Biological, clinical and ethical imperatives for involving diverse women in HIV clinical trials

Dr Catherine Orrell presenting to HIV Glasgow 2020.

Clinical trials have historically under-enrolled women, and research has too often ignored that females and males are biologically different, although women are disproportionately affected by HIV in sub-Saharan Africa. Women’s exclusion from trials is often motivated by a desire to protect them and their children from potential harm caused by a medication, but this results in inequity for women: unknown safety, efficacy and tolerance of most new medications.

This is how Dr Catherine Orrell, from the Desmond Tutu Health Foundation, University of Cape Town, opened a session on the involvement of women in clinical trials at the virtual HIV Glasgow 2020 congress last week.

She pointed out that to this day, a lot remains unknown about how to ensure that women receive the best treatment for any disease.

Glossary

transgender

An umbrella term for people whose gender identity and/or gender expression differs from the sex they were assigned at birth.

exclusion criteria

Defines who cannot take part in a research study. Eligibility criteria may include disease type and stage, other medical conditions, previous treatment history, age, and gender. For example, many trials exclude women who are pregnant, to avoid any possible danger to a baby, or people who are taking a drug that might interact with the treatment being studied.

clinical trial

A research study involving participants, usually to find out how well a new drug or treatment works in people and how safe it is.

foetus

An unborn baby.

rash

A rash is an area of irritated or swollen skin, affecting its colour, appearance, or texture. It may be localised in one part of the body or affect all the skin. Rashes are usually caused by inflammation of the skin, which can have many causes, including an allergic reaction to a medicine.

In general, women weigh less and have a higher percentage of body fat than men, which can alter the pharmacokinetics of a drug in their body. Likewise, hormonal changes occurring throughout the menstrual cycle and in pregnancy have an impact on how drugs are processed in the body, although this data are often not available. For example, it was long after the approval of the sleeping pill zolpidem that its standard dose was found to have double the concentration in women.

Men and women also have pharmacodynamic differences that, again, are not always discovered during the drug development process. For example, weight gain associated with dolutegravir disproportionately affects women, but the early studies had not even recorded weight gain as an adverse event. It is still unknown if weight gain will increase women’s metabolic risks, or if it will in fact be associated with lower all-cause mortality, as is often seen in women in sub-Saharan Africa. Another example of these pharmacodynamics issues is nevirapine, which induces hepatitis and rash at a much lower CD4 count in women than in men.

Large gaps persist in knowledge on pregnancy in women with HIV, as pregnant women are typically excluded from the trials of new medications. If a woman taking part in a clinical trial becomes pregnant, she is usually required to withdraw from the study.

Much of the limited data on antiretrovirals in pregnancy are only collected retrospectively after a drug has been approved by regulators, through initiatives such as the Antiretroviral Pregnancy Registry. The focus is on safety for the foetus, rather than for the adult woman.

Orrell underlined the significance of knowing more about:

  • Drug concentrations throughout pregnancy, which often become too low in the later trimesters (lopinavir/ritonavir is an example).
  • Transplacental drug transfer – particularly since there have been scares about neural tube defects with both efavirenz and dolutegravir.
  • Drug transfer through breastfeeding – as evidenced for dolutegravir but not investigated for all antiretrovirals.
  • The potential harm of isoniazid in pregnancy.

Until robust answers are given for these questions, many women might remain assigned to inferior antiretroviral regimens due to the fear of potential harm on babies by newer medications. This has been seen in women taking efavirenz rather than dolutegravir, or several years ago, nevirapine rather than efavirenz.

Dr Meg Doherty from the World Health Organization (WHO) explored the policy implications of having little or no clinical trial data on women and adolescent girls. Looking back at lessons learned from the dolutegravir and neural tube defects issue, she reminded us how difficult it had been to keep the drug as a recommended first-line antiretroviral.

WHO’s 2018 guidance had added a “note of caution” concerning women and adolescent girls of childbearing potential. This note of caution created concern about equitable access to the best drugs for women and was implemented in diverse ways in different countries.

Doherty said that it was regrettable that policymakers had had to rely on one major study (Tsempano) for data on safety in pregnancy, with a lack of other studies to provide a more comprehensive picture. In the meantime, women – including those who did not plan to become pregnant – strongly expressed the wish to have dolutegravir made available to them. This was based on the drug’s efficacy, side effects and resistance benefits that outweighed its potential risks.

Since then, programmes have scaled up access to dolutegravir in women. However, they have not scaled-up access to contraception and reproductive health services at the same time, as they have been urged to do. Doherty highlighted how necessary women’s advocacy is to push researchers, policy makers and implementers to overcome barriers.

She illustrated the under-representation of women in research with two other examples. US regulators have recently approved tenofovir alafenamide and emtricitabine as PrEP, but only for men who have sex with men and transgender women. A WHO review of clinical trials evaluating treatments for COVID-19 has found that of more than 700 trials, 75% excluded pregnant women.

Professor Maggie Little of Georgetown University explored the ethical issues relating to pregnant women and clinical trials. The specific exclusion of pregnant women contributes to the under-representation of women in research more generally, she suggested. Much of the reticence to enrol women is driven by concerns about the possibility that they may become pregnant. Onerous contraceptive requirements discourage many women from taking part.

While there are appropriate ethical concerns about harming the unborn child, this ignores the reality that medications will inevitably be used by pregnant women after regulatory approval, especially as half of pregnancies are unplanned. It’s therefore preferable to find out about any risks in the controlled environment of a clinical trial, with appropriate precautions and regulations, than for the drug to be used in everyday clinical practice without that information, Little argued. She described this as “exporting” the risk to an environment where many more women and unborn children will be affected.

Pregnant women living with HIV should not be protected ‘from’ clinical research, but protected ‘through’ research, she said. Women and their doctors need to have reliable data on dosing adjustments, foetal safety and maternal safety.

The exclusion from clinical trials results in inequities in access to new medications. Many people choose to take part in clinical trials due to the prospect of getting access to a potentially beneficial medication that is otherwise unavailable, but pregnant women do not have this opportunity. After regulatory approval, the lack of pregnancy-specific data frequently discourages clinicians, guideline committees and policy makers from offering new antiretrovirals to pregnant women. The inequitable access to drugs which may be more potent and have fewer side effects than existing medications often persists even after data does appear.

Longret Kwardem, an advocate from the Salamander Trust in London, said that an increase of women’s participation in trials would mean that they would learn how to navigate a system that is opaque to many. Women are often not approached about clinical trials, whereas they may have many reasons to join one: to achieve sexual and reproductive health and rights, access the benefits of involvement in a trial, and contribute to the improvement of care for other women in the future, for example.

With regards to clinical trials, women are confronted to many other challenges, from general fear of the unknown, to fear of side effects and the use of traumatic and blaming language (such as ‘mother to child transmission’). However, Kwardem voiced that women want to be meaningfully engaged in research from the start to the end. They also want women-specific research through the life course, with consideration for their mental health and quality of life.

How can all of this be achieved? By ensuring gender-equitable representation in trials, updating exclusion and inclusion criteria, investing in capacity-building, and building trust over the long-term. As women’s priorities change along the way, the focus of research must as well.

Michelle Ross, a transgender activist from CliniQ in London, addressed the numerous challenges that were more specific to her community. Transgender people are called ‘hard to reach’, while they are not, if one knows where to find them, she said. Transgender people are considered to be a key population with regards to HIV, but the lack of information for and by transgender people makes it difficult for them to know if this is really the case.

Black transgender women are at higher risk of HIV, yet are not involved in the design of the trials. Transgender men, many of them HIV positive, have been and are excluded from the global HIV response. More data is needed on the use of antiretrovirals together with gender-affirming hormones and surgery. Ross called for an increase in research that takes into account transgender people’s specific needs.