Imagine that you’re a young woman in southern Africa, giving birth to the child you’ve carried for nine months. Between the pain and the pushing, you feel both excitement and dread. At the antenatal clinic several months ago, you learned that you were infected with HIV. The doctor gave you antiretroviral (ARV) drugs to prevent your child from being born with HIV. You pray that they worked.
Six weeks later, while your newborn sleeps in your arms, the clinic nurse gives you the good news. Your daughter is not infected with HIV. You burst into tears of relief and joy. But wait, not so fast. Even though your baby isn’t infected with HIV, she was exposed to both HIV and ARVs in the womb.
You learn that the term for babies like your daughter is HIV-Exposed Uninfected (HEU) infants. And HEU infants in resource-limited settings like southern Africa are two to three times more likely to die within the first two years of life than babies who weren’t exposed to HIV or ARVs. The health and survival of your little girl is still at risk. Researchers are working urgently to understand why.
Aftereffects of Success
Figuring out how to prevent pregnant HIV-infected women from passing the virus to their infants is one of the most inspiring success stories of the AIDS epidemic. From research done at the Harvard AIDS Initiative (HAI) and elsewhere, we have learned how to reduce mother-to-child transmission rates from 30–45% without ARVS down to as low as 1% with ARVs in resource-limited settings, even when a mother breastfeeds her infant.
In 2010, the World Health Organization (WHO) endorsed the bold goal of eliminating mother-to-child transmission of HIV by 2015. With both scientists and health policy experts focused on preventing new infant infections, there had been an assumption that ensuring that a baby remained HIV-free would safeguard the child’s survival.
It is estimated that there are approximately 1.5 million HIV+ pregnant women annually,” said Dr. Elaine Abrams, a professor of epidemiology and pediatrics at Columbia University and an expert on mother-infant HIV transmission. “With successful prevention programs, we can hope to see HIV transmission rates as low as 2–5% and perhaps as many as one million HEU infants born each year.”
Fewer and fewer infants born to infected mothers became infected with HIV. That’s wonderful news. But with the number of HEU newborns surpassing a million each year, we must look closely at the health of these still-vulnerable children. An increasing body of evidence suggests that HEU babies are not like babies who have never been exposed to HIV. It’s a problem we’re just beginning to understand.
With increasing success of prevention efforts, the clinical and research community are shifting attention to HEU and only now beginning to delineate the particular health issues of this growing, highly vulnerable population,” said Abrams.
There’s a growing sense of urgency because we’ve only begun to appreciate the magnitude of this problem,” said Dr. Max Essex, Chair of HAI. “Bear in mind that until five or ten years ago, most at-risk infants weren’t even protected from HIV infection.”
Researchers at HAI are looking closely at how and why HEU infants differ from infants who were never exposed to HIV and ARVs. The difference is likely a combination of biological, social, and economic factors. “This is a complicated question that requires thoughtful, creative research,” said Essex.
The health of a mother is critical to the health of her child. The womb of an HIV-infected woman taking ARVs is different from that of an HIV-free woman. Recent studies have found that some HEU infants fail to get a healthy immune system because the mother’s immune system is compromised.
Many HIV-infected mothers, besides dealing with their own disease, tend to be more impoverished. They tend to have less access to a toilet and clean water in the home. Because HEU infants live in a household affected by HIV, they are often exposed to illness, death, and family disruptions at a young age.
The increased mortality of HEU infants is predominantly due to deaths from infectious diseases, namely complications of pneumonia and diarrhea. It is an open question whether these deaths that stem from immunological problems or from the disadvantages of being born into an HIV-affected household. It is likely a combination of both.
Growth is a good indicator of overall infant health. The first 1000 days of life are the most critical time for growth and affects a person’s entire lifetime. Some researchers have found that HEU infants are more likely to have stunted growth, lagging behind in both weight and length.
Growth is a kind of a barometer of how sturdy you’re going to be if you get sick early in life,” said Dr. Kate Powis, an HAI researcher whose work focuses on improving the health of HEU infants. “Children who have lower weight or length for age face a higher risk of mortality. If they get diarrhea or pneumonia, they’re more likely to need hospitalization or to die.”
Understanding why HEU infants have stunted growth and finding a solution is of utmost concern, especially in southern Africa, the epicenter of the HIV/AIDS epidemic.
What HAI Is Doing
HAI is a leader in HEU research. As Max Essex explains, “We’ve got people who know a lot about mother-to-infant transmission: how and why that occurs and how to prevent it. We also have people who know a lot about the immunology of human resistance to HIV infection and why it does or doesn’t work. A lot of that information is useful in determining what sort of mechanisms are compromised in children who didn’t get infected with HIV but are still at high risk for all these other conditions.”
In the African country of Botswana, where HAI has been working since 1996, approximately 30% of pregnant women are infected with HIV. Botswana’s Prevention of Mother-to-Child-Transmission (PMTCT) program is the most successful in Africa, with more than 95% of HIV-infected pregnant women having access to ARVs. Fewer than 4% of infants born to infected mothers become infected and the rate is expected to drop even lower, close to the 1% rate that HAI researchers have achieved in clinical trials. However, in the coming years, up to 30% of all infants born in Botswana will be born HIV Exposed Uninfected (HEU).
To address the needs of this growing group of children, HAI researchers are asking a number of important questions:
1. What are the safest drugs to prevent mother-to-child transmission of HIV for both the mother and the developing infant?
2. Which respiratory and gastro-intestinal infections cause the most problems for HEU infants?
3. Can we lower the risk of HEU babies dying from infectious diseases by giving them a widely available antibiotic during their most vulnerable first 1–2 years of life?
4. What is the impact of HIV exposure versus ARV exposure?
5. How is the immune system of HEU children different from unexposed children?
6. Can poor growth patterns in HEU children be reversed?
Building on Experience
Along with Essex, Drs. Shahin Lockman and Roger Shapiro have been conducting PMTCT research at the BHP for more than a decade. The landmark Mashi and Mma Bana clinical trials made important contributions to PMTCT research. The data from those trials will help Powis conduct a retrospective analyses of 1,930 women and their infants to look at the impact of giving mothers one drug versus a triple-drug cocktail and how that affects the health and growth of a developing child.
In new research, Shapiro is following children in Botswana from birth through two years of life to try to better understand infant mortality. Lockman is looking at the neurodevelopmental outcomes and mortality of HEU children compared to unexposed children and children with HIV. In another study, Lockman and Shapiro are testing whether giving a low-cost antibiotic called co-trimoxazole will help protect against death, diarrhea and pneumonia in nearly 3,000 HEU children. Powis is hoping to launch an innovative study that compares the gut microbiome of HEU infants with unexposed infants to learn more about differences in the development of the immune system.
Time to Act
The success of WHO-sanctioned ARV treatment and PMTCT programs will continue to increase the prevalence of HEUs. This is of particular importance in southern Africa, where HEUs may represent up to 30% of infants born in areas with a high HIV prevalence. What is becoming increasingly clear is that just keeping a baby HIV-free is insufficient.
In Botswana, almost every health metric has been improving since 2002. One metric that has not shown a marked improvement is the mortality of children under five. The higher mortality rate of HEU infants in Botswana has contributed to the plateaued under-five rate. Understanding and finding solutions to the HEU problem is essential to lowering child mortality rates, especially in sub-Saharan Africa.
As we look to the future, the number of infant HIV infections will decline, but the number of HEU infants will increase. Identifying modifiable risk factors that contribute to higher mortality among HEU children and implementing interventions to promote their health and survival should be a public health priority.