Mark R. Schleiss
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 |
* For antiviral agents for hepatitis B and hepatitis C, see Table 272.1 .
CMV, cytomegalovirus; HSV, herpes simplex virus.
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. 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.
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 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 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 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 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 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.
Cidofovir is an acyclic nucleotide analog that requires phosphorylation to its active form, cidofovir diphosphate, to exert its antiviral effect. Analogous to penciclovir, it has an extended intracellular half-life that contributes to its prolonged antiviral activity. Cidofovir is active against HSV, VZV, and CMV. In contrast to most of the other agents with activity against herpesviruses, cidofovir also exhibits broad-spectrum activity against other DNA viruses, most notably the poxviruses. Cidofovir has activity against the BK virus, a polyomavirus, and therapy may be warranted in some settings of BK reactivation post HSCT and post SOT. Cidofovir is useful in the management of adenovirus infections in the immunocompromised host. Cidofovir is also useful in the management of CMV disease caused by strains with documented ganciclovir resistance.
Cidofovir is administered intravenously and is cleared renally by tubular secretion. Extensive prehydration and co-administration of probenecid are recommended. Nephrotoxicity is commonly encountered, even with appropriate prehydration; cidofovir must be co-administered with care with other nephrotoxic medications. Other potential toxicities include reproductive toxicity and carcinogenesis.
Trifluridine is a pyrimidine nucleoside analog with activity against HSV, CMV, and adenovirus. It is formulated as a 1% ophthalmic solution and approved for topical use in the treatment of HSV keratitis and keratoconjunctivitis. Trifluridine is the treatment of choice for HSV keratitis, a disease that should always be managed in consultation with an ophthalmologist.
Vidarabine is a nucleoside analog that has activity against HSV. It was the first parenteral antiviral agent for HSV infection, although it is no longer available for intravenous administration. A topical preparation remains available to treat HSV keratitis and is considered a second-line agent for this indication.
Fomivirsen is an anti-CMV compound that was used as a second-line agent for CMV retinitis by direct injection into the vitreous space. It is an antisense 21-mer DNA oligonucleotide that binds directly to complementary messenger RNA. This agent is of interest because it was the first antisense antiviral agent approved by the US Food and Drug Administration (FDA). The drug is no longer marketed.
There is a major need for development of new, nontoxic antivirals for HSV infection. Two new agents are approaching licensure and will be very useful in the management of HSCT and SOT patients. The oral lipid conjugate prodrug of cidofovir, CMX001, has improved activity against herpesviruses compared with parenterally administered cidofovir and a markedly reduced risk of nephrotoxicity. Another novel agent, letermovir (AIC246), is highly orally bioavailable and has a novel mechanism of action, exerting its antiviral effect by interfering with the viral terminase complex. This agent demonstrates substantial promise as an alternative to more toxic antivirals in patients at high risk for CMV disease, particularly in the transplantation setting. It is also active against BK virus and poxviruses.
Antiviral therapies are available for many respiratory pathogens, including respiratory syncytial virus (RSV), influenza A, and influenza B. Antiviral therapy for respiratory viral infections is of particular value for infants, children with chronic lung disease, and immunocompromised children.
Ribavirin is a guanosine analog that has broad-spectrum activity against a variety of viruses, particularly RNA viruses. Its precise mechanism of action is incompletely understood but is probably related to interference with viral messenger RNA processing and translation. Ribavirin is available in oral, parenteral, and aerosolized formulations. Although intravenous ribavirin is highly effective in the management of Lassa fever and other hemorrhagic fevers, this formulation is not licensed for use in the United States. The only licensed formulations in the United States are an aqueous formulation for aerosol administration (indicated for RSV infection) and an oral formulation that is combined with interferon-α for the treatment of hepatitis C. (For more information about antivirals for hepatitis, see Chapter 385 .) Administration of ribavirin by aerosol should be considered for serious RSV lower respiratory tract disease in immunocompromised children, young infants with serious RSV-associated illness, and high-risk infants and children (children with chronic lung disease or cyanotic congenital heart disease). In vitro testing and uncontrolled clinical studies also suggest efficacy of aerosolized ribavirin for parainfluenza, influenza, and measles infections.
Ribavirin is generally nontoxic, particularly when administered by aerosol. Oral ribavirin is used in combination with other agents for therapy of hepatitis C (discussed later). There is no role for the use of oral ribavirin in the treatment of community-acquired viral respiratory tract infections. Ribavirin and its metabolites concentrate in red blood cells and can persist for several weeks and, in rare instances, may be associated with anemia. Conjunctivitis and bronchospasm have been reported following exposure to aerosolized drug. Care must be taken when using aerosolized ribavirin in children undergoing mechanical ventilation to avoid precipitation of particles in ventilator tubing; the drug is not formally approved for use in the mechanically ventilated patient, although there is published experience with this approach, which can be considered for mechanically ventilated patients, particularly in a “high-dose, short-duration” regimen (6 g/100 mL water given for a period of 2 hr 3 times a day). Concerns regarding potential teratogenicity from animal studies have not been borne out in clinical practice, although care should be taken to prevent inadvertent exposure to aerosolized drug in pregnant healthcare providers.
Amantadine and rimantadine are tricyclic amines (adamantanes) that share structural similarity. Both were indicated for prophylaxis and therapy of influenza A. The mechanism of action of the tricyclic amines against influenza A virus was unclear, but they appeared to exert their antiviral effect at the level of uncoating of the virus. Both agents are extremely well absorbed after oral administration and are eliminated via the kidneys (90% of the dose is unchanged), necessitating dosage adjustments for renal insufficiency. The toxicities of the tricyclic amines are modest and include CNS adverse effects such as anxiety, difficulty concentrating, and lightheadedness and gastrointestinal adverse effects such as nausea and loss of appetite.
Although these agents are still manufactured and available, the Centers for Disease Control and Prevention (CDC) no longer recommends the use of the adamantane agents in treatment or prophylaxis against influenza, due to emergence of widespread resistance.
Oseltamivir and zanamivir are active against both influenza A and B, although the importance of this broader spectrum of antiinfluenza activity in disease control is modest because influenza B infection is typically a much milder illness. Emerging strains of influenza, including H5N1 and the 2009–2010 pandemic strain, H1N1 (swine flu), are susceptible to oseltamivir and zanamivir but resistant to amantadine. Therefore these agents are emerging as the antivirals of choice for influenza infection. Neither agent has appreciable activity against other respiratory viruses. The mechanism of antiviral activity of these agents is via inhibition of the influenza neuraminidase.
Zanamivir has poor oral bioavailability and is licensed only for inhalational administration. With inhaled administration, >75% of the dose is deposited in the oropharynx and much of it is swallowed. The actual amount distributed to the airways and lungs depends on factors such as the patient's inspiratory flow. Approximately 13% of the dose appears to be distributed to the airways and lungs, with approximately 10% of the inhaled dose distributed systemically. Local respiratory mucosal drug concentrations greatly exceed the drug concentration needed to inhibit influenza A and B viruses. Elimination is via the kidneys, and no dosage adjustment is necessary with renal insufficiency, because the amount that is systemically absorbed is low.
Oseltamivir is administered as an esterified prodrug that has high oral bioavailability. It is eliminated by tubular secretion, and dosage adjustment is required for patients with renal insufficiency. Gastrointestinal adverse effects, including nausea and vomiting, are occasionally observed. The drug is indicated for both treatment and prophylaxis. The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days. Treatment should be initiated within 2 days of the appearance of symptoms. Recommended treatment dosages for children vary by age and weight. The recommended dose for children younger than 1 yr of age is 3 mg/kg/dose twice a day. For children older than 1 yr of age, doses are 30 mg twice a day for children weighing ≤15 kg, 45 mg twice a day for children weighing 15-23 kg, 60 mg twice a day for those weighing 23-40 kg, and 75 mg twice a day for children weighing ≥40 kg. Dosages for chemoprophylaxis are the same for each weight group in children older than 1 yr of age, but the drug should be administered only once daily rather than twice daily. Oseltamivir is FDA approved for therapy of influenza A and B treatment in children 2 wk of age and older, whereas zanamivir is recommended for treatment of children 7 yr of age and older. Current treatment and dosage recommendations for treatment of influenza in children and for chemoprophylaxis are available at: https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm . Oseltamivir has been described to produce neuropsychiatric (narcolepsy) and psychologic (suicidal events) side effects in some patient populations; the drug should be discontinued if behavioral or psychiatric side effects are observed. In late 2014 the FDA approved another neuraminidase inhibitor, peramivir, for treatment of influenza. It is available as a single-dose, intravenous option. The drug is currently approved for use in children >2 yr of age. The dose is 12 mg/kg dose, up to 600 mg maximum, via intravenous infusion for a minimum of 15 min in children from 2 to 12 yr of age. Children 13 and older should receive the adult dose (600 mg IV in a single, 1-time dose).
Oral baloxavir marboxil (Xofluza) is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset in people ≥12 yr. The safety and efficacy of baloxavir for the treatment of influenza have been established in pediatric patients ≥12 yr and older weighing at least 40 kg. Safety and efficacy in patients <12 yr or weighing less than 40 kg have not been established. Baloxavir efficacy is based on clinical trials in outpatients 12 to 64 yr of age; people with underlying medical conditions and adults >65 yr were not included in the initial published clinical trials. There are no available data for baloxavir treatment of hospitalized patients with influenza.
Seven antiviral agents have been approved by the FDA for treatment of adults with chronic hepatitis B in the United States. These agents are categorized as either interferons (IFN-α2b and peginterferon-α2a) or nucleoside or nucleotide analogs (lamivudine, adefovir, entecavir, tenofovir, telbivudine). Lamivudine is currently considered the first-line therapy in adult patients, but experience in children is limited. In 2012 tenofovir was FDA approved for children with chronic hepatitis B aged 12 yr or older weighing >35 kg. Entecavir was approved in the United States for use in children 2 yr and older with chronic HBV and evidence of active viral replication and disease activity and, with IFN-α, is emerging as a first-line antiviral regimen for children with hepatitis B who are candidates for antiviral therapy.
Adefovir demonstrates a favorable safety profile and is less likely to select for resistance than lamivudine, but virologic response was limited to adolescent patients and was lower than that of lamivudine. Most experts recommend watchful waiting of children with chronic hepatitis B infection, because current therapies are only modestly effective at best and evidence of long-term benefit is scant. Young children are often believed to be immune tolerant of hepatitis B infection (i.e., they have viral DNA present in serum but normal transaminase levels and no evidence of active hepatitis). These children should have transaminases and viral load monitored but are not typically considered to be candidates for antiviral therapy.
Only various combinations of interferons and ribavirin were approved by the FDA to treat adults and children with chronic hepatitis C (see Tables 272.1 and 272.2 ). The development of novel and highly effective antivirals for HCV has revolutionized the care of hepatitis C patients. These drugs are not yet licensed for pediatric use. Novel drugs include ledipasvir, sofosbuvir, daclatasvir, elbasvir, beclabuvir, grazoprevir, paritaprevir, ombitasvir, velpatasvir, and dasabuvir. Ledipasvir, ombitasvir, daclatasvir, elbasvir, and velpatasvir inhibit the virally encoded phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion, whereas sofosbuvir is metabolized to a uridine triphosphate mimic, which functions as an RNA chain terminator when incorporated into the nascent RNA by the NS5B polymerase enzyme. Dasabuvir and beclabuvir are also NS5B inhibitors. Paritaprevir and grazoprevir inhibit the nonstructural protein 3 (NS3/4) serine protease, a viral nonstructural protein that is the 70-kDa cleavage product of the hepatitis C virus polyprotein.
Past efforts to treat HCV prior to the advent of these new direct therapies had yielded mixed results. Although only 10–25% of adults treated with interferon had a sustained remission of disease, treatment with a combination of interferon and ribavirin achieves remission in close to half of treated adults. Randomized controlled trials indicated that patients treated with pegylated interferons (so called because they are formulated and stabilized with polyethylene glycol), both as dual therapy with ribavirin and as monotherapy, experienced higher sustained viral response rates than did those treated with nonpegylated interferons. The advent of new, direct therapies has led to permanent remission of HCV disease in adult patients. Data on the use of these agents in infants and children are limited. In early 2017 the combination of sofosbuvir with ribavirin and the fixed-dose combination of sofosbuvir/ledipasvir was approved by the FDA for treatment of children with chronic HCV infection 12 yr of age and older. The only drugs currently approved for children younger than 12 yr remain pegylated interferon and ribavirin. The use of IFN-α2b in combination with ribavirin has been approved by the FDA for chronic hepatitis C in this age group.
There are significant genotype-dependent differences in responsiveness to antiviral therapy; patients with genotype 1 had the lowest levels of sustained virologic response, and patients with genotype 2 or 3 had the highest response. The use of IFN-ααb in combination with ribavirin provides a much more favorable sustained virologic response in children with HCV genotype 2/3 than in those with HCV genotype 1. For genotype 1 hepatitis C treated with pegylated interferons combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment.
Immune globulins are useful adjuncts in the management of viral disease. However, they are most valuable when administered as prophylaxis against infection and disease in high-risk patients; their value as therapeutic agents in the setting of established infection is less clear. Varicella-zoster immune globulin (human) is valuable for prophylaxis against VZV in high-risk children, particularly newborns and immunocompromised children (see Chapter 280 ). Cytomegalovirus immune globulin is warranted for children at high risk for CMV disease, particularly SOT and HSCT patients, and can play a role in preventing injury to the infected fetus when administered to the pregnant patient (see Chapter 282 ). Palivizumab, a monoclonal antibody with anti-RSV activity, is effective for preventing severe RSV lower respiratory tract disease in high-risk premature infants and has replaced RSV immune globulin (see Chapter 287 ). Hepatitis B immune globulin is indicated in infants born to hepatitis B surface antigen-positive mothers (see Chapter 385 ).