Herpes Simplex Virus Serology in an Asymptomatic Patient

STIs • CLINICAL PRACTICE Herpes simplex virus serology in an asymptomatic patient

Belinda Sheary, BMed, is a general practice registrar, Charlestown, New South Wales. [email protected] Linda Dayan, BMedSc, MBBS, MM (SexHlth), DipRACOG, MRCMA, FACSHP, is Director, Sexual Health Services, Northern Sydney Health, Head, Sexual Health Department, Royal North Shore Hospital, Clinical Lecturer, Department of Public Health and Community Medicine, University of Sydney, and a general practitioner, Sydney, New South Wales.

BACKGROUND Genital herpes is one of the most common Genital herpes is one of the most common Up to 80% of Australian adults are HSV-1 sexually transmitted infections. While sexually transmitted infections (STIs) in seropositive,5 with only a third reporting ever genital herpes can present with self Australia. It can be due to either HSV-1 or having a ‘cold sore’.5 HSV-1 genital herpes limiting genital lesions, most people HSV-2 infection. HSV-1 genital herpes is may be increasing in incidence, especially with genital herpes simplex virus (HSV) associated with infrequent outbreaks.1 HSV- in younger people. In a Melbourne study, infection are asymptomatic or have 2 is responsible for the majority of recurrent the proportion of first episode genital unrecognised infection. Use of type genital herpes.2 herpes due to HSV-1 increased from 15.8 to specific serology for HSV antibodies can Most people with genital HSV infection 34.9% of cases between 1980 and 2003.6 identify these individuals. are either asymptomatic or experience The rising incidence of HSV-1 genital herpes OBJECTIVE ‘unrecognised’ symptoms, and so genital HSV could be the result of decreasing HSV-1 This article discusses the role and use of infection often remains undiagnosed. Genital seroprevalence and consequently a larger HSV serology in asymptomatic patients, herpes remains stigmatised despite relatively susceptible population and/or an increase in including pre- and post-test counselling minor physical morbidity and the availability of the popularity of oral sex. and interpreting results. effective treatment to manage symptoms. HSV-2 DISCUSSION Type specific HSV serology has been The indications for HSV serology in an used in research settings to estimate the The presence of HSV-2 antibodies essentially asymptomatic patient are limited. Patients prevalence of HSV antibodies in different confirms genital HSV infection4,7 as oral tested for HSV antibodies require careful populations. In clinical practice, a diagnosis HSV-2 is uncommon without concomitant assessment and counselling. Identifying of asymptomatic HSV infection may result genital infection.4 HSV-2 seroprevalence has asymptomatic genital herpes should in greater patient harm than benefit. In ranged from 11–65% in Australian based ideally only be done in cases where there symptomatic patients, a direct detection test studies.5,8,9 Prevalence is higher in females, may be clinical benefit. Limitations of type specific HSV serology need to be from the lesion via culture, nucleic acid tests and increases with age and number of sexual 10 considered when interpreting the results (NAAT) such as polymerase chain reaction partners. in low risk patients. (PCR), or antigen testing (IF) is preferable as Less than 25% of HSV-2 seropositive they are site specific. people report a clinical diagnosis of genital herpes. 5,8,9 Unrecognised infection is Epidemiology of HSV antibodies common, however studies demonstrate HSV-1 that 50–60% of ‘asymptomatic’ HSV- HSV-1 seropositivity can indicate either 2 seropositive people can identify clinical oro-pharyngeal or genital infection. 3,4 outbreaks after an educational session.11,12

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Role of HSV serology in the after learning a partner has been diagnosed and antiviral therapy for asymptomatic carriers asymptomatic patient with genital herpes. The Australian Herpes is not indicated or available as a subsidised Management Forum suggest testing in this benefit on the PBS. Sexual health screening situation may provide useful information and A HSV-2 negative result indicates the The Australian Herpes Forum Management enable appropriate counselling regarding a patient is at risk of acquiring the infection, group advise against the use of HSV serology partner’s risk of acquiring HSV infection.13 and it is important to explain this risk cannot in asymptomatic people.13 In asymptomatic Pre-test counselling and estimating the pre- be eliminated (although condoms provide HSV infection there is often no direct benefit test probability is essential. women with some protection). If patients in making the diagnosis as there is no cure test positive for HSV-1 they could potentially Pre-test counselling and the infection is life long. Harm to the infect a partner with HSV-1 genital herpes by patient may take the form of psychosocial Pre-test counselling for HSV serology aims to performing oral sex if their partner is HSV-1 morbidity14 with HSV-2 positive patients often provide the patient with sufficient information seronegative. If they test negative for HSV-1 concerned about potential transmission to to give informed consent and prepare the they are at risk of acquiring HSV-1 genital sexual partners. While abstinence during patient for either a positive or negative result. herpes through receptive oral sex. clinical outbreaks, condoms and antiviral Exploring the reasons behind a patient request Interpretation of serology results therapy may reduce the risk of transmission for HSV serology may uncover pertinent in symptomatic infection, absolute elimination information, helping to tailor counselling to Table 1 provides an overview of the of risk is not possible. the individual. Patient anxiety, if present, terminology used in evaluating diagnostic In a study of HSV serodiscordant couples needs to be addressed. The relatively minor tests. Accurate interpretation of a HSV advised to abstain from sexual contact during nature of this common viral skin infection and serology result requires consideration of the HSV recurrences, transmission occurred in its lack of serious physical sequelae should patient’s sexual history (plus examination 3.8% and 16.9% of susceptible male and be emphasised. Pre-test discussion could findings, if relevant) and the type of test used. female partners respectively over 12 months.15 also include information on HSV prevalence Clinical history and examination Condoms offer significant protection against and the proportion of infected people with male to female transmission of HSV, but not asymptomatic genital herpes and discussion When requesting HSV serology, an adequate vice-versa.16 Suppressive antiviral therapy of the limitations of serology tests. sexual history is important to evaluate the with valaciclovir reduces HSV transmission by pre-test probability of a positive result. Pre- Significance of HSV serology results almost 50%.17 However, the Pharmaceutical test probability is the perceived probability Benefits Scheme (PBS) restricts the use of If HSV-2 positive, the result may impact on of a diagnosis in a patient by a clinician. The antiviral medications to people with moderate the patient’s current or future relationships, number of lifetime sexual partners and a to severe recurrent genital herpes confirmed as disclosure (and sometimes nondisclosure) history of genital lesions suggestive of via a direct detection test. (Microbiological to partners can create anxiety. Risk of HSV infection are both risk factors.2 Having confirmation is not required in cases where transmission to a partner cannot be eliminated a current or previous partner with genital suppressive treatment was commenced before May 2004). It has yet to be established whether Table 1. Overview of terminology used in evaluating diagnostic tests there is a public health benefit in identifying asymptomatic people infected with HSV. Disease present Disease absent However despite this, and the difficulties Test result positine True positive (TP) False positive (FP) discussed above, patients may still want Test result negative False negative (FN) True negative (TN) to be tested. Studies have shown a wide Sensitivity is the proportion of people with the disease who test positive. range of acceptance rates for HSV serology Sensitive tests enable a diagnosis to be ‘ruled out’ when the result is negative. Sensitivity = TP/(TP+FN) in asymptomatic patients. In one study, less Specificity is the proportion of those without a disease who test negative. than 40% of sexual health clinic patients Specific tests enable a diagnosis to be ‘ruled in’ when the result is positive. 18 agreed to be tested for HSV, while in Specificity = TN/(FP+TN) another, over 90% said they would want to Positive predictive value is the proportion of people with a positive result who truly know if they had the infection.19 have the disease. Positive predictive value = TP/(TP+FP) Asymptomatic partner Negative predictive value is the proportion of people who test negative who truly do not have the disease. Negative predictive value = TN/(FN+TN) Patients may want to know their HSV status

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herpes is also significant, with HSV-2 Low pre-test probability High pre-test probability seroprevalence ranging from 35–70% in this population.5,7,17 Clinical examples of varying pre-test probability are shown in Figure 1. 18 year old man 29 year old woman 42 year old divorced 45 year old woman Type of test used 2 lifetime sexual 6 lifetime sexual male, 10 estimates >30 Western Blot partners, neither partners, lifetime sexual lifetime sexual with known inconsistent partners, ex-wife partners, Western Blot is regarded as the gold genital herpes, condom use, of 17 years history of recurrent standard for HSV serology,18 however, as it condoms new partner had genital genital lesions, is an expensive and labour intensive test, used for has genital herpes, has diagnosed as it is performed in only a few reference contraception, herpes, never used having genital laboratories. There may be a direct cost to asymptomatic asymptomatic condoms, herpes by previous the patient. asymptomatic GP Glycoprotein G based type specific test Figure 1. Pre-test probability for HSV-2 seropositivity Enzyme linked immunosorbent assays (ELISA) �� based on the type specific antigen glycoprotein estimated incidence of 3.2/100 000 births.21 �� G (gG) are commercially available; gG-1 and It can be secondary to HSV-1 or HSV-2, and ��

gG-2 differentiate HSV-1 and HSV-2. Although is the most serious potential complication �� the sensitivity and specificity of glycoprotein of HSV infection, with high mortality and �� G tests is high, the positive predictive value morbidity.22 The risk of neonatal herpes is �� can be poor in low prevalence populations. less than 1% in women with known genital �� This problem is illustrated in Figure 2, herpes.23 �� which uses the example of a test with 96% � �� Potential indication in an asymptomatic �� sensitivity and 97% specificity. Stated in pregnant woman another way, the test has an unacceptable Figure 2. Positive predictive value of a test with 96% rate of false positives when used in low A pregnant woman with a sexual partner sensitivity and 97% specificity prevalence populations (Figure 3 ). Hence with known genital herpes may request �� patients who test positive and have a low HSV serology to determine if she is at risk �� pre-test probability for HSV-2 antibodies may of acquiring HSV during the pregnancy. It �� be advised to have a Western Blot to confirm may be appropriate in this clinical scenario �� 2 the result. to screen for HSV antibodies, as the risk of �� neonatal herpes is 30–50% in babies born � Post-test counselling �� to women who acquire HSV shortly before � �� Reiteration of some of the issues discussed labour,22–24 and feasible measures can be �� in pre-test counselling may be required. taken to minimise this risk. Figure 3. Rate of false positives in a test with 96% Normalisation of HSV infection is important, sensitivity and 97% specificity Implications of HSV antibody status in so reinforcing the high prevalence of HSV is a pregnant woman criteria is met [and will not eliminate risk appropriate. The morbidity associated with entirely]). If the woman is HSV-1 seronegative, genital herpes for many people is mostly If a woman is HSV-2 seropositive, she can and a sexual partner is HSV-1 seropositive, she psychosocial – not physical, and so the stigma be reassured the risk of neonatal herpes should be advised to refrain from receptive of genital herpes should be addressed. is low, as discussed above. If she is HSV- oral sex in the third trimester.23,24 2 seronegative, sexual partner/s should Role in couples planning pregnancy Medicolegal aspects of HSV testing also be tested. If a sexual partner is HSV-2 Neonatal herpes seropositive, she may be advised to abstain It is important that patients requesting Screening pregnant women and their from penetrative sex during the third trimester sexual health ‘screening’ and testing for partners for HSV antibodies to prevent or practise ‘safe’ sex.23,24 HSV-2 positive asymptomatic sexually acquired infections neonatal herpes is not considered cost partners could be prescribed suppressive not only understand which infections they are effective in a low prevalence population.20 therapy with valaciclovir (although this will having tests for, but also those for which they Neonatal herpes is rare in Australia, with an require a private prescription unless PBS are not and the reasons why.

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Conclusion 6. Tran T, Druce JD, Catton MC, Kelly H, Birch CJ. 21. Morris A, Ridley GF, Elliot EJ. Australian Paediatric Changing epidemiology of genital herpes simplex Surveillance Unit: progress report. J Paediatr Child virus infection in Melbourne, Australia, between Health 2002;38:8–15. In general, HSV serology is not recommended 1980 and 2003. Sex Transm Infect 2004;80:277–9. 22. Brown ZA, Benedetti J, Ashley R, et al. Neonatal as an STI screening test. Asymptomatic 7. Lowhagen G-B, Tunback P, Anderson K, Bergstrom herpes simplex virus infection in relation to patients requesting HSV serology need to T, Johannisson G. First episodes of genital herpes in asymptomatic maternal infection at the time of be counselled adequately about HSV, genital Swedish STD population: a study of epidemiology labour. N Engl J Med 1991;324:1247–52. herpes and the implications of both a positive and transmission by the use of herpes simplex virus 23. Brown ZA, Wald A, Ashley Morrow R, Selke S, Zeh and negative result. A sexual history is (HSV) typing and specific serology. Sex Transm J, Corey L. Effect of serologic status and caesarean Infect 2000;76:179–82. delivery on transmission rates of herpes simplex virus required to assess their pre-test probability 8. Bassett I, Donovan B, Bodsworth NJ, et al. Herpes from mother to infant. JAMA 2003;289:203–9. for a positive result. Patients considered low simplex virus type 2 infection of heterosexual 24. Brown ZA, Selke S, Zeh J, et al. The acquisition of risk for HSV-2 antibodies may potentially have men attending a sexual health centre. Med J Aust herpes simplex virus during pregnancy. N Engl J false positive results. 1994;160:697–700. Med 1997;337:509–15. 9. Butler T, Donovan B, Taylor J, et al. Herpes simplex AFP Summary of important points virus type 2 in prisoners, New South Wales, Australia. Int J STD AIDS 2000;11:743–7. 10. Fleming DT, McQuillan GM, Johnson RE, et al. • Genital herpes presents with self limiting Herpes simplex virus type 2 in the United States, genital lesions, but most people infected 1976–1994. New Engl J Med 1997;337:1105–11. are asymptomatic or have unrecognised 11. Langenberg A, Benedetti J, Jenkins J, Ashley R, infection. Winter C, Corey L. Development of clinically Correspondence • Treatment is not indicated for asymptomatic recognisable genital lesions among women previously Email: [email protected] identified as having ‘asymptomatic’ herpes simplex HSV infection. virus type 2 infection. Ann Int Med 1989;110:882–7. • In general, HSV serology is not 12. Wald A, Zeh J, Selke S, et al. Reactivation of recommended as a ‘screening’ test in genital herpes simplex virus type 2 infection in asymptomatic patients. asymptomatic seropositive persons. N Engl J Med • As genital herpes remains a chronic and 2000;342:844–50. stigmatised infection, pre-test counselling is 13. Australian Herpes Management Forum. The use important in asymptomatic patients. of type specific serology for the diagnosis of genital herpes. Available at: www.ahmf.com.au/health_ • Assessing pre-test probability in professionals/guidelines/serology.htm. asymptomatic patients is necessary. In low 14. Melville J, Sniffen S, Crosby R, et al. Psychosocial prevalence populations there is a higher rate impact of serological diagnosis of herpes simplex of false positive results. virus type 2: a qualitative assessment. Sex Transm Infect 2003;79:280–5. 15. Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey Conflict of interest: none declared. L. Risk factors for the sexual transmission of genital herpes. Ann Int Med 1992;116:197–202. References 16. Wald A, Langenberg AGM, Link KMS, et al. Effect 1. Sucato G, Wald A, Wakabayashi E, Viera J, Corey L. of condoms on reducing the transmission of herpes Evidence of latency and reactivation of both herpes simplex virus type 2 from men to women. JAMA simplex virus (HSV)–1 and HSV-2 in the genital 2001;285:3100–6. region. J Infect Dis 1998;177:1069–72. 17. Corey L, Wald A, Patel R, et al. Once daily 2. Copas AJ, Cowan FM, Cunningham AL, Mindel A. valaciclovir to reduce the risk of transmission of An evidence based approach to testing for antibody genital herpes. N Engl J Med 2004;350:11–20. to herpes simplex virus type 2. Sex Transm Infect 18. Mullan HM, Munday PE. The acceptability of 2002;78:430–4. the introduction of a type specific herpes antibody 3. Ashley RL. Sorting out the new HSV type specific screening test into a genitourinary medicine clinic antibody tests. Sex Transm Infect 2001;77:232–7. in the United Kingdom. Sex Transm Dis 2003;79: 4. Wald A, Ashley-Morrow R. Serological testing for 129–33. herpes simplex virus (HSV)–1 and HSV-2 infection. 19. Fairley I, Monteiro EF. Patient attitudes to type Clin Infect Dis 2002;35(Suppl 2):S173–82. specific serological tests in the diagnosis of genital 5. Tideman RL, Taylor J, Marks C, et al. Sexual and herpes. Genitourin Med 1997;734:259–62. demographic risk factors for herpes simplex type 1 20. Mindel A, Taylor J, Tideman RL, et al. Neonatal and 2 in women attending an antenatal clinic. Sex herpes prevention: a minor public health problem in Transm Infect 2001;77:413–5. some communities. Sex Transm Inf 2000;76:287–91.

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