New data presented at the 2018 HIV Research for Prevention (HIVR4P) conference in Madrid, Spain, highlights the importance of studying differences in the way a person's sex can affect their metabolization of the experimental drug cabotegravir, which is being studied as an injectable, long-acting HIV prevention medication.
Cabotegravir is an integrase inhibitor with a long half-life, making it an exciting candidate for people who would prefer to receive an injection every several months rather than regularly taking a pill to protect against HIV, which is currently the only available form of pre-exposure prophylaxis (PrEP).
But researchers are also wary of the so-called pharmacokinetic tail, or the trace amounts of drug that linger in the body for months, and sometimes years, after an injection. These trace amounts of drug may not be enough to protect against HIV and may instead encourage drug resistance. In fact, initial results from a Phase II trial indicated that the pharmacokinetic tail lasted at least 52 weeks in roughly half of men involved in the study.
"This is the first time 'tail' data for females is going to be presented," said Raphael Landovitz, M.D., M.Sc., UCLA Center for Clinical AIDS Research & Education, speaking at an HIV4P press conference on Oct. 23.
When Landovitz examined the half-life of cabotegravir in men and women, he found a stark difference. Specifically, the half-life in females was 45% longer than in males. To a lesser extent, the same paradigm held true for body mass index -- meaning that every unit increase in body mass index correlated to a 2% increase in half-life.
Put simply, biological sex is a "really important predictor" of cabotegravir's pharmacokinetic tail, Landovitz said.
Landovitz and his colleagues collected this data by following 177 patients who had participated in the HIV Prevention Trials Network's Phase IIa study of cabotegravir injection, dubbed HPTN077. Patients enrolled in the study were given one of two doses: either 800mg every 12 week or 600mg every eight weeks. Two-thirds of the study participants were cisgender women.
By following men and women for over a year, researchers were able to obtain a full picture of what happened to each patient 18 months after his or her last injection. By then, only 13% of men but 42% of women still had cabotegravir in their blood.
By extrapolating those numbers out, researchers were able to determine the average time for cabotegravir to drop below detectable levels, as well as a range of times, for each group. For men, the average time for cabotegravir to drop to undetectable levels was 42.7 weeks or about 10 months. The range for men was 20 weeks (just under five months) to 134 weeks (roughly two and a half years).
Meanwhile, the average time for women was 66.3 weeks, or more than one year. Women also had a much wider range, from 18 weeks (just over four months) to 182 weeks (about three and a half years).
Thankfully, none of the patients tested positive for HIV in this period, despite the depleted levels of protective medication in their blood.
"When we reported the [HPTN077] data last summer, we reported one seroconversion in a woman with no detectable cabotegravir," Landovitz said. There were no additional seroconversions in patients followed and assessed for the "tail" portion of the study.
"Obviously, it's good news that we only saw that one seroconversion event," especially because the patient population included in the study is considered "low risk" for HIV transmission, Landovitz said. As well, the rates of "Grade 2" or higher serious adverse events were similar to the results presented in the initial HPTN077 and mostly confined to injection site reactions.
Two of the women became pregnant, and both babies were healthy. In fact, one of the babies was born while the mother still had detectable levels of cabotegravir in her blood.
All of this data is good news for the future of cabotegravir injections, which are currently moving into Phase III trials. However, researchers still need a better understanding of how the long tail of cabotegravir might interplay among people who have a higher risk of acquiring HIV.
The tail could either be a good thing, offering prolonged protection, or a liability, increasing the risk for seroconversions and leading to infection resistance, Landovitz said.
"It will only be when this compound is used in at-risk individuals ... that we'll get more information about what it means to have that prolonged pharmacokinetic tail," said Landovitz.