Zika Infection Risk From Semen Low, Short-lived, Study Finds

Janis C. Kelly

April 12, 2018

Most men with symptomatic Zika virus (ZIKV) infections had the ZIKV genetic footprint in their semen for at least 30 days after symptom onset, but only 4% had infectious virus, according to a prospective study reported April 12 in the New England Journal of Medicine.

Paul S. Mead, MD, MPH, an epidemiologist at the Centers for Disease Control and Prevention in Fort Collins, Colorado, and colleagues prospectively studied ZIKV shedding in semen (n = 184) and urine (n = 183) of men with symptomatic ZIKV infection. Samples were collected twice per month, and the analysis included 1327 semen samples and 1038 urine samples obtained 14 to 304 days after illness onset. ZIKV RNA shedding was measured by reverse transcriptase polymerase chain reaction (RT-PCR). Infectious virus was detected by Vero cell culture and plaque assay.

Mead et al report that ZIKV RNA was present in semen during the first 30 days after illness onset in more than 60% of men with symptomatic infection but decreased quickly and persisted for up to 9 months in only 1% of men.

However, infectious virus was present in only 4% of the semen specimens that were positive for ZIKV RNA (3 of 78).

"In contrast to the frequent and prolonged shedding of ZIKV RNA in semen, the shedding of infectious ZIKV that could be cultured was rare, short-lived, and limited to the few samples with at least 7.0 log10 ZIKV RNA copies per milliliter of semen," the authors write. "None of the 75 cultured samples with RNA loads lower than 7.0 log10 per milliliter yielded infectious ZIKV, and no sample that was obtained more than 30 days after illness onset yielded infectious ZIKV."

The authors note that most documented male-to-partner sexual transmission of ZIKV occurred within 20 days of symptom onset and all cases occurred within 41 days, which generally coincides with the time of highest infectious virus levels found in this study.

Mead and colleagues also found that only 1% of urine samples had ZIKV RNA, and none had infectious virus.

The mean time to clearance of ZIKV RNA from semen was 54 days, and the authors estimated that only 5% of men would have detectable ZIKV RNA at 158 days.

When they looked at risk factors associated with longer viral RNA presence, they found ZIKV RNA was detectable 12 days longer in men age 50 years than in men age 30 years, 12 days longer in men whose ZIKV symptoms did not include conjunctivitis, 27 days longer in men whose ZIKV symptoms did not include joint pain, and 21 days longer in men whose ejaculatory frequency was once per week vs four times per week.

Intermittent shedding, which was defined as a ZIKA RNA–negative sample followed by a positive sample, was observed in 13% of men (8 of 60). Because of this finding, the authors emphasize that a single negative ZIKA RNA result does not rule out future shedding of virus but estimate the likelihood at less than 1%.

Among the unanswered questions is whether maternal ZIKV infection due to sexual transmission poses risks to the fetus different from those associated with infection through mosquito-borne virus. The authors also note that their findings do not necessarily pertain to men with asymptomatic ZIKV infection.

The difference between semen ZIKV RNA levels and levels of infectious virus suggests that relying on molecular analysis might lead to overestimating the risk for sexual transmission in ZIKV infection, according to the authors.

This concern was also addressed in an accompanying editorial  by Heinz Feldmann, MD, from the Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.

Feldmann warns that the shift from reliance on virus isolation for proving infectivity to molecular methods such as RT-PCR for virus detection might have unexpected consequences for researchers trying to understand virus spread and prevention. And that concern, he notes, goes beyond ZIKV.

He writes, "In this study, 4% of the ZIKV RNA–positive semen samples were found to be infectious, and infectivity was observed only in samples that were obtained within 30 days after illness onset and that had a viral load of more than 7.0 log10 RNA copies per milliliter. This finding suggests that there is a short period during which ZIKV­infected men might transmit this virus through sexual contact. Likewise, the fact that sexual transmission could rarely be confirmed for [Ebola virus], despite the detection of RNA in the semen of survivors more than 1 year after acute infection, further shows the shortcomings of molecular detection alone in understanding transmissibility."

This issue will likely assume greater importance as more viruses not previously known to be sexually transmitted are detected in the semen of infected men. "On the research front, we need more rapid approaches for detection that measure virus infectivity rather than genome presence," Feldmann says.

The study was supported by the Centers for Disease Control and Prevention. The study authors and Feldmann have disclosed no relevant financial relationships.

N Engl J Med. 2018;378:1377-1385. Abstract, Editorial

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