Preventing mother-to-child transmission
More than a decade ago, researchers first found that antiretroviral (ARV) drugs given to women during childbirth could greatly reduce the risk of HIV transmission to their babies. Yet children are still acquiring HIV at an alarming rate. A 2004 report from the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated that 630,000 children worldwide were newly HIV-infected in 2003.
The transmission of HIV from mother-to-child can occur at three points: during pregnancy while the baby is still in the womb; during childbirth; or after birth from exposure to HIV-infected breast milk. Exactly how infection occurs at each of these points is unclear, but ARVs can help prevent a mother from transmitting HIV to her baby at each stage. In 1994, zidovudine (AZT) was the first drug found to reduce the risk of mother-to-child transmission of HIV. AZT was also the first drug approved by the US Food and Drug Administration as a treatment for HIV infection. Mothers who took AZT from early in pregnancy through childbirth could reduce transmission rates to as low as 8% after 18 months if they did not breast feed (PACTG 076), compared to a 25% transmission rate for those not taking AZT.
Another large study found a simpler way of lowering the risk of HIV transmission to newborns. HIVNET 012 was the name of a trial that took place in Uganda with the ARV nevirapine and concluded that just a single-dose given to the mother during labor and a single-dose to the baby (within three days of birth) was also effective at lowering the baby's risk of acquiring HIV. The rate of transmission after 12 months in breast feeding women was 16% with this course of treatment compared to rates upwards of 25% in those not taking nevirapine. Researchers hailed this approach because it was relatively simple to administer and successful at preventing transmission.
"Single-dose nevirapine gave countries overwhelmed by the problem of mother-to-child transmission the ability to start services. These services have provided the foundation for treatment access," said James McIntyre of the University of Witwatersrand in Johannesburg at a major HIV scientific conference held recently in the US.
Nevirapine remains the cheapest and most available method for preventing mother-to-child transmission (PMTCT) of HIV in many countries. But it is not the perfect solution. There is evidence that taking nevirapine only during pregnancy can negatively affect the mother's response to ARVs later on because it allows the virus to develop resistance to this type of drug. A single-dose of nevirapine is also unable to protect babies from HIV infection through breast feeding, which is responsible for many new infections in children.
Also, several other trials have since shown that combinations of ARVs can reduce risk of transmission even further. For these reasons, clinicians in Africa are calling for newer approaches to become available so that mother-to-child transmission can be eradicated.
Creating access and demand
Many countries have designed and implemented national PMTCT programs but the treatments offered can vary greatly by country due to the availability and cost of ARVs. The options can even vary by city. Thailand was one of the first countries to adopt a nationally-supported PMTCT program and now offers a short course of AZT plus single-dose nevirapine to mothers during the last weeks of pregnancy and childbirth and to the baby at all public hospitals. This program prevents 2,600 new pediatric HIV infections every year.
But in some countries where PMTCT programs are available, it is estimated that only 3% to 10% of women who are in need will access them this year. The lack of uptake occurs for many reasons. In some countries women cannot access programs in rural areas because services are not yet available. Some women may not find out they are HIV-infected until after childbirth. Others may not use any healthcare services at all during pregnancy and therefore miss the chance for PMTCT entirely. "Many women deliver at home and may not ever have the chance to benefit from a simple yet effective intervention," says Chrispin Kambili, IAVI's Regional Medical Director in Kenya.
In addition to getting more women access to PMTCT programs, physicians are also concerned with improving available treatments. In South Africa the only course of treatment nationally recommended for PMTCT is a single-dose of nevirapine. This is a controversial issue in countries like South Africa that are currently improving access to ARVs, according to Glenda Gray, Director of the Perinatal HIV Research Unit in Soweto, South Africa. Despite the simplicity of using nevirapine, taking this drug during childbirth could compromise a woman's response to ARV treatment with other drugs in the future.
After a single-dose of nevirapine during childbirth HIV can develop resistance to this drug that can last from several months to over a year. If a woman is placed on combination ARV therapy with nevirapine or a similar ARV soon after receiving single-dose nevirapine to prevent transmission to her baby, this resistance can result in a poorer response to treatment. Though all ARVs are associated with resistance, it is easy for HIV to develop resistance to nevirapine and other ARVs in the same class. Once this happens the drugs do not work as well against the virus.
Information about how many HIV-infected women will have virus that develops resistance after a single-dose of nevirapine varies between studies. The most recent reports suggest that as many as two-thirds of women in clinical trials may have resistant virus after receiving one dose of nevirapine. But the precise effect this resistance will have on future treatment is unknown.
A recent study by Gray and colleagues provides some of the first information on how resistance to nevirapine affects transmission rates during second pregnancies. This study suggests that single-dose nevirapine is still beneficial for PMTCT during a second delivery.
Apart from potential resistance problems, nevirapine has proven a safe and effective PMTCT drug. The side effects that are associated with long-term use of nevirapine—including possible liver damage—are not a problem when used as a single dose.
Moving beyond nevirapine
To avoid the development of resistant HIV in mothers, researchers set out to find better PMTCT treatments. Treating women with more than one ARV is one way to minimize the development of resistance. One approach is to give mothers a combination of nevirapine and Combivir (AZT and a similar drug called 3TC) during delivery, and Combivir alone to both mothers and babies for a week after childbirth. This can reduce the rate of HIV resistance and lower the HIV transmission rate to below 5%.
According to Gray this course of treatment is the next best thing to putting mothers on a combination of ARVs known as HAART (highly active antiretroviral therapy). Women receiving HAART will have a lower viral load, which is the best way to prevent babies from acquiring HIV. Mothers on this treatment have only a 2% chance of transmitting HIV to their babies. Gray hopes the South African government will adopt the nevirapine and Combivir approach for PMTCT in the absence of HAART.
"For us, nevirapine was a good place to start, but we need to move with the times. It is not eradicating pediatric AIDS cases. We should accept nothing less than complete eradication. Anything else is a compromise," she says.
The positive results from recent studies using combinations of drugs have renewed interest among researchers and activists to convince governments to offer treatments that are more effective. The Elizabeth Glaser Pediatric AIDS Foundation recommends single-dose nevirapine as a part of PMTCT programs only in places where there is no other option. The foundation recently released a statement after meeting with leaders in this field and referred to single-dose nevirapine as the "absolute minimum" all women should receive.
Researchers are also emphasizing the need for research into newer drugs to prevent children from contracting HIV. A newer ARV called tenofovir is a promising candidate for PMTCT because it is unlikely to cause resistance and would be easier to administer during childbirth than a combination of drugs. Trials to test its efficacy for PMTCT are still in the planning stages.
Limiting transmission through breast feeding
Researchers are also looking at interventions that can protect babies from becoming infected with HIV during breast feeding. The drugs administered during labor can only partially prevent transmission during the breast feeding period. It is estimated that half of all new pediatric HIV cases in 2003 occurred at this stage. The quantity of HIV in breast milk depends on a woman's viral load. In general, about 80% of breast milk samples from HIV-infected mothers contain the virus.
The most effective approach to avoid transmission through breast milk is to use infant formula for feeding. In more urban areas, women are likely to accept this as an alternative. The South African government provides formula free to HIV-infected mothers for the first six months, which is a relatively short time to transition to solid food. The government of Thailand provides new mothers with enough formula for the baby's first year.
This solution may be impractical in rural areas where women may lack the clean water necessary to prepare formula. Others choose not to use formula to avoid being stigmatized as HIV-infected within their community where breast feeding is more common. For women who breast feed, extended treatment with ARVs and early weaning can help lower the baby's risk of acquiring HIV. "Opportunities exist to stop transmission of HIV through breast feeding and should be used," says Gray.
Ideally all women would receive a combination of ARVs when they discover they are infected and this could prevent them from transmitting HIV to their babies during pregnancy, delivery, and throughout breast feeding. This is the goal in countries where treatment programs are becoming more widely available. "There should be no reason why women in South Africa don't receive combination therapy," says Gray.