To the Editor:
Since the ACTG076 trial results were published in 1994 [1], antiretroviral prophylaxis for the neonate as well as during pregnancy and delivery has been the cornerstone of prevention of mother-to-child transmission (MTCT) of HIV. In the second decade of the combination antiretroviral therapy (cART) era, around 90% of pregnant HIV-infected women in Western Europe receive antenatal cART, for their own health and/or for prevention of MTCT (PMTCT) [2-4]. The rationale for including neonatal prophylaxis in the ACTG076 trial included uncertainty regarding timing of MTCT and the desire to boost the infant’s in utero and intrapartum antiretroviral drug exposure with 6 weeks zidovudine prophylaxis, as a post-exposure prophylaxis (PEP) for newborns not infected with HIV in utero. Observational studies and trials subsequently demonstrated effectiveness of neonatal PEP for infants whose mothers received no antiretroviral drugs [5-7]. No trial data exist comparing the efficacy of different neonatal prophylaxis regimens for infants of women on cART. We investigated trends in neonatal prophylaxis use in the cART era in Western European sites of the European Collaborative Study, a cohort of HIV-infected pregnant women and their children; full methods are described elsewhere [4]. Logistic regression was used to investigate factors associated with receipt of neonatal prophylaxis. Variables considered in the multivariable model were antenatal antiretroviral use, mode of delivery, country and year of delivery, prematurity (<37 completed gestational weeks) and maternal antenatal HIV RNA viral load and CD4 count and were retained based on Akaike’s Information Criterion.
Data on 2668 mother-child pairs enrolled in January 1998 to June 2008 were analysed. Patterns of use of antenatal and neonatal ART changed over time, with increasing use of antenatal cART (Table). An increasing proportion of infants received no neonatal prophylaxis, particularly among those whose mothers received antenatal cART (Table). Duration of neonatal prophylaxis significantly decreased over time (Table). Infants born after 2001 were less likely to receive neonatal prophylaxis than other infants (AOR 0.39 [95%CI 0.31-0.48], p<0.001), as were those born in Southern versus Northern European sites (AOR 0.34 [95%CI 0.28-0.40], p<0.001) and those delivered vaginally or by emergency caesarean section (AOR 0.64 [95%CI 0.53-0.77], p<0.001). Conversely, maternal undetectable HIV RNA load at closest test prior to delivery and premature delivery were associated with significantly increased likelihood of receiving neonatal prophylaxis (AOR 1.35 [95%CI 1.11-1.65] p=0.003 and AOR 1.24 [95%CI 1.00-1.54] p=0.045) respectively).
Table. Use of antenatal and neonatal antiretroviral drugs and MTCT rates, by time period of delivery.
| 1998-2000 N (%) |
2001-2003 N (%) |
2004-2007 N (%) |
p-values |
|
|---|---|---|---|---|
|
| ||||
| Antenatal ART | ||||
| None | 97 (12) | 95 (9) | 47 (7) | |
| Monotherapy / dual therapy | 321 (39) | 192 (18) | 58 (8) | p<0.001 |
| cART | 402 (49) | 787 (73) | 606 (85) | |
|
| ||||
|
Neonatal prophylaxis, by antenatal
ART group |
||||
| Any neonatal prophylaxis | 636 (78) | 665 (62) | 418 (59) | p<0.001 |
| AN cART | ||||
| No NP | 63 (16) | 291 (38) | 251 (42) | |
| NP with one drug | 239 (61) | 387 (49) | 249 (42) | |
| NP with two drugs | 83 (21) | 88 (11) | 86 (14) | |
| NP with three drugs | 9 (2) | 18 (2) | 11 (2) | |
| AN mono / dual therapy | ||||
| No NP | 61 (20) | 77 (40) | 21 (38) | |
| NP with one drug | 195 (64) | 107 (56) | 30 (55) | |
| NP with two drugs | 46 (15) | 4 (2) | 1 (2) | |
| NP with three drugs | 2 (1) | 4 (2) | 3 (5) | |
| No AN ART | ||||
| No NP | 33 (35) | 36 (39) | 9 (19) | |
| NP with one drug | 36 (38) | 45 (48) | 31 (66) | |
| NP with two drugs | 21 (22) | 1 (1) | 2 (4) | |
| NP with three drugs | 5 (5) | 5 (12) | 5 (11) | |
|
| ||||
|
Children receiving 6 weeks or
more neonatal prophylaxis, by neonatal prophylaxis group |
||||
| Any neonatal prophylaxis | 346/420 (82) | 411/545 (75) | 201/311 (65) | p<0.01 |
| NP with one drug | 340/413 (85) | 399/530 (75) | 199/308 (65) | |
| NP with two drugs | 68/107 (64) | 15/93 (16) | 8/89 (9) | |
| NP with three drugs | 8/16 (50) | 14/33 (42) | 4/19 (21) | |
|
| ||||
|
Crude MTCT rates
% (95% CI) |
3.9 (2.6 - 5.6) | 1.7 (1.0-2.8) | 1.5 (0.6-3.2) | p=0.007 |
AN= antenatal; NP = neonatal prophylaxis
Practices of prescribing neonatal prophylaxis have changed over the past decade, with enduring variations in practice indicating lack of consensus regarding optimal management. We have documented for the first time in Europe a decline in neonatal prophylaxis use among infants of women receiving antenatal cART; this is not recommended by current guidelines [8,9]. This trend has occurred concomitantly with ongoing declines in MTCT rates. We lacked statistical power to compare relative effectiveness of different prophylactic approaches among infants of women taking cART. The declining use of neonatal prophylaxis and the shorter durations documented may partly reflect safety concerns [10] and highlight the need for more data for risk-benefit analyses and to guide clinical practice.
Acknowledgements
The ECS is a coordination action of the European Commission (PENTA/ECS 018865). Claire Thorne is supported by a Wellcome Trust Research Career Development Fellowship. This work was undertaken at Great Ormond Street Hospital /University College London Institute of Child Health which received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. The Centre for Paediatric Epidemiology and Biostatistics also benefits from funding support from the Medical Research Council in its capacity as the MRC Centre of Epidemiology for Child Health.
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