Maternal risk following short course HAART

1 April 2011. Related: Conference reports, Antiretrovirals, Pregnancy, CROI 18 (Retrovirus) 2011.

Polly Clayden, HIV i-Base

Roger Shapiro and colleagues from the Mma Bana Study, Botswana looked at maternal and infant outcomes among women receiving short course HAART for PMTCT during pregnancy and breastfeeding. [1]

In Mma Bana, pregnant women with CD4 counts >200 cells/mm3 (n=560) were randomised to receive regimens of either abacavir+AZT+3TC (arm A) or LPV/r+AZT+3TC (arm B) from week 26 to 34 gestation until the infants were weaned at 6 months post partum. [2] The study also included an observational arm (n=170) in which women indicated for HAART according to local guidelines received lifelong NVP+AZT+3TC. Participants were followed for 24 months post partum.

Randomised women re-started HAART with NVP+AZT+3TC when indicated for treatment (at a CD4 count of 200 cells/mm3 at the beginning and changed to 250 cells/mm3 during the course of the study). This occurred in 9% of randomised women and 25% overall (randomised and observational) continued HAART past 6 months for treatment.

At 24 months, there were 14 (1.9%) maternal deaths: 2 during pregnancy following HAART initiation (1 arm A, 0 arm B, 1 observational), 2 from delivery to 6 months postpartum (0 arm A, 0 arm B, 2 observational), and 10 from 6 to 24 months postpartum (5 arm A, 3 arm B, 2 observational).

There were deaths across all baseline CD4 strata among randomised women (4, 2, and 3 with baseline CD4 200 to 350, >350 to 500, and >500 cells/mm3, respectively). In this group, 8 of 9 deaths were from 6 to 24 months; and 5 of these women had not re-started HAART as treatment.

There was a mean CD4 increase from baseline to 24 months in all treatment arms (15% of randomised women re-started HAART): 68 cells/mm3, 98 cells/mm3, and 283 cells/mm3 in arms A, B and observational respectively. Among women with baseline CD4 >250 cells/mm3, there was a significantly higher CD4 increase in arm B vs A (86 vs 46 cells/mm3, p=0.04).

Data were available for 96% of 709 live-born infants at 24 months of follow up. The majority (97%) of infants were breastfed for a median of 5.8 months. Nine deaths occurred before breastfeeding was initiated (7 <3 days of age, 3 arm A, 2 arm B, 4 observational). There was an increase in infant mortality after weaning, only 5 (0.7%) deaths were during breastfeeding (0 arm A, 2 arm B, 3 observational), compared to 23 (3.2%) after weaning (10 arm A, 11 arm B, and 2 observational). Of these, •14 (2.0%) deaths occurred less than 3 months from weaning which accounted for 38% of all infant deaths in the study. The death rate during breastfeeding was 1.76/100 person-years compared to 5.71/100 person-years within 6 months post-weaning, p=0.02.

Eight children (1.1%) were HIV-infected at 24 months, which did not change from 6 months. HIV infection or death occurred in 6.1% of infants (6.4% arm A, 5.9% arm B, 5.8% observational)..

Causes of maternal and infant deaths are shown in Table 1.

The authors concluded that maternal HAART from pregnancy through 6 months of breastfeeding was associated with low overall maternal and infant mortality at 24 months. They noted that this study found similar maternal mortality/lower infant mortality than in Mashi, a previous Botswana non-HAART MTCT intervention study. Following their observation of a trend for increased maternal mortality after stopping HAART for PMTCT they suggest that 24-month mortality may be higher when stopping HAART in this situation than if it is continued.

Increased infant mortality among weaned infants has been seen previously and later weaning is now recommended by WHO but MTCT and mortality tradeoff are unstudied.

A related poster from the MTCT-Plus Initiative also looked at the impact of stopping HAART used during pregnancy for PMTCT on maternal HIV disease progression. [2] This study evaluated maternal CD4 count decline after MTCT prophylaxis.

MTCT-Plus was a multi-country HIV care programme for women, children, and families in eight African countries and Thailand.

ART-naive, HIV-positive pregnant women with CD4 count >400 cells/mm3 at enrollment were included in the analysis.

The majority of the women evaluated received single-dose nevirapine (sdNVP) or short-course ARV prophylaxis with AZT or AZT+3TC. HAART (AZT+3TC+NVP or nelfinavir) was initiated during pregnancy in programmes in Thailand and Kenya. All regimens were stopped shortly after delivery with a median duration of 10 weeks.

Of 1563 women, 172 (10.9%) initiated HAART, 689 (43.5%) sdNVP, 532 (33.6%) short-course ARV prophylaxis, and 190 (12%) women received no documented prophylaxis.

At baseline, women were a median of 27 (IQR 23-30) years of age with a median CD4 count of 469 (IQR 361-613) cells/mm3. The median follow up time was 26.1 (IQR 14.5-40.7) months. Overall, 11.6% of women with enrollment CD4 >250 cells/mm3 declined to <200 cells/mm3.

Among women who initiated prophylaxis with CD4 >400 cells/mm3, the cumulative probability to reach endpoint of CD4 count <350 cells/mm3 at 24 months was 28.0% (95% CI 24.6, 31.6), overall. The proportions by intervention were: 36.3% (95% CI: 27.4, 47.2), 21.5% (95% CI: 16.4, 27.9), and 27.8% (95% CI: 23.0, 33.2) in the HAART, AZT or AZT/3TC, and sd-NVP groups respectively.

Almost half (47.8% [95% CI 41.2-54.8%]) of the women with baseline CD4 counts of 400-499 cells/mm3 declined to <350 cells/mm3 during follow up, compared to 18.3% (95% CI, 14.9-22.3%) of those with higher baseline CD4 counts, p<0.001.

HAART was significantly associated with CD4 decline compared to short course AZT or AZT/3TC, AHR 2.2 (95% CI 1.5-3.3), p<0.0001. Of note, in this analysis, both undocumented intervention and s/d NVP were also associated but to a lesser extent than HAART, p=0.02 and p=0.001 for short course and s/d NVP respectively. The only other association observed was with age 25-35 years.

Of women receiving HAART, 60.3% (CI 43.5-77.5%) with baseline CD4 counts of 400-499 cells/mm3 declined to <350 cells/mm3 during follow up compared to 48.4% (95% CI 34.8 – 64.2) with baseline CD4 >500 cells/mm3.

The authors wrote their findings suggest that women exposed to HAART as MTCT prophylaxis were twice as likely to have CD4 decline below the threshold of treatment eligibility at 24 months after delivery, than women receiving other PMTCT interventions. They propose that women with baseline CD4 <500 cells/mm3 would benefit from lifelong treatment. They urge caution in interpreting their findings though, as women in this observational cohort received a relatively short duration of HAART during pregnancy only.

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As the Botswana investigators note, significantly increased infant mortality, as in their study, associated with early weaning has been reported elsewhere. Later weaning protected by maternal HAART or infant prophylaxis is now recommended by WHO, although the risk/benefit of breastfeeding beyond 6 months is a bit of an evidence free zone.

With respect to maternal health and mortality these reports raise important issues. Following the results of the Strategies for Management of Anti-Retroviral Therapy, or SMART study (and a smaller west African study Trivican) in 2006 – which showed that stopping HAART doubled the risk of morbidity and mortality compared to continuing – there was concern about the consequences for women receiving HAART in pregnancy and stopping. [3] This is a population where (at least in richer countries) giving short course HAART for PMTCT is standard of care.

At enrolment, SMART participants were receiving HAART (for a median of 6 years) and had a CD4 count of >350 cells/mm3. They were randomised to continue or stop and those that stopped re-start when they reached CD4 <250 cells/mm3. Although the duration of HAART received by a pregnant woman is shorter than the that received by the majority of people in SMART – in these studies about 10 weeks and 8 months in MTCT-Plus and Mma Bana respectively – the hazard ratio for OI or death from any cause in SMART was 1.6 for the subgroup that received HAART 0 to <3 years before stopping (albeit looking at small numbers).

However, data from WITS looking at progression after stopping showed, among pregnant women with CD4 >350 cells/mm3 starting HAART for PMTCT, changes in CD4 and viral load were similar at one year post partum whether women stopped or continued therapy after delivery. [4] None of the WITS women progressed to AIDS or death during the first year post partum.

Although the causes of death were not SMART events in the Botswana study and numbers are very small, these and MTCT-Plus results if shown in other studies may mean that it is not safe for women to stop HAART for PMTCT whatever their baseline CD4.

These presentations make the results of the PROMISE study important, as it will give randomised, data to definitively answer the question. If there really is a big difference between stopping and not stopping, then this part of PROMISE may be able to end early as there will be a DSMB monitoring during the course of the study there are stopping rules at each interim evaluation.

Also, in Mma Bana, 6 of 9 (67%) maternal deaths among those randomised occurred in the Arm A triple nucleoside group. Six of 8 (75%) mother-to-child transmissions were in Arm A and those infants were 3 times more likely to be infected than Arm B. Again, numbers are tiny, neither outcome was statistically significant and triple nucleosides are not standard of care, but there may be a difference by regimen between this strategy and PI or NNRTI based HAART. It is likely though that LPV/r-based regimens will remain the standard of care for women in this situation particularly as it is more available and cheaper in Africa and has more safety data.

References:

1. Shapiro R et al. Increased Maternal and Infant Mortality following Completion of HAART and Breastfeeding at 6 Months Postpartum in a Randomised PMTCT Trial: Botswana, the Mma Bana Study. 18th CROI. Boston. February 2011. Poster abstract 747.
   http://www.retroconference.org/2011/Abstracts/42502.htm
2. Ekouevi K et al. Maternal HIV Disease Progression after the Interruption of Triple ARV or Short-course ARV Prophylaxis to Prevent MTCT: MTCT-Plus. 18th CROI. Boston. February 2011. Poster abstract 753.
   http://www.retroconference.org/2011/Abstracts/41792.htm
3. Watts DH, et al. Treatment interruption after pregnancy: effects on disease progression and laboratory findings. Infect Dis Obstet Gynecol. 2009;2009:456717.
4. Danel C et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. The Lancet. 2006;367(9527):1981–1989