Treatment for babies can block HIV breast milk transmission

The preliminary results of the SIMBA study, reported as a late breaker at the 2nd IAS Conference on HIV Pathogenesis and Treatment in Paris, are that treating breast-fed babies with either nevirapine (NVP) or lamivudine (3TC) can greatly reduce, though not eliminate, breast milk transmission of HIV.

The study is open to different interpretations, since there was no untreated control group of babies, and so the evidence that NVP or 3TC prevented transmission depends on comparisons with other studies. However, the study is large enough to make it likely that there is, indeed, some protection. It is clear from large studies such as a recent one reported from Zimbabwe that breast milk transmission is a major contributor to the continuing high rates of HIV transmission to children in Africa, accounting for up to 40% of cases (Zijenah).

SIMBA is a randomised open-label clinical trial in Uganda and Rwanda. The babies' mothers received zidovudine (AZT) and didanosine (ddI) from 36 weeks of pregnancy until 1 week after the baby's birth, but were not otherwise receiving ARVs during the time for which the babies were treated.

397 infants born to women with HIV who had enrolled in the study were randomised to receive 3TC (n=199) or NVP (n=198). HIV status was assessed using HIV-1 DNA and RNA PCR from 4 weeks to 6 months of age. Exclusive breastfeeding for 3 to 6 months was strongly supported throughout the trial, through counselling. The great majority of infants in both arms of the study were exclusively breastfed: 90.5% in the 3TC arm and 86.5% in the NVP arm, exclusive bottle feeding was given to 2.5% and 3.5% respectively, and other babies received mixed feeding. The overall rate of HIV transmission to babies was 10% and the combined risk of HIV or death was 13%.

Antiviral treatment for the babies was given in the form of syrup, and was given at a lower dose for the first two weeks than for the remainder of the period on treatment. In the nevirapine group, this was 2mg/kg once daily followed by the same dose twice daily. Treatment continued for four weeks after the cessation of breast feeding. The estimated cost was around US $150 per baby for each course of treatment, although this might be reduced either through donations from international pharmaceutical companies or the wider availability of paediatric formulations from generic companies.

Over 5 months in which all but 3% of babies were breastfed, only 3 babies out of 358 became HIV positive - a rate of 2 per 100 baby years compared to an expected rate of 10 per 100 baby years (or more) without treatment. There was no significant difference between 3TC and NVP in mortality, HIV transmission rates or 'adverse events' - none of which were considered to be due to the study drugs.

This study may show how babies can be protected against HIV transmission without exposing them to the risks of formula feeding, in settings where formula feeding is unsafe and babies need the extra protection against infections that can be gained from breastfeeding. It also means that parents have an opportunity to protect their babies without questions being asked about why a mother is not breastfeeding.

This strategy also overcomes a potential hazard of short-course ARV treatment in the later stages of pregnancy, which is that women's viral load may rebound on ceasing treatment and actually increase the risk of HIV transmission during breastfeeding (Manigart).

There are a number of outstanding issues and questions which may need to be answered before this form of treatment is widely adopted.

There are still safety issues about the treatments given to the babies. There are serious concerns about using nevirapine for extended periods, especially in people whose immune systems are undamaged. It appears that the risk of severe liver damage is due to a kind of immune reaction that is more common in women, and especially those with CD4 counts over 350. The safety of 3TC in young infants is also of greater concern than its use in adults, to the point where AZT monotherapy is given to infants in mother-to-child transmission programmes rather than AZT plus 3TC.

Another related issue concerns the best form of treatment to prevent HIV transmission at the time of birth. There is now strong evidence that adding two doses of nevirapine, one to the mother and the other to the baby, improves the effectiveness of a short course of treatment with AZT or AZT+3TC.

The Ditrame Plus study team in Abidjan, Cameroon, added nevirapine given according to the HIVNET 012 protocol to AZT+3TC treatment given to pregnant mothers from week 32 (until three days after the baby's birth) and followed by giving AZT to the baby for the first 7 days of its life. The outcome was that they achieved an HIV transmission rate below 5%, although proving that this would be significantly better than the same regimen without the 3TC being given to the mother would need much larger numbers than they could enrol (Dabis).

This reinforces and adds to similar findings from Thailand (Lallemant). In this case, in a population where formula feeding is strongly encouraged, HIV transmission rates in a study that has enrolled 1844 women with 1805 babies, the overall HIV transmission rate is 3.1% including some babies born in a placebo treatment group, which was closed for recruitment after an interim analysis showed a significant advantage for babies treated with two doses of NVP (one to the mother, one to the baby) in addition to AZT.

Thailand has implemented large-scale treatment with AZT to prevent mother to child transmission, and as a result the number of babies diagnosed with AIDS has fallen from a peak of more than 1200 a year to less than 250 a year by 2001 and a rate that is now even lower. It will clearly be feasible to extend the treatment offered in Thailand, but it will be a challenge to match this achievement elsewhere. Less than 3% of women with HIV giving birth each year in Africa are currently receiving any medical help to reduce the risk of HIV transmission to their children, and the great majority remain unaware of their HIV status at the time of giving birth.

Whether short-course treatment is generally adopted, however, will depend on emerging information about the effects of resistance to nevirapine which is being observed in viruses from the mothers. One answer is, for those women whose CD4 count might justify it - with a threshold that might be 350 rather than 200 - to provide full-scale triple combination treatment. There is great interest among researchers in this field in the potential for using other drugs, and especially tenofovir, in place of one or more of the drugs currently being used. However, there is some frustration at the slow pace of clinical trials that could allow this and other options to become available.