HTB

Mother-to-child transmission, maternal health and women’s access to care

16 August 2000. Related: Conference reports, Pregnancy, .

Durban Reports by Polly Clayden, HIV i – Base

Mother-to-child-transmission

This was not a meeting that could be criticised for it’s lack of women-specific research and the overwhelming majority of this dealt with the issue of mother-to-child transmission (MTCT) and prophylactic interventions. The subject provoked much heated debate and polarised opinion – from a triumph of HIV prevention to a callous disregard for the mothers’ own health.

More than anything this issue underlines the vast disparity between north and south. While in the US use of words like elimination are now used in the context of vertical transmission [2] and the PACTG 316 trial is forced to stop because of it’s extremely low transmission rate [3], in the developing world rudimentary programmes are only just beginning to be implemented. Hopefully much that is currently being mooted will form some important first steps (resistance notwithstanding) and not a complete solution.

We learnt that the Gates Foundation is about to donate millions (or is it billions?) of dollars to preventing MTCT and although babies are undoubtedly far more magnetic to philanthropists than adults (of both genders), this news sat uneasily among sessions addressing another major topic for the meeting – orphans. Perhaps a more utopian goal would be that of Treatment Action Campaign’s slogan – ‘Treat all HIV+ women’

HAART > ART > monotherapy > none

Two MTCT studies with a particularly clear message for industrialised nations with access to antiretrovirals were presented. Dr Karen Beckerman’s group conducted a retrospective analysis entitled The impact of combination therapy on maternal health and pregnancy outcome of all the 99 known HIV-1 infected mothers and their infants born at San Francisco General Hospital and Moffit Long Hospital from January 1994 – December 1999 [4].

CD4 T-cell counts at baseline and delivery were available for 71 mothers and viral load for 41 for their analysis. Prior to the use of combination antiretroviral therapy (ART), the mean CD4 count for the population dropped 39 cells/mm3 from baseline to delivery. By 1997-9, 46 of 52 mothers elected to take 2, 3, or 4 drug combinations, resulting in a reduction of maternal viral load to undetectable in 26 and by an average of 1.5log10 copies/ml in the remaining 20.

Virological response improved amongst the mothers who used 3 drugs (HAART) 14/ 20 (70%) achieved an undetectable viral load compared with 11/33 (33%) mothers using two antiretrovirals or less. A mean CD4 gain of +102 cells/mm3 (P=0.043) was observed among treated mothers. Babies born to mothers who took two or more antiretrovirals during pregnancy were significantly less likely to be born before 37 weeks gestation (P=0.018) and showed a trend toward lower rates of low birth weight (P=0.18) when compared with mothers who had no antiretrovirals or zidovudine prophylaxis alone. Increasing maternal antiretroviral use was associated with a decline in vertical transmission. Overall the Caesarean section rate was 19%.

Length of rupture of membranes for greater than four and greater than 24 hours was significantly correlated with transmission (0 at <4 hours, 11% at 4-24 hours and 25% at >24 hours); however, this correlation was not evident among mothers receiving combination antiretroviral therapy during the antepartum period.

Of the six infants that were infected, 3 in 1994-96 were born to mothers who received either no therapy or zidovudine alone, and 2 to mothers who received either no prenatal care and were not identified in labour or 1 prenatal visit who was delivered by Caesarean section in 1997-99.

The investigators found combination antiretroviral therapy during pregnancy to be ‘practical, feasible, well tolerated and beneficialÉ We conclude that combination antiretroviral therapy of maternal HIV-1 disease during pregnancy provides significant and life-saving benefits to both mother and baby’.

To further substantiate this, a large retrospective analysis from the Women and Infants Transmission Study (WITS) conducted at six sites in the US, collected data from 1492 mother and infant pairs over a decade prior to September 1999 [6]. This study set out to evaluate the effectiveness of potent antiretroviral therapies on reducing perinatal transmission of HIV-1 looking at the effect of antiretrovirals on viral load at delivery and the effects of different viral loads on MTCT.

Uninfected infants were defined as having no positive and at least 3 negative tests (the first at one month or over). Of the women that transmitted, antiretroviral use was described as follows: none 391 (26%); ZDV monotherapy (prior to 4/15/94) 206 (14%); ZDV monotherapy (after 4/15/94) 529 (36%); Multi-ART-defined as 2 NRTIs/and or NNRTI but without PIs 179 (12%); HAART- defined as any 3 drug or more combination including PIs 187 (12%). The transmission rates for each group were 80 (20.5%); 40 (19.4%), p=0.76; 41 (7.8%), p=0.01; 7 (3.9%), p=<0.01 and 2 (1.1%), p=<0.01 respectively.

Transmission rates were also stratified according to maternal viral load – at plasma HIV-1 RNA levels at delivery of >100,000 (122 women); 40,000 – 100,000 (133 women); 3,000 – 40,000 (549 women); 400 – 3,000 (284 women); undetectable ie. <400 (216 women) with transmission rates of 38 (31.2%), p<0.01; 28 (21.0%), p<0.1; 62 (11.3%), p<0.01; 18 (6.3%), p<0.01; and 2 (0.9%), p<0.01 infected infants respectively.

Use of more complex therapy was associated with reduced rates of transmission and use of complex therapy was associated with reduced maternal viral load. On multivariate logistic regression analysis both increased complexity of antiretroviral therapies and reduced maternal viral load were associated with decreased vertical transmission. The investigators concluded that HAART>Multi-ART>ZDV>None.

d4T and ddI – New anti-retroviral options to prevent MTCT?

Amid many presentations showing the feasibility of interventions using ZDV/3TC or nevirapine for reducing MTCT in the developing world, one study looked at use of the (previously un-researched in this setting) nucleosides ddI and d4T. This research offers mothers and clinicians other possible antiretroviral options for reducing vertical transmission in resource poor populations.

Dr Glenda Gray’s group aimed to evaluate the efficacy, safety, tolerability, and PK of oral d4T vs. ddI vs. d4T plus ddI vs. ZDV in HIV-1 infected mothers for the prevention of vertical transmission to their (formula-fed) infants [7]. 204 pregnant HIV-1 infected antiretroviral naive women from South Africa who were at weeks 34-36 gestation were randomised to oral prepartum and intrapartum treatment of either d4T, ddI, d4T/ddI, or ZDV, followed by 6 weeks of oral postpartum therapy of the same drug to their babies. This was an interim analysis of this ongoing study.

At six weeks the analysis of 197 women revealed transmission rates that were 4.2%; 1.9%; 2.0% and 6.3% in the d4T; ddI; d4T plus ddI and ZDV arms respectively. An intention-to-prevent analysis including all lost to follow up and infant mortalities showed 8.3%; 3.8%; 10% and 14.3% an overall average of 9%. 17% of women had an viral load of<50 copies/ml and 35% of <400 copies/ml at birth.

No significant treatment related adverse events were observed in either mothers or their babies. There is yet no resistance data for these strategies but they will be reported in the forthcoming final analysis.

Breastfeeding

There is still no clear consensus on the risk/benefits breast vs. formula feeding despite the number of presentations devoted to this topic. The most shocking findings on this subject, were reported by Dr Ruth Nduati collected from her randomised clinical trial to determine the impact of breastfeeding on mortality in a group of HIV-1 infected women attending clinics in Nairobi [8].

425 women were randomised to either formula or breastfeed (212 in the breastfeeding arm and 213 in the formula feeding arm). 18 mothers from the breastfeeding arm and 6 from the formula arm died during follow up. At 24 months the probability of maternal death was 10.5% in the breastfeeding arm and 3.8% in the formula arm (p=0.02). 69% of the deaths in the breastfeeding arm were attributed to breastfeeding. Overall there was a threefold increased risk of maternal mortality associated with breastfeeding.

Findings from the PETRA trial attributed a significant number of cases of vertical transmission to breastfeeding in a cohort (70% breastfeeding population) receiving prophylaxis regimens [9]. 1754 HIV-infected women were randomised to one of the following arms: a] ZDV/3TC initiated at week 36 of pregnancy, then intrapartum and for both mother and baby for one week after delivery; b] ZDV/3TC intrapartum and one week after delivery – mother and baby; c] ZDV/3TC intrapartum only and placebo.

For both arms a] and b] transmission was reduced significantly at 6 weeks compared to placebo: 9.2%; 12.6% and 19.2% respectively and arm c] was no different from the placebo (18.4%). By 18 months no significant difference was found between arms – a] 20.7%; b] 24.4%; c] 25.7%; placebo 26.6%.

Note: 24 week data was presented at Durban by which time the placebo arm was discontinued (in December 98 after the publication of the Thai data [10].

The investigators are analysing the timing of the HIV-infection transmission at 6, 9 and 12 month of the babies’ life. They hope to then develop feasible strategies to overcome this.

Finally one study presented a method by which HIV-infected women may express and pasteurise their breast milk in a domestic setting [11] Called Pretoria Pasteurisation it uses the principle of passive heat transfer and simple and inexpensive apparatus. This method resulted in undetectable levels of HIV-1 virus in expressed breast milk and research into this novel strategy is ongoing.

Resistance

Resistance data was presented from the PACTG 316 trial [12] – to evaluate the efficacy of nevirapine vs. placebo to reduce mother-to-child-transmission, for women also receiving open label antiretrovirals (not including NNRTIs). The nevirapine resistance mutation K103N was detected in 4/32 of women with viral loads >3000 and 3 women also had resistance mutations to the PIs in their regimens.

Also new data from the HIVNet 012 trials [13] revealed resistance mutations in 7/30 (23%) of women whose infants were HIV-infected. All women were found to have the K103N mutation and 1 woman also had the Y181C and another the Y181C and V106A. The K103N mutation was detected in 1 infant and the Y181C mutation was detected in 2 infants. The maternal infant genotypes were different for each mother-infant pair, which suggests that NVP resistant HIV-1 variants in the infants may have been selected by the NVP rather than transmitted from mother to child.

Both presenting authors Dr John Sullivan and Dr Brooks Jackson, respectively, emphasised that these findings about nevirapine resistance should in no way influence any decision to delay prevention strategies. Dr Sullivan stated, ‘It should no way prevent implementation of this simple intervention for prevention of mother-to-child-transmission throughout the world’, and Dr Jackson agreed and when questioned, concluded that ‘It is important to recognise that treatment options are very rare in countries receiving this treatment’.

Comment

The finding that monotherapy ddI had such a strong impact on MTCT may be unexpected and deserves further investigation.

It may be that ddI, which works selectively in different cell-types to ZDV and d4T, has a disproportional impact on this mode of transmission.

References:

Unless stated otherwise, references are to the Programme and Abstracts of the XIII International AIDS Conference, 9-14 July 2000, Durban, South Africa.

  1. UNAIDS – Report on the global epidemic. Geneva. June 2000-08-02.
  2. Hammett et al. Progress towards elimination of perinatal infection in the United States. XIII International AIDS Conference; Durban, July 9-14. Abstract MoOrC239.
  3. Fiore et al. Challenges in performing a randomised double-blind clinical trial: the European arm of the PACTG-nevirapine trial. XIII International AIDS Conference; Durban, July 9-14. Abstract TuPeB3248.
  4. Beckerman et al. The impact of combination therapy on maternal health and pregnancy outcome. XIII International AIDS Conference; Durban, July 9-14. Abstract MoPeB2198.
  5. Blattner et al. Effectiveness of potent antiretroviral therapies on reducing perinatal transmission of HIV. XIII International AIDS Conference; Durban, July 9-14. Abstract Lb01.
  6. Gray et al. Preliminary efficacy, safety, tolerability and pharmacokinetics of short course regimens of nucleoside analogues for the prevention of mother-to-child transmission of HIV. XIII International AIDS Conference; Durban, July 9-14. Abstract TuOrB355.
  7. Nduati et al. Impact of breastfeeding on maternal mortality among HIV-1 infected women. XIII International AIDS Conference; Durban, July 9-14. Abstract WeOrC495.
  8. Gray et al. The PETRA study: early and late efficacy of three short ZDV/3TC combination regimens to prevent MTCT of HIV-1. XIII International AIDS Conference; Durban, July 9-14. Abstract LbOr5.
  9. Shaffer et al. Short course zidovudine for perinatal HIV-1 transmission in Bangkok Thailand. Lancet 353:773-780, 1999.
  10. Jeffery et al. Determination of the effectiveness of inactivation of HIV in human breast milk by Pretoria Pausteuisation. XIII International AIDS Conference; Durban, July 9-14. Abstract MoPeB2201.
  11. Sullivan et al. Genotypic resistance analysis in women participating in PACTG 316 with HIV-1 RNA >=10,000 copies/ml. XIII International AIDS Conference; Durban, July 9-14. Abstract LbOr14.
  12. Jackson et al. Selection of nevirapine resistance mutations in Ugandan women and infants receiving nevirapine prophylaxis to prevent HIV-1 vertical transmission (HIV NET 012). XIII International AIDS Conference; Durban, July 9-14. Abstract LbOr13.

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