New antiretrovirals for infants and children still needed

Carole Leach-Lemens
Published: 25 July 2012
Celia Christie-Samuels and Bernard Pécoul, co-chairs of the Catching children before they fall satellite session.

Promising new formulations of antiretroviral agents including tenofovir, fosamprevanir, dolutegravir, etravirine and raltegravir for treating the often neglected needs of infants, children and adolescents with HIV were presented today in an oral abstract session at the 19th International AIDS Conference (AIDS 2012) in Washington DC.

Improving the range of antiretroviral formulations available for the treatment of infants and children in low- and middle-income settings has been an important theme of the conference, with several satellite meetings and a major scientific session devoted to the subject.

Jaydeep Gogtay of Cipla, in a joint Drugs for Neglected Disease initiative (DNDi) and IAS-ILF satellite session on Sunday, presented plans to develop a four-in-one paediatric antiretroviral drug combination for HIV-infected children under three years of age, including those infected in the womb as well as those co-infected with TB.

Using data from the CHAPAS-2 trial, DNDi and Cipla plan to produce an optimised first-line therapy in a fixed-dose combination of Lopimune (lopinavir/ritonavir, 40/10mg) sprinkles, combined with two alternative nucleoside reverse transcriptase inhibitor combinations, abacavir/lamivudine (3TC) or zidovudine/lamivudine (AZT/3TC). Registration is anticipated by 2015.

Nevertheless, a critical need for dosing for pre-term babies persists, stressed Lynn Mofenson of the US National Institutes of Health, a co-moderator at the satellite.

A number of speakers highlighted concerns that treatment for children, and especially the development of new antiretroviral formulations, risk being neglected as governments focus on the target of achieving an AIDS-free generation through improvements in prevention of mother-to-child transmission.

Of the estimated 3.4 million children living with HIV, 95% live in sub-Saharan Africa. Fewer than 25% of children have access to treatment, compared to 54% of adults worldwide. Without treatment, 50% of children will die before their second birthday. Effective care and treatment in resource-rich settings has virtually eliminated vertical transmission.

Approval of a new formulation for paediatric use can take an average of 6.5 years after approval for use in adults. Even when drugs are approved for children, the youngest children will have to wait the longest because investigations for appropriate paediatric formulations are done according to de-escalated age bands, with infants and newborns the last to benefit.

See this related article for further information on dolutegravir, raltegravir and etravirine.

New formulations for infants and children

Tenofovir

A single dose of 600mg of tenofovir disproxil fumurate (TDF) given to a pregnant HIV-infected women during labour, followed by a daily dose of 6mg/kg to her newborn, is an effective and simple regimen offering an important alternative to nevirapine for prevention of mother-to-child transmission, Dr Karin Nielsen-Saines reported on behalf of the HPTN 057 study group.

HPTN 057 is a phase 1 trial looking at the pharmacokinetics (PK) of TDF dosing in pregnant HIV-infected women during labour, and in their newborns, in Malawi and Brazil.Limited information exists on the pharmacokinetics of TDF in this population.

TDF was approved for adults in 2001 and is a preferred nucleoside reverse transcriptase inhibitor (NRTI) in international guidelines.

A regimen of 600mg of tenofovir was given to the woman at the start of labour or four hours before a caesarean section, with daily doses of 6mg/kg TDF suspension given to the newborn for seven days.

The PK goal was achieved: to keep infant tenofovir concentration throughout the first week above 50ng/mL (the same as the mean trough TDF concentration in non-pregnant adults).

Among the 33 mother-infant pairs (16 in Malawi and 17 in Brazil), median delivery was 4.5 hours (0.6-11.4 hours) after dosing. 

Dr Nielsen-Saines noted that, while there was no advantage to giving a higher dose (900 mg), timing of the dose was critical.

The mean maternal TDF concentration at delivery was 108ng/mL. Mean cord-blood TDF concentration was 61 ng/mL with 77% (24/31) over 50ng/mL.

Dr Nielsen-Saines stressed that it was important to give the newborn the first dose as soon as possible after delivery since the maternal dose may not always cross over into the placenta.

Post-dose concentration in infants was over 50ng/mL in 90.3% (28/31), 96.4% (27/28) and 73.3% (22/30) 24 hours after the first, fourth and seventh doses, respectively. All infant TDF concentration was over 30ng/mL.

This dosing was well tolerated in all women and their newborns. There were no severe or life-threatening events or deaths.

Fosamprenavir

A number of protease inhibitors are approved for use in children. In the US, six are available in a liquid formulation, with three approved for use in children under three. In resource-poor settings, the options are much more limited.

Fosamprenavir (Telzir, Levixa) is a protease inhibitor developed by Glaxo SmithKline and now marketed by Viiv Healthcare. It is less widely used than other protease inhibitors in adults.

Dr Jorg Sievers, on behalf of the  APV20002 study, reported data from a phase II safety and efficacy study of a paediatric formulation of fosamprenavir combined with ritonavir.

This prospective open-label, multi-centre, 48-week cohort study looked at the PK, safety and antiviral activity of fosamprenavir and ritonavir in two cohorts of HIV-infected children, both protease-inhibitor naive and experienced, aged from six months to under two years (cohort 1) and from four weeks to under six months (cohort 2). The majority of infants and children in this study were located in Mexico and South Africa.

Out of a total of 59 infants, 78% were exposed to fosamprenavir for over 48 weeks. In total, 64% and 58% in cohorts 1 and 2, respectively, achieved undetectable viral load at 48 weeks. Nine infants had virological failure.

Of the twenty-two who experienced serious adverse events, three were considered drug-related and three died after these events.

Dr Sievers concluded that fosamprenavir/ritonavir dosing regimens in cohort 1 resulted in plasma APV exposure comparable to that achieved in adult approved regimens. While the minimal APV exposure was lower in cohort 2, the clinical outcomes were nonetheless comparable.

Overall safety, he added, was similar to that seen in older children and adults.

This combination provides another option for treatment with a PI for children in the US. The US Food and Drug Administration (FDA) has approved its use in children from four weeks of age.

References

Nielsen-Saines K et al. Tenofovir disoproxil fumarate (TDF pharmacokinetics (PK) with daily dosing in the first week of life (HPTN 057) 19th International AIDS Conference, abstract TUAB0201, Washington DC, July 2012.

View the abstract on the conference website.

View the webcast of the session on the conference website.

Cotton M et al. Pharmacokinetics, safety and antiviral activity of fosamprenavir/ritonavir-containing regimens in HIV-positive four weeks to < two year old children (48-week data, study APV20002, a prospective open-label, multi-centre, 48-week cohort study) 19th International AIDS Conference, Washington DC, abstract TUAB0202, July 2012.

View the abstract on the conference website.

View the webcast of the session on the conference website.

IAS-ILF and DNDi, Catching children before they fall: addressing the urgent drug development needs of children living with HIV Satellite session, 19th International AIDS Conference, Washington, DC, July 2012.

DNDi and Cipla, DNDi and Cipla to develop 4-in-1 pediatric antiretroviral drug combination, press release, Washington, DC; Geneva; Mumbai, July 20, 2012. View the press release about the new formulation onthe DNDi website.

In partnership with UNICEF