New Strides in Protecting Infants from HIV

Researchers continue quest to give pregnant women better options to prevent mother-to-child transmission

By Kristen Jill Kresge

More than a decade after researchers first found that antiretroviral (ARV) drugs given to women during childbirth could greatly reduce the risk of HIV transmission to their infants, children are still acquiring HIV at an alarming rate. The most recent data from UNAIDS, the Joint United Nations Programme on HIV/AIDS, 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 (in utero), during childbirth (intrapartum), or after birth through exposure to HIV-infected breast milk. Without any treatment intervention, about 30% of infants become infected through one of these routes. The first study that attempted to lower the mother-to-child transmission (MTCT) of HIV in 1994 showed that AZT—the first ARV approved by the US Food and Drug Administration—reduced the transmission rate to 8% through 18 months post-delivery in breast-feeding women. This strategy was immediately adopted throughout the US and Europe and the number of HIV-infected infants quickly began to decline. Now most HIV-infected pregnant women in wealthy countries with low CD4+ T cell counts receive highly active antiretroviral therapy (HAART), and transmission rates now hover between 1 and 2%. In the US, only around 200 babies are born HIV infected each year.

But using AZT to prevent transmission requires a lengthy course of treatment. Mothers have to receive the drug from early in pregnancy through childbirth and infants must receive treatment during their first six weeks, so women must be diagnosed with HIV infection and have access to prenatal care early during their pregnancy. This is often not possible in developing countries and therefore led researchers to explore alternative ways to halt MTCT.

In 1999 a subsequent study showed that nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), was easier to administer—only a single pill at the onset of labor and a single dose to the baby—and effective at cutting transmission rates by more than half. This was a breakthrough discovery that didn’t require extensive healthcare infrastructure. “Nevirapine is very safe, very simple, and very cheap,” says Marc Lallemant of the Perinatal HIV Prevention Trial Group that works in Thailand. The implementation of single-dose nevirapine programs drastically altered the landscape of MTCT programs, bringing women in developing countries a simple way to protect their newborns from HIV and that has, to date, saved countless infants from the fate of HIV infection.

Single-dose nevirapine still remains the most feasible, effective, and simple regimen for preventing MTCT in many countries. The potential side effects associated with its chronic use, severe and occasionally fatal liver toxicity, have not been reported with short-term use. But the single-dose regimen brings its own complications—the prospect of the emergence of drug-resistant virus. Pregnant women given nevirapine may develop virus resistant to nevirapine that could potentially compromise their future response to ARV treatment with either nevirapine or other NNRTIs like efavirenz. Currently there is sparse clinical evidence to show just how nevirapine resistance might affect treatment outcomes. The World Health Organization (WHO) reviewed the MTCT guidelines last year and decided to maintain single-dose nevirapine as an option based on insufficient evidence on the clinical ramifications of nevirapine resistance.

Meanwhile researchers are focused on balancing the need to preserve nevirapine use in areas where it is the only feasible and effective intervention with finding other regimens that reduce MTCT rates even further and avoid the emergence of viral resistance, maximizing the benefits to the newborn while reducing potential drawbacks for the mother. “If we can minimize resistance we should do that, but it’s not the end of the world. I wouldn’t throw out the baby with the bathwater,” says Lallemant. “We are trying to balance efficacy of the intervention with efficacy of future ARV treatment.”

Recent studies show that administering a combination of ARVs, including nevirapine, can reduce mother-to-child (vertical) transmission rates to below 5%, as well as limit development of nevirapine resistance. Such results inspired the WHO to consider changing its international MTCT guidelines again this year. Researchers in the field hope that the rollout of ARVs and access to newer regimens will help curb the number of pediatric AIDS cases throughout the world. “For us, nevirapine was a good place to start,” says Glenda Gray, director of the perinatal HIV research unit in Soweto. “But we should accept nothing less than complete eradication. Anything else is a compromise.”

Lallemant emphasizes that regardless of which treatment regimen is available, the most pressing crisis in the field is the failure to get women into MTCT programs at all. Estimates are that only 3% to 10% of women who are in need are accessing MTCT programs. This is due in part to the paucity of available services but, even where there are ARVs and prenatal clinics available, uptake is low because pregnant women often fear the stigma associated with HIV infection and will refuse HIV tests. Eradication of pediatric AIDS will require improved access to HIV testing and MTCT programs, not just newer regimens, and this remains one of the most substantial obstacles in many countries.

Pièce de résistance

The study that elucidated nevirapine’s role in preventing MTCT was the HIVNET 012 trial (Lancet 354, 795, 1999) in Uganda, which reported a 13% rate of transmission through 14-16 weeks in a breast-feeding population when both mother and infant received a single-dose of nevirapine. Soon after this trial new programs sprang up in other developing countries. Numerous subsequent follow-up studies have confirmed nevirapine’s efficacy at reducing MTCT to around this level (JAMA 292, 202, 2004; J. Acquir. Immune Defic. Syndr. 34, 274, 2003; J. Infect. Dis. 187, 725, 2003).

Recently the US National Institutes of Health, which ran the HIVNET 012 trial through its HIV Prevention Trials Network (HPTN), was accused of poor record keeping during the study. Although the Institute of Medicine and other independent groups have discredited these claims, the message reverberated throughout countries where nevirapine forms the basis of MTCT programs. Researchers who gathered at the Conference on Retroviruses and Opportunistic Infection (CROI) earlier this year attempted to set the record straight by highlighting the subject of MTCT and nevirapine’s crucial role in the field.

In addition to sparing many thousands of infants from HIV infection, the introduction of nevirapine-based MTCT programs have also served as the impetus for expanded treatment programs that benefit whole communities. According to Lallemant, women who access MTCT programs are more likely to receive ARV therapy when they become immunologically compromised. “Single-dose nevirapine gave countries overwhelmed by the problem of mother-to-child transmission the ability to do something and to start services,” said James McIntyre of the University of Witwatersrand in Johannesburg at CROI. “These services have provided the foundation for treatment access.”

But this year’s CROI meeting also continued the debate over HIV nevirapine resistance. There is now mounting evidence that a significant proportion of women who receive single-dose nevirapine during pregnancy will develop drug-resistant HIV. The development of resistance is problematic because both of the available NNRTIs (nevirapine and efavirenz) can be rendered ineffective by just a single signature point mutation in the virus, a lysine to asparagine substitution at position 103 in HIV’s reverse transcriptase (referred to as the K103N mutation). Many generic ARV combinations that are gradually rolling out in the developing world contain nevirapine.

The development of resistance from a single dose of nevirapine is not surprising. While the drug was an obvious choice for study in MTCT due to its antiviral and pharmacokinetic properties, its prolonged clearance does not come without complications. The drug’s 60-hour half-life translates to gradually declining plasma concentrations for extended periods after dosing, and effective concentrations (10 times the minimum inhibitory concentration) persist for 7 days after the single dose given to neonates. But this means that as nevirapine is slowly cleared thereafter, there is a lengthy widow of opportunity when HIV can develop resistance as doses fall below viral inhibitory concentrations.

Debate has been simmering among researchers for several years over how common and clinically significant this viral resistance will be in women who receive an intrapartum dose of nevirapine. A quarter of the women in the original HIVNET 012 trial had virus with detectable resistance after a single dose of nevirapine. Two other studies at CROI tackled the prevalence of nevirapine resistance. Both groups compared the detection of viral resistance using standard genotypic resistance tests and highly sensitive PCR assays. The sensitivity limitations of conventional genotypic sequencing require a resistant variant to comprise at least 20% of the virus population being tested. The real-time PCR assay has a lower limit of detection of 0.2%. With this approach, researchers found a higher percentage of the K103N mutation in samples from women given single-dose nevirapine MTCT trials. In a presentation by Jeffrey Johnson, from the US Centers for Disease Control and Prevention, viral resistance was reported in an additional 40% of women with undetectable resistance by traditional genotyping (J. Infect. Dis. 192, 16, 2005). In total, 65% of women in this study had detectable resistance mutations after single dose nevirapine.

“This study provides new insights, but as expected when you use a more sensitive technique you will find more resistance,” says Francois Dabis, a pioneer of MTCT research from the University Victor Segalen in Bordeaux, France.

In another presentation, Sarah Palmer of the US National Institutes of Health found that this more sensitive detection technique also revealed that NNRTI-resistance persists longer than originally thought—for at least one year following receipt of intrapartum nevirapine (J. Infect. Dis. 192, 24, 2005).

“Resistance is more frequent and lasts longer when you use more sophisticated assays, but what this means is very unclear,” adds Dabis. “This resistance pattern may have some immunological and clinical consequences but no one knows how important it will be.”

Another study at CROI demonstrated a correlation between the emergence of viral resistance and HIV subtype. Susan Eshleman from Johns Hopkins Medical Institutions in Baltimore, US, presented data indicating that individuals with subtype C HIV infection are more likely to develop nevirapine resistance after a single dose—69% of women with subtype C HIV developed resistance compared to only 19% with subtype A and 36% with subtype D (J. Infect. Dis. 192, 30, 2005).

But to date only one published study has evaluated the clinical relevance of nevirapine-associated viral resistance in women subsequently treated with a combination ARV regimen that contains nevirapine. The authors of this study (NEJM 351, 229, 2004) concluded that women with nevirapine-resistant virus were less likely to achieve viral suppression below detectable limits after six months of treatment with combination therapy containing an NNRTI. Although the treatment was less successful in women previously exposed to nevirapine, the regimen was not rendered completely ineffective.

The six-month interim results indicated that 49% of women in the nevirapine group had undetectable viral loads (<50 vRNA copies/ml), compared to 68% in the placebo group. “It’s nothing new that resistance has an impact on success of therapy, so this isn’t exactly a surprise,” says Lallemant, an author on the study. “The important question is how long these mutations remain biologically significant.”

He is currently collecting the one-year data from this study and will only hint at the expected results with guarded optimism. “We were concerned that women who did not reach viral suppression at six months would have a worse response at one year, but things do not seem to be getting worse,” he says.

Another presentation at CROI from Shayne Loubser of the National Institute for Communicable Diseases in Johannesburg gave researchers more reason to be cautiously optimistic. The K103N resistance mutation does not appear to be archived in viral DNA in the blood for longer than one year after single-dose nevirapine. However, the researchers did not look at virus that might be archived in other compartments and reservoirs.

Scott Hammer of Columbia University wrote in a recent editorial that there is a “moral imperative” to continue efforts to reduce the rate of MTCT while trying to limit the emergence of drug resistance (J. Infect. Dis. 192, 1, 2005) and there are now several options for doing just that. All public hospitals in Thailand offer women either AZT from the 28th week of pregnancy and a dose of nevirapine during labor or HAART if their immunological status mandates. This comprehensive program, which prevents 2,600 pediatric HIV infections every year, has been effective at lowering transmission rates in that country to almost 2%. This approach can be combined with an extended course of AZT to further protect women from nevirapine resistance and is known as adding a “tail” to MTCT therapy. If mothers continue taking AZT during the three-week period after receiving single-dose nevirapine, they are less likely to develop resistance mutations.

Dabis and his colleagues in Cote d’Ivoire presented another innovative, albeit more complicated, approach at CROI from a clinical trial that provided 320 pregnant women in Abidjan with AZT and 3TC, two nucleoside reverse transcriptase inhibitors, starting at 32 weeks gestation. The women also received an extra dose of AZT and 3TC along with a single dose of nevirapine during labor and 3 days of AZT/3TC postpartum. Infants received AZT for their first 7 days, with a single dose of nevirapine on day 2. The transmission rate through 6 weeks was just under 5%. Most importantly, the frequency of nevirapine-associated mutations was less than 2% in mothers. “Using nevirapine in a different way allows us to lower transmission rates and limit resistance,” says Dabis. “Single-dose nevirapine is not dead, there is just more variability in the way it’s used.”

According to Gray, this course of treatment is the next best thing to offering mothers HAART. The WHO is considering revising its guidelines to include this regimen in the menu of options available for preventing MTCT and Gray hopes the South African government will adopt this regimen for nationally-supported MTCT programs. But a combination regimen is obviously more expensive than single-dose nevirapine and will require the expansion of healthcare infrastructure, especially in rural areas. Nevirapine can be taken at home at the onset of labor and few interventions can aim to be that simple. “The only medical requirement for nevirapine is getting tested for HIV. The rest can be done at home,” says Lallemant.

For this reason, Gray is also emphasizing the need for research into newer ARVs that retain nevirapine’s simplicity. Tenofovir is a promising candidate for MTCT because it is unlikely to cause resistance and is available as a single pill, making it easier to administer than a combination of drugs. Trials to test its efficacy in preventing vertical transmission have been stuck in the planning stages. “It’s criminal that it is taking so long to develop these protocols,” laments Gray.

Limiting breast-feeding transmission

Researchers are also looking at interventions that can protect infants from becoming HIV infected through breast feeding. It is estimated that half of all new pediatric HIV cases in 2003 occurred by this route since the drugs administered during labor only offer partial protection during the breast-feeding period. The quantity of HIV in breast milk is dependent on plasma viral load, but about 80% of breast milk samples from HIV-infected mothers will contain the virus.

The most effective approach to avoid breast-feeding transmission is to use bottle feeding with a powdered milk substitute, and in more urban areas women are likely to accept this as an alternative. The South African government provides milk alternatives free to HIV-infected mothers for the first 6 months, which is a relatively short time to transition to solid food. The government of Thailand provides new mothers with enough bottled milk substitute for the infant’s first year.

But this approach has its limitations. Clean water is necessary to prepare the bottles and in some more rural areas potable water is not available. Some women may also choose not to use breast milk alternatives to avoid being stigmatized as HIV-infected within communities where breast feeding is more common. For women who do breast feed, extended treatment with ARVs and early weaning can help lower the baby’s risk of acquiring HIV. “Opportunities exist to stop transmission through breast feeding and should be used,” says Gray.

Again the biggest challenges for researchers and physicians are improving access to proven interventions where they are not available and convincing women to be tested and to access prenatal care where they are. “The real headline should be that only 5% of women are accessing mother-to-child transmission programs,” warns Lallemant.