First-line NNRTI and Protease Inhibitor Regimens Work Equally Well for Children with HIV

	SUMMARY: Initial antiretroviral therapy (ART) regimens containing protease inhibitors and those with non-nucleoside reverse transcriptase inhibitors (NNRTIs) both produced good outcomes for children with HIV, according to research published in the February 1, 2011 advance online edition of Lancet Infectious Diseases. Viral load dropped by a similar amount, but children who started on NNRTIs and those who waited longer to switch were more likely to develop drug resistance.

By Liz Highleyman

Children infected with HIV at or soon after birth face the prospect of a lifetime of antiretroviral treatment, underlining the importance of assessing drug durability and outcomes over a long follow-up period.

Investigators with the PENPACT-1 Study Team -- comprised of investigators with the Paediatric European Network for Treatment of AIDS (PENTA) and the Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT) in the U.S. -- assessed long-term outcomes of first-line ART regimens containing either protease inhibitors or NNRTIs. They also looked at viral load criteria for switching to second-line regimens for children.

This open-label trial included 266 HIV-infected children (median age 6.5 years) enrolled in Europe and North and South America between September 2002 and September 2005.

Participants were randomly assigned to receive either a protease inhibitor or NNRTI, in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). In addition, they were assigned to switch to a second-line regimen when their viral load rose to either 1000 or 30,000 copies mL. This design resulted in 4 arms: PI-low (n = 66), PI-high (n = 65), NNRTI-low (n = 68), and NNRTI-high (n = 67). Follow-up continued for a median of 5 years.

Results

	188 children (71%) were still on their first-line ART regimen at the end of the study.
	60 children switched to a second-line regimen during follow-up:
	28 receiving protease inhibitors; 32 receiving NNRTIs; 37 switching at the 1000 copies/mL threshold; 23 switching at the 30,000 copies/mL threshold.
	At 4 years, average reductions in HIV viral load were 3.16 log copies/mL for protease inhibitor recipients vs 3.31 log copies/mL for NNRTI recipients, not a significant difference (P = 0.26).
	HIV RNA reductions were 3.26 log copies/mL for those who switched at the 1000 copies/mL threshold vs 3.20 log/copies/mL for those who switched at the 30,000 copies/mL level, again not significantly different (P = 0.56).
	Protease inhibitor resistance was uncommon, and there was no increase in NRTI resistance in the high vs low switch threshold group.
	NNRTI resistance emerged early, and about 10% more children developed NRTI resistance mutations in the high compared with low switch threshold group.
	9 children developed new CDC stage C or AIDS-defining conditions.
	60 children experienced grade 3/4 (severe or life-threatening) adverse events, which occurred with similar frequency in all arms.

"Good long-term outcomes were achieved with all treatments strategies," the investigators concluded. "Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low."

In an accompanying editorial, Catherine Sutcliffe and William Moss from Johns Hopkins University said these findings supports the current recommendation to start treatment with a NNRTI and switch to more a durable protease inhibitor later, but such a change should be made without delay when viral load starts to rise, in order to prevent resistance.

2/18/11

References

A Babiker and others, PENPACT-1 Study Team. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infectious Diseases (abstract). February 1, 2011 (Epub ahead of print).

C Sutcliffe and W Moss. ART for children: what to start and when to switch (Editorial). Lancet Infectious Diseases. February 1, 2011 (Epub ahead of print).