28 Nov DTG-Based Medications May Allow Faster Suppression of HIV in Semen
MedicalResearch.com Interview with:
Arkaitz Imaz Vacas
HIV and STD Unit, Department of Infectious Diseases
Hospital Universitari de Bellvitge
MedicalResearch.com: What is the background for this study?
Response: Sexual transmission is the most common route of human immunodeficiency virus (HIV) acquisition in most regions of the world.
The male genital tract is a separate reservoir for HIV and may contribute to HIV shedding in seminal fluid even in individuals receiving antiretroviral (ARV) therapy (ART). Treatment of HIV-infected patients with currently available combined ART suppresses HIV in blood and also in genital fluids and reduces the risk of HIV acquisition by their sexual partners. However, sexual HIV transmission is possible even in patients on ART, especially if treatment was initiated recently. Thus, the ability of ARV drugs to penetrate into the male genital tract is a key factor for achieving HIV suppression in seminal fluid and preventing sexual transmission of the virus.
Dolutegravir (DTG) is a new integrase inhibitor (INI) with high antiviral potency and a high genetic barrier to resistance. In large phase III-a randomized clinical trials, DTG in combination with 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) has shown noninferiority compared with raltegravir and superiority to efavirenz or ritonavir-boosted darunavir as first-line therapy in treatment-naive HIV-1 infected patients. A study in healthy volunteers showed that DTG penetration in seminal fluid was <7% of DTG exposure in blood plasma (BP), and the median seminal concentration at the end of the dosing interval (C24h) was lower than the in vitro protein-adjusted (PA) 90% inhibitory concentration (IC90) for wild-type HIV-1. However, information about protein unbound DTG fraction in seminal fluid is lacking and there is no information regarding DTG concentrations in the semen of HIV-1infected patients or the antiviral activity of a DTG-based ARV combination in this compartment.
The aim of this study was to compare viral decay kinetics and DTG concentrations (total drug and unbound fraction) in the seminal plasma (SP) and BP in a group of treatment-naive HIV-1 infected patients starting DTG plus abacavir (ABC) and lamivudine (3TC) once daily.
MedicalResearch.com: What are the main findings?
Response: The median HIV-1 RNA decrease from baseline was significantly smaller in SP than in BP samples at all time points and HIV-RNA decline in SP was significantly more heterogeneous compared to BP. These findings are consistent with differing decay dynamics in the 2 compartments. To further evaluate the dynamics of viral decay after ART initiation based on HIV-1 RNA decreases in BP and SP samples, the model that best fit our data was 2-phase decay kinetics followed by a plateau.
Viral decay was significantly faster in BP than in SP in the first decay phase and statistically differences were not found in the second phase. Despite the initially faster HIV-1 RNA decay in BP, the median time to HIV-1 RNA >99%). However, the median free DTG fraction in SP was 48% of the total drug and therefore, we could estimate that the seminal unbound DTG C24h was higher than the in vitro unbound IC50 for wild type HIV-1 in all participants, with a median of 214-fold higher than this IC50.
MedicalResearch.com: What should readers take away from your report?
Response: The integrase inhibitors have demonstrated to achieve plasma HIV-1 RNA suppression faster than other ARV classes. In this study we observed that an ARV regimen containing the integrase inhibitor DTG also achieves rapid HIV-1 RNA suppression in semen. Taking into account that recent studies have demonstrated sexual HIV transmission during the first 6 months after ART initiation with other ARV classes, the rapid seminal HIV suppression achieved with this DTG-based regimen can be of interest especially for HIV-infected individuals with high risk sexual behavior.
Several ARV drugs are highly bound to blood plasma proteins that might limit the penetration into HIV reservoirs such as genital tract. However, binding protein concentrations is lower in SP than in BP and protein binding of certain ARV drugs has been found to be lower in SP. It was the case of DTG: the median free DTG fraction observed in BP was 0.45% of the total drug, whereas the median free DTG fraction in SP was 48% of the total drug.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The assessment of free-drug fractions is of interest to evaluate the effective penetration and activity of ARV drugs in the genital reservoir.
It could be of interest to evaluate the viral decay kinetics in seminal plasma with other integrase inhibitors as well as other new ARV agents or formulations.
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Citation:
J Infect Dis. 2016 Nov 15;214(10):1512-1519. Epub 2016 Aug 30.
HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen.
Imaz A1, Martinez-Picado J2,3,4, Niubó J5, Kashuba AD6, Ferrer E1, Ouchi D4, Sykes C6, Rozas N1, Acerete L1, Curto J1, Vila A1, Podzamczer D1.
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Last Updated on November 28, 2016 by Marie Benz MD FAAD