Late start for ART in pregnancy increases HIV transmission risk during breastfeeding period

A high viral load at the time of starting treatment during pregnancy and a shorter time on antiretroviral therapy (ART) before delivery continued to place mothers at risk of passing on HIV during the breastfeeding period for at least seven months after giving birth, researchers report in a sub-study of the Kisumu Breastfeeding Study in Kenya, published in the advance online edition of the Journal of Acquired Immune Deficiency Syndromes.

Among this cohort of 434 women, over 80% had an adherence rate equal to or greater than 95%.

Twenty-four infants were infected with HIV during the seven-month study period, with over 50% infected during delivery. Eleven of the mothers of infected infants had a viral load over 10,000 copies/ml. Viral load was linked to vertical (mother-to-child) transmission at delivery (p = 0.0028), at 14 weeks (p = 0.05) and at 24 weeks after delivery (p = 0.01).

These findings lend further support to the World Health Organization’s (WHO) guidelines of starting ART prophylaxis early, for the greatest reduction in maternal viral load, for the prevention of mother-to-child transmission (PMTCT).

HIV continues to be one of the leading causes of death in sub-Saharan Africa, where over half of those infected are women of reproductive age. ART has had a considerable effect on reducing death and disease among people with HIV.

Women in sub-Saharan Africa are often diagnosed during pregnancy and, depending on eligibility criteria (CD4 cell counts), start ART either for their own health or to prevent vertical transmission. For those women not eligible for treatment for their own health, ART throughout breastfeeding is recommended for infant protection.

CD4 cell counts and clinical staging, while imperfect, are used to determine eligibility and treatment response in resource-poor settings, where viral load monitoring is often unavailable. CD4 cell counts alone often do not have the sensitivity to detect rising viral load until treatment failure and HIV progression is apparent.

Good adherence is critical to improve health outcomes, delaying viral resistance as well as preventing transmission to the baby.

Since a high viral load is a risk factor for transmission, the goal of ART is to reduce viral load to undetectable levels. So the mother’s health will determine the health and survival of the infant.

With this in mind, the authors chose to evaluate immunologic response, viral load suppression and adherence among women receiving ART prophylaxis (consisting of lamivudine/zidovudine and either nevirapine or nelfinavir) in the Kisumu Breastfeeding Study. They also looked at other risk factors that affected time to viral load suppression.

The Kisumu Breastfeeding Study, an open-label clinical trial, enrolled women between July 2003 and November 2007 to look at the efficacy of, tolerance of, and adherence to, maternal triple ART for PMTCT up to 24 weeks after delivery.

Women were enrolled into this sub-study if they had adherence, viral load and CD4 data in at least three time points during the study period: from 32 to 34 weeks of pregnancy to 24 weeks after delivery.

Among the 434 women remaining in the sub-study, baseline demographic data, trends in CD4 cell count, and viral load at enrolment, delivery, 14 and 24 weeks after delivery were analysed. Pill counts, in addition to self-report and drug calendar, determined adherence rates. Adherence was defined as equal to or above 95%.

Significant improvements in virological response and immunological status provided solid support for triple ART for PMTCT in resource-poor settings.

Women with undetectable viral load at baseline increased from 6 to 79%; women with CD4 cell counts under 250 cells/mm³ decreased from 100 (23%) at baseline to 22 (5%) at 24 weeks after delivery.

Most women (84%) were adherent throughout the study period.

There were no significant differences in the proportion of women who achieved undetectable viral load at 24 weeks after delivery based on CD4 cell count categories.

However, the authors note their findings showed the importance of timing of maternal ART for PMTCT. The longer the women were on treatment before delivery the greater the chance of undetectable viral load: 35, 54, 71 and 81% of the women on ART for under 2 weeks, 2 to 4 weeks, 4 to 6 weeks and over 6 weeks, respectively, before delivery achieved undetectable viral load.

Since the intervention began in the third trimester, it is not surprising that a longer time on ART increased the possibility of undetectable viral load at delivery, they add.

More women achieved an undetectable viral load on a nelfinavir-based ART regimen, compared to a nevirapine-based ART regimen, and in a shorter time frame. At delivery 58% (130/226) of women on a nevirapine-based ART regimen compared to 82% (139/170) of women on a nelfinavir-based ART regimen achieved undetectable viral load.

The difference between the two regimens remained after controlling for baseline CD4 cell counts, baseline viral load and time on treatment (OR=2.02, 95% CI: 1.16-3.54, p=0.014).

While adherence is linked to viral suppression, the authors note that in a subset of women with CD4 cell counts above 250 cells/mm³ there was no correlation between adherence and viral suppression. So the authors question how much adherence is needed for viral suppression and how accurate are the measures used for assessing adherence? Or perhaps, they add, some women achieved undetectable viral load between tests and then rebounded within the same interval.

While close to 70% had increased CD4 cell counts equal to or above 500 cells/mm³ at 14 weeks, the proportion did not change at 24 weeks. This would suggest, note the authors, an immunological response to ART can be assessed as soon as 14 weeks after starting treatment.

The original study was designed to look at nevirapine-based ART for PMTCT and was later modified to include nelfinavir-based ART in some women. So the finding that nelfinavir-based ART improved virologic response is, the authors point out, an unplanned secondary analysis and the results are considered preliminary.

This study shows viral load remains a risk factor for MTCT. The findings suggest, the authors note, possibly more women would have achieved undetectable viral load by delivery had they started ART earlier. As such, these findings have important implications for PMTCT during pregnancy and delivery.

The authors conclude that: “to ensure long term success of PMTCT which involves extended use of ART, we must identify feasible and reliable tools to assess adherence and provide real-time interventions to support optimal adherence among these HIV-infected women”.