A pharmacokinetic study suggests that
ritonavir-boosted darunavir (Prezista)
and etravirine (Intelence) achieve
high concentrations in semen and rectal tissue, and could therefore help
avert HIV transmission and infection, especially in gay men. Concentrations of these
antiretrovirals were monitored over an eight-day period in HIV-negative
volunteers. The study is published in the online edition of the Journal of Acquired Immune Deficiency
The US investigators believe their findings
“provide pharmacologic plausibility for the use of darunavir plus ritonavir and
etravirine in secondary HIV prevention, in both infected and uninfected
Antiretroviral therapy has a central role
in combination HIV prevention efforts. Treatment that suppresses viral load has
been shown to reduce the risk of transmission in heterosexual couples by 96%.
Anti-HIV drugs can also reduce the risk of infection with HIV when used a
pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Incidence
of HIV remains high in gay men and they are therefore a priority for the use of
HIV treatment as prevention.
It is currently unknown if specific combinations
of antiretroviral drugs are more effective at preventing infection with HIV or
onward transmission of the virus. “Defining the antiretroviral exposures in biological
compartments that are vulnerable to acquisition and are sources of infection,
such as rectal tissue and semen, could assist in selecting regimens for HIV
prevention,” explain the authors.
They therefore designed a pharmacokinetic
study lasting eight days involving twelve healthy HIV-negative men.
Concentrations of darunavir/ritonavir and etravirine in blood, semen and rectal
tissue were monitored intensively on day one and again on days seven/eight.
The participants had a median age of 27
years and were racially diverse. All tolerated the medications well.
After the first dose, all three drugs were
detected in blood, semen and rectal tissue.
Levels of darunavir were between
82 and 92% lower in semen than blood one hour after the first dose. After multiple
doses, exposure in semen was 80 to 85% lower than in blood. However, concentrations
of the drug in semen accumulated 2 to 2.8-fold after multiple dosing.
Ritonavir was not detected in semen until
two hours after the first dose. Peak exposure was reached eight hours
post-dose. After the first dose, ritonavir exposures in semen were between
89 and 95% lower than in blood, and after multiple doses exposure was 93% lower.
Exposure to the drug in semen accumulated over the study, increasing by 1.4 to
Two hours after the first dose, etravirine
was detectable in semen. Exposure to the drug was between 83 and 87% lower in semen
after this first dose compared to blood, and exposure was 85 to 88% lower
after multiple dosing. Once again, the drug accumulated in semen after multiple
dosing (3.6 to 5.2 fold).
The investigators found that unbound levels (the element of the drug that has pharmacologic effect)
of all three drugs were higher in semen compared to blood. This is highly
significant for the preventive use of the drugs. The authors explain: “As
blood plasma protein binding decreases, there is a greater amount of
protein-unbound drug available to cross cellular membranes and distribute to
physiological compartments…we measured protein-unbound concentrations in
seminal plasma and confirmed that lower protein binding exists for all three
antiretrovirals in this compartment.”
Al three drugs were therefore capable of suppressing
viral load in semen. The investigators comment: “The unbound concentrations in
semen are higher than in blood and could be effective at suppressing HIV
replication in the male genital tract.”
There was also evidence that the study
medications could prevent exposure to HIV during anal sex.
One hour after the first dose,
concentrations of all three drugs were significantly higher in rectal tissue
compared to blood (darunavir, 1.1 to 1.2-fold higher; ritonavir, 5.8 to 12-fold
higher; etravirine, 15 to 16-fold higher).
Levels of the three antiretrovirals
remained higher in rectal tissue compared to blood after multiple doses
(darunavir, 2.3 to 2.7-fold higher; ritonavir, 13 to 27-fold higher; etravirine,
7.5 to 9.7-fold higher). Exposure to these drugs also accumulated with multiple
“The quick penetration and sustained
concentrations of darunavir and etravirine in rectal mucosa are desirable
characteristics for the prevention of HIV acquisition,” write the researchers. “Future
investigations will determine if these concentrations in rectal tissue and
semen can fully suppress viral shedding.”