Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VII
Chemotherapy of Microbial Diseases

chapter 58
Antiviral Agents (Nonretroviral)

Viruses are simple microorganisms that consist of either double- or single-stranded DNA or RNA enclosed in a protein coat called a capsid. Some viruses also possess a lipid envelope derived from the infected host cell, which, like the capsid, may contain antigenic glycoproteins. Effective antiviral agents inhibit virus-specific replicative events or preferentially inhibit virus-directed rather than host cell–directed nucleic acid or protein synthesis (Table 58–1). Host cell molecules that are essential to viral replication also offer targets for intervention. Figure 58–1 gives a schematic diagram of the replicative cycle of typical DNA and RNA viruses.

Table 58–1

Stages of Virus Replication and Possible Targets of Action of Antiviral Agents



Figure 58–1 Replicative cycles of DNA (A) and RNA (B) viruses. The replicative cycles of herpesvirus (A) and influenza (B) are examples of DNA-encoded and RNA-encoded viruses, respectively. Sites of action of antiviral agents also are shown. cDNA, complementary DNA; cRNA, complementary RNA; DNAp, DNA polymerase; mRNA, messenger RNA; RNAp, RNA polymerase; vRNA, viral RNA. The symbol images indicates a block to virus growth. A. Replicative cycles of herpes simplex virus, a DNA virus, and the probable sites of action of antiviral agents. Herpesvirus replication is a regulated multistep process. After infection, a small number of immediate-early genes are transcribed; these genes encode proteins that regulate their own synthesis and are responsible for synthesis of early genes involved in genome replication, such as thymidine kinases, DNA polymerases, etc. After DNA replication, the bulk of the herpesvirus genes (called late genes) are expressed and encode proteins that either are incorporated into or aid in the assembly of progeny virions. B. Replicative cycles of influenza, an RNA virus, and the loci for effects of antiviral agents. The mammalian cell shown is an airway epithelial cell. The M2 protein of influenza virus allows an influx of hydrogen ions into the virion interior, which in turn promotes dissociation of the RNP (ribonuclear protein) segments and release into the cytoplasm (uncoating). Influenza virus mRNA synthesis requires a primer cleared from cellular mRNA and used by the viral RNAp complex. The neuraminidase inhibitors zanamivir and oseltamivir specifically inhibit release of progeny virus.

DNA viruses include poxviruses (smallpox), herpesviruses (chickenpox, shingles, oral and genital herpes), adenoviruses (conjunctivitis, sore throat), hepadnaviruses (hepatitis B virus [HBV]), and papillomaviruses (warts). Most DNA viruses enter the host cell nucleus, where the viral DNA is transcribed into mRNA by host cell polymerase; mRNA is translated in the usual host cell fashion into virus-specific proteins. Poxviruses are an exception; they carry their own RNA polymerase and replicate in the host cell cytoplasm.

For RNA viruses, the replication strategy relies either on enzymes in the virion to synthesize mRNA or has the viral RNA serving as its own mRNA. The mRNA is translated into various viral proteins, including RNA polymerase, which directs the synthesis of more viral mRNA and genomic RNA. Most RNA viruses complete their replication in the host cell cytoplasm, but some, such as influenza, are transcribed in the host cell nucleus. Examples of RNA viruses include rubella virus (German measles), rhabdoviruses (rabies), picornaviruses (poliomyelitis, meningitis, colds, hepatitis A), arenaviruses (meningitis, Lassa fever), flaviviruses (West Nile meningoencephalitis, yellow fever, hepatitis C), orthomyxoviruses (influenza), paramyxoviruses (measles, mumps), and coronaviruses (colds, severe acute respiratory syndrome [SARS]). Retroviruses are RNA viruses that include human immunodeficiency virus (HIV); chemotherapy for retro-viruses is described in Chapter 59.

Table 58–2 summarizes currently approved drugs for nonretroviral infections. Their pharmacological properties are presented below, class by class, as listed in the table.

Table 58–2

Nomenclature of Antiviral Agents



Herpes simplex virus type 1 (HSV-1) typically causes diseases of the mouth, face, skin, esophagus, or brain. Herpes simplex virus type 2 (HSV-2) usually causes infections of the genitals, rectum, skin, hands, or meninges. Both cause serious infections in neonates. Acyclovir is the prototype of a group of antiviral agents that are nucleoside congeners that are phosphorylated intracellularly by a viral kinase and subsequently by host cell enzymes to become inhibitors of viral DNA synthesis. Related agents include penciclovir and ganciclovir.

ACYCLOVIR AND VALACYCLOVIR. Acyclovir is an acyclic guanine nucleoside analog that lacks the 2′ and 3′positions normally supplied by ribose. Valacyclovir is the L-valyl ester prodrug of acyclovir.


Acyclovir’s clinical use is limited to herpesviruses. Acyclovir is most active against HSV-1 (0.02-0.9 μg/mL), approximately half as active against HSV-2 (0.03-2.2 μg/mL), a tenth as potent against varicella zoster virus (VZV; 0.8-4.0 μg/mL) and Epstein-Barr virus (EBV), and least active against cytomegalovirus (CMV) (generally >20 μg/mL) and human herpesvirus 6 (HHV-6). Uninfected mammalian cell growth generally is unaffected by high acyclovir concentrations (>50 μg/mL).

THERAPEUTIC USES. In immunocompetent persons, the clinical benefits of acyclovir and valacyclovir are greater in initial HSV infections than in recurrent ones. These drugs are particularly useful in immunocompromised patients because these individuals experience both more frequent and more severe HSV and VZV infections. Because VZV is less susceptible than HSV to acyclovir, higher doses must be used for treating VZV infections. Oral valacyclovir is as effective as oral acyclovir in HSV infections and more effective for treating herpes zoster. Acyclovir is ineffective therapeutically in established cytomegalovirus (CMV) infections but ganciclovir is effective for CMV prophylaxis in immunocompromised patients. EBV-related oral hairy leukoplakia may improve with acyclovir. Oral acyclovir in conjunction with systemic corticosteroids appears beneficial in treating Bell palsy; valacyclovir is ineffective in acute vestibular neuritis. See the 12th edition of the parent text for details of dosage regimens for specific indications in treating HSV, VZV, and CMV.

MECHANISMS OF ACTION AND RESISTANCE. Acyclovir inhibits viral DNA synthesis via a mechanism outlined in Figure 58–2. Its selectivity of action depends on interaction with HSV thymidine kinase and DNA polymerase. Cellular uptake and initial phosphorylation are facilitated by HSV thymidine kinase. The affinity of acyclovir for HSV thymidine kinase is ~200 times greater than for the mammalian enzyme. Cellular enzymes convert the monophosphate to acyclovir triphosphate, which competes for endogenous dGTP. The immunosuppressive agent mycophenolate mofetil (see Chapter 35) potentiates the anti-herpes activity of acyclovir and related agents by depleting intracellular dGTP pools. Acyclovir triphosphate competitively inhibits viral DNA polymerases and, to a much lesser extent, cellular DNA polymerases. Acyclovir triphosphate also is incorporated into viral DNA, where it acts as a chain terminator because of the lack of a 3′-hydroxyl group. By a mechanism termed suicide inactivation, the terminated DNA template containing acyclovir binds the viral DNA polymerase and leads to its irreversible inactivation.


Figure 58–2 Mechanism of action of acyclovir in cells infected by herpes simplex virus. A herpes simplex virion is shown attaching to a susceptible host cell, fusing its envelope with the cell membrane, and releasing naked capsids that deliver viral DNA into the nucleus, where it initiates synthesis of viral DNA. Acyclovir molecules entering the cell are converted to acyclovir monophosphate by virus-induced thymidine kinase. Host-cell enzymes add 2 more phosphates to form acyclovir triphosphate, which is transported into the nucleus. After the herpes DNA polymerase cleaves pyrophosphate from acyclovir triphosphate (indicated by the red arrow in the inset), viral DNA polymerase inserts acyclovir monophosphate rather than 2′-deoxyguanosine monophosphate into the viral DNA (indicated by black arrows in the inset). Further elongation of the chain is impossible because acyclovir monophosphate lacks the 3′ hydroxyl group necessary for the insertion of an additional nucleotide, and the exonuclease associated with the viral DNA polymerase cannot remove the acyclovir moiety. In contrast, ganciclovir and penciclovir have a 3′ hydroxyl group; therefore, further synthesis of viral DNA is possible in the presence of these drugs. Foscarnet acts at the pyrophosphate-binding site of viral DNA polymerase and prevents cleavage of the pyrophosphate from nucleoside triphosphates, thus stalling further primer template extension. Red lines [III] indicate hydrogen bonding of the base pairs. (Adapted from Balfour HH. Antiviral drugs. N Engl J Med, 1999;340:1255–1268.)

Acyclovir resistance in HSV can result from impaired production of viral thymidine kinase, altered thymidine kinase substrate specificity (e.g., phosphorylation of thymidine but not acyclovir), or altered viral DNA polymerase. Alterations in viral enzymes are caused by point mutations and base insertions or deletions in the corresponding genes. Resistant variants are present in native virus populations and in isolates from treated patients. The most common resistance mechanism in clinical HSV isolates is absent or deficient viral thymidine kinase activity; viral DNA polymerase mutants are rare. Phenotypic resistance typically is defined by in vitro inhibitory concentrations of >2-3 μg/mL, which predict failure of therapy in immunocompromised patients. Acyclovir resistance in VZV isolates is caused by mutations in VZV thymidine kinase and less often by mutations in viral DNA polymerase.

ADME. The oral bioavailability of acyclovir is ~10-30% and decreases with increasing dose. Valacyclovir is converted rapidly and virtually completely to acyclovir after oral administration. This conversion is thought to result from first-pass intestinal and hepatic metabolism through enzymatic hydrolysis. Unlike acyclovir, valacyclovir is a substrate for intestinal and renal peptide transporters. The oral bioavailability of acyclovir increases ~70% following valacyclovir administration. Peak plasma concentrations of valacyclovir are only 4% of acyclovir levels. Less than 1% of an administered dose of valacyclovir is recovered in the urine; most is eliminated as acyclovir. Acyclovir distributes widely in body fluids, including vesicular fluid, aqueous humor, and cerebrospinal fluid (CSF). Compared with plasma, salivary concentrations are low, and vaginal secretion concentrations vary widely. Acyclovir is concentrated in breast milk, amniotic fluid, and placenta. Newborn plasma levels are similar to maternal ones. Percutaneous absorption of acyclovir after topical administration is low. The elimination t1/2 of acyclovir is ~2.5 h (range: 1.5-6 h) in adults with normal renal function. The elimination t1/2 of acyclovir is ~4 h in neonates and increases to 20 h in anuric patients. Renal excretion is the principal route of elimination.

UNTOWARD EFFECTS. Acyclovir generally is well tolerated. Topical acyclovir in a polyethylene glycol base may cause mucosal irritation and transient burning when applied to genital lesions. Oral acyclovir has been associated infrequently with nausea, diarrhea, rash, or headache and very rarely with renal insufficiency or neurotoxicity. Valacyclovir also may be associated with headache, nausea, diarrhea, nephrotoxicity, and CNS symptoms (confusion, hallucinations). Uncommon side effects include severe thrombocytopenic syndromes, sometimes fatal, in immunocompromised patients. Acyclovir has been associated with neutropenia in neonates. The principal dose-limiting toxicities of intravenous acyclovir are renal insufficiency and CNS side effects. Nephrotoxicity usually resolves with drug cessation and volume expansion. Hemodialysis may be useful in severe cases. Severe somnolence and lethargy may occur with combinations of zidovudine (see Chapter 59) and acyclovir. Concomitant cyclosporine and probably other nephrotoxic agents enhance the risk of nephrotoxicity. Probenecid decreases the acyclovir renal clearance and prolongs the elimination t1/2. Acyclovir may decrease the renal clearance of other drugs eliminated by active renal secretion, such as methotrexate.

CIDOFOVIR. Cidofovir is a cytidine nucleotide analog with inhibitory activity against human herpes, papilloma, polyoma, pox, and adenoviruses.

Because cidofovir is a phosphonate that is phosphorylated by cellular but not viral enzymes, it inhibits acyclovir-resistant thymidine kinase (TK)–deficient or TK-altered HSV or VZV strains, ganciclovir-resistant CMV strains with UL97 mutations (but not those with DNA polymerase mutations), and some foscarnet-resistant CMV strains. Cidofovir synergistically inhibits CMV replication in combination with ganciclovir or foscarnet.

THERAPEUTIC USES. Intravenous cidofovir is approved for the treatment of CMV retinitis in HIV-infected patients. Intravenous cidofovir has been used for treating acyclovir-resistant mucocutaneous HSV infection, adenovirus disease in transplant recipients, and extensive molluscum contagiosum in HIV patients. Reduced doses without probenecid may be beneficial in BK virus nephropathy in renal transplant patients. Topical cidofovir gel eliminates virus shedding and lesions in some HIV-infected patients with acyclovir-resistant mucocutaneous HSV infections and has been used in treating anogenital warts and molluscum contagiosum in immunocompromised patients and cervical intraepithelial neoplasia in women. Intralesional cidofovir induces remissions in adults and children with respiratory papillomatosis. See the 12th edition of the parent text for details of dosage regimens for specific indications.

MECHANISMS OF ACTION AND RESISTANCE. Cidofovir inhibits viral DNA synthesis by slowing and eventually terminating chain elongation. Cidofovir is metabolized to its active diphosphate form by cellular enzymes; the levels of phosphorylated metabolites are similar in infected and uninfected cells. The diphosphate acts as both a competitive inhibitor with respect to dCTP and as an alternative substrate for viral DNA polymerase.

Cidofovir resistance in CMV is due to mutations in viral DNA polymerase. Low-level resistance to cidofovir develops in up to ~30% of retinitis patients by 3 months of therapy. Highly ganciclovir-resistant CMV isolates that possess DNA polymerase and UL97 kinase mutations are resistant to cidofovir, and prior ganciclovir therapy may select for cidofovir resistance. Some foscarnet-resistant CMV isolates show cross-resistance to cidofovir, and triple-drug-resistant variants with DNA polymerase mutations occur.

ADME. Cidofovir has very low oral bioavailability. Penetration into the CSF is low. Topical cidofovir gel may result in low plasma concentrations (<0.5 μg/mL) in patients with large mucocutaneous lesions. Plasma levels after intravenous dosing decline in a biphasic pattern with a terminal t1/2 that averages 2.6 h. The active form, cidofovir diphosphate, has a prolonged intracellular t1/2 and competitively inhibits CMV and HSV DNA polymerases at concentrations one-eighth to one six-hundredth of those required to inhibit human DNA polymerases. A phosphocholine metabolite also has a long intracellular t1/2 (~87 h) and may serve as an intracellular reservoir of drug. The prolonged intracellular t1/2 of cidofovir diphosphate allows infrequent dosing regimens. Cidofovir is cleared by the kidney via glomerular filtration and tubular secretion. Over 90% of the dose is recovered unchanged in the urine. Probenecid blocks tubular transport of cidofovir and reduces renal clearance and associated nephrotoxicity. Elimination relates linearly to creatinine clearance; the t1/2 increases to 32.5 h in patients on chronic ambulatory peritoneal dialysis (CAPD). Hemodialysis removes >50% of the administered dose.

UNTOWARD EFFECTS. Nephrotoxicity is the principal dose-limiting side effect of intravenous cidofovir. Concomitant oral probenecid and saline prehydration reduce the risk of renal toxicity; however, probenecid alters renal clearance of many agents, albeit not of cidofidir. For example, probenecid alters zidovudine pharmacokinetics such that zidovudine doses should be reduced when probenecid is present, as should the doses of other drugs whose renal secretion probenecid inhibits (e.g., β-lactam antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs], acyclovir, lorazepam, furosemide, methotrexate, theophylline, and rifampin). On maintenance doses of 5 mg/kg every 2 weeks, up to 50% of patients develop proteinuria, 10-15% show an elevated serum creatinine concentration, and 15-20% develop neutropenia. Anterior uveitis that is responsive to topical corticosteroids and cycloplegia occurs commonly and low intraocular pressure occurs infrequently with intravenous cidofovir. Administration with food and pretreatment with antiemetics, antihistamines, and/or acetaminophen may improve tolerance. Concurrent nephrotoxic agents are contraindicated, and at least 7 days should elapse before initiation of cidofovir treatment is recommended after prior exposure to aminoglycosides, intravenous pentamidine, amphotericin B, foscarnet, NSAID, or contrast dye. Cidofovir and oral ganciclovir are poorly tolerated in combination at full doses.

Topical application of cidofovir is associated with dose-related application-site reactions (e.g., burning, pain, and pruritus) in up to one-third of patients and occasionally ulceration. Cidofovir is considered a potential human carcinogen. It may cause infertility and is classified as pregnancy Category C.

FAMCICLOVIR AND PENCICLOVIR. Famciclovir is the diacetyl ester prodrug of 6-deoxy penciclovir and lacks intrinsic antiviral activity. Penciclovir is an acyclic guanine nucleoside analog. Penciclovir is similar to acyclovir in its spectrum of activity and potency against HSV and VZV. It also is inhibitory for HBV.

THERAPEUTIC USES. Oral famciclovir, topical penciclovir, and intravenous penciclovir are approved for managing HSV and VZV infections. See the 12th edition of the parent text for details of dosage regimens for specific indications.

MECHANISMS OF ACTION AND RESISTANCE. Penciclovir is an inhibitor of viral DNA synthesis. In HSV- or VZV-infected cells, penciclovir is phosphorylated initially by viral TK. Penciclovir triphosphate is a competitive inhibitor of viral DNA polymerase (see Figure 58–2). Although penciclovir triphosphate is approximately one one-hundredth as potent as acyclovir triphosphate in inhibiting viral DNA polymerase, it is present in infected cells at much higher concentrations and for more prolonged periods. The prolonged intracellular t1/2 of penciclovir triphosphate, 7-20 h, is associated with prolonged antiviral effects. Because penciclovir has a 3′-hydroxyl group, it is not an obligate chain terminator but does inhibit DNA elongation. Resistance during clinical use is low. TK–deficient, acyclovir-resistant herpes viruses are cross-resistant to penciclovir.

ADME. Oral penciclovir has low (<5%) bioavailability. In contrast, famciclovir is well absorbed orally (bioavailability ~75%) and is converted rapidly to penciclovir by deacetylation of the side chain and oxidation of the purine ring during and following absorption. Food slows absorption but does not reduce overall bioavailability. The plasma elimination t1/2 of penciclovir averages ~2 h, and >90% is excreted unchanged in the urine. Following oral famciclovir administration, nonrenal clearance accounts for ~10% of each dose, primarily through fecal excretion, but penciclovir (60% of dose) and its 6-deoxy precursor (<10% of dose) are eliminated primarily in the urine. The plasma t1/2 averages 9.9 h in renal insufficiency (Clcr 30 mL/min); hemodialysis efficiently removes penciclovir.

UNTOWARD EFFECTS. Oral famciclovir is associated with headache, diarrhea, and nausea. Urticaria, rash, and hallucinations or confusional states (predominantly in the elderly) have been reported. Topical penciclovir (~1%) rarely is associated with local reactions. The short-term tolerance of famciclovir is comparable with that of acyclovir. Penciclovir is mutagenic at high concentrations. Long-term administration (1 year) does not affect spermatogenesis in men. Safety during pregnancy has not been established.

FOMIVIRSEN. Fomivirsen, a 21-base phosphorothioate oligonucleotide, provides antisense therapy.

The drug is complementary to the messenger RNA sequence for the major immediate-early transcriptional region of CMV and inhibits CMV replication through sequence-specific and nonspecific mechanisms, including inhibition of virus binding to cells. Fomivirsen is active against CMV strains resistant to ganciclovir, foscarnet, and cidofovir. Fomivirsen is given by intravitreal injection in the treatment of CMV retinitis for patients intolerant of or unresponsive to other therapies. Following injection, it is cleared slowly from the vitreous (t1/2 55 h) through distribution to the retina and probable exonuclease digestion. In HIV-infected patients with refractory, sight-threatening CMV retinitis, fomivirsen injections (330 μg weekly for 3 weeks and then every 2 weeks or on days 1 and 15 followed by monthly) significantly delay time to retinitis progression. Ocular side effects include iritis in up to one-quarter of patients, which can be managed with topical corticosteroids; vitritis; cataracts; and increases in intraocular pressure in 15-20% of patients. Recent cidofovir use may increase the risk of inflammatory reactions. The drug is no longer available in the U.S.

FOSCARNET. Foscarnet (trisodium phosphonoformate) is an inorganic pyrophosphate analog that is inhibitory for all herpesviruses and HIV.

THERAPEUTIC USES. Intravenous foscarnet is effective for treatment of CMV retinitis, including ganciclovir-resistant infections, other types of CMV infection, and acyclovir-resistant HSV and VZV infections. Foscarnet is poorly soluble in aqueous solutions and requires large volumes for administration. See the 12th edition of the parent text for details of dosage regimens for specific indications.

MECHANISMS OF ACTION AND RESISTANCE. Foscarnet inhibits viral nucleic acid synthesis by interacting directly with herpesvirus DNA polymerase or HIV reverse transcriptase (see Figures 58–1A and 58–2). Foscarnet has ~100-fold greater inhibitory effects against herpesvirus DNA polymerases than against cellular DNA polymerase-α. Herpesviruses resistant to foscarnet have point mutations in the viral DNA polymerase.

ADME. Oral bioavailability of foscarnet is low. Vitreous levels approximate those in plasma; CSF levels average 66% of those in plasma at steady state. Over 80% of foscarnet is excreted unchanged in the urine. Dose adjustments are indicated for small decreases in renal function. Plasma elimination has initial bimodal half-lives totaling 4-8 h and a prolonged terminal elimination t1/2 averaging 3-4 days. Sequestration in bone with gradual release accounts for the fate of an estimated 10-20% of a given dose. Foscarnet is cleared efficiently by hemodialysis (~50% of a dose).

UNTOWARD EFFECTS. Major dose-limiting toxicities are nephrotoxicity and symptomatic hypocalcemia. Increases in serum creatinine occur in up to one-half of patients but are generally reversible after cessation. High doses, rapid infusion, dehydration, prior renal insufficiency, and concurrent nephrotoxic drugs are risk factors. Saline loading may reduce the risk of nephrotoxicity. Foscarnet is highly ionized at physiological pH, and metabolic abnormalities are very common. These include increases or decreases in Ca2+ and phosphate, hypomagnesemia, and hypokalemia. Concomitant intravenous pentamidine administration increases the risk of symptomatic hypocalcemia. CNS side effects include headache (25%), tremor, irritability, seizures, and hallucinosis. Other reported side effects are generalized rash, fever, nausea or emesis, anemia, leukopenia, abnormal liver function tests, electrocardiographic changes, infusion-related thrombophlebitis, and painful genital ulcerations. Topical foscarnet may cause local irritation and ulceration, and oral foscarnet may cause GI disturbance. Preclinical studies indicate that high foscarnet concentrations are mutagenic. Safety in pregnancy or childhood is uncertain.

GANCICLOVIR AND VALGANCICLOVIR. Ganciclovir is an acyclic guanine nucleoside analog that is similar in structure to acyclovir. Valganciclovir is the L-valyl ester prodrug of ganciclovir. Ganciclovir has inhibitory activity against all herpesviruses and is especially active against CMV.

THERAPEUTIC USES. Ganciclovir is effective for treatment and chronic suppression of CMV retinitis in immunocompromised patients and for prevention of CMV disease in transplant patients. A ganciclovir ophthalmic gel formulation (ZIRGAN) is effective in treating HSV keratitis. See the 12th edition of the parent text for details of dosage regimens for specific indications.

MECHANISMS OF ACTION AND RESISTANCE. Ganciclovir inhibits viral DNA synthesis. It is monophosphorylated intracellularly by viral TK during HSV infection and by a viral phosphotransferase encoded by the UL97 gene during CMV infection. Ganciclovir diphosphate and ganciclovir triphosphate are formed by cellular enzymes. At least 10-fold higher concentrations of ganciclovir triphosphate are present in CMV-infected than in uninfected cells. The triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA and preferentially inhibits viral rather than host cellular DNA polymerases. Incorporation into viral DNA causes eventual cessation of DNA chain elongation (see Figures 58–1A and 58–2).

CMV can become resistant to ganciclovir by either of 2 mechanisms: reduced intracellular ganciclovir phosphorylation owing to mutations in the viral phosphotransferase and mutations in viral DNA polymerase. Highly resistant variants with both mutations are cross-resistant to cidofovir and variably to foscarnet. Ganciclovir also is much less active against acyclovir-resistant TK–deficient HSV strains.

ADME. The oral bioavailability of ganciclovir is 6-9% following ingestion with food. Oral valganciclovir is well absorbed and hydrolyzed rapidly to ganciclovir; the bioavailability of ganciclovir averages 61% following administration of valganciclovir. Food increases the bioavailability of valganciclovir by ~25%. Following intravenous administration of ganciclovir, vitreous fluid levels are similar to or higher than those in plasma and decline with a t1/2 of 23-26 h. Intraocular sustained-release ganciclovir implants provide vitreous levels of ~4.1 μg/mL. The plasma elimination t1/2 is ~2-4 h. Intracellular ganciclovir triphosphate concentrations are 10-fold higher than those of acyclovir triphosphate and decline much more slowly, with an intracellular elimination t1/2 >24 h. Over 90% of ganciclovir is eliminated unchanged by renal excretion. Plasma t1/2 increases in patients with severe renal insufficiency.

UNTOWARD EFFECTS. Myelosuppression is the principal dose-limiting toxicity of ganciclovir. Neutropenia occurs in ~15-40% of patients and is observed most commonly during the second week of treatment and usually is reversible within 1 week of drug cessation. Persistent fatal neutropenia has occurred. Recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim, lenograstim) may be useful in treating ganciclovir-induced neutropenia (see Chapter 37). Thrombocytopenia occurs in 5-20% of patients. Zidovudine and probably other cytotoxic agents increase the risk of myelosuppression, as do nephrotoxic agents that impair ganciclovir excretion. Probenecid and possibly acyclovir reduce renal clearance of ganciclovir. Oral ganciclovir increases the absorption and peak plasma concentrations of didanosine by approximately 2-fold and that of zidovudine by ~20%. CNS side effects (5-15%) range in severity from headache to behavioral changes to convulsions and coma. About one-third of patients must interrupt or prematurely stop intravenous ganciclovir therapy because of bone marrow or CNS toxicity. Infusion-related phlebitis, azotemia, anemia, rash, fever, liver function test abnormalities, nausea or vomiting, and eosinophilia also have been described. Ganciclovir is classified as pregnancy Category C.


Docosanol is a long-chain saturated alcohol that is approved as an over-the-counter 10% cream for the treatment of recurrent orolabial herpes. Docosanol inhibits the in vitro replication of many lipid-enveloped viruses, including HSV. It does not inactivate HSV directly but appears to block fusion between the cellular and viral envelope membranes and inhibits viral entry into the cell. Topical treatment beginning within 12 h of prodromal symptoms or lesion onset reduces healing time by ~1 day and is well tolerated. Treatment initiation at papular or later stages provides no benefit.


Idoxuridine is an iodinated thymidine analog that inhibits the in vitro replication of various DNA viruses, including herpesviruses and poxviruses. Idoxuridine lacks selectivity, in that low concentrations inhibit the growth of uninfected cells. The triphosphate inhibits viral DNA synthesis and is incorporated into both viral and cellular DNA. In the U.S., idoxuridine is approved only for topical (ophthalmic) treatment of HSV keratitis. Idoxuridine formulated in dimethylsulfoxide is available outside the U.S. for topical treatment of herpes labialis, genitalis, and zoster. Adverse reactions include pain, pruritus, inflammation, and edema of the eye or lids; allergic reactions are rare.


Trifluridine is a fluorinated pyrimidine nucleoside that has in vitro inhibitory activity against HSV types 1 and 2, CMV, vaccinia, and to a lesser extent, certain adenoviruses. Trifluridine inhibits replication of herpesviruses, including acyclovir-resistant strains, and also inhibits cellular DNA synthesis at relatively low concentrations. Trifluridine monophosphate irreversibly inhibits thymidylate synthase, and trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA; trifluridine is incorporated into viral and cellular DNA. Trifluridine-resistant HSV has been described.

Trifluridine currently is used for treatment of primary keratoconjunctivitis and recurrent epithelial keratitis owing to HSV types 1 and 2. Topical trifluridine is more active than idoxuridine and comparable with vidarabine in HSV ocular infections. Adverse reactions include discomfort on instillation and palpebral edema. Hypersensitivity reactions and irritation are uncommon. Topical trifluridine also appears to be effective in some patients with acyclovir-resistant HSV cutaneous infections.


Recently, there has been concern about the possibility of new influenza pandemics, stemming from small but severe outbreaks of H5N1 avian influenza and the novel 2009 influenza A H1N1, thought to be of swine origin. Four drugs are currently approved for the treatment and prevention of influenza virus infection: the adamantine antivirals, amantadine and rimantadine; oseltamivir; and zanamivir; peramivir, an investigational neuraminidase inhibitor, is available for intravenous use via emergency use authorization (EUA). Development of resistance to these drugs, and the spread of resistant viruses, are major challenges in the chemotherapy and chemoprophylaxis of influenza and are likely to drive future recommendations for use of these drugs in global populations.

AMANTADINE AND RIMANTADINE. Amantadine and its derivative rimantadine are uniquely configured tricyclic amines.


THERAPEUTIC USES. Although both drugs are useful for the prevention and treatment of infections caused by influenza A virus, vaccination against influenza is a more cost-effective means of reducing disease burden. Amantadine and rimantadine are active only against susceptible influenza A viruses (not influenza B); rimantadine is 4- to 10-fold more active than amantadine. Virtually all H3N2 strains of influenza circulating worldwide are resistant to these drugs.

Seasonal prophylaxis with either amantadine or rimantadine (a total of 200 mg/day in 1 or 2 divided doses in young adults) is ~70-90% protective against influenza A illness. These agents are efficacious in preventing nosocomial influenza and in curtailing nosocomial outbreaks during pandemic influenza. Doses of 100 mg/day are better tolerated and still appear to be protective against influenzal illness. Seasonal prophylaxis is an alternative in high-risk patients if the influenza vaccine cannot be administered or may be ineffective (i.e., in immunocompromised patients). Prophylaxis should be started as soon as influenza is identified in a community or region and should be continued throughout the period of risk (usually 4-8 weeks) because any protective effects are lost several days after cessation of therapy. Alternatively, the drugs can be started in conjunction with immunization and continued for 2 weeks until protective immune responses develop.

The amantadines are effective against influenza A H1N1 if treatment is initiated within 2 days of the onset of symptoms. In uncomplicated influenza A illness of adults, early amantadine or rimantadine treatment (200 mg/day for 5 days) reduces the duration of fever and systemic complaints by 1-2 days, speeds functional recovery, and sometimes decreases the duration of virus shedding. The usual regimen in children (≥1 year of age) is 5 mg/kg/day, up to 150 mg, administered once or twice daily. Resistant variants have been recovered from ~30% of treated children or outpatient adults by the fifth day of therapy.

MECHANISMS OF ACTION AND RESISTANCE. Amantadine and rimantadine inhibit an early step in viral replication, probably viral uncoating; for some strains, they also have an effect on a late step in viral assembly probably mediated through altering hemagglutinin processing. The primary locus of action is the influenza A virus M2 protein, an integral membrane protein that functions as an ion channel. By interfering with this function of the M2 protein, the drugs inhibit the acid-mediated dissociation of the ribonucleoprotein complex early in replication and potentiate acidic pH–induced conformational changes in hemagglutinin during its intracellular transport later in replication. Resistance to these drugs results from a mutation in the RNA sequence encoding for the M2 protein transmembrane domain; resistant isolates typically appear in the treated patient within 2-3 days of starting therapy.

ADME. Table 58–3 summarizes important pharmacokinetics properties of these anti-viral agents. The 2 adamantanes differ in several respects. Amantadine is excreted largely unmetabolized in the urine (t1/2 of elimination is ~12-18 h in young adults, increasing up to 2-fold in the elderly and even more in those with renal impairment). By contrast, elimination of rimantadine depends on hepatic function; the drug is subject to phase 1 and phase 2 reactions prior to renal excretion of metabolites (elimination t1/2 ~24-36 h; 60-90% is excreted in the urine as metabolites). The elderly require only one-half the weight-adjusted dose of amantadine needed for young adults. Amantadine is excreted in breast milk. Rimantadine concentrations in nasal mucus average 50% higher than those in plasma.

Table 58–3

Pharmacological Characteristics of Antivirals for Influenza


UNTOWARD EFFECTS. The most common side effects related to amantadine and rimantadine are minor dose-related CNS and GI effects: nervousness, light-headedness, difficulty concentrating, insomnia, and loss of appetite, and nausea. CNS side effects (5-33%) occur in patients treated with amantadine at doses of 200 mg/day but are significantly less frequent with rimantadine. The neurotoxic effects of amantadine appear to be increased by concomitant ingestion of antihistamines and psychotropic or anticholinergic drugs, especially in the elderly. At comparable doses of 100 mg/day, rimantadine is significantly better tolerated in nursing home residents than amantadine. High amantadine plasma concentrations (1.0-5.0 μg/mL) have been associated with serious neurotoxic reactions, including delirium, hallucinosis, seizures, and coma, and cardiac arrhythmias. Exacerbations of preexisting seizure disorders and psychiatric symptoms may occur with amantadine and possibly with rimantadine. Both drugs are considered pregnancy Category C.


Oseltamivir carboxylate is a transition-state analog of sialic acid that is a potent selective inhibitor of the neuraminidases of influenza A and B virus. Oseltamivir phosphate is an ethyl ester prodrug that lacks antiviral activity. Oseltamivir carboxylate has an antiviral spectrum and potency similar to that of zanamivir: it inhibits amantadine and rimantadine-resistant influenza A viruses and some zanamivir-resistant variants.

THERAPEUTIC USES. Oral oseltamivir is effective in the treatment and prevention of influenza A and B virus infections. Treatment of previously healthy adults (75 mg twice daily for 5 days) or children 1-12 years of age (weight-adjusted dosing) with acute influenza reduces illness duration by ~1-2 days, speeds functional recovery, and reduces the risk of complications leading to antibiotic use by 40-50%. Treatment is associated with approximate halving of the risk of subsequent hospitalization in adults. When used for prophylaxis during the typical influenza season, oseltamivir (75 mg once daily) is effective (~70-90%) in reducing the likelihood of influenza illness in both unimmunized working adults and in immunized nursing home residents; short-term use protects against influenza in household contacts.

MECHANISMS OF ACTION AND RESISTANCE. Influenza neuraminidase cleaves terminal sialic acid residues and destroys the receptors recognized by viral hemagglutinin, which are present on the cell surface, in progeny virions, and in respiratory secretions. This enzymatic action is essential for release of virus from infected cells. Interaction of oseltamivir carboxylate with the neuraminidase causes a conformational change within the enzyme’s active site and inhibits its activity. Inhibition of neuraminidase activity leads to viral aggregation at the cell surface and reduced virus spread within the respiratory tract. Influenza variants selected in vitro for resistance to oseltamivir carboxylate contain hemagglutinin and/or neuraminidase mutations. Seasonal influenza A (H1N1) has become virtually 100% resistant to oseltamivir worldwide. Importantly, novel H1N1 (nH1N1 or swine influenza) remains susceptible to oseltamivir.

ADME. Table 58–3 summarizes important pharmacokinetics properties of oseltamivir carboxylate. Oral oseltamivir phosphate is absorbed rapidly and cleaved by esterases in the GI tract and liver to the active carboxylate. Food does not decrease bioavailability but reduces the risk of GI intolerance. Bronchoalveolar lavage levels in animals and middle ear fluid and sinus concentrations in humans are comparable with plasma levels. Probenecid doubles the plasma t1/2 of the carboxylate, which indicates tubular secretion by the anionic pathway. Children <2 years of age exhibit age-related changes in oseltamivir carboxylate clearance and total drug exposure.

UNTOWARD EFFECTS. Oral oseltamivir is associated with nausea, abdominal discomfort, and, less often, emesis. GI complaints typically resolve in 1-2 days despite continued dosing, and are preventable by administration with food. An increased frequency of headache was reported in one prophylaxis study in elderly adults. Neither the phosphate nor the carboxylate form interacts with CYPs in vitro. Oseltamivir does not appear to impair fertility, but safety in pregnancy is uncertain (pregnancy Category C).

ZANAMIVIR. Zanamivir is a sialic acid analog that potently and specifically inhibits the neuraminidases of influenza A and B viruses. Zanamivir inhibits in vitro replication of influenza A and B viruses, including amantadine- and rimantadine-resistant strains and several oseltamivir-resistant variants.

THERAPEUTIC USES. Inhaled zanamivir is effective for the prevention and treatment of influenza A and B virus infections. Early zanamivir treatment (10 mg [2 inhalations] twice daily for 5 days) of febrile influenza in ambulatory adults and children >5 years of age shortens the time to illness resolution by 1-3 days and in adults reduces by 40% the risk of lower respiratory tract complications leading to antibiotic use. Once-daily inhaled zanamivir is highly protective against community-acquired influenza illness, and when given for 10 days, it protects against household transmission. Intravenous zanamivir (t1/2 ~1.7 h) is available in the U.S. as an emergency investigational new drug (EIND) and in the E.U. on a compassionate use basis for life-threatening resistant influenza.

MECHANISMS OF ACTION AND RESISTANCE. Zanamivir inhibits viral neuraminidase and thus causes viral aggregation at the cell surface and reduced spread of virus within the respiratory tract. In vitro selection of viruses resistant to zanamivir is associated with mutations in the viral hemagglutinin and/or neuraminidase. Hemagglutinin variants are cross-resistant to other neuraminidase inhibitors. Neuraminidase variants contain mutations in the enzyme active site that diminish binding of zanamivir, but the altered enzymes show reduced activity or stability. Zanamivir-resistant variants usually have decreased infectivity in animals.

ADME. Table 58–3 summarizes important pharmacokinetics properties of zanamivir. Oral bioavailability of zanamivir is <5%, and the commercial form is delivered by oral inhalation of dry powder in a lactose carrier. The proprietary inhaler device is breath-actuated and requires a cooperative patient. Following inhalation of the dry powder, ~15% is deposited in the lower respiratory tract and ~80% in the oropharynx. Overall bioavailability is 4-17%.

UNTOWARD EFFECTS. Orally inhaled zanamivir generally is well tolerated in ambulatory adults and children with influenza. Wheezing and bronchospasm have been reported in some influenza-infected patients without known airway disease, and acute deteriorations in lung function, including fatal outcomes, have occurred in those with underlying asthma or chronic obstructive airway disease. Zanamivir is not generally recommended for treatment of patients with underlying airway disease because of the risk of serious adverse events. Preclinical studies of zanamivir revealed no evidence of mutagenic, teratogenic, or oncogenic effects (pregnancy Category C). No clinically significant drug interactions have been recognized to date. Zanamivir does not diminish the immune response to injected influenza vaccine.


A number of agents are available for treatment of HBV and HCV infections. Several agents (e.g., interferons, ribavirin, and the nucleoside/nucleotide analogs lamivudine, telbivudine, and tenofovir) have other uses as well (see Chapter 59). Therapeutic strategies for hepatitis B and C are very different and are described separately.


HCV infection is associated with significant morbidity and mortality. Untreated, this virus can cause progressive hepatocellular injury with fibrosis and eventual cirrhosis. Chronic HCV is also a major risk factor for hepatocellular carcinoma. Although the virus is quite prolific, producing several billion new particles every few days in an infected individual, this RNA virus does not integrate into chromosomal DNA, and it does not establish latency per se. Therefore, the infection is, in theory, curable in all affected individuals. The current standard of care for treatment is a combination of peginterferon alfa and ribavirin, which produces a high cure rate in selected virus genotypes only.

Interferons. Interferons (IFNs) are potent cytokines that possess antiviral, immunomodulatory, and antiproliferative activities (see Chapter 35). Three major classes of human interferons with significant antiviral activity are: α, β, and γ. Clinically used recombinant α-IFNs (see Table 58–2) are non-glycosylated proteins of e19,500 Da, the pegylated forms predominating in the U.S. market.

IFN-α and IFN-β may be produced by nearly all cells in response to viral infection and a variety of other stimuli, including double-stranded RNA and certain cytokines (e.g., interleukin 1, interleukin 2, and tumor necrosis factor). IFN-γ production is restricted to T lymphocytes and natural killer cells responding to antigenic stimuli, mitogens, and specific cytokines. IFN-α and IFN-β exhibit antiviral and antiproliferative actions; stimulate the cytotoxic activity of lymphocytes, natural killer cells, and macrophages; and upregulate class I major histocompatibility (MHC) antigens and other surface markers. IFN-γ has less antiviral activity but more potent immunoregulatory effects, particularly macrophage activation, expression of class II MHC antigens, and mediation of local inflammatory responses. Most animal viruses are inhibited by IFNs, although many DNA viruses are relatively insensitive. The biological activity of IFN usually is measured in terms of antiviral effects in cell culture and generally is expressed as international units (IUs) relative to reference standards.

MECHANISMS OF ACTION. Following binding to specific cellular receptors, IFNs activate the JAK-STAT signal-transduction pathway and lead to the nuclear translocation of a cellular protein complex that binds to genes containing an IFN-specific response element. This, in turn, leads to synthesis of over 2 dozen proteins that contribute to viral resistance mediated at different stages of viral penetration (Figure 58–3).


Figure 58–3 Interferon-mediated antiviral activity occurs via multiple mechanisms. The binding of IFN to specific cell surface receptor molecules signals the cell to produce a series of antiviral proteins. The stages of viral replication that are inhibited by various IFN-induced antiviral proteins are shown. Most of these act to inhibit the translation of viral proteins (mechanism 2), but other steps in viral replication also are affected (mechanisms 1, 3, and 4). The roles of these mechanisms in the other actions of IFNs are under study. 2′5′A, 2′-5′-oligoadenylates; eIF-2α, protein synthesis initiation factor; IFN, interferon; mRNA, messenger RNA; Mx, IFN-induced cellular protein with anti-viral activity; RNase L, latent cellular endoribonuclease; tRNA, transfer RNA. (Modified from Baron S, Coppenhaver DH, Dianzani F, et al. Introduction to the interferon system. In: Baron S, Dianzani F, Stanton GJ, et al., eds. Interferons: Principles and Medical Applications, Galveston, TX: University of Texas Medical Branch Dept. of Microbiology; 1992:1–15. With permission.)

A given virus may be inhibited at several steps, and the principal inhibitory effect differs among virus families. Certain viruses are able to counter IFN effects by blocking production or activity of selected IFN-inducible proteins. For example, IFN resistance in HCV is attributable to inhibition of the IFN-induced protein kinase, among other mechanisms. Complex interactions exist between IFNs and other parts of the immune system, so IFNs may ameliorate viral infections by exerting direct antiviral effects and/or by modifying the immune response to infection. For example, IFN-induced expression of MHC antigens may contribute to the antiviral actions of IFN by enhancing the lytic effects of cytotoxic T-lymphocytes. Conversely, IFNs may mediate some of the systemic symptoms associated with viral infections and contribute to immunologically mediated tissue damage in certain viral diseases.

ADME. After intramuscular or subcutaneous injection of IFN-α, absorption is >80%. Plasma levels are dose related, peaking at 4-8 h and returning to baseline by 18-36 h. Increased levels of 2′-5′-oligoadenylate synthase [2-5(A) synthase] in peripheral blood mononuclear cells are apparent at 6 h and last for 4 days after a single injection. An antiviral state in peripheral blood mononuclear cells peaks at 24 h and decreases slowly to baseline by 6 days after injection. After systemic administration, low levels of IFN are detected in respiratory secretions, CSF, eye, and brain. Because IFNs induce long-lasting cellular effects, their activities are not easily predictable from usual pharmacokinetic measures. After intravenous dosing, clearance of IFN from plasma occurs in a complex manner. With subcutaneous or intramuscular dosing, the plasma t1/2 of IFN-α ranges from 3-8 h, due to distribution to the tissues, cellular uptake, and catabolism primarily in the kidney and liver. Negligible amounts are excreted in the urine. Clearance of IFN-a2B is reduced by ~80% in dialysis patients.

Attachment of IFN proteins to large inert polyethylene glycol (PEG) molecules (pegylation) slows absorption, decreases clearance, and provides higher and more prolonged serum concentrations that enable once-weekly dosing. Two pegylated IFNs are available commercially: peginterferon alfa-2a (PEGASYS) and peginterferon alfa-2B (PEG-INTRON). PegIFN alfa-2B has a 12 kDa PEG that increases the plasmat1/2 to ~30-54 h. PegIFN alfa-2A contains a branched-chain 40 kDa PEG bonded to IFN-α2A and has a plasma t1/2 averaging ~80-90 h. Increasing PEG size is associated with longer t1/2 and less renal clearance. About 30% of pegIFN alfa-2B is cleared by the kidneys; pegIFN alfa-2A also is cleared primarily by the liver. Dose reductions in both pegylated IFNs are indicated in end-stage renal disease.

UNTOWARD EFFECTS. Injection of recombinant IFN doses of ≥1-2 million units (MU) usually is associated with an acute influenza-like syndrome beginning several hours after injection. Symptoms include fever, chills, headache, myalgia, arthralgia, nausea, vomiting, and diarrhea. Fever usually resolves within 12 h. Tolerance develops gradually in most patients. Febrile responses can be moderated by pretreatment with antipyretics. Up to one-half of patients receiving intralesional therapy for genital warts experience the influenzal illness initially, as well as discomfort at the injection site, and leukopenia.

Dose-limiting toxicities of systemic IFN are myelosuppression; neurotoxicity (e.g., somnolence, confusion, and depression); autoimmune disorders including thyroiditis and hypothyroidism; and uncommonly, cardiovascular effects with hypotension. Elevations in hepatic enzymes and triglycerides, alopecia, proteinuria and azotemia, interstitial nephritis, autoantibody formation, pneumonia, and hepatotoxicity may occur. Alopecia and personality change are common in IFN-treated children. The development of serum neutralizing antibodies to exogenous IFNs may be associated infrequently with loss of clinical responsiveness. IFN may impair fertility; safety during pregnancy is not established. IFNs can increase the hematological toxicity of drugs such as zidovudine and ribavirin and may increase the neurotoxicity and cardiotoxic effects of other drugs. Thyroid function and hepatic enzymes should be monitored during IFN therapy. Pegylated IFNs are better tolerated than standard IFNs, with discontinuation rates ranging from 2-11%, although the frequencies of fever, nausea, injection-site inflammation, and neutropenia may be somewhat higher. Severe neutropenia and the need for dose modifications are higher in HIV-coinfected persons.

THERAPEUTIC USES. Recombinant, natural, and pegylated IFNs currently are approved in the U.S. for treatment of condyloma acuminatum, chronic HCV infection, chronic HBV infection, Kaposi sarcoma in HIV-infected patients, other malignancies, and multiple sclerosis. In addition, interferons have been granted orphan drug status for a variety of rare disease states including idiopathic pulmonary fibrosis, laryngeal papillomatosis, juvenile rheumatoid arthritis, and infections associated with chronic granulomatous disease.

Hepatitis B Virus. In patients with chronic HBV infection, parenteral administration of various IFNs is associated with serological, biochemical, and histological improvement in ~25-50% of the patients. Lasting responses require moderately high IFN doses and prolonged administration (typically 5-10 MU/day in adults and 6 MU/m2 in children 3 times per week of IFNα-2B for 4 to 6 months). Low pretherapy serum HBV DNA levels and high aminotransferase levels are predictors of response. PegIFN alfa-2A (180 μ-g once weekly for 24-48 weeks) appears superior to conventional IFN alfa-2A in HbeAg-positive patients. High-dose IFN can cause myelosuppression and clinical deterioration in those with decompensated liver disease.

Antiviral effects and improvements occur in about one-half of chronic hepatitis D virus (HDV) infections, but relapse is common unless HbsAg disappears. IFN does not appear to be beneficial in acute HBV or HDV infections.

Hepatitis C Virus. In chronic HCV infection, IFN alfa-2B monotherapy (3 MU 3 times weekly) is associated with ~50-70% rate of aminotransferase normalization and loss of plasma viral RNA, but sustained virologic remission is observed in only 10-25% of patients. Sustained viral responses are associated with long-term histological improvement and probably reduced risk of hepatocellular carcinoma and hepatic failure. Viral genotype and pretreatment RNA level influence response to treatment, but early viral clearance is the best predictor of sustained response. Nonresponders generally do not benefit from IFN monotherapy retreatment, but they and patients relapsing after monotherapy often respond to combined pegylated IFN and ribavirin treatment. IFN treatment may benefit HCV-associated cryoglobulinemia and glomerulonephritis. IFN administration during acute HCV infection appears to reduce the risk of chronicity.

Pegylated IFNs are superior to conventional thrice-weekly IFN monotherapy in inducing sustained remissions in treatment-naive patients. Monotherapy with pegIFN alfa-2A (180 μg subcutaneously weekly for 48 weeks) or pegIFN alfa-2B (1.5 μg/kg/week for 1 year) is associated with sustained response in 30-39%, including stable cirrhotic patients, and it is a treatment option in patients unable to take ribavirin. The efficacy of conventional and pegylated IFNs is enhanced by the addition of ribavirin to the treatment regimens, particularly for genotype 1 infections. Combined therapy with pegIFN alfa-2A (180 μg once weekly for 48 weeks) and ribavirin (1000-1200 mg/day in divided doses) gives higher sustained viral response rates than IFN-ribavirin combinations. The dose and duration of therapy depend on genotype of HCV infections. Approximately 15-20% of those failing to respond to combined IFN-ribavirin will have sustained responses to combined pegIFN-ribavirin.

Papillomavirus. In refractory condylomata acuminata (genital warts), intralesional injection of various natural and recombinant IFNs is associated with complete clearance of injected warts in 36-62% of patients, but other treatments are preferred. Relapse occurs in 20-30% of patients. Verruca vulgaris may respond to intralesional IFN-α. Intramuscular or subcutaneous administration is associated with some regression in wart size but greater toxicity. Systemic IFN may provide adjunctive benefit in recurrent juvenile laryngeal papillomatosis and in treating laryngeal disease in older patients.

Other Viruses. IFNs have been shown to have virological and clinical effects in various herpesvirus infections including genital HSV infections, localized herpes-zoster infection of cancer patients or of older adults, and CMV infections of renal transplant patients. However, IFN generally is associated with more side effects and inferior clinical benefits compared with conventional antiviral therapies. Topically applied IFN and trifluridine combinations appear active in acyclovir-resistant mucocutaneous HSV infections.

In HIV-infected persons, IFNs have been associated with antiretroviral effects. In advanced infection, however, the combination of zidovudine and IFN is associated with only transient benefit and excessive hematological toxicity. IFN-α (3 MU 3 times weekly) is effective for treatment of HIV-related thrombocytopenia resistant to zidovudine therapy.

Except for adenovirus, IFN has broad-spectrum antiviral activity against respiratory viruses. However, prophylactic intranasal IFN-α is protective only against rhinovirus colds, and chronic use is limited by the occurrence of nasal side effects. Intranasal IFN is therapeutically ineffective in established rhinovirus colds.

RIBAVIRIN. Ribavirin, a purine nucleoside analog with a modified base and D-ribose sugar, inhibits the replication of a wide range of RNA and DNA viruses, including orthomyxo-, paramyxo-, arena-, bunya-, and flavi-viruses in vitro. Therapeutic concentrations may reversibly inhibit macromolecular synthesis and proliferation of uninfected cells, suppress lymphocyte responses, and alter cytokine profiles in vitro.


THERAPEUTIC USES. Oral ribavirin in combination with injected pegIFN alfa-2A or alfa-2B is standard treatment for chronic HCV infection. Ribavirin aerosol is approved in the U.S. for treatment of RSV bronchiolitis and pneumonia in hospitalized children. Aerosolized ribavirin (usual dose of 20 mg/mL as the starting solution in the drug reservoir of the small particle aerosol generator unit for an 18 h exposure/day for 3-7 days) may reduce some illness measures, but its use generally is not recommended. Aerosol ribavirin combined with intravenous immunoglobulin appears to reduce mortality of RSV infection in bone marrow transplant and other highly immunocompromised patients.

Intravenous and/or aerosol ribavirin has been used occasionally in treating severe influenza virus infection and in the treatment of immunosuppressed patients with adenovirus, vaccinia, parainfluenza, or measles virus infections. Aerosolized ribavirin is associated with reduced duration of fever but no other clinical or antiviral effects in influenza infections in hospitalized children. Intravenous ribavirin decreases mortality in Lassa fever and has been used in treating other arenavirus-related hemorrhagic fevers. Intravenous ribavirin is beneficial in hemorrhagic fever with renal syndrome owing to hantavirus infection but appears ineffective in hantavirus-associated cardiopulmonary syndrome or SARS. Intravenous ribavirin is investigational in the U.S.

MECHANISMS OF ACTION AND RESISTANCE. Ribavirin alters cellular nucleotide pools and inhibits viral mRNA synthesis. Host cell enzymes phosphorylate ribavirin to mono-, di-, and tri-phosphate derivatives. In both uninfected and RSV-infected cells, the predominant derivative (>80%) is the triphosphate, which has an intracellular t1/2 <2 h. Ribavirin monophosphate competitively inhibits cellular IMP dehydrogenase and interferes with the synthesis of GTP and thus nucleic acid synthesis in general. Ribavirin triphosphate also competitively inhibits the GTP-dependent 5′ capping of viral messenger RNA and specifically influenza virus transcriptase activity. Ribavirin has multiple sites of action, and some of these (e.g., inhibition of GTP synthesis) may potentiate others (e.g., inhibition of GTP-dependent enzymes). Ribavirin also may enhance viral mutagenesis to an extent that some viruses may be inhibited from effective replication, so-called lethal mutagenesis. Emergence of viral resistance to ribavirin has been reported in Sindbis and HCV.

ADME. Ribavirin is actively taken up by nucleoside transporters in the proximal small bowel; oral bioavailability averages ~50%. Food increases plasma levels substantially. With aerosol administration, levels in respiratory secretions are very high but variable. The elimination of ribavirin is complex. The plasma t1/2 increases to ~200-300 h at steady state. Erythrocytes concentrate ribavirin triphosphate; the drug exits red cells gradually, with a t1/2 of ~40 days. Hepatic metabolism and renal excretion of ribavirin and its metabolites are the principal routes of elimination. Hepatic metabolism involves deribosylation and hydrolysis to yield a triazole carboxamide. Ribavirin should be used cautiously in patients with creatinine clearances of <50 mL/min.

UNTOWARD EFFECTS. Aerosolized ribavirin may cause conjunctival irritation, rash, transient wheezing, and occasional reversible deterioration in pulmonary function. When used in conjunction with mechanical ventilation, equipment modifications and frequent monitoring are required to prevent plugging of ventilator valves and tubing with ribavirin. Techniques to reduce environmental exposure of healthcare workers are recommended. Pregnant women should not directly care for patients receiving ribavirin aerosol (FDA pregnancy Category X).

Systemic ribavirin causes dose-related reversible anemia owing to extravascular hemolysis and suppression of bone marrow. Associated increases occur in reticulocyte counts and in serum bilirubin, iron, and uric acid concentrations. Bolus intravenous infusion may cause rigors. About 20% of chronic HCV infection patients receiving combination IFN-ribavirin therapy discontinue treatment early because of side effects. In addition to IFN toxicities, oral ribavirin increases the risk of fatigue, cough, rash, pruritus, nausea, insomnia, dyspnea, depression, and particularly, anemia. Preclinical studies indicate that ribavirin is teratogenic, embryotoxic, oncogenic, and possibly gonadotoxic. To prevent possible teratogenic effects, up to 6 months is required for washout following cessation of long-term treatment. Ribavirin inhibits the phosphorylation and antiviral activity of pyrimidine nucleoside HIV reverse-transcriptase inhibitors such as zidovudine and stavudine but increases the activity of purine nucleoside reverse-transcriptase inhibitors (e.g., didanosine) in vitro. It appears to increase the risk of mitochondrial toxicity from didanosine (see Chapter 59).

BOCEPREVIR. Boceprevir (VICTRELIS) inhibits hepatitis C virus non-structural protein 3 (NS3) serine protease.

Boceprevir is indicated for the treatment of chronic hepatitis gentotype 1 infection in adults >18 years old with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy. Boceprevir is administered in combination with peginterferon alfa and ribavirin. The recommended dose is 800 mg (four 200-mg capsules) three times daily (every 7-9 hours) with food. The t1/2 is ~3.4 h. The drug is metabolized mostly by aldoketoreductase and partly by CYP3A4/5, which the drug strongly inhibits. Side effects of combination treatment include fatigue, anemia, nausea, headache, and dysgeusia. Boceprevir is contraindicated in pregnancy.


Unlike HCV, HBV is transcribed into DNA that can be integrated into host chromosomal DNA and is capable of establishing lifelong chronic infection in ~10% of patients. Those with chronic HBV may develop active hepatitis that can lead to fibrosis and cirrhosis, and all such individuals have a greatly increased incidence of hepatocellular carcinoma.

Interferon, or a combination of interferon and ribavirin, can cure patients with chronic infection but is associated with a high rate of side effects, often leading to premature treatment discontinuation. Several antiretroviral nucleoside or nucleotide analog polymerase inhibitors, including lamivudine, telbivudine, and tenofovir, have potent anti-HBV activity and have provided a popular alternative therapy: chronic suppressive oral single agent or combination treatment. These regimens are much better tolerated than IFN-containing regimens but are not usually curative.

ADEFOVIR. Adefovir dipivoxil is a prodrug of adefovir, an acyclic phosphonate nucleotide analog of adenosine monophosphate.

THERAPEUTIC USES. Adefovir dipivoxil is approved for treatment of chronic HBV infections. In patients with HBV e-antigen (HbeAg)–positive chronic hepatitis B, adefovir dipivoxil (10 mg/day) reduces serum HBV DNA levels by 99% and, in about one-half of patients, improves hepatic histology and normalization of aminotransferase levels by 48 weeks. In patients with HbeAg-negative chronic HBV, adefovir is associated with similar biochemical and histological benefits. Regression of cirrhosis may occur in some patients. In patients with lamivudine-resistant HBV infections, adefovir dipivoxil monotherapy results in sustained reductions in serum HBV DNA levels. In patients with dual HIV and lamivudine-resistant HBV infections, adefovir dipivoxil (10 mg/day) causes significant HBV DNA level reductions.

MECHANISMS OF ACTION AND RESISTANCE. Adefovir dipivoxil enters cells and is de-esterified to adefovir, which cellular enzymes convert to the diphosphate, a competitive inhibitor of dATP at viral DNA polymerases and reverse transcriptases and also serves as a chain terminator of viral DNA synthesis. Its selectivity relates to a higher affinity for HBV DNA polymerase compared with cellular polymerases. Adefovir resistance has been detected in ~4% of chronically infected HBV patients during 3 years of treatment. Such variants have unique point mutations in the HBV polymerase but retain susceptibility to lamivudine.

ADME. The dipivoxil prodrug is absorbed rapidly and hydrolyzed in the intestine and blood to adefovir with liberation of pivalic acid, providing a bioavailability ~30-60%. Food does not affect bioavailability. Adefovir is eliminated unchanged by renal excretion. After oral administration of adefovir dipivoxil, ~30-45% of the dose is recovered within 24 h; the t1/2 of elimination is 5-7.5 h. Dose reductions are recommended for ClCr values >50 mL/min. Adefovir is removed by hemodialysis.

UNTOWARD EFFECTS. Adefovir dipivoxil causes dose-related nephrotoxicity and tubular dysfunction, manifested by azotemia and hypophosphatemia, acidosis, glycosuria, and proteinuria that usually are reversible months after discontinuation. The dose (10 mg/day) used in chronic HBV infection patients has been associated with fewer adverse events (e.g., headache, abdominal discomfort, diarrhea, and asthenia) and negligible renal toxicity than higher doses. Acute, sometimes severe exacerbations of hepatitis can occur in patients stopping adefovir or other anti-HBV therapies.

Adefovir is genotoxic, and high doses cause hepatotoxicity, lymphoid toxicity, and renal tubular nephropathy in animals. Adefovir dipivoxil is not associated with reproductive toxicity, although high intravenous doses of adefovir cause maternal and embryotoxicity with fetal malformations in rats (pregnancy Category C). Drugs that reduce renal function could decrease adefovir clearance. Ibuprofen increases adefovir exposure modestly. An increased risk of lactic acidosis and steatosis may exist when adefovir is used in conjunction with nucleoside analogs or other antiretroviral agents. Adefovir is transported efficiently into tubular epithelium by a probenecid-sensitive organic anion transporter (hOAT1).

ENTECAVIR. Entecavir is a guanosine nucleoside analog with selective activity against HBV polymerase.

THERAPEUTIC USES. Entecavir is indicated for the treatment of chronic HBV infection in adults with active viral replication and either evidence of persistent elevations in serum aminotransferases or histologically active disease. The recommended dose for nucleoside-treatment-naive adults is 0.5 mg once daily. For patients with lamivudine or telbivudine resistance, the dose is 1 mg once daily. Entecavir is superior to lamivudine in the degree of suppression and associated with a more frequent fall of HBV DNA to undetectable levels. Entecavir had negligible resistance (<1%) for up to 4 years and is active against adefovir-resistant HBV.

MECHANISMS OF ACTION AND RESISTANCE. Entecavir requires intracellular phosphorylation. Entecavir triphosphate competes with endogenous deoxyguanosine triphosphate and inhibits all 3 activities of the HBV polymerase (reverse transcriptase): base priming, reverse transcription of the negative strand from the pregenomic messenger RNA, and synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ. HIV reverse transcriptase variants containing the M184V substitution show loss of susceptibility to entecavir. Lamivudine and telbivudine resistance confers decreased susceptibility to entecavir.

ADME. Steady-state is reached after 6-10 days of once daily dosing. Administration with food decreases Cmax by 44-46% and AUC by 18-20%; thus entecavir should be administered on an empty stomach. It is primarily eliminated unchanged in the kidney. Renal clearance is independent of dose, suggesting that entecavir undergoes both glomerular filtration and net tubular secretion. Entecavir exhibits biphasic elimination, with a terminal t1/2 of 128-149 h; the active triphosphate has an elimination t1/2 of 15 h. Dose reductions are needed for patients with ClCr >50 mL/min, typically by extension of the dosing interval.

UNTOWARD EFFECTS. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-HBV therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for several months in patients who discontinue anti-HBV therapy. There is a potential for development of resistance to nucleoside reverse transcriptase inhibitors in HBV/HIV coinfection, especially if HIV is not being treated. Other common adverse reactions include headache, fatigue, dizziness, and nausea.

LAMIVUDINE. Lamivudine is a nucleoside analog that inhibits HIV reverse transcriptase and HBV DNA polymerase. It inhibits HBV replication with negligible cellular cytotoxicity. Its use as an antiretroviral agent is discussed in Chapter 59.

THERAPEUTIC USES. Lamivudine is approved for the treatment of chronic HBV hepatitis in adults and children. In adults, doses of 100 mg/day for 1 year cause suppression of HBV DNA levels, normalization of aminotransferase levels and reductions in hepatic inflammation in 40-50% of patients. Seroconversion with antibody to HbeAg occurs in <20% of recipients at 1 year. Prolonged therapy is associated with sustained suppression of HBV DNA and continued histological improvement. Prolonged therapy halves the risk of clinical progression and development of hepatocellular carcinoma in those with advanced fibrosis or cirrhosis. The frequency of lamivudine-resistant variants increases progressively with continued drug administration, reaching 67% after 4 years of treatment. The risk of resistance development is higher after transplantation and in HIV/HBV coinfected patients.

Combined use of IFN or pegIFN alfa-2A with lamivudine has not improved responses in HBeAg-positive patients consistently. In HIV and HBV coinfections, higher lamivudine doses are associated with antiviral effects and uncommonly anti-HBe seroconversion. Administration of lamivudine before and after liver transplantation may suppress recurrent HBV infection.

MECHANISMS OF ACTION AND RESISTANCE. Cellular enzymes convert lamivudine to the triphosphate. Lamivudine triphosphate is a potent competitive inhibitor of the DNA polymerase/reverse transcriptase of HBV and causes chain termination. Lamivudine shows enhanced antiviral activity in combination with adefovir or penciclovir against hepadnaviruses. Point mutations in the YMDD motif of HBV DNA polymerase markedly reduce susceptibility. Lamivudine resistance confers cross-resistance to related agents such as emtricitabine, and is often associated with an additional non-YMDD mutation that confers cross-resistance to famciclovir. Lamivudine-resistant HBV retains susceptibility to adefovir, tenofovir, and partially to entecavir. Viruses bearing YMDD mutations are less replication competent than wild-type HBV. However, lamivudine resistance is associated with elevated HBV DNA levels, decreased likelihood of HbeAg loss or seroconversion, hepatitis exacerbations, and progressive fibrosis and graft loss in transplant recipients.

ADME. The pharmacokinetic properties of lamivudine are described in Chapter 59. The intracellular t1/2 of the triphosphate averages 17-19 h in HBV-infected cells, so once-daily dosing is possible. Dose reductions are indicated for moderate renal insufficiency. Trimethoprim decreases the renal clearance of lamivudine.

UNTOWARD EFFECTS. At the doses used for chronic HBV infection, lamivudine generally has been well tolerated. Post-treatment aminotransferase elevations occur in ~15% of patients after cessation.

TELBIVUDINE. Telbivudine is a synthetic thymidine nucleoside analog with activity against HBV DNA polymerase.

THERAPEUTIC USES. Telbivudine is indicated for the treatment of chronic HBV in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. The recommended dose is 600 mg orally once daily without regard to food. An oral solution is also available. Telbivudine resistance is 25% after 2 years of treatment and higher than observed with other oral anti-HBV agents. Cross-resistance and treatment-emergent resistance limit the use of telbivudine for patients with chronic HBV, compared to alternative agents.

MECHANISMS OF ACTION AND RESISTANCE. Telbivudine is phosphorylated by cellular kinases to the active triphosphate form, which has a t1/2 of 14 h. Telbivudine 5′-triphosphate inhibits HBV DNA polymerase/reverse transcriptase by competing with the natural substrate, TTP. Incorporation of telbivudine 5′-triphosphate into viral DNA causes chain termination.

Lamivudine-resistant HBV strains expressing either the M204I substitution or the L180M/M204V double substitution have ≥1000-fold reduced susceptibility. HBV encoding the adefovir mutation A181V showed 3- to 5-fold reduced susceptibility. The A181T substitution is associated with decreased clinical response in patients with HBV treated with adefovir and entecavir.

ADME. At 600 mg once daily, steady state is achieved after ~5-7 days with ~1.5-fold accumulation. Telbivudine concentrations decline biexponentially with an elimination t1/2 of 40-49 h. The drug is eliminated unchanged in the urine. Patients with moderate-to-severe renal dysfunction require dose adjustments.

UNTOWARD EFFECTS. Telbivudine is generally well tolerated and safe. The most common adverse events resulting in telbivudine discontinuation included increased creatine kinase, nausea, diarrhea, fatigue, myalgia, and myopathy.

TENOFOVIR. Tenofovir is a nucleotide analog with activity against both HIV-1 and HBV. It is administered orally as the disoproxil prodrug. For more detail, see Chapter 59.

THERAPEUTIC USES. Tenofovir is approved for treatment of HBV infection in adults at a dose of 300 mg once daily without regard to food. In HBeAg-negative patients, tenofovir suppresses HBV DNA to >400 copies/mL in 93% of subjects at 48 weeks, compared to 63% for adefovir. Tenofovir resistance is not evident over 48 weeks of treatment. Due to its safety, efficacy, and resistance profile, tenofovir will likely supersede adefovir for the treatment of chronic HBV infection. Overall, tenofovir has a favorable resistance profile and has been effective in treating lamivudine-resistant HBV. The tenofovir dose should be adjusted for impaired renal function and during hemodialysis.


Clevudine is a nucleoside analog with potent activity against HBV. The oral drug is approved for use in South Korea and the Philippines. However, the drug caused myopathy in large phase 3 clinical trials, casting doubt on its future approval in the U.S.


IMIQUIMOD. Imiquimod is a novel immunomodulatory agent that is effective for topical treatment of condylomata acuminata, molluscum contagiosum, and certain other dermatologic conditions associated with DNA virus infections. It lacks direct antiviral or antiproliferative effects in vitro; rather, imiquimod induces cytokines and chemokines with antiviral and immunomodulating effects.

When applied topically as a 5% cream to genital warts in humans, imiquimod induces local IFN-α, IFN-β, and IFN-γ and TNFα responses and causes reductions in viral load and wart size. When applied topically (3 times weekly for up to 16 weeks), imiquimod cream results in complete clearance of treated genital and perianal warts in ~50% of patients in 8-10 weeks, with response rates higher in women than in men. Application is associated with local erythema, excoriation/flaking, itching, burning, and less often, erosions or ulcerations.