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AIDS 2012: New Antiretrovirals Formulations for Children Are Promising, More Still Needed

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Promising new formulations of antiretroviral agents including tenofovir and fosamprevanir for treating the often neglected needs of infants and children with HIV were presented in an oral abstract session at the recent XIX International AIDS Conference (AIDS 2012) in Washington, DC. Related presentations covered new treatments for HIV positive adolescents.

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

Jaydeep Gogtay from Indian generic drug manufacturer Cipla, in a joint Drugs for Neglected Disease initiative (DNDi) and International AIDS Society-Industry Liaison Forum satellite session on Sunday, July 22, presented plans to develop a 4-in-1 pediatric antiretroviral drug combination for HIV-infected children under 3 years of age, including those infected in the womb as well as those coinfected with tuberculosis.

Using data from the CHAPAS-2 trial, DNDi and Cipla plan to produce an optimized first-line therapy in a fixed-dose combination of Lopimune (lopinavir/ritonavir, 40/10 mg) sprinkles, combined with 2 alternative nucleoside reverse transcriptase inhibitor (NRTI) combinations, abacavir/lamivudine (abacavir/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 U.S. National Institutes of Health, a co-moderator at the satellite session.

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 pediatric 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 pediatric formulations are done according to de-escalated age bands, with infants and newborns the last to benefit.

Tenofovir

A single dose of 600 mg of tenofovir disproxil fumurate (brand name Viread) given to a pregnant HIV-infected women during labor, followed by a daily dose of 6 mg/kg to her newborn, is an effective and simple regimen offering an important alternative to nevirapine (Viramune) for prevention of mother-to-child transmission, 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 tenofovir dosing in pregnant HIV-infected women during labor, and in their newborns, in Malawi and Brazil. Limited information exists on the pharmacokinetics of tenofovir in this population.

Tenofovir was approved for adults in 2001 and is a preferred nucleoside/nucleotide reverse transcriptase inhibitor in international guidelines.

A regimen of 600 mg tenofovir was given to the woman at the start of labor or 4 hours before a caesarean section, with daily doses of 6 mg/kg tenofovir suspension given to the newborn for 7 days.

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

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

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

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

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 tenofovir concentration in infants was over 50 ng/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 tenofovir concentrations were over 30 ng/mL.

This dosing regimen was well tolerated by 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 U.S., 6 are available in a liquid formulation, with 3 approved for use in children under age 3. In resource-poor settings, the options are much more limited.

Fosamprenavir (brand name Lexiva or Telzir), a pro-drug of amprenavir (Agenerase, now discontinued) is a protease inhibitor developed by GlaxoSmithKline and now marketed by ViiV Healthcare. It is less widely used than other protease inhibitors in adults.

Jorg Sievers, on behalf of the APV20002 study team, reported data from a Phase 2 safety and efficacy study of a pediatric formulation of fosamprenavir combined with ritonavir.

This prospective open-label, multi-center, 48-week cohort study looked at the PK, safety, and antiviral activity of fosamprenavir and ritonavir in 2 cohorts of HIV-infected children, both protease-inhibitor naive and experienced, aged from 6 months to under 2 years (cohort 1) and from 4 weeks to under 6 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% of children in cohorts 1 and 2, respectively, achieved undetectable viral load at 48 weeks. Nine infants had virological failure.

Of the 22 infants who experienced serious adverse events, 3 events were considered drug-related and 3 children died after these events.

Sievers concluded that fosamprenavir/ritonavir dosing regimens in cohort 1 resulted in plasma amprenavir exposure comparable to that achieved in adult approved regimens. While the minimal amprenavir exposure was lower in cohort 2, 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 protease inhibitor for children in the U.S. The U.S. Food and Drug Administration (FDA) has approved its use in children from 4 weeks of age.

8/14/12

References

K Nielsen-Saines, M Mirochnick, N Kumwenda, et al. Tenofovir disoproxil fumarate (TDF pharmacokinetics (PK) with daily dosing in the first week of life (HPTN 057). XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract TUAB0201.

M Cotton, H Cassim, N Pavia-Ruz, 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) XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract TUAB0202.

Other Sources

IAS-ILF and DNDi. Catching children before they fall: addressing the urgent drug development needs of children living with HIV. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Satellite session.

DNDi and Cipla. DNDi and Cipla to develop 4-in-1 pediatric antiretroviral drug combination. Press release. July 20, 2012.