Low transmission rates and favourable pregnancy outcomes reported in the DREAM study

5 October 2009. Related: Conference reports, Pregnancy, IAS 5th Cape Town 2009.

Polly Clayden, HIV i-Base

Drug Resource Enhancement and Malnutrition (DREAM) is a large HAART programme with sites in sub-Saharan Africa attended by about 75,000 people. A major part of DREAM is nutritional supplementation and prevention of mother-to-child transmission of HIV.

Women in DREAM receive HAART in pregnancy irrespective of their CD4 counts. Those indicated for treatment with CD4 <350 cells/mm³ receive NVP-based HAART from 14 weeks gestation which is continued indefinitely. Women with CD4 >350 cells/mm³ receive HAART from 25 weeks gestation, which is stopped after weaning at 6 months post partum. Women who stop treatment continue to receive AZT/3TC for 21 days to cover the nevirapine PK tail. PCR DNA determines infant infection.

In two oral presentations, Leonardo Palombi presented data from Mozambique and Malawi describing transmission rates and infant outcomes. Both analyses were retrospective record reviews.

Rates of transmission and infant mortality

This analysis looked at:

1. HIV free survival at 1 and 6 months
2. Transmission rates by maternal CD4
3. Infant health at 6 months

Between July 2005 and December 2008, there were 3148 live births from 3273 pregnancies. At one month, 93 infants were lost to follow up, 7 had died, and 2,994 had test results. Of these 22/2994 (0.7%) were HIV-infected.

Transmission was 0.9% (26/2,707) in mothers who received at least one dose of HAART before delivery (median viral load 3.55 log) and 5.1% (2/39) in women who did not initiate HAART until delivery (VL 4.51 log), p<0.001. Infant HIV free survival at one month was 97.6%.

At 6 months, a further 143 infants were lost to follow up and 41 had died. Six-month testing found 15/2120 infected infants (5 awaiting confirmation). The cumulative 6-month transmission rate was 1.4-1.9%, the mortality rate was 2.1% and loss to follow up was 7.5%.

The investigators found that duration of antenatal HAART and the combined endpoint of infant infection or death were associated across baseline maternal CD4 counts: 1.3% (16/1231) vs 3.8% (6/157) infants were infected or died who had mothers with CD4 <350 cells/mm³ who received >=30 days and <=30 days HAART respectively, OR 0.33 (95% CI 0.12-0.86). And 0.7% vs 2% infants were infected or died who had mothers with CD4 >350 cells/mm³ who received >=30 days and <=30 days HAART respectively, OR 0.33 (95% CI 0.10-1.09).

In multivariate analysis at one month, adjusted for maternal baseline viral load, CD4, haemoglobin and BMI, there was an association between antenatal HAART-exposure and transmission or death: 2.4% with 1-30 days, 1.1 % with 31-90 days and 0.9% with >90 days, (OR 0.57; 95% CI 0.36-0.88).

At six months, 3.1% vs 8.8% infants were infected or died who had mothers with CD4 <350 cells/mm³ who received >30 days and <30 days HAART respectively, OR 0.33 (95% CI 0.16-0.7). And 1.8% vs 2.1% infants were infected or died who had mothers with CD4 >350 cells/mm³ who received >30 days and <30 days HAART respectively, OR 0.81 (95% CI 0.24-2.83). ). That is, at higher maternal CD4 counts the impact of HAART > 30 days vs <30 days was not significant.

In multivariate analysis at 6 months, duration of HAART and maternal viral load were associated with transmission or infant death.

At six months, HIV free survival was 90.9% in infants whose mothers had received <30 days pre-delivery HAART, and 96.6% for those whose mothers received >30 days pre-delivery HAART.

Dr Palombi noted that the effect of HAART observed in DREAM was found across all maternal CD4 counts and that mothers with >350 cells/mm³ comprised 37% of transmissions where they occurred

Overall transmission rate at 6 months was 2% in this cohort.

Outcomes

In the second analysis, the investigators looked at maternal health/mortality, and infant outcomes ie prematurity, spontaneous abortion and stillbirth (defined as foetal death at < or >32 weeks gestation respectively).

Overall they reported 42 maternal deaths giving a maternal mortality rate (MMR) of 1.2%. The majority of women in DREAM received longer duration of HAART but 68 women received none and 365 women <30 days HAART. Although infrequent, maternal mortality was significantly associated with HAART (7.4% if no HAART vs 0.7 >90 days antenatal HAART) and CD4 count (3.2% vs 0.7% if >200; p< 0.001).

Foetal death included 3.1% stillbirth and 2.1% spontaneous abortion. The prematurity rate was 19.1%.

Duration of antenatal HAART was associated with infant outcomes. The rate of abortion and stillbirth was 5.2% among infants whose mothers received >90 days HAART compared to 26.5% among those whose mothers received no HAART and 7.1% <30 days HAART, p<0.001.

Maternal CD4 was also associated with abortion and stillbirth, with a rate of 16.7% among mother with CD4 <200 cells/mm³.

In this cohort, prematurity was associated with shorter duration or no HAART. The investigators reported a 70.8% reduction (Mantel-Haenszel test) overall, OR=0.16 (95% CI, 0.12-0.21) and within each CD4 strata.

In multivariate analysis, BMI (OR 0.27; 95% CI,0.15-0.50) and viral load at delivery (OR 1.44; CL95% 1.22-1.70) were associated with prematurity (see Table 1). Low birth weight was 11.5% and not associated with HAART duration or CD4 count.

Table 1: Prematurity rates in DREAM

(Table reproduced from abstract)

The investigators found low incidence of SAEs: 8.6% women had grade 3/4 anaemia; 6.9% d4T-associated peripheral neuropathy; 2.2% grade 3/4 liver toxicity; and 2.4% grade 3/4 rash. However, Stevens-Johnson Syndrome was reported in 1.2% patients.

They also found no resistance in a small sub-study of women (n=26) who had discontinued HAART after weaning.

They wrote: “HAART was strongly associated with improved pregnancy outcomes including reduction in prematurity, regardless of CD4 strata. HAART is beneficial for PMTCT and protects against unfavorable pregnancy outcomes”.

Comment

The data from DREAM seem impressive and it was suggested that they demonstrate that the low rates of transmission now associated with HAART during pregnancy in resource-rich settings can be reproduced in a large roll-out programme in a resource-poor environment.

However, several things make these data very difficult to interpret including significant loss to follow-up and that the number of infants evaluated at different time points is different.

The data on premature delivery and HAART are curious. The authors conclude that short-duration of HAART is associated with prematurity, and at <30 days with as much as 71.4%, these rates are extremely elevated. But perhaps this finding is not surprising since duration is timed from initiation to delivery, and will inevitably be shorter in those who deliver preterm. Data reported by Karin van der Merwe from Johannesburg (reported on in this issue) looking at HAART vs no HAART and longer vs shorter HAART, found higher rates of preterm delivery with HAART and with longer HAART, completely contradicting the DREAM data.

The extensive use of nevirapine-based HAART in this study, with relatively little toxicity reported, despite use at CD4 counts >250 cells/mm³ is also noteworthy and adds to the extensive literature of uncertainty regarding nevirapine, pregnancy and CD4 cell counts.

So these data raise a lot of questions. It was unfortunate that neither the slides nor the webcast from these sessions were available online to check some of the information presented.

Reference:

1. Marazzi MC et al. Extended use of highly active antiretroviral therapy (HAART) during pregnancy in Southern Africa is highly protective in HIV-1 prevention of mother-to-child-transmission (PMTCT) also in women with higher CD4 cell counts. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Oral abstract TUAC101.
   http://www.ias2009.org/pag/Abstracts.aspx?AID=2013
2. Marazzi MC et al. Favorable pregnancy outcomes with reduction of abortion, stillbirth, and prematurity rates in a large cohort of HIV+ women in Southern Africa receiving highly active antiretroviral therapy (HAART) for prevention of mother-child-transmission (PMTCT) 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Oral Abstract TUAC102.
   http://www.ias2009.org/pag/Abstracts.aspx?AID=1874