aUniversité Paris Descartes, France
bUniversité Paris Descartes EA 3620, France
cAssistance Publique-Hôpitaux de Paris, Service d'Histologie-Embryologie-Biologie de la Reproduction, Hôpital Cochin-Saint Vincent de Paul, France
dAssistance Publique-Hôpitaux de Paris, Laboratoire de Virologie, Hôpital Necker-Enfants Malades, France
eDépartement mère-enfant, Unité d'assistance médicale à la procréation, Institut Mutualiste Montsouris, France
fAssistance Publique-Hôpitaux de Paris, Service de Gynécologie et Médecine de la Reproduction, Hôpital Cochin-Saint Vincent de Paul, France
gAssistance Publique-Hôpitaux de Paris, Service de Biostatistiques, Hôpital Cochin-Saint Vincent de Paul, France
hAssistance Publique-Hôpitaux de Paris, Service de Médecine Interne, Hôpital Cochin-Saint Vincent de Paul, France
iINSERM U567, France
jAssistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Hôpital Cochin-Saint Vincent de Paul, Paris, France.
Received 9 April, 2010
Accepted 21 April, 2010
Correspondence to Dr Emmanuel Dulioust, MD, PhD, Service d'Histologie-Embryologie-Biologie de la Reproduction, Hôpital Cochin-Saint Vincent de Paul, 123 Boulevard de Port Royal, 75014 Paris, France. E-mail: email@example.com
In the present debate around pre-exposure prophylaxis (PreP) and treatment as prevention (TasP), the residual risk of sexual HIV transmission via semen in patients on efficient HAART and the counselling for safe sex in such cases are highly relevant issues [1–6]. Although in a majority of HIV-1-infected men, undetectable viral loads are achieved in blood and semen after a few months of HAART [7,8], frequencies of detectable seminal viral loads in men on HAART ranging from 1.8% to as high as 31% have been reported since 2000 [7,9–13]. However, these highly different results were mainly obtained in small series and not in the most recent years. Important underlying questions are the frequency of discordant detectable seminal viral load in men with repeatedly undetectable blood viral load, the levels reached in such conditions as well as the factors that increase HIV shedding. The objective of this retrospective study was to estimate these endpoints over an 8-year period (2002–2009) in a large cohort of HIV-1-infected men from couples requesting medically assisted procreation (MAP). We also looked for factors associated with positive semen viral load in cases with undetectable blood viral load.
Between January 2002 and December 2009, 1049 semen samples from 541 men were analysed. Access to the fertility programme was open to all men in good health condition, with a CD4+ cell count over 200/μl, whatever their history of HIV infection and treatment status. According to French guidelines, HIV-RNA was systematically assessed on seminal fluid samples processed for MAP, with Cobas Monitor HIV-1 v1.5 until December 2006 and Cobas Taqman HIV-1 test (Roche Diagnostics, Meylan, France) from January 2007, with a detection threshold of 100 HIV-1 RNA copies/ml, as described previously [14,15]. Among the 541 men, 455 were on continuous HAART since at least 6 months with a regular follow-up and blood viral load less than 50 HIV-RNA copies/ml within the 2 months before and after semen collection. Seventeen (3.7%) of the 455 men had at least once an HIV-RNA positive seminal sample, ranging from 25 to 3000 copies/ml. In six men, the seminal viral load was above 1000 copies/ml; three of them had been on continuous HAART with blood viral load less than 50 copies/ml for more than 12 months. Overall, wide variations were observed as regards HAART duration (6–78 months) and time with blood viral load less than 50 copies/ml (2–76 months) that preceded the detection of HIV-RNA in semen. No significant relation was evidenced between seminal viral load and any of the other recorded parameters [age, HIV risk groups, time from HIV diagnosis, nadir of CD4+ T cells, hepatitis C virus (HCV) or hepatitis B virus (HBV) coinfection, HAART regimen, time on same HAART and time with blood viral load less than 50 copies/ml before positive semen sample, CD4 T+ cell count, seminal polynuclear leucocyte count and semen bacterial culture]. No patient reported genital symptoms at the time of semen collection. Furthermore, we found no significant association between the variables listed above and the occurrence of positive HIV-RNA in semen in a conditional logistic regression analysis (SAS software V9.1; SAS Institute, Cary, North Carolina, USA): each case was paired with two control patients who had both blood and semen undetectable viral load evaluated in the same period.
As presented in Fig. 1, the most striking finding was the decreasing prevalence over time of discordant cases of men with detectable HIV-RNA in semen and sustained undetectable blood viral load: all cases occurred between 2002 and 2005, whereas there was no case in the past 4 years. This highly significant change (P < 0.001, χ2 test) prompted us to look for evolutions in patients' characteristics and treatment over time. We found that HAART regimens, including nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) only were less frequent before 2005 than after (10 vs. 19%, P < 0.05) and that regimens associating NRTIs with protease inhibitors were more frequent from 2005 (50 vs. 38%, P < 0.05). Coinfections with HCV were also less frequent after 2005 than before (26.3 vs. 37.8%, P < 0.05). Although these observations do not demonstrate causal relations with the occurrence of discordant detectable HIV-RNA in semen, an improved efficiency of recent HAART regimens, especially in the genital tract, is likely to be involved. Moreover, though the motivations for seeking MAP remained identical in our population, other changes may have occurred over years.
Our data indicate that, at present time, the probability of detectable HIV-RNA in semen is extremely low in the population of men from couples with a child desire and who are on prolonged efficient HAART. Moreover, the residual risk of HIV transmission through infected cells potentially present in semen is probably also very low for these men on prolonged HAART with reduced HIV cell reservoirs [2,16]. We think that these new data will be of major help for counselling these couples. Indeed, maybe it is time to consider natural conception as safe provided that the couple fits the conditions for very low probability of HIV seminal shedding and transmission. However, it should be necessary to check that these conditions are maintained over time. PreP for the uninfected women could be also discussed in order to help the decision of going through natural conception for such couples. MAP should remain an option offered to all couples, particularly to those with impaired fertility.
Moreover, the extrapolation of our observations to all HIV-1-infected men requires much caution. Because of their life situation, including couple stability and child desire, our patients probably had good HAART observance and low risk of sexually transmitted diseases (i.e. conditions that minimize the risk of HIV seminal shedding). These conditions might not be fulfilled in other HIV-infected groups wherein dedicated studies are needed. Nevertheless, our results bring consistent information within the actual debate on unprotected sex in long-term efficiently treated patients and on large-scale treatment for prevention that could be efficient to reduce HIV epidemics.
E.D. and M.L-V. contributed to semen processing procedures and virological analyses. D.J. contributed to statistical analyses. E.D., M.L-V., J.G., A.F., O.L., P.S., P.J. and C.R. contributed to patients management. E.D., M.L-V. and C.R. contributed to study design, data analysis and manuscript writing. All authors contributed to manuscript revision.
We thank the ANRS (Agence Nationale de Recherche sur le SIDA et les hépatites virales) and the APHP (Assistance Publique-Hôpitaux de Paris) for their long-term support (ANRS: cohort NECO, cohort AZONECO; APHP: cohort BINECO) including financial funding for technical assistance and equipment.
1. Vernazza P, Hirschel B, Bernasconi E, Flepp M. HIV sero-positive persons without sexually transmitted diseases under fully suppressive antiretroviral treatment do not sexually transmit HIV. Bull Med Suisses 2008; 89:165–169.
2. Stürmer M, Doerr HW, Berger A, Gute P. Is transmission of HIV-1 in nonviraemic serodiscordant couples possible? Antivir Ther 2008; 13:729–732.
3. Attia S, Egger M, Müller M, Zwahlen M, Low N. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS 2009; 23:1397–1404.
4. Conseil National du SIDA. Avis suivi de recommandations sur l'intérêt du traitement comme outil novateur de la lutte contre l'épidémie d'infections à VIH. 9 April 2009. www.cns.sante.fr
5. Vandermaelen A, Englert E. Human immunodeficiency virus serodiscordant couples on highly active antiretroviral therapies with undetectable viral load: conception by unprotected sexual intercourse or by assisted reproduction techniques? Hum Reprod 2010; 2:374–379.
6. Powers KA, Poole C, Pettifor AE, Cohen MS. Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet Infect Dis 2008; 8:553–563.
7. Vernazza P, Troiani L, Flepp MJ, Cone RW, Schock J, Roth F, et al
. Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. AIDS 2000; 14:117–121.
8. Leruez-Ville M, Dulioust E, Costagliola D, Salmon D, Tachet A, Finkielsztejn L, et al
. Decrease of HIV-shedding in men receiving highly active antiretroviral therapy: an 18-month longitudinal study. AIDS 2002; 16:486–488.
9. 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.
10. Marcelin AG, Tubiana R, Lambert-Niclot S, Lefebvre G, Dominguez S, Bonmarchand M, et al
. Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma. AIDS 2008; 22:1677–1679.
11. Pasquier C, Sauné K, Raymond S, Moinard N, Daudin M, Bujan L, Izopet J. Determining seminal plasma human immunodeficiency virus type 1 load in the context of efficient highly active antiretroviral therapy. J Clin Microbiol 2009:2883–2887.
12. Sheth PM, Kovacs C, Kemal KS, Jones RB, Raboud JM, Pilon R, et al
. Persistent HIV-RNA shedding in semen despite effective antiretroviral therapy. AIDS 2009; 23:2050–2053.
13. Anderson DJ, Politch JA, Xu C, O'Brien WX, Bowman FP, Welles S, Mayer KH. Persistent HIV-1 shedding in semen of men on HAART is associated with high risk sexual behaviour. Fifth IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 19–22 July 2009.
14. Leruez-Ville M, De Almeida M, Tachet A, Dulioust E, Guibert J, Mandelbrot L, et al
. Assisted reproduction in HIV-1 serodifferent couples: the need for viral validation of processed semen. AIDS 2002; 16:2267–2273.
15. Pasquier C, Anderson D, Andreutti-Zaugg C, Baume-Berkenbosch R, Damond F, Devaux A. Multicenter quality control of the detection of HIV-1 genome in semen before medically assisted procreation. J Virol Methods 2006; 78:877–882.
16. Viard JP, Burgard M, Hubert JB, Aaron L, Rabian C, Pertuiset N, et al
. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 2004; 18:45–49.