Intensification of antiretroviral therapy reduces risk of late-term mother-to-child HIV transmission

Maternal and infant antiretroviral therapy (ART) intensification is very effective in preventing HIV transmission during labour and birth in pregnant women with HIV in Thailand who present late for care (with less than eight weeks of standard ART), Marc Lallemant told the Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) in Vancouver, Canada, last week.

Overall 88 mother/infant pairs took extra antiretrovirals in addition to the standard ART regimen (intensification) in this multicentre phase three adaptive single-arm trial conducted from December 2011 to July 2014. There were no HIV transmissions during labour and delivery.

There were no transmissions at the first interim analysis, but due to slow enrolment and corresponding small sample size (58) enrolment continued. At the second interim analysis (three had been planned), with no further reported transmissions, the Data and Safety Monitoring Board (DSMB) recommended stopping enrolment, reporting intensification efficacy.

Intensification appeared safe, providing over 80% probability of a two-fold reduced risk (RR<0.5) of transmission and 94.1% probability of superiority (RR<1) over standard of care.

The longer a woman living with HIV has been taking HIV treatment, the greater the chance of her attaining and maintaining an undetectable viral load. This greatly reduces the risk of transmitting HIV to her child. Pregnant women with HIV who are not seen in health care services until late in their pregnancy (often referred to as ‘presenting late’) are at increased risk of transmission during delivery. Late diagnosis puts their own health at risk, as well as that of their child. Reasons for late diagnosis are many and include distance to health care facilities, lack of transportation, fear of disclosure and stigma as well as financial constraints. Maternal/infant ART intensification during and immediately following delivery may significantly reduce the risk of vertical transmission.

With the aim of preventing HIV transmission during labour and delivery, 88 pregnant women with HIV who had taken less than eight weeks of standard ART (based on lopinavir/ritonavir, zidovudine and lamivudine) and their infants were given antiretrovirals in addition to the standard regimen (intensification).

Women took a single dose of nevirapine in labour and continued with ART for four weeks. Formula-fed newborns received zidovudine, lamivudine and nevirapine for two weeks, followed by two weeks of zidovudine and lamivudine instead of the standard one week of zidovudine.

Infants were tested for HIV at birth and then at one, two, four and six months. Intrapartum transmission was defined as a negative DNA polymerase chain reaction (PCR) at less than 48 hours of age followed by a positive PCR result.

With data from 3737 mother/infant pairs, which included 84 transmissions during delivery, in three randomised perinatal HIV prevention trials (PHPT) undertaken in the same setting, Dr Lallemant and colleagues defined a historical control and built an intrapartum transmission model. (The PHPT-5 trial comprising these three arms was stopped early due to changes in national and international guidelines. However, while transmission rates were similar across the three arms, over 80% of the observed transmissions were among mothers who had received ART for a short time during pregnancy.)

Dr Lallement outlined the concept of the principles of Bayesian Inference, the method used to determine probability distributions. Unlike traditional scientific methods which assume no prior knowledge, this method comprises: what data are known today [from the PHPT trials] (prior), what the new data could tell us and what we would then know (posterior probabilities).

Viral load during pregnancy was modelled according to antiretroviral regimen. A logistic model predicted intrapartum transmission with viral load, maternal/infant antiretrovirals, delivery mode and prematurity status as co-variables. Intrapartum transmission rates with and without ART intensification can then be predicted.

Of 1054 women screened, 336 consented and agreed not to breastfeed in accordance with national guidelines. 248 were observed and 88 received the intervention.

The women’s baseline characteristics at enrolment were similar with the exception of gestational age (GA). Median age was 27.7 years (interquartile range (IQR): 22.8-32.2) and 26.3 years (IQR: 22.3-33) in the observed and intervention arms, respectively with median CD4 cell counts of 359 cells/mm³ (IQR: 250-498) and 379 cells/mm³ (IQR: 256-502), respectively.

Median GA at start of ART was 19.1 weeks (IQR: 15-23.9) and 34 weeks (IQR: 32.4-36.3) in the observation and intervention arms, respectively.

Median GA at delivery was approximately 38.6 weeks in both arms. However, median duration of ART at delivery was 19.5 weeks (IQR: 14.1-23.3) and 4.3 weeks (IQR: 2.6-6.3) in the observed and intervention arms, respectively.

In both groups, the percentage undergoing caesarean section was similar, 41.5 % and 36.4% in the observed and intervention arms, respectively.

Median infant birth weight was also similar in both, 2.8 kg (IQR: 2.5-3.1) and 2.9kg (IQR: 2.7-3.1) in the observed and intervention arms, respectively.

Infant intensification quickly followed the birth with a median time of 0.7 hours (IQR: 0.5-1.5).

The posterior probability of transmission during delivery was 0.4% (95% credibility interval (CrI): 0.1%-1.4% with intensification compared to 2.0% (95%, CrI: 0.3%-5.2%) without.

Dr Lallemant concluded ART intensification for women presenting late only having had a short course of antiretrovirals is very effective in preventing HIV transmission during labour and delivery.