The prevalence of M. genitalium in our cohort of young men in Kisumu, Kenya, was high (10%) and the majority was asymptomatic (98%). The odds of urethral M. genitalium were nearly halved for circumcised men compared to uncircumcised men, controlling for behavioral risks. We are not aware of other published reports of circumcision status and behavioral factors associated with M. genitalium in men to which we can compare our results.
In our trial [18
] and the male circumcision trial in South Africa [19
], male circumcision did not protect against urethral N. gonorrhoeae
, C. trachomatis
, or T. vaginalis
. In men, M. genitalium
is considered primarily a urethral infection. However, a recent report of men with non-gonococcal urethritis found that men with M. genitalium
had more than a four times higher odds of balanoposthitis, controlling for CT and ureaplasma [20
]. Horner et al. suggest that M. genitalium
may be capable of infecting the poorly keratinized foreskin [20
], as in vitro
study has demonstrated that M. genitalium
can infect vaginal epithelial cells [21
]. Evaluation of the penile microbiome among participants in the circumcision trial in Uganda showed that circumcision led to a significant reduction in anaerobic and facultative anaerobic bacteria [22
]. As M. genitalium
is a facultative anaerobe, this may explain how M. genitalium
would be recovered more frequently in uncircumcised than circumcised men. In our study, while M. genitalium
was detected in urine, these two mechanisms (susceptibility of the foreskin to infection, anoxic microenvironment) provide explanation as to how the foreskin could provide a reservoir for urethral infection in uncircumcised men.
We found that men who reported cleaning their penis shortly after their last sexual intercourse were less likely to be infected with M. genitalium
. One of the mechanisms by which circumcision is thought to protect against genital ulcer disease [23
] and balanitis [24
] is through improved genital hygiene. Thus men with better genital hygiene may be reducing the M. genitalium
reservoir, decreasing likelihood of urethral infection, and this may be expected to have greater impact for uncircumcised men. While the interaction term was not statistically significant (p=0.19), for uncircumcised men, cleaning the penis ≤ 1 hour after intercourse had an OR of 0.28, and the OR was 0.68 for men who were circumcised.
In our study, HSV-2 seropositivity doubled the odds of M. genitalium infection. This association may represent an overlap in similar risk factors for these two sexually acquired infections. Another potential explanation is that M. genitalium was more likely to be detected among men with HSV-2, as men with HSV-2 may have greater inflammation, more persistent infection, or greater M. genitalium organism load. The effect of HSV-2 infection on detection of M. genitalium or on M. genitalium organism load has not been assessed. We are unaware of published studies reporting the effect of HSV-2 infection on the sensitivity and specificity of detection of NG, CT, or TV that may provide insight.
Infection with M. genitalium
was associated with CT infection but not with NG or TV. This may be related to differences in risks for acquisition, with risks for CT and M. genitalium
being more similar than risks for NG or TV. Two prospective cohort studies of female students in London [25
] and sex workers in Nairobi [15
] found more than a doubling of M. genitalium
risk associated with incident CT adjusted for demographics, behavioral risks, and other STIs. In the study of sex workers in Nairobi, NG also increased the risk of M. genitalium
. Among HIV-positive Kenyan women, M. genitalium
organism burden was higher for women who were co-infected with CT but was not associated with NG infection [16
]. Broad acceptance of M. genitalium
as a pathogenic STI is relatively recent. The overlapping epidemiology and potential biological synergism between M. genitalium
and other STIs have not been studied extensively and are not well-understood.
Most M. genitalium
infections (98%) were asymptomatic. The proportion of M. genitalium
infections that were asymptomatic among male STI clinic attendees in Scandinavia is 34–39% [26
], while results from a mobile STI service in South Africa found that 90% of M. genitalium
infections were asymptomatic [6
]. While the implications of pathogenesis and transmission of these asymptomatic infections in men are unclear, a high prevalence of M. genitalium
, even if largely asymptomatic in men, is a public health concern due to associated risks of upper reproductive tract infection in women [3
]. Determining the contribution of M. genitalium
to upper genital tract infection among women in this region will be necessary for implementing the most efficacious treatment regimens.
TV was detected in 2.5% of men by urine TMA, in contrast to the one infection detected by urine culture. The sensitivity of culture for TV compared to TMA is ≤50% [28
]. Throughout our trial and extended follow-up of the cohort, we used culture to identify TV. In our 24-month analysis [18
], the incidence of TV was 2.5 per 100 person-years. It is clear from the current results that our previous analysis significantly underestimated the burden of TV infection. Future research measuring TV should invest in sensitive, nucleic acid-based methods of detection, as this will have a significant impact on prevalence and identifying risks for infection, as well as examining TV as a risk factor for other outcomes, such as HIV and adverse pregnancy outcomes.
As this was a cross-sectional sample, temporal bias is a potential concern. However, most of the variables evaluated (circumcision status, HIV and HSV-2 status, and previous non-ulcerative STI infection status) were measured prior to detection of M. genitalium
infection. Because 85% of circumcised men in this sample had been circumcised for at least 2 years prior to detection of infection, it is unlikely that men were circumcised in response to M. genitalium
infection. While we have not identified significant differences between men who chose circumcision and those who remained uncircumcised after the trial ended with regard to age, number of recent sex partners, HSV-2 status, or non-ulcerative STI [30
], it is possible that the protective association observed between being circumcised and M. genitalium
infection is confounded by factors associated with choosing circumcision. Although we were unable to test all men in the cohort for M. genitalium
, those tested did not differ from those who were not tested with regards to behavioral risks, HIV status, or STI history, indicating that resource constraints did not produce significant selection bias.