Progress in Meeting Today s Demands in Genital Herpes: An Overview of Current Management

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1 S47 Progress in Meeting Today s Demands in Genital Herpes: An Overview of Current Management Raj Patel Department of Genito-Urinary Medicine, Royal South Hampshire Hospital, Southampton, United Kingdom Treatment of genital herpes requires accurate diagnosis, patient support, and effective treatment. Diagnosis is usually straightforward for classic presentations characterized by vesicular lesions but can be challenging for atypical presentations, which are more common. Diagnosis of asymptomatic infection requires access to molecular technology or type-specific serologic assays. Misconceptions about herpes simplex infection are common and patient education is essential. Patient concerns extend beyond disease frequency and severity the psychological impact should not be underestimated. Antiviral therapy is relevant at all stages of infection. Acyclovir, valacyclovir, and famciclovir are effective and well tolerated for genital herpes treatment. Continuous suppressive therapy controls all symptoms of recurrent disease and helps to relieve disease complications. The prodrugs valacyclovir and famciclovir offer easier, less-frequent dosing than required for acyclovir. Valacyclovir achieves effective suppression when taken once a day. Interventions to prevent genital herpes transmission and to control the global problem are urgently required. The impact of genital herpes is broad ranging, but particularly affects the infected person, immediate families, and society and poses a considerable economic burden on health care systems [1, 2]. The challenges of genital herpes and what effective management should strive for are reviewed elsewhere [3]. Such goals emanate from the perspectives of clinicians, the infected patients, and public health bodies. While some of the ideals have been achieved or are achievable in clinical practice today, some are only partially met. Despite extensive research efforts in recent years, vaccination for primary prevention of genital herpes simplex virus (HSV) type 2 infection is still not possible and reversal of HSV latency seems even farther away. Here I review current management practice in genital herpes, identify areas where improvements can be made in certain settings, and consider published findings that support the role and future potential of valacyclovir in light of other alternatives. My goal is to provide a practical evidence-based approach applicable predominantly to otherwise healthy immunocompetent adults, although I have included a short section on managing Presented in part: 4th Congress of the European Academy of Dermatology and Venereology, Brussels, October 1995 (abstract P187); 2d European Congress of Chemotherapy and 7th Biennial Conference on AntiinfectiveAgents and Chemotherapy, Hamburg, Germany, May 1998 (abstract M176). Financial support: honoraria for consultancy and funding for clinical research from GlaxoSmithKline under its present or former names (Wellcome Research Laboratories, UK; GlaxoWellcome R & D, UK and USA); 3M Pharmaceuticals (consultant). Reprints or correspondence: Dr. Raj Patel, Dept. of Genito-UrinaryMedicine, Royal South Hampshire Hospital, Brintons Terrace, Southampton, Hampshire SO14 OYG, United Kingdom (rp_suht@ .msn.com). The Journal of Infectious Diseases 2002;186(Suppl 1):S by the Infectious Diseases Society of America. All rights reserved /2002/18608S-0006$15.00 herpes in patients infected with human immunodeficiency virus (HIV). Effective management of genital herpes at the individual patient level relies on accurate and prompt diagnosis, the sharing of relevant and factual information, a psychosocial assessment of the impact of a diagnosis on the patient, and the appropriate use of antiviral therapy. Clinicians and patients need to appreciate the implications of genital herpes, whether or not the infection is symptomatic, and that the prevalence of HSV-2 infection is increasing in most regions of the world. Genital Herpes Diagnosis Although genital ulceration can be attributed to many causes, recognition of classic primary herpes infection or typical recurrent disease is usually straightforward. The classic lesions are papules that form shallow vesicular ulcers, which then scab and reepithelialize. One challenge is that few patients present with typical disease. Nonclassical (atypical) presentations are more common, and genital HSV infection (type 1 or type 2) should be considered routinely in the investigation of any patient with genital lesions or recurrent genital symptoms. The ability to confirm one s suspicions with an objective diagnostic test is essential. Genital HSV-2 infection may be associated with other sexually transmitted agents. At the time of genital herpes diagnosis, it is appropriate to consider risks and to instigate a range of investigations for other sexually transmitted pathogens. Diagnostic testing in genital HSV infection should allow uncertainties to be dispelled and subsequently for counseling to be patient specific and focused rather than hypothetical. In turn, this helps the patient make the necessary psychological and behavioral adjustments. The most widely used diagnostic test for patients presenting

2 S48 Patel JID 2002;186 (Suppl 1) with evidence of genital lesions is viral culture, which preferably should be type specific. If virus typing for HSV-1 and -2 is available, a degree of prognostication regarding recurrence frequency is possible [4]. The main disadvantage of viral culture is that results are not available for a few days, thus prolonging the period of anxiety for the patient facing a possible diagnosis of herpes and the need for a return visit to the physician for results. If the culture is positive, the physician should review the initial effectiveness of prescribed therapy and encourage the patient to participate in counseling programs. A rapid pointof-care antigen detection test would be a distinct advance in the diagnosis of genital herpes. It would offer more immediate diagnostic certainty, ensure prescription of the most relevant therapy, and prompt an earlier start to patient support initiatives. Selection of the diagnostic test should be tailored to the patient s situation. If genital lesions are apparent, direct detection tests on swabs of genital lesions are most relevant. In addition to viral culture, antigen tests such as EIA or the virus typespecific DNA polymerase chain reaction technique can be used. Atypical presentation of genital HSV infection, often characterized by recurrent bouts of genital discomfort without physical signs that are not satisfactorily managed from the patient s perspective, requires a more creative approach. Type-specific serologic testing may provide useful diagnostic insight. The point-of-care type 2-specific POCkit-HSV-2 test (Diagnology) is approved by the US Food and Drug Administration (FDA) for use in adults and is available in a number of other countries. Similarly an ELISA and immunoblot test (Focus Technologies) have been approved by the FDA, even for use in pregnant women. The availability and performance of type-specific serology tests for prior HSV infection has improved in recent years, although care must be taken to interpret results in a meaningful way in some situations (e.g., a positive result in a low-risk patient). Caution should also be exercised when considering serologic testing in suspected true primary genital HSV infection, since seroconversion can take up to 12 weeks and tests vary in their ability to detect the relevant HSV antibodies [5 7]. False-positive and false-negative results occur. The proportion of potentially misleading results is influenced by two factors: the sensitivity and specificity of the test and the prevalence of HSV infection in the patient s population group. In general, for any one test, the ability to correctly identify infection increases as the prevalence of infection increases; the higher the sensitivity and specificity of the test, the more likely it is to give an accurate result. These are the primary contributory factors to the positive predictive value of diagnostic tests. First-Episode Genital HSV Infection The first episode of HSV infection is frequently a systemic illness associated with vesicular ulcerative lesions and a prolonged disease course that may last up to 21 days. True primary genital herpes, defined as the first episode of genital herpes when the patient has no preexisting antibodies against HSV-1 or -2, is usually severe and prolonged [8, 9]. In the presence of antibodies against HSV-1, first episodes of genital HSV-2 infection are usually milder and defined as nonprimary [8]. Although most patients with first-episode disease have an uncomplicated course of infection, hospitalization may be required for urinary retention, meningism, or severe constitutional symptoms in association with adverse social circumstances. In the United Kingdom, if catheterization is required, suprapubic catheterization is preferred, both on practical and theoretical grounds (to prevent ascending infection). If a first episode is untreated, the patient may develop general (systemic) or local complications such as headache, photophobia, neck stiffness, and difficulty urinating. Antiviral therapy is normally highly effective and should be instigated in first-episode genital herpes on clinical suspicion alone. Supportive measures are important for keeping the patient comfortable and for preventing some complications. Analgesics, antipyretics, and the encouragement of hydration are usually necessary. Saline bathing of the local area and care with keeping lesions clean and dry should minimize the risk of superinfection and should help reduce the formation of adhesions. Topical ointments (e.g., steroids and antibiotics) are usually not recommended. Because of their limited effectiveness [10, 11], topical antivirals cannot be recommended for treatment of firstepisode genital herpes. Occasionally, severe external dysuria uncontrolled by analgesics will benefit from the judicious use of topical anesthetics. As these agents frequently cause sensitization and are known to delay healing, routine use should be avoided. Antiviral therapy with oral acyclovir, its prodrug valacyclovir, or with famciclovir, is effective in treating first-episode genital herpes. A large, randomized, double-blind trial of valacyclovir (1000 mg twice/day) versus acyclovir (200 mg 5 times/ day) showed valacyclovir to be as effective as acyclovir on lesion healing, loss of pain, and viral shedding [12]. Valacyclovir (500 mg twice/day) is considered sufficient for acute treatment of first-episode genital herpes because the plasma acyclovir concentrations following 500 mg twice a day therapy are higher than after oral acyclovir (200 mg 5 times/day) for 20 of 24 h and provide about twice the daily acyclovir exposure (daily area under the concentration-time curve, 99.5 and 49.3 mm.h for valacyclovir and acyclovir, respectively) [13, 14]. The efficacy of 500 mg twice a day therapy would, therefore, be expected to be equivalent to that of the widely approved 1000 mg twice a day regimen as recently confirmed in a study of valacyclovir [15]. Preliminary communications on famciclovir in first-episode genital herpes suggest that 250 mg 3 times a day for 5 days provides acceptable efficacy [16, 17], although famciclovir is not licensed for treatment of first-episode genital herpes in the United States. Use of prodrugs such as valacyclovir and

3 JID 2002;186 (Suppl 1) Management of Genital Herpes S49 famciclovir allows considerable simplification of the therapeutic regimens compared with the 5 times a day oral acyclovir regimen. Although trials of antiviral therapy in first-episode genital herpes have usually been conducted in patients presenting and commencing treatment within a few days (3 5) of the onset of clinical signs and symptoms, it is generally accepted that some benefits of treatment will extend to all patients whose symptoms have not completely resolved. The recommended duration of treatment appears to be led by clinical convention (5 10 days). If the shorter 5-day course of therapy is initially prescribed, it is important to evaluate the patient towards the end of treatment and to continue therapy if new lesions continue to form, if complications develop, or if systemic features have not settled. The establishment of HSV latency is thought to occur early in the course of primary infection [18, 19]. Treatment of a first episode of genital herpes with either oral or intravenous acyclovir has not been shown to influence the subsequent development of recurrent herpes [20, 21]. The only indication for the use of intravenous therapy is when the patient is unable to swallow or tolerate oral medication. There has been considerable recent interest as to whether high dosages of valacyclovir and famciclovir, as prodrugs of the nucleoside analogues acyclovir and penciclovir, administered early in the course of true primary genital HSV infection can affect HSV-2 latency and reactivation dynamics and, thus, limit the number and/or severity of subsequent recurrences. The hypothesis was generated by results from studies in the mouse ear pinna model of HSV infection, which showed some differential effects on HSV-1 and -2 titers within sensory ganglia after administration of valacyclovir and famciclovir [22 24]. However, studies in another model, the mouse eye, showed no differences between the agents [25]. A randomized controlled clinical trial also found no evidence for any long-term effect on recurrence frequency with high-dose prodrug therapy (valacyclovir, 1000 mg twice/day; famciclovir, 750 mg twice/day) for true primary genital herpes [26]. There is currently no basis for recommending anything other than standard doses of antivirals for the treatment of firstepisode genital HSV infection in immunocompetent persons. The choice between acyclovir and a particular prodrug should be based on local factors with considerations of price, patient acceptability, and compliance being paramount. Counseling of patients with first-episode genital herpes should include a discussion of possible source(s) of infection, provision of information on the natural history of HSV infection, including the risk of subclinical viral shedding, the risk of transmission (sex, other), and treatment options for future recurrences. The role and value of partner notification is unclear, although it would identify undiagnosed symptomatic cases who could be taught to recognize herpes episodes [27, 28]. However, to what extent this identifies a significant level of untreated illness or whether such a strategy would limit the spread of infection is disputed. When recurrences become evident, patients should be educated in early correct identification and management. Some may benefit from participation in patient support groups. There is considerable misinformation about the risks of HSV transmission from an infected woman to a fetus during pregnancy, and women should be reassured and encouraged to inform obstetricians and midwives of a history of genital herpes. They should be advised that HSV-associated risks exist throughout pregnancy (e.g., miscarriage in early pregnancy, prematurity, and vertical transmission of infection) [29]. Infected male partners should also be warned of the dangers of genital HSV transmission to their uninfected female partners since genital herpes acquired during the third trimester carries a significant risk of transmission during delivery[30]. Recurrent Genital Herpes In a patient with a prior diagnosis of genital herpes, the appearance of new vesicular genital lesions is usually indicative of HSV reactivation. In patients who lack a differential diagnosis at this stage, the opportunity to confirm the virus etiology should be taken. The high proportions of asymptomatic and unrecognized infections, plus the wide range of symptoms that characterize the clinical presentation of genital herpes are key contributors to underdiagnosis [31 33]. Most persons can be taught to recognize mild and some atypical symptoms of genital HSV recurrences [27, 28]. They should understand that asymptomatic or nonlesional shedding will occur in most cases of mild recurrent disease outbreaks. Patients with mild or asymptomatic infection may be more highly motivated to participate in sessions to help them detect the signs of a recurrent herpes episode if they understand the importance of asymptomatic shedding in disease transmission and also the greater benefit of episodic antiviral therapy if initiated early in the course of a recurrent outbreak. Recognized symptomatic herpes recurrences are characterized by high levels of infectivity, but the importance of infectivity remaining between symptomatic outbreaks cannot be overemphasized since most sexual HSV transmission occurs during asymptomatic periods. Strategies for avoiding sexual contact during lesional episodes or using barriers only occasionally are likely to be less effective in reducing the risk of genital HSV infection than regular condom use [34, 35]. However, even regular condom use may not be a foolproof strategy [36, 37]. When first-episode and recurrent genital herpes were compared, a series of differences were identified including symptom severity, viral reactivation patterns, and psychological aspects. This leads to somewhat different recommendations for treatment. The immediate psychological impact of a diagnosis of first-episode genital herpes should not be assumed to be com-

4 S50 Patel JID 2002;186 (Suppl 1) Table 1. Comparative efficacy of valacyclovir and acyclovir as episodic therapy for recurrent genital herpes. Regimens compared Hazard ratio (95% confidence interval), P Episode duration a Healing time b Valacyclovir 1000 mg 2 /day vs. placebo 1.76 ( ),! ( ),! mg 2 /day vs. placebo 1.94 ( ),! ( ),! mg 2 /day vs. acyclovir 200 mg 5 /day 0.93 ( ),.34 c 0.96 ( ),.62 c Acyclovir 200 mg 5 /day vs. placebo 1.71 ( ),! ( ).!.001 NOTE. Data are from [14, 43, 44] and Barber J (personal communication). a Defined as total duration of all signs and symptoms (intent-to-treat analysis). b Time to complete healing of vesicular lesions (excludes patients with aborted lesions). c Not significant. parable to that of symptomatic disease persisting over a number of years [38, 39]. For most patients, genital herpes recurrences are self-limiting and the symptoms they cause are generally considered minor by clinicians. Classic recurrences usually appear short-lived and are characterized by a few lesions that heal within 7 days. Decisions about how best to manage clinical recurrences ideally should be made by the physician in partnership with the patient. Treatment strategies include episodic and suppressive antiviral therapy. After explaining the benefits of antiviral therapeutic options, some patients with recurrent herpes may opt for a trial period of supportive measures only (e.g., good hygiene, general health care, and lifestyle) with analgesics as required. The most appropriate strategy for an individual is expected to vary over time and is influenced by recurrence frequency, symptom severity, and relationship status. Most persons with genital herpes adjust psychologically to the diagnosis and develop successful coping strategies, although recurrences may slow down or prevent this process. Thus, at each physician consultation attention should be paid to the patient s psychological well being. There should be appropriate referral for support or counseling as necessary. Antiviral therapy itself has a significant role in supporting psychological adjustment to the symptoms of recurrent herpes [39, 40]. A major concern with genital herpes, the most common cause of genital ulcer disease, is its role in facilitating the acquisition and transmission of HIV infection. Considerable biologic and epidemiologic evidence links genital herpes with HIV transmission. Epidemiologic studies have found a strong association between HIV and HSV-2 seropositivity [41, 42]. Furthermore, detection of HIV RNA in HSV-2 lesions suggests that HIV transmission is enhanced in the presence of HSV-2 [43]. Although not proven, interventions to control HSV recurrences may be expected to limit this risk. Clinical trials of suppressive antiviral therapy are needed. Episodic antiviral therapy for recurrent disease. Acyclovir, valacyclovir, and famciclovir are approved in most countries for the episodic treatment of genital herpes outbreaks. Compared with dosages of acyclovir 5 times a day, valacyclovir and famciclovir offer the advantages of convenience and discretion in twice-daily administration. Early trials of acyclovir (200 mg 5 times/day for 5 days) as episodic therapy for genital herpes showed clearly measurable benefits. Median reductions of 30 h in lesion healing and h in pain or discomfort were demonstrated in large placebo-controlled studies in unselected patients, persons who did not necessarily perceive the early signs of an HSV outbreak (prodrome) before starting treatment. Consequently, these studies may underestimate the likely impact of therapy in patients who can recognize early disease. Clinical trials of acyclovir demonstrate the importance of starting therapy early in the course of a recurrent herpes attack. Significantly improved results (vs. placebo) were seen in duration of viral shedding and time to crusting and healing when oral acyclovir was self-initiated by patients at the onset of prodrome or at the earliest symptoms compared with physicianinitiated treatment starting within 48 h of a recurrence [44, 45]. In order to ensure maximum benefit of episodic antiviral therapy, patients should be advised to carry their medication with them and to start a treatment course as soon as a recurrence is suspected. The efficacy and safety of valacyclovir were originally evaluated in 3 randomized double-blind controlled trials in which patients were required to self-initiate treatment within 24 h of the first signs or symptoms of a recurrent herpes outbreak [14, 46, 47]. Valacyclovir (500 or 1000 mg twice/day) and acyclovir (200 mg 5 times/day) administered for 5 days rapidly terminated HSV shedding, significantly accelerated lesion healing, and reduced the total duration of symptoms and signs (episode duration) compared with placebo [46, 47]. Another study showed no differences between valacyclovir (500 mg twice/day) and acyclovir (200 mg 5 times/day) on these end points [14]. Table 1 summarizes the study results by meta-analysis of the clinical end points. A placebo-controlled study of famciclovir (125 mg twice/day for 5 days) also demonstrated efficacy in lesion healing, symptom resolution, and viral shedding [48]. Patients were required to initiate treatment within 6 h of the first symptoms of a genital herpes recurrence. When acyclovir (200 mg 5 times/day for 5 days) was compared with famciclovir (125 mg twice/day) in a protocol requiring treatment initiations within 12 h of first

5 JID 2002;186 (Suppl 1) Management of Genital Herpes S51 symptoms of a recurrence, the 2 drugs had similar healing and symptom resolution rates [49]. An additional benefit was recently described for valacyclovir. The meta-analysis shown in table 1 utilized data on episode duration (all patients, n p 2926) and lesion healing, applicable to the subgroup whose herpes lesions progressed to the vesicle stage before healing ( n p 2219, 76%), thus identifying persons whose clinical outcome was an aborted lesion. An aborted lesion is defined as one that did not progress beyond the papule stage. Odds ratios (ORs) for the probability of herpes lesions aborting for both valacyclovir regimens (500 or 1000 mg twice/ day) compared with placebo were statistically significant, whereas the OR for acyclovir was not (table 2) [50]. The recommended valacyclovir regimen of 500 mg twice a day was associated with a 44% increased likelihood of lesions aborting. Another study of valacyclovir confirmed the logic of prompt valacyclovir treatment being associated with better clinical outcome. Analysis of aborted lesion rates in relation to the time of treatment initiation shows that the chance of genital herpes lesions aborting increases almost two-fold when treatment commences within 6 h of symptom onset compared with after 6 h (OR, 1.93; 95% confidence interval [CI], ) [51]. This benefit of valacyclovir was not seen by prospective analysis of controlled studies of acyclovir nor has it been described for famciclovir. It is an important benefit for patients too, since an aborted lesion as a clinical outcome means prevention of the development of painful vesicular lesions that must scab before healing. In controlled trials of antiviral treatment of recurrent genital herpes, the median duration of viral shedding in placebo-treated patients is 4 or 5 days [46 48]. With antiviral treatment, this is reduced to 2 or 3 days [14, 46 48]. Two recent studies investigated the feasibility of episodic valacyclovir therapy for 3 days and compared it with the conventional 5-day regimen, although neither study was placebo controlled [51, 52]. Overall, the 3-day regimen was as effective as treatment for 5 days (valacyclovir 500 mg twice/day) for the relief of clinical features of disease: Lesion healing required days and pain lasted days (median values across both studies and regimens). HSV shedding, monitored only in 1 study [51], persisted for a median of 1.8 days for the 5-day treatment group and 1.7 days for the 3-day group. Lesion abortion rates of about 25% were observed in both studies [51, 52]. Although potentially attractive, 3-day therapy courses should at present be used with caution, especially in patients with severe symptoms or prolonged recurrences where viral shedding and infectivity persist longer and for whom 5-day regimens are better tested. In all subjects prescribed episodic therapy, the therapeutic strategy should be reevaluated after a few courses to ensure that treatment is being used appropriately and that the patient is benefiting from therapy. The psychological reminder of a lifelong infection when genital herpes recurrences occur has a deleterious effect on many patients, which should prompt the Table 2. Comparative efficacy of valacyclovir and acyclovir in preventing development of vesicular lesions (aborting genital herpes lesions). Treatment regimen Probability of lesions aborting: odds ratio (95% confidence interval), P Valacyclovir 1000 mg 2 /day vs. placebo 1.31 ( ), mg 2 /day vs. placebo 1.44 ( ), mg 2 /day vs. acyclovir 200 mg 5 /day 1.02 ( ),.89 a Acyclovir 200 mg 5 /day vs. placebo 1.24 ( ),.18 a NOTE. Data are from [50]. a Not significant. physician to consider treatment alternatives. Episodic therapy is of limited benefit to patients with severe prodromal symptoms, such as those in whom HSV reactivation is associated with severe lumbar or sciatic nerve pain, in patients unable to recognize the early signs of a pending herpes outbreak, and in those who have the established features of psychosexual problems. These patients are better managed with continuous suppressive therapy. Continuous suppressive antiviral therapy. Suppressive therapy for recurrent genital herpes is highly effective for controlling all of the clinical features of the disease and can impact on a number of troublesome complications of infection. Trials of antiviral therapy have generally been conducted only in patients with 6 recurrences per year, but this has largely been for logistical and statistical reasons. Some patients with fewer recurrences will benefit from continuous suppressive therapy. When instigating suppressive therapy, it is important to review the patient s expectations of treatment and explain how therapy works, what it will achieve, and, of importance, what it will not. Patients can be safely advised that well-timed regular therapy should substantially reduce the frequency of recurrences. They should be told that suppressive therapy is not a cure for latent HSV infection and that, although it does not affect the natural history of recurrent disease, they may notice fewer recurrences (compared with the number before therapy) after suppression is discontinued. The patient should be encouraged to keep a record of any breakthrough episodes and to bring this to the next review, since an adjustment in treatment may be required. Women at risk of conception should be told to avoid pregnancy during therapy. Some controlled randomized trials for suppression have compared valacyclovir with acyclovir and placebo and acyclovir and famciclovir with placebo [53 57]. Although there is no direct head-to-head comparison of all 3 agents, the comparative data suggest that, at the approved dosages, these agents have comparable efficacy and prevent at least 70% of symptomatic recurrences over 1 year (figure 1). Recommended regimens of oral acyclovir for suppression of recurrent genital herpes vary in different countries; 400 mg twice a day is the most widely prescribed, but 200 mg 3 times a day is also common. Although highly effective, regimens should

6 S52 Patel JID 2002;186 (Suppl 1) Figure 1. Relative efficacy of suppressive therapy for genital herpes: valacyclovir, acyclovir, and famciclovir vs. placebo. Dosages are once a day (od) or twice a day (bd). Data from [53 57]. ideally meet the patient s need for simple dosing [58]. Famciclovir is more effective if administered twice a day [56]; valacyclovir is efficacious in 500- or 1000-mg once daily regimens [54, 55]. Genital herpes can be effectively controlled in most patients with valacyclovir dosages of 500 mg once a day since the average frequency of genital herpes outbreaks is about 5 a year for males and 4 a year for females [59]. The minority who has more frequent outbreaks may derive greater benefit from either valacyclovir 1000 mg once/day or 250 mg twice/day; the latter regimen is an approved alternative in some countries outside the United States [55]. Once daily regimens of either acyclovir or famciclovir are not considered sufficiently effective and cannot be recommended for routine clinical use [56, 60]. Pharmacokinetic-pharmacodynamic analysis of the large dose-ranging study in which patients with recurrent genital herpes were randomized to suppressive therapy with valacyclovir, acyclovir, or placebo for 1 year identified a close relationship between key plasma acyclovir pharmacokinetic parameters and observed efficacy (figure 2) [61]. Valacyclovir regimens that maintain plasma acyclovir concentrations above the acyclovir in vitro IC 50 value for HSV-2 for 8.8 h a day (i.e., 500 mg/ day as a single or divided dose) provide efficacy comparable to that of the widely used acyclovir regimen of 400 mg twice a day. Some patients may have breakthrough herpes episodes during suppressive therapy. Usually, these are infrequent and short lived but, if troublesome, episodic antiviral treatment can be instigated. If frequent breakthrough attacks continue despite the patient being fully compliant with the suppressive regimen, HSV should be cultured to confirm the nature of the breakthrough episodes. HSV resistance to antiherpes drugs remains very rare in immunocompetent patients [62 65] and an alternative diagnosis or misinterpretation of symptoms by the patient is likely. Considerable data have accumulated on the safety of longterm continuous acyclovir therapy in patients with genital herpes and data for valacyclovir and famciclovir are increasing with continuing use [66 68]. Valacyclovir, when used to manage HSV infections, appears to inherit the safety profile of oral acyclovir [67]. Patients have remained on acyclovir therapy for up to 10 years with no evidence of clinically significant adverse effects [66, 67, 69]. Stopping suppressive therapy does not appear to influence the natural history of genital HSV infection in that recurrence frequency after cessation of suppressive therapy for 1 year remains comparable with that prior to commencing suppression [70]. Extensive natural history studies suggest a gradual waning of symptoms and a decrease in disease frequency with time (i.e., 15 years) [71]. Patients who have disease well controlled with suppressive antiviral therapy should be advised to consider an occasional drug holiday to allow for reassessment of the underlying disease. The decision to stop therapy should be made with the patient and should take into account the patient s personal circumstances, lifestyle, and needs. Some patients request relatively short suppressive therapy courses to cover specific situations or periods of concern (e.g.,!1 month). Of note, for such an indication, therapy for 5 days is required before a reliable suppressive effect is achieved [72, 73]. Suppressive antiviral therapy is particularly valuable in managing some complications of recurrent genital herpes. Openlabel studies have shown an impact on the psychological disturbances associated with recurrent genital HSV disease [39, 74]. Such psychosexual disturbances are common in patients with severe recurrent disease. A recent well-designed placebocontrolled study of valacyclovir in 1479 patients with an annual recurrence rate of 6 attacks a year showed a significant improvement in quality of life measures during the suppressive therapy [40]. Suppression also favorably modified the features of rarer complications such as recurrent erythema multiforme

7 JID 2002;186 (Suppl 1) Management of Genital Herpes S53 Figure 2. Systemic acyclovir exposure (time above IC 50 value for HSV inhibition): Response relationship for valacyclovir and acyclovir suppressive therapy regimens [61]. and aseptic meningitis associated with recurrent herpes outbreaks [75 77]. The cost of suppressive antiviral therapy for genital herpes should not be seen as a barrier. Benefits already extend beyond those of an immediate impact on clinical symptoms, and further studies with valacyclovir are continuing to explore its potential in limiting transmission risk. In the United States, analysis of the costs of valacyclovir, acyclovir, and famciclovir prescribed for a 1-year period clearly indicate the economic advantage of the 500-mg valacyclovir once a day regimen [78]. By using the lowest average US wholesale prices today [79], costs for 1 year of suppressive therapy with valacyclovir (500 mg once/day), famciclovir (250 mg twice/day), and (generic) acyclovir (400 mg twice/day) would be $1235, $2683, and $1377, respectively. In some situations, drug discounting may result in a lower price to consumers for generic acyclovir than for the newer antivirals. Genital Herpes in HIV-Infected Persons HIV-infected patients are at high risk of disease attributable to reactivation of latent HSV and often have severe or frequent genital herpes recurrences. Before the introduction of highly active antiretroviral therapy (HAART), suppressive antiviral therapy rather than episodic treatment was commonly prescribed for genital herpes in patients with HIV/AIDS and was preferred by the patients. With HAART more widely available, the option of episodic therapy for recurrent HSV outbreaks may be reconsidered, for example, on grounds of better control of the declining immune system associated with fewer herpes outbreaks, cost, or patient preference for a reduced pill burden. There has been no specific study with acyclovir for the acute treatment of genital herpes in HIV-infected persons and few published trials have quantified the efficacy of suppressive acyclovir on HSV-1 or HSV-2 reactivation in HIV-infected subjects. Published studies of valacyclovir and famciclovir for herpes management in persons with HIV infections were done before the advent of HAART [80 82]. Valacyclovir (1000 mg twice/ day) had comparable efficacy to acyclovir (200 mg 5 times/day) as episodic treatment for recurrent anogenital herpes and was as effective as acyclovir on both episode duration and lesion healing [80]. Famciclovir (500 mg twice/day) was as effective as acyclovir (400 mg 5 times/day) in resolving the symptoms of HSV-1 and -2 outbreaks at genital and orolabial sites [81]. The efficacy and safety of valacyclovir (500 mg twice/day or 1000 mg once/day) for prevention of recurrences of anogenital HSV infection in HIV-infected persons was compared with acyclovir (400 mg twice/day) in a randomized trial. Patients were required to have 200 CD4 cells/mm 3 before the 1-year treatment period. No statistically significant differences were seen in the time to first recurrence or proportions of patients who were recurrence free for the valacyclovir or acyclovir regimens. However, valacyclovir (500 mg twice/day) appeared to provide better protection than the once daily 1000-mg regimen in this patient population (hazard ratio, 1.80; 95% CI, ; P p.001) [80]. Valacyclovir was well tolerated and there was no evidence suggestive of thrombotic microangiopathy-like syndrome. Famciclovir has not been investigated long term as suppressive therapy for symptomatic herpes in HIV-infected persons but it was evaluated in a small ( n p 56) 8-week placebo-con- trolled trial in HIV-infected persons in which the primary focus was symptomatic and asymptomatic HSV reactivation [82]. This study demonstrated clinically and statistically significant

8 S54 Patel JID 2002;186 (Suppl 1) reductions with famciclovir (500 mg twice/day) in the genital signs and symptoms associated with HSV reactivation and symptomatic and asymptomatic shedding. Disease Transmission Issues Many patients express fear about transmission of herpes to sex partners and may view continuous suppression as a means of managing the risk. Suppressive antiviral therapy significantly reduces the frequency of clinical and subclinical genital HSV shedding but does not completely eliminate it [72, 73, 83, 84]. Patients must be reminded of the risk of herpes transmission during asymptomatic periods [85, 86] and that some transmission risk probably remains throughout the course of suppressive therapy. The results of an ongoing study designed to assess the effect of suppressive valacyclovir on sexual transmission of genital HSV infection in immunocompetent couples are awaited and should help clinicians in counseling patients about transmission risk. Controversy remains about the role of counseling and condom use as means of substantially reducing transmission risk. However, since neither intervention has an adverse outcome, most clinicians advise their routine use. Recent data are supportive of the value of condoms to reduce risk of genital HSV transmission [37]; hence the importance of their routine use should be stressed to patients. Pregnant women with genital HSV infection can transmit the infection to the neonate during delivery. Caesarean section is one strategy for management and antiviral therapy is another option. Several small studies of suppressive acyclovir therapy (200 mg 4 times/day) in late pregnancy indicate that antivirals may reduce the clinical recurrence rate and the need for caesarean section [87 89]. Antiviral drugs are not licensed for use in pregnancy, and there is insufficient evidence to draw definitive conclusions about the risks associated with antivirals during pregnancy. However, in over 1000 pregnancies followed by the Acyclovir and Valacyclovir Pregnancy Registry, the rate of birth defects was no greater than in the general population and no pattern of defects was seen [90]. Transmission is of concern for patients with herpes, their sex partners, and unborn children. Moreover, because the genital HSV infection is pandemic worldwide, practical economic measures are urgently required to interrupt the spread of infection. Our hopes for the future lie in vaccination to prevent primary infection and immunotherapeutic agents to control the clinical symptoms of genital herpes, ideally to reduce infectivity between persons. Summary Although HSV infection is at present incurable in absolute terms, the clinician can do much to inform and empower patients so they share in the management of the disease. Accurate diagnosis of symptomatic infection is integral to the treatment of genital herpes today. Antiviral therapy is the current standard for managing symptoms and for alleviating some psychological aspects of herpes. Information and support through clinicianpatient counseling and via patient networks are valuable resources and can do much to redress the misinformation surrounding many aspects of HSV infection. References 1. Siegel JE. Estimates of the economic burden of STDs: review of the literature with updates. In: Eng TR, Butler WT, eds. The hidden epidemic: confronting sexually transmitted diseases. Washington DC: National Academy Press, 1997: Patel R, Boselli F, Cairo I, Barnett G, Price M, Wulf HC. Patients perspectives on the burden of recurrent genital herpes. Int J STD AIDS 2001;12: Corey L. Challenges in genital herpes simplex virus management. J Infect Dis 2002;186(Suppl 1):S29 33 (in this issue). 4. Lafferty WE, Coombs RW, Benedetti J, Critchlow C, Corey L. Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type. N Engl J Med 1987;316: Ashley RL. Current concepts in laboratory diagnosis of herpes simplex infection. In: Sacks SL, Straus SE, Whitley RJ, et al., eds. Clinical management of herpes viruses. Amsterdam: IOS Press, 1995: Lopez C, Arvin A, Ashley RL. Immunity to herpesvirus infections in humans. In: Roizman B, Whitley RJ, Lopez C, eds. The human herpesviruses. New York: Raven Press, 1993: Ashley RL. Type-specific antibodies to HSV-1 and -2: review of methodology. Herpes 1998;5: Cusini M, Ghislanzoni M. The importance of diagnosing genital herpes. J Antimicrob Chemother 2001;47(Suppl 1): Whitley RJ. Herpes simplex viruses. In: Fields BN, Knipe DM, Howley PM, et al, eds. Fields virology. 3d ed. Philadelphia: Lippincott-Raven, 1996: Kinghorn GR, Turner EB, Barton IG, Potter CW, Burke CA, Fiddian AP. Efficacy of topical acyclovir cream in first and recurrent episodes of genital herpes. Antiviral Res 1983;3: Corey L, Benedetti JK, Critchlow CW, et al. Double-blind controlled trial of topical acyclovir in genital herpes simplex virus infections. Am J Med 1982;73: Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis 1997;24: Patel R. Valaciclovir: development, clinical utility and potential. Exp Opin Invest Drugs 1997;6: Bodsworth NJ, Crooks RJ, Borelli S, et al. Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double-blind clinical trial. Genitourin Med 1997;73: Garcia A, Garcia S, Snachez JA, Garcia I, Lanchares JL. Valaciclovir en el tratamiento de la primoinfeccion por el virus del herpes genital: estudio comparativo. Enferm Infecc Microbiol Clin 2001;19: Loveless M, Harris W, Sacks S. Treatment of first episode genital herpes with famciclovir [abstract H-12]. In: Program and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco). Washington, DC: American Society for Microbiology, 1995: Loveless M, Sacks SL, Harris JRW. Famciclovir in the management of firstepisode genital herpes. Infect Dis Clin Pract 1997;6(Suppl 1):S Field HJ, Bell SE, Elion GB, Nash AA, Wildy P. Effect of acycloguanosine

9 JID 2002;186 (Suppl 1) Management of Genital Herpes S55 treatment on acute and latent herpes simplex infections in mice. Antimicrob Agents Chemother 1979;15: Wildy P. Herpes viruses: a background. Br Med Bull 1985;41: Mertz GJ, Critchlow CW, Benedetti J, et al. Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. JAMA 1984;252: Peacock JE, Kaplowitz LG, Sparling PF, et al. Intravenous acyclovir therapy of first episodes of genital herpes: a multicenter double-blind, placebocontrolled trial. Am J Med 1988;85: Thackray AM, Field HJ. Differential effects of famciclovir and valaciclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency. J Infect Dis 1996;173: Thackray AM, Field HJ. Comparison of effects of famciclovir and valaciclovir on pathogenesis of herpes simplex virus type 2 in a murine infection model. Antimicrob Agents Chemother 1996;40: Thackray AM, Field HJ. Famciclovir and valaciclovir differ in the prevention of herpes simplex virus type 1 latency in mice: a quantitative study. Antimicrob Agents Chemother 1998;42: LeBlanc RA, Pesnicak L, Godleski M, Straus SE. The comparative effects of famciclovir and valacyclovir on herpes simplex virus type 1 infection, latency, and reactivation in mice. J Infect Dis 1999;180: Leung DT, Sacks SL. Current recommendations for the treatment of genital herpes. Drugs 2000;60: Langenberg A, Benedetti J, Jenkins J, Ashley R, Winter C, Corey L. Development of clinically recognizable genital lesions among women previously identified as having asymptomatic herpes simplex virus type 2 infection. Ann Intern Med 1989;110: Koelle DM, Wald A. Herpes simplex virus: the importance of asymptomatic shedding. J Antimicrob Chemother 2000;45(Suppl 3): Pass R, Weber T, Whitley RJ, eds. Management strategies in herpes: herpesvirus infections in pregnancy. Worthing, UK: Parexel MMS Europe, Brown ZA, Benedetti J, Ashley R, et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med 1991;324: Corey L. The current trend in genital herpes. Progress in prevention. Sex Transm Dis 1994;21:S Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev 1999;12: Koutsky LA, Stevens CE, Holmes KK, et al. Underdiagnosis of genitalherpes by current clinical and viral-isolation procedures. N Engl J Med 1992; 326: Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med 1992;116: Bryson Y, Dillon M, Bernstein DI, Radolf J, Zakowski P, Garratty E. Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study. J Infect Dis 1993;167: Corey L, Langenberg AGM, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection. Two randomized controlled trials. JAMA 1999;282: Wald A, Langenberg AGM, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA 2001;285: Carney O, Ross E, Bunker C, Ikkos G, Mindel A. A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourin Med 1994;70: Carney O, Ross E, Ikkos G, Mindel A. The effect of suppressive oral acyclovir on the psychological morbidity associated with recurrent genital herpes. Genitourin Med 1993;69: Patel R, Tyring S, Strand A, Price MJ, Grant DM. Impact of suppressive antiviral therapy on the health related quality of life of patients with recurrent genital herpes infection. Sex Transm Infect 1999;75: Gwanzura L, McFarland W, Alexander D, Burke RL, Katzenstein D. Association between human immunodeficiency virus and herpes simplex virus type 2 seropositivity among male factory workers in Zimbabwe. J Infect Dis 1998;177: Auvert B, Ballard R, Campbell C, et al, HIV infection among youth in a South African mining town is associated with herpes simplex virus-2 seropositivity and sexual behaviour. AIDS 2001;15: Schacker T, Ryncarz AJ, Goddard J, et al. Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1 infected men. JAMA 1998;280: Nilsen AE, Aasen T, Halsos AM, et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet 1982;2: Reichman RC, Badger GJ, Mertz GJ, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA 1984;251: Spruance SL, Tyring SK, DeGregoria B, Miler C, Beutner K, and the Valaciclovir Study Group. A large-scale, placebo controlled, dose ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med 1996;156: Tyring SK, Douglas JM, Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. Arch Dermatol 1998;134: Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. JAMA 1996;276: Chosidow O, Drouault Y, Leconte-Veyriac F, et al. Famciclovir vs aciclovir in immunocompetent patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind clinical trial. Br J Dermatol 2001;144: Kinghorn GI, Fiddian AP. Prevention of lesion development in recurrent genital herpes with oral valaciclovir. J Eur Acad Dermatol Venereol 1995;5(Suppl 1):S Strand A, Patel R, Wulf HC, Coates KM. Aborted genital herpes simplex virus lesions: findings from a randomised, controlled trial with valaciclovir. Sex Transm Infect (in press). 52. Leone PA, Trottier S, Miller JM. Valacyclovir for episodic treatment of genital herpes: a shorter 3-day treatment course compared with 5-day treatment.. Clin Infect Dis 2002;34: Mertz GJ, Jones CC, Mills J, et al. Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. A multicenter double-blind trial. JAMA 1988;260: Patel R, Bodsworth NJ, Woolley P, et al. Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy. Genitourin Med 1997;73: Reitano M, Tyring S, Lang W, et al. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose rangefinding study. J Infect Dis 1998;178: Mertz GJ, Loveless MO, Levin MJ, et al. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Arch Intern Med 1997;157: Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. JAMA 1998;280: Alexander L. Optimizing the management of genital herpes patient s perspective. In: Whitley RJ, ed. Optimizing the management of genital herpes. Round Table Series 69. London: Royal Society of Medicine Press, 2000: Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994;121: Mindel A, Faherty A, Carney O, Patou G, Freris M, Williams P. Dosage and safety of long-term suppressive acyclovir therapy for recurrent genital herpes. Lancet 1988;1: Patel R, Bell AR, and the International Valaciclovir HSV Study Group.