General (Non-antiretroviral) Antiviral Drugs

5 Jun

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

Herpes labialis

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.

Herpes genitalis

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).

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