Routine acyclovir therapy: Isn't it time?

Routine acyclovir therapy: Isn't it time?

By Jody R. Murph, MD, and Charles Grose, MD

For almost 20 years, pediatricians have hesitated to useacyclovir for "minor" ailments like fever blisters and chickenpox.These authors make the case that even minor illnesses deserve this proventherapy--especially now that it is off-patent and reasonably priced. Seeif their argument persuades you.

An effective treatment for herpes simplex virus (HSV) and varicella-zostervirus (VZV) infections has been known ever since clinical trials demonstratedthe efficacy of acyclovir in the 1970s. Since those early trials, acyclovirhas been successful well beyond the initial expectations.¹ Bythe time the patent expired in 1997,² continued use for almosttwo decades had firmly demonstrated the safety of the antiviral compound.While many of the initial studies were conducted in patients with immunosuppressivediseases, acyclovir is now prescribed for otherwise healthy children andadults with HSV and VZV infections, with no evidence of the emergence ofacyclovir-resistant strains.

Despite this success story, many pediatricians have never prescribedacyclovir. The Redbook has been extremely conservative in its recommendations,continuing to include a phrase about potential unforeseen dangers.³Yet in the more than 17 years that acyclovir has been prescribed, no unusualtoxicities have been documented. The main side effects that have been notedare a reversible nephropathy and elevated creatinine levels, and this toxicityhas been seen only in patients receiving high doses of intravenous acycloviror those with preexisting renal impairment.

In making our case for more widespread use of this medication, we willreview the indications for oral acyclovir in treating HSV and VZV infectionsin healthy children and children with some chronic conditions. We will notdiscuss management of congenital and perinatal infections, nor will we reviewherpes infections in severely immunocompromised children or children infectedwithhuman immunodeficiency virus (HIV), subjects that have received considerableattention in the major pediatric textbooks.

Acyclovir and the newer derivatives

Acyclovir was discovered by scientists at the Wellcome Company, whichheld the patent until 1997. Their product is called Zovirax. Developed asan intravenous medication, it was later formulated for oral administration.Acyclovir is currently available as 200 mg, 400 mg, and 800 mg tablets,as a powder for IV infusion, and as a suspension with a concentration of200 mg per 5 mL.

Two newer derivatives are famciclovir (Famvir) and valacyclovir (Valtrex).These compounds were produced to achieve better bioavailability when administeredorally than oral acyclovir,¹ which is not well absorbed. Evenso, as we will show, oral acyclovir has been efficacious in children--probablybecause it is easy to administer a sufficiently high dosage on a mg perkg basis.

Now that acyclovir is no longer protected by patent, the cost has becomereasonable enough that pediatricians may wish to consider prescribing itfor a range of acute herpes viral infections (Table 1). Prescribing famcicloviror valacyclovir is problematic because neither drug is approved for childrenless than 18 years of age.

Herpesvirus-1 infections

Over 70% of people in the United States have been infected with HSV-1,and most of them acquired their primary infection during the first fiveyears of life. Infection with HSV-1 has several manifestations.

Herpetic gingivostomatitis. The most common presentation in childrenbeyond the neonatal period is herpetic gingivostomatitis, or fever blisters.In many children, the infection is unrecognized because the child remainsafebrile with only a few oral lesions. But the infection is not always sobenign. In some children, it progresses to a severe necrotizing gingivostomatitiswith fever, lymphadenopathy, and often dehydration secondary to poor fluidintake (Figure 1). Oral lesions and difficulties with drinking and eatingmay persist for two weeks or more. Extraoral lesions may occur around themouth and nostrils by direct extension, drooling, or hand-to-mouth behavior.Lesions may also appear on more remote sites when an infected child sucksher fingers or scratches her scalp. Auto-inoculation into the eye, whichmay lead to herpetic keratitis, can sometimes occur. An even rarer complicationis herpetic croup, secondary to extension of the viral infection from theoropharynx into the larynx, epiglottis, and trachea.

A latent state follows the acute infection, during which the virus remainsdormant in sensory neural ganglia innervating the areas of skin and mucousmembranes that were originally involved. Reactivation of the virus generallycauses milder disease than the primary infection, but occasionally severeintraoral recurrences are indistinguishable from primary disease.⁴Local trauma, sun exposure, febrile illness, or abrasions can stimulatethese recurrences. Children who have very severe primary gingivostomatitis,in particular, tend to have more severe recurrences in the years followingthe primary infection.

Most evidence suggests that, as with other transmissible childhood diseases,the rate of HSV-1 acquisition is higher in children who attend child-carecenters.⁵ Proximity enhances opportunities for the exchange ofsaliva and the transmission of viral organisms. Asymptomatic recurrent oralherpes is common, and children with symptomatic recurrences often secretevirus before they have obvious fever blisters.

The rate of HSV transmission in child care varies considerably from onefacility to another. In one study in a small, university-affiliated child-carecenter, four to eight children of different ages occupied each room.⁶By 5 years of age, 37% of children at the center had evidence of HSV-1infection either by serology or by virus isolation. One-fourth had gingivostomatitisduring primary HSV-1 infection. This study did not find widespread transmissionfollowing an outbreak in one room. By contrast, a report of HSV-1 infectionin a much larger child-care center had more dramatic findings and may berepresentative of larger facilities.⁷ In this center, which housed10 to 20 children of similar age in each room, discrete outbreaks of HSV-1infection led to the eventual infection of 73% to 100% of susceptible children.Over 90% of all primary infection was associated with clinically overt oralulcers and gingivostomatitis. Almost half the children with primary HSVinfection had fever greater than 39° C. In three fourths of them feverpersisted for three or more days, and in 10% it persisted for more thansix days. Thus, the morbidity for children with primary HSV-1 infectionis often considerable, necessitating exclusion from child care, parentalabsence from work, and occasionally hospitalization for IV hydration.

Because of early concerns about resistance, acyclovir has not been recommendedfor children with uncomplicated primary HSV-1 infection. Experience overthe last decade has shown, however, that acyclovir resistance has been documentedalmost exclusively in immunocompromised patients with chronic HSV infections.^8,9Nevertheless, some authorities continue to suggest that oral acyclovir bereserved for primary HSV infections of unusual severity. The conundrum thatrecommendation produces is this: In order for oral acyclovir treatment tobe efficacious, it must be initiated before the pediatrician knows whetherthe infection will become serious or not.

The argument for earlier treatment of primary HSV-1 infection has receivedan enormous boost from a recently published placebo controlled, double-blindedclinical trial.¹⁰ Efficacy of treatment was firmly demonstratedin a therapeutic study in Israel of 72 children with HSV gingivostomatitis(Figure 2). The youngest child was 10 months of age and the oldest was 6years. Treatment consisted of 15 mg/kg doses of acyclovir suspension givenfive times daily for seven days for a total daily dose of 75 mg/kg, or aplacebo. Viral shedding lasted only one day in the treated group, vs. fivedays in the untreated group. Furthermore, children in the treatment groupexperienced significantly fewer days of fever and oral lesions, fewer daysof difficulty eating, and fewer days of painful drinking. None of the acyclovir-treatedchildren required hospitalization after therapy began, whereas almost 9%of children in the placebo group were hospitalized for two to three daysfor rehydration. All treated children had significantly shortened periodsof clinical symptoms and no serious side effects. In the placebo group,83% of children continued to have oral lesions for seven days or more, and64% experienced difficulty eating or drinking for at least seven days. Duringthis symptomatic period, these children could not attend child care or kindergarten.Their parentspresumably had to miss work for a week or arrange alternativesick-child care.

On the basis of these data, we recommend that pediatricians considerearlier treatment of primary herpetic gingivostomatitis and severe recurrencesof orofacial herpes. Treatment for primary infection could use the dosagein the study. Other experts have suggested a slightly lower dosage of 15mg/kg qid (60 mg/kg/day).¹ Data from studies of genital herpessuggest a maximum daily dose of one gram. Suggested therapies for herpesvirusinfections are summarized in Table 2. Acyclovir has also been used successfullyfor prophylaxis in child-care centers after an outbreak of HSV-1 infection.¹¹

Herpetic whitlow. A small number of children with primary HSV-1 infectiondevelop a herpetic whitlow on one or more fingers, probably by auto-inoculation.Recurrences and severity of the whitlow vary from patient to patient, sotreatment must be individualized. Generally, a therapeutic dosage of oralacyclovir (15 mg/kg qid) is prescribed for seven to 10 days, followed bya suppressive dosage for two to three weeks. A suggested suppressive dosageis 10 mg/kg tid. An occasional patient needs a therapeutic dosage for severalweeks before the whitlow abates and does not recur upon cessation of therapy.

HSV-1 gladiatorum. Orofacial HSV-1 infection can be transferred not onlyto the fingers and hands of the same child by auto-inoculation, but alsoto the skin of playmates by close physical contact during roughhousing orathletic competition. In the Midwestern states, from Oklahoma to Minnesota,where wrestling is a popular varsity sport, herpes gladiatorum is a wellrecognized infection. The disease is transmitted by infected saliva froma wrestler with asymptomatic recurrent oral herpes into minute scratcheson the neck and trunk of his opponent.

All cases of acute herpetic skin disease in adolescents should be treatedwith oral acyclovir. The dosage for children weighing more than 15 kg isone gram per day for five to 10 days. Recurrences should also be treatedto decrease contagion from the index case to other wrestlers. Some coachesprefer that all wrestlers with an HSV recurrence be placed on a suppressiveacyclovir dosage of 400 mg bid for the duration of the wrestling season.

Herpesvirus-2

HSV-2 infection occurs in 15% to 20% of people in the US. Except forperinatal disease, most infections are acquired by sexual contact duringadolescence and early adulthood. The standard of care for treatment of primarygenital herpes infection in adolescents is one gram of oral acyclovir aday, given in five 200 mg doses for five to 10 days. Primary genital herpesof unusual severity can be treated initially with intravenous acyclovir(5 mg/kg every 8 hr); after defervescence, a 10-day course of treatmentis completed with oral acyclovir. Similarly, reactivations of genital herpesare treated with oral acyclovir at a daily dosage of one gram; the durationof therapy is five days. Because of the inconvenience of taking medicationfive times a day, some physicians prescribe acyclovir at two alternativeregimens: 400 mg tid or 800 mg bid. Both schedules seem to be successfulin some but not all patients, with symptomatic reactivations of genitalherpes infection in some cases. In our experience, some adolescents requiremore frequent doses of oral acyclovir.

Adolescents with frequent recurrences of genital herpes may benefit fromcontinual suppressive antiviral therapy; the dosage of oral acyclovir isusually 400 mg bid. Emergence of acyclovir-resistant strains of HSV-2 hasnot been a problem in otherwise healthy adolescents and young adults treatedfor several years with suppressive therapy.^8,9 Because of thereduced cost of acyclovir, suppressive therapy is no longer a major financialburden.

HSV-2 meningitis.This is an unusual entity that appears unrelated tothe far more serious diagnosis of HSV meningoencephalitis. One noteworthycase was in Iowa in 1998. The teenager presented with acute meningeal symptomson the first day of a long July Fourth weekend. The cerebrospinal fluidexamination showed a mildly elevated protein level as well as an increasednumber of lymphocytic cells. She was hospitalized for two days but dischargedwhen the CSF culture failed to grow bacteria. Because Iowa was in the midstof a summer enteroviral outbreak, the tentative diagnosis was enteroviralmeningitis, but since the patient had a history of recent sexual activity,the physician requested an HSV-2 specific PCR test on the CSF. Because ofthe holiday, the positive PCR result was not returned until six days afterthe lumbar puncture. The patient was contacted at home and found to be muchimproved symptomatically.

Even in retrospect, the patient did not recall any symptoms relatingto genital herpes. She was treated with one course of oral acyclovir forpresumed primary HSV-2 infection. Had the diagnosis of HSV-2 meningitisbeen made during the initial hospitalization, it would have been reasonableto treat her with high-dose intravenous acyclovir to diminish the durationof her severe headache. However, the delay in diagnosis also illustratedthat a patient with HSV-2 meningitis can recover without therapy or perhapsonly oral acyclovir.

Varicella-zoster virus

Primary VZV infection is usually described as relatively benign in children.The mortality rate for children 1 to 14 years of age is only about one in50,000. However, an extremely important statistical point documented consistentlyby the Centers for Disease Control and Prevention over the last 20 yearsis that the mortality rate in infants (birth to one year) is at least threetimes greater than the childhood rate.¹² Mortality rates alsorise gradually in late adolescence and early adulthood. Pregnant women withvaricella appear to be at especially high risk. In the US, approximately100 children and adults die each year from chickenpox and its complications.Most of the deaths occur in otherwise healthy infants, children, and youngadults.^12,13

Morbidity can be predicted on the basis of the clinical situation. Chickenpoxincreases in virulence as the infection is passed from the index case withina family to other siblings, probably because siblings in the same householdare in closer contact than children at school or in day care, so that theinoculum dose of virus is higher. Infants are at a particularly high riskof severe chickenpox when they contract the infection from an older sibling.Chickenpox also increases in severity in adolescents and young adults:Theexanthem is more widespread than in younger children, and varicella pneumonitisis more common. In addition to the viral complications, an association ofchickenpox with secondary streptococcal infections of the skin is becomingincreasingly common.

The availability of an effective vaccine to prevent chickenpox has not,unfortunately, made this discussion moot. While the American Academy ofPediatrics' recommendation of immunization for all children 1 to 2 yearsof age is gradually gaining acceptance, CDC statistics show that in 1998only 25% of children were immunized nationwide. In addition, the AAP recommendationfor "catch-up" immunization of older children who haven't hadchickenpox is proving less acceptable than the recommendation for youngchildren--possibly because medical insurance may not cover the higher costof the two varicella immunizations recommended for children over 12yearsof age.

Treatment. In light of these observations, we suggest that immunocompetentchildren in any of the following risk groups be considered for treatmentwith oral acyclovir when they are infected with VZV:

• all infants who do not fit the Redbook criteria for VZIG (varicella zoster immune globulin) or intravenous administration of acyclovir. The Red Book criteria are listed in Table 3.
• children who are the second and third cases of sequentially transmitted chickenpox within a family unit
• all postpubertal adolescents with chickenpox. Although the likelihood of pneumonitis in adolescents increases with the severity of the exanthem, by the time the severity of the exanthem is evident on day three, it is too late to initiate effective treatment with oral acyclovir. Therefore, the decision to treat must be made in the first 24 to 48 hours after diagnosis. Carefully controlled studies have shown that acyclovir treatment will reduce the number of vesicles substantially--by about 50%.^14,15

The Redbook recommends VZIG treatment for any newborn whose mother haschickenpox from five days before delivery until two days afterward. Infantsin this category have not received any maternal anti­VZV antibody inutero.³ The Redbook does not recommend VZIG for healthy full-terminfants exposed to chickenpox after two days of age, on the assumption thatthese infants have received maternal antibody.

Because of the higher mortality of chickenpox in infancy, we recommendthat all infants who contract chickenpox in the first month of life be consideredfor immediate hospitalization for intravenous acyclovir at a dosage of 10mg/kg every eight hours. Infants who have chickenpox during the second orthird month of life should be followed daily by telephone; by day threeof the illness a decision should be made on hospitalization for IV acycloviradministration. For infants between 4 and 12 months of age, we recommendroutine administration of oral acyclovir once chickenpox is apparent. Eventhough some herpesviral experts are reluctant to treat young children withoral acyclovir, the advisory group on chickenpox of the British Societyfor the Study of Infection now recommends oral acyclovir for treatment ofinfants 3 to 12 months of age.¹⁶ This recommendation has beenendorsed by infectious disease experts from the United States.¹⁷

The recommended oral acyclovir dosage for chickenpox is 20 mg/kg qidto a maximum of 800 mg qid for a 40 kg child. For children who weigh morethan 50 kg, we recommend 800 mg five times a day, or three doses of 800mg plus one dose of 1,600 mg. Although earlier recommendations stated thatacyclovir had to be started within 24 hours of the onset of symptoms, webelieve it is effective if started up to 48 hours after onset.¹⁰The maximum dosage should always be prescribed, especially for older childrenand adolescents who weigh more than 50 kg. For adolescents who balk at takinga large number of pills, a 500 mg famciclovir or a 1,000 mg valacyclovirtablet tid may be a more acceptable albeit more expensive alternative.

Renal toxicity is the main concern in acyclovir treatment. This sideeffect is most common in patients receiving intravenous acyclovir for longerthan three to five days. Nevertheless, children on oral acyclovir shoulddrink lots of liquids. If there is any question about normality of renalfunction, a serum creatinine level should be measured.

Children on steroid therapy. At the Children's Hospital of Iowa, we havefound oral acyclovir therapy to be especially practicalfor children withasthma who are receiving intermittent corticosteroid therapy. We explainto parents that these children are particularly vulnerable to infection,explain the importance of antiviral therapy, and ask them to notify thepulmonologist on call immediately if they observe any symptoms of chickenpox.Symptomatic children who are currently receiving steroid burst therapy areadmitted for intravenous acyclovir treatment. Those not currently on steroidsare given a telephone prescription for oral acyclovir, usually within hoursof the onset of chickenpox. This protocol has worked well to protect childrenwith asthma from the serious consequences of chickenpox.

Community-acquired chickenpox is a life-threatening illness if corticosteroidtherapy was begun during the incubation period. Any VZV­susceptiblechild with recurrent asthma therefore remains at risk. To avoid this risk,a protocol for varicella vaccination is presented in the box.

When oral acyclovir fails.What are the criteria for failure of oral therapy?As a rule, we consider oral therapy a failure when one of these criteriais met:

• fever of 101º F and higher
• vesicle count of 300 or more
• inability to drink and eat adequately.

The decision to admit a child for IV therapy must be made by the endof the third day, since most severe complications begin on day four andIV acyclovir takes at least 24 hours to work. The dosage of IV acycloviris 10 mg/kg every eight hours, up to 30 mg/kg/day. An alternative, higher-dosageregimen is based on 500 mg acyclovir/square meter every eight hours. Thelatter schedule usually is equivalent to about 12 mg/kg/dose. These patientsrequire an initial complete blood count with differential, a hepatic profile(transaminases), and renal profile (blood urea nitrogen and creatinine).A serum creatinine should be repeated every two to three days; if the creatininelevel reaches 1 mg, the dosage of acyclovir requires a downward adjustmentafter consultation with an infectious disease specialist.

What about prophylaxis? In the last five years, a question has arisenabout whether oral acyclovir should be prescribed prophylactically duringthe incubation period to eliminate the viremia and prevent clinical disease.The efficacy of this approach has been documented by published studies inpediatric centers in Asia.^18,19

In the US, VZIG prophylaxis is used extensively by hematology/oncologycenters to protect VZV­ susceptible children with leukemia and othertumors after exposure to chickenpox. Although we do not suggest changinga prophylaxis program that works well, there are exceptions to every rule.In the state of Iowa, the University Hospital is the only medical facilitythat routinely stocks VZIG. Two pediatric heart transplant recipients wholive in distant parts of the state have a four-hour drive to Iowa City.Both patients are over three years post-transplantation; both are VZV­susceptible,and neither is eligible to receive live varicella vaccine. During the chickenpoxseason, usually winter, the monthly round trip to Iowa City for VZIG injectionwould have to begin before daybreak and end after dark--unless a snow stormprevented the trip altogether. Therefore, working with a pediatric cardiologist,we have initiated a program to provide varicella-susceptible heart transplantpatients with oral acyclovir prophylaxis (rather than VZIG) following varicellaexposures. We prescribe a dosage used in the published study from Japan:40 mg/kg/day during the second week of the incubation period, that is, startingseven days after the first day of exposure. Once prophylaxis is begun, wemonitor progress by telephone consultation with the parents and the cardiologist.We do not recommend a general application of this protocol but offer itas an alternative for unusual or difficult situations. If either transplantrecipient were to develop clinical chickenpox, immediate admission for intravenousacyclovir treatment would be indicated.

Think it over

This article presents an argument for more extensive use of oral acyclovirto treat herpes and varicella infections in healthy children. The medicationis less expensive than most antibacterial agents. Treatment may benefitnot only the child but also the family that is dependent--as so many familiesare today--on group child care. Children with primary HSV-1 or VZV infectionmay be excluded from school for five to seven days. In families with morethan one child, sequential infection of siblings can lead to two weeks ormore of parental absence from work. Acyclovir treatment can shorten thatperiod by 30% to 50%. Finally, acyclovir suppressions of recurrent HSV-1can allow adolescent athletes to continue to participate in contact sports.

With regard to chickenpox, routine varicella vaccination is nearly alwayspreferable to acyclovir treatment, except for the immunocompromised childor the child during the first year of life. With regard to HSV-1 and HSV-2infections, however, no vaccine is near licensure so treatment remains theonly option.

DR. MURPH is Associate Professor, Divisions of General Pediatrics andInfectious Diseases, University of Iowa College of Medicine, Iowa City,IA.

DR. GROSE is Professor of Pediatrics and Director, Division of InfectiousDiseases, University of Iowa College of Medicine.

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