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Anogenital ulcers caused by HSV-2 are associated with an increased risk of HIV transmission. When compared to clinician examination, HIV/HSV-2 coinfected men who have sex with men are frequently unaware of anogenital ulcers. These data underscore the importance of condom use and the need for new HSV-2 prevention strategies.
Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted diseases (STD)1, 2. HIV-infected men who have sex with men (MSM) are at increased risk for HSV-2 infection compared to the general population, with 27% seroprevalence in HIV-negative MSM3 and 80% seroprevalence in HIV-positive MSM4. HSV-2 infection is an important risk factor for the acquisition of HIV5, 6, and the probability of HIV transmission per coital act is increased four-fold in the presence of genital ulcers in the HIV-positive partner7. High quantities of HIV RNA are found in most HSV-2 genital ulcers in HIV-infected men, suggesting a mechanism for this finding8. HSV-2/HIV co-infected MSM are also more likely to have HSV-2 detected on the genital skin or mucosa (“shedding”) than HSV-2 seropositive, HIV-seronegative MSM9, increasing the possibility of HSV-2 transmission. The risk of both HSV-2 related genital ulcers and HSV-2 shedding increases as CD4+ T cell counts fall9, 10.
The 2010 Centers for Disease Control STD Treatment Guidelines recommend that persons with genital herpes avoid sexual activity when lesions or prodromal symptoms are present11. In HIV-1 seropositive persons this advice is even more pertinent given the potential to transmit both HIV and HSV-2. To determine the ability of patients to accurately recognize genital herpes recurrences, we compared participant recognition of genital symptoms or lesions with clinician identification of HSV-2 genital ulcers and HSV-2 detection in HIV-1/HSV-2 co-infected MSM with a history of symptomatic genital herpes.
Ten HIV-1 and HSV-2 seropositive MSM were enrolled in a study conducted in Seattle, Washington from June-September 1995. This study was approved by the University of Washington Human-Subjects Review Committee. All participants gave written informed consent. HIV-1 seropositivity was confirmed by commercial enzyme immuno-assay (EIA) and Western blot. Serologic testing for antibodies to HSV-1 and HSV-2 was done by Western blot12
At study entry, each participant received genital herpes education, including review of symptoms and techniques for self-examination. Each day, participants used a diary to record the presence or absence of symptoms (itching, redness, skin splits) and lesions (ulcers, sores) in the penile and perianal (“anogenital”) region, identified using self-examination13 and performed a single swab from the entire genital area. Participants were seen by a clinician daily (Monday through Friday) over an 8 week period to assess for anogenital lesions and to obtain penile and perianal swabs. Additional samples were collected from the buttocks when signs or symptoms of HSV-2 recurrences were present. Swabs were placed in 1ml vials containing 1X PCR buffer and placed at −200C. HSV DNA was quantitated using liquid hybridization polymerase chain reaction (PCR), with a positive result defined as detection of more than 500 copies HSV DNA per ml of PCR buffer14.
Herpes lesions were defined as blisters, ulcers, sores or crusts on the penile, perianal, or buttock region as reported by the clinician. HSV swabs were considered positive for a given day if either the participant or clinician collected swab had HSV detected. HSV detection rates in the presence and absence of lesions, and overall, were calculated by determining the number of days with HSV detected over the total number of days with swabs collected, per anatomic site. A generalized estimating equation (GEE) Poisson model with an exchangeable correlation structure and robust covariance estimator for correlated data was used to determine the probability that participants reported symptoms on days when clinicians observed lesions or when HSV was detected. A two-sided P-value <0.05 was considered statistically significant. Data were analyzed using Stata 10.0.
Ten HIV-1 and HSV-2 co-infected MSM were enrolled. The median age was 44 years (range 38–57); 9 were Caucasian, one was African-American. All participants were HSV-2 seropositive; 7 were also HSV-1 seropositive. Education level was available for 4 participants; 2 had completed high school and 2 were college graduates. The median time from genital herpes diagnosis to study enrollment was 8.1 years (range 2 to 15 years). At study entry, the median CD4 count was 236 (range 64–541), and the median log10 plasma HIV RNA level/ml was 4.2 (range 3.5–5.0).
Follow up was performed for a median of 55 days per participant (range 35–57 days), for a total of 529 days of observation. Swabs were obtained from the genital, perianal and buttock region for PCR on 520 (98%) of 529 possible days. Overall, 1069 anogenital swabs were collected.
Nine (90%) participants reported penile, perianal or buttock symptoms or lesions during the study. Lesions or symptoms were reported on 158 of 529 days (30%); on the penis on 17 (3%) days, the perianal area on 106 (20%) days and buttocks on 45 (9%) days. Eight (80%) participants had typical herpes ulcers reported by clinicians during the study. Clinicians reported a total of 192 (36%) days with lesions, with penile lesions noted on 22 (4%) days, perianal lesions on 127 (24%) days and buttock lesions on 54 (10%) days (Table 1). Participants had a 51% probability of reporting penile or perianal symptoms on days that a clinician reported an anogenital lesion (probability=0.51, 95% CI=0.28–0.92, p=0.02, for the test that agreement=100%). In a sensitivity analysis in which only anogenital ulcers reported in the presence of HSV detection were included, participants had only a 75% probability of noting symptoms in the presence of an ulcer (data not shown).
Eight (80%) participants had HSV detected from the penile, perianal or buttock region during the study period. HSV was detected from the penile or perianal area on 165 (35%) of 520 days and from 222 (21%) of 1069 swabs (Table 2a). Careful examination by a clinician identified genital lesions on 84 (51%) days. Participants reported penile or perianal symptoms or lesions on only 72 (44%) days with HSV detected (Table 2b). Participants were unlikely to report penile or perianal symptoms or lesions on days when HSV was detected at these sites (probability of reporting symptoms=0.34, 95% CI=0.19–0.76, p=0.006).
The relationship between anogenital HSV shedding, clinician reported anogenital lesions, and participant reported anogenital symptoms or lesions is shown in Figure 1. Of 165 days with HSV detected, only 67 (41%) were days in which participants had symptoms of a clinical recurrence in the presence of a lesion. On 33 (20%) days with HSV shedding, a lesion was noted by a clinician in the absence of symptoms, and on 57 (34%) days HSV shedding was noted in the absence of lesions and participant symptoms. On 8 (5%) days with HSV shedding, symptoms were reported by the participant, in the absence of clinician reported lesions.
Our objective was to rigorously determine how frequently MSM who have both HIV and HSV-2 infections recognized genital herpes recurrences in the presence of a documented anogenital ulcer. We found that men in our cohort were frequently unaware of the presence of anogenital ulcers, with only a 51% probability of describing symptoms or lesions in the presence of an ulcer. As HIV transmission occurs more frequently in the presence of genital ulcers7, and genital ulcers harbor HIV RNA8, the inability to recognize lesions may have significant consequences for both HIV and HSV-2 transmission11.
With careful, daily examination, it is possible that genital ulcers were overestimated by the clinician. In systematically training our participants in self-examination and the manifestations of genital herpes, we increased the likelihood that participants would detect signs and symptoms of anogenital herpes recurrences. As most individuals with HSV-2 are unaware of their infection15, it is likely that the inability to recognize a genital herpes recurrence would be even more profound in the general population. This study was conducted with a PCR assay which used a higher cutoff and thus was less sensitive than our currently used PCR assays16, suggesting that HSV shedding, both in the presence and absence of a lesion, was underestimated in this study. Due to the intensive nature of this study, we were restricted to a small sample size.
Although this study was performed in the pre-HAART era these data remain relevant for HIV-infected persons today. While some studies have shown that HAART decreases the risk of genital ulcers17, others have shown no difference in genital ulcer frequency during HAART as compared to pre-HAART18. In addition, HSV-2 genital ulcers are a leading cause of the immune reconstitution inflammatory syndrome19.
Our data raise the issue of what therapeutic intervention might be useful for HIV-1-infected MSM with HSV-2 infection. In HSV-2 discordant heterosexual couples without HIV-1 infection, suppressive valacyclovir decreased HSV-2 transmission by only 48%20, and suppressive acyclovir does not prevent heterosexual HIV transmission from an HIV-1/HSV-2 coinfected partner21. While condoms are quite effective for prevention of HIV transmission22, they are only partly effective for HSV-2 transmission23. More effective strategies for interruption of HSV-2 transmission are needed.
Funding: National Institutes of Health/National Institute for Allergy and Infectious Disease AI030731 (AW, LC), National Institutes of Health K24 AI071113 (AW), K23 AI079394 (CJ)
CJ has received grant support from GlaxoSmithKline and is a research investigator for AiCuris.
LC has received consulting fees from AiCuris, which is developing treatments for HSV and cytomegalovirus infections, is listed as a coinventor on several patents describing antigens and epitopes to which T-cell responses to HSV-2 are directed (these proteins have the potential to be used in candidate vaccines against HSV), and has received fees for serving as the head of the scientific advisory board of Immune Design, including equity shares that are less than 1% ownership.
AW has received funding from GlaxoSmithKline, and is a consultant for AiCuris.
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MIS, MSaracino, MShaughnessy, DB, TS; no conflicts