Vaginal microbicides may not be safe for rectal use: gels being reformulated

Researcher Peter Anton MD, University of California, Los Angeles
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A gel, used as a vaginal microbicide, when used rectally showed signs of efficacy, but raised safety concerns, the 18th Conference on Retroviruses and Opportunistic Infections (CROI) heard yesterday.

Researcher Peter Anton of the University of California, Los Angeles told the conference that although the gel, which was identical to the tenofovir-containing gel used in last year’s CAPRISA 004 vaginal microbicide trial, was 80% effective in inhibiting HIV from infecting rectal cells, it produced adverse gastrointestinal events such as cramps and discomfort in some users and was unpopular, with only 25% of users liking it.

The gel is now being reformulated specifically for rectal use, with various compounds already being tested on cell cultures, and a formulation given as a douche or enema has also been devised.

Glossary

topical

Applied directly to the affected area, as opposed to systemic.

concentration

The level of a drug in the blood or other body fluid or tissue.

hypo

Prefix meaning lower than usual.

gastrointestinal

Relating to or affecting the stomach, gut or bowel.

endpoint

In a clinical trial, a clearly defined outcome which is used to evaluate whether a treatment is working or not. Trials usually have a single primary endpoint (e.g. having an undetectable viral load) as well as a few secondary endpoints, covering other aspects of treatment safety, tolerability and efficacy.

The CAPRISA 004 result seems to have breathed new life into the microbicide field, with numerous experimental microbicides being presented at the conference, including hi-tech ones containing broadly neutralising antibodies, which would act like a short-lived ‘mucosal vaccine’.

However the study presented by Peter Anton was only the second study of a rectal microbicide on human volunteers.

The study followed a complex and exacting design and required considerable commitment from its 18 HIV-negative subjects (14 men and four women), Anton commented. The subjects were first given a single dose of oral tenofovir and then waited two weeks. During this time the subjects underwent five rectal sigmoidoscopies and had biopsies of rectal and colonic cells taken. 

Then they were given a single dose of either the CAPRISA tenofovir gel or a placebo hydroxyethylcellulose (HEC) gel and again waited two weeks and had biopsies taken at another five timepoints. Finally they were asked to use either the tenofovir or the inert gel once a day for seven days and had some final biopsies done. Altogether 2000 biopsies were taken.

The purpose of so many biopsies was so that the microbicide-treated cells could be used in an ‘ex vivo’ infection model: cellular explants were kept alive on gel rafts and subjected to challenge by large doses of HIV. This explant model, which was first aired at the 2008 Microbicides Conference in Delhi, are the nearest we can get to having a surrogate in early safety and dosing studies to evaluate the protective effect of a microbicide against real-life infection.

The trial also allowed the researchers to compare the levels of tenofovir seen in blood and in rectal tissues after oral and topical dosing. Not surprisingly blood concentrations of tenofovir were 30 times higher after oral dosing than after the single or multiple rectal dose, while the concentration of tenofovir inside rectal cells was 100 times higher after the single rectal dose and 500 times higher after seven rectal doses than in the oral dose.    

No significant resistance to viral infection was seen in cell biopsies after the single oral dose or the single rectal dose, but after seven days of rectal use there was an 80% decline in viral infectivity.

So the gel shows signs of considerable efficacy, but there were also significant safety concerns, and it was not popular in volunteers. 

The ‘primary safety endpoint’ of the trial had been the occurrence of adverse events of grade three or four, meaning severe or worse, and in fact two volunteers did report grade three adverse events, meaning diarrhoea, cramps and discomfort. These occurred after three or four doses of the tenofovir gel and the volunteers did not complete the seven-day course.

Declines in the secretion of two immune activation makers were also seen in rectal cells after the seven-day course, indicating some cell damage. No similar effects were seen with the HEC gel.

Only 25% of volunteers said they liked the tenofovir gel, compared with 50% liking the HEC gel, although 75% said they would be prepared to use it again if it proved protective against HIV.

New formulations

Given these safety concerns, the tenofovir gel is being reformulated to be less toxic to cells. Experiments by Charlene Dezzutti of the University of Pittsburgh – who last year found that a number of commercial sex lubes were toxic to cells – have produced a gel that is less hyperosmolar. This means it contains lower concentrations of sugars and salts and would tend less to draw liquid out of cells, a primary reason for cellular toxicity.

There have been early trials by Craig Hendrix and his team at Johns Hopkins University (Leyva) of potential enemas as delivery vehicles, given that many men and women douche before anal sex. Nine gay men tried two different enema formulations, one hyperosmolar and one iso-osmolar (having the same balance of salts and sugars as the body’s own fluids) and also used distilled water as a third, hypo-osmolar douche. The iso-osmolar douche was preferred by the users, penetrated much further up the colon (and would therefore protect a larger area) and was less toxic to cells even than distilled water.

Abstracts and webcast

You can view the abstracts from this research on the official conference website:

Abstract 34LB: www.retroconference.org/2011/Abstracts/42556.htm

Abstract 983: www.retroconference.org/2011/Abstracts/41118.htm

Abstract 993: www.retroconference.org/2011/Abstracts/42536.htm

You can also watch webcasts of presentations made at the conference.

The webcast from the conference session HIV Prevention: HSV2, Topical and Oral PrEP, and Circumcision, includes the speaker Peter Anton.

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References

Anton P et al. RMP-02/MTN-006: a phase 1 placebo-controlled trial of rectally applied 1% vaginal TFV gel with comparison to oral TDF. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 34LB, 2011.

Dezzutti C et al. TFV gel reformulation results in improved product safety for rectal application. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 983, 2011.

Leyva F et al. Comparison of 3 rectal douches as safe, preferred delivery vehicle for rectal microbicides. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 993, 2011.