Many clinical conditions are caused by viral infections and may range from encephalitis to gastroenteritis to rashes to mucous membrane lesions. In the past, the practitioner was limited to only treating symptoms as the virus ran its course. New developments in antiviral therapy are now progressing at an increasingly rapid pace and promise innovative treatment of viral infections.
The ﬁrst portion of this chapter contains descriptions of viruses for which antivirals have been developed and approved. Viral infections are lumped by taxonomic group. In the latter part of this chapter, Food and Drug Administration (FDA)-approved and investigational non-HIV antiviral agents are discussed. (Table 3.1).
Well-known, established viruses continue to create mor- bidity and mortality worldwide, particularly in developing
countries (Fig. 3.1). Not only are the well-recognized viruses unchecked, but new viruses emerge each year—recently exposed to new host populations. Only a few of the newer dis- eases have antivirals or vaccines. Vaccines beneﬁt the individ- ual, but are only effective for the community if a signiﬁcant number are vaccinated. Those who remain unvaccinated rely on post-exposure therapy, which may or may not be available.
The number of antiviral agents available to combat viral infection is expanding rapidly. Most of the approved drugs
have been targeted for use for only a few viral infections, but many of these drugs may lead to new applications for other viral diseases or to the development of other agents that are more effective. New uses for these drugs are always under evaluation. This chapter provides an overview of viral infec- tions that are targeted by these drugs and provides informa- tion on the wide range of efﬁcacy of each antiviral agent. Antiviral drugs are introduced by chemical taxonomic group- ing. Clinical studies and published reports of therapy provide valuable information to the reader. Molecular structure and the mechanism of action are also provided.
VIRAL INFECTIONS OTHER THAN HIV Herpes Simplex Virus (HSV-1 and -2)
Herpes simplex virus occurs in both immunocompetent and immunocompromised populations. Herpes labialis, as charac- terized by orofacial herpes, fever blisters, and cold sores, is usu- ally due to infection with HSV-1 (even though HSV-2 can also be a cause). Up to 30% of the American population may be affected by herpes labialis. Asymptomatic infection as detected by serum antibodies to HSV-1 is present in 60–80% of the gen- eral population and 95% of HIV positive patients. Genital her- pes is usually caused by HSV-2, although the prevalence of HSV-1 in these infections is increasing. Other expressions of HSV-1 and HSV-2 are eczema herpeticum, herpetic encephali- tis, neonatal herpes, herpes gladiatorum, herpetic whitlow, her- petic keratoconjuctivitis, and gingivostomatitis. Erythema multiforme is usually an indirect manifestation of HSV infec- tion. Arguments for the initiation of antiviral drugs for the sup- pression of genital herpes are shown in Table 3.2. HSV-1 and -2 are unique in that these viruses may recur even though humoral immunity is present. These recurrences, called reacti- vation of latent infection, may affect the mucosal membranes or skin or may even result in encephalitis, keratoconjunctivitis, etc. Histopathological characteristics of primary and secondary occurrences focus on the inﬂammatory response from cell
death. Although asymptomatic infection is the most common, patients may present with oropharyngeal outbreaks, genital disease, central nervous system degeneration, and neonatal HSV caused by exposure of the infant to the mother’s genital secretions during delivery.
HSV infection occurs when the virus comes in contact with mucosal surfaces or abraded skin. The infection causes cell ballooning and loss of plasma membranes. Pools of viral material collect between the dermis and epidermis, causing an inﬂammatory response. The vesicular ﬂuid becomes pustu- lar during healing with resultant scabbing. Shallow ulcers may occur.
Once viral replication occurs at the entry site, the virus moves to the dorsal root ganglia via retrograde transport of the virus (Fig. 3.2). After more replication, latency occurs and the severity and frequency of reactivation of the virus appears to be dependent upon the severity of the initial infection. Diag- nosis of HSV-1 and 2 is by tissue culture, serology, and poly- merase chain reaction (PCR). Currently, there is no approved vaccine for HSV-1 and -2. Prevention through education and
use of condoms is warranted, especially for adolescents and adults who seem to be at the greatest risk. Neonatal infection is avoided through careful use of sterile instruments, cae- sarian section deliveries occurring within a few hours of an outbreak, care of maternal tissue which could be infective, and preventing exposure of the infant to any possible contaminant for HSV. Herpes-1 virus has been associated with Bell’s palsy, treatable with acyclovir combined with prednisone (1).
HSV is treated with the nucleoside analogs (e.g., acyclo- vir) as well as foscarnet and triﬂuridine. Table 3.3 is an over- view of how multiple manifestations of one virus (HSV) may be treated by a variety of therapies. As is often observed, drug resistance becomes a problem as new drugs with better efﬁ- cacy become available, providing more options for treatment. HSV is an excellent model as it has been treated with numer- ous nucleoside analog antivirals.
Table 3.3 Treatment of Herpes Simplex Virus Infections
Topical application of 1% penciclovir cream every 2 hours while awake for 4 days. (Mucous membrane application is not recommended).
Topical application of 10% docosanol cream 5 times daily.
Acyclovir is often used off-label for oral treatment of herpes labialis, at 400 mg 3–5 times daily for 5 days.
Famciclovir is often used off-label for oral treatment of herpes labialis, at 125 mg twice daily (b.i.d.) for 5 days, although a recent study showed that higher dosages are more optimal (500 mg 3 times a day (t.i.d.) for 5 days).
Valacyclovir is often used off-label for oral treatment of herpes labialis, at 500 mg twice daily for 5 days, but FDA approval is for 2 g b.i.d. for 1 day.
For chronic suppression, if needed (off-label): Acyclovir 400 mg twice daily, or famciclovir 250 mg twice daily or valacyclovir 500 mg once daily.
Acyclovir 200 mg ﬁve times daily (or 400 mg t.i.d.) for 10 days (initial infection) or 5 days (recurrent attacks). Intravenous acyclovir may be given for severe primary infections, at 5 mg/kg over 1 hour every 8 hours for 7 days, followed by oral therapy. Daily suppressive therapy may be given to prevent frequent attacks, at 400 mg twice daily.
Valacyclovir 1 gram twice daily for 10 days for initial episodes, and 500 mg twice daily for three-ﬁve days for recurrent attacks. For chronic suppressive therapy, 1 gram daily is given for patients with 10 or more recurrences per year, and 500 mg once daily is given for those with less frequent outbreaks.
Famciclovir 250 mg t.i.d. for 10 days for initial episodes, and 125 mg twice daily for 5 days for recurrent outbreaks. For continuous suppressive therapy, 250 mg twice daily is given.
Other cutaneous HSV infections (i.e., herpetic whitlow)
No controlled studies have evaluated acyclovir, valacyclovir, or famciclovir for therapy of HSV infections in other cutaneous areas. If disease is severe and recurrent, prescribe oral acyclovir (or valacyclovir or famciclovir) initially at dosages utilized to treat primary genital HSV infections. If suppressive therapy is planned, those dosages utilized for frequently recurrent genital HSV infection are appropriate.
Mucocutaneous HSV infections in immunocom- promised patients
Intravenous acyclovir infusion at 5 mg/kg over 1 hour, given every 8 hours for 7 days. For children less than 12 years of age, the dosage is 250 mg/m2 at the same schedule.
For limited disease, topical application of acyclovir 5% ointment every 3 hours (6 times daily) for 7 days. Famciclovir 500 mg twice daily for 7 days. This same dosage is also used on a daily basis for chronic suppression of recurrent episodes in HIV-infected persons.
Recurrent orolabial or genital HSV infections in HIV-infected patients
Famciclovir 500 mg twice daily for 7 days. This same dosage is also used on a daily basis for chronic suppression of recurrent episodes in HIV-infected persons.
Valacyclovir 500 mg to 1000 mg b.i.d. can also be used for episodic therapy (e.g., 7 days) or on a daily basis for chronic suppression in these patients.
Herpes simplex keratoconjuc- tivitis
Triﬂuridine 1% ophthalmic solution for primary keratoconjunctivitis and recurrent epithelial keratitis due to HSV, given as one drop in the affected eye(s) every 2 hours while awake (maximum of 9 drops per day). This is continued until re-epithelialization of the corneal ulcer occurs, followed by one drop every 4 hours while awake for 7 more days.
Topical acyclovir for HSV ocular infections is effective, but probably not superior to triﬂuridine, and is no longer recommended.
Herpes simplex encephalitis
Intravenous acyclovir infusion at 10 mg/kg over 1 hour, given every 8 hours for 14 days. For children 6 months to 12 years of age, the dosage is adjusted to 500 mg/m2.
Neonatal herpes simplex infection Acyclovir-resistant HSV infections
Intravenous acyclovir infusion at 10 mg/kg over 1 hour, given every 8 hours for 14 days (SEMa disease) to 21 days (encephalitis or multiorgan disease). Intravenous foscarnet infusion at 40 mg/kg over 1 hour either every 8 or 12 hours, for 2–3 weeks or until all lesions are healed.
Cidofovir 1% cream or gel may be compounded as an alternative therapy.
Varicella Zoster Virus (VZV)
VZV is spread in the air or via direct contact and then (Fig. 3.3) replicates in the nuclei of cells (2). Nucleocapsids of VZV are produced in the nuclei of infected host cells. Capsids receive a primary viral envelope from the inner nuclear membrane. Eventually these attach to rough endoplasmic reticulum (RER). Nucleocapsids move through the cytosol to the Golgi apparatus (trans-Golgi network) where they obtain a ﬁnal envelope. The distribution of VZV is worldwide, but is less prevalent in tropical climates than those that are more tem- perate. Varicella zoster virus infection occurs as chickenpox in the young and manifests itself as shingles (herpes zoster) when reactivated in adults. More than 90% of the adult popu- lation has serological evidence of prior infection with VZV, although they may not have had an active, recordable case. Primary VZV infection in adults, adolescents, and immuno- compromised patients may be more severe and require extended treatment. Shingles, the recurrence of VZV, is asso- ciated with painful lesions that heal but may leave the patient with post-herpetic neuralgia (PHN) for months or even years. Painful PHN has been associated with high suicide rates among the elderly. Antiviral therapies are ﬁrst line treatment options although higher doses are utilized for the slower grow- ing, more fastidious VZV than for HSV infection. Varicella in children manifests itself as a rash that requires two weeks to
heal and fever that lasts approximately 5 days. Prior to the development of vaccines for infants and children to prevent “chickenpox,” most children were exposed to chickenpox as an aerosol by close contact with classmates who were incubating VZV prior to their development of a rash. Complications include external bacterial infections in the skin and internal infections in the lungs. Reye’s syndrome is not seen as fre- quently as physicians now instruct parents not to give aspirin for the symptomatic treatment of the fever associated with chickenpox outbreaks. Varicella may cause neutropenia and thrombocytopenia, renal complications, arthritis, joint, or ocu- lar complications. In the immunocompromised, varicella, com- bined with other secondary infections, may be fatal. Zoster has become the greater health hazard when compared with vari- cella. The localized skin eruptions occur with reactivation of the virus often at an advanced age. Zoster eruptions in older patients may cause painful, long-lasting inﬂammation of the nerves (i.e., PHN). Symptomatic treatment for pain associated with PHN has been lacking although initiation of gabapentin concomitant with a nucleoside analog within the ﬁrst 72 hours of vesicle eruption shows promise for decreasing the incidence, severity, and duration of PHN (3). Acyclovir is indicated for the treatment of varicella (chickenpox) but valacyclovir and famciclovir are also used in adolescents and adults; all three nucleoside analogs can be used to treat zoster (shingles).