Treatment response and duration of first line treatment in European infants

1 December 2011. Related: Paediatric care.

Polly Clayden HIV i-Base

Investigators from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord evaluated response to antiretroviral therapy (ART) and predictors of switching or interrupting treatment in children starting in infancy up to 5 years from treatment initiation. Findings from this study were reported in the 28 November 2011 edition of AIDS.

The study evaluated data from nine observational cohorts in 13 European countries. A total of 437 HIV-infected, ART na? infants, less than 12 months of age, born between 1996 and 2008 were included.

The infants started ART at a median of 3.7 (IQR 2.1-5.8) months. About 40% were from UK/Ireland and 20% each from France and Italy. About half were black and half female. Just over a third had been exposed to maternal antiretrovirals in pregnancy and just under a third neonatal prophylaxis. One third were breast-fed.

The median duration of follow up after starting ART was 5.9 (IQR 2.3 – 7.6) years. During this time 20 children died and 32 were lost to follow up. The median CD4 percentage and viral load at treatment initiation of were 29% (IQR 17 – 39%) and 5.7(IQR 4.9 – 5.9) log10 copies/mL respectively.

The majority (76%) started ART before 6 months of age. Twenty four percent started on an NNRTI plus 2 NRTIs, the most common backbone being ddI/d4T from 1996 – 1999 and AZT/3TC from 2000 onwards. Four drug regimens, most frequently NNRTI plus 3NRTIs, were used more often in the later time period (18% compared to 3%) and in UK/Ireland. Boosted PIs were used only from 2001 onwards (34% 2004-2008). Nelfinavir use declined over calendar time.

Just over half (53%) the infants initiating ART in 1996 – 1999 had viral load <400 copies/mL by 12 months, this increased to 57% in 2000 – 2003 and 77% in 2004 – 2008, but the difference was not statistically significant, p=0.09. Infants aged 6 -12 months at ART initiation were more likely to be suppressed than those aged <3 months AOR 1.98 (95% CI 0.92 – 4.25), but again, this difference did not reach statistical significance, p=0.06.

Four-drug NNRTI regimens were associated with significantly better viral load suppression; AOR 3.00 (95% CI 1.24 – 7.23) compared to three drug NNRTI (reference) regimens, p<0.001. But boosted PI plus 2 NRTI regimens performed similarly to the reference regimen, AOR 1.39 (0.62 – 3.13). Higher baseline viral load was associated with less likelihood of virological suppression, AOR 0.67 per log10 copies/mL (95%CI 0.50 – 0.89), p=0.01.

For infants with data available, median baseline and 12 month CD4 count, CD4 percentage and CD4 z-score were 520 (IQR 271 – 1340) cells/mm3, 6% (-6 to 16%) and 0.92 (-0.14 to 2.34), respectively. Median CD4 z-score increase was 2.29 in infants receiving four-drug NNRTI regimens compared to 0.65 in those receiving three-drug NNRTI regimens and 0.91 for boosted PI regimens, p=0.04.

Eighteen percent of infants switched to second line treatment. The cumulative incidence of switching was 10.2% (95% CI 7.5 – 13.4) and 16.7% (13.0 – 20.7%) by 2 and 5 years respectively. Children starting treatment with a four drug NNRTI or boosted PI-based regimen were slower to switch; AHR 0.41 (95% CI 0.15 – 1.14) and AHR 0.26 (95% CI 0.06 – 1.19) respectively, p=0.03. Although the investigators noted data were sparse.

Twenty eight percent of children experienced at least one treatment interruption of more than 14 days, no factors predicted interruption.

Sixty five percent of children remained on treatment without interruption at last follow-up. Of these 36% had been treated for at least 5 years. The estimated probability of remaining on first-line ART without interruption was 79.3% (95% CI 75.1 – 83.1%) and 63.8% (95% CI 58.7 – 68.9%) by 2 and 5 years from starting ART respectively.

comment

That boosted PI-based regimens performed similarly to NNRTI-based is contradictory to findings from IMPAACT 1060 that showed 20% higher rates of failure at 24 weeks in children aged 2 months to 3 years receiving NNRTI-based regimens compared to PI-based (whether or not they had been NNRTI exposed through PMTCT). Although IMPAACT 1060 was an RCT and these are cohort data – the difference in length of follow up is considerable.

That four drug NNRTI-based regimens did well is notable and induction/maintenance strategies in young children remain under explored.

Reference:

European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Early antiretroviral in HIV-1 infected infants, 1996-2008; treatment response and duration of first-line regimens. AIDS: 25(18):2279-2287, 28 November 2011.