Intravenous AZT does not provide extra protection against vertical transmission in mothers with undetectable viral load

Carole Leach-Lemens
Published: 09 September 2013

Intravenous (IV)-zidovudine (AZT or ZDV) during labour and delivery is effective in reducing mother-to-child transmission (MTCT) among HIV-positive women with virological failure (viral load at or above 1000 copies/ml), even if on antiretroviral therapy (ART) during pregnancy, according to an analysis from the French Perinatal Cohort (ANRS-EPF) published in the advance online edition of Clinical Infectious Diseases.

However, for the majority (77%) with well-controlled viral load (at or under 400 copies/ml) at delivery and without obstetrical risk factors (premature rupture of membranes, preterm delivery, fever or bleeding) IV-zidovudine was not significantly associated with a lower risk of transmission.

These findings, note the authors, support recent changes in French and US guidelines to no longer recommend systematic IV-zidovudine during labour and delivery when viral load is low and no obstetrical risk factors exist.

Findings from this study – comprising over 11,000 women with HIV, on ART and not breastfeeding, who delivered at 90 centres throughout France between January 1,1997 and December 30, 2010 – show that without IV-zidovudine overall MTCT rates among women with virological failure was higher than with, 7.5% and 2.9%, respectively, p = 0.01.

Among newborns given zidovudine monotherapy the MTCT rate was 10.2%. However, giving newborns zidovudine + lamivudine or a protease inhibitor (PI)-based ART regimen eliminated any difference in transmission rates between mothers who got IV-zidovudine and those who did not, 4.1% and 4.8%, respectively, p = 0.83.

The availability of ART in resource-rich settings has dramatically reduced MTCT rates to approximately one percent. However, the precise role ART plays during pregnancy, labour and delivery is difficult to determine as transmission can happen at any time throughout.

Studies before the era of ART, showed that most cases of MTCT happened during labour and delivery.  So, in 1994, US and French researchers designing the pivotal trial ACTG076-ANRS024 recommended IV-zidovudine during labour or caesarean as a link between pre- and post-natal prophylaxis. IV-zidovudine was then included in guidelines in all resource-rich countries as a component of preventing MTCT.

With the advent of ART the benefits of IV-zidovudine have been questioned.

Following previous findings of data (1997-2004) from this cohort, before ART was recommended for all pregnant women living with HIV, updated guidelines suggest IV-zidovudine may not be necessary for women on ART with well-controlled viral load near delivery (not defined in the 2010 French guidelines and defined in the updated July 2012 US guidelines as under 400 copies/ml).

The authors looked at the effect of IV-zidovudine on MTCT according to maternal characteristics, viral load and obstetric conditions.

There were no specific HIV treatment and obstetric care recommendations for women included in the cohort. From 1994, antenatal prophylaxis consisted of zidovudine prophylaxis; from 1997 of dual nucleoside therapy with elective caesarean section (C-section) based on a risk/benefit evaluation.

ART initially recommended for pregnant women needing it for their own health was revised in 2004 to include all pregnant women living with HIV. From 2002, elective caesarean for preventing MTCT was restricted to women not on ART and with a viral load over 400 copies/ml near delivery. Up until July 2010 IV-zidovudine and newborn prophylaxis was systematically recommended.

The MTCT rate was compared between women getting IV-zidovudine and those not, analysed according to viral load at delivery (under 400, 400 to 999, and at or above 1000 copies/ml) and stratified according to mode of delivery, term of delivery (under or over 37 gestational weeks) and type of post-natal prophylaxis.

For the analysis, CD4 counts and percentages and plasma viral load were obtained closest to the time of delivery and not more than seven days after delivery.

Of the 11,538 women included in the analysis, 95.2% (10,984) got IV-zidovudine while 554 did not. A PI-based ART regimen was the last one prescribed during pregnancy for the majority of women (60.2%), with 7.2% a non PI-based ART regimen, 2.6% three or more nucleoside reverse transcriptase inhibitors (NRTIs), 17.5% two NRTIs, 10.2% NRTI monotherapy and 0.9% an integrase inhibitor or CCR5-based regimen.

The median CD4 count at delivery was 461 cells/mm3 (IQR: 319-636).

Close to 80% of newborns were given monotherapy prophylaxis.

This analysis shows IV-zidovudine did not have an effect on MTCT in women with well-controlled viral load and no apparent childbirth risk factors, but remained effective in reducing MTCT among women with virological failure at delivery, even among those on ART during pregnancy.

While the study’s main strength is the large number of patients, the relative small number (5%) not getting IV-zidovudine is its main limitation.

Women not getting IV-zidovudine were more likely to be over 35, to have given birth previously, to have delivered preterm and vaginally and with high viral load at delivery. The authors hypothesize this may be because they presented in advanced labour, too late to start IV-zidovudine.

Preterm delivery is a risk factor for MTCT. Vaginal delivery in the absence of ART or with zidovudine monotherapy alone is linked to higher transmission rates compared to elective C-section.

However, there was a significant five-fold increased risk of MTCT without IV-zidovudine than with (9.5% compared to 1.8%, p = 0.01) among women with virological failure delivering at term by elective C-section.

No transmission occurred among women with viral load under 400 copies/ml (0/369) or even under 1000 copies/ml (0/28) who did not get IV-zidovudine compared to 0.6% (42/7576), p = 0.17 and 0.9% (5/556), p = 0.61, respectively among those who got IV-zidovudine.

This finding led the authors to comment that given the large size of the cohort and few infected infants, the study lacked the power to evaluate the safety of withholding IV-zidovudine in cases of obstetrical risk factors. They propose, while awaiting more data, IV-zidovudine be continued in women, even with low viral load, in cases of complicated deliveries.

These results, consistent with the authors’ previous findings (1997-2004), allowed the authors to look at IV-zidovudine with an increased power and within the context of systematic ART recommended for all pregnant women since 2004. The proportion of those on PI-based regimens increased from 38% in 1997-2004 to 86% in 2005-2010.

Evaluation of HIV-uninfected infants in the first six months of life showed IV-zidovudine was not associated with increased short-term haematological toxicity or lactate levels.

Reference

Briand N et al. Is intrapartum intravenous zidovudine for mother-to-child transmission still useful in the cART era? Advance online edition Clin Infect Dis, May 31, 2013.

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