Chapter 245. Antiviral Therapy

Advances in molecular virology, with the identification of viral-specific enzymes, led to the development of a number of antiviral agents. Effective antivirals currently are available for the management of infections caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), hepatitis B and C viruses, influenza A and B viruses, and human immunodeficiency virus (HIV). To maximize therapeutic efficacy, treatment should be initiated as early in the course of infection as possible. Under some circumstances (eg, recurrent herpes simplex virus infections and exposure to influenza virus), antivirals may be effective in the prevention of infection. Development of resistance to antivirals is emerging as a problem, especially in the immunocompromised host population and more recently with influenza viruses circulating in the general population.

Subtle modifications of antiviral compounds have led to the development of drugs with increased bioavailability after oral administration. Many of these drugs are now used extensively in the outpatient setting (Table 245-1). However, severe viral infections, especially in immunocompromised hosts, require aggressive parenteral therapy, often with high doses of antiviral drugs (Table 245-2).1-3

This chapter will focus on antiviral therapy of infections caused by herpes viruses (herpes simplex virus, varicella-zoster virus, and cytomegalovirus), respiratory viruses (especially influenza A and B viruses), and hepatitis B and C. The therapy of HIV infections is discussed in Chapter 315.

Herpes Simplex Virus and Varicella-Zoster Virus

Acyclovir is the most useful agent for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Acyclovir is a synthetic purine nucleoside analog that has specificity for the viral thymidine kinase, which phosphorylates the drug to the monophosphate form. The drug is then further phosphorylated by host cell thymidine kinases to the triphosphate form, which inhibits the viral DNA polymerase. Acyclovir is most active against HSV-1 and HSV-2. It also has substantial activity against VZV but requires approximately 10-fold higher concentrations to inhibit replication as compared with HSV.4 Acyclovir is not effective against cytomegalovirus (CMV) infection, because CMV replication does not require thymidine kinase. Acyclovir inhibits Epstein-Barr virus (EBV) in vitro, but has limited efficacy in treating clinical EBV disease. Topical antiviral agents available to treat keratoconjunctivitis caused by HSV include trifluorothymidine, iododeoxyuridine, and vidarabine ophthalmic drops.5 The topical formulation of acyclovir has limited efficacy in mucocutaneous disease. Newer topical formulations of penciclovir and docosanol also have limited activity against mucocutaneous HSV disease.

The decision to treat HSV-1, HSV-2, and VZV infections depends on whether the infection is primary or recurrent; the clinical presentation; and host factors, such as age and underlying conditions. Primary infections are more often treated than recurrent infections because of the absence of viral-specific immunity. Because neonates and other immunodeficient hosts infected with HSV or VZV can experience substantial morbidity and mortality, antiviral therapy for these patients is recommended.

Acyclovir is safe and generally well tolerated, although patients should be monitored for potential side effects. Neurotoxicity (paresthesias and other neurologic symptoms such as tremor, ataxia, and hallucinations) can occur in patients receiving acyclovir, particularly if renal impairment is present. In addition, if acyclovir is administered with an inadequate volume of fluid or too rapidly, it can precipitate in the renal tubules, causing acute renal injury. Serum creatinine should be monitored in patients treated with acyclovir, especially if more than 5 to 7 days of therapy is anticipated. The dosage should be reduced if the serum creatinine concentration is above 1.5 mg/dL. Acyclovir can reduce the white cell count, but this is reversible with dose reduction or discontinuation. Acyclovir also can cause gastrointestinal symptoms, including anorexia, nausea, vomiting, and diarrhea.

Acyclovir is available in oral formulations; however, less than 20% of an orally administered dose is absorbed. Therefore, oral administration is appropriate only for nonlife-threatening infections. Valacyclovir is the l-valyl ester of acyclovir, which is rapidly converted to acyclovir by hepatic first-pass metabolism after oral administration. Its bioavailability after oral administration exceeds 50%.6 Although valacyclovir has been used in adults for the treatment and suppression of genital herpes infections, there is currently no oral suspension available for children, and pediatric pharmacokinetic data are limited.

The diagnosis of infection caused by HSV-1 or HSV-2 in neonates is an indication for intravenous antiviral therapy. The use of high-dose intravenous acyclovir (60 mg/kg/day) has favorably impacted the mortality and morbidity of herpes encephalitis.7 Antiviral therapy also is indicated for immunocompromised children with primary HSV-1 or HSV-2 infection. Although the risk of life-threatening dissemination is low, even among severely compromised patients, severe local symptoms can persist for 2 weeks or longer.

Acyclovir can be considered for treatment of serious herpes simplex virus infections in other patients in whom the indications are less well established. Examples of such patients include otherwise healthy children with severe herpes gingivostomatitis and children with eczema herpeticum. If the patient is hospitalized, intravenous acyclovir may be used, but if the patient is ambulatory, oral therapy may be appropriate. Acyclovir in the oral capsule formulation is licensed for treating primary and recurrent genital herpes simplex virus infection, usually caused by HSV-2. The recommended dosage for adults and adolescents is 200 mg 5 times per day. Sexually active teenagers or abused children may present with this infection and should be treated if the clinical symptoms are significant and the child is able to take capsules. Severe primary genital herpes simplex virus should be treated with intravenously administered acyclovir.

Alternatives to acyclovir for herpes simplex virus infections include penciclovir and its oral diacetyl ester prodrug, famciclovir. Both drugs have the same spectrum of activity as acyclovir. Following oral administration, famciclovir is converted by the liver into the active drug, penciclovir. Its bioavailability is ~70%. Famciclovir has been used in the suppression of genital herpes.8

HSV isolates resistant to acyclovir, on the basis of mutations in the viral thymidine kinase or viral DNA polymerase genes, have been reported. Although these isolates have demonstrated diminished virulence in animal models, they have been associated with progressive mucosal infections in immunocompromised hosts. Alternative antiviral agents to consider for the therapy of patients infected with acyclovir-resistant isolates include foscarnet and cidofovir.9 Foscarnet is an inorganic pyrophosphate analog that has activity against all human herpesviruses. It must be given intravenously because of its poor bioavailability. Side effects of foscarnet include significant nephrotoxicity and electrolyte disturbances, including symptomatic derangements of both calcium and phosphate. Cidofovir is an acyclic phosphonate nucleotide analog that does not require viral thymidine kinase to convert it to its active form. Therefore, it is well suited to treat viruses that are resistant to acyclovir because of alterations in viral thymidine kinase. Cidofovir has a very long half-life because it accumulates intracellularly; it can be given once per week. Cidofovir therapy is associated with significant nephrotoxicity.

Acyclovir has good activity in vitro against varicella-zoster virus, but its use in acute varicella should be limited to patients at high risk for severe disease, such as children older than age 12 or immunocompromised individuals. If acyclovir is administered within 24 hours of the onset of rash, a more rapid decrease in fever and a modest reduction in the total number of lesions can be expected. Acyclovir also is effective in the treatment of reactivated varicella-zoster virus. For immunocompromised patients with zoster who have a high risk of dissemination, high-dose intravenous acyclovir should be administered. In healthy individuals, treatment with acyclovir can decrease acute pain but may not have an impact on the development of postherpetic neuralgia. Oral valacyclovir or famciclovir is approved for the treatment of herpes zoster in adults, but no pediatric formulations are available for these drugs.10

Ganciclovir was the first effective antiviral agent available for the treatment of infections due to cytomegalovirus (CMV). Ganciclovir is an acyclic analog of the nucleoside guanosine, which is phosphorylated by CMV viral kinase. It is subsequently triphosphorylated by host kinases. The triphosphate form of the drug has high affinity for CMV DNA polymerase and can inhibit viral replication. Ganciclovir has been used extensively in bone marrow and solid organ transplant recipients in prophylactic, preemptive, and treatment regimens.11 It also has been shown to be effective in the treatment of CMV retinitis in patients infected with HIV. In addition, ganciclovir has shown limited benefit in newborns with symptomatic congenital CMV infection.12 Ganciclovir has very poor oral bioavailability and should only be administered intravenously. Valganciclovir, the l-valine ester of ganciclovir, has excellent bioavailability after oral administration and has been used to prevent CMV disease in transplant patients.

The main side effects of ganciclovir include myelosuppression (primarily neutropenia and to a lesser extent anemia and thrombocytopenia) and nephrotoxicity. Therefore, blood counts and serum creatinine should be monitored during treatment. Because many CMV infections, even in immunocompromised hosts, resolve spontaneously, ganciclovir should be restricted to severe CMV infections in immunocompromised hosts. CMV isolates that are resistant to ganciclovir because of mutations in the CMV thymidine kinase have been described. Infections due to CMV isolates that are resistant to ganciclovir can be treated with either foscarnet or cidofovir.

Although influenza vaccination remains the best strategy to reduce morbidity and mortality attributable to influenza virus infection, antiviral drugs are also effective for both prophylaxis and treatment. Two main classes of antivirals are available—adamantanes and neuraminidase inhibitors.

Amantadine and rimantadine are the two adamantanes that historically have been used for both prevention and treatment of influenza A virus infections. They have been shown to reduce the attack rate among household contacts of individuals infected with influenza A and to decrease the duration of fever and other influenza-related symptoms by about 1 day, if therapy is initiated within 48 hours of the onset of symptoms. Unfortunately, neither drug is active against influenza B virus. The mechanism of action of these drugs involves binding to the M2 ion channel, preventing acidification of host endosomes, a step that is essential for virus uncoating. The known side effects of these drugs include dizziness, ataxia, confusion, and anxiety. Rimantadine is better tolerated than amantadine. Unfortunately, the widespread use of these agents has resulted in a high prevalence of resistance among circulating strains of influenza A virus, and therefore their use is no longer generally recommended.

The neuraminidase inhibitors—oseltamivir and zanamivir—act by inhibiting the release of newly formed influenza virus from host cells. They have in vitro activity against both influenza A and B viruses and have shown promise in both prevention and treatment of infections caused by these viruses. Oseltamivir or zanamivir, given to household contacts of influenza-infected individuals as prophylaxis, has been shown to reduce the incidence of proven influenza infections by 68% to 89%. Treatment with either drug, if initiated within 2 days of onset of symptoms, has been shown to shorten the duration of fever and other symptoms by 1 to 2 days. Oseltamivir is available as a suspension or tablet and is approved for children older than 1 year. For prophylaxis or treatment, a 5-day course is indicated. Nausea and vomiting are the most common side effects. Zanamivir is administered by aerosol twice daily for 5 days. Its primary side effects include bronchospasm. It is approved only for treatment of influenza in children older than age 7 years, and for prophylaxis in children 5 years and older. Resistant viruses have been identified, but they are not widespread.13

Primary respiratory syncytial virus infection often causes pneumonia or bronchiolitis, which can be particularly severe in children with chronic lung disease, congenital heart disease, or immunodeficiency, and in infants younger than 6 weeks.

Ribavirin is a nucleoside analog that inhibits a wide spectrum of RNA and DNA viruses. It is approved by the US Food and Drug Administration (FDA) for administration as an aerosol to treat lower respiratory tract infections caused by respiratory syncytial virus; however, its use has not been widespread because of its limited efficacy. Ribavirin may reduce the duration of mechanical ventilation in infants with respiratory failure due to respiratory syncytial virus infection; however, data supporting this benefit have been inconsistent.14 The American Academy of Pediatrics suggests that therapy with ribavirin should be considered among those at high risk of serious respiratory syncytial virus disease and those who are severely ill as judged by blood gas determinations and lack of clinical response to other therapies.

Ribavirin accumulates in red blood cells and can cause a hemolytic anemia. In addition, significant teratogenic effects have been observed. The drug must be administered with a small-particle aerosol generator (SPAG), which can result in environmental exposure for health care personnel, although these units now contain a “scavenger” that decreases the amount of drug in the environment. The toxicity of aerosolized ribavirin appears to be minimal, although the drug can precipitate bronchospasm and has caused irritation of the eyes and skin of exposed health care workers.

Treatment options for chronic hepatitis B and hepatitis C infections include interferon alfa and nucleoside or nucleotide analogs such as lamivudine and ribavirin. Interferon alfa is part of the type I interferon family produced by the body in response to viral infection. These drugs do not exert their antiviral effect directly but rather stimulate both the innate and adaptive immune system to clear virus-infected cells. For hepatitis B, interferon alfa is given subcutaneously 3 times per week. Pegylated interferon-alfa is a newer formulation that prolongs the half-life of the drug, allowing once-per-week administration. For hepatitis C, interferon-alfa therapy combined with oral ribavirin has been shown to be effective. The main adverse effects seen are an influenza-like illness, which usually resolves with continued therapy. Neuropsychiatric problems are somewhat common as well, occurring in 10% to 20% of patients. Neutropenia and thrombocytopenia also occur.15

Lamivudine is a nucleoside reverse transcription inhibitor used in the treatment of chronic hepatitis B. Although virologic response occurs with lamivudine therapy, the development of resistance occurs rapidly. Continuation of lamivudine therapy once resistance is detected is controversial, because significant viral suppression can still be seen despite the development of lamivudine resistance. Combination treatment with both interferon-alfa and lamivudine is not recommended for chronic hepatitis B infection. Adefovir and entecavir are two new nucleic acid analogs approved in adults for the treatment of hepatitis B, but no pharmacokinetic data are available for children.16

Oral ribavirin, in combination with interferon-alfa, has been approved by the FDA for treatment of chronic hepatitis C in children older than 3 years. This combination appears to be more effective for treatment of genotype 1, the most common hepatitis C genotype in the United States. Side effects include fever, headache, fatigue, and influenza-like illness. Anemia and neutropenia are commonly seen.17