Recent research showing that a quick-dissolving, rectal suppository designed to prevent HIV infection is safe could herald the start of a new “take-as-needed” era in HIV prevention, writes Laura Lopez Gonzalez for Spotlight.
However, the efficacy remains to be tested in clinical trials, some of which will be conducted in South Africa.
The small study, involving 23 HIV-negative men and women in the US, found that the suppository – no bigger than a fingernail – that contains two antiretroviral drugs is safe, researchers said last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2023) in Seattle, US.
The pill-like suppository, combining the antiretrovirals tenofovir, alafenamide and elvitegravir, is designed to be inserted in the rectum before receptive anal sex to ward off HIV infection. Small studies like these are designed only to gauge whether a new medicine is safe but not whether it works.
Still, scientists say the suppository released promisingly high and long-lasting doses of antiretrovirals into patients’ rectal tissue and fluid.
As part of the study, participants began with a single dose of the suppository. Samples of their blood as well as rectal fluid and tissues were taken on the same day and for the next three days. Up to seven weeks later, people in the trial returned and were given two doses of the suppository before daily samples were again taken over three days.
The samples showed that the drugs stayed exactly where they are needed most to prevent HIV infection – the rectum. Although testing revealed high levels of the antiretrovirals in rectal tissue and fluids, patients’ blood work showed very little of the drugs circulating throughout the body.
When the researchers in the laboratory exposed them to HIV, drug levels were high enough to prevent infection, said University of Pittsburgh assistant professor of infectious diseases Sharon Riddler. The results echo the findings of previous studies in which the suppository was used vaginally.
Scientists are planning to conduct a larger study of the suppository’s vaginal use among 60 women across the US, Kenya and South Africa. It will be the first trial of the suppository in Africa.
If future trials prove the suppository works to prevent HIV, it will become the newest form of pre-exposure prophylaxis (PrEP) or products using antiretrovirals to prevent HIV infection.
All the PrEP, none of the planning
The suppository could fill a critical gap in PrEP, Riddler said. It is clear from more than a decade of research that the HIV prevention pill and a new HIV prevention shot, using the long-acting antiretroviral cabotegravir, works, she said, “but it’s also clear that PrEP uptake – particularly with oral and injectables – is much lower than we’d like… because of cost, availability (and) desirability”.
If the new suppository works, anally or vaginally, it could finally offer women and transgender men a PrEP option they can take just when they need it.
“Currently, the only on-demand product option for PrEP has only been tested in cisgender men,” she said. “If proven to be effective, (this new) product – which provides protection, potentially both vaginally and rectally – would be a real game changer.’
Study details
Safety and PK/PD of a tenofovir alafenamide/ elvitegravir insert administered rectally
Riddler SA, Kelly C, Hoesley C, et al.
Presented at the 30th CROI (Conference on Retroviruses and Opportunistic Infections), 19-22 February 2023.
Rectal inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) provided high rectal fluid and tissue concentrations of EVG, tenofovir (TFV), and tenofovir diphosphate (TFV-DP, the active form of TAF) in a study of 17 men and 6 women without HIV. Being studied for pre-exposure prophylaxis (PrEP), the inserts were safe and participants tolerated them well in this short study. The fast-dissolving rectal inserts to protect people from sexual transmission of HIV contain 20 mg of the reverse transcriptase inhibitor TAF and 16 mg of the integrase inhibitor EVG. The inserts protected monkeys from vaginal or rectal [simian HIV (SHIV) infection, and the researchers have completed a phase 1 pharmacokinetic and safety study in women. The new trial set out to explore the PKs and safety of the TAF/EVG rectal insert at two doses of one insert and two inserts.
The study group consisted of healthy HIV-uninfected adults at low risk for HIV infection and not taking pre-exposure prophylaxis (PrEP) against HIV. The aim was to finish the trial with 20 evaluable participants with one rectal insert and 20 with two inserts. Twenty-one of 23 participants completed the first dosing visit evaluating the impact of one insert. After at least a 7-day washout, volunteers used two inserts, and 19 completed this phase of the trial. The MTN team measured EVG, TAF, and TFV in blood, rectal fluid, and rectal tissue homogenates. They measured TFV-DP in rectal tissue cell isolates. Seventeen participants were male and 6 female; 8 were black, 13 white, and 2 some other race or ethnicity. Median age stood at 34 years (interquartile range 24 to 43) and median body mass index at 30.8 kg/m2, just over the obesity threshold (interquartile range 26 to 37). Nine participants reported 17 adverse events, only one of which (mild anal erythema) was related to the insert.
The only two grade 2 adverse events (reactogenicity to the COVID vaccine and gastritis) were not related to the insert. Median peak blood plasma concentrations with 1 and 2 inserts were 1.73/2.39 ng/mL for EVG, 29.5/41.9 ng/mL for TAF, and 2.64/4.42 ng/mL for TFV. Concentrations of EVG and TFV plateaued near the peak concentration for 6 hours. Insert administration yielded higher rectal fluid and tissue levels than blood plasma levels of TFV and EVG. Median rectal fluid concentrations with 1 and 2 inserts at 24 hours were 2234/2597 ng/mL for EVG and 2909/8277 ng/mL for TFV. Rectal tissue TFV-DP levels almost always exceeded rectal tissue levels after oral dosing of tenofovir disoproxil fumarate (TDF) in an earlier trial. After HIV challenge of rectal tissue, HIV p24 antigen levels proved significantly lower than baseline p24 at every interval measured—2, 24, 48, and 72 hours after insertion of both the first and second TAF/EVG insert. At those four time points, median change from baseline p24 ranged from -1.2 to -1.6 log10 with a single insert, and from -1.7 to -2.0 log10 with 2 inserts.
These pharmacokinetic findings, coupled with protection from SHIV challenge in monkeys justify continued study of TAF/EVG rectal inserts.
See more from MedicalBrief archives:
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Innovative delivery implant for long-term PrEP administration