By Laura López González – July 26, 2019
In September, the country will switch to a new way of treating HIV that is expected to save the nation billions and result in more than 600,000 fewer infections over the next two decades. South African researchers are changing how we treat the virus here and abroad. But what does this mean for the world's largest HIV treatment program and the women who participate in it?
More than a year ago, American researcher Rebecca Zash made a terrifying discovery in the most dramatic of places: a commuter train. It was speeding away from downtown Boston and heading toward what Zash thought would be a relaxing weekend with her children.
It wasn't.
Zash is a faculty member in the infectious diseases division at Beth Israel Deaconess Medical Center in the city. For nearly four years, she was part of a team that analyzed how well antiretroviral (ARV) drugs, including a new type of drug called dolutegravir, fared in HIV-positive mothers and their babies in Botswana.
Dolutegravir was the new king of HIV treatment. By 2013, studies showed that the new drug could reduce the level of HIV in someone's blood to such low levels that they would be unable to transmit 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 other drugs it could be used with when given as part of combination HIV therapy.
You can also take dolutegravir on an empty stomach. Furthermore, it was more forgiving than other ARVs when it came to missed doses, so it is less likely to lead to drug resistance, according to 2015 research published in the journal AIDS Reviews.
That day, on the train, Zash was reviewing the latest data from the Botswana study, and what he saw was shocking: four of the 426 women who had conceived while taking dolutegravir had given birth to babies with severe deformities. These birth defects, called neural tube defects, affect the spine and skull. Three of the babies were stillborn.
But women who started the drug while already pregnant showed no such signs: something must have happened within the first 28 days of pregnancy when the spine and head of the fetus begin to form, but what?
The World Health Organization (WHO) issued a warning about the drug it had recommended only a few years earlier as part of the standard treatment for HIV worldwide: pregnant women taking dolutegravir should continue taking the drug, it said, but those who could become pregnant and who could not guarantee "consistent contraception" should return to the old drug regimen.
The domino effects were enormous: countries that were hoping to launch the drug stopped in their tracks, waiting to see if further research would confirm Zash's preliminary data.
In the background, Zash and scientists around the world continued working, investigating whether the birth defects were truly linked to the drug and filling in the gaps in essential data about how well the drug would work in the people and places that needed it most.
Meanwhile, women living with HIV who knew the power of dolutegravir responded against the WHO guidance, which echoed drug regulators in the United States and the European Union.
They didn'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 benefits,
How real is the risk?
Today, we know that what Zash found on the train that day hasn't exactly disappeared. However, the risk 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 antiretroviral therapy (ARV) in Botswana, of which about 1,700 were conceived while the women were taking dolutegravir.
Three of those defects occurred for every 1,000 births among women who were taking the drug when they conceived, compared with one deformity for every 1,000 births among women who were taking other ARVs, International AIDS Society Anton Pozniak explained to reporters at a briefing before the conference.
But a similar study of approximately 1,500 Brazilian women on antiretroviral drugs (ARVs), a quarter of whom became pregnant while taking dolutegravir, found not a single birth defect. Scientists continue to monitor the phenomenon worldwide.
"This data provides strong evidence that the risk should be taken seriously and monitored over time," Pozniak said.
Meanwhile, after reviewing the research and consulting with HIV-positive women, the WHO decided to recommend dolutegravir as the standard HIV treatment for everyone, including women who could become 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 wish, they can consider another medication."
Meg Doherty, coordinator of treatment and care for HIV, hepatitis and sexually transmitted infections at the WHO.
So, what should women living with HIV understand about the new recommendations?
Meg Doherty is the WHO's treatment and care coordinator for HIV, hepatitis, and sexually transmitted infections. This is how she said she would explain the WHO's new thinking on dolutegravir to women:
"I would say that neural tube defects occur in all pregnancies and can be related to many other things besides 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 medication if she felt it would be better for her."
From Hillbrow to Geneva
In Hillbrow, Michelle Moorhouse was already in her randomized controlled clinical trial with dolutegravir when Zash's discovery made the news in 2018. Moorhouse spearheaded work on HIV treatment strategies for Ezintsha, part of the Wits Institute for Reproductive Health and HIV, which is based in the same Johannesburg neighborhood.
In studies like these, participants are randomly assigned to groups so their outcomes can be compared. This random assignment ensures that any characteristics, such as sex or age, that might influence the results are distributed equally between the groups. Because of this, randomized controlled trials are better at determining cause and effect than other types of studies and are often called the "gold standard" in research.
In his study, Moorhouse hoped to provide the first evidence that dolutegravir, along with another new drug, tenofovir alafenamide, could work as well as South Africa's standard treatment. To do this, he tested two drug regimens containing dolutegravir against the country's current treatment, which is typically administered as a daily three-in-one pill.
“As is often the case with new drugs, the [initial] registration studies are largely conducted in high-income countries, so they primarily enroll white, male participants who don’t really reflect the epidemic,” Moorhouse explained from Mexico City, where she presented the research. “By the time these drugs reach the market, we really don’t know how well they work in the larger populations that would be treated with these drugs: people living with HIV in low- and middle-income settings, women, people who contract TB…”
When the news from Botswana came out, Moorhouse's team explained the findings to the women who had signed up for their clinical trial. Then, they asked them again if they were sure about participating in the study.
No one was excluded. And they made history.
The Moorhouse study, which involved about 600 people, ultimately showed that dolutegravir, when combined with tenofovir alafenamide (an older form of tenofovir) and a third common antiretroviral (ARV), worked as well as South Africa's current three-drug combination for treating HIV. Patients reported few side effects, regardless of which of the three regimens, or "arms," they were taking.
"The big takeaway message is that all the regimens were very effective at suppressing the virus, and all were very well tolerated," Moorhouse explains.
"The only problem related to weight gain."
Study participants generally gained weight regardless of which of the three different drug combinations they were on. However, the research showed that this was greater—around 5 kg after one year—for those taking dolutegravir.
It was worse for those who had the miracle drug and the other new ARV, tenofovir alafenamide. European studies found similar results, and when the WHO analyzed all the research on dolutegravir and weight gain together, it found that, on average, people gained between 3 and 5 kg after a year.
Moorhouse says they still don't know why, or what it means. Until science knows more, the WHO is recommending that doctors and nurses talk to patients not only about possible birth defects but also about the potential risks of being overweight.
It warns that living a healthy and active lifestyle may become increasingly important for patients taking the new drug.
Today, more than 75 low- and middle-income countries are preparing to put patients on the WHO-recommended regimen containing dolutegravir. In approximately half of these nations, governments are already purchasing stock.
Women had a voice, but will they have a choice?
When she took the podium this week in Mexico City, Moorhouse said that 78 women in her study had become pregnant, and the vast majority had taken dolutegravir. Approximately 15 had abortions, and eight are still waiting to give birth.
Almost a quarter opted for safe abortions.
These numbers are too small to answer persistent questions about the low risks of birth defects associated with dolutegravir, but they speak to an issue that has been at the center of much of the work presented in Mexico City.
Choice.
Because they participated in a clinical trial, the women in Moorhouse's study likely had easier access to abortion services in a country where less than 5% of public health facilities offer them, according to a 2017 telephone survey by Bhekisisa.
In consultation with activists, the WHO combined its new recommendations on dolutegravir with a 40-page report on contraception within HIV programs.
“In 2018, a signal of a potential risk of neural tube defects was reported among infants whose mothers were taking dolutegravir-based ARV therapy,” the WHO writes. “This issue and the WHO guidance issued on it have highlighted the importance of access to contraceptive care for women and adolescents living with HIV and the importance of [their] rights… to make their own informed decisions about their health – including sexual and reproductive health.”
Whether or not the new ARV is found to lead to birth control, the agency argues, there is now an opportunity to ensure that women living with HIV have a real choice when it comes to birth control.
A 2019 study of nearly 500 women in South Africa found that those who reported unplanned pregnancies were more likely to struggle to stay on treatment, something that persisted, on average, even four years after birth, according to research published in the journal AIDS.
South Africa will begin its rollout of dolutegravir in September. Models presented at the 2016 International AIDS Conference suggest the move will not only save the country billions over the next two decades, but as patients taking the drug reap its benefits and their viral loads can fall more rapidly on a more tolerable medication, more people will become unable to transmit the virus, contributing in part to 616,000 fewer new infections by 2028, according to the research.
Over the next two decades, switching to a dolutegravir-based regimen will also save 21,200 lives.
In June, as the country struggled to emerge from nearly two years of nationwide contraceptive shortages, the results of another landmark study rolled 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 programs, Depo-Provera, increased a woman's chances of contracting HIV.
Published in the medical journal The Lancet, the study found that this was not the case, but it did find astronomical rates of HIV infection among the women it followed for approximately a year and a half.
The headlines read: "Popular contraceptives do not increase the risk of HIV."
In an opinion piece, Yvette Raphael, a longtime HIV activist and program manager for Advocates for HIV Prevention in Africa, wrote: “You will hear many people say that Depo-Provera is the most popular family planning method in Africa. But that is not actually true.
“‘Popular’ implies that people choose Depo-Provera over other contraceptive options because they like it better,” she explained. “The reality is that women rely every day on clinics where it’s the only contraceptive option offered.”
In: https://bhekisisa.org/article/2019-07-26-whats-in-a-pill-promise-uncertainty-rands-lives-loves-but-rights-what-the-next-big-thing-in-hiv-treatment-for-sa-shows-us/