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Truvada Drug Levels in Vaginal and Rectal Tissue Offer Clues to HIV PrEP Puzzle

The 2 drugs in the Truvada pill -- tenofovir and emtricitabine -- reach different concentrations in human cervical, vaginal, and rectal mucosa tissues and fluids, according to new research published in the December 7, 2011, issue of Science Translational Medicine. Lower drug levels in the female genital tract suggest that women may need higher doses to achieve a prophylactic effect, which may help explain conflicting results from some recent biomedical HIV prevention trials.

A series of large trials over the past 2 years have produced mixed findings about the benefits and risks of pre-exposure prophylaxis (PrEP), or use of antiretroviral drugs by HIV negative people in an effort to prevent infection.

The iPrEx study of gay and bisexual men in several countries and the TDF2 trial of heterosexual women and men in Botswana both showed that daily oral tenofovir/emtricitabine dramatically reduced the risk of HIV infection when given along with risk-reduction counseling, free condoms, and other prevention services.

The Partners PrEP trial of serodiscordant heterosexual couples found that both daily tenofovir/emtricitabine and oral tenofovir alone reduced the risk of infection, by 73% and 62%, respectively.

In contrast, the FEM-PrEP trial did not find a prevention benefit of daily oral tenofovir/emtricitabine for heterosexual women in Kenya, South Africa, and Tanzania; that trial was halted this past April after an interim review showed a similar number of new HIV infections in the tenofovir/emtricitabine and placebo arms.

Most recently, the VOICE trial, looking at women in South Africa, Uganda, and Zimbabwe, halted its oral tenofovir monotherapy arm in September after an interim analysis found that the study could not demonstrate that it was more effective than placebo. But another study arm testing tenofovir/emtricitabine was  allowed to continue, suggesting the combination performed better in the interim analysis.

The reasons for these conflicting results are not clear, but researchers have noted that, overall, tenofovir-based PrEP appears to work somewhat better for men than for women, leading some to speculate that the drugs may not behave the same at different anatomical sites.

Kristine Patterson and Myron Cohen from the University of North Carolina Chapel Hill and colleagues designed a study to look at pharmacological properties of tenofovir and emtricitabine in genital and colon-rectal mucosal tissue from 15 healthy HIV negative volunteers, 8 men and 7 women.

Cohen was the principle investigator of the HPTN 052 study -- presented to much fanfare at the International AIDS Society conference this summer in Rome -- which showed that if the HIV positive partner in a serodiscordant couple started immediate ART upon diagnosis regardless of CD4 cell count, the risk of HIV transmission was reduced by 96%; HPTN was mostly conducted in low- and middle-income countries, however, and use of tenofovir/emtricitabine was uncommon (10% overall, but zero at several sites).

Participants in the current study received a single oral dose of Truvada. Starting 24 hours later and over the next 14 days, the researchers measured tenofovir and emtricitabine (aka FTC) levels in blood plasma and genital secretions using a sensitive assay with a lower limit of 0.1 ng/mL. Active metabolites of these drugs -- tenofovir diphospate and FTC triphosphate, respectively -- were also measured in rectal, vaginal, and cervical tissue samples in the laboratory.

The authors explained that previous studies have carefully examined pharmacokinetic profiles of tenofovir and emtricitabine and their active metabolites during the first 24 hours after dosing, so they looked at longer-term changes.

Results

• Tenofovir and emtricitabine both were detected in blood plasma 14 days after administration of a single dose.
• The area under the concentration-time curve from 24 hours to 14 days (AUC_1–14d) -- a measure of total exposure over time -- for emtricitabine in genital secretions was 27-fold greater than blood plasma AUC.
• In contrast, the AUC_1–14d for tenofovir was only 2.5-fold greater in genital secretions than in blood plasma.
• Rectal tissue concentrations of tenofovir/tenofovir diphospate were 100-fold higher than concentrations in vaginal and cervical tissue.
• Conversely, vaginal and cervical tissue concentrations of emtricitabine were 10-fold to 15-fold higher than rectal tissue levels.
• In rectal tissue, tenofovir and tenofovir diphospate were detectable for 14 days after dosing.
• Even though emtricitabine reached high concentrations in vaginal and cervical tissue, FTC triphosphate was only detectable for 2 days in all tissue types.

Based on these findings, the study authors summarized, exposure to tenofovir, tenofovir diphospate, emtricitabine, and FTC triphosphate was "wide ranging depending on the type of mucosal tissue."

These results, they continued, "demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV."

"The [tenofovir] concentration in rectal mucosa was greater and existed longer than the [emtricitabine] concentration, whereas the [emtricitabine] concentration in vaginal and cervical tissue was greater than the [tenofovir] concentration," they elaborated in their discussion. "This differential penetration may provide insight into the variable level of protection reported with different PrEP drug combinations in diverse populations in the different trials."

They pointed out that the protection against vaginal viral exposure demonstrated in mice and monkeys that were given tenofovir without or without emtricitabine, compared with the failure of daily oral ART to prevent HIV acquisition in FEM-PrEP and VOICE, "raises the possibility that the concentrations of [tenofovir] and [emtricitabine] in animal studies may be different from those achieved in humans, and that the concentrations achieved in humans are not sufficient to prevent HIV acquisition."

The researchers added that tenofovir diphospateconcentrations in vaginal tissue achieved using the 1% tenofovir microbicide gel tested in the successful CAPRISA 004 trial were 100 times greater than those observed in the current study after oral dosing, but were similar to the levels achieved in rectal tissue with oral use.

As an added piece of evidence, they noted, studies have shown that more than half of HIV positive women on ART with undetectable plasma viral load have detectable HIV in their genital secretions -- higher than the number of men on suppressive ART who have detectable HIV in their semen.

"Vaginal acquisition of HIV may require a stronger barrier to infection than that provided by oral dosing with a [tenofovir/emtricitabine] combination," the investigators concluded. "The results of the current study and recent PrEP clinical trials indicate that more work needs to be done to elucidate the appropriate pharmacological barrier required to prevent HIV acquisition."

Investigator affiliations: University of North Carolina School of Medicine, Chapel Hill, NC; University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC; Gilead Sciences, Foster City, CA.

12/9/11

Reference

KB Patterson, HA Prince, NJ Shaheen, MS Cohen, et al. Penetration of Tenofovir and Emtricitabine in Mucosal Tissues: Implications for Prevention of HIV-1 Transmission. Science Translational Medicine 3(12): 112re4. December 7, 2011.

Other Source

American Association for the Advancement of Science. Unequal Penetration of HIV Drugs. Press release. December 8, 2011.