HIV RNA Replication in Semen Occurs During Antiretroviral Therapy

The male genital tract is an important milieu for HIV replication. Even when HIV-infected men have suppressed HIV RNA in blood plasma with antiretroviral therapy (ART), they can still shed the virus in the genital secretion and potentially transmit it to their partners, according to a study recently published in Clinical Infectious Disease.¹

In a prospectively randomized, open-label, phase 2 clinical trial, 36 treatment-naive participants were randomly assigned 1:1:1 to receive tenofovir-DF plus emtricitabine and cobicistat-boosted elvitegravir (EVG_cobi, integrase inhibitor), rilpivirine (RPV, nonnucleoside reverse transcriptase inhibitor), or ritonavir-boosted darunavir (DRV_rtv, protease inhibitor). The primary endpoint was the proportion of individuals with undetectable HIV RNA in seminal plasma at week 12.

Despite the limited sample size, this study found that all participants in the RPV and the EVG_cobi groups reached an undetectable viral load in semen by week 12, but surprisingly, only 58.3% in the DRV_rtv group did so (P =.003). Interestingly, for both EVG_cobi and RPV, the drug concentrations in seminal plasma were >2-fold the protein binding-adjusted EC90 for wild-type HIV-1, whereas only about one third of the DRV_rtv seminal plasma showed concentrations above the protein binding-adjusted EC90, suggesting poor penetration of this drug in the genital compartment.

Another recent study was presented at the 2017 American Urological Association Annual Meeting and included longitudinal seminal samples collected from 230 HIV-infected men undergoing semen screening between 2012 and 2015.² Overall, 112 (48%) of semen samples tested positive for HIV RNA, and 81 (35%) of men produced at least 1 HIV positive sample. All men receiving ART had undetectable HIV RNA in blood plasma. Nevertheless, the authors found that 20% of all men taking combinations of reverse transcriptase inhibitors (N=28/137), 41% of men taking an integrase inhibitor-based regimens (N=18/44), and 23% of men taking a protease inhibitor-based regimen (N=9/39) presented at least 1 HIV RNA-positive seminal sample. In contrast to the study published in Clinical Infectious Disease,¹ antiviral combinations containing an integrase inhibitor seemed to be less effective in reducing HIV RNA shedding in semen. However, this study was retrospective and not randomized, and therefore more susceptible to selection bias and confounding factors.

In an interview with Infectious Disease Advisor, Babafemi O. Taiwo, MBBS, chief of infectious diseases in the Department of Medicine at Northwestern Feinberg School of Medicine, Chicago, Illinois, commented that “the proportions of ART-treated patients with genital HIV RNA shedding in these studies are higher than expected. Clinicians and patients should be aware that the viral kinetics in blood and genital secretion can be different, and that especially during the first months of ART, genital viral shedding is not uncommon.”

“Many questions remain open regarding genital HIV shedding: for example, we still don’t know how intermittent shedding of HIV RNA at low level in semen or vaginal secretion translate in terms of HIV transmission, or what factors are associated with HIV RNA shedding, and whether there are differences between different drug classes. These questions will need to be carefully investigated, particularly for newer drug combinations such as 2-drug regimens,” concluded Dr Taiwo, who was not involved in either of the studies.

References

1. Gutierrez-Valencia A, Benmarzouk-Hidalgo OJ, Rivas-Jeremías I, et al. Viral kinetics in semen with different antiretroviral families in treatment-naïve HIV-infected patients: a randomized trial [published online April 25, 2017]. Clin Infect Dis. doi: 10.1093/cid/cix358

2. Eyre RE, Kiessling A. Current anti-retroviral treatments do not eliminate HIV from semen. Presented at: American Urological Association (AUA) 2017 Annual Meeting; Boston, Massachusetts; May 12-16, 2017. Abstract PNFLBA-01.