Performance of PMTCT in routine programme matches clinical trials, Botswana reports

Formula-fed infants born to women who started ART during pregnancy under routine programme conditions in Botswana, without frequent viral load monitoring or specialised care, were fourteen times less likely to become infected with HIV compared to infants born to mothers who got zidovudine and/or single-dose nevirapine.

Scott Dryden-Peterson and colleagues report the findings in a prospective observational study published in the advance online edition of the Journal of Acquired Immune Deficiency Syndromes.

The observed transmission rate in mothers on ART (0.4% 95% CI: 0-2.2%) is among the lowest reported to date, “supporting the effectiveness of ART for PMTCT outside the context of a clinical trial.” And, in accordance with Botswana’s treatment guidelines the women on ART had lower CD4 cell counts than those getting zidovudine and/or single-dose nevirapine. Yet, lower CD4 cell counts are strongly associated with vertical transmission.

The 2010 World Health Organization (WHO) guidelines for prevention of mother-to-child transmission recommend that pregnant women who need treatment for their own health (those with CD4 cell counts under 350 cells/mm³ or WHO clinical stage 3 or 4), start ART.

For those pregnant women not yet in need of treatment, WHO recommends either ART or zidovudine with single-dose nevirapine if zidovudine has been used for under four weeks, followed by infant prophylaxis.

Observational evidence suggests that maternal ART may lead to greater reductions in MTCT in women at all CD4 cell counts. However, a recent randomised trial, the Kesho Bora study, did not find a significant difference between ART and zidovudine among women with CD4 cell counts over 350 cells/mm³.

The authors note that few studies have looked at comparing the effectiveness of these strategies within a resource-poor programme setting.

Given that government and programme managers are having to decide which strategy to use for PMTCT the authors chose to compare rates of HIV infection among infants born to mothers taking ART or zidovudine in the Botswana national programme.

Between February 2009 and April 2010 the authors enrolled consenting HIV-infected women who had delivered live-born infants on the maternity wards of Scottish Livingstone (a district referral hospital) and the Princess Marina Hospital (the largest national hospital). They prospectively followed the infants (93% of whom were formula-fed), 60% of whose mothers took ART (258 infants) and 40% of whom took zidovudine (170 infants) during pregnancy.

The Botswana national programme provides free HIV treatment including PMTCT interventions to all its citizens. The programme also provides free infant formula. In 2009 93% of the 32% of pregnant women who were HIV-infected took part in the PMTCT programme.

Botswana national guidelines at the time of the study recommended three-drug antiretroviral therapy when the CD4 count fell below 250 cells/mm³. Pregnant women with CD4 counts above this level received AZT prophylaxis during pregnancy and single-dose nevirapine at the time of delivery.

Infants were followed from birth until six months of age. HIV infant testing was done at one month and repeated at six months in breast-fed infants. Positive results were confirmed by repeat testing. Infants who did not return for testing were followed-up in their homes.

Among the 415 (97%) infants for whom final HIV status could be determined, ten infants (2.5%) became HIV-infected; nine (5.5%, 95% CI: 2.6-10.2%) in the zidovudine group and one (0.4%, 95% CI: 0-2.2%) in the ART group.

HIV transmission in the zidovudine group was also analysed according to the new WHO-recommended threshold for maternal antiretroviral treatment, in order to assess the programmatic performance of giving zidovudine prophylaxis according to current WHO guidelines.

This analysis found that the relative risk of transmission in women with CD4 counts at or above 350 was similar to the overall rate (RR: 13.3, 95% CI: 1.6-112, p=0.007), indicating that even in women with CD4 counts above the recommended level for treatment, zidovudine prophylaxis was associated with a much higher rate of vertical transmission than was seen in women with CD4 counts below 250 treated with triple-drug ART.

Infant free survival until six months of age was greater in the ART group than in the zidovudine group, 95.7% and 90.4%, p=0.040, respectively.

The authors note their findings “do not support the equivalemce of zidovudine and ART for prevention of MTCT”. Five of the nine infant infections in the zidovudine group happened in mothers with CD4 cell counts equal to or greater than 350 cell/mm³.

While late start of ART was associated with an increased risk of MTCT, it did not differ significantly between the two groups.

The authors highlight that providing zidovudine beyond four to six weeks did not lead to further reductions in viral load or to a greater proportion of women with an undetectable viral load at delivery. Both of which, they note, are important predictors of MTCT risk.

The study raises operational challenges, note the authors. Delays in CD4 testing and getting women onto ART resulted in nine women (8.3%) not getting ART before delivery; one subsequently transmitted HIV to her infant. Only 22.7% (5) of women who had been on zidovudine for under four weeks got single-dose nevirapine.

However, the authors note the primary reason in both groups for a shortened time on ART during pregnancy was prematurity rather than a delay in starting ART. They add “nearly one third of the newborns in this cohort were premature or low birthweight, emphasizing the importance of improving access to neonatal services in parallel with PMTCT programmes.”

The authors acknowledge the non-randomised design and earlier start of ART “limits a conclusive assessment of ART versus zidovudine.”

However, the authors conclude “the findings of this study indicate that a strategy to provide ART for all HIV-infected women, as is currently being piloted in Botswana, could nearly eliminate infant HIV infection.”