Treatment and prevention of herpes simplex virus type 1 infection
INTRODUCTION — The treatment and prevention of herpes simplex virus type 1 (HSV-1) infection depends upon a variety of considerations including:
The site of infection
The severity of symptoms
The frequency of recrudescence
The immunologic status of the patient
The standard treatments for HSV infections include various nucleoside derivatives that interfere with the synthesis of viral DNA. Acyclovir, an acyclic nucleoside analog, has become the cornerstone of treatment for most serious HSV infections and is the most widely prescribed antiviral medication. Alternative agents include valacyclovir, famciclovir, vidarabine, and foscarnet. (See "Acyclovir: An overview" and see "Valacyclovir: An overview" and see "Famciclovir: An overview" and see "Foscarnet: An overview").
Drugs are also in development that inhibit the helicase-primase enzyme of HSV-1 and -2 and represent a new target for antiviral activity [1,2]. Two of these agents, BILS 179 BS and BAY 57-1293, were effective in clearing both HSV-1 and -2 in murine models of infection following oral administration; BILS 179 BS appeared to be active even if administered as late as 65 hours after infection [1] and BAY 57-1293 may decrease the frequency and severity of recurrences [2]. Neither drug is active against latent virus, and neither has been subjected yet to clinical trials in humans.
Most drug development has been focused on inhibition of viral proteins. However, the extensive use of medications that target HSV proteins has led to the development of mutations and subsequent drug resistance. To address this problem, host cell proteins are being explored as potential targets for drug development [3].
The recommendations for treatment and prophylaxis of primary and recurrent HSV-1 infections in the normal and immunocompromised patient will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of HSV-1 infections are discussed separately. (See "Epidemiology of herpes simplex virus type 1 infection" and see "Clinical manifestations and diagnosis of herpes simplex virus type 1 infection").
HERPES GINGIVOSTOMATITIS AND LABIALIS — Herpes gingivostomatitis is the principle manifestation of primary HSV-1 infection, and herpes labialis is the most common presentation of HSV-1 infection and generally represents HSV-1 reactivation. The treatment of herpes gingivostomatis and labialis have been subjects of far less study than therapy for genital HSV infection.
Primary infection — Gingivostomatitis is the principle manifestation of primary HSV-1 infection. Involvment of other organs can occur (see below).
Treatment — Children who present with gingivostomatitis often require either topical or oral administration of analgesics and, in severe cases, intravenous rehydration. Short-term relief (10 to 15 minutes) can be achieved via mouth rinses with viscous lidocaine. Zilactin, a nonprescription topical medication containing hydroxypropyl cellulose, adheres to mucosa and may be used to protect lesions from trauma and irritants [4]. Ziladent, a similar agent with the addition of benzocaine, a topical anesthetic, can provide pain relief for up to one to six hours. In more severe cases, oral opiates, usually in the form of elixirs, may be required for adequate pain relief. Adults may also benefit from topical analgesics but rarely require oral pain medications. In addition, antiseptics may hasten drying of lesions and decrease the risk of superinfection in both children and adults [5].
Compared to genital HSV infection, antiviral treatment of labial HSV disease is less well studied [6,7]. Studies suggest that acyclovir may be beneficial if begun early during primary (or recurrent) infections since the drug acts only during active viral replication, which generally precedes symptoms. In a randomized, double-blind, placebo-controlled trial, children with herpes gingivostomatitis treated early (<72 hours after the onset of lesions) with acyclovir (15 mg/kg up to a dose of 200 mg PO, with each dose taken five times daily for seven days) had the following results [8]:
Shorter duration of lesions (median 4 versus 10 days)
Earlier disappearance of fever (1 versus 3 days)
Earlier resolution of extraoral lesions (0 versus 5.5 days)
Decreased duration of eating difficulties (4 versus 7 days)
Reduced viral shedding (1 versus 5 days)
The conclusion of this trial was that oral acyclovir begun within the first three days of onset of lesions shortens the duration of all clinical manifestations and the infectivity of affected children. Topical acyclovir, which is available as a 5 percent polyethylene glycol ointment, has not been promising in the treatment of primary oral lesions since it has poor penetration to the sites of replication [9].
Most clinicians would treat primary herpes labialis with acyclovir (200 mg PO five times per day or 400 mg PO three times per day) for seven to ten days [10]. Intravenous acyclovir may be required in severe cases, such as ulcerative pharyngitis, and especially when herpes labialis is associated with other infections (eg, pneumococcal sepsis). There are no clinical trials on the use of valacyclovir or famciclovir for primary herpes labialis.
Prevention — There is currently no vaccine effective against HSV [11] and, because most adults have been exposed to HSV-1, there are no recommendations regarding postexposure prophylaxis with antiviral medications for immunocompetent individuals exposed to a patient with HSV-1. Children, however, have been shown to benefit from antiviral treatment during periods of known exposure to active HSV lesions. In one study, 45 children exposed to herpetic gingivostomatitis in a daycare center were randomized to treatment with acyclovir (30 to 50 mg/kg five times daily) or no treatment [12]. Among the 23 children randomized to treatment, none developed clinical HSV disease and only 8 seroconverted compared to 18 cases of clinical HSV infection and 20 seroconversions among the 22 untreated children.
Prevention of primary infections with HSV-1 and prophylaxis against recurrent attacks may be recommended in certain cases, depending upon the history of exposure, frequency of recrudescence, age, and immunologic status of the patient. Nonpharmacologic methods of prevention include the use of gloves and condoms to avoid direct contact with active lesions and the avoidance of excessive sun exposure in UV light-induced recurrent herpes labialis. However, when pharmacologic intervention is warranted, acyclovir is the drug of choice.
Recurrent infection
Treatment — Most immunocompetent individuals with recurrent herpes labialis do not require treatment other than the occasional use of local analgesics (see above).
Treatment trials have addressed a variety of strategies of managing HSV in patients with recurrent symptoms, including initiation of therapy before a stimulus well-known to trigger oral herpes [13,14]. For example, in a study of 237 skiers with a history of recurrent labial herpes triggered by sun exposure found no difference in the prevention of lesions or healing rate for acyclovir (800 mg BID PO initiated 12 to 24 hours before sun exposure and continued for three to seven days) compared with placebo [13].
Other trials have evaluated whether beginning therapy at the first sign of prodromal symptoms (eg, pain, tingling) has any significant benefit. Most have demonstrated that early initiation of therapy has a modest effect on time to healing and decreased pain. The following observations illustrate the range of findings:
The largest trial included 1573 patients who were randomly assigned to 1 percent penciclovir cream or a vehicle control cream [15]. The time to healing (4.8 versus 5.5 days) and days of pain (3.5 versus 4.1) were decreased in the group receiving penciclovir regardless of whether it was initiated early (prodrome or erythema stage) or late (papule or vesicle stage) [15]. Viral shedding was reduced significantly only in the group receiving penciclovir early.
In one trial, 174 immunocompetent patients were randomly assigned to oral acyclovir (400 mg taken five times daily) versus placebo within one hour of the first sign or symptom of recurrence [16]. The frequency of HSV culture positive lesions decreased by 48 percent, but the development of lesions and the maximum size of lesions was not altered by drug treatment. In the subgroup of patients able to start therapy in the prodromal stage or when the lesion was only erythematous, acyclovir decreased pain duration by 36 percent and the time to healing by 27 percent.