Back HIV Prevention Pre-exposure (PrEP) Study Suggests Truvada PrEP Should Start 1 Week Before and Continue 4 Weeks After Sex

Study Suggests Truvada PrEP Should Start 1 Week Before and Continue 4 Weeks After Sex

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An intensive pharmacokinetic study of tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) showed that blood and rectal drugs levels corresponding to high PrEP activity for men who have sex with men (MSM) are reached after about 1 week of daily dosing and appear to remain adequate for several days after the last pill, according to a report in the March 1 edition of Clinical Infectious Diseases. It is not known, however, whether this dosing schedule would work as well for women or other groups.

Research has shown that Truvada PrEP reduces the risk of HIV infection by more than 90% among gay and bisexual men when taken once-daily. The iPrEx Open-Label Extension studyfound no new infections among men who took Truvada at least 4 times per week. More recently, 2 trials of different PrEP regimens for MSMdemonstrated real-world effectiveness of 86%. PrEP efficacy has been lower but still good in studies of heterosexual couples, yet studies of African women have been unable to demonstrate protection due to low adherence.

However, it is not yet certain how soon protection is achieved after starting Truvada or how long it lasts after stopping. According to the Centers for Disease Control and Prevention (CDC) PrEP guidelines, issued in May 2014, data suggest that maximum intracellular concentrations of tenofovir diphosphate (the active form of tenofovir disoproxil fumarate or TDF) "are reached in blood after approximately 20 days of daily oral dosing, in rectal tissue at approximately 7 days, and in cervico-vaginal tissues at approximately 20 days."

Sharon Seifert from the University of Colorado at Denver and colleagues estimated the number of daily Truvada doses that would be required to achieve and maintain intracellular drug concentrations high enough to protect against HIV infection for men who have sex with men.

In an intensive pharmacokinetic study dubbed "Cell-PrEP," the researchers measured concentrations of tenofovir diphosphate in peripheral blood mononuclear cells (PBMCs) and rectal mononuclear cells -- the type of immune system white blood cells susceptible to HIV infection.

Cell-PrEP included 11 HIV negative adult men and 10 women. About half were white and half were African-American, with 1 Hispanic participant. The average weight was 81 kg (178 lb) and body mass index was 27.2 (considered overweight). They had normal kidney function at study entry.

Drug levels were measured over 30 days of daily Truvada dosing and 30 days of follow-up after stopping PrEP. PBMC samples were collected on days 1, 3, 7, 20, 30, 35, 45, and 60. Rectal biopsy samples were collected once for each participant at 2 hours after dosing. Adherence was determined based on pill counts, self-reports, and a dosing calendar.

The investigators used a regression formula for HIV risk reduction derived from PBMC drug levels in the pivotal iPrEx study to calculate inferred risk reduction, and the time needed to reach a steady-state level of tenofovir diphosphate in rectal mononuclear cells was also determined.

Results

  • All but 2 participants completed all study visits (1 discontinued due to elevated phosphorus -- a biomarker of possible kidney dysfunction -- and 1 withdrew for personal reasons).
  • Collectively, the participants reported missing only 5 Truvada does, indicating overall adherence of 99%.
  • The inferred HIV risk reduction based on PBMC tenofovir diphosphate concentrations reached 77% after 1 dose, 96% after 3 daily doses, and 99% after 5 and 7 daily doses; it did not reach 100% during the study.
  • In sensitivity analyses, the corresponding inferred risk reduction from 75%-81% after 1 dose, 95%-97% after 3 doses, and 98%-99% after 5 and 7 doses.
  • The inferred risk reduction remained above 90% for 7 days after stopping Truvada, from steady-state conditions.
  • 55% of PBMC samples had tenofovir diphosphate levels that reached the 90% effective concentration (EC90) in iPrEx after 3 doses, 77% did so after 5 doses, 89% did so after 7 doses, and 99% did so after 13 doses.
  • 71% of rectal mononuclear cell samples had an estimated protective level of tenofovir after 3 doses, 88% did so after 5 doses, and 94% did so after 7 doses.
  • However, 2 rectal samples had undetectable tenofovir diphosphate concentrations from the first dose visit, and another fell below this level from day 3.
  • In a pharmacokinetic analysis, the mean tenofovir diphosphate steady-state concentration was 103 fmol/106cells and the average half-life was 3.5 days.
  • The mean emtricitabine triphosphate steady-state concentration was 6 pmol/106cells, with an average half-life of 33 hours.
  • There were no significant differences between men and women in steady-state tenofovir triphosphate or emtricitabine triphosphate levels.

"High PrEP activity for MSM was achieved by approximately 1 week of daily [Truvada] dosing," the study authors summarized. "[F]or optimal benefit, PrEP should be started approximately 1 week before it is needed."

While this analysis included women, it only measured rectal -- not cervical-vaginal -- drug concentrations, and it was only intended to estimate protective levels for gay men, since inferred protection was based on drugs levels in iPrEx, which enrolled only MSM and a small number of transgender women (male-to-female).

"Understanding and applying pharmacokinetic/pharmacodynamic analyses for PrEP in women, and populations other than MSM, is an urgent research priority," the researchers wrote.

How to safely stop PrEP after the last potential HIV exposure are not as straightforward, they noted in their discussion.

"The present study found that high PrEP activity was evident for several days after dosing was stopped," they wrote. "The inferred risk reduction exceeded 90% for 7 days, and 80% of participants remained above the iPrEx EC90 for 2 days after stopping PrEP."

"However, an important consideration for discontinuing PrEP is how long it takes for HIV to be completely cleared from the body following the last potential exposure," they continued. "There appears to be little consensus on this issue given that several variables may affect the HIV clearance process...These considerations underlie the current [post-exposure prophylaxis] recommendations to treat potential HIV exposures for 28 days."

The authors added that PrEP differs from PEP in that early HIV replication is presumably blocked by PrEP, "perhaps allowing for a faster HIV clearance rate," they wrote. "These considerations suggest that shorter durations of dosing might be adequate for PrEP following the last potential HIV exposure, but not enough information is available to make specific recommendations."

"Although effective intracellular drug concentrations persist for several days after stopping PrEP, a reasonable recommendation is to continue PrEP dosing for 4 weeks after the last potential HIV exposure, similar to recommendations for post-exposure prophylaxis," they concluded.

5/6/15

Reference

SM Seifert, DV Glidden, AL Meditz, PL Anderson, et al. Dose Response for Starting and Stopping HIV Preexposure Prophylaxis for Men Who Have Sex with Men. Clinical Infectious Diseases 60(5):804-810. March 1, 2015.