In September, the country will switch to a new way of treating HIV that is expected to save the country billions and result in more than 600,000 fewer infections in the next two decades. South African researchers are changing the way we treat the virus here and abroad. But what does it mean for the world’s largest HIV treatment programme and the women in it?
More than a year ago, US researcher Rebecca Zash made a terrifying discovery in the most undramatic of places — a commuter train. It was speeding away from central Boston and towards what Zash thought would be a relaxed weekend with her kids.
Zash is a faculty member in the division of infectious diseases at the city’s Beth Israel Deaconess Medical Center. For almost four years, she’d been part of a team looking at how well HIV-positive mothers and their babies in Botswana fared on antiretroviral drugs (ARVs) — including a new kind of medication called dolutegravir.
Dolutegravir was the reigning belle of the ball when it came to HIV treatment. By 2013 studies showed that the new drug could bring the level of HIV in someone’s blood down to levels so low it made them incapable of transmitting the virus. Dolutegravir could do this — also known as viral suppression — much faster than the standard drug, efavirenz, a research review published in the journal Clinical Pharmacokinet found. And dolutegravir had fewer restrictions on what types of other drugs it could be used with when given as part of combination HIV treatment.
You could also take dolutegravir on an empty stomach. Plus, it was more forgiving than other ARVs when it came to missed doses, making it less likely to lead to drug resistance, according to 2015 research published in the journal AIDS Reviews.
On the train that day, Zash was looking through the latest data from the Botswana study and what she saw was shocking: Four of the 426 women who had conceived while on dolutegravir had delivered babies with severe deformities. These birth defects, called neural tube defects, affect the spine and the skull. Three of the babies had been stillborn.
But women who had started the drug while already pregnant showed no such signs — something must have happened within the first 28 days of pregnancy when a fetus’ spine and head begin to form, but what?
The World Health Organisation (WHO) issued a warning about the drug that it just a few years earlier had recommended as part of standard HIV treatment globally: Pregnant women on dolutegravir should continue to take the medicine, it said, but those who could fall pregnant and who couldn’t ensure “consistent contraception” should go back to the old drug regimen.
The ripple effects were huge: Countries that had hoped to roll out the drug stopped dead in their tracks, waiting to see if more research would confirm Zash’s preliminary data.
In the background, Zash and scientists around the world kept working — investigating whether birth defects were really linked to the drug and filling in the gaps in essential data on how well the medicine would work in the people and places that needed it most.
Meanwhile, women living with HIV who knew dolutegravir’s power kicked back against the WHO’s guidance, which had been echoed by drug regulators in the US and European Union.
Don’t make our access to one of the best HIV treatments available conditional on signing up for birth control, they said. That’s our choice, not yours.
They argued: Trust us to weigh the risks and the benefits,
How real is the risk?
Today, we know that what Zash found on the train that day hasn’t exactly gone away. The risk, however, may be lower than previously thought, suggests new research presented at the International AIDS Conference on HIV Science in Mexico City this week. The study evaluated 119 000 births among women on ARVs in Botswana — about 1700 of which were conceived while on dolutegravir.
Three such defects occurred per 1,000 deliveries among women who were on the drug when they conceived compared to about one such deformity per 1,000 births among women taking other ARVs, explained International AIDS Society President Anton Pozniak to journalists in a briefing before the conference.
But similar research among about 1500 Brazilian women on ARVs — a quarter of whom fell pregnant while on dolutegravir — found not a single birth defect. Scientists are continuing to monitor the phenomenon around the world.
“This data provide solid evidence that the risk needs to be taken seriously and followed up over time”, Pozniak said.
Meanwhile, after reviewing the research and consulting with HIV-positive women, the WHO has decided to recommend dolutegravir as standard HIV treatment for everyone — including women who could fall pregnant. And no one should be forced to take contraception to get the drug, the WHO says.
“There should be a discussion with young women about their understanding of the possible small risk of birth defects and, if they want, they can consider another drug if they want.”
Meg Doherty, the WHO’s coordinator of treatment and care for HIV, hepatitis and sexually transmitted infections.
So what should women living with HIV understand about the new recommendations?
Meg Doherty is the WHO’s coordinator of treatment and care for HIV, hepatitis and sexually transmitted infections. This is how she said she’d explain the WHO’s new thinking on dolutegravir to women:
“I would say that neural tubal defects occur in all pregnancies and can be related to many things other than drugs… diabetes, being overweight…The benefits of taking dolutegravir for [standard HIV] treatment outweigh the harm.
“But there should be an individual discussion with the young woman, especially if she is interested in becoming pregnant, about her understanding of… the small and potentially real risk of a neural tube defect.”
Doherty concluded: “She could also consider taking another drug if she felt that it would be better for her.”
From Hillbrow to Geneva
In Hillbrow, Michelle Moorhouse was already well into her randomised controlled clinical trial into dolutegravir when Zash’s discovery made headlines in 2018. Moorhouse heads up work on HIV treatment strategies for Ezintsha, part of the Wits Reproductive Health and HIV Institute, which is based in the same Johannesburg neighbourhood.
In studies like these, participants are randomly assigned to groups so that their outcomes can be compared. This randomisation ensures that any characteristics like gender or age that could influence the results are equally distributed among groupings. Because of this, randomised controlled clinical trials are better at determining cause and effect than other types of studies and are often called the “gold standard” in research.
In her study, Moorhouse was hoping to provide the first evidence that dolutegravir — alongside another new drug, tenofovir alafenamide — could work just as well as South Africa’s standard treatment. To do this, she tested two dolutegravir-containing drug regimens against the country’s current treatment, which typically comes as a three-in-one daily pill.
“As is often the case with new drugs, [initial] registration studies are done largely in high-income countries, so they enrol mainly white, male participants who are not really reflective of the epidemic,” Moorhouse explained from Mexico City, where she presented the research. “By the time these drugs come to market we don’t really know how well they work in the biggest populations that would be treated with these drugs – people living with HIV in lower and middle-income settings, women, people who get TB…”
When the news from Botswana broke, Moorhouse’s team explained the findings to the women who had signed up to be part of her clinical trial. Then, she asked them again whether they were sure they wanted to be in the study.
No one opted out. And they made history.
Moorhouse’s study, which involved about 600 people, ultimately proved that dolutegravir when paired with tenofovir alafenamide — or an older form of tenofovir — and a third common ARV worked just as well as South Africa’s current three-drug combination to treat HIV. Patients reported few side effects regardless of which of the three regimens — or “arms” — they were on.
“The big take-home message is that the regimens were all very effective in suppressing the virus, they were all very well tolerated”, Moorhouse explains.
“The one concerning issue was around the weight gain.”
Participants in the study generally picked up kilograms no matter which of the three different drug combos they were on. However, the research showed this was greater — about 5 kgs after a year — for those that were on dolutegravir.
It was worse for those that had the wonder drug and the other new ARV, tenofovir alafenamide. European studies found similar results, and when the WHO looked at all the research on dolutegravir and extra kilos together, it found that on average, people picked up about 3 to 5 kgs after a year.
Moorhouse says they still don’t know why — or what it means. Until science knows more, the WHO is advising doctors and nurses to talk to patients not only about possible birth defects but also the potential of extra pounds.
Living a healthy, active lifestyle may be increasingly important for patients on the new drug, it cautions.
Today, more than 75 low and middle-income countries are preparing to put patients on the WHO’s recommended dolutegravir-containing regimen. In about half of these nations, governments are already purchasing stock.
Women had a voice, but will they have a choice?
By the time she took the podium this week in Mexico City, Moorhouse says 78 women in her study had fallen pregnant, and the vast majority had been on dolutegravir. About 15 miscarried and eight are still waiting to deliver.
These numbers are too small to answer lingering questions about low risks of birth defects associated with dolutegravir, but they do speak to an issue that has been at the core of so much of the work presented in Mexico City.
Because they participated in a clinical trial, women in Moorhouse’s study likely had easier access to abortion services in a country where less than 5% of public health facilities offer it, according to a 2017 Bhekisisa telephonic survey.
In consultation with activists, the WHO paired its new recommendations on dolutegravir with a 40-page report on contraception within HIV programmes.
“In 2018, a signal was reported of a potential risk of neural tube defects among babies whose mothers were taking dolutegravir-based ARV therapy”, the WHO writes. “This issue and the WHO guidance issued around it has brought to the forefront the importance of both access to contraceptive care for women and adolescent girls living with HIV and the importance of the [their] rights… to make their own informed choices about their health — including sexual and reproductive health.”
Whether the new ARV is eventually found to lead to birth control or not, the body argues, , there is now an opportunity to ensure that women living with HIV have real choice when it comes to birth control.
A 2019 study among almost 500 women in South Africa found that those who reported having unplanned pregnancies were more likely to struggle to stay on treatment — something that persisted, on average, even four years after birth, research published in the journal AIDS found.
South Africa will begin its dolutegravir roll out in September. Modelling presented at the 2016 International AIDS Conference suggests the move will not only save the country billions over the next two decades. But as patients on the drug reap its benefits and their viral loads are able to fall more quickly on a more forgiving drug, more people will become incapable of transmitting the virus — leading in part to 616 000 fewer new infections by 2028, the research argued.
In the next two decades, the move to a dolutegravir-based regimen will also save 21 200 lives.
In June, as the country struggled to emerge from almost two years of nationwide contraceptive shortages, the results of another landmark study came out of Moorhouse’s Hillbrow office — this time as part of a WHRI-led trial to finally answer a decades’ old question: Whether the birth control that forms the backbone of many government contraception programmes — Depo-Provera — increased a woman’s chance of contracting HIV.
Published in The Lancet medical journal, the study found it didn’t — but it did find astronomical HIV infection rates among the women it followed for about a year and a half.
The headlines read: “Popular contraceptive does not increase HIV risk.”
In an opinion piece, longtime HIV activist and programme manager for Advocates for the Prevention of HIV in Africa Yvette Raphael wrote: “You’ll hear a lot of people say Depo is Africa’s most popular family planning method. But that’s not actually true.
“‘Popular’ implies people choose Depo over other contraceptive options because they like it more”, she explained. “The reality is women are, every day, dependent on clinics where it is the only contraceptive choice on offer.”