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Robert W. Coombs, John N. Krieger, Semen as the Way Forward to Understand HIV-1 Transmission, The Journal of Infectious Diseases, Volume 214, Issue 10, 15 November 2016, Pages 1473–1474, https://doi.org/10.1093/infdis/jiw409
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(See the major article by Imaz et al on pages 1512–9.)
The central role of semen in sexual transmission of human immunodeficiency virus (HIV) type 1 infection is well established. Of the estimated 2.1 million new HIV-1 infections worldwide in 2015, the overwhelming majority occurred by sexual transmission, and semen is the most important genital fluid for such transmission events [1].
The simplest mathematical model for male-associated HIV-1 forward transmission includes 3 variables: (1) the probability of transmission within a partnership (transmission per sex act and number of sex acts); (2) the duration of seminal infectiousness (ie, time above a critical threshold level of infectivity); and (3) the number of sexual partners. The product of these 3 variables defines the basic reproductive number (Ro), which is the average number of secondary cases of infection generated by a primary case in a susceptible population [2]. If Ro remains >1, then transmission of HIV-1 increases. Thus the goal is to effect both behavioral changes and therapeutic interventions to decrease Ro to <1.
Two major public health measures have been proved to diminish the forward transmission of HIV-1 from men to men and from men to women. The first is the implementation of safe sexual practices along with antiretroviral preexposure (and to a lesser extent postexposure) prophylaxis for HIV-1–seronegative at risk persons. Preexposure prophylaxis (PrEP) is highly effective in preventing transmission if the current antiretroviral drug combination with tenofovir and emtricitabine is used consistently [3]. The second public health measure relies on antiretroviral therapy (ART) for systemic viral suppression among persons already infected with HIV-1 [4]. Importantly, among serodiscordant couples, the integrated delivery of both ART and PrEP is associated with almost no viral transmission to the susceptible partner [5].
The caveat to these public health messages is that a small proportion of HIV-1–infected men (<10%) achieve viral suppression in their blood but continue to shed HIV-1 episodically in their semen, albeit at levels that are very low (<1000 HIV-1 RNA copies/mL of seminal plasma in 80% of shedding episodes) [6, 7]. Such low-level viral shedding in semen might be below a threshold necessary for sexual transmission; however, it is not known to what extent this low-level shedding in semen contributes to the residual HIV transmission risk that persists after the first 6 months of ART [8]. Thus, for HIV-serodiscordant couples in which the infected partner starts ART, other prevention options are needed, such as PrEP, until systemic viral suppression is achieved. Demonstrating the rapid suppression of seminal HIV-1 shedding after ART initiation would represent an important contribution toward decreasing the infectious level, shortening the duration of transmissible infectivity, and quickly decreasing Ro.
In this issue of The Journal of Infectious Diseases, Imaz et al [9] provide reassuring data from 15 ART-naive men who started abacavir, lamivudine, and dolutegravir once per day. Dolutegravir, a new integrase strand transfer inhibitor, reduces HIV-1 RNA in semen and in blood plasma. Dolutegravir (and the integrase strand transfer inhibitor agents as a class) is a potent antiretroviral agent but is highly bound to albumin and is also a substrate for the efflux transporter P-glycoprotein and breast cancer resistance protein, which are both known to limit penetration of dolutegravir into the semen, similarly to findings reported elsewhere for the protease inhibitor atazanavir [10]. In semen, the favorable viral decay kinetics and dolutegravir concentration of protein-unbound fractions, exceeding the in vitro median inhibitory concentration by 214-fold, are indeed reassuring because of the recommendation to use dolutegravir as first-line ART [11].
As discussed by Imaz et al [9], the association between seminal dolutegravir levels and viral suppression was weak. Furthermore, 4 of 5 participants with the lowest total dolutegravir concentrations had rapid suppression of seminal HIV-1 RNA even before suppression in blood plasma. These observations raise some important questions about interpreting seminal antiretroviral drug concentrations, the potential sources of HIV-1 RNA in semen, and compartmentalization of HIV-1 in the genital tract.
The effect of ART on seminal HIV-1 RNA levels is complicated. A variety of mechanisms contribute to poor tissue penetration of ART, and multiple sources of HIV-1 contribute to the final HIV-1 RNA levels measured in seminal plasma [12]. The hypothesis that tissue penetration of ART through the blood-testes-barrier can be blocked by P-glycoprotein and breast cancer resistance protein–like mechanisms and thus, contribute to a drug-impermeable sanctuary for HIV-1 replication and recrudescence is attractive but simplistic, given that there are multiple genital tract sources of HIV-1 that may contribute to the differences in HIV-1 RNA first-phase decay rates noted between plasma (half-life, 4.5 days) and semen (8.6 days) in this study and others [9, 13, 14].
For example, the contribution of testicular-associated HIV-1 to semen is generally considered minimal because vasectomy has no effect on the HIV-1 RNA level in seminal plasma [15], and other sources of virus from the more distal genital tract glandular structures (eg, prostate, seminal vesicles, bulbourethral glands, urethral glands of Littré, and periurethral submucosal and semen-associated mononuclear cells) are probably more important sources of semen virus. HIV-1 RNA levels measured in urethral swab fluid and voided urine after prostatic massage are independent predictors of seminal HIV-1 RNA level, which supports a urethral mucosal (or submucosal) or periurethral source for a good portion of the semen-associated virus [12]. Taken together, these observations suggest that antiretroviral drug levels in seminal plasma may underestimate the levels in any of the aforementioned genital tract sites that contribute HIV-1 to seminal plasma.
Despite the limitations associated with semen studies, including small sample sizes, difficulty in obtaining repeated semen samples, limited seminal fluid volume, and the complex biological sources of HIV-1 in semen, there is a need to replicate the pharmacokinetic study by Imaz et al [9] with the new, longer-acting ART drugs on the clinical horizon. These agents offer the potential to improve first-line ART and simplify PrEP, to decrease Ro to <1.
Notes
Financial support. This work was supported by the National Institutes of Health (University of Washington Fred Hutchinson Center for AIDS Research P30 AI27757) and the AIDS Clinical Trials Group (grant UM1 AI106701).
Potential conflict of interest. Both authors: No potential conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.