Increased risk of preterm delivery with protease inhibitor based HAART in Mma Bana

1 October 2011. Related: Pregnancy.

Polly Clayden HIV i-Base

The Mma Bana trial compared antiretroviral regimens to prevent mother-to-child transmission in pregnancy, with highly efficacious results and some of the lowest reported in Africa [1]

The investigators performed a secondary analysis to look at the occurrence of preterm delivery (PTD) among women in the trial with CD4 counts >200 cells/mm3 randomised to receive either ABC+AZT+3TC or LPV/r+AZT+3TC initiated at 26 to 34 weeks gestation. We reported the results from this analysis – presented at CROI 2011 – earlier this year [2]

Kathleen Powis and colleagues published the complete results of the PTD analysis in the August 15 2011 edition of the Journal of Infectious Diseases with an accompanying commentary from Athena P Kourtis and Mary Glenn Fowler. [3, 4]

There were 263 and 267 women in the NRTI and PI groups respectively in this study. Baseline characteristics were similar in the two groups, the women were a median age of 26.4 years with CD4 counts of about 400 cells/mm3 and approximately 67% were between 26 and 28 weeks gestation at enrollment. Overall 88 (16.7%) women had spontaneous PTDs.

Gestational age was calculated using an algorithm that combined maternal reported last monthly period and ultrasound.

In a multivariate analysis, adjusted for self reported maternal income (p=0.02 for 3 df), the investigators found PI-based HAART was associated with a two-fold higher rate of PTD compared to triple NRTI-based HAART, 21.4% vs 11.8%, AOR 2.02 (95% CI 1.25-3.27), p=0.003.

The investigators proposed that less weight gain in pregnancy due to possible gastrointestinal side effects of the PI might explain the increased PTD risk. However, although the mean change in BMI on HAART was lower in the PI group (p<0.001) this was not significantly associated with PTD.

Of the 464 women who initiated HAART before 32 weeks gestation, 12 (2.6%) had very PTDs (<32 weeks gestation). Of these, 8 (3.3%) were in the PI group and 4 (1.8%) in the NRTI group, p=0.39. The investigators noted that, only 3 of 12 women who had very PTDs completed 30 days of HAART prior to delivery limiting the interpretation of these findings.

By 6 months of age, preterm infants were significantly more likely to have a least one severe or life threatening respiratory tract infection than term infants, 9.1% vs 2.0%, p=0.03. Preterm infants were more likely to be hospitalised than term infants, 22.7 vs 12.7%, p=0.02. Their mortality was also higher in the first 6 months, 6.8% vs 1.4%, OR 5.3 (95% CI 1.7-16.9), p=0.002, compared to term infants.

When the investigators looked at infant morbidity and mortality by maternal treatment arm the only difference they found was infants born to mothers randomised to the NRTI arm were more likely to experience meningitis, 1.9% vs 0%, p=0.03.

In their commentary, Kourtis and Fowler explain that this is the first randomised clinical trial to demonstrate a difference between rates of PTD according to antiretroviral regimen. Although observational studies and analyses have suggested a risk with PI use others have not found this association.

They note that the Mma Bana trial was not designed to look at PTD specifically so the sample size may not be sufficiently powered to do so. Assuming a background PTD rate of 20%, in the general population in Botswana, a much larger sample would be needed to detect an increase in the risk of PTD of the size that was observed in the PI group. They point out that one unexplained finding is the lower rate of PTD seen in the NRTI group whereas the rate in the PI group does not appear to differ from the background rate in Botswana.

Their commentary suggests that the study by Powis et al may, “raise more questions than it answers”, despite providing interesting data, obtained in a randomised fashion from a resource limited setting, in a field were more is needed.

They raise the issue of the timing of treatment (ie the relatively late initiation), noting a third of women who delivered prematurely had only received less than 30 days of HAART, which is too short a period for there to have been an association with immune reconstitution and the resulting cytokine shift, which is one proposed mechanism for PTD. The design of the study also limits the investigation of very PTDs, which result in the most severe infant outcomes.

The only other randomised trial that may offer some more information is Kesho Bora, which did not show elevated PTD rates among women receiving PIs compared to AZT and single dose NVP (started between 28 and 36 weeks except the NVP), respectively 13% vs 11%.

They caution against the possible interpretation of these data and write, “it is too early to rush into recommendations without validation from further studies and careful consideration of the question at hand?”.

comment

Although not the primary study endpoint, these are the first RCT data showing an association between PI use in pregnancy and PTD. This is consistent with observational UK and European data, though not all from the US.

This association will be related to the PTD rate in the general population and other factors including timing of treatment.

References:

1. Shapiro R et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010; 326:2282-94. http://www.nejm.org/doi/full/10.1056/NEJMoa0907736
2. Clayden P. Preterm delivery and HAART. HTB April 2011.
   https://i-base.info/htb/14823
3. Powis KM et al. Increased risk of preterm delivery among HIV-infected women randomised to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis 2011, 204: 506-13. http://www.ncbi.nlm.nih.gov/pubmed/21791651
4. Kourtis P and Fowler MG. Antiretroviral use during pregnancy and risk of preterm delivery: more questions than answers. J Infect Dis 2011, 204: 493-4. http://jid.oxfordjournals.org/content/204/4/493.full