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Virologic Failure in 40% of Perinatally Infected US
Children--Regimen Switching Slow
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20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
Combination antiretroviral therapy (cART) failed at least once in a 2374-child analysis of perinatally infected US youngsters in two cohorts [1]. Three quarters of children stayed on their failing regimen for 12 months, a lapse that could encourage further emergence of resistance mutations. Since peaking in 2001, however, failure prevalence fell to low levels in recent years.
Antiretroviral adherence remains a huge challenge in HIV-positive adolescents. Among children infected perinatally, poor adherence typically peaks in the early teen years. In the United States and other Western countries, antiretroviral access dating to the late 1980s means many children infected in those years began treatment with one or two antiretrovirals. As a result, these children often have a pre-cART failure history and an array of archived resistance mutations that complicates current cART planning.
To get a better understanding of trends in virologic failure among children and adolescents, researchers analyzed data from all perinatally infected US children enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials 219C study and the Pediatric HIV/AIDS Cohort Study between 1993 and 2012. They defined virologic failure as two consecutive viral loads above 1000 copies at least 1 month apart and 6 months after starting cART. They defined cART as a combination of at least three antiretrovirals from at least two antiretroviral classes. Baseline date was the date when cART began.
The analysis involved 2747 children in the two cohorts, 2433 of whom (89%) ever received cART and 2374 of whom (86%) received cART for at least 6 months. Of these 2374 youngsters, 1210 (51%) were girls and 1164 boys. Most (60%) were non-Hispanic black, while 26% were Hispanic and 13% non-Hispanic white. Median age when children took their first antiretroviral stood at 1.7 years (interquartile range [IQR] 0.4 to 4.5), while median age when cART began was 6.8 (IQR 3.3 to 10.1). Total median duration of antiretroviral use stood at 4 years (IQR 1.5 to 6.7).
Of the 2374 children on cART for at least 6 months, 939 (40%) had a study-defined virologic failure, with no difference in failure rate between boys and girls. Median duration of antiretroviral use before cART was significantly less in children with virologic failure (3.7 versus 4.2 years, P= 0.021), while maximum pre-cART viral load was slightly but significantly higher in the failure group (5.1 versus 5.0 log10 copies/mL, P= 0.005). Nadir CD4 percent did not differ significantly between children with or without failure (17% and 18%, P = 0.615), but nadir data were missing for 28% of children.
The researchers noted that the highest proportion of virologic failures, 24%, occurred in 2001 and that failure rates were low in the most recent years, but they did not report failure rates year by year. After the most recent cART failure, high proportions of children remained on their failing regimen for 3 to 12 months:
-- 3 months after failure: 92% still on failing regimen
-- 6 months after failure: 85% still on failing regimen
-- 12 months after failure: 73% still on failing regimen
-- Maximum follow-up after failure: 42% still on failing regimen
Rates at which children stayed on a failing regimen did not differ between those with failure before or after 2001. Among children with 12 months of follow-up after virologic failure, the 27% not still on a failing regimen included 5% who had switched to a one-, two-, or three-drug non-cART regimen and 7% had stopped all antiretrovirals.
Among 939 children with virologic failure, 789 (84%) had no previous failures, 139 (15%) had one previous failure, and 11 (1%) had two or more previous failures. Time from cART initiation to failure got shorter starting in the year 2000. Before 2000, median time to failure after cART initiation stood at 35 months (IQR 23 to 47), while in 2000 and later years, median time to failure fell to 18 months (IQR 12 to 29).
The investigators suggested that sustained treatment with a failing cART regimen reflects "the limited availability of pediatric formulations of antiretrovirals for these children and the reluctance of practitioners to start a new regimen in the face of probable nonadherence."
US pediatric antiretroviral guidelines advise that "continued treatment of a child with persistently detectable viremia increases the risk of immunologic decline or clinical disease progression and leads to further accumulation of resistance mutations, possibly further limiting future treatment options" [2]. But, the panel adds, "even in children with advanced clinical and/or immunologic status, initiating a new regimen in the face of persistent adherence difficulties is unlikely to result in virologic suppression, and it is likely to promote accumulation of additional resistance." US adult and adolescent antiretroviral guidelines concede that "there is no consensus on the optimal time to change therapy for virologic failure" [3]. But the guidelines add that when virologic failure is confirmed, "generally the regimen should be changed as soon as possible to avoid progressive accumulation of resistance mutations."
"The researchers did not venture an opinion on why single- or double-antiretroviral duration before cART was significantly less in children with than without failure.
References
1. Fairlie L, Karalius B, Patel K, et al. PHACS Team and IMPAACT. Characteristics and management of HAART failure among perinatally HIV+ children and adolescents: US. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 948. http://www.retroconference.org/2013b/PDFs/948.pdf
2. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Department of Health and Human Services. November 5, 2012.
3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013.
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