Ebola Sexual Transmission 6 Months After Illness Confirmed

Janis C. Kelly

October 14, 2015

Two Ebola virus (EBOV) studies published online today in the New England Journal of Medicine translate to one piece of advice: Men who have survived Ebola virus disease (EVD) should use condoms and treat semen as a potential source of infection, and not just for the previously recommended 6-months of post-EVD convalescence.

Suzanne E. Mate, PhD, from the Center for Genome Sciences, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, and colleagues report the landmark proof that sexual transmission of EBOV via semen is possible. They analyzed and matched EBOV genomes from blood samples of a female patient in Liberia with new-onset EVD and from a semen sample from the Liberian male EVD survivor with whom she had a single instance of unprotected vaginal intercourse.

This case was originally reported May 1, 2015, as a possible sexual transmission of EBOV, in the Centers for Disease Control and Prevention (CDC)'s Morbidity and Mortality Weekly Report. The case occurred 30 days after isolation of the most recent previously confirmed EVD case in Liberia. In the initial report, the authors concluded that the male EVD survivor, whose semen was polymerase chain reaction (PCR)-positive for EBOV RNA 199 days after disease onset, was the likely source of infection, but they could not be confirm the transmission without complete genomic sequencing of the virus from both partners.

Now Dr Mate and colleagues, most of whom were also coauthors of the earlier report, demonstrate that connection. The molecular analysis showed that the EBOV genomes from the male EVD survivor's semen and from the female patient's blood samples shared three unique substitutions, that these three substitutions were not seen in 796 other EBOV genomes from western Africa, that these sequences were distinct from the EBOV transmission chain documented in Liberia before this case, and that the 199-day persistence of viral nucleic acids in semen was "more than four times as long as the [World Health Organization]-defined waiting period for declaring a country to be free from EVD."

"Although the semen sample contained no detectable infectious EBOV, the assembly of a nearly complete genome suggested the possible presence of infectious particles. In addition, from the evidence of the sexual transmission between the patient and the survivor, we can infer that infectious EBOV was present in the survivor at least 179 days after the onset of disease (155 days after the clearance from blood)," the authors conclude.

EBOV Fragments More Common Than Not

The extended risk for EBOV transmission via semen was further demonstrated in a second paper published online October 14 in the New England Journal of Medicine by Gabrilla Deen, MD, from the Sierra Leone Ministry of Health and Sanitation in Freetown, and colleagues. The team reported notable persistence of EBOV viral RNA in semen up to 9 months after onset of EVD.

The researchers enrolled a convenience sample of 100 male EVD survivors in Sierra Leone in a pilot study of Ebola RNA persistence in semen. Eligibility criteria included age 18 years or older; an official survivor certificate issued by the Ministry of Health and Sanitation, which is provided to patients with laboratory-confirmed EVD upon hospital discharge; and ability to provide written informed consent.

The researchers used a quantitative reverse transcriptase–PCR (RT-PCR) assay with target gene sequences of NP and VP40 to measure levels of viral RNA in semen samples from 93 men taken at different times after recovery from EVD. Three men were withdrawn from the study because of an inability to provide a specimen at two consecutive visits, and four men were excluded because of problems with the RT-PCR assay.

The assay detected EBOV viral RNA in 100% (9/9) of men tested at 2 to 3 months after the onset of EVD, 65% (26/40) of men tested 4 to 6 months after the onset of EVD, and 26% (11/43) of men tested 7 to 9 months after the onset of EVD, and results were indeterminate for a man tested 10 months after the onset of EVD.

The longest time semen remained RT-PCR-positive was 284 days (9 months) after onset of EVD symptoms. The shortest time before an initial semen sample was negative was 128 days (4 months) after onset of EVD symptoms. Semen specimens remained RT-PCR-positive for 3 to 9 months after discharge from treatment.

The authors conclude that the data "showed the persistence of Ebola virus RNA in semen and declining persistence with increasing months since the onset of EVD." They caution that the extent to which RT-PCR Ebola positivity translates to virus infectivity is still unknown.

Also unknown is the risk for transmission from female EBD survivors to their sexual partners. Dr Deen's group plans to test additional body fluids in both male and female EVD survivors.

In an editorial that accompanies the two studies, Armand G. Sprecher, MD, MPH, from the Medical Department, Médecins Sans Frontières, Brussels, Belgium, emphasizes that sexual transmission of Ebola "remains a rare event." He noted that there are more than 17,000 survivors of the current EVD outbreak, about half of whom are male, but there have been fewer than 20 suspected sexually transmitted infections reported.

Cautious Communication Warranted

The CDC advised in a press release about the new studies, "Until more is known, the more than 8,000 male Ebola survivors across the three countries need appropriate education, counselling and regular testing so they know whether [EBOV] persists in their semen; and the measures they should take to prevent potential exposure of their partners to the virus. Until a male Ebola survivor's semen has twice tested negative, he should abstain from all types of sex or use condoms when engaging in sexual activity. Hands should be washed after any physical contact with semen."

Dr Deen and colleagues note that semen testing is not universally available in the affected countries.

Looking ahead, Dr Sprecher warned of the need for caution in how the risk posed by EVD survivors is communicated to the public. He agreed that the data from Dr Mate and colleagues suggest that surveillance for late EVD should be extended because of transmission from survivors, but said it must be done in a humanitarian manner.

"[W]e cannot ask western Africa to be alert for late presentation of new cases without calling attention to the risk posed by male survivors," Dr Sprecher writes, "Communities within and beyond western Africa have not dealt kindly with perceived risks when it comes to Ebola. Survivors have been very poorly treated during this outbreak, and male survivors have already been singled out for oppressive measures." He notes that detecting the next case of sexually transmitted EVD will be difficult if people conclude that a patient with EVD faces either "death in a frightening treatment unit or survival to return as a social outcast."

Dr Deen and colleagues echo that point. "Persons who survive EVD face myriad challenges. Many survivors have family members and friends who died from EVD. Many are unemployed, face stigma from their communities, and have lingering sequelae in addition to the risk of persisting virus in semen. Due respect and continuing efforts that have strong sustainable support from within the local communities are crucial in mitigating negative effects in terms of further stigma attached to survivors."

Dr Mate and coauthors have disclosed no relevant financial relationships. Dr Deen and many coauthors have disclosed no relevant financial relationships, with the exception of two coauthors, who report a pending patent related to methods and reagents for detecting EBOV. Dr. Sprecher have disclosed no relevant financial relationships.

N Engl J Med. Published online October 14, 2015. Mate abstract, Deen abstract, Editorial full text

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