Impact of adding raltegravir to antiretroviral regimens in patients with blood viral suppression but persistent seminal viral shedding

Highly active antiretroviral therapy (HAART) is a potent suppressor of HIV-1 replication in both blood and seminal fluids of HIV-infected men. However, several studies have described discordant virologic responses and genotypic drug sensitivities between these compartments, with a possible increased risk of sexual transmission for a category of men termed ‘seminal super-shedders’. These divergent patterns and intermittent seminal viral shedding in spite of undetectable viral load in blood are observed in 7–15% of patients receiving HAART [1–7]. Sexual transmission of HIV may be highly affected by ‘inoculum size’, that is the amount of virus present in genital fluids. As well, assisted reproduction programs were established to offer HIV-1-infected men the means to safely procreate [8]; no seroconversion was reported in serodiscordant couples undergoing assisted reproduction [9]. However, the efficiency of sperm washing techniques used in assisted reproduction in removing HIV varies according to the seminal viral load [10]. Thus, HIV-1 seminal intermittent and/or supershedders might benefit of treatments with drugs that successfully distribute into the male genital tract. We selected patients among a group of HIV-1-infected individuals enrolled in an ongoing study on immunovirological aspects of genital fluids. We selected three men on HAART from at least 6 months: two patients on TDF + FTC (Truvada) and LPV/r (Kaletra), and another on TDF + FTC + EFV (Atripla). All men had undetectable blood plasma viral load, but persistent seminal plasma viral load. For specific drug toxicity, we decided to switch therapy choosing raltegravir (Isentress), which was associated in all the cases with LPV/r. The patients provided semen samples at the same time of blood sampling: at baseline and after 1, 2, 4 and 6 months. Semen, collected by masturbation after 48 h of abstinence, and allowed to liquefy for approximately 30 min at 37°C, was added with 2 ml of transport medium (2 ml of RMPI 1640 with 2 mMol l = glutamine and 10% fetal bovine serum, with the addition of 100 U/ml penicillin). Blood and semen samples were analyzed for HIV-1 viral load: for this purpose, seminal plasma was separated from seminal cells by centrifugation at 700 × g for 12 min within 4 h of collection and stored at −80°C. HIV-1 RNA quantification in blood and semen samples was performed using a commercially available technique (artus HI Virus-1 RG RT-PCR Kit) according to the manufacturer's instructions. The lower detection limit of the kit used was 80 copies/ml. Sequence analysis of HIV-1 protease and reverse transcriptase reading frames on seminal HIV-1 RNA was performed using the TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System (Visible Genetics, Inc., Toronto, Canada), according to the manufacturer's recommendations and the data were analyzed as described elsewhere [11]. At baseline, all patients had undetectable blood plasma viral load and 42 500, 33 000 and 2100 copies/ml of seminal plasma viral load, respectively. No mutations associated with resistance, neither to RT inhibitors, nor protease inhibitors, were detected in seminal samples. As soon as after 1 month on therapy with raltegravir, seminal plasma viral loads were undetectable in all patients, as it was for blood. This result was confirmed in the sequential controls over 6 months to rule out the possibility of an intermittent shedding. Although based on a small patient series, to our knowledge, our data report for the first time a successful control of seminal plasma viral load in HIV ‘super shedders’ by using raltegravir. This result was not a result of compartmentalization of drug-resistant viruses in the male genital tract because no resistance-associated mutation was detected. It was demonstrated that raltegravir and maraviroc concentrations in semen are several fold higher than those attained in blood and those required to inhibit viral replication in this compartment [12]. The antiviral effects of maraviroc in semen were observed in a case report [13]. Our data show similar effects for raltegravir. It is speculated that, by virtue of being slightly lipophilic and 83% bound to blood plasma proteins, raltegravir distributes into and accumulates within seminal plasma by passive diffusion [14,15]. It is known that some HIV-infected patients may shed high amounts of virus in their genital fluids in spite of efficient HAART. These patients are at higher risk of sexual transmission and seem cautious to maintain the recommendations for safe sex. When assisted reproduction technologies are employed for serodiscordant couples desiring to have a child, seminal viral load should carefully be evaluated. Our results clearly suggest that the use of raltegravir in HAART regimens might be proposed in patients with high seminal viral loads to reduce viral shedding, with important implications for sexual transmission and safety of assisted reproduction programs. Acknowledgements Conflicts of interest There are no conflicts of interest.

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