Principles of Antiviral Therapy


Antiviral chemotherapy typically requires a delicate balance between targeting critical steps in viral replication without interfering with host cellular function. Because viruses require cellular functions to complete replication, 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 ( Table 272.1 ).

Table 272.1
Currently Licensed Antiviral Drugs
ANTIVIRAL TRADE NAME MECHANISM OF ACTION
Acyclovir Zovirax Inhibits viral DNA polymerase
Adefovir Hepsera Nucleotide reverse transcriptase inhibitor
Amantadine * Symmetrel Blocks M2 protein ion channel
Baloxavir Xofluza Inhibits polymerase acidic endonuclease, blocking viral replication
Beclabuvir BMS-791325 Inhibitor of HCV NS5B
Boceprevir Victrelis Inhibitor of HCV NS3 serine protease
Active against HCV genotype 1
Cidofovir Vistide Inhibits viral DNA polymerase
Daclatasvir Daklinza Inhibitor of HCV NS5A
Used in varying combinations with sofosbuvir, ribavirin, and interferon
Dasabuvir Exviera Inhibitor of HCV NS5B
Used together with the combination medication ombitasvir/paritaprevir/ritonavir (Vikiera Pak)
Activity limited to HCV genotype 1
Elbasvir (Zepatier) Inhibitor of HCV NS5A
Used in combination with the NS3/4A protease inhibitor grazoprevir under the trade name Zepatier, either with or without ribavirin
Entecavir Baraclude Nucleoside reverse transcriptase inhibitor
Active against HBV
Famciclovir Generic Inhibits viral DNA polymerase
Fomivirsen Vitravene Phosphorothioate oligonucleotide inhibits viral replication via antisense mechanism
Foscarnet Foscavir Inhibits viral DNA polymerase and reverse transcriptase at pyrophosphate-binding site
Ganciclovir Cytovene Inhibits viral DNA polymerase
Grazoprevir (Zepatier) Inhibitor of HCV NS3-4A serine protease Used in combination with elbasvir under the trade name Zepatier, either with or without ribavirin
Idoxuridine Herplex Inhibits viral DNA polymerase
Interferon-α Intro-A (interferon-α2b)
Roferon-A (interferon-α2a)
Infergen (interferon alfacon-1)
Produces multiple effector proteins that exert antiviral effects; also directly interacts with immune system components
Interferon-α2b plus ribavirin Rebetron Not established
Lamivudine (3TC) Epivir Inhibits viral DNA polymerase and reverse transcriptase; active against HBV
Ledipasvir (with Sofosbuvir: Harvoni) Inhibitor of HCV NS5A
Ombitasvir (Viekira Pak) Inhibitor of HCV NS5A
Used in combination with paritaprevir, ritonavir and dasabuvir in Viekira Pak
Active against HCV genotype 1
Oseltamivir Tamiflu Neuraminidase inhibitor; interference with deaggregation and release of viral progeny
Paritaprevir (Viekira Pak)
(Technivie/Viekirax)
Inhibitor of HCV NS3-4A serine protease Used in combination with ombitasvir, ritonavir and dasabuvir (Viekira Pak), or in combination with ombitasvir and ritonavir (Technivie/Viekirax)
Pegylated interferon PEG-Intron (α2b), Pegasys (α2a) Same as interferon
Penciclovir Denavir Inhibits viral DNA polymerase
Peramivir Rapivab Neuraminidase inhibitor
Ribavirin Virazole, Rebetol, Copegus Interference with viral messenger RNA
Rimantadine * Flumadine Blocks M2 protein ion channel
Simeprevir Olysio Inhibitor of HCV NS3-4A serine protease Active against genotype 1 ± genotype 4
Used with include sofosbuvir or ribavirin and pegylated interferon-alfa
Sofosbuvir (Harvoni) Inhibitor of HCV NS5B
Used in combination with Ledipasvir (Harvoni)
Telaprevir Incivek
Incivio
Inhibitor of HCV NS3-4A serine protease
Active against HCV genotype 1
Telbivudine Tyzeka Interferes with HBV DNA replication
Tenofovir Viread Nucleoside reverse transcriptase inhibitor
Active against HBV
Trifluridine Viroptic Inhibits viral DNA polymerase
Valacyclovir Valtrex Same as acyclovir
Valganciclovir Valcyte Same as ganciclovir
Velpatasvir (Epclusa, Sofosvel, Velpanat) Inhibitor of HCV NS5A
Used in combination with sofosbuvir (Epclusa, Sofosvel, Velpanat)
Active against all 6 HCV genotypes
Vidarabine ara-A Inhibits viral DNA polymerase (and to lesser extent, cellular DNA polymerase)
Zanamivir Relenza Neuraminidase inhibitor; interference with deaggregation and release of viral progeny
FDA-APPROVED COMBINATION THERAPIES
Interferon-α2b + ribavirin Rebetron (Intron-A plus Rebetol)
Interferon-α2a + ribavirin Roferon-A + ribavirin
Pegylated interferon-α2b + ribavirin (3 yr and older) PEG-Intron + Rebetol
Pegylated interferon-α2a + ribavirin (5 yr and older) Pegasys + Copegus

* No longer recommended by Centers for Disease Control and Prevention for treatment of influenza.

No longer marketed in United States.

No longer available.

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 272.2 ). 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 272.2
Antiviral Therapies for Non-HIV Clinical Conditions *
VIRUS CLINICAL SYNDROME ANTIVIRAL AGENT OF CHOICE ALTERNATIVE ANTIVIRAL AGENTS
Influenza A and B Treatment Oseltamivir (>2 wk old) Zanamivir (>7 yr old)
Peramivir (>2 yr old)
Prophylaxis Oseltamivir (>3 mo old) Zanamivir (>5 yr old)
Respiratory syncytial virus Bronchiolitis or pneumonia in high-risk host Ribavirin aerosol
Adenovirus In immunocompromised patients:
Pneumonia
Viremia
Nephritis
Hemorrhagic cystitis
Cidofovir
CMV Congenital CMV infection Ganciclovir (IV) Valganciclovir (if oral therapy appropriate; long-term oral valganciclovir investigational but may improve developmental and hearing outcomes)
Retinitis in AIDS patients Valganciclovir Ganciclovir
Cidofovir
Foscarnet
Ganciclovir ocular insert
Pneumonitis, colitis; esophagitis in immunocompromised patients Ganciclovir (IV) Foscarnet
Cidofovir
Valganciclovir
HSV Neonatal herpes Acyclovir (IV)
Suppressive therapy following neonatal herpes with central nervous system involvement Acyclovir (PO)
HSV encephalitis Acyclovir (IV)
HSV gingivostomatitis Acyclovir (PO) Acyclovir (IV)
First episode genital infection Acyclovir (PO) Valacyclovir
Famciclovir
Acyclovir (IV) (severe disease)
Recurrent genital herpes Acyclovir (PO) Valacyclovir
Famciclovir
Suppression of genital herpes Acyclovir (PO) Valacyclovir
Famciclovir
Cutaneous HSV (whitlow, herpes gladiatorum) Acyclovir (PO) Penciclovir (topical)
Eczema herpeticum Acyclovir (PO) Acyclovir (IV) (severe disease)
Mucocutaneous infection in immunocompromised host (mild) Acyclovir (IV) Acyclovir (PO) (if outpatient therapy acceptable)
Mucocutaneous infection in immunocompromised host (moderate to severe) Acyclovir (IV)
Prophylaxis in bone marrow transplant recipients Acyclovir (IV) Valacyclovir
Acyclovir-resistant HSV Foscarnet Cidofovir
Keratitis or keratoconjunctivitis Trifluridine Vidarabine
Varicella-zoster virus Chickenpox, healthy child Supportive care Acyclovir (PO)
Chickenpox, immunocompromised child Acyclovir (IV)
Zoster (not ophthalmic branch of trigeminal nerve), healthy child Supportive care Acyclovir (PO)
Zoster (ophthalmic branch of trigeminal nerve), healthy child Acyclovir (IV)
Zoster, immunocompromised child Acyclovir (IV) Valacyclovir
CMV, cytomegalovirus; HSV, herpes simplex virus.

* For antiviral agents for hepatitis B and hepatitis C, see Table 272.1 .

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 (ID 50 ), 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. Because these assays are often not readily available and take considerable time to complete, genotypic analysis for antiviral susceptibility is increasingly being offered. Such assays may be useful for patients on long-term antiviral therapy.

Clinical context is essential in making decisions about antiviral treatment, along with knowledge of a patient's immune status. For example, antiviral treatment is rarely if ever indicated in an immunocompetent child shedding cytomegalovirus (CMV) but may be lifesaving when administered to an immunocompromised solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) patient. Antivirals can be used with a variety of clinical goals in mind. Antivirals can be used for treatment of active end-organ disease, as prophylaxis to prevent viral infection or disease, or as preemptive therapy aimed at reducing risk of progression to disease (i.e., a positive signal indicating viral replication but in the absence of clinical evidence of end-organ disease). In preemptive therapy, a patient will usually have a positive signal for polymerase chain reaction–based identification of viral nucleic acids in a clinical sample (blood or body fluid) but have no symptoms. However, SOT and HSCT patients are at high risk of developing disease in this setting (particularly due to CMV infection), a scenario that warrants preemptive treatment with an antiviral agent. In contrast, prophylaxis is administered to seropositive patients who are at risk to reactivate latent viral infection but do not yet have evidence of active viral replication or shedding.

A fundamental concept important in the understanding of the mechanism of action of 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. 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) or protein modification (protease inhibitors); and viral assembly, release, or deaggregation (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 in immunocompromised patients because these patients are more likely to have multiple or long-term exposures to an antiviral agent.

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). Thus acyclovir can be activated only in cells already infected with HSV that express the viral TK enzyme, a strategy that maximizes selectivity and reduces the potential for cellular toxicity in uninfected cells. Acyclovir is most active against HSV and is also active against varicella-zoster virus (VZV); therapy is indicated for infections with these viruses in a variety of clinical settings. Activity of acyclovir against CMV is less pronounced, and activity against Epstein-Barr virus is minimal, both in vitro and clinically. Therefore, under most circumstances, acyclovir should not be used to treat CMV or Epstein-Barr virus infections.

The biggest impact of acyclovir in clinical practice is in the treatment of primary and recurrent genital HSV infections. Oral nucleoside therapy plays an important role in the management of acute primary genital herpes, treatment of episodic symptomatic reactivations, and prophylaxis against reactivation. Acyclovir is also indicated in the management of suspected or proven HSV encephalitis in patients of all ages and for treatment of neonatal HSV infection, with or without central nervous system (CNS) involvement. With respect to neonatal HSV infection, the routine empirical use of acyclovir as empiric therapy against presumptive or possible HSV infection in infants admitted with fever and no focus in the 1st 4 wk of life is controversial. Acyclovir should be used routinely 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. Some advocate initiation of acyclovir in all febrile neonates. Other experts 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 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 for genital HSV and for recurrent oropharyngeal infections (herpes labialis) is also effective. Acyclovir is also recommended for less commonly encountered HSV infections, including herpetic whitlow, eczema herpeticum, and herpes gladiatorum. In addition, acyclovir is commonly used for prophylaxis against HSV reactivation in SOT and HSCT patients. Severe end-organ HSV disease, including disseminated infection, is occasionally encountered in immunocompromised or pregnant patients, representing another clinical scenario where acyclovir therapy 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 and can be associated with a substantial risk of maternal mortality, particularly if pneumonia is present.

Acyclovir is available in topical (5% ointment), parenteral, and oral formulations, including an oral suspension formulation for pediatric use. Topical therapy has little role in pediatric practice and should be avoided in favor of alternative modes of delivery, particularly in infants with vesicular lesions compatible with herpetic infection, where topical therapy should never be used. The bioavailability of oral formulations is modest, with only 15–30% of the oral dose being absorbed. There is widespread tissue distribution following systemic administration, and high concentrations of drug are achieved in the kidneys, lungs, liver, myocardium, and skin vesicles. Cerebrospinal fluid concentrations are approximately 50% of plasma concentrations. Acyclovir crosses the placenta, and breast milk concentrations are approximately 3 times plasma concentrations, although there are no data on efficacy of in utero therapy or impact of acyclovir therapy on nursing infants. Acyclovir therapy in a nursing mother is not a contraindication to breastfeeding. The main route of elimination is renal, and dosage adjustments are necessary for renal insufficiency. Hemodialysis also eliminates acyclovir.

Acyclovir has an exceptional safety profile. Toxicity is observed typically only in exceptional circumstances: for example, if administered by rapid infusion to a dehydrated patient or a patient with underlying renal insufficiency, acyclovir can crystallize in renal tubules and produce a reversible obstructive uropathy. High doses of acyclovir are associated with neurotoxicity, and prolonged use can cause neutropenia. The favorable safety profile of acyclovir is underscored by recent studies of its safe use during pregnancy, and suppressive therapy in pregnant women with histories of recurrent genital HSV infection, typically with valacyclovir (see later), has become standard of care among many obstetricians. One uncommon but important complication of long-term use of acyclovir is the selection for acyclovir-resistant HSV strains, which usually occurs from mutations in the HSV TK gene. Resistance is rarely observed in pediatric practice but should be considered in any patient who has been on long-term antiviral therapy and who has an HSV or VZV infection that fails to clinically respond to acyclovir therapy.

Valacyclovir

Valacyclovir is the l -valyl ester of acyclovir and is rapidly converted to acyclovir following oral administration. This agent has a safety and activity profile similar to that of acyclovir but has a bioavailability of >50%, 3-5–fold greater than that of acyclovir. Plasma concentrations approach those observed with intravenous acyclovir. Valacyclovir is available only for oral administration. A suspension formulation is not commercially available, but an oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500-mg caplets for use in pediatric patients for whom a solid dosage form is not appropriate. Suppressive therapy with valacyclovir is commonly prescribed in the 2nd and 3rd trimesters of pregnancy in women who have a clinical history of recurrent genital herpes. It is important to be aware that perinatal transmission of HSV can occur, leading to symptomatic disease in spite of maternal antenatal antiviral prophylaxis. In such settings, the possibility of emergence of acyclovir-resistant virus should be considered.

Penciclovir and Famciclovir

Penciclovir is an acyclic nucleoside analog that, like acyclovir, inhibits the viral DNA polymerase following phosphorylation to its active form. Compared with acyclovir, penciclovir has a substantially longer intracellular half-life, which in theory can confer superior antiviral activity at the intracellular level; however, there is no evidence that this effect confers clinical superiority. Penciclovir is licensed only as a topical formulation (1% penciclovir cream), and this formulation is indicated for therapy of cutaneous HSV infections. Topical therapy for primary or recurrent herpes labialis or cutaneous HSV infection is an appropriate use of penciclovir in children older than 2 yr of age.

Famciclovir is the prodrug formulation (diacetyl ester) of penciclovir. In contrast to penciclovir, famciclovir may be administered orally and has bioavailability of approximately 70%. Following oral administration, famciclovir is deacetylated to the parent drug, penciclovir. The efficacy of famciclovir for HSV and VZV infections appears equivalent to that of acyclovir, although the pharmacokinetic profile is more favorable. Famciclovir is indicated for oral therapy of HSV and VZV infections. There is currently no liquid or suspension formulation available, and experience with pediatric use is very limited. The toxicity profile is identical to that of acyclovir. In a clinical trial, valacyclovir was found to be superior to famciclovir in prevention of reactivation and reduction of viral shedding in the setting of recurrent genital HSV infection.

Ganciclovir and Valganciclovir

Ganciclovir is a nucleoside analog with structural similarity to acyclovir. Like acyclovir, ganciclovir must be phosphorylated for antiviral activity, which is targeted against the viral polymerase. The gene responsible for ganciclovir phosphorylation is not TK but rather the virally encoded UL97 phosphotransferase gene. Antiviral resistance in CMV can be observed with prolonged use of nucleoside antivirals, and resistance should be considered in patients on long-term therapy who appear to fail to respond clinically and virologically. Ganciclovir is broadly active against many herpesviruses, including HSV and VZV, but is most valuable for its activity against CMV. Ganciclovir was the first antiviral agent licensed specifically to treat and prevent CMV infection. It is indicated for prophylaxis against and therapy of CMV infections in high-risk patients, including HIV-infected patients and SOT or HSCT recipients. Of particular importance is the use of ganciclovir in the management of CMV retinitis, a sight-threatening complication of HIV infection. Ganciclovir is also of benefit for newborns with symptomatic congenital CMV infection and may be of value in partially ameliorating the sensorineural hearing loss and developmental disabilities that are common complications of congenital CMV infection.

Ganciclovir is supplied as parenteral and oral formulations. Ganciclovir ocular implants are also available for the management of CMV retinitis. The bioavailability of oral ganciclovir is poor, <10%, and hence oral ganciclovir therapy has been supplanted by the oral prodrug, valganciclovir, which is well absorbed from the gastrointestinal tract and quickly converted to ganciclovir by intestinal or hepatic metabolism. Bioavailability of ganciclovir (from valganciclovir) is approximately 60% from tablet and solution formulations. Significant concentrations are found in aqueous humor, subretinal fluid, cerebrospinal fluid, and brain tissue (enough to inhibit susceptible strains of CMV). Subretinal concentrations are comparable with plasma concentrations, but intravitreal concentrations are lower. Drug concentrations in the CNS range from 24% to 70% of plasma concentrations. The main route of elimination is renal, and dosage adjustments are necessary for renal insufficiency. Dose reduction is proportional to the creatinine clearance. Hemodialysis efficiently eliminates ganciclovir, so administration of additional doses after dialysis is necessary.

Ganciclovir has several important toxicities. Reversible myelosuppression is the most important toxicity associated with ganciclovir therapy and commonly requires either discontinuation of therapy or the intercurrent administration of granulocyte colony–stimulating factor. There are also the theoretical risks for carcinogenicity and gonadal toxicity; although these effects have been observed in some animal models, they have never been observed in patients. The decision to administer ganciclovir to a pediatric patient is complex and should be made in consultation with a pediatric infectious disease specialist.

Foscarnet

Foscarnet has a unique profile, insofar as it is not a nucleoside analog but rather a pyrophosphate analog. The drug has broad activity against most herpesviruses. Like the nucleoside analogs, foscarnet inhibits viral DNA polymerase. On the other hand, foscarnet does not require phosphorylation to exert its antiviral activity, thus differing from the nucleoside analogs. It binds to a different site on the viral DNA polymerase to exert its antiviral effect and therefore retains activity against strains of HSV and CMV that are resistant to nucleoside analogs. Its clinical utility is as a second-line agent for management of CMV infections in high-risk patients who cannot tolerate ganciclovir and as an alternative for patients with persistent or refractory HSV, CMV, or VZV disease with suspected or documented antiviral drug resistance.

Foscarnet is available only as a parenteral formulation and is a toxic agent that must be administered cautiously. Nephrotoxicity is common, and reversible renal insufficiency is often observed, as evidenced by an increase in serum creatinine. Abnormalities in calcium and phosphorus homeostasis are common, and electrolytes and renal function must be monitored carefully during treatment.

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