What Antiviral Therapies are Used?

HSV is most commonly treated with antiviral therapies because studies have shown the efficacy of them  in reducing the duration and severity of genital and oral herpes..  There are two different approaches to antiviral management of HSV, both of which depend wholly on the nature of the disease, lifestyle and psychosocial consideration.  These include "episodic" oral antiviral therapy (where antiviral therapy is used intermittently by the patient during a recurrence), or "suppressive" antiviral therapy (where the antiviral therapy is taken continuously to prevent recurrences) (Miller, AHMF).

ORAL HERPES (HSV-1)
Primary oral-facial HSV infections are usually diagnosed as gingivostomatitis or pharyngitis and are seen in young children or adults.  The first antiviral cream to be approved for cold sores was penciclovir (Denavir).  It heals sores about one day faster than without treatment, stops viral shedding, and reduces the amount and duration of pain associated with blisters.  One study showed that foscarnet (Foscavir) reduced the size of the blisters and increased the rate of healing when HSV-1 was induced by intense sunlight.  Another study showed that an ointment composed of caffeine and interferon (a component of the immune system) increased healing time compared to using the interferon alone.  A new antiviral therapy, Ascoxal, a solution applied to the sores with a cotton ball, is composed of ascorbic acid (Vitamin C) and substances that fight the typical symptoms associated with the oral virus--it is showing promise  (WebMD).  Acyclovir (ACV, more information in next section), the primary antiviral therapy used in HSV-2 infections, has not been found to be entirely beneficial for recurring eruptions; however, it is used, quite successfully, for severe primary eruptions.  Oral antiviral therapies may be effective, but they are not FDA approved for use in oral-facial herpes infections.  This is due to the fact that chronic topical application of ACV cream has proved ineffective in the suppression of recurrences, although oral ACV has been somewhat successful.

GENITAL HERPES (HSV-2)
ACYCLOVIR (ACV)

Chemical Structure (Pielop et al.)


Molecules "R" Us
Conversion of acyclovir to acyclovir triphosphate leading to DNA chain termination
Acyclovir, a nucleoside analog, is a potent inhibitor if viral replication, and has been in clinical use for 15 years because of its extreme selectivity  (see figure below).  Its specificity for reducing replication of only those cells infected with HSV (it is not activated by uninfected cells) is based on its dependence on two virally encoded enzymes for its activity: thymidine kinase (TK) which monophosphorylates ACV (shown above left; thymidine kinase grouped with HSV), allowing subsequent formation of ACV triphosphate by cellular enzymes, and viral DNA polymerase which is inactivated by ACV triphosphate  (Furman et al., 1984).  ACV is a poor substrate for TK and the viral polymerase is ten times more selective than cellular DNA polymerase.  Early studies indicate that intravenous ACV (5mg/kg every 8 hours for 5 days) significantly reduces the duration of viral shedding, increases the speed of lesion healing, prevents the development of new lesions,  decreases the amount of pain, and possibly decreases the incidence of neurologic complications (urinary retention)  (Corey et al., 1983).  Two important facts are that IV ACV did not affect the rate of future recurrences of HSV-2, and  it is mainly used in severe primary genital herpes infections or for immunocompromised hosts.  Some immunocompetent hosts require hospitalization when a primary genital herpes infection is apparent.  Oral ACV (200mg), five times per day for 10 days, is a convenient form of therapy and it produces similar results as the intravenous form.  Regardless of the severity of the initial infection, it is not advisable to intensify the dosage because gastrointestinal side effects may result.  Topical ACV 5% cream or ointment applied to lesions also decreases the amount of pain and duration of viral shedding from the sores, increases the rate of healing, and prevents new sores from forming.  The FDA approved its use every 3 hours, six times daily, for 7 consecutive days.  As with intravenous ACV, the topical form does not influence recurrence rates  (Pielop et al., 2000).
 

Inhibition of HSV (Pillay)

VALACYCLOVIR (VAL)

Chemical Structure (Pielop et al.)

Valacyclovir, a valine ester prodrug of ACV, has a bioavailability three to five times that of ACV.  This antiviral drug is rapidly converted to ACV after oral consumption, resulting in higher plasma ACV concentrations than those of oral ACV, comparable to those of IV ACV.  Because of this, VAL can be taken orally twice daily as opposed to five daily doses of ACV.  One study compared oral VAL 1000mg twice daily versus ACV 200mg five times daily for 10 days.  Both courses of antiviral treatment were equally effective, according to the FDA.  At the end of the experiment, however, it was determined that a one dose improvement over the ACV 400mg three time daily dosage commonly prescribed by physicians is more expensive.  It is thought that the decreased dosage frequency may improve compliance and thus ultimately clinical efficacy  (Pielop et al., 2000).

FAMCICLOVIR (FAM)

Chemical Structure (Pielop et al.)
 

Famciclovir, oral form, undergoes extensive first-pass metabolism to penciclovir (PCV, a nucleoside analogue that has a similar mechanism of action as ACV) after consumption, reaching maximum levels in less than an hour if taken while fasting.  PCV has been shown to be effective against a small percentage of acyclovir-resistant HSV strains in vitro  (Lazarus et al., 1999).  FAM has an improved bioavailability (77%, compared to ACV's 20%), and significantly longer intracellular half-life in its PCV triphosphate form (10-20 hours, compared to ACV's triphosphate form of 1 hour).  This allows for less frequent dosages.  VAL and FAM are similar in their high absorption and bioavailability, safety profile, and efficacy in treating primary episodes of genital herpes.  FAM is often prescribed 250mg three times daily for 5-10 days to treat primary primary infections, but it is not FDA approved for this usage  (Pielop et al., 2000).

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