An insert (suppository) designed for PEP or PrEP and containing the antiretrovirals elvitegravir and tenofovir alafenamide (TAF) was safe to use and produced drug levels in rectal tissues that stayed well above protective levels for over a day, and in the case of tenofovir, for over three days.
The first human safety study of rectal use of the insert was presented at this week’s 30th Conference on Retroviruses and Opportunistic Infections (CROI 2023) by Dr Sharon Riddler of the University of Pittsburgh. Data from vaginal use of the insert presented in 2021 at the HIVR4P conference found similar results.
The insert is designed to be gently inserted in the vagina or rectum, where it dissolves within a few hours. It looks like an oral tablet and is quite small – about 1.5cm long and less than 1cm wide. The insert contains 60 milligrams (mg) of elvitegravir and 20mg of TAF.
Animal studies published last year showed that it was 100% effective as PEP and 91% effective as PrEP in monkeys challenged vaginally with human-analogue SHIV virus. Another study found that the same dose was only 73% efficacious in monkeys challenged rectally, but this increased to 93% when a double dose – two inserts – was used.
In the phase I human study presented on Tuesday, researchers assessed the safety and pharmacokinetics (drug levels) of a single insert in the 72 hours after rectal insertion. The study was then repeated using two inserts. Twenty-three HIV-negative people, 17 men and six women, took part with 21 having the single dose and 19 the double dose.
All adverse events of grade 2 (mild but noticeable) and above were recorded. Drug levels were measured in blood, rectal fluid, cervicovaginal fluid (if applicable) and in rectal tissue samples, and also the levels of tenofovir diphosphate (TFV-dp) inside rectal tissue cells – this being the active substance TAF turns into once it enters a cell. Samples were taken one, two, four and six hours after dosing during the first study visit and then at return visits 24, 48 and 72 hours after dosing.
The average age of participants was 34 and their average BMI was quite high at 30.8 kg/m2. Eight were of Black ethnicity, 13 White and two other.
Only one grade 2 adverse event related to the drug was seen: mild anal inflammation seen after the single dose, which soon resolved.
Drug level measurements in fluids and tissue showed, as in the vaginal study, that elvitegravir levels were sustained for 24 hours but then declined; TAF levels declined in blood but TFV-dp levels in tissue samples scarcely changed. Levels after taking a double dose were not significantly different than after a single dose. In intracellular samples, TFV-dp levels were sustained above the level regarded as equivalent to seven-days-a-week oral TAF dosing for 48 hours. By 72 hours, four out of nine samples taken and analysed after a single dose were below this level, and three below the level equivalent to four oral doses a week. But after a double dose, eight out of eight samples were still comfortably above the seven-days-a-week oral dose level after 72 hours.
An early estimate of efficacy was made using what’s called an ex-vivo model. This means rectal tissue samples were exposed in the laboratory dish to 100% infectious doses of HIV and then either incubated with the drug or, as a control, with saline. Readings of the amount of the p24 HIV antigen – the first viral protein to be produced when replication happens – were then taken.
After a dose equivalent to one implant, p24 levels were 40 times lower than the control after two hours but only 16 times lower by 72 hours. After a double dose, however, p24 was 100 times lower than the control at two hours and still 50 times lower at 72 hours.
Sharon Riddler concluded that these promising results justified further evaluation of the elvitegravir/tenofovir insert as a new kind of both PEP and PrEP.
Riddler SA et al. Safety and PK/PD of a tenofovir alafenamide/elvitegravir insert administered rectally. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 164, 2023.