):57-64

Background We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir.

Methods This was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional.

Results 31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected.

Conclusions Despite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effectiveconcentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis

Authors: Colbers A,  Gingelmaier A, van der Ende M, Rijnders, B, Burger D.

Published in: AIDS 2014;28(2): 288-290

Authors: Bailey H, Townsend C, Semenenko I, Malyuta R, Cortina-Borja, Thorne C; for the Ukraine European Collaborative Study in EuroCoord

Published in: BMC Public Health. 2014; 24(14):993

Background Poor adherence to antiretroviral therapy (ART) is associated with HIV disease progression and, during

pregnancy, increased mother-to-child transmission risk. In Ukraine, access to combination ART is expanding but data

on adherence are scarce.

Methods Cross-sectional surveys of HIV-positive women were conducted i) at delivery (on antenatal ART adherence)

and ii) during the first year postpartum (on ART adherence in the preceding four weeks). Factors associated with a

score ≤11 on the self-report Case Adherence Support Evaluation (CASE) index or ≥1 self-reported missed dose were

assessed using Fisher’s exact test.

Results Of 185 antenatal participants and 102 postnatal participants, median ages were 27.5 and 29.5 years

respectively: 28% (50/180) and 27% (26/98) reported an unplanned pregnancy, and 13% (24/179) and 17% (17/98) an

illicit drug-use history (excluding marijuana). One quarter (49/180 antenatally, 27/101 postnatally) screened positive for

depression. The proportion reporting ‘low’ ART-related self-efficacy (i.e. unable to do ≥1/5 ART-taking activities) was

20% (28/141) antenatally and 17% (11/66) postnatally. Antenatally, 14% (95% CI 10-21%) had a CASE score ≤11 and

35% (95% CI 28-42%) reported missing ≥1 dose. Factors associated with a CASE score ≤11 were unplanned pregnancy

(25% (12/48) vs. 11% (13/120) where planned, p = 0.03) and living with extended family (23% (13/57) vs. 10% (12/125)

living with partner/alone, p = 0.04). Self-report of ≥1 missed dose antenatally was additionally associated with

younger age (p = 0.03) and lower self-efficacy (50% (14/28) reported ≥1 missed dose vs. 28% (30/108) of those

with high self-efficacy, p = 0.04). Of 102 postnatal participants, 8% (95% CI 4-15%) had a CASE score ≤11 and 31%

(95% CI 22-41%) reported ≥1 missed dose. Of 11 women with low self-efficacy, 3 (27%) had a CASE score ≤11

compared with 3/55 (5%) of those with high self-efficacy (p = 0.05). Current smokers more commonly reported ≥1

missed dose postnatally (50% (13/26) vs. 25% (18/72) of non-smokers, p = 0.03).

Conclusions Our results highlight unmet needs for counselling and support. We identify some groups at risk of

poor ART adherence, including women with markers of social vulnerability and those with low ART-related

self-efficacy, who may benefit from targeted interventions.

Authors:  Colbers A, Hawkins D, Hidalgo-Tenorio C, van der Ende M, Kabeya K, Gingelmaier A, Weizsäcker K, Lambert J, Rockstroh J, Burger D; on behalf of the PANNA network

Published: 23rd Conference on Retroviruses and Opportunistic Infections, March 3rd-6th 2014, Boston. P_892

Authors: Blonk M, Colbers A, Hidalgo-Tenorio C, Weizsäcker K, Moltó J, Hawkins D, van der Ende M, Gingelmaier A, Taylor G, Burger D; on behalf of the PANNA network

Published: 23rd Conference on Retroviruses and Opportunistic Infections, March 3rd-6th 2014, Boston. P_890

Authors: Colbers A, Moltó J, Ivanovic J, Hawkins D, Sadiq T, Kabeya K,  Gingelmaier A, Weizsäcker K, Taylor G, Burger D; on behalf of the PANNA network

Published: 23rd Conference on Retroviruses and Opportunistic Infections, March 3rd-6th 2014, Boston. P_887