Sexual transmission of Zika virus and other flaviviruses: A living systematic review

Abstract

Background: Health authorities in the United States and Europe reported an increasing number of travel-associated episodes of sexual transmission of Zika virus (ZIKV) following the 2015-2017 ZIKV outbreak. This, and other scientific evidence, suggests that ZIKV is sexually transmissible in addition to having its primary mosquito-borne route. The objective of this systematic review and evidence synthesis was to clarify the epidemiology of sexually transmitted ZIKV.

Methods and findings: We performed a living (i.e., continually updated) systematic review of evidence published up to 15 April 2018 about sexual transmission of ZIKV and other arthropod-borne flaviviruses in humans and other animals. We defined 7 key elements of ZIKV sexual transmission for which we extracted data: (1) rectal and vaginal susceptibility to infection, (2) incubation period following sexual transmission, (3) serial interval between the onset of symptoms in a primary and secondary infected individuals, (4) duration of infectiousness, (5) reproduction number, (6) probability of transmission per sex act, and (7) transmission rate. We identified 1,227 unique publications and included 128, of which 77 presented data on humans and 51 presented data on animals. Laboratory experiments confirm that rectal and vaginal mucosae are susceptible to infection with ZIKV and that the testis serves as a reservoir for the virus in animal models. Sexual transmission was reported in 36 human couples: 34/36 of these involved male-to-female sexual transmission. The median serial symptom onset interval in 15 couples was 12 days (interquartile range: 10-14.5); the maximum was 44 days. We found evidence from 2 prospective cohorts that ZIKV RNA is present in human semen with a median duration of 34 days (95% CI: 28-41 days) and 35 days (no CI given) (low certainty of evidence, according to GRADE). Aggregated data about detection of ZIKV RNA from 37 case reports and case series indicate a median duration of detection of ZIKV of 40 days (95% CI: 30-49 days) and maximum duration of 370 days in semen. In human vaginal fluid, median duration was 14 days (95% CI: 7-20 days) and maximum duration was 37 days (very low certainty). Infectious virus in human semen was detected for a median duration of 12 days (95% CI: 1-21 days) and maximum of 69 days. Modelling studies indicate that the reproduction number is below 1 (very low certainty). Evidence was lacking to estimate the incubation period or the transmission rate. Evidence on sexual transmission of other flaviviruses was scarce. The certainty of the evidence is limited because of uncontrolled residual bias.

Conclusions: The living systematic review and sexual transmission framework allowed us to assess evidence about the risk of sexual transmission of ZIKV. ZIKV is more likely transmitted from men to women than from women to men. For other flaviviruses, evidence of sexual transmissibility is still absent. Taking into account all available data about the duration of detection of ZIKV in culture and from the serial interval, our findings suggest that the infectious period for sexual transmission of ZIKV is shorter than estimates from the earliest post-outbreak studies, which were based on reverse transcription PCR alone.

Fig 1. A schematic representation of the sexual transmission of Zika virus and 7 key elements.

Numbered circles show the 7 key elements. Dark blue circles are elements for which evidence is based on empirical research. Light blue circles denote elements derived from mathematical modelling studies and in vivo studies. (A) Transmission between 2 individuals. The horizontal arrows show the time course of the disease for the primary infected individual (I), who is infected, and the secondary individual (S), who starts as susceptible (element 1). The vertical red arrow represents a Zika virus transmission event, after which there is an incubation period (element 2) before symptoms develop. Element 3 is the serial interval, i.e., the period between the start of symptoms in the primary and the secondary individual. Element 4 is the duration of infectiousness. After the infection, individuals can become immune. (B) Relation between different elements at population level. The reproduction number (element 5) is the result of the contact rate, the probability of transmission per act (element 6), and the duration of infectiousness (4). The transmission rate (element 7) can be estimated using the reproduction number (5) and the serial interval (3). Adapted with permission from World Health Organization [16].

Fig 2. Flow diagram of reviewed studies.

Numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage.

Fig 3. ZIKV detection in semen by RT-PCR.

The x-axis indicates time in days from symptom onset. The labels on the y-axis represent the date of publication of the studies, in chronological order, with the last date indicating the date of this analysis. Green lines represent the duration of RT-PCR positivity in individuals from case reports and case series (n = 119), extending to the last positive RT-PCR measurement. Green dots at day 0 represent an assumption of RT-PCR positivity for patients with no sample taken at symptom onset. Blue lines represent the interval between the last positive measurement and the first subsequent negative measure (red dot). The black dotted line represents the publication of the WHO interim guidelines [2] and the suggested duration of protected sexual intercourse advised in the guidelines (6 months, black triangle). The black dots and whisker bars represent median aggregated values and 95% confidence intervals for [a] a prospective cohort (n = 55 men) [20] and [b] the aggregation of all available case reports and case series. Maximum values in these datasets are shown with a red diamond or a red greater than symbol (for values outside the range of the graph). Lines for which the date is not provided are from the same date as the line above. RT-PCR, reverse transcription PCR; ZIKV, Zika virus.