Manguzi is little more than a village in the far north east of South Africa, in the KwaZulu-Natal province, against the Mozambican border. The province, once the centre of King Shaka Zulu’s empire and the site of bloody contests with the British colonial project, is subtropical and swelters in heat and humidity for most of the year. Occasional respite comes in the form of violent thunderstorms and rainy deluges which have been known to cause devastating floods. The province has also been the site of significant political violence, notably in 1990s and recently in response to former president Jacob Zuma’s imprisonment. The province, like the rest of the country, is plagued by gender-based violence which is a driver of HIV transmission in the province which has the highest prevalence of the virus in the country – almost a third of people in KwaZulu-Natal live with the virus. Life there is not easy.
Yet, it is also beautiful, with rolling fertile hills of sugar cane leading towards the towering Drakensberg range in the interior. The writer Alan Paton once wrote of the province in Cry, The Beloved Country that the hills are “grass-covered and rolling, and they are lovely beyond any singing of it”. On the coastline, strelitzia and palms sway over the golden beaches.
‘It was very painful… They told me the child was sick’
Grace Mutwa*, 38, lives in Manguzi where she works as a baker at a local grocery chain called Shoprite. She works the traditionally early mornings of those in her trade. Grace is awake well before dawn and is tired when she returns home to do her “chores”. It’s not an easy job and it doesn’t pay very well, but she gets by and can provide for her six-year-old son Lukhanyo* as a single mother.
Lukhanyo was born premature on the 20th of March 2018. Grace was rushed to hospital and before giving birth underwent the usual blood tests. It was a difficult birth but the aftermath would prove to be even more challenging.
“I was about to give birth to the child,” says Grace. “And in the eight months leading up to the birth they were doing regular tests which all came back saying, ‘Fine’. Then the child wanted to come out and they tested again.”
Grace was HIV positive. So was Lukhanyo.
“It was very painful,” she says. “They told me the child was sick… for me it was okay because I know what I did [to acquire HIV] but the child he didn’t do anything wrong. And that is very painful and sad for me.”
That day, a doctor came to see Grace. The doctor told Grace about a study called Baby Cure, saying Lukhanyo would be a good candidate. They would provide regular medication and both mother and child would be well-looked-after.
“I told him to give me time to think about it,” says Grace. “He said, ‘You can take your time and we can meet tomorrow.’ And so that’s what Grace did. On the 21st of March 2018, Grace and Lukhanyo went to meet the doctor and enrolled Lukhanyo in Baby Cure. “Even though it wasn’t easy,” she says, “I have to do what is better for the child… if he takes the medication now, maybe one day he will be able to stop taking it. It isn’t easy to see your child drinking medication every day.”
‘Kids have a higher potential for achieving cure’
Professor Philip Goulder is a professor of immunology at the University of Oxford and runs the Baby Cure study in KwaZulu-Natal in South Africa with the help of a team of medical researchers, nurses, and case workers.
“The Baby Cure study came about as a result of a paper published in the New England Journal of Medicine in 2013,” says Goulder. “It reported a case of a baby called the Mississippi Baby. It was born in Mississippi and was treated very early at 30 hours of age. And the levels of [HI] virus went down to undetectable within a month. And then the child remained in therapy to 18 months and then was lost for follow up for six months and didn’t take any therapy during that time. And then when she came back to clinic, instead of her viral load, which is the amount of virus in the blood, being like a million copies or 100,000 copies – which is what it would normally be – it was undetectable. And in fact, they dug deeper into the immune system and checked if there was any evidence of HIV DNA there and there wasn’t any and there were no antibodies. This child was actually indistinguishable from an HIV-negative child. That kind of started the idea that maybe kids have a higher potential for achieving cure, on the basis that, you know, you could start therapy very early, you know, immediately they were born.”
Baby Cure started in July 2015 and looks at creating a research cohort from mother and child pairs where the baby has acquired HIV in utero (in the womb) and treatment with ARTs (anti-retroviral therapy) is begun on the children hours after birth. The aim is to start early treatment in an attempt to limit the capacity of the HI virus to form what is known as viral reservoirs in the cells of the body. By starting treatment early the virus is less able to establish itself in the cells and so when treatment is stopped the virus may, in theory, be less able to overwhelm the body’s immune system.
Why would treatment be stopped? As part of the study, stopping treatment is the means to an end. This is called “Analytical Treatment Interruption” and the goal is to treat HIV-positive children by bombarding the virus with ARTs. Then treatment will be halted and the children are monitored carefully to see whether they achieve “remission” or something close to “cure” where the virus is undetectable in their system; or whether they “rebound” and the virus is detectable once more.
In the case of the Mississippi Baby, the child did in fact rebound.
However, Baby Cure is breaking new ground in replicating and improving upon the results of the Mississippi baby. The study has found five male children, out of a cohort of approximately 100 children, who exhibit “cure potential”. These five boys have been off therapy and are effectively in remission, which means they are currently indistinguishable from HIV-negative children. Lukhanyo is one of these boys.
Once a month Grace and Lukhanyo make the 400km journey to the nearest Baby Cure site in Empangeni at Queen Nandi Regional Hospital. The trip is long, arduous, and expensive and they are required there for only a short time.
“They make us do tests,” says Grace. “They take us to a room and take the blood and then we wait for 90 minutes to get the results.”
During that time Grace gets a chance to watch her son play.
‘Every time the doctor brings sweets and my child takes the sweets to the other children and that makes them very happy too’
“Let’s say when he’s playing I’m like, ‘This is okay.’ You can see that, ‘Oh my child is not different from other kids,’ you see. He can enjoy being around other people. When he is tired of playing he goes to the office and helps the doctor with files because it makes him very happy. And every time the doctor brings sweets and my child takes the sweets to the other children and that makes them very happy too.”
Lukhanyo doesn’t know anything about his HIV status.
“I don’t see the reason to tell him now because he wouldn’t even understand,” she says. “Maybe, you tell him and he is going outside and telling other children, ‘My mom tells me I’m dealing with HIV.’ That would not be good for him. Maybe he will be stigmatised.”
Stigma is a constant threat in many communities.
“Even now,” Grace says, “they don’t take HIV as like any disease. Some people do think you are different from them, but they don’t understand.”
When the test results come back, they show that Lukhanyo is doing well, but every time Grace shuts her eyes tightly in anticipation. “He is no longer taking medication,” she says, referring to the analytical treatment interruption. “And every time I am nervous and I pray. It’s not easy to think that maybe the results will be bad and that the HIV will come back.”
The Baby Cure study and its success, recently published in Nature Medicine, may have its immediate roots in the case of the Mississippi Baby, but long-standing and ongoing treatment studies created the bedrock which allowed for the existence of cohorts like Goulder’s.
Emeritus Professor Mark Cotton, of Stellenbosch University in South Africa’s Western Cape province, has been instrumental in the field of paediatric HIV. In his 32 years as a clinician dealing with HIV in children he has been in a prime position to observe and play a key role in the changes which the field has undergone.
‘People realised that there’s a big problem in Africa’
In the late ‘90s in South Africa, HIV was beginning to establish itself as an epidemic among adults in their reproductive years and this was adversely affecting many children who acquired the virus in utero. At the height of the virus, says Cotton, “there were about a million pregnancies a year in South Africa and… a third were living with HIV. So, it’s 300,000 people each year”.
However, “the government of South Africa refused to recognise HIV as a condition requiring treatment and resources, so it was a real uphill battle.” Here, Cotton is referring the years of HIV/AIDS “denialism” – under then-president Thabo Mbeki – which caused “unconscionable loss of human life,” according to Amy Roeder, writing for the Harvard T.H. Chan School of Public Health.
Cotton went through five years of failed grant applications and attempts to establish treatment programmes for children born with HIV. “It was really not possible to do it,” he says. “The medicines weren’t available… You know, we [South Africans] only got access to antiretrovirals in 2004.”
Then, in 2005, the “landscape changed”.
“People realised that there’s a big problem in Africa and, in fact, that’s how the CHER trial started,” says Cotton. “We were successful to get funding and the idea was to create infrastructure and do work that is relevant locally because at that stage, very little of the work done in well-resourced places such as United Kingdom and the US and Europe was relevant.”
The CHER trial (Children with HIV Early Antiretroviral Therapy) was set up to establish treatment for children born with HIV in the early stages of life. This Cotton says, is essential for ensuring quality of life and limiting disease progression (the overwhelming of the body’s immune system which may eventually lead to AIDS).
“The [CHER] trial established the importance of early antiretroviral therapy – because at that stage the guidance was that you start these medicines when you need them and you need them when your CD4 count drops to a certain level. A threshold or when you’re sick, you know? Then you need it. And that’s how everyone was doing it, including in children,” Cotton says. “In the CHER trial, we started immediate time-limited treatment either before the 1st or the 2nd birthday or standard of care, which at that time was when your CD4 count dropped. At that stage we said at 25 per cent [of healthy CD4 count] in your first year of life you just go on to continuous treatment.
“So that’s how the CHER trial started and I think we’d been going for about 18 months when it was clear to the Data Safety Monitoring Board that actually early therapy was essential. It was not only saving life, there was a huge difference in mortality and in manifestations of HIV, you could call it disease progression. It was clear, there was just no doubt about it.”
As a result, early treatment with antiretrovirals became the standard of care and was adopted by the World Health Organisation (WHO) and was applied internationally. However, even though the study was done in South Africa, the country was “one of the slower ones,” to adopt CHER’s recommendations.
Another crucial element to the CHER trial’s historical importance was the fact that treatment interruption was built into the trial. It showed that you could stop treatment for a time and the virus would remain suppressed but it would come back. However as part of the treatment interruption, Cotton and his team conducted a neurodevelopmental sub-study which asked “How well does the brain work after stopping treatment and restarting it?”
“Once we had stopped, you know, therapy and restarted therapy, we found that there was actually the kids were performing, on the whole, at the same level as what we call control children,” says Cotton. “So these were age- and community-matched children, some of whom had been exposed to HIV, but didn’t acquire it themselves because of prevention therapy. But we could show that at between five and six years of age, they’re actually all doing pretty well. In broad brush strokes we were able to say that stopping therapy for quite a long time was actually okay.”
Today stopping treatment is more rigorous than what was done in the earlier days of the CHER trial (which simply monitored the CD4 count of patients) and involves the intense and regular monitoring of the blood which Lukhanyo must undergo at his regular clinic visits. Cotton’s work has allowed for the existence of Goulder’s study.
Cotton was also instrumental in discovering the South African Child, a young boy who went off treatment and managed to suppress the virus. Today, the South African Child is 18 years-old and remains “off antiretrovirals”. Scientists can detect HIV DNA in his cells but it’s not “entering the blood as RNA” – effectively, the virus is not replicating.
“We’ve been looking at what makes this boy so unique,” says Cotton.
Goulder is asking the same questions of Lukhanyo and the other four Baby Cure boys who are currently controlling the HI virus without ART.
What does seem to be a trend, outside of the Mississippi Baby, is that many of the young people showing cure potential are male.
“There are huge sex differences,” says Goulder, referring to the way male and female immune systems work. This has been one of the key outcomes of Baby Cure. The typically weaker immune response of these particular boys appears to be more effective in helping them to control the virus. This, as opposed to the more “active innate immune response” in females. Additional biological differences have also come to light. “Female foetuses are more susceptible [to HIV],” says Goulder. “In adolescents, females are infected three times as much as males.”
However, the story is more complicated than this because in adults, women typically handle the virus better than men. “When male and female adults are infected with HIV, the response to HIV in females is much more effective,” he says.
The lesson from these findings?
For Goulder the lesson is that the kind of immune responses that are effective when treating the virus may be the opposite of what’s needed to achieve cure.
Speaking about Goulder’s study, Cotton also points towards these differences in immune response between sexes of children. “He found firstly that the boys were there was a sex difference in who acquires HIV and that girls were acquiring it more than boys. And it also turned out that the boys, their virus was sensitive to a chemical that the body makes called interferon – that’s an antiviral protein – whereas the girls’ ones weren’t. And so there would seem to be a difference. And also that the boys, the ones that have developed this remission for some reason, their virus was a weaker virus than in many of the other children. So it seems like there’s a coalescence of a few factors that could make these children go into remission.”
So, how do the findings of Baby Cure lead to a cure for HIV? Well, things are slightly more complicated than one might hope.
“[The study] is not itself going to lead to cure or remission, but it starts unpacking the complexities of what’s going on, to get a better understanding,” says Cotton.
“So it’s quite a complicated story,” says Goulder. “But it actually illustrates, I suppose, one of the things that is sort of becoming clear, really: that these studies that we do in HIV, are important to understanding HIV, in itself, but they also shed light on how the immune system functions and how it doesn’t function.
“I don’t want to make it sound like this study is going to open the door to cure for the 39 million people living with HIV. Huge amounts still need to be done and there’re going to be many other factors contributing to understanding what is needed to achieve cure. Early therapy is just one of them,” says Goulder.
The hope is that armed with the knowledge of how these young boys are able to control the virus, researchers will come to understand the immune system better and, in doing so, may one day be able to “hack” the immune systems of all people living with the virus so that they can control it too and achieve functional cure.
“If you’re thinking of a million-piece jigsaw puzzle,” says Cotton, “the South African Child added a piece and… Professor Goulder’s study has added three or four pieces.”
‘I don’t know what’s going to happen’
Grace’s voice crackles in and out of the phone call. There is bad phone reception in KwaZulu-Natal. She is tired after a long day at work but has made the time anyway.
How has her life changed since joining Baby Cure?
“It’s really helped me a lot,” she says. In 2024 Grace took her first aeroplane journey and for the first time left the borders of South Africa when she was invited to speak at a conference in Kenya on behalf of the mothers and children involved in Baby Cure. “It made me realise that I’m not alone in living with HIV and that there are people out there who are even proud of talking about living with HIV/AIDS. It taught me that we can be strong.”
And as for the future?
“If we continue with Baby Cure, I don’t know what’s going to happen,” says Grace, who pauses thoughtfully on the other end of the line. “But I can see that it will brighten my child’s life.”
This hope for the future doesn’t end with one child. The discovery of Lukhanyo’s genetic gifts are a step towards brightening the lives of many for generations to come – and that would make them very happy too.
*Grace and Lukhanyo’s names have been changed to protect their identities