Chapter 237 Principles of Antiviral Therapy

Antiviral chemotherapy typically involves a delicate interplay between host cellular functions and viral targets of action. Many antiviral agents exert significant host cellular toxicity, a limitation that has hindered antiviral drug development. In spite of this limitation, a number of agents are licensed for use against viruses, particularly herpesviruses, respiratory viruses, and hepatitis viruses. In addition to licensed antivirals and recommended regimens (see Table 237-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com), several studies are actively enrolling children for evaluation of novel antiviral therapeutic approaches. These studies are funded by the National Institutes of Health and administered through the Collaborative Antiviral Study Group (CASG), and up-to-date information is available about active clinical protocols at the CASG web page (http://medicine.uab.edu/Peds/CASG/).

Table 237-1 CURRENTLY LICENSED ANTIVIRAL DRUGS*

* See Chapter 268 for antiretroviral drugs.

In making the decision to commence antiviral drugs, it is important for the clinician to obtain appropriate diagnostic specimens, which can help clarify the antiviral of choice. The choice of a specific antiviral is based on the recommended agent of choice for a particular clinical condition, pharmacokinetics, toxicities, cost, and the potential for development of resistance (Table 237-2). Intercurrent conditions in the patient, such as renal insufficiency, should also be considered. Clinicians must monitor antiviral therapy closely for adverse events or toxicities, both anticipated and unanticipated.

Table 237-2 ANTIVIRAL THERAPIES FOR NON-HIV CLINICAL CONDITIONS

In vitro sensitivity testing of virus isolates to antiviral compounds usually involves a complex tissue culture system. The potency of an antiviral is determined by the 50% inhibitory dose (ID₅₀), which is the antiviral concentration required to inhibit the growth, in cell culture, of a standardized viral inoculum by 50%. Because of the complexity of these assays, the results vary widely, and the actual relationship between antiviral sensitivity testing and antiviral therapy outcomes is sometimes unclear. Moreover, these assays are not widely available, limiting their utility and value in clinical practice.

Knowledge of the precise status of a patient’s immune system, particularly the cell-mediated arm of the immune response, is important in the decision making for using an antiviral agent. Treatment of cytomegalovirus (CMV) infection in an immunocompetent patient is seldom necessary, whereas antiviral therapy may be lifesaving when administered to an immunocompromised patient. Antivirals can be employed with a variety of clinical goals in mind. Antivirals can be used as treatment of active disease, as prophylaxis to prevent viral infection or disease, and as preemptive treatment of viral infection to prevent viral disease (CMV infection in bone marrow transplant recipients).

A fundamental concept to understanding most antivirals is that viruses must use host cell components to replicate. Thus, mechanisms of action for antiviral compounds must be selective to virus-specific functions whenever possible, and antiviral agents may have significant toxicities to the host if these compounds impact cellular physiology. Many of the approved antiviral drugs active against the herpesviruses are analogs of deoxynucleosides and subsequently inhibit viral DNA polymerase. Some of the more commonly targeted sites of action for antiviral agents include viral entry, absorption, penetration, and uncoating (amantadine, rimantadine); transcription or replication of the viral genome (acyclovir, valacyclovir, cidofovir, famciclovir, penciclovir, foscarnet, ganciclovir, valganciclovir, ribavirin, trifluridine); viral protein synthesis (interferons); and viral assembly, release, or de-aggregation (oseltamivir, zanamivir, interferons).

An understudied and underappreciated issue in antiviral therapy is emergence of resistance, particularly in the setting of high viral load, high intrinsic viral mutation rate, and prolonged or repeated courses of antiviral therapy. Resistant viruses are more likely to develop or be selected for immunocompromised patients, because these patients are more likely to have multiple or long-term exposures to an antiviral agent in the face of impaired immunity.

Antivirals Used for Herpesviruses

The herpesviruses are important pediatric pathogens, particularly in newborns and immunocompromised children. Most of the licensed antivirals are nucleoside analogs that inhibit viral DNA polymerase, inducing premature chain termination during viral DNA synthesis in infected cells.

Acyclovir

Acyclovir is a safe and effective therapy for herpes simplex virus (HSV) infections. The favorable safety profile of acyclovir derives from its requirement for activation to its active form via phosphorylation by a viral enzyme, thymidine kinase (TK). Acyclovir is most active against HSV and also is active against varicella-zoster virus (VZV); therapy is indicated for these infections under a variety of circumstances. Activity against CMV is less pronounced, and activity against Epstein-Barr virus (EBV) is modest, both in vitro and clinically. Acyclovir should not be used to treat CMV or EBV infections.

The greatest clinical roles for acyclovir are for the treatment of primary and recurrent genital HSV infections, the management of HSV encephalitis, and all manifestations of neonatal HSV infection. The routine empirical use of acyclovir in infants admitted with fever of unknown origin in the first 4-8 wk of life is controversial. Clearly, acyclovir should be routinely empirically used in infants born to women with risk factors for primary genital herpes or infants presenting with any combination of vesicular lesions, seizures, meningoencephalitis, hepatitis, pneumonia, or disseminated intravascular coagulation (DIC). Some experts advocate initiation of acyclovir in all febrile infants pending the collection and analysis of viral culture and polymerase chain reaction (PCR) studies. Others have argued that a selective approach based on the history and physical exam is more appropriate when making decisions about the use of acyclovir in febrile infants. Given the safety of the drug, prudence would dictate the use of the acyclovir in such patients if HSV infection cannot be excluded.

Acyclovir is indicated for the treatment of primary HSV gingivostomatitis and for primary genital HSV infection. Long-term suppressive therapy, both for genital HSV and recurrent oropharyngeal infections (herpes labialis), is also effective. Long-term suppressive therapy (i.e., for the first 6 mo of life) to prevent recurrent episodes of neonatal HSV infection may be useful in preventing recurrences, although this use is investigational. Acyclovir is also recommended for less commonly encountered HSV infections, including herpetic whitlow, eczema herpeticum, and herpes gladiatorum. Life-threatening HSV disease, including disseminated infection, can occur in immunocompromised or pregnant patients, representing another clinical scenario where acyclovir is warranted.

Acyclovir modifies the course of primary VZV infection, although the effect is modest. Acyclovir or another nucleoside analog should always be used in localized or disseminated VZV infections, such as pneumonia, particularly in immunocompromised patients. Primary VZV infection in pregnancy is another setting where acyclovir is indicated; this is a high-risk scenario, particularly if pneumonia is present.

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