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Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma on a 2002-2011 survey (HIV+ Men/heterosexual discordant couples)
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AIDS May 2012
Lambert-Niclot, Sidoniea,b,c; Tubiana, Rolandb,c,d; Beaudoux, Celineb; Lefebvre, Gillese; Caby, Fabienneb,c,d; Bonmarchand, Manuelaf; Naouri, Michelee; Schubert, Benoitg; Dommergues, Marce; Calvez, Vincenta,b,c; Flandre, Philippea,b,c; Poirot, Catherinec,g; Marcelin, Anne-Genevievea,b,c
aLaboratoire de Virologie, APHP, Hopital Pitie-Salpetriere, ParisbINSERM U 943, PariscUPMC Univ Paris 06dService des Maladies Infectieuses et TropicaleseService de Gynecologie-ObstetriquefService de Medecine InternegUnite de Biologie de la Reproduction, APHP, Hopital Pitie-Salpetriere, Paris, France.
Abstract
Objectives: To estimate the frequency of detectable seminal HIV-1 viral load in men with repeatedly undetectable blood viral load, in the recent past years and over a 10-year period (2002-2011) in a large cohort of HIV-1-infected men from couples requesting assisted reproduction technologies. We also searched for an association between HIV-1 RNA seminal viral load, HIV-1 RNA plasma viral load measured by ultrasensitive assay, and blood HIV-1 DNA in a subgroup of 98 patients.
Methods: Three hundred and four HIV-1 infected men have provided 628 paired blood and semen samples. In a subset of 98 patients for which a blood sample was available, residual viremia, HIV-1 RNA in semen and HIV-1 DNA were studied.
Results: Twenty of 304 patients (6.6%) had detectable HIV-1 RNA in semen, ranging from 135 to 2365 copies/ml, corresponding to 23 samples, although they had concomitantly undetectable HIV-1 RNA in blood while they were under antiretroviral therapy. This prevalence was stable over time even in recent years. There was an association between HIV-1 RNA plasma viral load measured by ultrasensitive assay and HIV-1 DNA in blood, but both were not associated with seminal HIV-1 RNA viral load.
Conclusion: It seems cautious individually to maintain the recommendations of safe sex and the recourse to ART, or at least to inform the couple of the residual potential risk, in serodiscordant couples desiring a child.
Introduction
Over the last decade, considerable progress has been made in multidrug highly active antiretroviral therapies (HAARTs), modifying the life expectancy and the quality of life of HIV-infected patients and reducing the number of new cases of AIDS and mortality resulting from this disease. As a consequence, many HIV-infected men and women wished to safely conceive a child and requested assisted reproduction technologies following a growing consensus [1]. Indeed, assisted reproduction technologies allowed great security for serodiscordant couples to conceive, protecting the HIV-negative partner as well as the future child. Although few months of HAART reduces HIV viral loads in both blood and seminal compartments [2,3], frequencies of detectable seminal viral loads in men on HAART ranging from 1.8% to as high as 31% have been reported since 2000 [3-8]. These large discrepancies may be explained in part by the frequency of sampling that differs considerably from one study to another. However, Barreiro et al.[9] published an article in favor of conception by unprotected sexual intercourse during fertile days for HIV-serodiscordant couples treated by HAART with an undetectable viral load. In January 2008, the Swiss Federal AIDS Commission stated that HIV-infected people on effective antiretroviral therapy and without other sexually transmitted infections (STDs) were sexually noninfectious [10]. More recently, a study showed that in the recent past years (2006-2009), the probability of detectable HIV-RNA in semen is extremely low in the population of men requesting medically assisted procreation program and who are on prolonged efficient HAART, concluding to consider natural conception as safe under these conditions [5].
The blood HIV-1 DNA level is an interesting marker that reflects the size of cellular HIV reservoir. Recently, Chun et al.[11] demonstrated that residual plasma viremia correlated with the size of HIV proviral DNA reservoirs in infected patients receiving effective antiretroviral therapy. It would be interesting to assess whether blood HIV-1 DNA or HIV-1 RNA plasma viral load measured by ultrasensitive assay could reflect residual viremia in genital compartment.
These recent past years' new antiretroviral drugs are more potent and better tolerated and allow having a durably sustained full viral suppression in blood plasma for the vast majority of patients. The objective of this retrospective study was to estimate the frequency of detectable seminal viral load in men with repeatedly undetectable blood viral load, these recent past years and over a 10-year period (2002-2011) in a large cohort of HIV-1-infected men from couples requesting assisted reproduction technologie. We also searched for an association between HIV-1 RNA seminal viral load, HIV-1 RNA plasma viral load measured by ultrasensitive assay, and blood HIV-1 DNA in a subgroup of 98 patients.
Methods
Since 2002, our center managed HIV-1-serodiscordant couples with a male-infected partner to allow pregnancies with assisted reproduction technologies using sperm washing. Thus, the population studied here involved heterosexual men with a stable female partner engaging in assisted reproduction techniques and did not represent the whole male HIV-1-infected population, especially men who have sex with men (MSM) with multiple partners. Sperm washing consists of a separation following density gradient centrifugation. The 90% fraction was then centrifuged and washed [12]. According to French guidelines, HIV-1 RNA was systematically assessed with Cobas Taqman HIV-1 assay (Roche Diagnostics, Meylan, France) with a detection threshold of 20 or 40 copies/ml in blood and 100 or 200 copies/ml in seminal plasma, according the period described previously [13,14]. Residual plasma viremia and cellular HIV-1 DNA were measured as previously described [15,16] with a limit of quantification of 1 copy/ml and 5 copies/150 000 cells, respectively. Three hundred and four HIV-1-infected men requesting assisted reproduction technologies in the Pitie-Salpetriere Hospital have provided 628 paired blood and semen samples between January 2002 and June 2011, each patient providing one to eight samples. The median number of samples by patient was two [interquartile range (IQR) 1-3] and the mean time lag between two samples collection was 8 months (SD 11.4 months). One hundred and seven blood plasma samples were detectable and the median level of HIV-1 RNA in plasma was 297 copies/ml (IQR 74; 4666). Forty-nine seminal plasma samples were detectable and the median level of HIV-1 RNA in semen was 1115 copies/ml (IQR 375; 3790).
Results
Twenty of 304 patients (6.6%) had at least one HIV-RNA-positive seminal sample, although the plasma viral load was undetectable, ranging from 135 to 2365 copies/ml and corresponding to 23 samples (Table 1). In three men, the seminal viral load was above 1000 copies/ml. All these patients had been on continuous HAART with blood viral load less than 40 copies/ml for more than 6 months and had no other STDs that are systematically screened in the assisted reproduction technologies program.
Prevalence of discordant cases of men with detectable HIV-RNA in semen and sustained undetectable blood viral load is stable over time between 2002 and 2011 (Fig. 1).
In a subset of 98 patients for which a blood sample was available, residual viremia and HIV-1 DNA were studied. Fifty-five percent of HIV-1 RNA viral load in blood were less than 1 copy/ml and 11% had an undetectable HIV-1 DNA. Six patients had HIV-1 RNA detectable in seminal plasma with a median of 1043 copies/ml (IQR 135; 1750). Among these six patients, four had a corresponding plasma HIV-1 RNA viral load less than 1 copy/ml and all had less than 40 copies/ml HIV-1. All six patients except one presented a detectable HIV-1 DNA in blood. Neither residual viremia nor HIV-1 DNA was associated with HIV-1 excretion in semen. There was an association between residual viremia and blood HIV-1 DNA (Kruskal-Wallis test, P = 0.002).
Discussion
These results showed, in our cohort, that 6.6% of patients had detectable HIV-1 RNA in semen, although they had concomitantly undetectable HIV-1 RNA in blood while they were under HAART, and this prevalence did not decrease during the past years despite the use of more and more potent drugs. This does not seem to be related to a specific treatment, because these patients were treated by various therapies comprising non nucleosidique reverse transcriptase inhibitor-based, protease inhibitor-based or raltegravir-based regimen. Indeed, among the 20 patients with discordant HIV-1 RNA, 16 of them had at least once in their follow-up an undetectable concordant result in blood and semen while the majority of them received the same HAART. Also, one single measurement with undetectable HIV-RNA in seminal plasma does not account for a guarantee of noninfectivity, as HIV-1 shedding in semen is intermittent.
Some drugs are known to have poor diffusion in the male genital tract, such as enfuvirtide, stavudine, efavirenz, etravirine and most of protease inhibitors. However, Sheth et al.[8] and Marcelin et al.[6] previously showed that there was no association between isolated semen shedding and local level of any drug or regimen even if they were receiving drugs known to have good penetration in the male genital tract, such as indinavir or tenofovir. In the Monark study, Ghosn et al.[17] showed no local semen viral production despite the local absence of therapeutic antiretroviral drug concentrations in the five patients receiving lopinavir/ritonavir alone and despite the pharmacological properties of lopinavir that make the male genital tract virtually inaccessible to this drug. In MONOI trial, Lambert-Niclot et al.[18] showed a low frequency of HIV-1 RNA shedding in three of 45 patients, although they had undetectable HIV-1 RNA in plasma and despite a good penetration of darunavir into the male genital tract. These data emphasize the complexity of the relationship between effective HAART with a good penetration or not in male genital tract and isolated semen shedding. We showed that HIV-1 RNA plasma viral load measured by ultrasensitive assay and HIV-1 DNA in blood were associated, but these two factors cannot in practice and individually be used to predict detectable seminal HIV-1 RNA viral load.
Several studies have reported an important decreased acquisition of HIV-1 by sexual partners of patients receiving antiretroviral therapy [19-21]. These results have been extrapolated to suggest that the use of early antiretroviral therapy could reduce the spread of the virus in a population [22]. These results certainly support the use of antiretroviral treatment as a part of a public health strategy to reduce the spread of HIV-1 infection. Other studies analyzing available data and reviewing arguments about heterosexual infectivity [23,24] or conception by assisted reproduction technologies versus the use of a strategy of unprotected sexual intercourse [25]. These studies concluded to limitations of the existing literature and highlighted the need for further infectivity research and the importance to consider cofactor effects on individual aspect of transmission. Moreover, previous studies showed that HIV-1 excretion was intermittent [4,8,26] and our results confirmed this phenomenon. To date, our comprehension of HIV compartmentalization is still poor [27] and we do not know the threshold of infectivity regarding viral load in semen and whether this intermittent shedding in semen may result in sexual transmission in this setting.
Also, in the light of current knowledge and after showing that viruses could be present in 6.6% of cases over a 10-year period (2002-2011) with a stable prevalence over time even in recent years, it seems cautious individually to maintain the recommendations of safe sex and the recourse to assisted reproduction technologies, or at least to inform the couple of the residual potential risk, in serodiscordant couples desiring a child. This is true particularly in countries where access to this option for procreation is fairly easy, sometimes supported by health system as in France, and where the risk may be virtually zero. Further studies are needed to evaluate this prevalence in MSM in the context of successful therapy.
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