U=U applies for some pregnancies, but not breastfeeding

The risk of vertical HIV transmission – from mother to child during pregnancy or delivery – is zero when a mother has a fully suppressed viral load from the time of conception until after giving birth, an analysis combining 138 studies and 82,723 month-infant pairs has concluded.

The analysis found that if viral load is above 50 copies but below 1000 copies during pregnancy, the risk of vertical transmission is approximately one in 77 – in other words, for every 77 pregnancies where viral load is detectable but below 1000 copies, one will result in vertical HIV transmission.

The study by Dr Caitlin Dugdale of Harvard University and colleagues is published in The Lancet.

The analysis also looked at 13 studies which assessed the relationship between viral load and vertical transmission in the postnatal period, finding that for each month of breastfeeding when viral load was suppressed below 50 copies/ml, the risk of vertical transmission was 0.1%, or one in a thousand.

The analysis also investigated the risks associated with vaginal or caesarean delivery and found no difference in risk between the two modes of delivery when the mother’s viral load was below 1000 copies/ml.

The authors carried out a systematic review of studies published between 1989 and 2024 that reported on the association between maternal viral load near birth or during breastfeeding and the risk of vertical transmission. They identified 147 studies that contained sufficient data to include in a meta-analysis; 138 provided data on perinatal transmission and 13 provided data on postnatal transmission.

The authors carried out three sets of analyses: a pooled analysis of all studies, subgroup analyses according to the point at which antiretroviral treatment was initiated before birth, and an analysis of studies which looked at the risk of transmission during the breastfeeding period.

In the pooled analysis of perinatal transmission by maternal viral load and ART use at birth, the authors assessed transmission risk at ten viral load cut-offs: above or below 50 copies/ml, above or below 400 copies/ml, above or below 1,000 copies/ml and above or below 10,000 copies/ml, as well as viral loads in the ranges 50-399 or 50-999 copies/ml.

For inclusion in this analysis, studies needed to measure maternal viral load no more than four weeks prior to delivery or one week after delivery.

The analysis found that when the mother was taking ART at the time of birth, the risk of vertical transmission ranged from 0.2% when viral load was below 50 copies/ml, 0.5% when viral load was below 1000 copies/ml and 0.6% when viral load was below 10,000 copies/ml. When mothers not taking ART at the time of delivery were included in the analysis, the risk at viral loads below 1000 copies/ml was similar, but at viral loads above 1000 copies/ml, the risk was consistently greater (>1000 copies/ml, 5.1%; >10,000 copies/ml, 12.7%).

In a subgroup analysis restricted to studies which reported on women who started ART before conception and had a viral load below 50 copies/ml near the time of delivery (4675 participants), the risk of vertical transmission was zero.

And for mothers who started ART during pregnancy and who had a viral load below 50 copies/ml near the time of delivery, the risk of vertical transmission was 0.4%.

The subgroup analysis of postnatal transmission looked at person-months at risk. The monthly risk was 0.1%, 0.3% if the most recent viral load was above 50 copies/ml and 0.7% if the most recent viral load was above 400 copies/ml.

In an accompanying comment article, Professor Grace John-Stewart and Dr Irene Njugana of the University of Washington, Seattle, say that the findings on postnatal transmission are timely as high-income countries begin to endorse shared decision-making approaches to breastfeeding for women with HIV. But they caution that for women with a viral load below 50 copies/ml, the estimated cumulative risk of vertical transmission is 1.2% after one year of breastfeeding and 2.4% after two years of breastfeeding.

While the findings suggest that undetectable equals untransmissible for women who start antiretroviral treatment before conception and maintain viral suppression throughout pregnancy, U=U does not apply to women who start antiretroviral treatment during pregnancy or who breastfeed while virally suppressed, John-Stewart and Njugana conclude.

“Early diagnosis, ART adherence and viral suppression are crucial for mothers,” they conclude. “Safeguarding an uninterrupted supply of ARTs for women during pregnancy and postpartum is essential to avert vertical transmission and is threatened by lapses in financing or supply chains.”

In a separate systematic review and meta-analysis published in Lancet HIV, Magdalene Walters of Imperial College, London, and colleagues assessed factors associated with vertical transmission in 110 studies of vertical transmission probabilities. Their meta-regression analysis found that higher CD4 count, greater time on ART during pregnancy and integrase inhibitor-based treatment each reduced the risk of vertical transmission.

Among women not taking ART, each 100-cell increase in CD4 count was associated with a 20% reduction in risk of vertical transmission (odds ratio. 0.80, 95% confidence interval 0.75-0.84).

In women who took ART during pregnancy, each additional week on ART before delivery reduced the risk of vertical transmission by 5.6% (95% CI 4.2-7.0). Starting integrase-inhibitor based treatment by week 20 of pregnancy was associated with a 64% reduction in the risk of vertical transmission when compared to non-nucleoside reverse transcriptase inhibitor-based therapy (OR 0.36, 95% CI 0.14-0.94).