Forced to choose: No contraceptive, no ARVs

A new drug could save 25 000 women living with HIV but could it come at the cost of their babies lives? Mail & Guardian health news editor LAURA LOPEZ GONZALEZ explores.

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 antiretroviral (ARV).

On Zash’s computer was the latest data from eight sites in the country. In 2016, Botswana 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. 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.

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.

In March 2016, doctors, nurses and researchers sat in a dimly-lit room on the fifth floor of the Sandton Convention Centre in Johannesburg. Jan van Lunzen, medical director for pharmaceutical company ViiV Healthcare, was talking about dolutegravir, a new drug that would soon be on the market.

When doctors switched out efavirenz for dolutegravir as part of a three-drug combo, he said, about 10 percent 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.

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.

Van Lunzen told the 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 at the 22nd International Aids Conference in Amsterdam.

Activists and health workers were quick to begin calling for access to the drug.

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.

But of course few if any of these studies included pregnant women.

Zash’s latest analysis for the WHO which compared how pregnant women faired on the new drug to efavirenz showed that 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.

“I was freaking out,” she remembers. “I was saying [to myself] someone needs to tell me that I’ve done this right, that I didn’t make a mistake. I emailed everybody.”

Not long after, on May 18 2018, WHO warned: 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.

“It’s still too early to tell whether there’s any link between dolutegravir and birth defects,” Zash explains.

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.”

However, 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 one a candidate for an abortion even in countries such as Malawi where voluntary procedures are illegal.

Seventy-one nations have already included dolutegravir as part of standard HIV treatment, according to WHO’s Meg Doherty. 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.

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 percent said they would want information on the risks and let them decide whether they would take the drug with or without birth control, says Doherty.

“There are so many other things involved in [women’s choices] than just the pregnancy part when deciding on HIV treatment,” Zash says. n