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 . 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.
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 .
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 . 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 , genital tract infections and shedding of semen polymorphonuclear cells .
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 . 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 . More studies are also needed because of its possible impact on the long-term efficacy of HAART.
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.
1. Kalichman SC, Di Berto G, Eaton L. Human immunodeficiency virus viral load in blood plasma and semen: review and implications of empirical findings. Sex Transm Dis 2008; 35:55–60.
2. Lowe SH, Wensing AM, Droste JA, ten Kate RW, Jurriaans S, Burger DM, et al
. No virological failure in semen during properly suppressive antiretroviral therapy despite subtherapeutic local drug concentrations. HIV Clin Trials 2006; 7:285–290.
3. Zhang H, Dornadula G, Beumont M, Livornese L Jr, Van Uitert B, Henning K, Pomerantz RJ. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med 1998; 339:1803–1809.
4. Lafeuillade A, Solas C, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Differences in the detection of three HIV-1 protease inhibitors in nonblood compartments: clinical correlations. HIV Clin Trials 2002; 3:27–35.
5. Craigo JK, Patterson BK, Paranjpe S, Kulka K, Ding M, Mellors J, et al
. Persistent HIV type 1 infection in semen and blood compartments in patients after long-term potent antiretroviral therapy. AIDS Res Hum Retroviruses 2004; 20:1196–1209.
6. Leruez-Ville M, Dulioust E, Costabliola D, Salmon D, Tachet A, Finkielsztejn L, et al
. Decrease in HIV-1 seminal shedding in men receiving highly active antiretroviral therapy: an 18 month longitudinal study (ANRS EP012). AIDS 2002; 16:486–488.
7. Delobel P, Nugeyre MT, Cazabat M, Pasquier C, Marchou B, Massip P, et al
. Population-based sequencing of the V3 region of env for predicting the coreceptor usage of human immunodeficiency virus type 1 quasispecies. J Clin Microbiol 2007; 45:1572–1580.
8. Ghosn J, Chaix ML, Peytavin G, Bresson JL, Galimand J, Girard PM, et al
. Absence of HIV-1 shedding in male genital tract after 1 year of first-line lopinavir/ritonavir alone or in combination with zidovudine/lamivudine. J Antimicrob Chemother 2008; 61:1344–1347.
9. Coombs RW, Lockhart D, Ross SO, Deutsch L, Dragavon J, Diem K, et al
. Lower genitourinary tract sources of seminal HIV. J Acquir Immune Defic Syndr 2006; 41:430–438.
10. Le Tortorec A, Le Grand R, Denis H, Satie AP, Mannioui K, Roques P, et al
. Infection of semen-producing organs by SIV during the acute and chronic stages of the disease. PLoS ONE 2008; 3:e1792.
11. Sadiq ST, Taylor S, Kaye S, Bennett J, Johnstone R, Byrne P, et al
. The effects of antiretroviral therapy on HIV-1 RNA loads in seminal plasma in HIV-positive patients with and without urethritis. AIDS 2002; 16:219–225.
12. Bujan L, Daudin M, Matsuda T, Righi L, Thauvin L, Berges L, et al
. Factors of intermittent HIV-1 excretion in semen and efficiency of sperm processing in obtaining spermatozoa without HIV-1 genomes. AIDS 2004; 18:757–766.
13. Ghosn J, Chaix ML, Peytavin G, Rey E, Bresson JL, Goujard C, et al
. Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. AIDS 2004; 18:1958–1961.
14. Isaac A, Taylor S, Cane P, Smit E, Gibbons SE, White DJ, et al
. Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen. J Antimicrob Chemother 2004; 54:498–502.
15. Chan DJ, Ray JE. Quantification of antiretroviral drugs for HIV-1 in the male genital tract: current data, limitations and implications for laboratory analysis. J Pharm Pharmacol 2007; 59:1451–1462.
16. Eron JJ, Vernazza PL, Johnston DM, Seillier-Moiseiwitsch F, Alcorn TM, Fiscus SA, Cohen MS. Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. AIDS 1998; 12:F181–F189.
17. Eyre RC, Zheng G, Kiessling AA. Multiple drug resistance mutations in human immunodeficiency virus in semen but not blood of a man on antiretroviral therapy. Urology 2000; 55:591.
18. Liuzzi G, Chirianni A, Zaccarelli M, Zinzi D, Esposito V, Guadagnino V, et al
. Differences between semen and plasma of nucleoside reverse transcriptase resistance mutations in HIV-infected patients, using a rapid assay. In Vivo 2004; 18:509–512.
19. Ghosn J, Viard JP, Katlama C, de Almeida M, Tubiana R, Letourneur F, et al
. Evidence of genotypic resistance diversity of archived and circulating viral strains in blood and semen of pretreated HIV-infected men. AIDS 2004; 18:447–457.
20. Barreiro P, Castilla JA, Labarga P, Soriano V. Is natural conception a valid option for HIV-serodiscordant couples? Hum Reprod 2007; 22:2353–2358.