Persistent differences in the antiviral effects of highly active antiretroviral therapy in the blood and male genital tract

Highly active antiretroviral therapies (HAART) usually reduce the blood plasma virus load (BPVL) of HIV-1 to undetectable levels in most naïve patients within 3 months. The semen virus load (SVL) is correlated with the BPVL if HAART is effective [1–3]. But some cross-sectional studies have found differences between the BPVL and the SVL [4,5] and differences in the rates at which the virus loads in the blood and semen decrease [6]. Thus, patients on effective HAART with an undetectable BPVL may have unsuspected HIV-1 genital tract replication that could influence the long-term efficiency of HAART or result in the sexual transmission of HIV during unprotected intercourse. We describe a case of persistent HIV-1 RNA shedding into semen despite HAART-controlled BPVL. A 34-year-old untreated HIV-1-infected man presented for medically assisted procreation in February 2006. A HAART regimen was initiated in June 2006 because his SVL was greater than 4 log copies/ml in two successive samples (Table 1). His BPVL was undetectable 4 months later, but the SVL remained unchanged at 6 months. The treatment was modified in May 2007. His BPVL was still undetectable 1 month later, but the SVL remained unchanged after 6 months on the new treatment. The SVL subsequently decreased slowly to less than 400 copies/ml after 11 months on the new treatment and 22 months after initiation.Table 1: Evolution of blood plasma HIV-1 virus load, semen plasma HIV-1 virus load and semen parameters during follow-up.The resistance genotypes of the blood and seminal virus were determined in order to understand why HIV shedding into the semen persisted. The viruses in both compartments were wild-type before treatment initiation and in November 2007. Genotyping and phenotyping showed that the viruses in the same samples were R5 [7]. The patient's semen parameters were normal throughout the follow-up period. Hepatitis B virus, hepatitis C virus, syphilis and chlamydia serology remained negative and he had no reported history of other sexually transmitted infections. BPVL and SVL are usually undetectable within 1 year after treatment initiation [8]. However, this case report confirms that HAART may act at different rates in the blood and semen and that HIV-1 may continue to be shed into the semen despite effective control of HIV-1 in the blood. Treatment adherence seemed good in this case, with 10 undetectable BPVLs during the 2-year follow-up. No biological factors known to be associated with HIV-1 shedding were present, and the patient was asymptomatic, although his SVL was higher than his BPVL before treatment. The sources of the HIV-1 shed into the semen are not clear, but the lower genital tract seems to be the main one [9,10]. Known factors associated with genital shedding are urethritis [11], genital tract infections and shedding of semen polymorphonuclear cells [12]. The absence of any response to HAART during the first regimen and the retarded response to the second were probably linked to the poor penetration of the antiretroviral drugs, particularly protease inhibitors, into the male genital tract. Only the lopinavir and ritonavir concentrations could be measured in March 2008: they were 3.20 and 0.13 mg/l in the blood plasma and 0.08 and less than 0.01 mg/l in the seminal plasma, respectively. The lopinavir concentration in the semen was low, as previously reported [13,14]. By contrast, the concentrations of reverse transcriptase inhibitors in the semen are reported to be higher than in blood [15]. This rate of SVL reduction does not indicate that HAART has a direct effect on virus replication in the genital tract but that HIV-1 replication may be slowly stopped by interrupting the supply of HIV-1-infected cells from the blood. The concentrations of these drugs in the various tissues and cell types of the male genital tract are unknown. This absence of virus selection in the genital tract, despite high virus replication, indicates that the intracellular drug concentrations are too low to inhibit virus replication and to induce virus selection. Resistance mutation has been detected in genital tract viruses, and the mutation patterns are different from those of blood virus [16–19]. Nevertheless, the emergence of resistance mutations from the genital tract has never been confirmed. Furthermore, semen virus always has fewer resistance mutations. This evidence obtained from studies in a few patients does not suggest that the male genital tract is directly implicated in HAART failure. Counselling on the prevention of sexual transmission should include the possibility of occult persistent HIV-1 replication within the genital tract, particularly in the context of giving a ‘license to love’ to patients with undetectable BPVL [20]. More studies are also needed because of its possible impact on the long-term efficacy of HAART. Acknowledgements C.P. is responsible for data collection and analysis and for the writing of the manuscript. N.M., M.D. contributed to the clinical follow-up of the patient and performed semen quality testing. C.S. is responsible for HIV tropism testing. K.S. is responsible for HIV resistance testing. M.L. is responsible for antiretroviral drug concentrations measurement. J.I. contributed to data analysis and the editing of the manuscript. L.B. contributed to the clinical follow-up of the patient, data analysis and the editing of the manuscript.

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