Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men

Abstract

One likely mechanism of virological failure is poor antiretroviral drug diffusion in sites of viral replication such as the genital tract. We measured antiretroviral drug concentrations in blood and semen in 13 HIV-infected men failing treatment. Enfuvirtide did not cross the blood-testis barrier, whereas tenofovir accumulated in semen. Unlike indinavir, semen concentrations of lopinavir, amprenavir, saquinavir and efavirenz were ineffective. These are worrying findings, because suboptimal semen drug concentrations may enhance the risk of sexually transmitted drug-resistant HIV variants.

Pharmacovirological Impact of an Integrase Inhibitor on Human Immunodeficiency Virus Type 1 cDNA Species In Vivo

“…The combined pharmacovirological in vivo analysis could conceivably be extended to other cellular, anatomical, and pharmacological reservoirs (23,55,58). The gastrointestinal tract, genital tract, and central nervous system comprise major sanctuaries for HIV and may underlie drug-and compartment-specific pharmacokinetic and pharmacodynamic effects (15,30,43). This may be of particular relevance for INI activity, since a superior pharmacokinetic profile of raltegravir for targeting HIV sanctuaries has been hypothesized, though in one study it was not favored due to poor prediction of the clinical data upon modeling (42).…”

Quantification of antiretroviral drugs for HIV-1 in the male genital tract: current data, limitations and implications for laboratory analysis

“…Didanosine also appears to penetrate semen well (Gatti et al 2001). Seminal tenofovir exceeds the expected blood concentration of 22 ng mL −1 (Ghosn et al 2004a). This may be explained by active drug transport, a small molecular size, a relatively long half-life or a partitioning effect due to the dissociation constant of the drug.…”

“…Enfuvirtide does not accumulate appreciably in seminal plasma (concentrations are below 50 ng mL −1 ) (Ghosn et al 2004a). There are two possible reasons.…”

“…The vitamin E component of amprenavir capsules (Yu et al 1999) is thought to increase overall drug solubility and penetration. Amprenavir, unlike indinavir, does not inhibit cellular transporters when boosted with low-dose ritonovir in semen (Chaudry et al 2002), which may explain static seminal amprenavir levels with boosting (Ghosn et al 2004a).…”

“…We appreciate that full validation is sometimes limited by the availability of adequate semen volume; Ghosn et al (2004a) Enfuvirtide, efavirenz and protease inhibitors…”