The low representation of women in clinical trials has led to some efficacy and safety differences between men and women being missed, reports Dr Shuang Zhou of the United States Food and Drug Administration (FDA). African-American women were particularly underrepresented in clinical trials of new antiretrovirals.
Women make up the majority of people with HIV globally, but there is a chronic underrepresentation of cisgender women in antiretroviral clinical trials. This lack of representation results in sex-based differences being unknown. Some side effects, such as weight gain and rashes, have been reported more frequently by female patients.
All drugs must be approved by regulators such as the FDA before they can be used by the general population. Before a drug is approved it needs to be developed through different clinical trial phases. Phase III recruits a large group of people to evaluate the safety and effectiveness of a new treatment, compared to what is currently available.
The study team looked at clinical trial data that was submitted to the FDA after 2010, enabling them to evaluate clinical trials of newer HIV treatments. The study looked at eighteen phase III clinical trials in adults starting HIV treatment.
The trials evaluated a range of HIV treatment classes: nine non-nucleoside reverse transcriptase inhibitors, 20 integrase strand transfer inhibitors and seven protease inhibitors. All trials were multi-centre across a range of countries.
The study team used the Participation to Prevalence Ratio (PPR) to calculate how well women were represented among overall study participants. An PPR of 1 is achieved when the percentage of a group recruited to a study reflects the percentage in the real world. Therefore, to be representative, clinical trials need to have a PPR between 0.8 and 1.2 female participants.
Safety and efficiency differences
The study team looked at 18 trials which included just over 13,000 participants (including just under 5,300 US participants). In total, 15% were female, 65% were White, and 21% were Black, 7% were Asian. Of the female participants, 45% were White, and 36% were Black. Of the male participants, 69% were White and 18% were Black.
Looking at the US-based participants only, 11% were female. Of them, 62% were Black and 34% were White. Female participants were on average five years older than their male counterparts. They also had significantly lower CD4 counts.
Fifteen of the 18 trials did not have proportionate representation; US female participants were underrepresented. The overall PPR was 0.58. This reflects the fact that 11% of participants were women whereas 19% of people with HIV in the US are women.
When broken down according to gender and race, 11% of all people with HIV in the US are Black women but they made up 7% of the clinical trial participants. White women are 4% of people with HIV in the US and were 4% of the trial participants. Therefore the study team found that the PPR for White females was 1.0, while for Black females it was 0.63.
Male participants were more likely to become undetectable within 48 weeks than female participants in both the global and US sites. The response rates favoured males: the odds ratio was 0.79 across the global sites and 0.71 among US participants.
The authors paid attention to different side effects: if the drugs impacted liver (serum alanine aminotransferase and serum aspartate aminotransferase) and kidney (serum creatinine) function, as well as levels of haemoglobin (a protein that transports oxygen in the blood).
The study team found that haemoglobin levels generally decreased in women, but not men. However, these were not likely to cause health issues. Generally, there were no differences between males and female participants in regards to drug-related rashes.
The underrepresentation of any group means important public health questions are left unanswered. The lack of data also affects future research. For example, the authors noted that the low number of female participants impacted their ability to detect sex differences in safety and effectiveness.
The authors looked at clinical trials over a 10-year period and noted that enrolment has not improved in that time. HIV treatment may work differently in men and women, but the lack of female representation across all clinical trials means this question largely goes unanswered.
The authors call for innovative ways to improve the recruitment of women, however, this suggests that women are a special and elusive sub-category. Instead, it is time for researchers to no longer view cisgender men as the default human and acknowledge how their recruitment practices favour them.
The authors call upon pharmaceutical companies to plan “for recruitment and retention of females in antiretroviral trials and encourage them to actively include key opinion leaders, investigators, and the HIV-1 community as part of their advisory boards and protocol review.”
Zhou S et al. Participation of HIV-1 infected treatment-naïve females in clinical trials and sex differences in efficacy and safety outcomes. AIDS, online ahead of print 9 January 2023.