ART use in mothers with low CD4 cell counts reduces breastfeeding transmission fivefold: Malawi

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The use of antiretroviral therapy (ART) by breastfeeding mothers greatly reduced the risk of HIV transmission to their infants after a 14-week course of infant HIV prophylaxis was stopped, according to a study performed in Malawi and presented to the Sixteenth Conference on Retroviruses and Opportunistic Infections (CROI) on Tuesday. However, ART use did not significantly reduce transmission risk in mothers with CD4 cell counts above 250 cells/mm3.

The best means of preventing mother-to-child transmission of HIV (MTCT) during breastfeeding is currently the subject of much research and discussion. Formula feeding is not a viable alternative to breastfeeding in most resource-poor settings, as lack of clean water presents essentially as great a risk to infants as the risk of HIV transmission through breastfeeding.

The PEPI-Malawi study had previously found that a 14-week course of daily infant antiretroviral prophylaxis, initiated at birth, can reduce infant HIV infection rates from breastfeeding by upwards of 65%. Other studies such as the Kisumu Breastfeeding Study (KiBS) have found that ART use by breastfeeding mothers reduces MTCT.

Glossary

mother-to-child transmission (MTCT)

Transmission of HIV from a mother to her unborn child in the womb or during birth, or to infants via breast milk. Also known as vertical transmission.

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

hazard

Expresses the risk that, during one very short moment in time, a person will experience an event, given that they have not already done so.

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

opportunistic infection (OI)

An infection that occurs more frequently or is more severe in people with weakened immune systems, such as people with low CD4 counts, than in people with healthy immune systems. Opportunistic infections common in people with advanced HIV disease include Pneumocystis jiroveci pneumonia; Kaposi sarcoma; cryptosporidiosis; histoplasmosis; other parasitic, viral, and fungal infections; and some types of cancer. 

This new study, reported to CROI by Taha Taha of Johns Hopkins University on behalf of a US/Malawian research team, investigated the effects of ART use by breastfeeding mothers on MTCT after infant HIV prophylaxis was stopped.

The researchers identified 2318 infants who were HIV-negative at 14 weeks of age, and monitored their HIV status until they reached 24 months of age. The researchers also defined three categories for the mothers' use of ART:

  • ART-eligible and untreated (CD4 cell count 3 but no ART);
  • ART-eligible and treated (CD4 cell count 3 and received ART); and
  • ART-ineligible (CD4 cell count ≥ 250 cells/mm3).

Although 624 women were eligible for ART at some point postpartum, only 310 (13%) received it. All regimens were the standard first-line ART regimen used in Malawi: nevirapine, d4T (stavudine) and 3TC (lamivudine).

One hundred and thirty of the 2318 infants (5.6%) acquired HIV between the ages of 14 weeks and 24 months. MTCT occurred at an incidence rate of 10.6 per 100 person-years (p-y) in ART-eligible, untreated women (95% confidence interval [CI], 7.9 to 13.8), but only 1.8 per 100 person-years (p-y) in ART-eligible, treated women (95% CI, 0.6 to 4.2) – an adjusted hazard ratio [AHR] of 0.18 (95% CI, 0.07 to 0.44). In other words, ART use represented an 82% reduction in MTCT among ART-eligible women.

MTCT was also significantly less likely in women who were ART-ineligible – in other words, women with CD4 cell counts of 250 and above – compared to ART-eligible, untreated women (incidence rate, 3.7/100 p-y (95% CI, 2.9 to 4.6), for an AHR of 0.35 (95% CI, 0.25 to 0.50). (The lower likelihood of MTCT in healthier women with higher CD4 counts is consistent with other existing data.) There was no significant difference in MTCT between ART-ineligible women, and ART-eligible women who were on treatment.

The health benefits of ART for the women themselves, also an essential part of the overall picture, were not presented at this session but are currently being analysed. The researchers concluded that, due to the 82% reduction seen in MTCT, eligible breastfeeding women “should start ART early for their own health and to reduce postnatal HIV transmission to their infants.”

PMTCT during breastfeeding: what works best?

In a plenary presentation to CROI on Wednesday morning, Jeff Stringer of the Centre for Infectious Disease Research in Zambia discussed current knowledge, knowledge gaps and practice recommendations regarding breastfeeding and HIV. Some of the key questions and issues include the following:

Should ART be used as PMTCT in women with higher CD4 cell counts?

While the Taha study found no significant effect of ART in such women, the KiBS study did find that maternal ART reduced MTCT during breastfeeding, regardless of whether the mothers' CD4 counts qualified them for treatment.

Nevertheless, women with lower CD4 cell counts – below 350 cells/mm3, and most especially below 200 cells/mm3 – are at much higher risk of transmitting HIV to their infants, as well as risk of disease themselves – than women with higher counts (as demonstrated by the Zambia Exclusive Breastfeeding Study (ZEBS) and other studies.) The cold realities of practical constraints might argue for the strategic use of treatment where it will have the most effect. However, this should not be used as an argument for failing to treat as many people as resources permit.

How should the twin PMTCT tools of maternal ART and infant prophylaxis be used during breastfeeding?

Stringer and Taha both argued that, for healthier women with higher CD4 cell counts, current evidence points to infant prophylaxis as the better intervention during breastfeeding – at least until there are more data from controlled trials. As described above, Taha found no significant prevention effect of maternal ART in these women. He also argued that, since antiretroviral drugs are absorbed into infant's bodies by way of breast milk, there is the potential for excessive drug levels if infant prophylaxis and maternal ART are used simultaneously.

Several larger prospective trials are currently examining these questions. The BAN (Breastfeeding, Antiretrovirals and Nutrition) study is a three-arm trial comparing extended infant prophylaxis and maternal ART to a control arm of short-course infant prophylaxis. The PROMISE study, a complex protocol with multiple randomisations, is comparing several prepartum ART regimens, postpartum HAART and infant prophylaxis, and continued versus terminated treatment for both mothers and infants after weaning. The results of these studies should provide needed evidence for breastfeeding recommendations in resource-poor settings.

References

Taha T et al. Effect of maternal HAART on postnatal HIV-1 transmission after cessation of extended infant antiretroviral prophylaxis. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 92, 2009.

Stringer J Prevention of breast-feeding transmission of HIV-1. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal. Plenary presentation, abstract 127, 2009.

Thomas T et al. PMTCT of HIV-1 among breastfeeding mothers using HAART: the Kisumu breastfeeding study, Kisumu, Kenya, 2003-2007. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 45aLB, 2008.