In response to the letter from Tobian et al. , we too were surprised that we did not find a protective effect of medical male circumcision (MMC) against herpes simplex virus type 2 (HSV-2). On the basis of the results from their trial in Uganda , the trial South Africa , results from meta-analysis , and the reduction in genital ulcer disease (GUD) in our own trial, we expected a reduction in HSV-2 for circumcised men compared with uncircumcised men. Tobian et al.  suggest that we did not find an association due to poor assay specificity. We investigated this as a possibility, but believe there are other potentially more plausible explanations for this lack of association between MMC and HSV-2 among our participants in Kenya.
Although the sensitivity (95%) and specificity (91%) of the Kalon test for detecting HSV-2 in sub-Saharan Africa are high , we found a lower sensitivity (92%) and specificity (79%) in a validation study among men aged 18–24 years in Kisumu . This amount of misclassification could obscure a small effect of MMC on HSV-2 acquisition. However, in keeping with the analysis conducted by Tobian et al.  and as reported in our article, to assess the effect of misclassification due to imperfect specificity, we varied the optical density cut-off index value (1.5, 2.0, 2.5, 3.0 and 3.5), with higher values corresponding with higher specificity. Here we present the detailed results of that analysis (Table 1); the relative risk remained close to 1, indicating no protective effect of MMC against HSV-2, and that the results were unaffected by increased specificity.
As we noted, the lack of association between MMC and HSV-2 acquisition also could be due to the location of lesions. Unlike HIV, transmission of HSV-2 can result from contact between skin or mucosa throughout the genital region  or may be acquired orally , and this may render HSV-2 acquisition less dependent upon the presence of foreskin mucosa. Among circumcised men, 37% of clinically detected genital ulcers were detected on the penile shaft. Comparable results on lesion location are not reported for the MMC trials in Rakai and Orange Farm.
Citing their own work and that of others, Tobian et al.  note that the majority of genital ulcers are caused by HSV-2. By serological testing, we also found that a majority, but barely so, of GUD was associated with HSV-2 (55% at baseline prior to randomization and 55% of GUD over follow-up). A large proportion of GUD was associated with no sexually transmitted infection (STI) cause. In a sample of clinically detected genital ulcers, 38% were not associated with HSV or Treponema pallidum by PCR or serology. In the Rakai trial, 58% of clinically detected GUD did not have an STI-associated pathogen  and an ulcerative STI pathogen was not detected in 32% of GUD specimens in female sex partners . The relative reduction in GUD among circumcised men was similar for those who remained HSV-2 seronegative throughout follow-up compared with those who were HSV-2 seropositive, indicating that reductions in GUD were not limited to those caused by HSV-2. As we stated, if MMC provided protection against herpetic GUD, we would expect to see a reduction in genital ulcers for HSV-2 seropositive circumcised men compared with uncircumcised men, with no reduction in GUD among HSV-2 seronegative men who were circumcised. If MMC provided protection against both herpetic and nonherpetic ulcers, then we would expect to observe a stronger protective effect of MMC against GUD in HSV-2 seropositive men, resulting from the protection against herpetic GUD in addition to protection against nonherpetic GUD. Thus, our finding of no difference in the reduction in GUD by HSV-2 serostatus is consistent with our finding of no protective effect of MMC against HSV-2.
Our null findings do not negate the reductions in HSV-2 associated with MMC observed in the Ugandan and South African trials. Despite having such consistent results with regards to the primary outcome (HIV incidence) and secondary outcomes (incidence of nonulcerative STIs and GUD), it is possible that the trials can have different findings for other parameters, due to differences in populations studied or other unmeasured variables. While it would be convenient for all three trials to have the same findings for all measures, differences indicate new, potentially productive avenues of research and expanded knowledge – in this case, regarding the cause of GUD and variation in different populations.
Conflicts of interest
There are no conflicts of interest.
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