HIV is mainly transmitted via the sexual route. Thus, semen plays a major role in the transmission of HIV. Empirical studies conducted in serodiscordant couples have estimated the risk of HIV-1 transmission per sexual act in the absence of treatment to range between 0.0005 and 0.01 depending on the type of sexual intercourse with receptive anal intercourse among men who have sex with men (MSM) bearing the highest risk [1,2]. The risk of HIV transmission has been shown to be significantly correlated with blood plasma HIV-1 RNA [blood plasma HIV viral load (bpVL)] . The increasing availability over the last couple of years of newer, simpler, more potent and better tolerated antiretroviral drugs had allowed the achievement of durably sustained full viral suppression in blood plasma for the vast majority of patients, including pretreated patients harboring resistant HIV strains. The Swiss federal Commission for HIV/AIDS recently stated that HIV-infected individuals receiving effective antiretroviral therapy (ART), with undetectable HIV-RNA in blood plasma for at least 6 months, with optimal adherence to their treatment and no other genital infections, cannot transmit HIV through sexual contact . This statement has been highly debated because our understanding of the activity of combined ART (cART) in the male genital tract is poor, and because there are no data on precise quantification of the residual risk of HIV transmission in the context of effective cART .
In this issue, Sheth et al.  report results from a longitudinal study to assess the impact of cART initiation both on bpVL and seminal plasma viral load (spVL). Such results are timely in the context of the debated role of cART in the prevention of HIV transmission, as they will help us to better understand the dynamics of spVL in this setting and identify predictive factors of persistence of HIV-RNA in semen of successfully treated men. The strength of this study is in its design, providing longitudinal sequential measurements of HIV-RNA in paired samples of blood plasma and seminal plasma, in addition to phylogenetic analysis of the viral strains isolated in each compartment and pharmacological measurement of antiretroviral drug concentrations in seminal plasma.
There are available data showing that spVL strongly correlates with bpVL. Studies supporting these data are, however, limited by the fact that most of them are cross-sectional, the only ones with sequential longitudinal sampling being conducted in the context of assisted reproduction , which can hardly be extrapolated to the whole population of HIV-infected men. In addition, sample size is often small, ranging from 10 to 128 men (reviewed in ). Finally, these studies often involved untreated HIV-infected men.
Sheth et al. provide not less than eight paired samples of blood plasma and seminal plasma collected within a 6-month period in HIV-1-infected men starting a first-line cART. Men were intensively screened for other genital infections at each visit, and adherence to treatment was evaluated. They first confirmed that the dynamics of HIV-RNA decrease after cART initiation in blood did not parallel that in semen for some patients. Second, they confirm compartmentalization of HIV between blood and the male genital tract by phylogenetic analysis showing that sequences derived from semen were distinct from that derived from blood. Third, they show evidence for intermittent shedding of HIV-RNA in semen of patients with concomitant undetectable bpVL. This intermittent shedding was observed even in patients for whom undetectable spVL had already been achieved, emphasizing the difficulty to interpret one single HIV-RNA measurement in seminal plasma. To better fit with the Swiss statement criteria, the authors also measured spVL and bpVL in paired samples of blood and semen collected from 13 HIV-infected men on prolonged cART with fully sustained undetectable bpVL; they found evidence for detectable spVL in four out of 13 men. The question remaining unanswered is whether such levels of HIV-RNA in semen are infectious, that is, whether there is a transmission threshold. We should, however, keep in mind that spVL level might not be the only limiting factor for HIV sexual transmission. Endogenous factors that affect the efficiency of sexual viral transmission may play a key role. Amyloid fibrils in semen may drastically enhance the infectiousness of HIV by promoting virion–cell attachment and fusion .
Surprisingly, in keeping with Marcelin et al.  and unlike other studies, there was no association between isolated semen shedding and local level of any drug, emphasizing the complexity regarding the understanding of the presence of HIV-RNA in semen in patients with undetectable bpVL and receiving drugs known to have good penetration in the male genital tract such as indinavir or tenofovir . The small sample size and the heterogeneity of cART could have limited any significant conclusion to be drawn. Interestingly, treatment strategies are evolving, especially with the recent availability of potent and well tolerated drugs belonging to ‘old’ antiretroviral classes or to new ones. One of the promising strategies being extensively investigated is boosted protease inhibitor monotherapy, and the few existing data on the quantification of spVL in this setting are conflicting [11,12]. Data are needed on the penetration of new antiretroviral agents in the male genital tract, as well as on their impact, among cART, on HIV-RNA shedding in semen. Fortunately, Sheth et al. did not evidence any resistant strain in the male genital tract in this short-term study. Resistant strains have already been isolated in semen, mutational pattern being distinct between blood and semen for some patients . These resistant strains can be transmitted via the sexual route , establish themselves as the dominant viral population in the recently infected individual  and persist for lengthy periods of times in blood  and in semen .
Last but not the least, Sheth et al. identified pretherapy semen viral load (not blood) to be predictive of the occurrence of intermittent viral shedding in semen.
Altogether, these results suggest that, though it is clearly demonstrated that cART does significantly reduce the risk of HIV-1 sexual transmission, this risk is likely to be very low but not zero for all patients on successful cART. Multiple factors such as adherence to treatment, concomitant asymptomatic genital infection, penetration of drugs in the male genital tract, pretherapy spVL, amyloid fibrils might also play an important role. A recently published systematic review suggested that available data on the risk of sexual transmission from a treated HIV-1-infected partner with bpVL less than 400 copies/ml were compatible with one transmission per 79 person-years and highlighted the urgent need for data on the risk of transmission in MSM in the context of effective cART . A model-based analysis also suggested that the risk of HIV transmission in heterosexual partnerships in the presence of effective cART was low but nonzero and that the transmission risk in MSM is high over repeated exposures even if the infected partner had sustained bpVL less than 10 copies/ml .
We are facing a resurgent HIV-1 epidemic, especially among MSM, in countries where potent cART is widely available and increasing rates of successful treatment are achieved . There is at present insufficient evidence for a general claim of noninfectiousness for HIV-infected individuals successfully treated with cART, especially given the lack of data on the risk of transmission between MSM in the context of successful cART. Further studies, focused on specific patient groups, are needed to better understand the origin and cause of intermittent viral shedding in semen of men on an effective cART and to assess whether this intermittent viral shedding in semen may result in sexual transmission in this setting.
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