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PENPACT-1 trial results published in The Lancet Infectious Diseases

01 February 2011

The PENPACT-1 study reveals effective anti-HIV drugs for starting treatment in children with HIV, and shows that delaying switching to second-line drugs does not affect long-term benefit.

Children with HIV will need anti-HIV medicines for longer than adults, so questions about which anti-HIV drugs to start with and when to switch to different drugs if the virus levels start to increase need to be answered. According to the results of the PENPACT-1 trial, published Online First in The Lancet Infectious Diseases, two types of drugs—protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs)—are equally effective as part of initial (first-line) treatment for HIV-infected children, and delaying the switch to second-line drugs when the viral load starts to increase does not affect long-term viral load outcomes.*

The findings of this first long-term (average follow-up of 5 years) study to assess which first-line ART to give HIV-infected children and when to switch to second-line ART, will be particularly important for low-income countries where most children with HIV live, and where the availability of second-line ART and laboratories to monitor treatment (using viral load) are limited.

The PENPACT-1 study was designed to compare the long-term effectiveness of first-line PI-based ART with NNRTI-based ART and to determine when to switch to second-line ART. 266 children from 68 clinics across 13 countries were randomly assigned to begin treatment with two nucleoside reverse transcriptase inhibitor drugs (NRTIs) plus one of four options: a PI and then switch to second-line ART when viral load increased to 1000 copies per mL (66 children); a PI and then delay switching until viral load reached 30 000 copies per mL (65); an NNRTI and switch at 1000 copies per mL (68); or an NNRTI and switch at 30 000 copies per mL (67).

After 4 years of treatment, the proportion of children with viral load less than 400 copies per mL was similar between PI and NNRTI-based ART. Additionally, there was no difference in 4-year viral load between the early (1000 copies per mL) and delayed (30 000 copies per mL) switch groups, and the level of drug resistance to PIs and NNRTIs was similar in these groups. However, over 5 years children starting with NNRTI-based treatment compared to those on PI-based treatment were more likely to develop resistance to NRTIs if switching treatment was delayed until viral load levels reached 30 000 copies per mL.

The authors point out that regular treatment monitoring using viral load is unlikely to prevent the development of NNRTI resistance because it happens very soon after the viral load rises. But continuing on an NNRTI-based regimen which is not suppressing viral load increases the risk that resistance to the NRTI drugs will occur, thus compromising their future use.

Most children responded well, whether starting PI or NNRTI-based first-line ART—71% were still taking their first-line ART at the end of the study and second-line ART failed in only 7%. The number of children experiencing side-effects did not differ between the treatment groups.

The authors, who included Professor Diana Gibb and Linda Harrison from the Medical Research Council Clinical Trials Unit and Dr. Gareth Tudor-Williams from Imperial College London, conclude:

"Little difference exists between PI and NNRTI containing initial anti-HIV treatment for children; both result in good long-term viral load outcomes…For children on PI-based treatment, the lack of a difference in the NRTI and PI resistance, suggests that delayed switching might be reasonable in circumstances and settings where future drug options are limited."

* Viral load measures the amount of HIV in the blood. Reducing viral load to a low level, (under 400 copies per mL), shows that antiretroviral therapy (ART) is working. ART typically refers to three anti-HIV drugs given together—either a PI or an NNRTI, together with two nucleoside reverse transcriptase inhibitor drugs (NRTIs)). If the viral load starts to increase, there is a risk that the virus might become resistant to the drugs and stop working so well.

The study was published in The Lancet Infectious Diseases on the 1st February 2011.

The PENPACT-1 trial was sponsored jointly by the Paediatric European Network for Treatment of AIDS (PENTA) Foundation, Agènce Nationale de Recherche sur le Sida et les hepatites virales (ANRS) and the Pediatric AIDS Clinical Trials Group (PACTG), subsequently the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT). Centres in the UK received financial support from the Medical Research Council (MRC) and sites in the UK, Germany, Brazil, Austria, Ireland, Italy and the Bahamas were co-ordinated by the MRC Clinical Trials Unit.