International Journal of srD & AIDS 1991; 2: 313-317
EDITORIAL REVIEW
Management of genital herpes simplex infection R N Thin MD FRCP Department of Genitourinary Medicine, (Sexually Transmitted Diseases), St Thomas' Hospital, London SEI 7EH, UK Summary: Herpes simplex infection of the genitals is a common condition, more often due to herpes simplex virus (H5V) type 2 than to type 1 virus. There is a severe first attack followed by mild recurrences which are more common and more frequent after H5V-2 than after H5V-1 genital infection. Clinical features with prodrome, vesicles and erosions may be characteristic allowing rapid clinical diagnosis. When possible laboratory confirmation should be attempted. General management includes simple hygiene, avoidance of sexual transmission, use of condoms, and notifying partners. Oral acyclovir (Zovirax, Wellcome) is the drug of choice for initial attacks and should be considered for all women with this diagnosis. Intravenous acyclovir may be used for very severe attacks. Men with initial attacks may be treated with oral acyclovir but mild disease affecting only skin may be treated with 5% acyclovir cream. Recurrences are short so acyclovir has less effect. Frequent recurrences can be troublesome and may be suppressed by continuous oral acyclovir, or individual attacks may be aborted with intermittent therapy. Various systemic complications may occur; an important but rare problem is primary herpes in late pregnancy. Acyclovir is effective in the treatment of the troublesome herpes simplex disease associated with human immunodeficiency infection. Acyclovir is one of the more expensive treatments for sexually transmitted diseases. At present in many countries costs are being examined, and application of the principles outlined here should help to minimize cost and maximize care. Keywords: Genital herpes simplex, management, acyclovir
INTRODUCTION
CLINICAL FEATURES
Genital herpes simplex infection is due to herpes simplex virus (H5V) and can be classified into types 1 and 2 by monoclonal antibody staining which is more convenient than techniques such as endonuclease restriction cleavage". Genital herpes is usually due to H5V-2 while oro-labial and ophthalmic infections are usually due to H5V-1. Transmission of H5V occurs during close contact with an infected person shedding virus from an infected lesion or secretion. H5V enters through the mucous membrane, or small cracks or other skin lesions, and ascends sensory nerves to the root ganglia where it establishes latent infection. Latency follows clinical and subclinical initial infection; and H5V 2 has been isolated from 53 and 54 sensory root ganglia-. Genital herpes has increased during recent years in a number of countries-. Its treatment may account for a large proportion of a clinic drug budget and a large proportion of non-salary expenditure, or may be a major expense for an infected individual. It is therefore timely to review the management of this condition.
Genital herpes is characterized by a severe first clinical attack followed by mild recurrences. The pattern of clinical features may allow an accurate clinical diagnosis, but this should be supported whenever possible by viral identification to maximize clinical acumen and ensure a firm basis for counselling, treatment, and partner notification. In genital herpes simplex the incubation period between infection and the first clinical feature has been reported as 1-26 days with a mean around 7 days3- 5, but may be much longer". First episode
Primary attack The first attack of genital herpes in someone who has had no previous H5V infection is severe, and is called the true primary attack. The age range at which this most commonly occurs is 18-25 years, the same as other sexually transmitted diseases (5TDs)7. Primary attacks often start with a prodrome comprising one to several days of malaise, fever, headache, general bone and muscle aches,
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root pains down the legs, and itch and irritation on the genitals. Widespread bilateral lesions appear on the genitals sometimes extending to the surrounding skin; they start as macules or maculopapules, rapidly become vesicles or vesicopustules, and ulcerate. Lesions appear in crops and are associated with lymphadenopathy developing a week or more after the lesions appear. Vaginal discharge may occur in women and urethral discharge in men. Lesions are sometimes seen on the cervix and rarely an acute necrotic cervicitis may be observed. Pharyngeal infection with a sore throat may occur. The whole episode takes a mean of 16.5 days in men and 19.5 days in women to complete re-epitheltalization-. A rise in titre of circulating antiherpes antibodies between acute and convalescent sera may support the diagnosis of a true primary attack-.
Non-primary first attack When there has been previous infection with HSV the first attack is milder but follows a similar pattern. For example, this will occur when HSV-2 genital infection follows HSV-1 oro-labial infection. In practice it may not be possible or worthwhile to test for circulating antibodies; in these circumstances the first attack can be called first episode or more simply initial genital herpes. Initial attacks are worse in women than in men. Recurrence Though genital herpes simplex is common there are few good studies on frequency of recurrence. During the first 12 months after the initial attack recurrence occurs in 90% of people infected with HSV-2 and in 60% of those with HSV-1 genital infection. After HSV-2 primary infection, a median of 5 episodes a year occur in the first 2 years-. Recurrence in HSV-1 genital infection is less common. The clinical pattern of a recurrent attack follows that of initial disease but is shorter. The prodrome lasts a few hours to 2 days, there is only one crop of lesions usually localized to an area about 1 cm in diameter, and healing is complete in 8-9 days". Recurrence may be more frequent in those who are anxious or under stress, may follow sexual intercourse, and in women may be related to the premenstruum or the onset of menstruationvv'", but attacks develop without any apparent precipitating factors. Episodes of symptoms may occur without lesions!'. Some women may fail to recognize recurrence and these episodes may be important in the spread of infection 12•
Asymptomatic viral shedding Between clinical recurrences HSV may occasionally be cultured from cervical swabs in women and urethral swabs in men, while virus may also be shed from lesions not visible on examination-. HSV-2 circulating antibodies are common among SID clinic
attenders; in addition unrecognized HSV-21esions may occur more often among those with HSV-1 and HSV-2 antibodies, than patients with HSV-2 antibodies alone-'. According to one report asymptobe associated with matic cervical shedding inguinal lymphadenopathy1 .
mal
MANAGEMENT
Diagnosis
Laboratory methods The first step in management is accurate diagnosis. Cell culture has been widely used but is time consuming and may be expensive. It is long established and is more sensitive and specific than other methods, so is the standard against which others are judged. Eighty per cent of positive cultures are detectable by visible cytopathic effect within 2 days, and more than 99% are detectable after 4 daysIs. Results may be available more rapidly by immunofluorescent or immunoperoxidase staining of cell cultures after 24 h 2 • Centrifugation-enhanced culture in shell vials also gives a result in 24 h and can be as sensitive as conventional cell culture and is highly specific-s, though not all laboratories have found it to be sensitive2. At present it is suggested as the most promising alternative to conventional isolation, and might produce savings for laboratories with heavy HSV workloads15. Immunofluorescence with monoclonal antibodies has been reported to have a sensitivity of 74% and specificity of 85% compared with viral isolation but may be more reliable when specimens are taken early in the course of the illness!", Enzyme immunoassay may be more sensitive than immunofluorescence for it detects intracellular and extracellular antigens, unlike immunofluorescence where infected cells must be collected in clinical specimens for reliable results. In one report an enzyme immunoassay kit showed a sensitivity of 95% and specificity of 100%18. Results with immunofluorescence and enzyme immunoassay give results within a few hours. Latex agglutination and electronmicroscopy lack sensitivity compared to isolationvl". DNA probes and the polymerase chain reaction (PCR) are coming into use in clinical laboratories and give rapid results1S,20 and PCR may be especially applicable to cerebrospinal fluid 2o. Cytology is also quick, and though lacking in sensitivity (30-80%), it is specific', and is useful in less developed countries. Another technique is enzyme assay of the virus transport medium used to transfer a specimen to the laboratory, though this appears to lack sensitivity-". Clinical diagnosis The clinical features are often characteristic allowing accurate clinical diagnosis. The natural history of prodrome, vesicles and ulceration, noted by an observant patient, are almost pathognomic.
Thin Management of genital herpes
The widespread distribution and crops of lesions in initial disease, and characteristic grouped or clustered lesions in recurrence are highly suggestive. Vesicles on the genitals are rarely due to other causes. Differential diagnosis Common causes of genital ulceration include trauma with or without secondary infection and erosive balanitis, but unlike herpes they have no prodrome or vesicles. In men scabies cause itchy erosions. Primary syphilis is painless, persistent and nontender unless there is secondary infection. Chancroid is common in many tropical areas and causes painful tender ulcers; they have characteristic irregular margins and are associated with large inguinal nodes (buboes). In genital herpes the nodes are only moderately enlarged; though there may be mild erythema of the overlying skin the nodes do not suppurate unless there is secondary infection. Other tropical conditions include donovanosis (granuloma inguinale) which has characteristic chronic flat spreading granulomas and inguinal swelling. Lymphogranuloma venereum is often mentioned in relation to genital ulceration but a genital lesion is rarely seen and the common manifestation is matted inguinal lymph node enlargement. Secondary syphilis causes erosions and other clinical features. Less common conditions include herpes zoster which has a characteristic distribution and appearance, reactive arthropathy or Reiter's syndrome (urethritis, arthritis and conjunctivitis) in which the non-genital features should indicate the diagnosis, Behcet's disease, Stevens-Johnson syndrome, Vincent's ulcers, and tuberculosis. General management (counselling) Once the diagnosis has been established, the disease should be explained to patients, including the natural history, sexual transmission and avoidance of sexual contact when lesions are present or suspected, and risk of neonatal infection. Regular cervical cytogical smears are still recommended though HSV appears only to be a co-factor in the development of cervical and other intraepithelial neoplasias-t. As with all STDs partner change should be minimized, and at-risk partners should be notified that they should seek medical advice. Condoms should be recommended to minimize transmission of asymptomatically shed virus and recent publicity over human immunodeficiency virus infection has made them more acceptable. Factors associated with recurrence must be discussed. Time spent counselling at this stage minimizes subsequent anxiety which may otherwise be disabling. Simple hygiene and counselling may be all that is required in patients with mild infrequent recurrences. Patients with initial attacks
315
and more severe or frequent recurrence need antiviral therapy. Antiviral therapy
Initial genital herpes Despite claims for various agents, only a guanine derivative acyclovir (Zovirax, Wellcome) has been consistently effective in double blind placebo controlled trials in the treatment of genital herpes-, Acyclovir acts by interrupting viral replication so is only effective early in each episode. It is available in intravenous, oral and topical formulations. In placebo controlled trials of intravenous acyclovir (5 mg/kg of body weight by slow infusion 8 hourly for 5 days) in initial disease, the duration of viral shedding, new lesion formation, local and systemic symptoms and time to healing were all significantly reduced23•24• Oral acyclovir (200mg 5 times daily for 5 days) has a similar effect25•26 . Acyclovir 5% cream 5 times daily till healing is complete or for a maximum of 10 days showed significant reductions in healing times and duration of viral shedding but had less effect on symptoms and new lesion formation than systemic therapy-", Intravenous therapy should be reserved for very severe initial disease and neurological complications, though it has only been studied in encephalitis. Oral therapy is suitable for all stages and all lesions. Cream should only be applied to skin lesions. Most patients with initial disease can be managed as outpatients provided they present early; women frequently have severe initial disease and routine treatment with oral acyclovir minimizes admission to hospital. A patient who presents early with an initial attack may appear to have mild disease but this may worsen without antiviral therapy. Cream may be suitable for men or women with a mild attack and external skin lesions. Recurrent genital herpes Recurrent genital herpes has a short course so therapy should start as soon as possible. Early studies of oral acyclovir failed to take account of this but statistically significant reductions in viral shedding, lesion duration and new lesion formation were reported-', Five per cent acyclovir cream also shortens healing times in recurrent disease-", Treatment of individual episodes has no effect on subsequent recurrence. So far there has been no report of sustained viral resistance after treatment in immunocompetent patients; resistant organisms have rarely been isolated during individual attacks and sensitive isolates have been recovered from the following episode-s. Suppressive therapy Five to 10% of patients with recurrent disease suffer frequent attacks (6-12 or more a year). Oral acyclovir 200 mg 2-5 times daily for 3 months to 3 or 4 years has been effective in suppressing frequent recurrence-". Multiple doses are more effective than
~
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International Journal of SID & AIDS Volume 2 September/October 1991
infrequent dosing; for example, 200 mg 4 times daily is more effective than 400 mg twice daily or 800 mg once daily30. In practice the daily dose should be reduced to the minimum that is effective for the individual. Therapy should be stopped every 6-12 months to reassess recurrence and the need for daily therapy. The treatment plan should be discussed with patients in advance so they understand that therapy will be stopped but restarted if required.
Delivery
When there is primary infection at parturition, Caesarian section should be considered for the risk of transmission to the fetus dUrin~ vaginal delivery has been estimated as 20-50% . When there is a history of recurrence careful clinical examination should be undertaken at the beginning of labour. If lesions are present specimens for laboratory investigation should be collected and Caesarian section considered though the probability Abortive therapy of fetal infection during vaginal delivery is only Another approach to patients with frequent recur- 0-8%39. Further development of rapid sensitive rence is based on the method of treating individual specific cheap easy laboratory detection of HSV will attacks described by Forsbeck et al.31 Patients carry allow more rational management. Repeated viroacyclovir tablets with them at all times and begin logical screening during the last few weeks of therapy at the start of the firstsymptom. Formaximum pregnancy is no longer recommended as it fails to effect time should be spent establishing the first identify those at risk, and is not cost effective40,41. symptom and identifying its onset. In this way 80% Recently a plea was made for large scale detailed of recurrences may be aborted or shortened by at least studies of women with and without genital herpes 50%; oral acyclovir 200mg 5 times daily or 400 mg to give sound data to provide a basis for reducing neonatal herpesv, Such studies would need to be twice daily for 5 days appear equally effective". multicentre and in countries with more cases than Tolerance Britain. Adverse effects are usually mild and infrequent. Acyclovir is not licensed for use in pregnancy but Intravenous therapy should be given by infusion has been given to more than 100 women without rather than bolus injection to avoid crystalluria. untoward effects! while anecdotal reports indicate Cream applied to large raw areas may give rise to many more women have received the drug without burning related to the base and not the drug29. adverse effects to the fetus. Systemic therapy has Several other guanine derivatives have been des- been advised for disseminated visceral infection in cribed and evaluated as inhibitors of herpes simplex pregnancy as this carries a high mortality-. virus in cell cultures and animal infections; one compound currently under clinicaltrial in human subjects Neonatal infection is a prodrug, famcyclovir(Smith Kline Beecham)32,33. Skin, eye and mouth disease affects 35% of infected neonates who have a good prognosis, encephalitis plus or minus skin eye or mouth disease affects 33% COMPLICAnONS who have an intermediate prognosis, and disComplications in immunocompetent patients in- seminated disease affects the remainder who have clude urinary difficulty and retention-", enceph- a poor prognosis36.43. When neonatal infection is alitis with HSV-l and meningitis with HSV-2, and suspected energetic management is indicated. rarely hepatitis, pneumonia, thrombocytopenia, or Specimens for laboratory confirmation should be other neurological disease'. There may also be a taken at once and intravenous acyclovir (10 mg per link with subsequent intraepithelial neoplasia and kg bodyweight B hourly) started without delay44. carcinoma though human papillomavirus appears to have a more important causative role 22,3!;. GENITAL HERPES AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION Pregnancy HSV infection at any site may reactivate in human The natural history of genital herpes is rarely altered immunodeficiency virus (HIV) infection, and the by pregnancy. A few cases of dissemination with more advanced the HIV disease the worse is the primary infection during pregnancy have been herpes. Chronic and progressive herpetic disease is reported. Primary infection in the first trimester a feature. Intravenous and oral acyclovir control has rarely been associated with spontaneous individual attacks though higher doses for longer abortion-", Estimations of primary HSV-2 infection courses may be needed. Continuous oral therapy per 1000 pregnancies in London were reported as may be required. Though no controlled studies have 2.4 in Asian women, 5 in white women and 20 in been reported to help to decide optimum regimens, black women". The main risk to the fetus is when acyclovir 400mg orally 3 or 4 times daily has proved a mother close to term develops primary genital effective". herpes. This may be followed by premature labour, intrauterine growth retardation, and neonatal References intection'". Infection usually occurs during vaginal delivery and may affect 1: 3000 to 1: 20,000 live 1 Fife KH, Corey L. Diagnostic testing for herpes simplex virus. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ, eds. births-,
Thin Management of genital herpes
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Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990:941-52 Corey L. Genital herpes. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner Pl. eds, Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990;391-414 Corey L, Spear PG. Infections with herpes simplex virus, part 1. N Engl J Med 1986;314:686-91 Thin RN. Management of genital herpes simplex infections. Am J Med 1988;85(2A):3-6 Mindel A. Herpes simplex infections. London: Springer-Verlag, 1989:50 Thin RN. Does first episode genital herpes have an incubation period? Int J STD AIDS 1991;2:285-6 Carroll BR. Prospective study of patients with herpes genitalis. University of London: MD Thesis, 1977:214,221 Whatley JD, Thin RN. Episodic acyclovir therapy to abort recurrent genital herpes simplex attacks. J Antimicrob Chemother 1991;27:677-81 Goldmeier D, Johnson A. Does psychiatric illness affect recurrence rate of genital herpes? Br I Vener Dis 1982;58:40-3 Mindel A. Herpe« simplex infections. London: Springer-Verlag, 1989;65 Sacks SL. Frequency and duration of patient-observed recurrent genital herpes simplex virus infection: characterisation of nonlesional prodrome. I Infect Dis 1984;150:873-7 Langenburg A, Benedetti J, Jenkins J, Ashley R, Winter C, Corey L. Development of clinically recognisable genital lesions among women previously identified as having 'asymptomatic' herpes simplex virus type 2 infection. Ann Intern Med 1989;110:882-7 Koutsky LA, Ashley RL, Holmes KK, et al. The frequency of unrecognised type 2 herpes simplex virus infection among women. Sex Transm Dis 1990;17:90-4 Barton SE, Wright LK, Link CM, Munday PE. Screening to detect asymptomatic shedding of herpes simplex virus (HSV) in women with recurrent genital HSV infection. Genitourin Med 1986;62:181-5 Lee PC, Hallsworth P. Rapid viral diagnosis in perspective. BM/1990;300:1413-18 Espy MJ, Smith TF. Detection of herpes simplex virus in conventional tube cell cultures and in shell vials with a DNA probe kit and monoclonal antibodies. I Clin Microbiol 1988;26:22-44 Lafferty WE, Krofft S, Remington M, et al. Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a highprevalence population. I Clin MicrobioI1987;2S:323-6 Dascal A, Chan-Thim ], Morahan M, Portnoy J, Mendelson J. Diagnosis of herpes simplex virus infection in a clinical setting by a direct antigen detection enzyme immunoassay kit. I Clin MicrobioI1989;27:700-4 Halstead DC, Beckwith DG, Sautter RL, Plosila L, Schneck K. Evaluation of a rapid latex slide agglutination test for herpes simplex virus as a specimen screen and culture identification method. I Clin MicrobioI1987;2S:936-7 Aurelius E, Johansson 5, Skoldenberg 5, Staland A, Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991;337:189-92 Verano L, Michalski FJ. Herpes simplex virus antigen direct detection in standard virus transport medium by Du Pont Herpchek enzyme-linked immunosorbent assay. I Clin MicrobioI1990;28:2555-8 Spear PG. Biology of the herpes viruses. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ, eds. Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990;379-89 Mindel A, Adler MW, Sutherland S, Fiddian AP. Intravenous acyclovir treatment for primary genital herpes. Lancet 1982;i:697-700
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24 Corey L, Benedetti J, Critchlow C, et al. Treatment of primary first-episode genital herpes simplex virus infections with acyclovir: results of topical, intravenous and oral therapy. I Antimicrob Chemother 1983;12B:79-88 25 Nilsen AE, Aasen T, Halsos AM, et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet 1982;ii:571-3 26 Bryson YJ, Dillon M, Lovett M, et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomised double blind controlled trial in normal subjects. N Eng11 Med 1983;308:916-21 27 Fiddian AP, Kinghorn GR, Goldmeier D, et al. Topical acyclovir in the treatment of genital herpes: a comparison with systemic therapy. I Antimicrob Chemother 1983;12B:67-77 28 Collins P. Viral sensitivity following the introduction of acyclovir. Am I Med 1988;85(2A):129-134 29 Davey PG. New antiviral and antifungal drugs. BMI 1990;300:793-8 30 Mindel A. Herpes simplex uirus. London: Springer-Verlag 1989:142 31 Ruhnek-Forsbeck M, Sandstrom E, Anderson B, et al. Treatment of recurrent genital herpes simplex infection with oral acyclovir. I Antimicrob Chemother 1985;16:621-8 32 Boyd MR, Bacon TH, Sutton D, Cole M. Antiherpes activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL39123) in cell culture. Antimicrob Agents Chemother 1987;31:1238-42 33 Hodge RAV, Sutton D, Boyd MR, Harnden MR, [arvest RL. Selection of an oral prodrug (BRL 422222810; famciclovir) for the antiherpes agent BRL 39123 [9-(4-hydroxy-3hydroxymethylbut-1-yl)guanine; penciclovir]. Antimicrob Agents Chemother 1989;33:1765-73 34 Oates JK, Greenhouse PRDH. Retention of urine in anogenital herpetic infection. Lancet 1978;i:691-2 35 Shah KV. Biology of human genital tract papillomaviruses. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ, eds. Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990:425-2 36 Stagno S, Whitley RJ. Herpes virus infection in the neonate and children. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ eds. Sexually transmitted diseases 2nd edn. New York: McGraw Hill, 1990;872-87 37 Ades AE, Peckham CS, Dale GE, Best }M, [eansson S. Prevalence of antibodies to herpes simplex virus types 1 and 2 in pregnant women, and estimated rates of infection. I Epidemiol Commun Health 1989;43:53-60 38 Brown ZA, Vontver LA, Benedetti J, et al. Genital herpes during pregnancy: risk factors associated with recurrences and asymptomatic shedding. Am I Obstet Gynecol 1985; 153:24-30 39 Arvin AM, Hensleigh PA, Prober CG, ei al. Failure of antepartum maternal cultures to predict the infant's risk of exposure to herpes simplex virus at delivery. N Engl] Med 1986;315:7%-800 40 Kelly J. Genital herpes during pregnancy. 8MI 1988; 297:1146-7 41 Whatley}D, Thin RNT. Herpes in pregnancy. Maternal Child Health 1990;15:326-30 42 Mercey DE, Mindel A. Preventing neonatal herpes? Genitourin Med 1991;67:1-2 . 43 Whitley R, Arvin A, Prober C, et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engll Med 1991;324~450-4 44 Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engll Med 1991:324:444-9
(Accepted 7 February 1991)
EDITORIAL REVIEW
Management of genital herpes simplex infection R N Thin MD FRCP Department of Genitourinary Medicine, (Sexually Transmitted Diseases), St Thomas' Hospital, London SEI 7EH, UK Summary: Herpes simplex infection of the genitals is a common condition, more often due to herpes simplex virus (H5V) type 2 than to type 1 virus. There is a severe first attack followed by mild recurrences which are more common and more frequent after H5V-2 than after H5V-1 genital infection. Clinical features with prodrome, vesicles and erosions may be characteristic allowing rapid clinical diagnosis. When possible laboratory confirmation should be attempted. General management includes simple hygiene, avoidance of sexual transmission, use of condoms, and notifying partners. Oral acyclovir (Zovirax, Wellcome) is the drug of choice for initial attacks and should be considered for all women with this diagnosis. Intravenous acyclovir may be used for very severe attacks. Men with initial attacks may be treated with oral acyclovir but mild disease affecting only skin may be treated with 5% acyclovir cream. Recurrences are short so acyclovir has less effect. Frequent recurrences can be troublesome and may be suppressed by continuous oral acyclovir, or individual attacks may be aborted with intermittent therapy. Various systemic complications may occur; an important but rare problem is primary herpes in late pregnancy. Acyclovir is effective in the treatment of the troublesome herpes simplex disease associated with human immunodeficiency infection. Acyclovir is one of the more expensive treatments for sexually transmitted diseases. At present in many countries costs are being examined, and application of the principles outlined here should help to minimize cost and maximize care. Keywords: Genital herpes simplex, management, acyclovir
INTRODUCTION
CLINICAL FEATURES
Genital herpes simplex infection is due to herpes simplex virus (H5V) and can be classified into types 1 and 2 by monoclonal antibody staining which is more convenient than techniques such as endonuclease restriction cleavage". Genital herpes is usually due to H5V-2 while oro-labial and ophthalmic infections are usually due to H5V-1. Transmission of H5V occurs during close contact with an infected person shedding virus from an infected lesion or secretion. H5V enters through the mucous membrane, or small cracks or other skin lesions, and ascends sensory nerves to the root ganglia where it establishes latent infection. Latency follows clinical and subclinical initial infection; and H5V 2 has been isolated from 53 and 54 sensory root ganglia-. Genital herpes has increased during recent years in a number of countries-. Its treatment may account for a large proportion of a clinic drug budget and a large proportion of non-salary expenditure, or may be a major expense for an infected individual. It is therefore timely to review the management of this condition.
Genital herpes is characterized by a severe first clinical attack followed by mild recurrences. The pattern of clinical features may allow an accurate clinical diagnosis, but this should be supported whenever possible by viral identification to maximize clinical acumen and ensure a firm basis for counselling, treatment, and partner notification. In genital herpes simplex the incubation period between infection and the first clinical feature has been reported as 1-26 days with a mean around 7 days3- 5, but may be much longer". First episode
Primary attack The first attack of genital herpes in someone who has had no previous H5V infection is severe, and is called the true primary attack. The age range at which this most commonly occurs is 18-25 years, the same as other sexually transmitted diseases (5TDs)7. Primary attacks often start with a prodrome comprising one to several days of malaise, fever, headache, general bone and muscle aches,
• 314
International Journal of SID & AIDS Volume 2 September/October 1991
root pains down the legs, and itch and irritation on the genitals. Widespread bilateral lesions appear on the genitals sometimes extending to the surrounding skin; they start as macules or maculopapules, rapidly become vesicles or vesicopustules, and ulcerate. Lesions appear in crops and are associated with lymphadenopathy developing a week or more after the lesions appear. Vaginal discharge may occur in women and urethral discharge in men. Lesions are sometimes seen on the cervix and rarely an acute necrotic cervicitis may be observed. Pharyngeal infection with a sore throat may occur. The whole episode takes a mean of 16.5 days in men and 19.5 days in women to complete re-epitheltalization-. A rise in titre of circulating antiherpes antibodies between acute and convalescent sera may support the diagnosis of a true primary attack-.
Non-primary first attack When there has been previous infection with HSV the first attack is milder but follows a similar pattern. For example, this will occur when HSV-2 genital infection follows HSV-1 oro-labial infection. In practice it may not be possible or worthwhile to test for circulating antibodies; in these circumstances the first attack can be called first episode or more simply initial genital herpes. Initial attacks are worse in women than in men. Recurrence Though genital herpes simplex is common there are few good studies on frequency of recurrence. During the first 12 months after the initial attack recurrence occurs in 90% of people infected with HSV-2 and in 60% of those with HSV-1 genital infection. After HSV-2 primary infection, a median of 5 episodes a year occur in the first 2 years-. Recurrence in HSV-1 genital infection is less common. The clinical pattern of a recurrent attack follows that of initial disease but is shorter. The prodrome lasts a few hours to 2 days, there is only one crop of lesions usually localized to an area about 1 cm in diameter, and healing is complete in 8-9 days". Recurrence may be more frequent in those who are anxious or under stress, may follow sexual intercourse, and in women may be related to the premenstruum or the onset of menstruationvv'", but attacks develop without any apparent precipitating factors. Episodes of symptoms may occur without lesions!'. Some women may fail to recognize recurrence and these episodes may be important in the spread of infection 12•
Asymptomatic viral shedding Between clinical recurrences HSV may occasionally be cultured from cervical swabs in women and urethral swabs in men, while virus may also be shed from lesions not visible on examination-. HSV-2 circulating antibodies are common among SID clinic
attenders; in addition unrecognized HSV-21esions may occur more often among those with HSV-1 and HSV-2 antibodies, than patients with HSV-2 antibodies alone-'. According to one report asymptobe associated with matic cervical shedding inguinal lymphadenopathy1 .
mal
MANAGEMENT
Diagnosis
Laboratory methods The first step in management is accurate diagnosis. Cell culture has been widely used but is time consuming and may be expensive. It is long established and is more sensitive and specific than other methods, so is the standard against which others are judged. Eighty per cent of positive cultures are detectable by visible cytopathic effect within 2 days, and more than 99% are detectable after 4 daysIs. Results may be available more rapidly by immunofluorescent or immunoperoxidase staining of cell cultures after 24 h 2 • Centrifugation-enhanced culture in shell vials also gives a result in 24 h and can be as sensitive as conventional cell culture and is highly specific-s, though not all laboratories have found it to be sensitive2. At present it is suggested as the most promising alternative to conventional isolation, and might produce savings for laboratories with heavy HSV workloads15. Immunofluorescence with monoclonal antibodies has been reported to have a sensitivity of 74% and specificity of 85% compared with viral isolation but may be more reliable when specimens are taken early in the course of the illness!", Enzyme immunoassay may be more sensitive than immunofluorescence for it detects intracellular and extracellular antigens, unlike immunofluorescence where infected cells must be collected in clinical specimens for reliable results. In one report an enzyme immunoassay kit showed a sensitivity of 95% and specificity of 100%18. Results with immunofluorescence and enzyme immunoassay give results within a few hours. Latex agglutination and electronmicroscopy lack sensitivity compared to isolationvl". DNA probes and the polymerase chain reaction (PCR) are coming into use in clinical laboratories and give rapid results1S,20 and PCR may be especially applicable to cerebrospinal fluid 2o. Cytology is also quick, and though lacking in sensitivity (30-80%), it is specific', and is useful in less developed countries. Another technique is enzyme assay of the virus transport medium used to transfer a specimen to the laboratory, though this appears to lack sensitivity-". Clinical diagnosis The clinical features are often characteristic allowing accurate clinical diagnosis. The natural history of prodrome, vesicles and ulceration, noted by an observant patient, are almost pathognomic.
Thin Management of genital herpes
The widespread distribution and crops of lesions in initial disease, and characteristic grouped or clustered lesions in recurrence are highly suggestive. Vesicles on the genitals are rarely due to other causes. Differential diagnosis Common causes of genital ulceration include trauma with or without secondary infection and erosive balanitis, but unlike herpes they have no prodrome or vesicles. In men scabies cause itchy erosions. Primary syphilis is painless, persistent and nontender unless there is secondary infection. Chancroid is common in many tropical areas and causes painful tender ulcers; they have characteristic irregular margins and are associated with large inguinal nodes (buboes). In genital herpes the nodes are only moderately enlarged; though there may be mild erythema of the overlying skin the nodes do not suppurate unless there is secondary infection. Other tropical conditions include donovanosis (granuloma inguinale) which has characteristic chronic flat spreading granulomas and inguinal swelling. Lymphogranuloma venereum is often mentioned in relation to genital ulceration but a genital lesion is rarely seen and the common manifestation is matted inguinal lymph node enlargement. Secondary syphilis causes erosions and other clinical features. Less common conditions include herpes zoster which has a characteristic distribution and appearance, reactive arthropathy or Reiter's syndrome (urethritis, arthritis and conjunctivitis) in which the non-genital features should indicate the diagnosis, Behcet's disease, Stevens-Johnson syndrome, Vincent's ulcers, and tuberculosis. General management (counselling) Once the diagnosis has been established, the disease should be explained to patients, including the natural history, sexual transmission and avoidance of sexual contact when lesions are present or suspected, and risk of neonatal infection. Regular cervical cytogical smears are still recommended though HSV appears only to be a co-factor in the development of cervical and other intraepithelial neoplasias-t. As with all STDs partner change should be minimized, and at-risk partners should be notified that they should seek medical advice. Condoms should be recommended to minimize transmission of asymptomatically shed virus and recent publicity over human immunodeficiency virus infection has made them more acceptable. Factors associated with recurrence must be discussed. Time spent counselling at this stage minimizes subsequent anxiety which may otherwise be disabling. Simple hygiene and counselling may be all that is required in patients with mild infrequent recurrences. Patients with initial attacks
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and more severe or frequent recurrence need antiviral therapy. Antiviral therapy
Initial genital herpes Despite claims for various agents, only a guanine derivative acyclovir (Zovirax, Wellcome) has been consistently effective in double blind placebo controlled trials in the treatment of genital herpes-, Acyclovir acts by interrupting viral replication so is only effective early in each episode. It is available in intravenous, oral and topical formulations. In placebo controlled trials of intravenous acyclovir (5 mg/kg of body weight by slow infusion 8 hourly for 5 days) in initial disease, the duration of viral shedding, new lesion formation, local and systemic symptoms and time to healing were all significantly reduced23•24• Oral acyclovir (200mg 5 times daily for 5 days) has a similar effect25•26 . Acyclovir 5% cream 5 times daily till healing is complete or for a maximum of 10 days showed significant reductions in healing times and duration of viral shedding but had less effect on symptoms and new lesion formation than systemic therapy-", Intravenous therapy should be reserved for very severe initial disease and neurological complications, though it has only been studied in encephalitis. Oral therapy is suitable for all stages and all lesions. Cream should only be applied to skin lesions. Most patients with initial disease can be managed as outpatients provided they present early; women frequently have severe initial disease and routine treatment with oral acyclovir minimizes admission to hospital. A patient who presents early with an initial attack may appear to have mild disease but this may worsen without antiviral therapy. Cream may be suitable for men or women with a mild attack and external skin lesions. Recurrent genital herpes Recurrent genital herpes has a short course so therapy should start as soon as possible. Early studies of oral acyclovir failed to take account of this but statistically significant reductions in viral shedding, lesion duration and new lesion formation were reported-', Five per cent acyclovir cream also shortens healing times in recurrent disease-", Treatment of individual episodes has no effect on subsequent recurrence. So far there has been no report of sustained viral resistance after treatment in immunocompetent patients; resistant organisms have rarely been isolated during individual attacks and sensitive isolates have been recovered from the following episode-s. Suppressive therapy Five to 10% of patients with recurrent disease suffer frequent attacks (6-12 or more a year). Oral acyclovir 200 mg 2-5 times daily for 3 months to 3 or 4 years has been effective in suppressing frequent recurrence-". Multiple doses are more effective than
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International Journal of SID & AIDS Volume 2 September/October 1991
infrequent dosing; for example, 200 mg 4 times daily is more effective than 400 mg twice daily or 800 mg once daily30. In practice the daily dose should be reduced to the minimum that is effective for the individual. Therapy should be stopped every 6-12 months to reassess recurrence and the need for daily therapy. The treatment plan should be discussed with patients in advance so they understand that therapy will be stopped but restarted if required.
Delivery
When there is primary infection at parturition, Caesarian section should be considered for the risk of transmission to the fetus dUrin~ vaginal delivery has been estimated as 20-50% . When there is a history of recurrence careful clinical examination should be undertaken at the beginning of labour. If lesions are present specimens for laboratory investigation should be collected and Caesarian section considered though the probability Abortive therapy of fetal infection during vaginal delivery is only Another approach to patients with frequent recur- 0-8%39. Further development of rapid sensitive rence is based on the method of treating individual specific cheap easy laboratory detection of HSV will attacks described by Forsbeck et al.31 Patients carry allow more rational management. Repeated viroacyclovir tablets with them at all times and begin logical screening during the last few weeks of therapy at the start of the firstsymptom. Formaximum pregnancy is no longer recommended as it fails to effect time should be spent establishing the first identify those at risk, and is not cost effective40,41. symptom and identifying its onset. In this way 80% Recently a plea was made for large scale detailed of recurrences may be aborted or shortened by at least studies of women with and without genital herpes 50%; oral acyclovir 200mg 5 times daily or 400 mg to give sound data to provide a basis for reducing neonatal herpesv, Such studies would need to be twice daily for 5 days appear equally effective". multicentre and in countries with more cases than Tolerance Britain. Adverse effects are usually mild and infrequent. Acyclovir is not licensed for use in pregnancy but Intravenous therapy should be given by infusion has been given to more than 100 women without rather than bolus injection to avoid crystalluria. untoward effects! while anecdotal reports indicate Cream applied to large raw areas may give rise to many more women have received the drug without burning related to the base and not the drug29. adverse effects to the fetus. Systemic therapy has Several other guanine derivatives have been des- been advised for disseminated visceral infection in cribed and evaluated as inhibitors of herpes simplex pregnancy as this carries a high mortality-. virus in cell cultures and animal infections; one compound currently under clinicaltrial in human subjects Neonatal infection is a prodrug, famcyclovir(Smith Kline Beecham)32,33. Skin, eye and mouth disease affects 35% of infected neonates who have a good prognosis, encephalitis plus or minus skin eye or mouth disease affects 33% COMPLICAnONS who have an intermediate prognosis, and disComplications in immunocompetent patients in- seminated disease affects the remainder who have clude urinary difficulty and retention-", enceph- a poor prognosis36.43. When neonatal infection is alitis with HSV-l and meningitis with HSV-2, and suspected energetic management is indicated. rarely hepatitis, pneumonia, thrombocytopenia, or Specimens for laboratory confirmation should be other neurological disease'. There may also be a taken at once and intravenous acyclovir (10 mg per link with subsequent intraepithelial neoplasia and kg bodyweight B hourly) started without delay44. carcinoma though human papillomavirus appears to have a more important causative role 22,3!;. GENITAL HERPES AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION Pregnancy HSV infection at any site may reactivate in human The natural history of genital herpes is rarely altered immunodeficiency virus (HIV) infection, and the by pregnancy. A few cases of dissemination with more advanced the HIV disease the worse is the primary infection during pregnancy have been herpes. Chronic and progressive herpetic disease is reported. Primary infection in the first trimester a feature. Intravenous and oral acyclovir control has rarely been associated with spontaneous individual attacks though higher doses for longer abortion-", Estimations of primary HSV-2 infection courses may be needed. Continuous oral therapy per 1000 pregnancies in London were reported as may be required. Though no controlled studies have 2.4 in Asian women, 5 in white women and 20 in been reported to help to decide optimum regimens, black women". The main risk to the fetus is when acyclovir 400mg orally 3 or 4 times daily has proved a mother close to term develops primary genital effective". herpes. This may be followed by premature labour, intrauterine growth retardation, and neonatal References intection'". Infection usually occurs during vaginal delivery and may affect 1: 3000 to 1: 20,000 live 1 Fife KH, Corey L. Diagnostic testing for herpes simplex virus. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ, eds. births-,
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Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990:941-52 Corey L. Genital herpes. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner Pl. eds, Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990;391-414 Corey L, Spear PG. Infections with herpes simplex virus, part 1. N Engl J Med 1986;314:686-91 Thin RN. Management of genital herpes simplex infections. Am J Med 1988;85(2A):3-6 Mindel A. Herpes simplex infections. London: Springer-Verlag, 1989:50 Thin RN. Does first episode genital herpes have an incubation period? Int J STD AIDS 1991;2:285-6 Carroll BR. Prospective study of patients with herpes genitalis. University of London: MD Thesis, 1977:214,221 Whatley JD, Thin RN. Episodic acyclovir therapy to abort recurrent genital herpes simplex attacks. J Antimicrob Chemother 1991;27:677-81 Goldmeier D, Johnson A. Does psychiatric illness affect recurrence rate of genital herpes? Br I Vener Dis 1982;58:40-3 Mindel A. Herpe« simplex infections. London: Springer-Verlag, 1989;65 Sacks SL. Frequency and duration of patient-observed recurrent genital herpes simplex virus infection: characterisation of nonlesional prodrome. I Infect Dis 1984;150:873-7 Langenburg A, Benedetti J, Jenkins J, Ashley R, Winter C, Corey L. Development of clinically recognisable genital lesions among women previously identified as having 'asymptomatic' herpes simplex virus type 2 infection. Ann Intern Med 1989;110:882-7 Koutsky LA, Ashley RL, Holmes KK, et al. The frequency of unrecognised type 2 herpes simplex virus infection among women. Sex Transm Dis 1990;17:90-4 Barton SE, Wright LK, Link CM, Munday PE. Screening to detect asymptomatic shedding of herpes simplex virus (HSV) in women with recurrent genital HSV infection. Genitourin Med 1986;62:181-5 Lee PC, Hallsworth P. Rapid viral diagnosis in perspective. BM/1990;300:1413-18 Espy MJ, Smith TF. Detection of herpes simplex virus in conventional tube cell cultures and in shell vials with a DNA probe kit and monoclonal antibodies. I Clin Microbiol 1988;26:22-44 Lafferty WE, Krofft S, Remington M, et al. Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a highprevalence population. I Clin MicrobioI1987;2S:323-6 Dascal A, Chan-Thim ], Morahan M, Portnoy J, Mendelson J. Diagnosis of herpes simplex virus infection in a clinical setting by a direct antigen detection enzyme immunoassay kit. I Clin MicrobioI1989;27:700-4 Halstead DC, Beckwith DG, Sautter RL, Plosila L, Schneck K. Evaluation of a rapid latex slide agglutination test for herpes simplex virus as a specimen screen and culture identification method. I Clin MicrobioI1987;2S:936-7 Aurelius E, Johansson 5, Skoldenberg 5, Staland A, Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991;337:189-92 Verano L, Michalski FJ. Herpes simplex virus antigen direct detection in standard virus transport medium by Du Pont Herpchek enzyme-linked immunosorbent assay. I Clin MicrobioI1990;28:2555-8 Spear PG. Biology of the herpes viruses. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ, eds. Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990;379-89 Mindel A, Adler MW, Sutherland S, Fiddian AP. Intravenous acyclovir treatment for primary genital herpes. Lancet 1982;i:697-700
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24 Corey L, Benedetti J, Critchlow C, et al. Treatment of primary first-episode genital herpes simplex virus infections with acyclovir: results of topical, intravenous and oral therapy. I Antimicrob Chemother 1983;12B:79-88 25 Nilsen AE, Aasen T, Halsos AM, et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet 1982;ii:571-3 26 Bryson YJ, Dillon M, Lovett M, et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomised double blind controlled trial in normal subjects. N Eng11 Med 1983;308:916-21 27 Fiddian AP, Kinghorn GR, Goldmeier D, et al. Topical acyclovir in the treatment of genital herpes: a comparison with systemic therapy. I Antimicrob Chemother 1983;12B:67-77 28 Collins P. Viral sensitivity following the introduction of acyclovir. Am I Med 1988;85(2A):129-134 29 Davey PG. New antiviral and antifungal drugs. BMI 1990;300:793-8 30 Mindel A. Herpes simplex uirus. London: Springer-Verlag 1989:142 31 Ruhnek-Forsbeck M, Sandstrom E, Anderson B, et al. Treatment of recurrent genital herpes simplex infection with oral acyclovir. I Antimicrob Chemother 1985;16:621-8 32 Boyd MR, Bacon TH, Sutton D, Cole M. Antiherpes activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL39123) in cell culture. Antimicrob Agents Chemother 1987;31:1238-42 33 Hodge RAV, Sutton D, Boyd MR, Harnden MR, [arvest RL. Selection of an oral prodrug (BRL 422222810; famciclovir) for the antiherpes agent BRL 39123 [9-(4-hydroxy-3hydroxymethylbut-1-yl)guanine; penciclovir]. Antimicrob Agents Chemother 1989;33:1765-73 34 Oates JK, Greenhouse PRDH. Retention of urine in anogenital herpetic infection. Lancet 1978;i:691-2 35 Shah KV. Biology of human genital tract papillomaviruses. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ, eds. Sexually transmitted diseases, 2nd edn. New York: McGraw Hill, 1990:425-2 36 Stagno S, Whitley RJ. Herpes virus infection in the neonate and children. In: Holmes KK, Mardh P-A, Sparling PF, Wiesner PJ eds. Sexually transmitted diseases 2nd edn. New York: McGraw Hill, 1990;872-87 37 Ades AE, Peckham CS, Dale GE, Best }M, [eansson S. Prevalence of antibodies to herpes simplex virus types 1 and 2 in pregnant women, and estimated rates of infection. I Epidemiol Commun Health 1989;43:53-60 38 Brown ZA, Vontver LA, Benedetti J, et al. Genital herpes during pregnancy: risk factors associated with recurrences and asymptomatic shedding. Am I Obstet Gynecol 1985; 153:24-30 39 Arvin AM, Hensleigh PA, Prober CG, ei al. Failure of antepartum maternal cultures to predict the infant's risk of exposure to herpes simplex virus at delivery. N Engl] Med 1986;315:7%-800 40 Kelly J. Genital herpes during pregnancy. 8MI 1988; 297:1146-7 41 Whatley}D, Thin RNT. Herpes in pregnancy. Maternal Child Health 1990;15:326-30 42 Mercey DE, Mindel A. Preventing neonatal herpes? Genitourin Med 1991;67:1-2 . 43 Whitley R, Arvin A, Prober C, et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engll Med 1991;324~450-4 44 Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engll Med 1991:324:444-9
(Accepted 7 February 1991)
