EPIICAL

30

Mar, 2019

Time to viral suppression in perinatally HIV-infected infants depends on the state of HIV disease progression at start of ART

 

Authors: Schröter J.

Published: Oral presentation at 26th International HIV Dynamics & Evolution, March 24th-27th, 2019, Cascais, PT

26

Mar, 2019

Nucleoside reverse transcriptase inhibitor backbones and pregnancy outcomes

 

Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group

Published in: Aids. 2019;33(2):295-304.

Objectives The aim of this study was to investigate whether specific nucleoside reverse transcriptase inhibitor (NRTI) backbones are associated with risk of adverse pregnancy outcomes among pregnant women starting antiretroviral therapy (ART).

Design Seven observational studies across eight European countries of pregnancies in HIV-positive women.

Methods Individual-level data were pooled on singleton pregnancies conceived off-ART in which a single combination ART regimen was initiated at least 2 weeks before delivery, and ending in a live birth in 2008-2014. Preterm delivery (PTD) was defined as less than 37 gestational weeks and small-for-gestational-age (SGA) as less than 10th percentile according to INTERGROWTH standards. Poisson regression models were fitted to investigate associations between NRTI backbones and PTD/SGA.

Results Out of 7193 pregnancies, 45% (3207) were in UK/Ireland, 44% (3134) in Ukraine. 10% (722/7193) of deliveries were preterm and 11.1% (785/7089) of newborns SGA. The most common NRTI backbones were zidovudine (ZDV)-lamivudine (3TC) (71%), tenofovir (TDF)-XTC (16%) and abacavir (ABC)-3TC (10%) with TDF-containing backbone use increasing over time. Overall, 77% of regimens contained ritonavir-boosted lopinavir (LPV/r). There was no association between NRTI backbone and PTD in main adjusted analyses [adjusted prevalence ratios (aPRs) 0.97 (95% confidence interval, 95% CI 0.73-1.28] for ABC-3TC and aPR 1.06 (95% CI 0.83-1.35) for TDF-XTC, both vs. ZDV-3TC) or in 4720 pregnancies on LPV/r [aPR 1.03 (95% CI 0.74-1.43) for ABC-3TC and aPR 1.16 [0.85-1.57] for TDF-XTC, both vs. ZDV-3TC]. Infants exposed to ABC-3TC or TDF-XTC in utero were less likely to be SGA than those exposed to ZDV-3TC [aPR 0.72 (95% CI 0.53-0.97) and aPR 0.70 (95% CI 0.53-0.93), respectively].

Conclusion Results support the safety of TDF-XTC backbones initiated in pregnancy with respect to gestation length and birthweight.

26

Mar, 2019

Birth Defects After Exposure to Efavirenz-Based Antiretroviral Therapy at Conception/First Trimester of Pregnancy A Multicohort Analysis

 

Authors: Martinez de Tejada B; European Pregnancy and Paediatric HIV Cohort Collaboration Study Group.

Published in: J Acquir Immune Defic Syndr. 2019;80(3):316-324

 

Background To investigate the association between efavirenz (EFV) use during conception or first trimester (T1) of pregnancy and the occurrence of birth defects.

Setting Seven observational studies of pregnant HIV-positive women across 13 European countries and Thailand.

Methods Individual-level data were pooled on singleton pregnancies included in participating cohorts in 2002-2015. Birth defects were coded according to ICD-10 and the EUROCAT classification. We performed mixed-effects logistic regression models to assess the association between EFV exposure in utero and likelihood of birth defects.

Results We included 24,963 live births from 21,093 women. At conception, 30.2% (7537) women were on a non-EFV-based regimen, 4.8% (1200) on EFV, and 65% (16,226) were unexposed to antiretroviral therapy (ART). There were 412 infants with ≥1 birth defect, a prevalence of 1.65% (95% confidence interval: 1.50 to 1.82). Limb/musculoskeletal and congenital heart defects were the most common defects reported. Birth defects were present in 2.4%, 1.6%, and 1.3% of infants exposed to non-EFV, EFV, and unexposed to ART during conception/T1 (P = 0.135), respectively. The association between exposure to ART during conception/T1 and birth defects remained nonsignificant in adjusted analyses, as did exposure to EFV versus non-EFV (adjusted odds ratio 0.61; 95% confidence interval: 0.36 to 1.03, P = 0.067). Among the 21 birth defects in 19 infants on EFV, no neural tube defects were reported.

Conclusions Prevalence of birth defects after exposure to EFV-based compared with non-EFV-based ART in conception/T1 was not statistically different in this multicohort study, and even lower. EFV is at least as safe as other ART drugs currently recommended for antenatal use.

25

Mar, 2019

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

 

Authors: Chan MK, Goodall R, Judd A, et al.

Published in: Aids. 2019; 33(7):1155-1165

Objective To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy.

Design Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC).

Methods Infants with perinatal HIV starting cART aged <6 months with ≥1 viral load (VL) measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last VL≥400 and first VL<400copies/ml.

Results Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% UK/Ireland, 15% Eastern Europe and 3% Thailand; 46% and 54% started a boosted protease inhibitor- or non-nucleoside reverse transcriptase inhibitor- based regimen, respectively. At cART initiation, the median age, CD4% and VL were 2.9 (IQR:1.4-4.1) months, 34 (IQR:24-45)% and 5.5 (IQR:4.5-6.0) log10copies/ml, respectively. Overall, an estimated 89% (95%CI:86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age (aHR:0.84 per month older; P < 0.001), higher CD4% (aHR:1.11 per 10% higher; P = 0.010) and lower log10 VL (aHR:0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression.

Conclusion We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long term health.

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21

Mar, 2019

c4c Call for tender – Business school

 

The c4c consortium has issued a call for tender for subcontracting a specialised business school or company that can assist in the development of a sustainable business model for a pan-European paediatric clinical trials network. An important element of c4c is the push for a well-functioning business model and long-term sustainability, making sure that the network will continue to assume its pivotal function in a this way. External support will be crucial to complement the specific skills and expertise of the leading partners, in particular regarding more broadly the options for business concept development, a more extensive understanding of the markets, sector specific legal and organisation management competences related to the not for profit Public-Private sector across Europe.

To carry out the above-mentioned tasks, the c4c Consortium needs to involve an external organisation with the right expertise in the field of business concept / management / economics / sustainable financing. Expertise doing similar activities in the field of management / health systems / public private collaboration will be taken into consideration in the evaluation process.

The contract duration is set at 5 years, and the deadline for application is April 5th 2019, at 12pm CET.

If you are interested please read the full call text.

18

Mar, 2019

The Global Health Festival, Padova, 5th-7th April

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The first edition of the Global Health Festival (‘Festival della Salute Globale’) is to take place in Padova, Italy on 5th-7thApril 2019. In partnership with Comune di Padova, Università degli Studi di Padova and Medici con l’Africa CUAMM, the event will take an unconventional look at the fundamental issues concerning global health today. Through an interactive programme, the public is invited to consider the broader social, environmental, economic and cultural conditions when evaluating the health of an individual or community. The festival encourages us to look beyond our immediate surroundings when it comes to health. In a world which is increasingly interconnected and ‘small’, looking after the health of those who are farther away means treating and preventing the diseases of those around us.

Presenting the programme, the scientific director of the festival, Walter Ricciardi,underlined: “We want to shed light on the relationship between diseases, wars, poverty, the environment, rights. We want to illustrate the interconnections between the third Sustainable Development Goal – regarding health – and others, starting from the fight against poverty and hunger, education, women’s empowerment, the right to clean water, right up to the promotion of peaceful and inclusive societies. What we want is a Festival which is also an opportunity for ‘intelligence’, because the traditional methods for dealing with epidemic emergencies are no longer sufficient. We need virologists, infectious disease specialists, epidemiologists and public health experts to work together.”

A whole host of international experts have been invited to attend in April. The festival will be opened Jeffrey Sachs, economist at Colombia University, nominated by Time magazine as one of 100 people that have changed the world. Children will also play a key role in the proceedings, with the forum between Carlo Giaquinto, Giorgio Perilongo and Giuseppe Remuzzi. Don Dante Carraro from CUAMM will participate on the topic: “That which remains unspoken – Stories of trust and the future from Italy to Africa”. Meanwhile, Alessandra Biffi of the paediatric Onocology-Haematology clinic in Padova and Antonella Viola, scientific director of the paediatric research institute Città della Speranzawill speak on the potential and problems associated with new treatments.

Other notable guests include:

  • Michel Kazatchkine, Professor of Medicine at Université René Descartes, Paris, Special Adviser to the Joint United Nations Program on HIV / AIDS (UNAIDS) for Eastern Europe and Central Asia,
  • Mario Raviglione, Director of the Global Tuberculosis Programme at the World Health Organization,
  • Suerie Moon, Adjuct Lecturer at the Harvard Global Health Institute,
  • Mark Dybul, Co-Director of the Global Fund to Fight AIDS, Tuberculosis and Malaria,
  • Rino Rappuoli, Chief Scientist & Head of External R&D at GSK Vaccines
  • Santino Severino, Coordinator of Public Health and Migration at the WHO Regional Office for Europe
  • Richard Horton, Editor-in-chief of The Lancet

The full programme will be made available soon on the website: www.festivalsaluteglobale.it

15

Mar, 2019

CROI 2019: Oral presentation by members of the EPIICAL team

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The annual Conference on Retroviruses and Opportunistic Infections (CROI) was held on 4-7 March 2019, at the Washington State Convention Center in Seattle, Washington. CROI brings together top basic, translational, and clinical researchers from around the world to share the latest studies, important developments, and best research methods in the ongoing battle against HIV/AIDS and related infectious diseases.

At this year’s event, EPIICAL team member Sara Dominguez Rodriguez delivered the following oral presentation:

NEONATAL ART < 7 DAYS VS 7-28 DAYS REDUCED TIME TO SUPPRESSION

Alfredo Tagarro, Sara Dominguez Rodriguez, Thanyawee Puthanakit, Paolo Palma, Caroline Foster, Thidarat Jupimai, Nicola Cotugno, Jintanat Ananworanich, Santiago Jimenez de Ory, Paola Zangari, Maria Luisa Navarro, Paolo Rossi, Eleni Nastouli, Carlo Giaquinto, Pablo Rojo Conejo

This important study illustrated recent results that provide further evidence that supports the earliest antiretroviral therapy initiation in infants. Early antiretroviral therapy (ART) in children is associated with better clinical and virological outcome. The hypothesis explored is that HIV-perinatally infected neonates initiating ART within <7 days of life have a better long-term clinical and virological response than neonates treated ≥7 days and ≤28 days of life.

You can find the full webcast of the presentation here.

14

Mar, 2019

ODYSSEY poster presentation at CROI 2019

 

We are pleased to announce that ODYSSEY project team members Pauline Bollen and Anna Turkova successfully presented a poster with the results of an important pharmacokinetic sub-study on the use of adult Dolutegravir 50mg tablets in children living with HIV and weighing 20-25kg. The poster session took place at the recent Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, and was also attended by the ODYSSEY ERC members Hermione Lyall and Alasdair Bamford. The poster generated a significant amount of interest at the congress, suggesting that adult doses of an antiviral drug could offer a practical and accessible option for children in that weight band living with HIV.

Dolutegravir (DTG) is an antiviral drug, which has been shown to be effective and safe as part of once-daily treatment for adults with HIV at a daily dose of 50mg. Smaller dose tablets have been developed for children (e.g. 25mg) but are not widely available in Africa. ODYSSEY is a large ongoing global trial evaluating dolutegravir-based treatment in 700 children, mostly from Africa. In a previous pharmacokinetic sub-study, we showed that the adult dose (50mg) provides appropriate drug blood levels for children weighing over 25kg; this practical dosing has been included in the World Health Organization (WHO) dosing guidelines.

The current presentation focuses on children in the 20-25kg weight bracket, around one in four of all children living with HIV worldwide. This sub-study compared the standard 25mg film-coated tablet with a higher-dose film-coated tablet (50mg), and 30mg of dispersible tablets (which provide the same levels of drug in the blood as the 50mg film-coated tablet).

The study showed that the 50mg film-coated and 30mg of dispersible tablets gave very similar and appropriate drug levels of dolutegravir in the blood and were better than the 25mg film-coated tablet. The short-term safety data in the sub-study was also reassuring.

The sub-study concluded that either the 50mg film-coated tablet or 30mg (six 5-milligram) dispersible tablets should be used in children weighing 20-25kg. This conclusion has already been incorporated into the updated tables of antiretroviral drugs produced by WHO, and means that treatment for children heavier than 20kg can be the same as for adults.

7

Mar, 2019

EMA publication – “From laboratory to patient: the journey of a centrally authorised medicine”

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The European Medicines Agency (EMA) has recently published a booklet covering the process undertaken for medicines for human use and which are authorised through the EU centralised procedure. With a user-friendly layout, it communicates the steps that are taken from the initial research stages of a new medicine to when it is eventually marketed to the public.

The convenient and accessible manual explains how the EMA provides scientific advice to support the timely and sound development of high-quality, effective and safe medicines, for the benefit of patients. Medicine regulators have unique knowledge and experience of how medicines should be developed, and are able to provide specific scientific advice where existing general guidelines only address general situations. Scientific advice is all about advising medicine developers on the most appropriate way to generate robust evidence on a medicine’s benefits and risks. The advice provided builds on existing scientific guidelines but, more importantly, is tailored to the specific medicine and the group of patients in need of care.

Patients are often involved in scientific advice. They are invited to share their real-life perspective and experience in relation to a particular medicine in their disease area. This can help medicine developers and regulators better understand what will work for that patient group and what they consider important.

Moreover, discounts in application fees have been made available to certain groups. There is a 75% fee reduction for medicines for rare diseases (a.k.a. ‘orphan medicines’), whereas SMEs are entitled to a 90% fee reduction.

Questions during scientific advice can relate to quality aspects, methodological issues, clinical aspects and non-clinical aspects. Some of the questions to be addressed may include:

• Are the patients to be included in a study sufficiently representative of the population for whom the medicine is intended?
• Does the study last long enough and include enough patients to provide the necessary data for the benefit-risk assessment?
• Is the medicine being compared with an appropriate alternative?
• Are the plans to follow the long-term safety of the product appropriately designed?


Read the booklet in full here for more information.

4

Mar, 2019

GARDP and Penta partner to accelerate the development of children’s antibiotics to tackle AMR

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Penta have joined forces with GARDP (The Global Antibiotic Research & Development Partnership) to tackle drug-resistant infections in children. Our strategic collaboration aims to accelerate paediatric development of antibiotic treatments including: clinical trials designed to meet regulatory requirements; and trials with a focus on public health interventions to inform treatment guidelines.

Globally, more than three million childhood deaths result from infectious diseases, such as pneumonia and sepsis. Children are also particularly affected by antimicrobial resistance (AMR). In Europe, a recent study found that infants under one-year-old bear the highest burden of drug-resistant infections, with a major impact on health, economy and society. The impact is expected to be even more severe in many low and middle-income countries.

“Ending unnecessary childhood deaths is a global health priority” said Dr Manica Balasegaram, Executive Director, GARDP. “Yet, severe lack of evidence is preventing the development of child-appropriate antibiotics for the treatment of drug-resistant infections. In response to this urgent global public health need, GARDP and Penta have embarked on a joint mission to develop and deliver accessible antibiotic treatments to tackle serious bacterial infections in children.”

Tackling AMR and its effects on children is critical to the attainment of the Sustainable Development Goals (SDGs), in particular the children’s health targets under SDG 3, which aims to ensure healthy lives and promote wellbeing for all. Prioritising the development of child-friendly antibiotics is an essential component of this.

Children, particularly babies and infants, need medicines that are adapted to their specific needs. Scarce evidence means child-friendly antibiotic treatment options are often limited, with paediatric evaluation of antibiotics only happening years after treatments are registered for use in adults.

GARDP and Penta’s partnership consolidates plans to help overcome this gap through the development of a global children’s antibiotic platform. Building on Penta’s international network of clinical trial sites and paediatric experts, the platform objectives include to: develop streamlined paediatric development plans acceptable to regulatory authorities; accelerate regulatory approval of treatments by ensuring children’s trials are started as early as possible; and incorporate innovative designs to maximise the information that can be gained from each trial.

Clinical trials in children involve highly complex ethical, regulatory and study-design issuessaid Carlo Giaquinto. “This partnership consolidates existing efforts between GARDP and Penta, allowing us to maximise our expertise in the fields of paediatric treatments and AMR, including Penta’s strong partnership with the Medical Research Council’s Clinical Trial Unit in London. 

“The knowledge created can help public health and industry partners to efficiently design and conduct their paediatric plans. This will speed-up access to antibiotics and facilitate the dissemination and routine implementation of global treatment guidelines”.

GARDP and Penta have established strong relationships with academic and/or government institutions from across Asia, Africa, Europe and South America. Partnerships with countries including Kenya, Greece, India, South Africa and Thailand underpin recent GARDP and Penta collaborations. These include apharmacokinetic clinical trial in Kenya, to assess safety and dosing of the antibiotic fosfomycin in new-borns, which recently completed enrolment; and a large-scale global observational study on neonatal sepsis, collecting clinical information in up to 3,000 new-borns in 19 hospitals in 11 countries.

Such engagement from countries worldwide, will be critical to the success of the platform and its trial networks.

Country partnerships are critical for the children’s antibiotic platform to flourish and reach its full potential” concluded Dr Balasegaram. “GARDP and Penta call on governments worldwide, as well as academics, donors, maternal child health organizations, public institutions, the private sector, scientists and more, anyone with an interest in overcoming AMR in children – to join us.”

A briefing note with further background on the need for children’s antibiotics and the partnership is available here.

 

About GARDP

GARDP is a not-for-profit R&D organization that addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavouring to ensure their sustainable access. Initiated by the WHO and the Drugs for Neglected Disease initiative (DNDi), GARDP is an important element of WHO’s Global Action Plan on Antimicrobial Resistance that calls for new public-private partnerships to encourage R&D of new antimicrobial agents and diagnostics. GARDP’s programmes on sexually-transmitted infections, neonatal sepsis, paediatric antibiotics and antimicrobial memory recovery, evaluation and exploratory research are designed to address global public health priorities. Projects include the sponsoring of a phase III clinical trial for a novel, first-in-class oral antibiotic to treat drug-resistant gonorrhoea.

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