Genital herpes simplex virus [HSV]-2 is considered the highest prevalence sexually transmitted infection in the United States, with an estimated 17% of all adolescents and adults infected.1 Although asymptomatic in most persons, HSV-2 causes a range of important problems, including recurrent genital ulcerations, devastating neonatal infection, and enhanced HIV transmission, with estimates that HSV-2 may account for 25% to 35% of HIV infections in sub-Saharan Africa.2 Conventional tools for prevention and control (e.g., curative therapy, vaccines) do not exist for HSV-2. However, strategies that do exist—serologic tests for diagnosis, disclosure to partners, the use of condoms,3,4 and antiviral therapy that suppresses symptoms and reduces transmission5—are analogous to those in use for HIV prevention, and, over the past decade, the magnitude of the population burden associated with HSV-2 has stimulated discussion about the value of initiating broad prevention programs.6–10
The appropriate use and likely effect of these approaches, particularly the role of widespread serologic testing, has generated controversy. Since over 80% of infected persons are unaware of their diagnosis1 and most transmission is from individuals with unrecognized infection,11 identifying those who are infected is a logical starting point for prevention. Type-specific serologic tests for herpes, available over the past decade, represent a major improvement over the earlier, nonspecific, whole antigen tests.12 However, based on concerns over test performance in low-prevalence populations and lack of data about benefit of testing, screening has not been recommended in general populations, although there continues to be debate about its role in targeted populations such as those attending sexually transmitted disease [STD] clinics.13,14
Given this uncertainty, more information about real-world feasibility and impact of HSV-2 testing in STD clinics would be useful, and in this issue of the journal, investigators from Indianapolis build on their earlier work that characterized acceptance of testing and return for results in several clinical settings15,16 by assessing implementation of routinely offered HSV-2 testing in their STD clinic.17 Stated rationales for implementation included client interest, desire to provide more comprehensive STD services, and potential importance of HSV-2 as a cofactor for HIV acquisition in the largely minority population attending the clinic. Modifications to their original protocol included use of rapid testing to enhance return rates, a fee to support testing costs, and a prescription for low-cost acyclovir. The results were modestly encouraging. Overall, 13% of patients chose to be tested, 98% of whom had not been diagnosed previously with genital herpes. In addition, 65% of newly diagnosed patients accepted a prescription for suppressive acyclovir as a means of reducing transmission, an approach of plausible although unproven benefit in this context.13,18 However, testing rates in demographic groups of greatest concern for both HSV-2 and HIV transmission (e.g., men who have sex with men, blacks, females) were no greater or even lower than the clinic-wide rate, and there were no data on perceived personal benefit to those tested. In addition, the study did not evaluate possible public health benefit, that is, whether testing positive resulted in behavioral changes that might reduce transmission (e.g., recognition of herpetic outbreaks, disclosure to partners, use of condoms, acyclovir therapy).
While focus of the study was STD clinic-based testing as a client service, the overarching rationale for HSV-2 testing is “a reduction in HSV-2 incidence and prevalence” as the authors note.17 Given that persons attending STD clinics comprise only a small minority of those with sexually transmitted infection (e.g., only 17% of all reported chlamydial infections in 200719), if HSV-2 testing is to have a plausible population impact, it will need to be implemented in a broader range of clinical settings. Thus, 10 years since HSV type-specific serologic tests have become commercially available, an important remaining question is their performance in general populations. Currently, there are several Food and Drug Administration-cleared assays for type-specific HSV-2 serologic testing, all of which use the glycoprotein G2 antigen, whether native or recombinant. These include both rapid point-of-care tests that can be performed on either capillary blood or serum and laboratory-based tests, suitable for either large or small volume labs. Test sensitivity has been estimated to be 80% to 100% and specificity ≥96%.13
Such performance characteristics may well be adequate for use among high prevalence populations such as persons attending STD clinics. One study found the positive predictive value (PPV) in such a setting to be 96%,20 although more recently, the PPV of a newer test was only 84% among males attending the same clinic.21 More concerning are results in lower prevalence settings. Mark et al.,22 testing sexually active college students without a history of genital herpes, found the PPV to be much lower (37.5%), similar to other low prevalence settings.23,24 Suggested approaches to increase PPV include use of higher than standard cutoff values,20,25 adjusting the cutoff based on presence of HSV-1 antibody,21 and use of confirmatory testing.24,26 Unfortunately, none of these approaches have been broadly evaluated, and the only widely accepted confirmatory test is the Western Blot, a validated but expensive option available only in reference laboratories.12
A larger question is whether prevention strategies for those diagnosed with HSV-2 infection are effective enough to reduce HSV-2 transmission. As noted above, potential prevention measures include both behavioral and biomedical approaches. But how convincing is the accumulated evidence that such approaches would contribute importantly to reducing HSV-2 transmission? Regarding behavioral approaches, there is some evidence that knowledge of a partner’s genital herpes is associated with delayed acquisition of infection; a study of individuals with newly acquired genital herpes and their partners found that the median time to HSV-2 acquisition was greater among participants whose partners disclosed that they had genital herpes compared with participants whose partners did not (270 vs. 60 days).3 However, such a result may be less relevant to asymptomatic HSV-2 seropositive individuals, since little is known about their likelihood of disclosure. There are few studies assessing the extent to which serologic testing modifies subsequent behavior among those testing positive, and the limited available data do not indicate much effect. Crosby et al.27 offered rapid HSV-2 testing to STD clinic attendees with standardized HSV-2 counseling based on CDC guidelines13 and found that after 3 months, testing HSV-2 positive was not associated with adoption of self-reported sexual behaviors that would protect against transmission of HSV-2 (e.g., condom use, avoiding sex because of STD concerns).
The biomedical approach of greatest interest is the use of suppressive antiviral treatment, shown in a recent study to reduce HSV-2 transmission to steady sex partners of symptomatic patients by almost 50%.5 Assuming that suppression is equally effective among those with asymptomatic infection,18 models have evaluated the potential impact that use of suppressive therapy could have on population spread of HSV-2.28 While minimal impact would be expected at current levels of antiviral coverage (estimated at 3.2% of those with HSV-2), the models demonstrate that impact can be substantially increased by providing suppressive therapy for as many infections as possible, as soon as possible after infection is acquired (when viral shedding is most frequent), and for as long as possible.28 Unfortunately, there is little information about the proportion of those with asymptomatic infection who would accept suppressive therapy for the primary purpose of prevention or about their adherence and duration of treatment. Developing a public health approach to identify asymptomatic infection soon after acquisition is also problematic, since this would require knowing when to begin testing for HSV-2, among whom, and at what intervals.
Suppressive HSV-2 therapy has also been the subject of great interest as an HIV prevention strategy given the strong evidence that HSV-2 increases HIV transmission29; if proven successful, such a strategy would provide a convincing rationale for broader HSV-2 serologic testing. Unfortunately, recent studies evaluating this strategy failed to find a reduction in either HIV acquisition or transmission.30–32 Thus, it seems that addressing the HSV-HIV connection for HIV prevention impact will require redirected focus to the primary prevention of HSV-2 through either the strategies described above or preventive vaccines in the future.33
There have been important advances over the past decade in our understanding of possible approaches for preventing genital HSV-2 infection; however, as outlined above, many critical questions remain. In the absence of a single highly effective prevention modality, it is likely that a combination of HSV-2 prevention approaches will provide greater benefit than any single one, as is now being realized for HIV prevention.34 The challenge for HSV-2 prevention over the coming years is to better assess the effectiveness of these combinations and how they can be most appropriately and cost-effectively implemented for population impact.
In the meantime, what should STD clinics consider with regard to offering HSV-2 testing? Clearly, clinics providing STD services should have access to and offer testing (e.g., culture, PCR, serology) as a diagnostic tool in the management of clinical problems (e.g., persons with symptoms, sexual contact with genital herpes).13 However, using serologic tests to screen asymptomatic persons is a different matter. The primary mission of public health clinical services is to improve population health, through both primary prevention (e.g., preventing ongoing transmission of infection) and secondary prevention (e.g., preventing individual complications through early treatment). This mission may be served by offering high-quality services that provide primarily personal health benefit, if doing so helps reach the clientele needed to achieve public health impact. However, with declining public health infrastructure in the United States and the many challenges facing STD clinics (e.g., resurgent syphilis, high levels of chlamydia and gonorrhea, renewed emphasis on HIV testing, and partner services), programs face increasing need to prioritize services. At the present time, those choosing to offer HSV-2 testing should do so as a personal health service, rather than as an as yet unproven public health intervention.
1. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006; 296:964–973.
2. Abu-Raddad LJ, Magaret AS, Celum C, et al. Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa. PLoS One 2008; 3:e2230.
3. Wald A, Krantz E, Selke S, et al. Knowledge of partners’ genital herpes protects against herpes simplex virus type 2 acquisition. J Infect Dis 2006; 194:42–52.
4. Martin ET, Krantz E, Gottlieb SL, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med 2009; 169:1233–1240.
5. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004; 350:11–20.
6. Corey L. Raising the consciousness for identifying and controlling viral STDs: Fears and frustrations–Thomas Parran Award Lecture. Sex Transm Dis 1998; 25:58–69.
7. Handsfield HH, Stone KM, Wasserheit JN. Prevention agenda for genital herpes. Sex Transm Dis 1999; 26:228–231.
8. Corey L, Handsfield HH. Genital herpes and public health: Addressing a global problem. JAMA 2000; 283:791–794.
9. Hook EW, Leone P. Time to translate new knowledge into practice: A call for a national genital herpes control program. J Infect Dis 2006; 194:6–7.
10. Rietmeijer CA, Low N. Herpes complex. Sex Transm Infect 2008; 84:330–331.
11. Mertz GJ. Asymptomatic shedding of herpes simplex virus 1 and 2: Implications for prevention of transmission. J Infect Dis 2008; 198:1098–1100.
12. Ashley RL, Wald A. Genital herpes: Review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev 1999; 12:1–8.
13. Centers for Disease Control and Prevention Sex Transm Dis Treatment Guidelines, 2006. MMWR Recomm Rep 2006; 55:1–94.
15. Fortenberry JD, Zimet GD, Brady R, et al. Return for results after herpes simplex virus type 2 screening. Sex Transm Dis 2004; 31:655–658.
16. Zimet GD, Rosenthal SL, Fortenberry JD, et al. Factors predicting the acceptance of herpes simplex virus type 2 antibody testing among adolescents and young adults. Sex Transm Dis 2004; 31:655–658.
17. Fife KH, Van Der Pol B, Roth AM. Sex Transm Dis Implementation of routine access to herpes simplex virus 2 antibody testing in a public health STD clinic. Sex Transm Dis. In press.
18. Sperling RS, Fife KH, Warren TJ, et al. The effect of daily valacyclovir suppression on herpes simplex virus type 2 viral shedding in HSV-2 seropositive subjects without a history of genital herpes. Sex Transm Dis 2008; 35:286–290.
19. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance, 2007. Atlanta, GA: U.S. Department of Health and Human Services, 2008.
20. Whittington WL, Celum CL, Cent A, et al. Use of a glycoprotein G-based type-specific assay to detect antibodies to herpes simplex virus type 2 among persons attending sexually transmitted disease clinics. Sex Transm Dis 2001; 28:99–104.
21. Golden MR, Ashley-Morrow R, Swenson P, et al. Herpes simplex virus type 2 (HSV-2) Western blot confirmatory testing among men testing positive for HSV-2 using the focus enzyme-linked immunosorbent assay in a sexually transmitted disease clinic. Sex Transm Dis 2005; 32:771–777.
22. Mark HD, Nanda JP, Roberts J, et al. Performance of focus ELISA tests for HSV-1 and HSV-2 antibodies among university students with no history of genital herpes. Sex Transm Dis 2007; 34:681–685.
23. Turner KR, Wong EH, Kent CK, et al. Serologic herpes testing in the real world: Validation of new type-specific serologic herpes simplex virus tests in a public health laboratory. Sex Transm Dis 2002; 29:422–425.
24. Morrow RA, Friedrich D, Meier A, et al. Use of “biokit HSV-2 Rapid Assay” to improve the positive predictive value of Focus HerpeSelect HSV-2 ELISA. BMC Infect Dis 2005; 5:84.
25. Ashley-Morrow R, Nollkamper J, Robinson NJ, et al. Performance of focus ELISA tests for herpes simplex virus type 1 (HSV-1) and HSV-2 antibodies among women in ten diverse geographical locations. Clin Microbiol Infect 2004; 10:530–536.
26. Eing BR, Lippelt L, Lorentzen EU, et al. Evaluation of confirmatory strategies for detection of type-specific antibodies against herpes simplex virus type 2. J Clin Microbiol 2002; 40:407–413.
27. Crosby RA, Head S, DiClemente RJ, et al. Do protective behaviors follow the experience of testing positive for herpes simplex type 2? Sex Transm Dis 2008; 35:787–790.
28. Williams JR, Jordan JC, Davis EA, et al. Suppressive valacyclovir therapy: Impact on the population spread of HSV-2 infection. Sex Transm Dis 2007; 34:123–131.
29. Freeman EE, Weiss HA, Glynn JR, et al. Herpes simplex virus 2 infection increases HIV acquisition in men and women: Systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20:73–83.
30. Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008; 358:1560–1571.
31. Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: A randomised, double-blind, placebo-controlled trial. Lancet 2008; 371:2109–2119.
32. Celum C, Wald A, Lingappa J, et al. Twice-daily acyclovir to reduce HIV-1 transmission from HIV-1 / HSV-2 co-infected persons within HIV-1 serodiscordant couples: A randomized, double-blind, placebo-controlled trial [abstract no.WELBC101]. Paper presented at: 5th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 2009; Cape Town, South Africa.
33. White RG, Freeman EE, Orroth KK, et al. Population-level effect of HSV-2 therapy on the incidence of HIV in sub-Saharan Africa. Sex Transm Infect 2008; 84(suppl 2):ii12–ii18.
34. Vermund SH, Allen KL, Karim QA. HIV-prevention science at a crossroads: Advances in reducing sexual risk. Curr Opin HIV AIDS 2009; 4:266–273.