HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen

Abstract

Background. The objective of this study was to quantify human immunodeficiency virus (HIV) type 1 RNA decay and dolutegravir (DTG) concentrations in the semen of HIV-infected patients receiving DTG-based first-line therapy.Methods. This was a prospective, single-arm, open-label study including 15 HIV-1-infected, antiretroviral therapy-naive men starting once-daily treatment with DTG (50 mg) plus abacavir-lamivudine (600/300 mg). HIV-1 RNA was measured in seminal plasma (SP) and blood plasma (BP) at baseline, on days 3, 7, and 14, and at weeks 4, 12, and 24. The HIV-1 RNA decay rate was assessed using nonlinear mixed-effects models. Total and free DTG concentrations were quantified 24 hours after the dose at weeks 4 and 24 by means of a validated liquid chromatography-tandem mass spectrometry method.Results. Viral decay was faster in BP than in SP in the first decay phase (half-life, 4.5 vs 8.6 days; P = .001) with no statistically significant differences in the second phase. HIV-1 RNA suppression (<40 copies/mL) was reached earlier in SP (4 vs 12 weeks; P = .008) due to lower baseline HIV-1 RNA levels. The median total DTG 24 hours after the dose in SP was 119.1 ng/mL (range, 27.2-377 ng/mL), which represents 7.8% of BP exposure. The median DTG free-fraction in SP was 48% of the total drug. Seminal protein-unbound DTG concentrations exceeded the in vitro 50% inhibitory concentration (0.21 ng/mL) by a median of 214-fold.Conclusions. DTG concentrations in SP are sufficient to contribute to rapid seminal HIV-1 RNA suppression.

Semen as the Way Forward to Understand HIV-1 Transmission

“…A variety of mechanisms contribute to poor tissue penetration of ART, and multiple sources of HIV-1 contribute to the final HIV-1 RNA levels measured in seminal plasma [12]. The hypothesis that tissue penetration of ART through the blood-testesbarrier can be blocked by P-glycoprotein and breast cancer resistance protein-like mechanisms and thus, contribute to a drug-impermeable sanctuary for HIV-1 replication and recrudescence is attractive but simplistic, given that there are multiple genital tract sources of HIV-1 that may contribute to the differences in HIV-1 RNA first-phase decay rates noted between plasma (half-life, 4.5 days) and semen (8.6 days) in this study and others [9,13,14].…”

“…As discussed by Imaz et al [9], the association between seminal dolutegravir levels and viral suppression was weak. Furthermore, 4 of 5 participants with the lowest total dolutegravir concentrations had rapid suppression of seminal HIV-1 RNA even before suppression in blood plasma.…”

“…In this issue of The Journal of Infectious Diseases, Imaz et al [9] provide reassuring data from 15 ART-naive men who started abacavir, lamivudine, and dolutegravir once per day. Dolutegravir, a new integrase strand transfer inhibitor, reduces HIV-1 RNA in semen and in blood plasma.…”

“…Despite the limitations associated with semen studies, including small sample sizes, difficulty in obtaining repeated semen samples, limited seminal fluid volume, and the complex biological sources of HIV-1 in semen, there is a need to replicate the pharmacokinetic study by Imaz et al [9] with the new, longer-acting ART drugs on the clinical horizon. These agents offer the potential to improve first-line ART and simplify PrEP, to decrease R o to <1.…”

Exploring the anatomical HIV reservoirs

“…This blood-testis barrier may indeed significantly decrease the penetration of antiretroviral drug into the testes. For example, tissue penetration of cART through the blood-testes-barrier can be blocked by efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which are both known to limit penetration of atazanavir and darunavir into semen [10, 11]. However, the testes as a drug-impermeable compartment for HIV-1 replication is attractive but simplistic given that there are multiple genital tract sources of HIV-1 [11-13].…”