Epstein-Barr Virus (EBV)

5 Jun

Epstein-Barr virus (EBV) is found  in human mucosal epithe- lial  cells  and  B lymphocytes. Other cell  types may  also  be infected. Burkitt’s lymphoma, originally identified in  Africa, was found  to be due to Epstein-Barr virus, named after its two discoverers (4). Epstein-Barr virus later became associated with not  only African Burkitt’s lymphoma, but  Hodgkin’s dis- ease  and  nasopharyngeal carcinoma (5,6). Infectious mononu- cleosis  is the  most  common manifestation  of EBV.  Infectious mononucleosis has  a large public  health impact on young  col- lege students and  military recruits. Both  are  populations liv- ing in close quarters, exposed to many new people, and  where mucosal contact via  oral  secretions may  occur. Symptoms present in >50% of patients include fever, pharyngitis and  sore throat, lymphadenopathy, malaise, headache, and  splenome- galy.  Complications involve  the  neurological, respiratory, car- diac,  hematological, hepatic and  renal systems. There is  a rash in 10% of the  cases (7). EBV-associated lymphoprolifera- tive   diseases and   malignancies occur   as  solid   tumors (nasopharyngeal carcinoma and  cervical lymphadenopathy), B-cell  lymphoproliferative  disorders  (Hodgkin’s lymphoma, Burkitt’s lymphoma, and  lymphoproliferative disease in  the immunocompromised), and  T-cell lymphoproliferative disorders (oral  lymphoma in  HIV-infected patients, angiocentric cutane- ous lymphoma including papules, nodules, bullae, panniculitis, histiocytoid cutaneous lymphoma, and  vesiculopapular lesions of the  face)  (8). In  HIV-positive persons, oral  hairy leukopenia (OHL) is a benign focus of hyperplasia. EBV is sometimes iden- tified in breast tumors (911). EBV has  a latent circular genome and  a linear genome. OHL  develops when the  linear genome replicates via a viral polymerase. Antiviral agents which inhibit this enzyme are  an effective therapy for OHL. These include: 1) high  doses  of acyclovir (800 mg five times/day); 2) valacyclovir and  famciclovir (with better bioavailability); and  3) ganciclovir, foscarnet or cidofovir  for HIV-infected patients with CMV (OHL seems to improve at the  same time).

Cytomegalovirus (CMV)

A variety of cutaneous manifestations may  occur  with CMV mononucleosis syndrome, congenital CMV infection, and  coin- fection of HIV with CMV. In vitro, CMV infection shows  sen- sitivity to many of the  antiviral agents used to treat HSV and VZV. CMV  infection can  be  life-threatening to  neonates, transplant recipients, and  HIV-positive patients. CMV retini- tis  requires particular attention to  prevent  blindness. CMV replicates by rolling-circle replication. For  CMV to  replicate requires eleven genetically determined proteins to be in place. These proteins are  contained within a variety of related mol- ecules: DNA  polymerase, a  polymerase-associated protein, single-stranded DNA  binding protein, helicase primase, transactivators, and  two unknown functions (12). This  specific- ity provides a number of molecular targets for potential antiviral drug development and  intervention. As with many viruses, transmission is relatively simple and may occur through intrau- terine infection from primary-infected mothers, perinatal infec- tion  from breast milk,  postnatal infection primarily from saliva and/or sexual contact, blood transfusions, and  organ transplan- tation. Laboratory diagnoses of active CMV infection include PCR,  histopathology, isolation of the  virus, antigen detection, and  serological assays. CMV  can  be  prevented by  utilizing seronegative blood  for  transfusions, especially for  pregnant women and  immunocompromised patients.  Day  care  centers may  be the  reservoir for transmission of CMV among a variety of individuals. CMV is asymptomatic in most  cases, but  saliva, a saliva-coated toy, or eating utensils (fomites) may  spread the disease among teethers, droolers, and  toddlers. Children may then infect siblings, pregnant mothers or  day  care  workers. Infected workers risk transmittal  to  the  children. Since  this mode  of transmission occurs  within the  realm of daycare cen- ters, daycare workers must be  careful to  utilize appropriate hand washing and  other good hygiene practices.

Exposure to CMV appears to be a life-long event. The per- centage of women with IgG antibodies against CMV increases as  their ages  increase. Approximately 40%  of women under the  age  of 16  have IgG  antibodies against CMV  compared with nearly 80%  of those women over  41  years of age  (13). CMV in the  immunosuppressed can  also  have serious conse- quences. Studies indicate that seronegative CMV transplant recipients can  acquire CMV  from  organs of seropositive donors (14).  CMV  has   been   associated with thrombotic microangiopathy in HIV-infected patients (15,16). Vaccines for better protection are  needed and  are  being  developed and tested. The  antivirals,  ganciclovir, valganciclovir, foscarnet, cidofovir, and  fomivirsen, are  FDA approved for treatment of CMV. These currently available drugs have issues of toxicity, modest efficacy  and  poor oral  bioavailability. New  compounds being  tested include novel  inhibitors of protein kinase and viral proteins of DNA origin. Certain non-nucleosides also can inhibit the  viral process (17).

Human Herpesvirus 8 (HHV-8)

Kaposi’s   sarcoma (KS)  occurs  as  four  main types. Classic Kaposi’s  sarcoma occurs  in  elderly Mediterranean  men  or those of Ashkenazi Jewish descent. An endemic form  affects persons of all ages in tropical Africa. The two most common forms seen  in  the  medical profession are  an  immunosuppressive form  in organ transplant recipients and  the  AIDS-associated form.  Mediterranean, Jewish, Arabic, or African ancestry is often  associated with KS  in  organ transplant  recipients. In Africa,  where endemic KS is the  cause of up to 10% of all his- tologically proven malignancies, sexual transmission  is believed to be the  most  common mode  of transmission. Perin- atal transmission from  mother to child  is also  suspected (18). Kaposi’s  sarcoma, prior to  the  introduction of highly active antiretroviral therapy (HAART),  affected nearly  20%  of patients with AIDS  (19–21), and  was  primarily treated with destructive therapies similar to those used with HPV.  Radia- tion  therapy and  chemotherapy were  also  used. The  develop- ment of alitretinoin, a gene  expression regulator, has  shown promise in treating Kaposi’s  sarcoma with a topical, at-home therapy. However, alitretinoin  is not  as effective for the  large fungating lesions, but  it could  be combined with chemother- apy  for treatment of large tumors. Antiherpes drugs seem  to be  more  effective as  a  preventive drug for  KS  in  HHV-8 infected immunosuppressed persons than  as  a  therapy for active KS.  KS  is composed of large latently infected spindle cells.  These antiviral drugs seem  to  block  the  lytic  phase of viral replication which occurs  when HHV-8  is  establishing itself   in  the  dermis (22–25). Interferon-alpha  is  currently FDA-approved for treatment of Kaposi’s  sarcoma (26).

Human Papillomavirus (HPV)

HPV  is  the  most  commonly sexually transmitted disease in the  United States. HPV  expresses itself  as  genital warts or lesions on the cervix  and  the virus has  been directly connected to the  development of cervical cancer (27). There are  over 100 genotypes of HPV  with genotypes 16 and  18 most  commonly associated with the  development of cervical cancer (Fig. 3.4).

Fig. 3.4 Relational map  of human papillomaviruses by genotypes.

The  prevalence of genotypes worldwide demonstrates  isola- tion  by distance with additional pockets of introduced geno- types or mutations  occurring overtime. Sexual behavior and possibly fomite contamination are  leading causes of transmis- sion.  Electrocautery and  laser therapy present a  risk to the surgeon and  other medical staff  as HPV  DNA is contained in the  smoke caused by the  procedure (28).

The  genetic make-up of the  infected person may  affect development of cervical dysplasia or neoplasia. There appears to be genetic propensity to develop either long-term infection leading to  cervical cancer (if left  untreated) or  automatic clearing of the  infection (experienced by  the  majority of women). Other lesions indicate HPV  infection, including, but not  limited to,  plantar  warts, common warts, flat  or  planar warts (29,30),  epidermodysplasia verruciformis, other ano- genital diseases, respiratory papillomatosis (especially in chil- dren), and  other mucosal papillomas (Fig. 3.4).

While  treatment with antiviral drugs is needed to help those already infected, vaccine development is also needed as a  preventive method. Most  treatments for  HPV  have been ablative— trichloroacetic acid,  podophyllotoxin, cryotherapy, laser ablation, surgical excision, and  electrosurgery/cautery. Not  only  can  genital warts be  treated with antiviral drugs, but  some of the  therapies may prove  effective in treating com- mon  warts. Imiquimod users have a 56% complete response rate with a 13% relapse rate for the  treatment of anogenital warts (31,32).  Interferon-alpha is also  FDA approved for the treatment of HPV  (i.e., condyloma acuminatum).

Molluscum Contagiosum Virus (MCV) and other Poxviruses

Currently, no antiviral agents are FDA-approved for treatment of MCV lesions. Most  lesions are  treated with cytodestructive methods. There are  reports of various antiviral agents having some  efficacy  in  treating MCV, but  more  thorough investiga- tions and  clinical studies are  needed. In HIV-positive patients, antiretroviral agents, such  as highly active antiretroviral ther- apy  (HAART),  improve the  immune system and  contribute to the  success of additional antiviral drugs (33,34).

Two other poxviruses have gained recent attention: small- pox as a bioterrorism threat and  monkeypox as a hitchhiker to the United States on the Gambian pouched rat with subsequent infection of U.S.-endemic prairie dogs  being  sold  as  pets. The handlers of the  pet  prairie dogs  then developed monkeypox. Monkeypox was  initially identified as  a poxvirus in laboratory primates before  it was  linked to an  orthopoxvirus from  central and  western Africa.  It is a rare zoonosis and  isolation of most cases makes vaccine development unlikely. However, the  poten- tial  for animal to animal and  human to human transmission (Fig.  3.5) may  stimulate development of new  vaccines or addi- tional antiviral therapy. Prior to this event in  the  summer of

2003, monkeypox transmission was only by monkeys and  squir- rels  to humans and  human to humans subsequently. Skinning or  handling wild  animals and  consumption of incompletely cooked wild monkey meat was  thought to be the  primary route of transmission. Smallpox vaccination reduces susceptibility to monkeypox and  lessens the  severity of the  disease (33).

Initially variolation with pustule fluid  or  scab  material was used to protect against smallpox. Refinements in vaccine development led  to  the  eradication of epidemic smallpox.

Recent advances in smallpox vaccine development and  adminis- tration are discussed in chapter 4 (Vaccines). A possible treatment for complications from  vaccination is vaccinia immune globulin. Cidofovir has  antipoxvirus effects  and  the  potential to treat vac- cinia and smallpox (34). Ribavirin displays modest antiviral activ- ity against cowpox.  Trifluridine is used to treat ocular keratitis.

Hepatitis B Virus (HBV)/Hepatitis C Virus (HCV)

HBV and HCV have similar treatments and are sensitive to sim- ilar  drugs. Both  hepatitis B and  C have the  potential to develop fatal sequellae, such  as cirrhosis of the  liver  and  hepatocellular carcinoma. Injection drug use  accounts for 21% of the  known cases in the United States and Western Europe (35). The primary means for HBV transmission is through blood or blood products, sexual contact or perinatal exposure. Fomites, such  as contami- nated dental instruments, acupuncture needles, tattoo needles, and  other invasive medical instruments, may also transmit hep- atitis B. Travelers are  subject to infection, particularly those in third-world countries. Transfusion and  dialysis are  other modes of transmission.  Seven genotypes, encompassing 12 subtypes, have been  described. Nearly 5% of the  world’s  population has chronic HBV  infection (36). The  incubation period for  HBV ranges from  60 to 180  days. Patients may  experience jaundice and, perhaps, liver  failure (37,38).  Unfortunately, patients may not know  they have HBV until they present with ascites, bleed- ing  esophageal variances, or  encephaly (39).  Biochemically, serum bilirubin and  aminotransferase levels  are  used for initial diagnosis but  serological and   virological confirmation  is required. Necrotizing vasculitis and  polyarteritis nodosa are associated with HBV infections, and  are  linked to cryoglobuline- mia (35,40,41). Chronic infection may occur in hemodialysis, dia- betic,  and  elderly stroke or head injury patients with very  high rates (43–59%)  of chronic infection after an acute exposure. HIV positive patients are also at greater risk. Treatment of symptoms without knowledge of the presence of HBV can be problematic as many drugs are  potentially hepatotoxic.

With  better diagnostics for HCV infection, it is estimated that 3.9  million Americans (1.8%  of the   population) are infected with HCV (42) with over 170 million infected worldwide.

The  genome displays genetic heterogeneity  which makes it less likely  to activate the human immune system. Appropriate animal models for HCV are  lacking and  mechanistic molecu- lar  studies of replication have been  limited. Humans may  be multiply infected overtime and  there may  be  a  failure to develop a  high  rate of immunity after the  initial infection occurs  (43,44). As with other hepatitis infections, clinical man- ifestations do not  occur  until the  disease has  become  chronic. The presence of fibrosis is the end stage of hepatitis C over time and  is predictive of progression to cirrhosis. HCV  progresses over  a period of 10–30  years from  infection to liver  cirrhosis. There are  six definite genotypes with subtypes of each  geno- type. Leukocytoclastic vasculitis, lichen planus, poryphyria cutanea tarda, and  polyarteritis nodosa have been  linked to chronic HBV and/or HCV infections (39,45,46). Prevention via modification of risky behaviors, passive immunoprophy- laxis, and  immunization (i.e., HBV) are  the best  strategy. Edu- cation and  information campaigns to reduce the  transmission of hepatitis B and  vaccines have been  effective in reducing the numbers of cases of hepatitis B in the  United States (35). Cur- rently approved treatments for hepatitis B include interferon- alpha, adefovir, and  lamivudine. Lamivudine is  discussed in chapter 2  Page 48.  Hepatitis C treatments are  pegylated (PEG)  interferon-alpha, and  PEG-interferon-alpha + ribavirin. Currently available drugs have issues of toxicity, modest effi- cacy, and poor oral bioavailability. New compounds being  tested include novel  inhibitors of protein kinase, viral protease, and viral proteins of DNA origin. Certain non-nucleosides also  can inhibit the  viral process (17).

Influenza Virus

Influenza is responsible for pandemic or worldwide outbreaks of new  strains of flu  that originate in  localized geographic areas. The  advent of world  travel has  opened every  country’s door  to  a  sudden invasion of new  influenza strains at a moment’s notice. Fortunately,  faster and  better communica- tions about the  disease—prevention, clinical manifestations, treatment, etc.—assist with harnessing resources to prevent further spread. Animals, particularly those domesticated for

agricultural use, are  often the  culprit, such  as the  swine influ- enza virus that was  responsible for the  1918  pandemic with

40  million deaths  worldwide. There are   three influenza viruses: A, B, and  C. Only A is subdivided and  only five of those subtypes are  known to affect  humans. A and  B have eight dif- ferent RNA segments; C has  only seven.

Rapid detection of influenza in  pediatric patients  is important for  early therapy. The  use  of an  enzyme-linked immunosorbent assay can  detect influenza A. The  end  result is that this rapid detection system decreases the  use  of ancil- lary  tests and  indiscriminate use  of antibiotics (47). On  the other hand, for adults, clinical modeling indicates that testing strategies for influenza before  prescribing antivirals is more expensive than just prescribing the  antiviral. Running tests for influenza are  more  costly and  less effective when the  prob- ability of influenza exceeds 30% (48).

Human influenza virus may  co-infect with an  animal strain to produce new  pandemic strains, much as  hybridiza- tion  occurs  among higher level  organisms. In  this case,  how- ever, replication occurs  and  the new viral strain has  few, if any, enemies. Each strain requires a  new  set  of antibodies to  be produced for future resistance.

Pandemic influenza viruses are  characterized by  rapid onset and  easy dissemination of infection. The short (only days) incubation periods accompanied by high  levels  of virus in respi- ratory secretions at the onset of illness create multiple waves of infection. Hands or fomites may  also spread influenza (49).

Factors which contribute to  the  spread of an  influenza virus are  travelers, seasonally by geographic area, and  initia- tion  of school in the  fall. Mortality rates are  highest in the  eld- erly  and  the  very  young, particularly those with respiratory or cardiovascular disease. Nursing home  outbreaks require spe- cial care  and  a number of recommendations have been  made to avoid  major outbreak catastrophes  (49–51). Nosocomal infec- tions occur where there are  high  concentrations of people.

Influenza outbreaks vary  by the  proportional activity of the  three subtypes. Dramatic changes occur  in  those propor- tions annually. Thus, this year’s  vaccine combination may  not be effective for the  following years. The ancestral genetic origin

of pandemic strains is  often  avian. A limitation on  vaccina- tions for influenza is the “drift” (proportional reassortment) of wild  virus strains each  year (52). For  example, the  composi- tion  of the  2002–2003 vaccine was

A/Moscow/10/99 (H3N3)- like,  A/Ner  Caledonia/20/99 (H1N1)-like, and  B/Hong  Kong/

330/2001-like strains (53).

Treatment of influenza is  symptomatic and  antiviral. Ventilation may  be necessary. Antivirals such  as amantadine, ramantadine, oseltamivir and  zanamivir are  effective. Ribavi- rin  is under investigation as is interferon-alpha (54–56).

Respiratory Syncytial Virus (RSV)

Respiratory syncytial virus (RSV) is the  most  common cause of inflammation in the small airways in the lung and pneumonia in infants and  small children. Most  children have had  RSV by the age  of 3 (57). RSV is seasonal and  peaks in  February. Native Americans and Alaskan natives seem to be more susceptible (58).

RSV  is  a  labile paramyxovirus that  causes human cell fusion-the syncytial effect.  Two strains, A and  B, cause either asymptomatic illness (Type B) or more  clinical illness (Type A).

Babies who are  born  premature and  are  less  than 6 weeks of age, with congenital problems, such  as heart disease, chronic lung disease, and  immunodeficiency, are at high risk. Other con- tributing factors are  lower  socioeconomic states, crowded living conditions, presence of secondary cigarette smoke, older siblings in the home, and daycare attendance. Breast-fed infants seem to be at less risk than their bottle-fed counterparts.

Children with runny noses (rhinorrhea), wheezing and coughing, low-grade (102°F)  or  higher (104°F)  fever  (if coin- fected), and  nasal flaring may  have RSV. RSV can be positively identified by using direct antigen tests that provide a positive response in little over an hour. RSV has  been indicated as a risk factor for asthma development. An antiviral, such  as ribavirin, inhibits replication during the  viral replication stage (54–57).

Rhinovirus

Rhinovirus infection has  been responsible for years for the com- mon  cold, which was  treated symptomatically. Rhinovirus has also been associated with complications, such as acute sinusitis, otitis media, acute bronchitis, and  pneumonia. Rhinovirus is also  associated with the  development of asthma and  cystic fibrosis exacerbations in children.

Rhinosinusitis  involves the  nasal passages, paranasal sinuses, naso-  and  oropharynx, Eustachian tubes, middle ear, larynx, and  large airways. Systemic involvement is  usually mild  in adults. Rhinovirus infections in immunocompromised patients, as with other infections, are  more  serious when com- bined with multiple infections.

Adults who are taught the characteristics of allergic rhin- itis  and  cold are  able  to distinguish between the  two (59).

Symptomatic and  anti-inflammatory treatment includes decongestants, fever  relief, cough  cessation, etc.,  but  does  not cure  the  infection. Antivirals identified for their potential use- fulness include interferon α to reduce viral replication. Capsid binding agents and  3 C protease inhibitors are  being  evaluated. Pleconaril and AG7088 are under investigation in clinical trials.

NUCLEOSIDE ANALOGS

The  (non-antiretroviral) nucleoside analogs include acyclovir, valacyclovir, famciclovir, penciclovir, ganciclovir, and  valganci- clovir  as  well  as  ribavirin. Nucleoside analogs are  important antivirals in the  therapy of HIV and  herpesvirus infections.

Most  nucleoside analogue antivirals have the  capacity to induce chromosomal aberrations,  but  these aberrations are not  evident in gene  arrays. Genotoxicity is being  investigated in this group but, thus far, there is no conclusive evidence that nucleoside analogs cause tumors in humans. Antiviral nucleo- sides  for  HIV  therapy, in  addition to  being  highly effective, may also cause side effects  that become  serious enough to con- sider alternative therapies (60).

Acyclovir

Introduction

Acyclovir, an  analog of 2′-deoxyguanosine, has  become  the most  widely  prescribed antiviral in the  world  since  its  intro- duction in  1983  (Fig.  3.6). Acyclovir  does  not  appear to alter

Fig. 3.6 Associated names, structure, and  applicability of acyclovir.

the  development of long-term immunity to  varicella zoster virus when administered for the  treatment of chickenpox in otherwise healthy patients. A limiting factor is considered to be its poor bioavailability. Viral  resistance to acyclovir is not a major concern in normal clinical practice, but  has  occurred in a few patients with immunosuppression. There are  conflicting studies as to whether acyclovir treatment in AIDS patients is associated with prolonged survival. Use  of highly active anti- retroviral therapy (HAART)  has  virtually eliminated further studies of acyclovir as an agent for prolonged survival in AIDS patients.

Mechanisms of Action

Acyclovir  is first phosphorylated to acyclovir monophosphate by the  virus-specific enzyme, thymidine kinase (Fig. 3.7). Host cellular enzymes further phosphorylate the  compound to con- vert it to its  active triphosphate form  (61). The  final product inactivates viral DNA polymerase which leads to irreversible inhibition of further viral DNA  synthesis  (62–65). Acyclovir potency against HSV-1  replication can  vary  among cell lines. It has  been  suggested that the  effect of acyclovir is due to pro- ficient phosphorylation of acyclovir and/or a favorable dGTP/ acyclovir triphosphate level in macrophage cells (66).

Studies to Support Use  of Acyclovir Acyclovir  has  been  extensively studied for treatment of many viral diseases. Studies of interest are  shown in Table 3.4 (64,65,67–120).

Treatment

Acyclovir  can  be  administered  topically, orally or  intrave- nously with few adverse events (Table 3.5). Acyclovir is consid- ered  to  be  safe  and  well-tolerated with a  20  year history of usage, although its  bioavailability (15–20%)  is a limiting fac- tor. Acyclovir  is effective in decreasing severity in chickenpox (121,122). Acyclovir 5% ointment is used to treat initial herpes genitalis and  limited mucocutaneous herpes simplex virus infections in immunocompromised patients. Acyclovir  in oint- ment form  is used cutaneously and  should not  be applied to the  eye. Acyclovir  is noncarcinogenic and  nonteratogenic (i.e., class  B) (123).

Intravenous  acyclovir is  more  readily assimilated and can  be used for serious or disseminated infections. Immuno- compromised patients  with HSV  or  VZV infections who develop chickenpox, disseminated herpes zoster, severe cases of trigeminal zoster (particularly ophthalmic zoster), eczema herpeticum (Kaposi’s  varicelliform eruption), herpes encepha- litis, and  neonatal herpes may  be treated with intravenous acyclovir. During administration of intravenous acyclovir, ade- quate fluid  intake by patients is important and  renal insuffi- ciency  may  require dosage adjustments.

Acyclovir  and  its  related analogs are  ideal for  treating and  suppressing genital herpes and  related HSV  episodes.

Treatment should be initiated for a variety of reasons. These are summarized in Table 3.5. The  argument is that the  therapy is based on reducing the  available time of exposure to others, thus preventing transmission, and the suppression of painful lesions.

Once  therapy is  needed to  control HSV  infection, there are  a number of therapies available, depending upon  the  age and  immune status of the  patient.

Adverse Events

In general, acyclovir is well tolerated by most  patients, whether administered topically, orally, or intraveneously. There are  few rare adverse events present, if they occur at all. These are:

Nausea. Vomiting. Diarrhea. Headache.

Central nervous system. If patients have a preexisting renal impairment, treatment  with acyclovir may  in- duce  nephrotoxicity or  neurotoxicity. One  patient, treated for  suspected viral meningoencephalitis with acyclovir, began to improve until right arm myoclonia developed followed  by  a  progressive comatose state. Acyclovir  neurotoxicity should be suspected if continu- ing treatment with acyclovir is accompanied by worsen- ing neurological status. High  plasma and  CSF acyclovir levels  can confirm the  toxicity. Hemodialysis may  be ef- fective  in reducing levels  of acyclovir. Measuring blood creatinine permits prompt dosage adjustment (124).

Crystalluria. Adverse reactions of crystalluria include urinary insufficiency, elevated serum creatinine, and altered renal function that may  lead  to acute tubular necrosis. Risks that promote crystal development are dehydration, high  dose of acyclovir and  rapid induction rate (125). Crystalluria may  occur in patients if the  in- fusion rate for the  administration of intravenous  acy- clovir occurs  too rapidly. Therefore it is important that each  dose of acyclovir be administered evenly during a one-hour period. Crystalline formation may  cause renal impairment which  is usually reversible. In at least one incidence, discontinuation of acyclovir resulted in reso- lution of crystalluria with 24 hours with no evidence of renal toxicity (126).

Phlebitis and infusion-site inflammation. Both  phle- bitis and   inflammation at the   infusion site   may   be caused by the  intravenous administration of acyclovir.

Other Considerations

Acyclovir-resistant herpes simplex virus. Labora- tory  isolates and  clinical specimens reveal that  the

frequency of acyclovir resistance ranges from  7.5  ×10 −4   to  15  × 10−4  and  are  not  significantly different (127,128).

Acyclovir-resistent varicella-zoster infection in HIV- positive patients. Acyclovir resistance has  been  repor- ted  in  HIV-positive patients  who  are  coinfected with VZV (129132).

Pregnant women and breast-fed infants. Data from the  treatment of 1000  pregnant women who  received acyclovir before  or  during early pregnancy indicates that there was  no increase in  rates of miscarriage or in birth defects of the  offspring. However, it is recom- mended that  acyclovir be  given   to  pregnant  women only  if  the   benefit outweighs the   risk to  the   fetus. Acyclovir may concentrate in breast milk as it has  been shown that breast milk  acyclovir concentrations  may be 0.6 to 4.1 times greater than the  drug concentra- tion  in  the  corresponding maternal plasma (89). The amount of acyclovir exposure to breast-fed infants de- pends upon  the  maternal dose  of acyclovir and  quan- tity  of milk ingested. In mothers who received acyclovir in dosages ranging from  200–800 mg five times daily, the  level of acyclovir in the  infants equated to a dosage of 0.2 mg/kg/day to 0.731  mg/kg/day (8991). This quantity is less  than the  dosage indicated for infants with herpes encephalitis (30 mg/kg/day) that is given intravenously.

Transfer of antiviral agents to breast milk may provide therapeutic benefits in  reducing the  vertical transmis- sion of viruses and  clinical sequelae in the breast-feeding infant (133).

Probenicid coadministration. If  probenicid is  coad- ministered with intravenous acyclovir, there may be an increased half-life and  systemic exposure of acyclovir, requiring dose adjustments.

Coadministration with antiretrovirals. Acyclovir, famciclovir, and  valacyclovir are  all  safe  and  effective in HIV  seropositive patients and  have no negative in- teractions with HAART (134,135).

Fig. 3.8 Associated names, structure, and  applicability of valacyclovir.

Valacyclovir

Introduction

Valacyclovir  is  a  prodrug of acyclovir with  significantly improved bioavailability (136) (Fig. 3.8). Once  absorbed, over 99% of the  dosage is hydrolyzed by valacyclovir hydrolase to acyclovir. The  oral  bioavailability of valacyclovir is 3–5 times that of  acyclovir, but   the   bioavailability of  valacyclovir remains lower  than that of famiciclovir. The  increased bio- availability provides valacyclovir with the  benefit of less  fre- quent dosing, a  boon  for  those who  tend to  forget to  take medications. Valacyclovir was  approved by the  FDA  in  1995 for use  in  the  treatment of herpes simplex viruses and  vari- cella  zoster virus infections. A variety of off-label  uses is also known. It is likely  that valacyclovir will eventually replace acy- clovir for treatment of HSV or VZV infections in HIV-positive or other immunocompromised persons (137).

Mechanism of Action

Valacyclovir is the  L-valyl ester and  prodrug of acyclovir. The conversion of valacyclovir to acyclovir by valacyclovir hydro- lase  translates into  higher blood levels  of acyclovir (Fig. 3.9). The metabolism and  mechanism of action are  identical to that of acyclovir. The  greater affinity (100 times greater than that of penciclovir triphosphate) of acyclovir triphosphate  for viral DNA  polymerase is  such  that viral DNA  chain termination

requires less concentrations of acyclovir. Acyclovir and  valacy- clovir  are  obligate viral DNA  terminators. It is  unknown  if there is  any  importance to  the  relationship between the greater viral DNA  polymerase affinity and  obligate/condi- tional viral DNA chain termination.

Clinical  Studies to Support the  Use  of Valacyclovir

Valacyclovir is  used to  treat HSV,  VZV, and  (occasionally) CMV (136,138–150) (Table 3.6). Valacyclovir is considered to be as  effective as  acyclovir and  famciclovir, with more  conve- nient dosing than with acyclovir.

Treatment

Valacyclovir is  administered  orally with limited adverse events, similar to  acyclovir and  famciclovir. In  addition, the increased bioavailability of valacyclovir means that patients only take medications 2–3 times per  day  rather than 5 times (with acyclovir). Table 3.7  highlights treatment  options for HSV-1  and  -2 and  VZV.

Adverse Effects

Like acyclovir, side effects  do not differ  significantly from those of the  placebo. There are  a few rare adverse effects  such  as:

Nausea. Headaches.

Thrombotic microangiopathy (TMA). Thrombotic microangiopathy, similar to  thromboic thrombocy- topenic purpura/hemolytic  uremic syndrome (TTP/ HUS),  may  occur  in  immunosuppressed patients  who have received high  dosages of valacyclovir (8 g/day)  for extended periods of time when used for suppression of CMV. Valacyclovir has  not  been  shown to be the  cause of the  TMA as rates seen  in this study were  similar to those of all patients with advanced HIV disease. Of 18 patients, eight developed TMA during treatment with the study drug, whereas 10 patients developed TMA af- ter it had  been  discontinued for a median of 8 weeks.

This  syndrome has  not  been  observed in  healthy pa- tients who  received doses  of 3 g/day  nor  has  it been seen  in HIV-positive patients receiving valacyclovir for suppression of genital herpes.

Probenecid and cimetidine coadministration. Coad- ministration of valacyclovir with probenecid causes re- duced renal clearance of acyclovir. Dosage adjustments are  not  necessary unless renal impairment exists and is not  clinically significant in patients with normal re- nal  function.

Neurologic toxicity. Valacyclovir very  rarely may  cause neurotoxicity as its bioavailability is 54% compared with

20%  for  acyclovir. Valacyclovir hydrolyzes  to  acyclovir following systemic exposure and  may  cause unexpected overdoses, but  clinical manifestations are  rare (148).

Treating Bell’s Palsy

Antivirals bind  to viral enzymes so the  viruses do not  repli- cate. Adverse effects  of valacyclovir are  rare but  can  include headache, nausea, diarrhea, constipation, and  dizziness (149,

150) (see Table 3.6). When treatment begins within 3 days  of onset of paralysis caused by Bell’s palsy, patients treated with acyclovir have less  neural degeneration and  more  favorable recoveries (150).  Therefore, valacyclovir is  being  studied for this indication.

Famciclovir

Introduction

Famciclovir, an  oral  prodrug of penciclovir expresses  the highest bioavailability (77%)  of the  nucleoside analogues. Like  acyclovir, famciclovir, a diacetyl-6-deoxy analog, is effec- tive against HSV-1, HSV-2, and VZV (Fig. 3.10). It is approved for the  treatment of herpes zoster and  for the  episodic treat- ment and  suppression of recurrent genital herpes in  other- wise  healthy  adults.  Originally FDA-approved in  1995, famciclovir has  been  found  to significantly reduce the  pain, burning, tenderness, and  tingling of recurrent genital herpes and  its  metabolite, penciclovir, is used for therapy of herpes labialis (151). For the  immunocompromised, famciclovir is an effective treatment  for  herpes zoster although famciclovir,

like  valacyclovir, is not  currently approved for the  treatment of herpes zoster in this population (152).  Famciclovir can  be used to  treat  ophthalmic zoster (153)  as  well  as  shorten zoster-associated pain (154).

Mechanisms of Action

Famciclovir is  a  guanine analog that is  also  classified as  a purine analog, a modified cyclic or acyclic sugar. Famciclovir is metabolized to the  active agent, penciclovir triphosphate. In hepatitis B guanine analogs inhibit priming by  binding to tyrosine at the  priming site  of the  polymerase. They  also inhibit DNA elongation of both  strands of DNA of the  virus. Although elongation is initiated, it is terminated only  two or three nucleotides later. Famciclovir is  a  prodrug, and   its deacytylation and  oxidation form,  penciclovir, is  the  active antiviral form  (Fig. 3.11). D-famciclovir is more  potent than l- famciclovir (155). Once it is rapidly metabolized to penciclovir by the  gastrointestinal tract, blood,  and  liver, the  remaining metabolism is identical to that of acyclovir (156).

Clinical  Studies and  Published Reports to Support the  Use of

Famciclovir

Famciclovir studies often  compare the  efficacy  of famciclovir with acyclovir (153,157–170) (Table 3.8).  For  herpes zoster, famciclovir generally is as effective or more  effective than acy- clovir. Famciclovir is  also  useful in  both  immunosuppressed and  immunocompetent patients. Aoki,  in  a  review, cites  the use  of famciclovir in the  treatment of both  HIV-negative and HIV-positive patients for the  management of recurring genital herpes (HSV)  (171).  In  the  treatment of VZV adult patients, famciclovir is usually prescribed at 500 mg orally three times a day  in the  USA and  250 mg three times daily  in most  other countries. Famciclovir and  valacyclovir are  preferred over oral acyclovir for  the  treatment of zoster in  otherwise healthy adults (172). In a comparison study to treat Chinese patients with hepatitis B, lamivudine was  significantly more  effective than famciclovir (173).

Treatment

Dosages for treatment vary  according to the  disease treated, the  severity of an  outbreak, and  the  recurrence rate of out- breaks as shown in Table 3.9.

Adverse Events

Headache. Nausea. Diarrhea.

Increased serum concentrations of penciclovir. Serum concentrations of penciclovir may  occur  if famciclovir is

used concurrently with probenecid (or other drugs signif- icantly eliminated by active renal tubular secretion).

Special Considerations

Renal impairment. For  patients with renal impair- ment, all regimens in Table 3.9 will require dosage ad- justments.

Coadministration with probenecid or  other relat- ed  drugs. Administration of drugs eliminated by ac- tive renal tubular secretion with famciclovir may cause increased serum concentrations of penciclovir.

Drug resistance. For  hepatitis B, five domains (labeled A–E) have been  identified. Domains B and  E may  affect primary and  template positioning. Structural changes in  these domains may  affect  oral  resistance to nucleo- side  analogues. Famciclovir promotes mutations in the B domain. A mutation at position 528 (Leu replaced by

Met or Val) also occurs  during lamivudine therapy and may  cause cross-resistance. A summary of susceptible positions for the  B-domain resistance for famciclovir is shown in Table 3.10.

Approval. Famciclovir has  been  approved for the  episodic therapy and  for chronic suppression of recurring HSV as well as treatment of herpes zoster in North America and  in some,  but  not  all, European countries (137).

Penciclovir

Introduction

Penciclovir is acyclic  nucleoside analogue which has  in  vitro activity against HSV-1, HSV-2, and VZV (175) (Fig. 3.12). FDA approval is only for topical treatment of recurrent herpes labi- alis  as  the  oral  bioavailability is extremely low. Intravenous penciclovir shows  promise for the treatment of mucocutaneous herpes simplex infections in  those with immunosuppression.

The  active form  of penciclovir is significantly more  stable in HSV-infected cells (in vitro half-life of 10–20 hours) when com- pared to acyclovir (0.7 to 1 hour) (174).

Mechanisms of Action

Like  acyclovir, penciclovir must  be  phosphorylated by  viral thymidine kinase and  cellular kinases prior to its competitive inhibition of viral DNA polymerase (Fig 3.13). However, pen- ciclovir is not an obligate DNA-chain terminator like acyclovir (175,176).

Clinical  Studies to Support the  Use  of Penciclovir

There is  only  one  major study involving immunocompetent patients that demonstrates that penciclovir treatment results in  improvement in  a  variety of facets. These improvements were  observed at all stages of a herpes labialis outbreak: pro- drome, erythema, papule, and  vesicle. Table 3.11  (151)  high- lights the  parameters measured and  analyzed.

Treatment

Herpes labialis lesions may  be  treated  with topical cream (Table 3.12). Treatment should be initiated as  early as  possi- ble during the  course of an  outbreak. The  systemic uptake of penciclovir is negligible.

Adverse Events

Adverse events are similar to those of acyclovir and valacyclovir.

Ganciclovir

Introduction

Ganciclovir, a nucleoside analogue, is used to prevent and  treat the  manifestations of CMV in  immunocompromised patients (177–179). This  is important as CMV infection in immunocom- petent individuals tends to be brief  and  self-limited. However, CMV can be severe and life-threatening in neonates, transplant recipients, and  HIV-positive patients. Oral ganciclovir is avail- able for CMV prophylaxis, but it is not considered to be as effec- tive as other means. Valganciclovir a prodrug of ganciclovir, has improved bioavailability. Ganciclovir may also have in vitro effi- cacy against EBV (HHV-4)  replication (Fig. 3.14).

Mechanism of Action

The  viral-encoded phosphotransferase  (thymidine kinase) monophosphorylates ganciclovir, a nucleoside analogue, to the active triphosphate form.  This  triphosphate form  becomes part of a newly  synthesized DNA chain. This  inhibits further

DNA synthesis by inhibiting DNA polymerase and  by induc- ing  premature  chain termination  (180–183) (Fig.  3.15).  The thymidine kinase (TK) encoded by HSV  or VZV has  a broad substrate  specificity that permits interaction by acyclovir or ganciclovir. Phosphorylation  of ganciclovir in  CMV-infected cells is dependent upon a protein kinase. The role of the kinase is not  completely understood and  is under study. In HHV-6,  a similar mechanism activates ganciclovir. Mutations for drug resistance most  often  occur  in the  UL97  gene  that affects the monophosphorylation process or the  UL54  gene that codes for DNA  polymerase in  human CMV  (184).  Graft-versus-host- disease can be prevented when donor T cells are  transfected to express herpes simplex virus thymine kinase. Cells that express this enzyme are  susceptible to ganciclovir, which opens a new avenue for addressing drug resistance.

Clinical  Studies and  Reports that  Support the  Use  of

Ganciclovir

Oral ganciclovir is available for CMV prophylaxis, but  is not as effective as intravenous treatment. Valganciclovir has  bet- ter availability (177,178,183,185–193) (Table 3.13).

Treatment

Intravenous ganciclovir is the  drug of choice  for treatment of CMV in transplant recipients or AIDS patients (194) (Table 3.14). The ocular implant of ganciclovir for treatment of CMV retini- tis provides a better clinical outcome for disease regression and the  convenience of ambulatory therapy. This, however, must be balanced against the  potential of intra-ocular side  effects  or contralateral eye infection by CMV (185). Late-onset cytomeg- alovirus disease among organ transplant recipients is common and  the  current thought is that antiviral prophylaxis, such  as with ganciclovir, be  used preemptively. Allograft rejection is often  associated with CMV risk. Those  patients on ganciclovir may  benefit from  extended and/or enhanced antiviral prophy- laxis  (195). Stem cell transplantation (SCT)  has  similar chal- lenges in that SCTs  are  at increased risk of developing CMV pneumonia where the  best  available therapy has  a mortality

rate of 45–78%; therefore, post-operative prevention of CMV is critical (196).

Adverse Effects

Dosage of ganciclovir must often  be limited due  to:

Bone marrow suppression. Bone marrow suppression may  also  be  accompanied by  thrombocytopenia, neu- tropenia, anemia, and  granulocytopenia.

Retinal toxicity. High  doses  of intravitreal ganciclovir may  cause retinal damage (197).

Also involved may  be: Renal insufficiently. Neutropenia.

Fever. Rash. Headache.

Irritation and phlebitis. Irritation and  phlebitis may occur at the  infusion site.

Nausea. May  occur  with arginine butyrate combined with ganciclovir to treat Epstein-Barr tumors.

Ganciclovir resistance. A recent study demonstrated that 26 of 210 patients with CMV retinitis expressed phenotypic or genotypic ganciclovir-resistance  (198).

Special Considerations

Animal studies. Ganciclovir was  found  to be teratoge- nic, carcinogenic, and  mutagenic in animal studies. It also caused aspermatogenesis.

Combination therapy with foscarnet. In cases of fail- ure  of monotherapy, ganciclovir can  be combined with foscarnet for treatment.

Monitoring of  CMV  infection in immunocompro- mised transplant patients. The results of quantitative antigenemia, which uses buffy  coat  cell  preparations, may  differ  significantly from  quantitative PCR,  which uses plasma for the  analysis of ganciclovir resistance. Once  ganciclovir is initially introduced for treatment of CMV, quantitative PCR levels  drop. A subsequent use of both  quantitative PCR and  antigenemia may  be indica- tive of the emergence of ganciclovir-resistant CMV. Once foscarnet is administered, both  the  PCR  and  antigene- mia levels  drop. The results of the  quantitative PCR can often  be used to provide pre-emptive treatment  before traditional clinical indicators appear (199).  PCR  with plasma performed best in a comparison with seven other laboratory assays. This  permitted pre-emptive treat- ment with ganciclovir (200).

Arginine butyrate/ganciclovir treatment of  EB tumors. Arginine butyrate/ganciclovir treatment  does not  appear to activate HIV transcription rates (187).

Pregnant women. Only limited studies have been  done, but  no large-scale safety data exists (201).

Neonates  and pediatric  patients. Ganciclovir has been  used effectively in pediatric transplant patients, but  safety of use  in neonates with CMV infection has not been  established (202).

Effect of corticosteroids on  efficacy. In transplant pa- tients, corticosteriod use  may  promote early pp65  anti- genemia rather than emergence of a ganciclovir-resistant virus. Therefore, an  immediate switch from  ganciclovir to foscarnet (with more  severe side  effects)  may  not  be warranted. Instead, dose intensification with ganciclovir should continue to be the  medication of choice (203,204).

Valganciclovir

Introduction

Valganciclovir is used to treat CMV retinitis, an  infection in eyes of immunocompromised patients. Valganciclovir does not cure  CMV, but  it can  keep  symptoms from  becoming worse  or

Fig. 3.16 Associated names, structure,  and  applicability of valganciclovir.

cause some  improvement. Oral valganciclovir has  increased availability when compared with oral  ganciclovir. As with all other antivirals, valganciclovir-resistant strains are  emerging (205) (Fig. 3.16).

Mechanism of Action

Valganciclovir is  a  valylester prodrug of ganciclovir with approximately 10 times the  bioavailability of oral  ganciclovir (Fig. 3.17).

Clinical  Findings and  Reports That Support the  Use  of

Valganciclovir

Valganciclovir has  been  used to  treat CMV  retinitis (205) (Table 3.15).

Treatment

Oral tablets are  available in the  United States. Adults should take 900 mg two times a day with food (Table 3.16).

Adverse Effects

Anemia and other blood problems. Valganciclovir can suppress the  numbers of white blood  cells,  increasing the  opportunity for infection. Valganciclovir also  low- ers  blood  platelet number which may  increase blood clotting time.

Gastrointestinal. Presence of blood  in  urine or  stools, with stools  possibly appearing black  or tarry, and  pain- ful or difficult urination are  common side effects  of val- ganciclovir. Abdominal pain, diarrhea,  nausea, and vomiting are  normally less  serious side  effects.

Respiratory distress or infection. Cough, hoarseness, troubled breathing, nasal  congestion, sore  throat, chills, fever, lower  back  or side  pain, unusual bleeding, bruising, or fatigue could  be seen  if a patient is taking valganciclovir.

Mucocutaneous. Ulcers, sores or  white spots may  ap- pear in the  mouth, paler than usual appearance of the skin, pinpoint red  macules on  skin, or  allergic (hive- like)  swelling or  itching are  indicators of adverse  ef- fects  of valganciclovir.

Ophthalmological. Seeing flashes of light, floating spots before  the  eyes,  or a “veiled  curtain” appearing across the field of vision  can be indicators of side effects of valganciclovir.

Neurological. Rare but  serious side  effects  may  be con- fusion, illogical thinking, seizures, or false  sensations. Agitation may  also  occur.

Special Considerations

Concomitant  therapy. Taking valganciclovir with didanosine, mycophenolate, or probenecid may  increase the  chance of side  effects.

Pregnant and breast-feeding women. Valganciclovir has  not  been  studied in  pregnant women but  animal studies indicate that  valganciclovir causes birth de- fects  and  other problems. Men  who are  taking valgan- ciclovir  should use  a  condom   to  avoid  impregnating their spouse, not  only  during the  course of treatment but  for  at least 90  days  following treatment. Use  of valganciclovir during  pregnancy  should  be  avoided whenever possible.

Studies to  determine the  transfer of valganciclovir from  nursing mothers to  their infants have not  been completed. Valganciclovir is not  recommended during breast-feeding because it may  cause unwanted effects in nursing babies.

Pediatric use. No studies have been  done  on pediatric patients.

Elderly. No studies have been  done  on elderly patients and  it is not  known if valganciclovir causes different side  effects  or problems in older  people.

Kidney disease. Valganciclovir increases the  chances of side  effects  as  it accumulates in the  blood  in patients with kidney disease.

Blood diseases. Low  platelet count, low red  blood  cell count, or low white blood cell count may be exacerbated by valganciclovir.

Ribavirin

Introduction

Severe viral pneumonia—respiratory syncytial virus RSV—in children can  be effectively treated  by ribavirin. Ribavirin is a broad-spectrum antiviral nucleoside. In addition to being  used to treat RSV pneumonia, it is also used to treat strains of influ- enza A and  B and  Lassa fever, off-label.  It is emerging as  a

Fig. 3.18 Associated names, structure, and  applicability of ribavirin.

possible treatment  for  adenovirus (206).  As summarized by Gavin and  Katz, adenovirus sites are  found  throughout the body as cystitis, pneumonia, enteritis, colitis, hepatitis, nephri- tis,  etc.,  and  survival-rate improvements are  high  enough to consider IV ribavirin a feasible treatment modality (206). Many other viruses respond to  ribavirin, including hepatitis A, B, and  C, particularly when combined with pegylated interferon- alpha (for more  information, refer to ribavirin-PEG-interferon, page 213).  Ribavirin is a white crystalline powder with high solubility in water and  limited solubility in anhydrous alcohol. Figure 3.18 shows  the  structure of ribivarin.

Mechanisms of Action

Ribavirin, a broad-spectrum antiviral nucleoside (guanosine) analog, phosphorylates easily. Although the  mechanisms of ribavirin remain unclear (207), ribavirin appears to be a non- specific  antiviral with most  of its efficacy  due to incorporation of the  ribavirin into  the  viral genome. Ribavirin undergoes dehydration synthesis to form new products (Fig. 3.19). When cells are  exposed to ribavirin, there is a reduction in intracel- lular guanosine triphosphate—a requirement for translation, transcription, and  replication in viruses and  a reason for the broad-spectrum attributes of ribavirin (208). Ribavirin signif- icantly increases the  mutation rate of RNA in poliovirus and

Fig. 3.19 Ribavirin bonding to cytosine and  uracil.

reduces viral fitness (Fig. 3.20). Thus, an understanding of the in-depth mechanisms of ribavirin activity could  contribute to the  development of lethal mutagenesis as an  effective antivi- ral  strategy.

Studies that  Support Treatment with  Ribavirin

Ribavirin may help treat orthopoxviruses, influenza and chronic hepatitis A and  B (206,209,210) (Table 3.17).

Treatment

Ribavirin is usually prescribed as an inhalant for infants and small children. Elderly patients, teenagers, and  adults are usually not prescribed ribavirin. Ribavirin is readily absorbed with oral  administration and  there is  a  linear relationship between the  time of last administration and   the  dosage. Although the  tablets are  taken with food, there is insufficient data to determine the effect of different types of diets (high  fat, high  protein, vegetarian, etc.)  on  ribavirin absorption. Dos- ages  and  types of administration are  shown in Table 3.18.

Adverse Effects

Unusual tiredness and weakness. May  occur  in  pa- tients taking ribavirin by mouth or injection for Lassa fever.

Headache. Occurs rarely.

Itching, redness, and swelling of  the eyes. Occurs rarely.

Skin rashes. Occurs rarely.

Fig. 3.20    Mechanisms of action of ribavirin. Ribavirin is a nucleoside analog that readily phosphorylates to ribavirin triphosphate. Ribavirin is incorporated into  the  viral genome by binding to cytosine and  uracil.

Combination Therapy with  Interferon-alpha. The adverse events of this combination therapy are  signif- icant and  include severe depression with suicidal ten- dencies,  hemolytic anemia,  suppression  of  bone marrow function, pulmonary dysfunction, pancreatitis, and  diabetes.

Special Considerations

Combination with Interferon-alpha. Combination therapy of ribavirin with interferon alpha has  been shown to be effective in  the  treatment of hepatitis C. Ribavirin monotherapy is not effective. However, there may  be severe adverse effects  (see  the  preceding sec- tion).  For  example, patients with autoimmune hepati- tis become  worse  when treated with this therapy.

Allergies. Some  patients are  allergic to  ribavirin. The possibility exists that children who are  allergic to food, preservatives, dyes, or other substances may also be al- lergic  to ribavirin.

Pregnancy. Ribavirin for  inhalation therapy for  very young  children may cause exposure to women who are pregnant (or  may  become   pregnant) if  they spend time at the  bedside when the  inhalation therapy is being  administered. The  effect  of ribavirin on prena- tal development has  not been  tested in  humans, but breast milk  containing ribavirin has  been  shown to cause birth defects and  other problems in certain an- imal  studies.

Hepatic dysfunction. In  patients with decreased he- patic function, the  pharmacokinetics of ribavirin can- not be accurately predicted. Therefore, the  dosage may need  to be increased for efficacy, but  monitored careful- ly to reduce adverse effects.

Breast milk. In  animal studies, ribavirin passes to the offspring through breast milk  and  can  cause problems in  nursing animals and  the  young. There have been no tests on humans.

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