Study shows that use of darunavir/ritonavir and etravirine in HIV treatment as a prevention method is biologically plausible

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 Syndromes.

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 individuals”.

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 2.3-fold.

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 dosing.

“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.”

Brown KC et al. Single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and rectal tissue of HIV-negative men.  J Acquir Immune Defic Syndr, online edition. DOI: 10. 1097/QAI.0b013e3185cb645, 2012.