Low rates of mother to child transmission in the DREAM and MTCT-Plus programmes
Polly Clayden, HIV i-Base
There is ongoing discussion around the best way to manage pregnant women not indicated for treatment for their own health. Two recent publications reported findings from alternative approaches offering treatment at all disease stages and a ‘two tiered strategy’. Both report low rates of mother-to-child- transmission (MTCT).
The DREAM programme
The Drug Resource Enhancement against AIDS and Malnutrition (DREAM) programme is a large ART programme with sites in sub-Saharan Africa. A major part of the DREAM programme is nutritional supplementation and prevention of mother-tochild transmission (PMTCT) of HIV.
A paper authored by Leonardo Palombi and coworkers published in AIDS supplement 4, 2007, presented findings from a comparison of two cohorts of pregnant women enrolled in the DREAM programme. The cohorts were followed prospectively and the investigators evaluated transmission rates and infant morbidity and mortality.
In this programme HIV-positive pregnant women receive HAART (3TC and nevirapine, plus either AZT or d4T) free of charge from 25 weeks gestation, at all clinical stages, CD4 counts, and viral loads. The infants receive post-exposure prophylaxis.
The investigators explained: Many PMTCT programmes fail to provide continuing treatment and care to mothers. It is difficult to have to tell a woman that she can avoid transmitting the infection to her child, but that little can be done for her own health. Under these circumstances, the refusal rates and no-return rates for those who are tested remain high.
From 2004 to 2006, women in Mozambique, Tanzania, and Malawi received water filters and formula milk for the first 6 months of the infants life. In the second cohort starting in 2005 until 2006 in Mozambique, women received HAART for up to 6 months after delivery and were given the option to breastfeed. In the first cohort, 879 live-born infants were delivered after 914 pregnancies, with 809 evaluable infants at 1 and 6 months.
In the second cohort, 341 infants were delivered and evaluable at 1 month, and 251 infants were evaluable at 6 months. Follow up is ongoing in this cohort.
At 1 month, HIV transmission rates (TR) were 4/341 (1.2%) among breastfed infants and 7/809 (0.8%) among formula-fed infants. At age 6months, TR was 2/251 (0.8%) among breastfed infants of women receiving HAART and 15/809 (1.8%) among formula-fed infants (p=0.38).
The cumulative incidence rate at 6 months was 2.7% for formula-fed infants and 2.2% for breastfed infants (p=0.60). The investigators noted a trend for TR to be slightly greater among formula-fed infants. They suggested that this is probably explained by some mixed feeding in this cohort. Overall, mother-to-child transmission rates in both cohorts were extremely low.
Most infants did well on both feeding regimens. Observed Z scores were greater than among the general infant population. Z scores </=2.0 for weight by age occurred in 92/809 formula-fed infants (11.4%) and in 28/251 breastfed infants (11.1%).
The rates of anaemia in the infants were also lower than that of the general population. 40/809 (4.9%) formula-fed infants and i17/251 (6.8%) breastfed infants (p=0.33) had a hemoglobin value <8g/dl.
Infant mortality rates were similar in the two cohorts. At 6 months 27 per 1000 person years among formula-fed and 28.5 per 1000 person years among breast- fed infants. (Compared to 100 per 1000 person years observed in Mozambique).
The investigators wrote: Our data clearly demonstrate that decreasing the rates of transmission of HIV from mother to child in Africa to those reported by high-income countries is feasible, efficacious, safe, and highly achievable even in the poorest of settings. Prenatal administration of HAART, starting as early as 25 weeks of gestation in our programme, was highly tolerable and was safe for mothers.
The MTCT-Plus programme
A paper in the PLoS medicine authored by Besign Tonwe-Gold and coworkers reported an evaluation of the two-tired PMTCT strategy of The MTCT-Plus Initiative in Abidjan, Cote DIvoire. In this programme women receive either HAART if indicated for their own health or short-course antiretroviral (scARV) PMTCT. The study included all HIV-positive pregnant women and their live-born infants enrolled between August 2003 and April 2005 and followed until their HIV status was confirmed.
261 HIV-positive pregnant women were enrolled and 250 were prescribed ARVs before and/or during delivery. The majority of women eligible for HAART (102/107), received AZT+3TC+ NVP Treatment was initiated at a median of 30 weeks gestation. The median CD4 count of eligible women was 189 cells/mm3 (IQR 135-266 cells/mm3). Of the 143 women who received scARV for PMTCT, the median CD4 count was 467 cells/mm3 (IQR 368602 cells/mm3).
Median gestational age at prophylaxis initiation was 34 week (IQR 3236 wk) and median number of days on scARV drug regimens was 46 days (IQR 3165 days); 103 women (72.0%) received sc(AZT+3TC) with sdNVP during labour, 26 (18.2%) scAZT with sdNVP, and 14 (9.8%) sdNVP alone.
All infants received AZT syrup for 7 days and sdNVP syrup on day 3. Most (75%) of the infants were breast-fed for a median of 5 months.
Overall HIV status could be determined for 225 infants (97.4%); 12 were diagnosed HIV-positive. The overall probability of HIV infection was 2.2% (95% CI 0.3%4.2%): 1.0% (95% CI 0.0%3.1%) in the HAART group and 3.1% (95% CI 0.1%6.1%) in the scARV for PMTCT group. At 12 months, 5.7% (95% CI 2.5%9.0%) of the infants were diagnosed HIV-positive: 3.3% (95% CI 0.0%6.9%) in the HAART group and 7.5% (95% CI 2.8%12.3%) in the scARV for PMTCT group (p= 0.18).
In multivariate analysis, low birth weight (<2,500 g) was the only factor associated with HIV infection, with an adjusted hazard ratio of 5.63 (95% CI 1.6219.49, p = 0.006). 191 infants were thus included in a post natal transmission analysis (87 in the HAART group and 104 in the scARV for PMTCT group) including 138 breast-fed infants (52 in the HAART group and 86 in the scARV for PMTCT group).
The median duration on HAART in breast-feeding women was 14.9 months (IQR 14.516.2 months) when the final infant diagnoses were determined. Overall, four infants had a confirmed postnatal infection (2.3% [95% CI 0.8%7.3%]). In the HAART group, one case of postnatal infection was identified from 52 infants (1.9% [95% CI 0.04%10.2%]) breast-fed for a median 4.7 months (IQR 3.36.3 months). In the scARV for PMTCT group, three cases of postnatal infection were identified from 86 infants (3.5% [95% CI 0.7%9.9%]) breast-fed for a median of 5.7 months (IQR 4.37.1 months).
The investigators hypothesised that if the three cases with unknown timing were postnatal cases, this would give a rate of postnatal transmission of 3.8% (0.4%12.9%) in the HAART group and 5.7% (1.8%12.7%) in the PMTCT group.
No case of postnatal infection was identified among the 53 infants who were formula fed (upper limit of 95% CI, 6.7%). One death of an HIV-positive, formula-fed infant was reported. The overall probability of HIV infection or death among all infants aged 12 months was 11.7% (95% CI 7.5%15.9%); the probability was 11.2% (95% CI 5.0%17.4%) among infants born to HAART-treated women, and 12.1% (95% CI 6.4%17.9%) among infants whose mothers received scARV for PMTCT only (p = 0.90). In multivariate analysis (n = 231): low birth weight (AHR 3.71 [95% CI 1.539.03], p = 0.004) and female sex (AHR 0.35 [95% CI 0.140.88], p = 0.035) were associated with HIV infection or death.
There were 18 deaths in this cohort: 10/99 (10.1%) infants born to woman who had initiated HAART during pregnancy and 8/132 (6.0%) infants who were born to women who received short-course antiretroviral prophylaxis. This report also included some data on maternal health. 9/107 (8.4%) pregnant women initiating HAART required one switch in their regimen before delivery. One woman switched from NVP to efavirenz after 6 weeks of treatment (32 weeks gestation) following diagnosis of tuberculosis.
There were a number of toxicities. Eight women (7.5%) developed grade 3 or 4 adverse events associated with HAART: five women developed grade 3 rash attributed to NVP and were switched to nelfinavir, and two women developed grade 4 liver toxicity attributed to NVP, with alanine aminotransferase levels over 50 times and over 5 times the upper limit of normal value, respectively in the two groups of women; one woman developed severe anaemia attributed to AZT.
All adverse events were resolved with drug switches and no deaths were reported. In the cohort of women receiving scARV for PMTCT, no grade 3 or 4 toxicities were observed and no ART changes were made.
Stillbirths and neonatal deaths in the first 28 days of life were comparable in the HAART and scARV for PMTCT groups: 6.7% and 5.6%, respectively (p = 0.80). There was no significant difference in the rates of premature births (gestational age <37 week) between the two groups (7.8% and 7.9% respectively, p = 1.00).
A higher proportion of low birth weight (<2,500 g) was observed in infants whose mothers had received HAART, 26.3% compared with 12.4% among those having received a scARV for PMTCT regimen (p <0.001).
Caution over giving HAART to all pregnant women irrespective of disease stage has been driven by concerns about maternal toxicity particularly associated with nevirapine and preterm delivery and other complications with the infant. Investigators from the DREAM programme previously reported low incidence of grade 34 adverse reactions associated with nevirapine toxicity (hepatotoxicity, skin rashes and StevensJohnson syndrome) of 6.5, 2.4 and 1.1%, respectively. Their data did not confirm an association between hepatic toxicity and high CD4 cell count. 
Concerning preterm deliveries, miscarriage and still birth the DREAM investigators suggest that these events appear to be significantly reduced in women receiving HAART in pregnancy in this programme [personal communication]. They are currently preparing to present these findings.
The MTCT-Plus study also found that HAART was relatively safe during pregnancy, although these numbers are small do not offer any information about women receiving HAART with higher CD4 counts. 7.5% of women receiving HAART developed side effects requiring a change in their medications.
There was no significant difference in the rate of preterm delivery between the two groups but infants born to women receiving HAART were more likely (26.3%) to have low birth weight than babies born to women who received short course ARV (12.4%).
- Palombi L, Marazzib MC, Voetbergc A et al. Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV. AIDS 2007, vol 21(supp 4):S65-S71.
- Tonwe-Gold B, Ekouevi DK, Viho I et al. Antiretroviral treatment and prevention of peripartum and postnatal HIV transmission in West Africa: Evaluation of a two-tiered approach. PLoS Medicine Vol. 4, No. 8, e257 doi:10.1371.
- Marazzi MC,Germano P,G Liotta G et al. Safety of nevirapine-containing antiretroviral triple therapy regimens to prevent vertical transmission in an African cohort of HIV-1-infected pregnant women. HIV Medicine (2006), 7, 338344.