The Treatment of Herpes Simplex Infections an Evidence-Based Review

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REVIEW ARTICLE The Treatment of Herpes Simplex Infections An Evidence-Based Review

Christina Cernik, MD; Kelly Gallina, MD; Robert T. Brodell, MD

enital and labial herpes simplex virus infections are frequently encountered by primary care physicians in the United States. Whereas the diagnosis of this condition is often straightforward, choosing an appropriate drug (eg, acyclovir, valacyclovir hydrochloride, or famciclovir) and dosing regimen can be confusing in view of (1) com- Gpeting clinical approaches to therapy; (2) evolving dosing schedules based on new research; (3) approved regimens of the Food and Drug Administration that may not match recommendations of the Centers for Disease Control and Prevention or of other experts; and (4) dissimilar regimens for oral and genital infections. The physician must first choose an approach to treatment (ie, intermittent episodic therapy, intermittent suppressive therapy, or chronic suppressive therapy) based on defined clinical characteristics and patient preference. Then, an evidence-based dosing regimen must be selected. In this review, data from all sources are tabulated to provide a handy clinical reference. Arch Intern Med. 2008;168(11):1137-1144

Acyclovir, valacyclovir hydrochloride, and data regarding optimal treatment regi- famciclovir are the 3 antiviral drugs rou- mens. Three approaches to treatment are tinely used to treat symptomatic herpes described: intermittent episodic therapy simplex virus (HSV) infections. Diagnos- (IET), chronic suppressive therapy (CST), ing HSV infections is usually straightfor- and intermittent suppressive therapy (IST). ward in immunocompetent patients, and An outbreak of genital or labial herpes all the available drugs have an excellent is categorized as a primary HSV infection margin of safety because they are con- if the patient was seronegative for HSV verted by viral thymidine kinase to the ac- types 1 and 2 before the episode and as a tive drug only inside virally infected cells. nonprimary HSV infection if previous in- Unfortunately, confusion often arises be- fections had occurred. Without acquired cause various dosing regimens are recom- immunity, initial primary infections are mended for (1) each of the 3 available generally more severe than recurrences. drugs; (2) HSV vs herpes zoster; (3) sup- Constitutional symptoms such as fever, pressive vs intermittent episodic indica- chills, fatigue, and muscle aches accom- tions; (4) primary vs secondary infec- pany the disease and last 10 to 14 days. A tions; (5) oral and genital infections; and first episode of genital or oral herpes in a (6) evolving treatment strategies ap- patient already seropositive for HSV is proved by the Food and Drug Adminis- termed a nonprimary initial infection, and tration. Following a literature review to these infections tend to be less severe. The document important clinical informa- disease course after initial infection is vari- tion about HSV infections, we discuss the able; some patients have recurrent infections, and others never experience a sec- Author Affiliations: Northeastern Ohio Universities College of Medicine, ond episode. Rootstown (Drs Cernik and Brodell); First Capital Dermatology, Adena Health Labial herpes typically results from in- System, Chillicothe, Ohio (Dr Gallina); and Departments of Dermatology, Case fection with HSV type 1 and is com- Western Reserve University School of Medicine, Cleveland, Ohio, and University monly contracted during childhood or of Rochester School of Medicine, Rochester, New York (Dr Brodell). adolescence. In the US, 57% to 80% of

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Episodic Dosing for Initial Primary Labial Herpes

Level of FDA Antiviral Drug Dosing Schedule Evidence Approved Acyclovir 15 mg/kg 5 times a day for 7 d II3,21 No Valacyclovir hydrochloride 1 g twice a day for 7 d V22 No Famciclovir 500 mg twice a day for 7 d V22 No

Abbreviation: FDA, Food and Drug Administration.

of involvement in women, yet the clinically silent disease. Although the Figure. Grouped vesicopustules are present on classic clinical picture is that of pain- treatment approaches used for oral the right side of the chin just below the ful and disfiguring vaginal and vul- and genital HSV infections are more vermillion border 48 hours after the patient first 12 noted tingling and burning at this site. This is var lesions. Men typically develop similar than different, randomized the 25th recurrence at this site in 10 years. lesions on the glans, prepuce, or shaft controlled trials (RCT) have uni- of the penis. The natural course of dis- formly studied these infections sepa- adults are seropositive for the vi- ease progression is decreased fre- rately. Therefore, dosage schedules rus, with a larger proportion of these quency and severity of recurrences derived from these trials are not people being of lower socioeco- over time. However, roughly a third identical. nomic status.1-4 Many people ex- of patients do not experience this posed to HSV demonstrate asymp- time-dependent regression.17 IET in Labial Herpes Simplex tomatic seroconversion. Initial Herpes zoster and other blister- primary episodes, however, can be ing diseases can mimic HSV infec- Initial Primary Infections. In mod- severe, causing widespread 1- to tions. The diagnosis of herpes erate and severe cases, antiviral treat- 2-mm blisters associated with se- infections can be confirmed imme- ment is often recommended for un- vere discomfort that interferes with diately by Tzanck preparation, complicated episodes of primary oral eating and drinking to the point of within hours using immunofluores- herpes in healthy patients (Table 1).6 dehydration, last 10 to 14 days, and cence techniques, and within 48 Oral acyclovir suspension, 15 mg/kg occur 1 to 26 days after inocula- hours using viral culture. 5 times daily for 1 week, signifi- tion.4 Recurrent labial herpes af- The clinical courses of genital cantly decreased the disease dura- fects roughly one third of the US herpes caused by HSV types 1 and tion and the period of infectivity in population, and these patients typi- 2 are indistinguishable. There is typi- children in a small RCT. Median du- cally experience 1 to 6 episodes per cally a 2- to 21-day incubation pe- ration of oral lesions was 4 days vs 9 year.5-9 These infections appear at the riod following viral inoculation days for the placebo group, and me- vermillion border of the lip in about when randomly distributed vesicles dian time to negative viral cultures 90% of cases, the palate in 5% of clustered on a red base appear. Tiny was 1 day vs 5 days.21 Valacyclovir hy- cases, and elsewhere above the chin papules develop into vesicles, which drochloride, 1 g twice a day for 7 days, or on the oral mucosa more rarely subsequently ulcerate and crust.18 and famciclovir, 500 mg twice a day (Figure). Papules on an erythema- Soreness, itching, dysuria, and in- or once a day for 7 days, are also logi- tous base become vesicles within guinal or femoral lymphadenopa- cal regimens, although RCTs have not hours and subsequently progress thy may accompany constitutional been performed.3,22 Treatment is most through ulcerated, crusted, and heal- symptoms, and dysuria is common effective when initiated promptly. ing stages within 72 to 96 hours.10,11 in women.18,19 Untreated eruptions However, early treatment does not ap- Before skin lesions appear, 60% of of genital herpes typically last longer pear to diminish recurrences. patients experience the prodromes than those of the oral variety, with tingling, itching, and burning.11 a primary episode enduring for 2 to Recurrent Infections. The intermit- Genital herpes is most com- 4 weeks. Recurrent genital herpes tent use of an oral antiviral agent is monly contracted between the ages of produces localized vesicles on an effective in the treatment of recur- 15 and 30 years, coinciding with in- erythematous base, which persist for rent labial herpes when initiated creased sexual activity in this age 7 to 12 days without treatment.19,20 within 48 hours of an outbreak group.12 It affects approximately 22% (Table 2). Randomized con- of the US population, with roughly INTERMITTENT EPISODIC trolled trials have shown systemic 38% of symptomatic individuals ex- THERAPY acyclovir (400 mg 5 times daily for periencing 6 or more recurrences per 5 days) decreases healing time and year.13,14 Genital herpes can result As is the case with most disease pro- viral shedding and ameliorates from infection with either HSV type cesses, HSV infections are com- symptoms when initiated early.11,23 2 or type 1, mainly HSV type 2 in this monly treated with the first clinical Valacyclovir, the prodrug of acyclo- country, which typically causes more sign or symptoms. This form of in- vir, provides a 3- to 5-fold increase recurrent and severe manifestations termittent treatment is termed epi- in bioavailability of acyclovir.24 Two of disease.2,15,16 Infection of the cer- sodic and focuses on management of large RCTs demonstrated that single- vix, often subclinical, is the main site isolated, acute episodes of a chronic, day administration of valacyclovir

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 (2 g given twice in 24 hours) significantly reduces episode dura- Table 2. Intermittent Episodic Therapy or Recurrent Labial Herpes tion, time to lesion healing, and time to cessation of pain and discomfort Level of FDA when compared with placebo. A Antiviral Drug Dosing Schedule Evidence Approved 1-day reduction in lesion duration Acyclovir 400 mg 5 times a day for 5 d II23 No 24 was documented. Valacyclovir hydrochloride 2 g twice a day for 1 d I Yes Famciclovir Three 500-mg tablets as a single dose I10,25 Yes Famciclovir, the oral prodrug of Topical therapy penciclovir, offers increased bioavail- Penciclovir cream, 1% Apply every 2 h during waking hours for 4 d I26-28 Yes ability as well as a substantially longer Acyclovir cream, 5% Apply 5 times a day for 4 d I27,29 Yes half-life compared with acyclovir. In an RCT, famciclovir, given as either a Abbreviation: FDA, Food and Drug Administration. single 1500-mg dose or as two 750-mg doses during a 24-hour period, decreased healing time and provided Table 3. Episodic Dosing for Initial Primary Genital Herpes symptomaticrelief.Timetolesionheal- ing and normal reepithelialization was Level of FDA CDC 2 days shorter and symptom resolu- Antiviral Drug Dosing Schedule Evidence Approved Recommended tion was 1 day faster when compared Acyclovir 400 mg 3 times a day for 7-10 d V38-41 No Yes with the control group.10,25 200 mg 5 times a day for 7-10 d I38,40 Yes Yes Intermittent episodic therapy with Valacyclovir 1 g twice a day for 7-10 d I40 Yes Yes topical acyclovir and penciclovir hydrochloride Famciclovir 250 mg 3 times a day for 5-10 d I42,43 No Yes (10-d creams have been shown to decrease regimen) lesion healing time and symptom severity in recurrent labial her- Abbreviations: CDC, Centers for Disease Control and Prevention; FDA, Food and Drug Administration. pes.11,26,27,29-32 Other studies, however, failed to prove acyclovir ointment and cream efficacious.33,34 (200 mg 5 times daily) and valacy- cacy.42,43 Famciclovir 3 times a day Overall, topical treatments do not ap- clovir (1000 mg twice a day) found should enhance compliance when pear to be as effective as systemic no statistically significant differ- compared with the 5 times daily dos- medications. For instance, famciclo- ence between the 2 in terms of dis- age of acyclovir. vir decreases lesion healing time by ease outcome measures.40 How- 2 days, efficacy that has not been dem- ever, valacyclovir, when taken once Recurrent Infections. In the 1980s, onstrated with topical therapy.10,26,35-37 or twice daily, is likely to increase oral acyclovir (200 mg 5 times daily compliance compared with acyclo- for 5 days) was found to signifi- IET in Genital Herpes Simplex vir, which is taken 5 times a day.40 cantly decrease viral shedding, has- Similarly, an RCT comparing the ten lesion healing, and decrease the Initial Primary Infections. Pa- efficacy of 5- and 10-day regimens incidence of new lesion forma- tients with primary episodes of geni- of several famciclovir dosages (250 tion.41,44,45 It was also associated with tal herpes are effectively treated mg, 500 mg, or 750 mg 3 times a day a truncated course of pain and dis- with antiviral drugs when taken for 5 days and 125 mg, 250 mg, or comfort, but had no effect on recur- within 72 hours of lesion appear- 500 mg 3 times a day for 10 days) rences.41,44 Abbreviated courses using ance (Table 3). Oral and intrave- with acyclovir (200 mg 5 times a day higher dosages of acyclovir, 800 mg nous acyclovir have been used to for 5 or 10 days) in first-episode twice a day for 5 days and 3 times a shorten the course of primary geni- genital herpes cases found no sig- day for 2 days, have proven to be as tal herpes infections for decades. Un- nificant differences between the two effective as earlier regimens.46,47 like topical acyclovir, the oral form drugs. Duration of viral shedding, Moreover, the higher dosage was ef- can prevent new lesion formation median time to lesion healing, and fective in healing established le- and modify accompanying consti- time to symptom resolution were sions in men, even when initiated af- tutional symptoms, and does not comparable between both treat- ter the prodromal period.46 cause local irritation on applica- ment groups.42,43 The 10-day treat- Oral valacyclovir (500 mg twice tion.38 Oral acyclovir is more prac- ment arm of the study demon- a day for 5 days and 1 g once a day tical than the intravenous route for strated that higher doses of for 5 days) has been shown in pla- immunocompetent patients.38 Acy- famciclovir (250 mg and 500 mg) cebo-controlled and head-to-head clovir (1 g to 1200 mg/d) produces were superior to the 125-mg regi- studies to match acyclovir in terms results matching those of higher dos- men. The Centers for Disease Con- of decreasing episode length, viral ages (4 g/d). Neither regimen ap- trol and Prevention has chosen to shedding, and healing time.45,48 The pears to affect the frequency or recommend the 10-day dosing 3-day valacyclovir regimen (500 mg course of future genital herpes schedule, although the 5 and 10- twice a day) was shown to be as ef- recurrences.39 day regimens of famciclovir (250 mg fective as 5 days of treatment.49 Mul- Head-to-head trials comparing 3 times a day and all 500-mg groups) tiple studies have also demon- 10-day regimens of oral acyclovir demonstrated comparable effi- strated that valacyclovir significantly

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 recurrences of labial herpes has been Table 4. Intermittent Episodic Therapy for Recurrent Genital Herpes demonstrated in RCTs. In the early 1990s, trials demonstrated that oral Level of FDA CDC acyclovir (400 mg twice a day) was Antiviral Drug Dosing Schedule Evidence Approved Recommended an effective mode of therapy. At the Acyclovir 200 mg 5 times a day for 5-10 d I41,44,45,53 Yes No end of 4 months there was a 41% re- 400 mg 3 times a day for 5 d V No Yes duction in the number of patients ex- 400 mg 3 times a day for 5-10 da VNoYes 800 mg twice a day for 5 d II46 No Yes periencing labial herpes recur- 800 mg 3 times a day for 2 d II47 No Yes rences, and a 53% decrease in total Valacyclovir 500 mg twice a day for 3 d I49 Yes Yes number of outbreaks when com- hydrochloride 1 g twice a day for 5-10 da II54 No Yes pared with placebo-treated sub- 1 g once a day for 5 d I48 No Yes jects.8 The efficacy of valacyclovir 51,52 Famciclovir 125 mg twice a day for 5 d I No Yes was first demonstrated in a 4-month 500 mg twice a day for 5-10 da II55 Yes (7-d Yes regimen) trial: valacyclovir prophylaxis (500 1 g twice a day for 1 d I14 Yes Yes mg once a day) resulted in 60% of treatment group patients remain- Abbreviations: CDC, Centers for Disease Control and Prevention; FDA, Food and Drug Administration. ing disease free, compared with 38% a For human immunodeficiency virus–positive patients, suggested regimens were derived from studies of subjects in the placebo group. of patients with genital herpes. However, we expect these treatments to also be useful for patients with labial herpes. Mean time to first recurrence was significantly longer in the treatment group (13.1 weeks) com- decreases the duration and severity ease Control and Prevention guide- pared with the control group (9.6 of pain and discomfort associated lines discourage the use of the topi- weeks).9 In addition, a crossover with genital herpes episodes.50 There cal formulations, stating that they study comparing valacyclovir given is conflicting evidence regarding the offer “minimal clinical benefit.”59 for 6 months as intermittent reac- ability of valacyclovir to abort out- tive therapy (two 2-g doses sepa- breaks when taken at the onset of CHRONIC SUPPRESSIVE rated by 12 hours) and CST (1 g symptoms before any lesions are ap- THERAPY once daily) showed the chronic sup- parent. Data trends and our clinical pressive regimen to significantly de- experience suggest that at least some Although most patients with HSV crease frequency of recurrences and recurrences can be aborted through infections do not require CST, pain severity scores.66 this approach.45,48,50 those with frequent recurrences No RCTs have been conducted to In addition, varying dosages of who experience severe pain or dis- specifically evaluate the ability of famciclovir (125 mg, 250 mg, or 500 figurement, have difficulty swal- famciclovir to prevent recurrent la- mg twice a day for 5 days) signifi- lowing, or experience a protracted bial herpes when given chronically cantly affect the characteristics men- disease course are appropriately (Table 5). The fact that short tioned previously. No dose- treated with CST.8,9 Of all patients courses of prophylactic famciclovir dependent advantages exist between with labial herpes, 5% to 10% (250 mg or 500 mg twice a day for regimens. Therefore, the lowest dos- experience frequent recurrences 10 days started 1 day before the pro- age of 125 mg twice a day is recom- (Ն6 per year). Of patients infected cedure) given in special circum- mended. Viral shedding is de- with genital herpes, 20% to 50% stances (ie, facial laser resurfacing) creased by 11⁄2 days and roughly have symptomatic, recurrent have been shown to prevent recur- leads to complete lesion healing 1 flares.60 Patients have a median of 4 rent episodes of labial herpes sug- day faster than placebo. There is a recurrences the year after a first gests long-term treatment may be 50% absolute risk reduction of de- symptomatic episode and usually efficacious.67 veloping new lesions compared with enjoy a decline in frequency of out- placebo, and the treatment group en- breaks over time.61,62 Recurrences CST in Genital Herpes Simplex joyed at least a half-day reduction in of any frequency can negatively lesion-associated pain and discom- affect a patient’s quality of life. Acyclovir was the first drug exten- fort.51,52 A single-day, 2-dose regi- Thus, CST is appropriate for sively studied and proven to mark- men demonstrated a 2-day reduc- patients who are psychologically edly reduce genital herpes recur- tion in median time to healing and distressed by their disease.63 Long- rences when taken daily for long overall efficacy equal to that of mul- term prophylactic therapy for geni- periods in the immunocompetent tiple day, lower-dose famciclovir tal herpes may also be used in an population. A small trial in 1984 regimens.14 Table 4 summarizes effort to decrease the risk of trans- found that daily acyclovir (200 mg these data. mission to uninfected partners.64,65 3 times a day) taken for 125 days sig- The efficacy of topical acyclovir nificantly decreased the number of cream used as treatment in primary CST in Recurrent genital herpes recurrences. All pa- or recurrent episodes of genital her- Oral Herpes Simplex tients in the placebo group and 25% pes varies between RCTs and overall of subjects in the treatment group does not appear to be as reliable as oral Efficacy of acyclovir and valacyclo- experienced at least 1 recurrence acyclovir.56-58 Current Centers for Dis- vir as CST in patients with frequent during a 4-month period.68

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Studies have focused on efficacy in suppressing recurrences, safety Table 5. Chronic Suppressive Therapy for Labial Herpes profile, optimal dosage, and the effect on recurrence rates after treat- Level of FDA ment is discontinued. During the Antiviral Drug Dosing Schedule Evidence Approved first year of a 6-year multicenter trial, Acyclovir 400 mg twice a day II8 No 9 acyclovir (400 mg twice a day) sig- Valacyclovir hydrochloride 500 mg once a day II No 1 g once a day II66 No nificantly increased the number of 500 mg twice a daya patients remaining recurrence free Famciclovir 500 mg twice a day V67 No (44% vs 2%) and median time to first outbreak (246 days vs 18 days) com- Abbreviation: FDA, Food and Drug Administration. pared with placebo.69 The follow- a Human immunodeficiency virus–positive patients. ing years of the trial demonstrated a “gradual and additional improve- ment” in response to therapy, with Table 6. Chronic Suppressive Therapy for Genital Herpes about 70% of patients remaining re- Level of FDA CDC currence free during the fifth year of Antiviral Drug Dosing Schedule Evidence Approved Recommended 62,69-71(p586) the trial. Overall, studies 61,69,71,81 suggest that acyclovir given as CST Acyclovir 400 mg twice a day I Yes Yes 400-800 mg twice to 3 times a daya I89 No Yes for 1 year allows 43% to 50% of pa- Valacyclovir 1 g once a day I81,90 Yes Yes tients to remain recurrence free, with hydrochloride 500 mg once a day I79,80 Yes Yes a median time to first recurrence 500 mg twice a daya I89,91 Yes Yes ranging from 246 to 274 days.69,72-74 250 mg twice a day I61,81 No No When control was not achieved at Famciclovir 250 mg twice a day I60,65,82 Yes Yes a 87 lower doses, most initial nonre- 500 mg twice a day II No Yes sponders were controlled with in- Abbreviations: CDC, Centers for Disease Control and Prevention; FDA, Food and Drug Administration. creased doses ranging from 1000 to a Human immunodeficiency virus–positive patients. 1600 mg/d.62,75 Unfortunately, once suppressive therapy is discontinued, outbreaks of- the 250 mg once a day dosage (22% 3 times a day, 250 mg 3 times a day, ten recur. When discontinued within recurrence free) and placebo and 250 mg twice a day) signifi- a year, episodes recur at a frequency (5%).80,81 More complete suppres- cantly increase time to first recur- comparable to subjects’ baselines be- sion was attained in patients with rence and percentage of patients fore chronic prophylactic therapy was baseline disease activity of less than remaining recurrence free for 1 year. initiated.76 Of note, a prolonged treat- 10 recurrences per year, with the 500 Results attained with 250 mg of ment schedule of 5 years was shown mg once a day dosage typically suf- famciclovir twice a day or 3 times a in one study to lower recurrence rates ficient for control. Patients with 10 day have been similar. Thus, the relative to previous baseline in about or more recurrences per year often twice-daily dosing schedule has two-thirds of patients.70 To date, no needed twice-daily dosing or 1 g 80,81 been suggested to provide a “conve- RCTs have shown significant ad- once a day for adequate control. nient, effective, and well-tolerated verse effects related to prolonged Famciclovir has also been proven 60(p892) 62,68-74,76-78 regimen.” treatment. effective as CST for genital herpes, The length of CST has not been de- The first RCT conducted on vala- demonstrating best efficacy when fined by the Food and Drug Admin- cyclovir (500 mg once a day), a large taken multiple times per days. A study istration and is patient- and disease- 16-week study, demonstrated a sig- conducted only in women evaluated course dependent.70-72,78 Suppression nificant reduction in recurrences multiple famciclovir dosages (125 mg (69% vs 9.5% recurrence free) and once or twice daily, 250 mg once or for a year or longer is appropriate a significant increase in median time twice daily, and 500 mg once a day) in many patients with frequent Ͼ recurrences. Patients with herpes- to first recurrence ( 112 vs 20 days) and found the famciclovir dosage of 83 in the treatment group compared 250 mg twice a day to be the most ef- associated erythema multiforme, with the placebo group.79,80 An- fective regimen in significantly pro- eczema herpeticum (Kaposi varicel- 84 other study evaluating daily single- longing time to first clinically and vi- liform eruption), and herpetic kera- 85 dose regimens (250 mg, 500 mg, and rally confirmed recurrence. Once- titis, and immunocompromised 1 g), 250 mg twice a day, 400 mg daily dosing schedules were less populations, including human im- twice a day, and placebo found 500 effective or provided no significant munodeficiency virus–positive indi- mg once a day, 1 g once a day, 250 benefit.65 A larger study evaluating viduals, may require indefinite sup- mg twice a day, and 400 mg twice a 250 mg of famciclovir twice a day pressive therapy.54,86-88 Acyclovir day of similar efficacy with regard to demonstrated that 70% of those re- resistance occasionally occurs in im- the percentage of patients remain- ceiving the drug were recurrence free munocompromised patients.88 A re- ing recurrence free (40%, 48%, 50%, for 1 year, compared with only 20% cent meta-analysis was performed to and 49%, respectively) after 1 year. of patients in the placebo group.82 elucidate the best CST regimens for All these regimens were superior to Various regimens of the drug (125 mg genital herpes (Table 6).61

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Intermittent Suppressive cially if the infection is primary, con- (manufacturer of Famvir) and Therapy sequences to the fetus can be devas- GlaxoSmithKline (manufacturer of tating. These cases are routinely Valtrex and Zovirax). When recurrences can be antici- managed with cesarean section, but pated, IST can be initiated to pre- anticipatory treatment offers a more REFERENCES vent oral and genital herpes out- practical solution. Decision making breaks. Oral antiviral drugs are can be guided with vaginal herpes cul- 1. Klein RS. Epidemiology of herpes simplex virus used for short periods when tures at regular intervals during the type 1 infection. http://uptodate.com/. Ac- known precipitating factors might third trimester. Acyclovir initiated at cessed February 1, 2008. otherwise trigger reactivation of 36 weeks’ gestation has significantly 2. Xu F, Sternberg MR, Kottiri BJ, et al. 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Single-dose, patient-initiated famciclovir: a ran- shown to significantly decrease domized, double-blind, placebo-controlled trial recurrence rates of labial herpes in Accepted for Publication: Decem- for episodic treatment of herpes labialis. JAm patients undergoing dental proce- ber 18, 2007. Acad Dermatol. 2006;55(1):47-53. 11. Woo S, Challacombe SJ. Management of recur- dures. A study of patients prophy- Correspondence: Robert T. Brodell, rent oral herpes simplex infections. Oral Surg lactically treated with valacyclovir MD, Brodell Medical Inc, 2660 E Oral Med Oral Pathol Oral Radiol Endod. 2007; before dental procedures found that Market St, Warren, OH 44483 (rtb 103(suppl):S12.e1-S12.e18. clinical lesions appeared in 11.3% of @neoucom.edu). 12. Felman YM, Nikitas JA. Genital herpesvirus test group patients and 20.6% of pa- Author Contributions: Drs Cernik infection. N Y State J Med. 1979;79(8):1216- 1218. tients receiving a placebo, illustrat- and Brodell had full access to all the 13. Engel JP. Long-term suppression of genital ing a 46% reduction in the number data in the study and take respon- herpes. JAMA. 1998;280(10):928-929. of clinically evident lesions.7 sibility for the integrity of the data 14. Aoki FY, Tyring S, Diaz-Mitoma F, Gross G, Gao Intermittent suppressive therapy is and the accuracy of the data analy- J, Hamed K. Single-day patient-initiated famciclovir therapy for recurrent genital herpes: a ran- also useful in special populations to sis. Study concept and design: Gallina domized, double-blind, placebo-controlled trial. decrease the risk of virus transmis- and Brodell. Acquisition of data: Clin Infect Dis. 2006;42(1):8-13. sion to noninfected individuals. Al- Cernik. Analysis and interpretation of 15. Solomon L, Cannon MJ, Reyes M, Graber JM, though only 5% to 10% of reproduc- data: Cernik and Brodell. Drafting of Wetherall NT, Reeves WC; Task Force on Her- tive-age women have a history of the manuscript: Cernik and Brodell. pes Simplex Virus Resistance. Epidemiology of recurrent genital herpes simplex virus types 1 genital herpes lesions, 25% to 30% are Critical revision of the manuscript for and 2. Sex Transm Infect. 2003;79(6): seropositive for HSV type 2. Roughly important intellectual content: Gallina 456-459. 5% to 10% of pregnant women expe- and Brodell. Study supervision: 16. Sauerbrei A, Wutzler P. Herpes simplex and vari- rience a symptomatic herpes infec- Gallina and Brodell. cella zoster virus infections during pregnancy: current concepts of prevention, diagnosis, tion at some point during preg- Financial Disclosure: Dr Brodell and therapy, part 1: herpes simplex virus nancy. If such a recurrence occurs has received honoraria for speak- infections. Med Microbiol Immunol. 2007; during the peripartum period, espe- ing engagements from Novartis 196(2):89-94.

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