Poor levels of T-20 seen in semen of HIV-positive men

Concentrations of the fusion inhibitor T-20 (enfuvirtide, Fuzeon) in the genital tract are suboptimal, risking the development of resistant HIV, according to a small French study published in the September 24^th edition of AIDS. The study also found that concentrations of the protease inhibitors amprenavir, lopinavir and saquinavir in the genital tract, even when boosted by ritonavir, are also below therapeutic levels, as are concentrations of the non-nucleoside, efavirenz. However, the investigators did find that concentrations of the nucleotide analogue tenofovir (Viread) was actually higher in semen than in blood.

The investigators from Paris were concerned that the evolution of HIV in specific compartments in the body could be contributing to the development of antiretroviral resistance in individuals failing HAART. In particular it is feared that transmission of drug resistant virus is being enocuraged by poor penetration of some antiretrovirals into the seminal tract.

The researchers wished to determine the concentrations of T-20 and tenofovir in semen as these have not previously been described.

Thirteen HIV-positive men who had been failing their current HAART regimen (which comprised an average of four antiretroviral drugs), for at least eight weeks were recruited to the study. The men had a median age of 42.5 years, median CD4 cell count at baseline was 240 cells/mm³, although the median nadir CD4 cell count was 36 cells/mm³. Median viral load in blood was 35,000 copies/ml, and the median viral load in semen was 800 copies/ml.

A self-completed questionnaire reporting adherence over the four days prior to the study found that individuals had been 100% adherent to their treatment regimens.

Blood and semen samples were obtained within one hour and the concentrations of antiretroviral drugs in them determined.

T-20 did not achieve therapeutic concentrations in the semen of the four men who were taking it, even though good blood concentrations of the drug were recorded. The investigators believe that the drug failed to penetrate the testis adequately because of its high molecular weight and also because it is not ionised.

However, higher concentrations of tenofovir, taken by four men, were found in semen than in blood. This was attributed to the drug’s small molecule and long half-life.

Concentrations of protease inhibitors, other than indinavir (taken by five patients), in semen can be low because this class of antiretrovirals is lipophilic and is extensively bound to blood plasma protein. The investigators did indeed find that although amprenavir (two patients), lopinavir (eight patients) and saquinavir (two patients), when boosted with ritonavir, reached therapeutic concentrations in the blood, they failed to achieve adequate concentrations in semen.

Further, the investigators also found that even though the three patients taking efavirenz had adequate blood levels of the drug, it could not be detected in their semen.

“The blood-testis barrier preventing drug distribution to sites of viral replication remains a likely mechanism of virological failure,” write the investigators, concluding that it is “crucial to deliver adequate drug concentrations to all compartments where the virus can replicate in order to ensure the long-term efficacy of antiretroviral therapy and reduce the risk of sexually transmitted drug-resistant HIV strains.”