Uncounted: Too few pregnant women are included in clinical studies and new data from Botswana about an important new ARV is casting a spotlight on their absence.
It was Friday afternoon and Rebecca Zash had just one more thing between her and the weekend. She boarded a commuter train home from Boston’s city centre and reached for her computer.
For almost four years, Zash, a faculty member in the division of infectious diseases at the city’s Beth Israel Deaconess Medical Center in the United States, along with a team of researchers, had been looking at how well mothers and babies in Botswana fared on antiretrovirals (ARV).
On Zash’s computer, was the latest data from eight sites in the country.
In 2016, the country became the first in sub-Saharan Africa to debut a new ARV, dolutegravir. It would replace an older drug efavirenz — associated with more side effects — as part of the country’s standard, three-drug HIV treatment course.
The data on dolutegravir looked great and months later Brazil announced plans to roll out the drug. Countries all over the world would soon begin to look at how they too could use the new medicine.
But something was missing. Because pregnant women pose ethical challenges for researchers, they — as well as children — are mostly not included in clinical trials. As a result, almost no (97%) drugs approved for use in the US between 2000 and 2010 were tested to see if they posed a risk to foetal development, 2011 research published in the American Journal of Medical Genetics shows.
The World Health Organisation (WHO) thought Botswana presented a chance to fill in the gaps, so they asked Zash and her team to compare outcomes among mothers on the new drug to those on efavirenz.
“We said [to the WHO] it’s going to be about 400 [women], we don’t think it’s going to tell you much,” Zash remembers.
“They said, you know what? We really need anything that we have.”
In March 2016, doctors, nurses and researchers sat in a dimly-lit room on the fifth floor of the Sandton Convention Centre in Johannesburg. Their eyes were glued to a projector screen. Jan van Lunzen, medical director for pharmaceutical company ViiV Healthcare, stood to one side bathed in a blueish glow from his PowerPoint slides on the screen. He was talking about a new drug that would soon be on the market in South Africa.
It was dolutegravir.
When doctors switched out efavirenz for dolutegravir as part of a three-drug combo, he said, about 10% more of patients were able to bring the amount of the HIV in their blood down to levels so low they were undetectable by laboratory standards. Van Lunzen was quoting a study presented at the 2012 Interscience Conference on Antimicrobial Agents and Chemotherapy.
Patients who sustain this low level of HIV in their blood, also known as being virally suppressed, cannot transmit the virus sexually, studies have shown.
Plus, Van Lunzen told clinicians, the drug could be taken without food and was more forgiving than other ARVs when it came to missed doses, making it less likely to lead to drug resistance — a claim backed by 2015 research published in the Journal of Antimicrobial Chemotherapy.
Dolutegravir also had fewer side effects than efavirenz. In clinical trials, up to half of people on efavirenz reported side-effects such as hallucinations, nightmares and depression within the first few months of starting the drug. The new wonder drug allowed patients’ CD4 counts — a measure of the strength of their immune systems — to bounce back faster once they started treatment, according to presentations made this week at the 22nd International Aids Conference in Amsterdam.
Activists and health workers were quick to begin calling for access to the drug that Van Lunzen said would be on the market in just months in the private sector.
The World Health Organisation (WHO) had already included the drug as part of its recommended standard HIV treatment regimen in 2016 guidelines after it reviewed 71 clinical trials conducted among about 34 000 patients. There has been strong evidence that, when compared with patients on efavirenz, people who used dolutegravir were less likely to stop taking treatment, a WHO review presented at the conference found.
But of course very few if any of these studies included pregnant women.
Nothing for us, without us: Protesters demand access to dolutegravir and the right to resist ultimatums that pit their right to better treatment against their right to choose what kind of contraception works best for them. (Marten van Dijl)
On a Boston commuter train on the United States’ East Coast, Rebecca Zash settled into her seat and flipped open her laptop. The deadline for her latest analysis for the WHO comparing how pregnant women faired on the new drug compared to efavirenz was two weeks away and she’d been putting off getting started. But she figured she could get through a preliminary analysis before she got home.
“I was like, okay I am going to finish this,” she remembers.
“Then I looked at the analysis and saw these findings.”
Four of the 426 women in Botswana who had conceived while on dolutegravir had delivered babies with severe deformities called neural tube defects, which 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 foetus’s spine and head begin to form, but what? And was her analysis even right?
As the city rolled passed in the windows, Zash crunched the numbers again and again until she got off the train.
“I was freaking out,” she remembers. “I was mostly just saying [to myself] someone else needs to tell me that I’ve done this right, that I didn’t make a mistake.
“I emailed everybody.”
With team members on vacation and abroad, it wouldn’t be until later that weekend that she heard back. Zash spent Saturday and Sunday with her children, checking her email every three minutes.
By Monday, Massachusetts General Hospital geneticist and study researcher Lewis Holmes had made the call: “This looks like something you need to report.”
Not long after, on 18 May 2018, the WHO issued a warning: Pregnant women on dolutegravir should continue to take the drug but women who could fall pregnant and who couldn’t ensure “consistent contraception” should go back to the old drug regimen. Drug regulators from the US and Europe followed with similar cautions.
Since May, Zash and her team have tracked 170 more mothers who conceived while on dolutegravir. But they found no more birth defects. Brazil too is monitoring women and has not found a single case of neural tubal defects among an initial 160 women.
It’s still too early to tell whether there’s any link between dolutegravir and birth defects, Zash explains: “This is preliminary: we don’t know exactly how to explain this and whether it’s a real [side effect of the drug] or not.”
Watch: Why women aren’t taking no for an answer when it comes to this new ARV
South Africa already has a working group looking at what a tender for the new drug might look like — and cost, which is not a small factor for a nation that expects to pay about R40-billion for HIV treatment by 2033, according to 2015 estimates contained in the health department’s investment case report.
New modelling presented at the Amsterdam conference suggests switching out the older ARV efavirenz for dolutegravir would double the percentage of new infections averted between 2019 and 2038 in South Africa. Dolutegravir would also be more effective at cutting Aids-related deaths and lead to almost immediate cost savings, found research by Gesine Meyer-Rath from the Health Economics and Epidemiology Research Office at the University of the Witwatersrand found. Meyer-Rath is based at the university’s Health Economics and Epidemiology Research Office.
A separate modelling study by the US Medical Practice Evaluation Centre projected the switch would avert more than 25 000 deaths of South African women between 15 and 49 years of age in a country with stubbornly high maternal deaths. It would also prevent 5 000 more mother-to-child infections.
But, researchers warned, that if a link between dolutegravir was true, it could also lead to more deaths among children. At the same time, it could save three times as many women.
But framing this as a decision about whose life to save is risky, experts and activists warn.
“Don’t pit us against our children,” Martha Akello from International Community of Women Living with HIV says.
“Some women with HIV definitely want to have babies, it’s a motivation for us to live another day, to live for tomorrow and see their children graduate and have a life”, she explains.
“Women living with HIV are also not homogenous. I could be done having children… I could actually be in my reproductive age and not feel like having children. We definitely see the need to exercise choice.”
But real choice means being able to offer women on dolutegravir access to contraception — if they want it. A fact increasingly complicated by the US government’s gag rule, which has closed hundreds of clinics in southern Africa alone, reproductive health organisation Population Services International told Bhekisisa in February. Also known as the Mexico City Policy, the gag rule cuts US funding to any organisation that in any way promotes abortion as part of sexual and reproductive health services, even if that is by referring women to other organisations for the procedure.
If there is a link between dolutegravir taken very early in pregnancy and birth defects, then more women may need abortions or information to avoid having to deliver stillborn or severely deformed foetuses — conditions that make a person a candidate for an abortion even in countries such as Uganda where voluntary procedures are illegal, executive director of the international organisation Health Gap Asia Russell explains.
“This is precisely what the global gag rule undermines.”
For deputy director of South Africa’s Desmond Tutu HIV Centre Linda-Gail Bekker — the questions around dolutegravir’s safety could be a chance for the world to get its act together when it comes to birth control.
“We may find, as more pregnancy cases come in, it’s nothing [and there is no link between dolutegrevir and birth defects]. It may be that there really is something there in which case we’re going to have to figure out what we do with women with fertility intent,” Bekker explains.
“Either way, we should be dealing with women better than we are in our clinics. For too long, we’ve considered HIV without considering sexual reproductive health and it makes absolutely no sense. In some ways, this could be the silver lining.”
South Africa, meanwhile, is approaching month eight of a national birth control shortage.
An unexpected discovery from researcher Rebecca Zash’s (third from right) rocked worldwide plans to adopt a new wonder drug, and put a conversation about choice centre stage.
Zash’s unexpected findings have set off a chain reaction and a global conversation about choice: How countries will choose to weigh up the pros and cons of the new drug and how much choice they’ll give women in accessing it.
Seventy-one nations have already included dolutegravir as part of standard HIV treatment, according to data presented by the WHO’s Meg Doherty this week at the Aids conference in Amsterdam. But on the heels of Zash’s discovery, almost one in five of these countries have now either banned dolutegravir completely for women of reproductive age or made access conditional to long-acting contraception use.
Less than a handful are even willing to discuss options with women according to their guidelines, leading many to wonder whether women living with HIV are being given any real choice at all about ARVs or birth control.
In a recent poll, the WHO asked HIV-positive women how they would react if they were given an ultimatum: No contraception, no dolutegravir.
Almost 60% of women said they’d want their healthcare worker to give them information on the risks and let them decide whether they’d take the drug with or without birth control, Doherty says.
The WHO softens previous messages about dolutegravir in new HIV guidelines released this week. The document still bears a warning about the ARV and says women should be counselled about its risks but the body hasn’t prohibited women from taking it. But at the guidelines’ launch, more than a dozen activists including women living with HIV marched through the aisles of the air-conditioned hall at the RAI convention centre in southern Amsterdam.
“Women demand DTG now,” protestors can be heard chanting on cell phone footage, using the common abbreviation for dolutegravir “DTG”.
Russell says the WHO is not doing enough to tell countries such as Malawi, Uganda and Tanzania that have blanket bans on dolutegravir for women of reproductive age that they are going against WHO guidance.
“Many high burden countries have already decided that women under 50 should not get dolutegravir. That doesn’t add up. Dolutegravir is clearly a superior drug. Women need access to information and they can make the decision about whether it makes sense for them,” Russell explains.
Countries are partly, she says, weighing up the benefits of giving the drug to pregnant women, including cheaper and gentler treatment, with the possible risks to foetuses.
That can go two ways: Blanket bans — or empowering health workers to talk to women.
Russell explains: “Perhaps, the doctor is very worried — and doctors often get very worried about foetuses. Then a woman says, I’m not at risk of getting pregnant so thank you very much for your concern, I still need dolutegravir.”
But she says fear isn’t the only motivation: “It’s a lack of trust. Ultimately, the decision will be in the hands of a woman — she will walk out of the clinic and take the drug and you have to trust she is calculating the risks in a way that makes sense for her. You might not understand it. That’s what the pushback is about — an unwillingness to trust women.”
“There are so many other things involved in [women’s choices] than just the pregnancy part when deciding on HIV treatment,” Zash says.
In Amsterdam, Zash has just finished her second panel of the day. The queue of people waiting to talk to her stretches five-deep at some points. Half an hour later, she finally breaks free and walks down the aisle of the 300-seater auditorium.
A colleague leans over and jokes, “‘Becca, this is all your fault”.
“We presented data on pregnancy at the last Aids conference too — back then it seemed like no one cared,” Zash says.
Since the day on the train, she says her thinking has gone from initial shock and panic to focusing on a single thread: Choice
“At first, I was thinking about this as someone who has been pregnant in the not-so-distant past: How I would have felt knowing this and the decisions I would have probably made and how I thought everybody should decide.
“Then I started thinking much more about what it would be like to not be me. There are so many other things involved in [women’s choices] than just the pregnancy part when deciding on HIV treatment.”