Topical gels as PEP and PrEP: animal and human studies

Simon Collins, HIV i-Base

The conference included a similarly broad range of studies looking at antiretroviral-based microbicide gels.

Rectal use of tenofovir gel protections against ex vivo exposure

Peter Anton from the University of California presented late breaker results from a phase 1 study of rectal use of the tenofovir gel used in the Caprisa 004 study. [1]

HIV-negative participants (14 men and four women) received sequentially a single oral dose of tenofovir, single rectal dose of tenofovir gel or placebo, and seven days rectal dosing, also randomised, each separated by a two week wash out and sampling period. The study measured efficacy by ex vivo infectibility of in vivo exposed cells from rectal biopsies, and monitored plasma drug concentrations in multiple compartments and general product acceptability.

Primary endpoint was safety defined by grade >/= 2 events and secondary safety by a large panel tests relating to mucosal injury that were developed for an earlier HPTN 056 rectal microbicide study.

Most side effects were grade 1 and occurred during the seven-day rectal use, more frequently with the active gel (12 vs 2 people, p=0.001; 37 vs 6 events, p=0.002) were gastrointestinal (GI). However, two people reported five grade 3 GI events. The only differences seen between groups in the panel of mucosal indices were decrease in two cytokines (IL1-beta and TNF-alpha) only seen at 30 minutes post dosing after the seven-day exposure.

Neither gel was particularly liked (25% tenofovir, 50% placebo) but approximately 75% in each group said they would use it if it proved to be effective.

As expected, plasma dosing achieved significantly higher levels (approximately 2 logs higher) in plasma compared to tissue, with rectal dosing not accumulating tenofovir levels in plasma.

Importantly, active drug levels of tenofovir diphosphate, 30 minutes post dosing with single rectal dose were >100-fold higher in rectal tissue compared to oral dose, achieved in 80% of samples, and were five times higher following the 7 day dosing.

Rectal biopies taken 30 minutes post dose were infectible at baseline. Single oral dose showed no effect and single rectal dose showed a trend to an effect but after 7 day rectal dosing the tenofovir exposed cells showed significantly greater resistance to infection.

This allows the first analysis to show a strong positive correlation between tenofovir DP drug level following in vivo exposure and HIV inhibition (r2=0.33, p=0.0011).

While the study concluded that although the acceptability of the gel was lower, the gel was safe in terms of tissue exposure, and topical application achieved tissue concentrations of tenofovir diphosphate that demonstrated ex vivo protection from infection.

Oral tenofovir vs daily gel vs both

Craig Hendrix from Johns Hopkins University, Baltimore, and colleagues presented results from an open-label phase 2 study of daily oral tenofovir, daily gel and dual oral/gel in 144 sexually active HIV-negative women (aged 18-45) at four US and three African sites. This was a three-stage cross over study with each stage lasting six weeks separated by one week washout. [2]

The study looked at safety, adherence, acceptability and pharmacokinetics.

The gel resulted in levels of tenofovir diphosphate that were 100-fold higher in vaginal tissues compared to oral dosing, and dual dosing made no additional impact on tissue concentrations.

Although excellent adherence was reported (>90% all doses reported as taken; and >80% people taking >90% of doses) the drugs levels observed at any time point in the pharmacokinetic study showed that 35-65% of the people in all groups had drug levels below the 99% confidence interval from historical reference cohorts.

No differences in side effects overall were seen between the three regimens, though nausea, diarrhoea and headache were more common during the oral and dual stages (all <15%). Vaginal symptoms and reduced phosphates (general transient) were similar between stages. Nine cases of grade 3/4 hypophosphatemia occurred in 4 oral, 2 gel and 3 dual participants.

The presentation noted that although active concentration in the target site were good from the gel, and not increased by additional oral dosing, the optimum dose required for efficacy is not known and this is an important point.

Raltegravir as a topical gel in macaques

Charles Dobard and colleagues from the CDC Atlanta presented data from using a 1% raltegravir-based gel applied three hours after vaginal exposure in six macaques. [3]

The rationale for this approach is that it is easier to use an intervention after exposure than to accurately predict when protection would be needed for a pre-exposure dosing – whether this involves a 24 hour or 2 hour preexposure window. Integrase inhibitors are a potential target for PEP/PrEP because they block later stages of the viral replication cycle, allowing an activity window 8-10 hours post exposure compared to 2 hours associated with RT inhibitors.

The gel formulation developed by this group was a clear, odourless gel that was stable for several years at room temperature. The macaques received vaginal SIV challenges twice weekly for up to 20 exposures.

Four control animals all became infected (after 10–20 viral challenges). In contrast, 5/6 macaques using the active gel remained protected through 20 exposures (p<0.005). Although one infection occurred, resistance did not develop while the gel was continued, although this was only for a short period. Systemic viral load in this animal was similar to control data, although levels of vaginal shedding were significantly lower.

Oral tenofovir/FTC protects macaques rectally exposed to FTC-resistant virus

Protection against exposure to FTC-resistant virus was reported by Gerardo Garcia-Lerma, also from the CDC, from macaques using oral tenofovir/FTC and following rectal exposure. [4]

The rationale for this study is to determine whether tenofovir protects against the common M184V mutation as one of the more common resistant mutations reported in drug resistance surveillance studies.

Five macaques received oral tenofovir/FTC in human equivalent doses 3 days before and two hours after rectal exposure, which was administered weekly for up to 14 weeks. Five untreated animals were included as controls. None of the treated animals become infected compared to all five control animals (p=0.0008).


Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February-–2 March 2011, Boston.

Webcasts are available at the following link:

  1. 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. Oral poster 34LB.
  2. Hendrix C et al. MTN-001: a phase 2 cross-over study of daily oral and vaginal TFV in healthy, sexually active women results in significantly different product acceptability and vaginal tissue drug concentrations. Oral poster 35LB
  3. Dobard C et al. High protection against vaginal infection in macaques by PEP with gel containing RAL. Oral abstract 30.
  4. Garcia-Lerma G et al. Complete protection against rectal transmission of an emtricitabine-resistant SHIV162p3-M184V mutant by intermittent prophylaxis with Truvada. Oral abstract 31.

Links to other websites are current at date of posting but not maintained.