The government should look at the science and not the myths perpetuated about nevirapine, reports Belinda Beresford
If South Africa wants to save 70000 children a year from a premature death, then the duststorm of confusion about the use of anti-retroviral drugs to prevent pregnant women from passing the HI virus on to their babies needs to be dampened down.
Catalysed by the Treatment Action Campaign’s court case against the Department of Health, the debate over the drug nevirapine appears to have bewildered even eminent thinkers on the science of the issue.
About 200000 HIV-positive women give birth each year in South Africa. Without treatment, about a third of them are likely to transmit HIV to their offspring, either during the pregnancy (intrauterine), during labour and birth (intrapartum) or by breastfeeding after birth (post-partum).
In countries such as the United States, the use of anti-retroviral drugs has helped to make the birth of HIV-positive children a rare event.
In 1994 studies showed that the anti-retroviral drug, zidovudine more familiarly known as AZT could halve the chances of a pregnant woman giving HIV to her child. According to the American Centres for Disease Control (CDC), before AZT was used, up to a quarter of HIV- positive women in North America and Europe passed the virus on to their children. By 2000/2001 anti-retroviral drugs, coupled with other interventions, had reduced the transmission rate in the US to less than 2%.
In its latest guidelines on the issue, the CDC says: ”The birth of every perinatally HIV-infected infant is a sentinel health event signaling either a missed prevention opportunity or, more rarely, a failure of prophylaxis.”
In 1999 a study in Uganda known as Hivnet 012 found that nevirapine was almost 50% more effective than AZT at saving newborns from HIV infection. By the time they were between 14 and 16 weeks old, just more than 13% of babies dosed with nevirapine were carrying the virus, compared to just more than 25% of those given AZT.
The nevirapine regime, which gave the mother a pill during labour and a dose to the child within three days of birth, was also much easier to administer than the AZT treatment, which had to be given over several weeks before labour.
The trial had a placebo arm, where the mother was not given a drug, to see what would happen if there was no intervention. But when a study in Thailand confirmed the effectiveness of AZT in cutting infection of newborns, the placebo arm was dropped because it was considered unethical not to provide the drug.
The health department’s lawyer has described nevirapine as a ”brand new drug”. In fact it was one of the first drugs of its kind when it hit the market in 1996. The first clinical trial into the use of nevirapine for pregnant women was reported three years later in Uganda.
A significant argument for not providing all pregnant women with access to nevirapine has been the drug’s toxicity. Like all other anti-retrovirals, it is a highly potent and therefore potentially an extremely poisonous compound. However, its effectiveness and relatively low price mean it is widely used to treat HIV/Aids.
Nevirapine is a non-nucleoside reverse transcriptase inhibitor, also known as an NNRTI or a ”non nuke”. These block the enzyme that retroviruses like HIV use to hack into the DNA of host cells, and convert them into virus production factories. Unfortunately they also affect normal chemical processes in the body, producing varying side effects. For nevirapine the most common ones are rashes and liver problems extreme cases of both kill patients.
A crucial point that appears to be misunderstood by many arguing against the use of nevirapine in mother-to-child transmission is that the side effects come from repeated use of the drug during ongoing treatment of HIV. They do not occur when just one pill is given to a patient, which is all that the mother need take to slash the chances of her child catching HIV during labour. The newborn is then treated with another dose within 72 hours of birth.
Researchers think that nevirapine works in two different ways. It kills the virus circulating in the mother during labour, reducing the chances that it will infect the child. And in the baby it kills the virus before it can entrench itself in its cells.
Although several anti-retrovirals have been tested for use in protecting unborn children, nevirapine is very popular in developing countries. The drug quickly moves across the placenta to the child and into the breast milk, and it has a long half life. This means that it takes a long time to be cleared from the body, so one dose will work quickly which is why it can be given during labour and for an extended period of time.
Unfortunately this property also contributes to a more problematic aspect of nevirapine therapy: resistance.
One of the keys to HIV’s success is its ability to quickly become resistant to medication. A careless virus, HIV frequently makes mistakes when replicating, meaning that high numbers of mutations are produced, and some of these confer immunity to drugs on the virus. In long-term therapy anti-retrovirals are almost always given in groups of two or more so that even if the virus is resistant to one drug, it will be susceptible to the other.
The implications of resistance are huge: HIV proof against one drug may also be immune to all other drugs in the same class. And since there are only four classes of antiretrovirals, the unfortunate drug-resistant carrier faces greatly reduced treatment options.
While this is bad news for the patient, even more worrying from a public health point of view is the prospect of the drug-resistant strain being transmitted to other people.
Unfortunately, HIV just needs one commonly found mutation to become resistant to nevirapine. Studies in Kenya found that about a quarter of women show resistance to nevirapine after taking just one pill. This has been a highly publicised concern of the public health service, with government officials raising the spectre of thousands of women and children becoming resistant to nevirapine.
However, follow-up studies show that the drug-resistant strain appears to disappear a few months after the nevirapine has been taken. It reverts to the ”wild type” that the woman was originally infected with.
On a practical level, drug resistance is only a problem if the patient is likely to receive chronic anti-retroviral therapy. Since, at least in the immediate term, the vast majority of South Africans currently infected with HIV are unlikely to even see anti-retroviral drugs, let alone be treated with them, it is not really that pressing an issue.
The government’s aim is to ensure that children born to HIV-infected mothers are able to grow into healthy, HIV-negative two year olds. The problem, it says, is that children protected by being given nevirapine at birth will simply be infected later through breastfeeding. So giving nevirapine will be a waste of resources unless it is accompanied by a full programme including counselling and safe access to formula feeding. But to bottle-feed, women need clean water, facilities to sterilise feeding equipment and cheap or free formula food. For decades doctors have pushed the ”breast is best” message, driven by the horrendous levels of illness and child mortality associated with bottle feeding by impoverished mothers.
Giving nevirapine means that about half the children at risk of catching HIV from their mother during birth will be saved from the virus. Of these, some will definitely be infected later through breastfeeding.
No matter how powerful, a pill given at birth cannot protect a child a year later. But it can reduce the cumulative chances of that child being infected with HIV in its first two years by lowering the odds against it from birth.
The government has argued that a Ugandan trial, the Petra study, showed that by the time they were two years old there was no different between treated and untreated children.
But other research, including the subsequent Hivnet trial in Uganda, has shown that the children who received anti-retrovirals maintain an advantage over those who do not, albeit one that diminishes as the length of breastfeeding continues.
In citing Petra, officials miss one crucial fact: the women surveyed breastfed for an average of 18 months. In the Hivnet study, the women only breastfed for an average of nine months. This simple intervention of reducing the period of breastfeeding meant that the dramatic difference in HIV infections among treated and untreated children continued for a full two years of monitoring.
But in South Africa surveys indicate that women breastfeed for an average of only six months. So the cumulative odds against a child are much lower, especially if he or she is given nevirapine at birth.
Eric Goemere, of Mdcins sans Frontires, started a clinic in Khayelitsha that provides AZT therapy to cut mother-to-child transmission. Unlike the government, he believes that his clinic has shown that women in peri-urban or urban areas can feed their children with formula rather than breast milk, especially if formula food is provided free or cheaply.
The Treatment Action Campaign court case argues that giving access to nevirapine to about 90 000 pregnant women at risk of giving their child HIV is unfair to the 100 000-odd also at risk but not covered by the national pilot programme. Just as in Uganda it was unethical to continue with the use of a placebo, so increasing numbers of doctors argue that it is unethical to fail to provide access to nevirapine to all.
Dr Glenda Gray, based at Chris Hani Baragwanath hospital, is one of the world’s leading researchers into the issue. She believes that the known benefits of nevirapine greatly outweigh the known risks. Other potential problems such as long-term resistance should be researched, but not used as a justification to hold back on treatment: ”These issues are being debated in the armchairs of science, but as yet there is little practical significance as far as we can see. Do all these theoretical unknowns outweigh the benefits of nevirapine? Is it better to kill babies with HIV and withhold nevirapine because of future unknowns?”