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CROI 2011: Safety and Acceptability of Tenofovir Gel and Tablets for Pre-exposure Prevention

A vaginal microbicide gel containing tenofovir was found to be generally well tolerated and acceptable by American and African women, though some study participants preferred taking a pill for HIV pre-exposure prophylaxis (PrEP), according to study findings reported this week at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston. A related study found that the vaginal gel was not suitable for rectal use, and researchers are working on a more tolerable formulation.

An experimental vaginal gel containing a 1% concentration of tenofovir is being studied to prevent HIV transmission. Tenofovir (marketed as Viread and also included in the Truvada and Atripla coformulations) is widely used as part of combination antiretroviral therapy for the treatment of HIV infection.

In an oral presentation at CROI, Craig Hendrix from Johns Hopkins University described an open-label crossover study comparing the 1% vaginal gel versus oral tenofovir in 144 HIV negative women in Africa and the U.S.

Women in the study used the pill alone, the gel alone, and the pill and gel together (dual regimen) each for 6 weeks. The women served as their own controls in the study, using the 3 regimens in a randomized order.

The researchers looked at pharmacokinetic parameters (drug levels), markers of adherence, and product acceptability of the 3 regimens.

Results

• Both tenofovir formulations were generally well tolerated.
• Nausea and headache were more common in the oral and dual arms compared with the gel arm.
• No differences in genital symptoms between groups were observed.
• Tenofovir drug concentration was 100 times greater in vaginal tissue when using the gel compared to the pill.
• Drug concentration in plasma was around 2% with the gel compared to the pill.
• No additive drug concentration was seen in either the plasma or vaginal tissue when the gel and pill were used together.
• Self-reported adherence was greater than 90% in all arms, with no statistically significant differences seen between arms.
• However, measurements of drug concentrations suggested between 35%-65% non-adherence, with no differences across study arms.
• There were no differences in product acceptability between the gel and pill among African women.

o      100% of African women said they would use either formulation if found to be effective in preventing HIV infection.

o      African women reported greater sexual satisfaction using the gel.

• However, 72% of American women preferred the pill form to the gel.

The researchers concluded that both tenofovir formulations were equally safe and tolerable, and that expected differences were seen in drug concentrations in plasma and vaginal tissues based on drug delivery system.

Further, they saw significant differences between African and American women in terms of acceptability of the formulations. These findings, Hendrix said, suggest that multiple formulations should be available so products can match varying preferences.

Rectal Use of Tenofovir Gel

In another oral presentation at CROI, Peter Anton from the University of California Los Angeles described a study of the safety, pharmacokinetics, and acceptability of 1% tenofovir vaginal gel when used rectally.

This study included 18 participants, of whom 78% were male and 22% female. Participants were given an initial single oral dose of tenofovir in pill form. They were then randomized in a 2:1 fashion to receive either placebo gel or 1% tenofovir gel, first as a single dose followed by 7-day dosing; 2 week washout periods followed each dosing. Multiple pharmacokinetic and tissue samples were collected for 2 weeks following each dosing.

Results

• Adverse events were reported more often in the tenofovir gel group compared to the placebo group.

o      Most adverse events involved the lower gastrointestinal (GI) tract.

o      2 study participants receiving the gel formulation experienced serious (grade 3) lower GI adverse events.

• More than 75% of participants in both groups said they would use the product again.
• Tenofovir plasma concentrations when using the gel were about 2% compared to the pill.
• Tenofovir concentrations were 100 times higher in rectal tissue with the gel compared to the pill.
• Tenofovir concentrations in plasma were 2 logs higher with the pill than with the gel.
• No accumulation of tenofovir was seen in plasma or tissue after 7-day dosing.
• No rectal injury was seen in either arm of the study.
• Tissue samples exposed to HIV in the laboratory were significantly less likely to be infected when using tenofovir gel.

The researchers concluded that the 1% tenofovir gel formulation was "sub-optimal in terms of safety," but most study participants said they would use the product again "if it were found to be useful."

As expected, drug concentrations in the rectal tissue were significantly higher with the gel than the pill, while the opposite was true in plasma. Anton said they are now working on a gel formulation with lower osmolarity, which may reduce lower GI side effects.

Investigator affiliations:

Abstract 35LB: Johns Hopkins Univ, Baltimore, MD; RTI International, Research Triangle Park, NC' MRC, Durban, South Africa; Univ of Pittsburgh, Pittsburgh, PA; Case Western Reserve Univ, Cleveland, OH; Makerere Univ-Johns Hopkins Univ Research Collaboration, Kampala, Uganda; Univ of Alabama at Birmingham, Birmingham, AL; Columbia Univ, New York, NY; National Institutes of Health, Bethesda, MD; Univ of Washington, Seattle, WA.

Abstract 34LB: David Geffen School of Medicine, Univ of California, Los Angeles, CA; Univ of Pittsburgh, Pittsburgh, PA; Columbia Univ, New York, NY; Univ of North Carolina at Chapel Hill School of Pharmacy, Ctr for AIDS Research, Chapel Hill, NC; Magee-Womens Research Inst, Univ of Pittsburgh, Pittsburgh, PA; Microbicides Trials Network, Pittsburgh, PA; Univ of California, Los Angeles School of Public Health, Los Angeles, CA; CONRAD, Arlington, VA.

3/4/11

References

C Hendrix, A Minnis, V Guddera, and others.  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. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 35LB. [http://www.retroconference.org/2011/Abstracts/42418.htm]

P Anton, R Cranston, A Carballo-Dieguez, and others. 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. February 27-March 2, 2011. Abstract 34LB. [http://www.retroconference.org/2011/Abstracts/42556.htm]