The unfolding evidence on anti-Aids drug dolutegravir has highlighted the harmful consequences of the status quo, whereby women often make up the majority of a medicine’s users, but are often not well enough represented in early clinical trials.

In September 2017, on the back of a major pricing agreement, the National Department of Health (NDoH) announced that a dolutegravir-based regimen would replace the existing efavirenz-based regimen for the first-line treatment of HIV in the public sector as early as April 2018.

Described as a “game changer” for the HIV field, dolutegravir’s advantages included its lower cost and the fact that it has fewer side effects than efavirenz. In a 2017 press statement the NDoH said switching the country’s millions of antiretroviral therapy (ART) patients to dolutegravir would save the country R11-billion over six years.

Dolutegravir was shown to suppress patients’ viral load more quickly than previous treatments. Viral load is the amount of virus in a patient’s blood. A person with an undetectable viral load cannot transmit the virus to others.

The new drug was also less prone to the development of drug resistance. Drug resistance can develop when the virus mutates in such a way that specific medicines no longer suppress the replication of HIV in the body. This can happen when people do not take their medication as directed, or skip doses, for example due to medicines stock-outs. Patients who develop resistance to first-line treatment have to be switched to second or third-line regimens, which are often much more expensive.

“Dolutegravir is more forgiving, meaning if you miss a dose or two, you won’t get resistance. With efavirenz there is a low bar for resistance; just missing a few doses can cause resistance,” says Dr Nomathemba Chandiwana, a senior research clinician from Ezintsha at Wits University. 

“Efavirenz also interacts with certain hormonal contraception [rendering a number of contraception methods ineffective in many cases]. But dolutegravir doesn’t have those interactions.”

Additionally, she says, dolutegravir does not have many of the side effects associated with the efavirenz regimen, including insomnia, dizziness and depression.

1.3m patients switched

Despite these advantages, the nationwide transition to dolutegravir only began in earnest in February 2020, almost two years after the initial planned introduction, according to NDoH spokesperson Popo Maja.

Speaking to Spotlight, he reveals that, as of August 2020, 1.3 million patients (representing 26% of the total), had been switched to dolutegravir.

What was the reason for the delay?

According to Chandiwana, the answer lies in the evidence, which is increasingly showing that dolutegravir “is not a perfect drug”. Moreover, South Africa may not have responded optimally to the emerging evidence.

On 18 May 2018, the World Health Organisation, European Medicines Agency and the United-States’ Food and Drug Administration unanimously issued warning statements about a possible link between dolutegravir and birth defects, based on data from the Tsepamo study in Botswana.

However, more recent research has found the risk to be minimal, and, some believe, negligible. For every 1,000 pregnancies in women on dolutegravir, there is a risk for one child being born with neural tube defects, down from a previous estimate of three per 1,000 in 2018, according to data presented at the 23rd International Aids Conference in July.

Acknowledgement of risk form

Based on the 2018 data, the South African Health Products Regulatory Authority (SAHPRA) reached out in November 2018 to the eight manufacturers that supply the government with dolutegravir, in the form of a fixed-dose combination with two other drugs, tenofovir and lamivudine, to develop an acknowledgement of risk form. Women of childbearing age, who make up the majority of the South African ART programme, would have to sign this form, acknowledging that they are aware of the birth defect risk, before they could be switched to the dolutegravir regimen.

Such a measure was “highly peculiar”, according to Prof Francois Venter from the Wits Reproductive Health and HIV Institute, as many drugs, for example, common epilepsy drugs, have the same side effect and do not require this level of bureaucratic red tape.

In December 2019, four provinces began the transition to the dolutegravir regimen, but they were required to get women to sign the acknowledgement of risk form.

But by February, when the remaining five provinces started transitioning patients, it was apparent that this piece of paper was impeding uptake.

“This form scared both patients and healthcare workers and knocked the introduction of dolutegravir on its head,” says Venter. He added that “we have never before done anything like this for any other side effects and lots of drugs have side effects, including this particular side effect”.

“It’s the role of the healthcare worker to explain side effects to patients. It was a badly thought out decision and a terrible mistake,” he says.

“Women are not baby-making machines. No other drug has been held to the standard that dolutegravir was held to,” says Chandiwana. “Essentially, we had authorities making decisions for women about their bodies. Many women of reproductive potential may not want to have a child.”

By February 2020 the form was retracted, with government realising its negative impact on the transition to dolutegravir.

In an NDoH circular dated February 24, then deputy director-general Dr Yogan Pillay stated: “It has also been brought to our attention that the SAHPRA acknowledgement of risk form for female patients does present an operational challenge to transitioning female patients of childbearing potential. After extensive representation by the [NDoH], SAHPRA has agreed to withdraw the risk acknowledgement form.”

But just as the programme seemed to overcome this hurdle, Covid-19 and the lockdown occurred the following month – delaying the transition further. 

Risk of weight gain

The risk of birth defects link turned out to be negligible, especially when compared to a side effect only discovered more recently – weight gain.

According to data from the local Advance trial, which is for the first time examining the effect of the drug in the population where it will be used most – black South African women – weight gain is a serious factor.

“Some women have gained 30 to 40kg in three years. Some are so heavy, doctors don’t recognise them when they come into the clinic,” says Dr Andrew Hill, from Liverpool University.

According to Chandiwana, the level of weight gain has been found to be substantially different between men and women.

The Advance trial has three arms: One looking at the existing first-line efavirenz-based treatment; another looking at dolutegravir with tenofovir and lamivudine (the regimen currently being used in South Africa); and a third looking at dolutegravir with a new version of tenofovir (tenofovir alafenamide) and lamivudine.

At 96 weeks of treatment, women in the tenofovir alafenamide arm gained an average of 8.2kg, women in the tenofovir arm gained 4.6kg, and 3.2kg in the efavirenz arm.

Men, however, gained far less. After 96 weeks, men in the tenofovir alafenamide arm gained 5.2kg, in the tenofovir arm they gained 3.6kg, and in the efavirenz arm they only gained 1.4kg.

“The difference is significant,” says Chandiwana.

According to Hill, it’s worrying that “there is no sign of the weight gain plateauing” and “one in three women in the trial are clinically obese after three years”.

Despite this, the weight gain side effect hasn’t equated to patients dropping out of the trial or stopping their medication. 

“Some people don’t want to be thin. With HIV there is an obvious stigma around being thin,” says Hill. Regardless, he says, “obese people have a higher risk of developing diabetes, having heart attacks… and pregnant obese women have higher risks of adverse outcomes related to pregnancy”.

He urged the NDoH to continue with the tenofovir regimen and resist pressure from drug companies to switch to the tenofovir alafenamide combination in future.

The situation appears to have come full circle: Just as the initial concerns about birth defects have been put to bed, this new side effect has been found to cause harm to pregnant women and their babies.

“Children born to obese women are more likely to miscarry; the risks are higher for stillbirths and for babies being born small for their gestational age. There are also higher risks for other complications during pregnancy,” says Chandiwana.

‘Women are under-represented’

Activists and experts, like Chandiwana, point to the fact that if new drugs were initially tested in populations they were largely meant to treat, such as black women, the field would have known about these adverse effects sooner and the delays in introducing the drugs, as we have seen in South Africa, might not have happened.

“These risks should have been known before a drug goes out to market, but women are under-represented in clinical trials. Most trials are conducted in high-income countries among white male, and often older, participants. 

“While the biggest consumers of these drugs, especially ARVs, are young black African women. There is a disconnect – trials are not being done in the right populations for us to get enough data,” she says.

Women constitute around 60% of people living with HIV in sub-Saharan Africa, including South Africa.

“Efficacy, or how well drugs work, is often the same in men and women, but side effects are often different,” says Chandiwana.

“But drugs have their warts – there is no perfect drug. We thought dolutegravir was the best thing ever, but now we know there are issues. 

“While emerging data in women is a let-down to many, it is the best thing for the ART world. For too long we have ignored that women exist. This signal should make people stop and think: Before drugs come to market, there have to be female participants in clinical trials. 

“All drugs have side effects, but these should not only be seen once the drug is already being used,” she says. 

“This situation is not only true for ARVs, but for all drugs. Women need to be included, women need to be followed up – as well as their babies. But not only women who have children – all women.” DM/MC

This article was produced by Spotlight – health journalism in the public interest. Sign up for our newsletter.