Acyclovir suppression to prevent recurrent genital herpes...

Acyclovir suppression to prevent recurrent genital herpesat delivery

L. L. Scott1, L. M. Hollier1, D. McIntire1, P. J. Sanchez2, G. L. Jackson2 andG. D. Wendel, Jr.1

1Department of Obstetrics and Gynecology, and2Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas,TX

Objective: To determine if suppressive acyclovir near term decreased the frequency of clinical recurrences atdelivery in women with recurrent genital herpes simplex virus (HSV) infection.Methods: We conducted a prospective, double-blind, randomized trial in 234 women with recurrent genitalherpes. Women with genital infection of any frequency were enrolled. Patients received either suppressive oralacyclovir 400 mg three times daily or an identical placebo after 36 weeks’ gestation. Clinical lesions were identified,and HSV cultures were obtained at delivery. The frequencies of clinical and subclinical HSV recurrences at deliverywere evaluated.Results: Six percent of patients treated with acyclovir, and 14% of patients treated with placebo had clinical HSV atdelivery (p = 0.046). No patients in the acyclovir group had positive HSV cultures, compared with 6% ofplacebo-treated patients (p = 0.029). There was no significant difference in subclinical HSV shedding in theacyclovir group (0%) compared with the placebo-treated group (3%) (p = 0.102).Conclusions: Suppressive acyclovir therapy significantly decreased the incidence of clinical genital herpes and theoverall incidence of HSV excretion at delivery in patients with previous herpes infection.

Key words: ANTIVIRAL AGENTS; PREGNANCY COMPLICATIONS, INFECTIOUS; HERPES GENITALIS; HERPES

SIMPLEX; CESAREAN DELIVERY

It is estimated that 5% of the general population hasa known history of genital herpes1. This creates alarge population of women known to be at risk fortransmitting herpes simplex virus (HSV) to theirinfants during delivery, should they have a peri-partum recurrence. To avoid intrapartum HSVexposure and neonatal infection, it is currentlyrecommended that pregnant women with visiblegenital herpes lesions or prodromal symptoms atthe time of labor have a Cesarean delivery.Gravidas without visible lesions or prodromalsymptoms should be allowed to continue in laborbecause they have a low risk of neonatal HSV

transmission1,2. Using these guidelines, it is esti-mated that one poor neonatal outcome fromHSV infection is averted for every 1580 Cesareandeliveries performed for maternal clinical HSVrecurrences3 (at a cost of US$2.5 million).

Suppressive acyclovir therapy decreases the fre-quency of clinical and subclinical HSV reactivationin non-pregnant adults4. A typical suppressive dosein the non-pregnant adult is 400 mg orally, twiceper day5. However, pharmacokinetic studies interm gravidas have shown that 400 mg orally,three times daily (t.i.d.) may be necessary toachieve similar therapeutic serum levels6. We have

Infect Dis Obstet Gynecol 2002;10:71–77

Correspondence to: Laurie Scott, MD, 580 NW 108th Avenue, Plantation, FL 33324, USA. E-mail: [email protected]

Clinical study 71

previously shown that suppressive acyclovirtherapy, given from 36 weeks’ gestation untildelivery, is effective in preventing recurrences ofgenital herpes at delivery in patients who experi-enced their first genital herpes episode in thatpregnancy7. However, the efficacy and safety ofsuch therapy for patients with genital herpes pre-dating their pregnancy is unknown. The purposeof this study was to determine if acyclovir suppres-sive therapy, administered in the last few weeks ofpregnancy,would decrease the frequency of symp-tomatic genital HSV at delivery in women whohave a history of recurrent genital herpes.

MATERIALS AND METHODS

Eligible patients included any gravida with genitalherpes diagnosed by a viral culture positive forHSV or by the patient’s recollection of a healthcare provider’s clinical diagnosis before the currentpregnancy. Gravidas were eligible for enrollmentwith any frequency of recurrences. Herpes simplexviral serology was not performed. These criteriawere selected to represent those used in typicalcontemporary clinical practice.

Exclusion criteria included serum creatininegreater than 1.5 mg/dl, immunosuppressive dis-eases (e.g., HIV infection), a known requirementfor Cesarean delivery (e.g. previous Cesarean witha classical uterine incision), enrollment in anotherstudy protocol, a gestational age of greater than36 weeks upon identification, delivery before36 weeks’ gestation or previous acyclovir intoler-ance. A patient was considered to be non-compli-ant if she had not taken any study medication oneach of the seven days immediately prior to deliv-ery. All subjects with known outcomes wereincluded in an intent-to-treat analysis.

Patients were recruited from the prenatal clinicsat Parkland Health and Hospital System andSt. Paul Medical Center. Both of these clinic sys-tems serve a young, indigent population with ahigh incidence of sexually transmitted diseases.Informed consent was obtained from eligiblepatients by 36 completed weeks of gestation. At36 weeks estimated gestational age, a schedulegenerated from a random number table was con-sulted, and women were assigned to receive eitheracyclovir 400 mg (GlaxoSmithKline, Research

Triangle Park, NC) or an identical-appearingplacebo, orally, t.i.d until delivery. The acyclovirand placebo were dispensed in coded bottles, andthe patients and their physicians were blinded tothe study assignment. An individual not involvedwith patient care maintained the randomizationlist and assigned the study drug group.

Hypothesizing a symptomatic genital herpesrecurrence rate at delivery of 13%8, a 50% decreasein recurrences at delivery in the treated group, andan 80% power, a sample size of 326 patients in eachgroup (acyclovir and placebo) was projected. TheFood and Drug Administration granted an Investi-gational Drug Number for this protocol; and theinvestigational review boards of the University ofTexas Southwestern Medical Center, ParklandHealth and Hospital System and St. Paul MedicalCenter granted approval for the study.

The women were evaluated weekly after36 weeks’ gestation and were questioned at eachvisit about genital lesions, prodromal symptoms,compliance and side effects from the treatment.Prodromal symptoms were defined as tingling,itching, or other sensations that the patient typi-cally related to the onset of her herpes recurrence.Pill counts were performed at return visits and atdelivery, when possible; and we also relied onreported compliance. Non-compliance wasdefined as no study medication for seven days priorto delivery. An examination for genital HSVlesions was performed at each visit. Herpes cultureswere obtained only if the patient described pro-dromal symptoms or if a lesion was identified. Thecollection, handling and culture technique hasbeen described previously7,9. Upon presentationfor delivery, the patients were examined for genitallesions and questioned regarding prodromal symp-toms. For asymptomatic patients, a combinedherpes culture of the usual lesion site and cervixwas obtained to detect asymptomatic viral shed-ding. For symptomatic women, any visible genitalor cervical lesions were also cultured for HSV.Obstetric residents or nurse practitioners that hadbeen instructed in proper viral culture collectiontechnique collected the samples from patientsupon their admission to the Labor and Deliveryunit. Study medications were not continued intra-partum. Patients were delivered by Cesarean sec-tion if prodromal symptoms or lesions suspicious

Acyclovir suppression at term Scott et al.

72 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY

for genital herpes were present, regardless of thelength of time the amniotic membranes had beenruptured. They were allowed to labor if prodromalsymptoms and lesions were absent.

The pediatricians were informed of themother’s participation in the study, and a physicalexam was performed upon the infant’s admissionto the newborn nursery. Neonatal HSV cultureswere taken from the conjunctiva, oropharynx andrectum 24–48 hours after delivery; the specimenswere combined in one culture. The infants wereobserved for the duration of their routine neonatalstay for clinical evidence of acyclovir toxicity(abnormal renal, liver or central nervous systemfunction) and HSV infection. Prophylactic acyclo-vir therapy was not administered unless the infantwas thought to have been exposed to an activeherpes lesion. In that case, the decision to initiatetreatment was left to the discretion of the attendingpediatrician. Mothers were instructed to contactthe investigators for any problems in the firstmonth after discharge, and the infants’ medicalrecords were reviewed at least one month afterdelivery.

Statistical analysis

Statistical analysis included chi-square and two-tailed Fisher exact tests to evaluate differencesbetween the acyclovir and placebo treatmentgroups. Odds ratios were calculated with 95%exact confidence limits. A p value less than 0.05was considered statistically significant. The pri-mary outcome measured was the frequency ofclinical genital herpes recurrences at delivery.Secondary outcomes included the frequency ofasymptomatic viral shedding, the frequency oftotal viral shedding, and the frequency of Cesareandelivery for recurrent herpes between the twogroups. All comparisons were done using anintent-to-treat format. Outcomes were not com-pared by frequency of recurrences, for there weretoo few women with six or more recurrencesannually.

RESULTS

Between February 1, 1992 and January 31, 1998,234 women with a history of genital herpes were

identified and agreed to participate in the study.Because only 36% of the anticipated sample sizewas enrolled after six years, we felt that an addi-tional ten years necessary to complete enrollmentwas not feasible. Further recruitment was termi-nated at that time, but patients who had alreadyenrolled were allowed to complete the study.

Selected maternal and neonatal characteristicsare presented in Table 1. One hundred sixteenwomen were randomized to acyclovir and 118were randomized to placebo. Twenty-onepatientsin each group did not complete the study. Out-come information was available for all but three ofthese patients (all in the placebo group) who werelost to follow-up. Differences between theacyclovir and placebo groups for the variousanalyses are presented in Table 2. Two hundredthirty-one patients with known outcomes wereconsidered in an intent-to-treat analysis; 116 wereassigned to acyclovir and 115 to placebo. Sixpercent (7/116) of the acyclovir-treated patientshad clinically evident genital herpes at the time ofdelivery, compared with 14% (16/115) of theplacebo treated patients (p = 0.046). This was a57% relative decrease in the incidence of clinicalreactivations of genital herpes at the time ofdelivery. However, the difference in frequency inCesarean delivery between the two groups wasnot significant (Table 3).


INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 73

CharacteristicsAcyclovir

(n = 116)Placebo

(n = 115)

EthnicityBlackWhiteHispanicOther

AgeParity*Outbreaks/yearOutbreaks during studyGestational age at deliveryBirthweightFive minute Apgar*Cord pH

40%31%28%

1%24.8

02.61.1

39.4 weeks3352 g

97.28

47%31%20%

1%240

2.61.4

39.4 weeks3401 g

97.26

Data presented as percentage, mean, or median* of sample

Table 1 Maternal and neonatal characteristics

There was no significant difference between thetwo groups in the incidence of asymptomatic(subclinical) HSV shedding at the time of delivery.There was no significant difference between thetreatment groups in the incidence of viral recoveryfrom clinically apparent lesions. However, whenthe total viral recovery (subclinical shedding +shedding from clinical lesions) was compared,there was a significant difference between thetreatment groups. None (0/102) of the acyclovir-treated patients, but 6% (6/102) placebo-treatedpatients had virus recovered from the genital tractat presentation for delivery (p = 0.029).

One infant in the placebo group receivedprophylactic acyclovir therapy until his culturesreturned negative. Although the mother had aCesarean delivery, she had virus recovered fromlesions on her cervix and labia, and the infant hadtransiently elevated liver transaminases after birth.Ultimately he did well. Two other infants from theplacebo group whose mothers had genital lesionsbut delivered vaginally were observed without

treatment. Their HSV cultures returned negative,and neither developed any signs of neonatal infec-tion. No infant in either the acyclovir or placebogroup had clinical evidence of HSV infection,although one infant born vaginally to a motherwho was not compliant with acyclovir treatmentdid have a transiently positive HSV culture. Themother’s cultures taken at admission for labor werenegative. The infant was observed without treat-ment, and subsequent HSV cultures were nega-tive. No other infants experienced any clinicallyapparent neurologic, hepatic or renal complica-tions or other adverse effects attributable toacyclovir during the neonatal period.

DISCUSSION

In an effort to prevent intrapartum HSV trans-mission, obstetricians generally resort to Cesareandelivery when a patient presents for delivery withrecurrent genital herpes lesions or prodromalsymptoms. Under current guidelines, a vaginaldelivery is appropriate in the absence of thesefindings1,2. Daily acyclovir therapy suppressesrecurrent genital HSV outbreaks in the non-pregnant adult4, and it has been suggested that thistreatment be considered as a means to preventherpes reactivation at delivery2.

Our study demonstrated that pregnant womenwith a history of recurrent genital herpes mightdecrease their risk of clinical reactivation at thetime of delivery by more than 50% by usingsuppressive acyclovir therapy. These findings aresimilar to those reported by Brocklehurst andcolleagues10. These investigators reported a clini-cally important reduction in the incidence ofherpes lesions present at the time of delivery, but



Outcome measure at Acyclovir Placebo p value OR [95% CI]

Clinical HSV recurrenceCesarean for HSVHSV recovery from lesionsb

Asymptomatic HSV sheddingb

Total HSV viral excretionb

7/116 (6%)8/116 (7%)

0/5 (0%)0/97 (0%)

0/102 (0%)

16/115 (14%)14/115 (12%)

3/16 (19%)3/86 (3%)

6/102 (6%)

0.046a

0.172a

0.549c

0.102c

0.029c

0.40 [0.13, 1.08]0.53 [0.19, 1.44]

0 [0, 8.32]0 [0, 2.13]0 [0, 0.83]

OR, odds ratio; CL, confidence limits; HSV, herpes simplex virus; aChi-square analysis, intent-to-treat; bn is less than total number ofpatients since some patients did not have cultures obtained; cFisher exact test, 2-tailed

Table 2 Differences between acyclovir and placebo groups for various outcome measures, at presentation fordelivery

IndicationAcyclovir

(n = 116)Placebo

(n = 115)

RepeatFailure to progressMalpresentationFetal distressOtherHSV

TOTAL

410

3228a

29 (25%)

410

430

14b

35 (30%)

aIn a breach of the study protocol, one patient had a Cesareandelivery for genital herpes without a clinical recurrence at delivery;bTwo patients with genital lesions inadvertently delivered vaginallydue to rapid delivery and protocol error

Table 3 Indications for Cesarean delivery

terminated the study early due to enrollment diffi-culties. Unfortunately, the Brocklehurst study didnot have adequate power to rule out a significantdifference.

The significant reduction in clinical herpesrecurrences for our acyclovir treated patients didnot translate into a similar significant reduction inCesarean deliveries. Possible explanations include:the decision to perform a Cesarean delivery basedonly on a history of genital herpes (in spite of thecurrent ACOG recommendations)2, inadvertentvaginal delivery, and other indications forCesarean (such as breech presentation) in additionto the presence of a herpes lesion (Table 3).

A recent cost-benefit analysis was performed forthe use of acyclovir suppression in the last severalweeks of pregnancy. The authors concluded thatsuppressive therapy would cost less, would result indecreased maternal morbidity and mortality, andwould result in fewer cases of neonatal herpes thandeferring acyclovir treatment and resorting toCesarean delivery for clinical reactivations11.

A theoretical concern is whether symptomaticrecurrences would be converted to asymptomaticshedding episodes by suppressive treatment, thuspotentially increasing an infant’s perinatal expo-sure to HSV through a vaginal delivery12. Thereported incidence of asymptomatic HSVshedding at any given time in pregnant womenwith genital herpes is about 1–2%13–15. Wald andcolleagues16 reported that acyclovir suppressiondecreased asymptomatic shedding by 96% in non-pregnant patients, but this reduction has not yetbeen confirmed in pregnant women. We founda significant decrease in clinical genital lesions(14% versus 6%), but no difference in subclinicalshedding (3% versus 0%) in the group treated withsuppressive acyclovir therapy. There was no evi-dence that clinical lesions were replaced by asymp-tomatic shedding.

In fact, acyclovir suppressive therapy signifi-cantly decreased the total incidence of virusrecovered at presentation for delivery. This hasimportant implications in that the primary time offetal exposure is during the intrapartum period,regardless of whether the infant is deliveredvaginally or by Cesarean section. The decreasedincidence of viral shedding may decrease thepotential for intrapartum HSV exposure.

On short-term follow-up, there were no appar-ent adverse effects on any of the neonates who hadprenatal exposure to acyclovir, 1200 mg daily, atterm. Data from the Acyclovir in PregnancyRegistry do not suggest adverse outcomes attribut-able to acyclovir in over 1200 prenatal exposures,regardless of gestational age17. Additional anec-dotal evidence of acyclovir’s safety is providedindirectly through reported pediatric clinical expe-rience. Both term and preterm infants treated dailywith intravenous acyclovir tolerate the drugwell18,19. Furthermore, the fetal serum levels ingravidas taking 1200 mg acyclovir daily have beenreported to be much lower than the acyclovirlevels achieved during neonatal parenteraltreatment6,18,19. However, clinical evaluation isrelatively insensitive to identify sequelae from drugtreatment, and we cannot conclude that prenatalsuppressive acyclovir therapy is completely safe forthe fetus. This study was not designed or poweredto specifically test for newborn safety. Furtherevaluation of short- and long-term neonatal out-comes is necessary. In particular, this shouldinclude the evaluation of the impact of maternalacyclovir suppression on the fetal and neonatalkidney.

There are some limitations to our trial. First, wedid not discriminate between HSV-1 and HSV-2recurrent genital infections. Since HSV-1 genitalinfection tends to reactivate less frequently thanHSV-220, it is possible that the lower frequency ofclinical reactivation in the acyclovir treatedpatients was due to an over-representation ofHSV-1-infected patients in the acyclovir group.However, randomization of the patients shouldhave resulted in similar numbers of women witheach type of infection in each treatment group. Infact, the mean annual incidence of clinical herpesreactivations prior to pregnancy was the same ineach group (Table 1).

Another limitation is the lack of culture-proveddiagnoses in all patients considered eligible forparticipation. However, the practicing clinicianoften has only the history of the patient to rely onwhen making a decision regarding management ofherpes in pregnancy. Ninety percent of adults witha clinical picture and history compatible withfirst-episode genital herpes had positive cultures ina recent series21. It is possible that some of these



patients were misdiagnosed and did not actuallyhave genital herpes. Randomization of the patientsshould have resulted in similar numbers of mis-diagnosed patients in each treatment group.

The main limitation is that our enrollment wasterminated before our planned sample size wasreached. It is possible that early termination intro-duced bias. However, the number of patientsenrolled is over twice the size of the enroll-ment in each of the only other two randomizedclinical trials of acyclovir in late pregnancy10,22. In

addition, one of these trials was also halted earlydue to low enrollment10.

In summary, acyclovir suppression in the lastseveral weeks of pregnancy significantly reducedthe incidence of clinically evident genital herpes aswell as the overall viral excretion rate at the time ofdelivery in patients with previous herpes infection.We did not observe any short term, adverse effectsof treatment on the fetus or neonate; however,further investigation is needed to determine thesafety of antenatal acyclovir exposure.

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management of pregnancies complicated by genitalinfections with herpes simplex virus. Clin Infect Dis1992;15:1031–8

2. American College of Obstetricians and Gynecolo-gists. 1999. Management of herpes in pregnancy.ACOG Practice Bulletin Washington, D.C.1999;8

3. Randolph AG, Washington AE, Prober CG.Cesarean delivery for women presenting withgenital herpes lesions. J Am Med Assoc 1993;270:77–82

4. Wald A, Corey L, Cone R, et al. Frequent genitalherpes simplex virus 2 shedding in immuno-competent women: effect of acyclovir treatment.J Clin Invest 1997;99:1092–7

5. Centers for Disease Control and Prevention. 1998Guidelines for treatment of sexually transmitteddiseases. MMWR 1998;47(RR-1):20–6

6. Frenkel LM, Brown ZA, Bryson YJ, et al.Pharmacokinetics of acyclovir in the term humanpregnancy and neonate. Am J Obstet Gynecol 1991;164:569–76

7. Scott LL, Sanchez PJ, Jackson GL, et al. Acyclovirsuppression to prevent Cesarean delivery after first-episode genital herpes. Obstet Gynecol 1996;87:69–73

8. Brown ZA, Vontver LA, Benedetti J, et al. Genitalherpes in pregnancy: risk factors associated withrecurrences and asymptomatic viral shedding. Am JObstet Gynecol 1985;153:24–30

9. Hankins GDV, Cunningham FG, Luby JP, et al.Asymptomatic genital excretion of herpes simplexvirus during early labor. Am J Obstet Gynecol 1984;150:100–1

10. Brocklehurst P, Kinghorn G, Carney O, et al.A randomised placebo controlled trial of suppres-sive acyclovir in late pregnancy in women withrecurrent genital herpes infection. Br J ObstetGynaecol 1998;105:275–80

11. Randolph AG, Hartshorn RM, Washington AE.Acyclovir prophylaxis in late pregnancy to preventneonatal herpes: a cost-effectiveness analysis. ObstetGynecol 1996;88:603–10

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13. Arvin AM, Hensleigh PA, Prober CG, et al. Failureof antepartum maternal cultures to predict theinfant’s risk of exposure to herpes simplex virus atdelivery. N Engl J Med 1986;315:796–800

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15. Prober CG. Herpetic vaginitis in 1993. Clin ObstetGynecol 1993;36:177–87

16. Wald A, Zeh J, Barnum G, et al. Suppression ofsubclinical shedding of herpes simplex virus type 2with acyclovir. Ann Intern Med 1996;124:8–15

17. Reiff-Eldridge R, Heffner CR, Ephross SA, et al.Monitoring pregnancy outcomes after prenataldrug exposure through prospective pregnancyregistries: a pharmaceutical company commit-ment. Am J Obstet Gynecol 2000;182:159–63

18. Hintz M, Connor JD, Spector SA, et al. Neonatalacyclovir pharmacokinetics in patients with herpesvirus infections. Am J Med 1982;73:210–14

19. Yeager AS. Use of acyclovir in premature and termneonates. Am J Med 1982;73:205–9



20. Benedetti J, Corey L, Ashley R. Recurrence ratesin genital herpes after symptomatic first-episodeinfection. Ann Intern Med 1994;121:847–54

21. Löwhagen G-B, Tunbäck P, Andersson K, et al.First episodes of genital herpes in a Swedish STDpopulation: a study of epidemiology and

transmission by the use of herpes simplex virustyping and specific serology. Sex Transm Inf 2000;76:179–82

22. Stray-Pedersen B. Acyclovir in late pregnancy toprevent neonatal herpes simplex. Lancet 1990;336:756

RECEIVED 07/03/01; ACCEPTED 11/30/01



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