Treatment of Viral Infections

The treatment of most viral infections is primarily the responsibility of physicians (Table 5).10-13 However, two of the known Herpesviridae, HSV-1 and HSV-2 are responsible for primary and recurrent mucocutaneous herpetic infections and HSV-1 is predominately associated with orolabial infections.14 Consequently, the diagnosis and management of orolabial herpetic infections fall, to a great extent, within the purview of oral healthcare providers.

Table 5. Indications for Antiviral Chemotherapy.10-13
Mechanism of actionDrugs*Indications
Inhibitors of viral attachmentMaravoricCCR5-tropic HIV-1 infections
Inhibitors of viral entryEnfuvirtideHIV infections
DocosanolHSV infections
Inhibitors of viral uncoatingAmantadine
Rimantadine
Influenza A infections
Inhibitors of viral gene expressionBoceprevir
Ledipasvir
Ombitasvir
Paritaprevir
Simeprevir
Telaprevir
Chronic HCV (genotype 1) infections
Anti-herpesvirus nucleoside analogsAcyclovir
Valacyclovir
HSV and VZV infections
Famciclovir
Penciclovir
HSV infections
Idoxuridine
Trifulodine
Vidarabine
HSV keratitis
Ganciclovir
Valganciclovir
HCMV infections
CidofovirHCMV retinitis
Anti-HBV nucleoside analogsAdefovir
Emtricitabine
Entecavir
Lamivudine
Telbivudine
HBV infections
Anti-HCV nucleoside analogsSofosbuvirChronic HCV infections
Anti-HIV nucleoside analogues (reverse transcriptase inhibitors)Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
HIV infections
Anti-herpesvirus non-nucleoside DNA polymerase inhibitorsFoscarnetHSV and HCMV infections
Anti-HIV non-nucleoside reverse transcriptase inhibitorsDelaviridine
Efavirenz
Etravirine
Nevirapine
Rilpivirine
HIV infections
Anti-HCV non-nucleoside RNA polymerase inhibitorsDasabuvirHCV infections
Inhibitors of viral integrationDolutegravir
Raltegravir
Elvitegravir
HIV infections
Inhibitors of viral maturation (protease inhibitors)Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
HIV infections
Inhibitors of viral releaseOseltamivir
Zanamivir
Influenza A and B infections
*FDA-approved information on specific antiviral agents is available at DailyMed - the website is a user-friendly, look-up-and-download resource that provides comprehensive, up-to-date information on individual drugs.3

The most common initial presentation of orolabial HSV-1 infection is primary herpetic gingivostomatitis (Figures 9a and 9b). Following primary infection, the virions enter sensory nerve endings and are transported via retrograde axonal transport to regional sensory ganglia, i.e., the trigeminal ganglia. In the trigeminal ganglia the virus establishes latency in neuronal cell bodies and persists in an immunologically shielded state until reactivated.

Figure 9.
Primary herpetic gingivostomatitis in an immunocompetent patient.

Upon reactivation, the virions are delivered by anterograde axoplasmic transport to orolabial sites and manifest as recurrent infections. Recurrent orolabial HSV infections most commonly presents as recurrent herpes labialis (Figures 10a and 10b); less frequently, recurrent herpetic stomatitis (Figures 11a and 11b) attributed to traumatic triggers such as dental injections or thermal burns. Herpetic infections in immunocompromised patients tend to be more severe.

Figure 10.
Recurrent herpes labialis in an immunocompetent patient.
Figure 11.
Recurrent herpes stomatitis in immunocompetent patients.

Herpetic whitlow may occur with either HSV-1 or HSV-2 inoculation into a finger. Herpetic keratoconjunctivitis in most adult is likely the result of autoinoculation. Less frequently, primary and recurrent HSV infection of the skin may present as herpes gladiatorum or eczema herpeticum. A substantial number of erythema multiforme cases are believed to be related to the herpes simplex virus (herpes-associated erythema multiforme).

Orolabial herpetic infections in immunocompetent patients are usually self-limiting. Treatment is palliative and supportive directed at controlling fever, dehydration, and pain; and monitoring for evidence of systemic viremia. Antiviral agents may be prescribed to patients with moderate-to-severe primary herpetic gingivostomatitis; to patients with recurrent orolabial herpetic infections; and to immunocompromised patient, who are inherently at risk of complications (Table 6).11,12,15-25

Table 6. Antiviral Agents for the Treatment and Prevention of Orolabial HSV Infections.11,12,15-25
InfectionDrugAdult dosage
Moderate-to-severe primary herpetic gingivostomatitis
     • Immunocompetent patients
acyclovir400 mg, PO, tid for 7-10 days
OR
15 mg/kg (oral suspension), PO, 5x/day for 7 days
famciclovir500 mg, PO, bid/tid for 7-10 days
valacyclovir1 g, PO, bid for 7-10 days
Recurrent orolabial infections
     • Immunocompetent patient
docosanol*10% cream, 5x/day until healed
penciclovir*1% cream, q2h while awake for 4 days
acyclovir*5% cream, 5x/day x 4 days
     • Immunocompetent patients
     • Immunocompromised patient
famciclovir1500 mg, PO, single dose
valacyclovir2 g, PO, 2x/day x 1 day
acyclovir400 m, PO, 5x/day for 5 days
Suppression of recurrences
     • Immunocompromised patients
acyclovir400 mg,, PO, bid
valacyclovir500 mg, PO, once/day
famciclovir500 mg, PO, bid
Suppression of dental procedure-related recurrences
     • Immunocompetent patients
valacyclovir2 g, PO, 2x/day, the day of procedure
then
1 g, PO, 2x/day, the day after procedure
Mucocutaneous herpetic infections
     • Immunocompromised patients
acyclovir400 mg, PO, 5x/day for 7/10days
famciclovir500 mg, PO, bid for 7-10 days
valacyclovir500 – 1000 mg, PO, bid for 7-10 days
Acyclovir-resistant mucocutaneous infections
     • Immunocompetent patients with moderate-to-severe primary herpetic gingivostomatitis
     • Immunocompromised patients
foscarnet40 mg/kg, IV, q8h x 12-21 days
*Immunocompromised patients should not be treated with topical antiviral agents.

The recommendation of oral acyclovir for the treatment of moderate-to-severe primary herpetic gingivostomatitis in immunocompetent patients is based on limited-quality evidence.12,15 In a placebo controlled study, children on acyclovir experienced reduction in the duration of lesions, fever, difficulty eating and drinking, and viral shedding. Oral valacyclovir or famciclovir are recommended as acceptable alternatives to oral acyclovir.11

The recommendation of oral acyclovir, valacyclovir, or famciclovir for the treatment of recurrent herpes labialis in immunocompetent and immunocompromised patients is based on good-quality evidence.11,12,16-18 The drugs have been found to be effective in reducing viral shedding, pain, and healing time. Based on good-quality evidence, oral acyclovir, valacyclovir, or famciclovir are also recommended for the suppression of frequent recurrent infections.11,22

Oral acyclovir, valacyclovir, and famciclovir are well tolerated and associated adverse reactions are similar.3 Common ADRs include nausea, vomiting, diarrhea, malaise, and headaches. Rare ADRs include myalgia, rash, Stevens-Johnson syndrome, tremors, lethargy, confusion, hallucinations, seizures, and coma. Resistance to acyclovir is uncommon, but HSV strains resistant to acyclovir are also resistant to valacyclovir and famciclovir.11

Topical docosanol, 10% cream, a 22-carbon saturated alcohol, is approved by the FDA as an over-the-counter agent for the treatment of recurrent herpes labialis in immunocompetent patients. Based on good-quality evidence the drug is somewhat effective. Treatment within 12 hours of prodromal signs and symptoms decreased pain (2.2 vs. 2.7 days) and healing time (4.1 vs. 4.8 days).12,22 Common ADRs at the site of application include rash and pruritis.3

Topical penciclovir, 1% cream, based on good-quality evidence is helpful in the treatment of herpes labialis in immunocompetent adults.12,23 The application of penciclovir versus placebo beginning within one hour of the first signs and symptoms of recurrence reduced median duration of pain (4.1 to 3.5 days) and healing time (5.5 to 4.8 days).24 The drug did not affect the medial time for viral shedding (3 vs. 3 days). Systemic absorption of penciclovir is negligible.

Treatment with topical acyclovir, 5% cream, beginning within one hour of the onset of signs and symptoms of recurrence, based on good-quality evidence, has been shown in two parallel and independent trials to reduce the duration of recurrent herpes labialis in immunocompetent patients by about half a day.12,25 In study 1, the mean duration of lesions was reduced from 4.8 to 4.3 days. In study 2, the mean duration of lesions was reduced from 5.2 to 4.6 days.25

Patients with moderate-to-severe primary herpetic gingivostomatitis and immunocompromised patients with acyclovir-resistant mucocutaneous herpetic infections may respond to intravenous foscarnet.11 Potential ADRs include electrolyte imbalances; seizures; anemia and neutropenia; fever; nausea, vomiting, and diarrhea; headache; and reversible renal dysfunction, especially in patients with inadequate hydration, is not uncommon.3