Chapter 58: Antiviral Agents (Nonretroviral)

The immunosuppressive agent mycophenolate mofetil (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.

Acyclovir resistance in HSV has been linked to one of three mechanisms: 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.

Absorption, Distribution, and Elimination. The oral bioavailability of acyclovir ranges from 10-30% and decreases with increasing dose (Wagstaff et al., 1994). Peak plasma concentrations average 0.4-0.8 μg/mL after 200-mg doses and 1.6 μg/mL after 800-mg doses. Following intravenous dosing, peak and trough plasma concentrations average 9.8 and 0.7 μg/mL after 5 mg/kg every 8 hours and 20.7 and 2.3 μg/mL after 10 mg/kg every 8 hours, respectively.

Valacyclovir is converted rapidly and virtually completely to acyclovir after oral administration in healthy adults. 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 relative oral bioavailability of acyclovir increases 3-5 fold to ~70% following valacyclovir administration (Steingrimsdottir et al., 2000). Peak acyclovir concentrations average 5-6 μg/mL following single 1000-mg doses of oral valacyclovir and occur ~2 hours after dosing. 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 mean plasma elimination t_1/2 of acyclovir is ~2.5 hours (range: 1.5-6 hours in adults with normal renal function). The elimination t_1/2 of acyclovir is ~4 hours in neonates and increases to 20 hours in anuric patients (Wagstaff et al., 1994). Renal excretion of unmetabolized acyclovir by glomerular filtration and tubular secretion is the principal route of elimination. Less than 15% is excreted as 9-carboxymethoxymethylguanine or minor metabolites. The pharmacokinetics of oral acyclovir and valacyclovir appear to be similar in pregnant and nonpregnant women (Kimberlin et al., 1998).

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 central nervous system (CNS) symptoms. High doses of valacyclovir have been associated with confusion and hallucinations, nephrotoxicity, and uncommonly, severe thrombocytopenic syndromes, sometimes fatal, in immunocompromised patients. Acyclovir has been associated with neutropenia in neonates. Chronic acyclovir suppression of genital herpes has been used safely for up to 10 years. No excess frequency of congenital abnormalities has been recognized in infants born to women exposed to acyclovir during pregnancy (Ratanajamit et al., 2003).

The principal dose-limiting toxicities of intravenous acyclovir are renal insufficiency and CNS side effects. Preexisting renal insufficiency, high doses, and high acyclovir plasma levels (>25 μg/mL) are risk factors for both. Reversible renal dysfunction occurs in ~5% of patients, probably related to high urine levels causing crystalline nephropathy. Manifestations include nausea, emesis, flank pain, and increasing azotemia. Rapid infusion, dehydration, and inadequate urine flow increase the risk. Infusions should be given at a constant rate over at least an hour. Nephrotoxicity usually resolves with drug cessation and volume expansion. Neurotoxicity occurs in 1-4% of patients and may be manifested by altered sensorium, tremor, myoclonus, delirium, seizures, or extrapyramidal signs. Phlebitis following extravasation, rash, diaphoresis, nausea, hypotension, and interstitial nephritis also have been described. Hemodialysis may be useful in severe cases.

Severe somnolence and lethargy may occur with combinations of zidovudine and acyclovir. Concomitant cyclosporine and probably other nephrotoxic agents enhance the risk of nephrotoxicity. Probenecid decreases the acyclovir renal clearance and prolongs the elimination t_1/2. Acyclovir may decrease the renal clearance of other drugs eliminated by active renal secretion, such as methotrexate.

Therapeutic Uses. In immunocompetent persons, the clinical benefits of acyclovir and valacyclovir are greater in initial HSV infections than in recurrent ones, which typically are milder in severity. 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 varicella-zoster infections than for HSV infections. Oral valacyclovir is as effective as oral acyclovir in HSV infections and more effective for treating herpes zoster.

Herpes Simplex Virus Infections. In initial genital HSV infections, oral acyclovir (200 mg five times daily or 400 mg three times daily for 7-10 days) and valacyclovir (1000 mg twice daily for 7-10 days) are associated with significant reductions in virus shedding, symptoms, and time to healing (Kimberlin and Rouse, 2004). Intravenous acyclovir (5 mg/kg every 8 hours) has similar effects in patients hospitalized with severe primary genital HSV infections. Topical acyclovir is much less effective than systemic administration. None of these regimens reproducibly reduces the risk of recurrent genital lesions. Acyclovir (200 mg five times daily or 400 mg three times daily for 5 days or 800 mg three times daily for 2 days) or valacyclovir (500 mg twice daily for 3 or 5 days) shortens the manifestations of recurrent genital HSV episodes by 1-2 days. Frequently recurring genital herpes can be suppressed effectively with chronic oral acyclovir (400 mg twice daily or 200 mg three times daily) or with valacyclovir (500 mg or, for very frequent recurrences, 1000 mg once daily). During use, the rate of clinical recurrences decreases by ~90%, and subclinical shedding is markedly reduced, although not eliminated. Valacyclovir suppression of genital herpes reduces the risk of transmitting infection to a susceptible partner by ~50% over an 8-month period (Corey et al., 2004). Chronic suppression may be useful in those with disabling recurrences of herpetic whitlow or HSV-related erythema multiforme.

Oral acyclovir is effective in primary herpetic gingivostomatitis (600 mg/m² four times daily for 10 days in children) but provides only modest clinical benefit in recurrent orolabial herpes. Short-term, high-dose valacyclovir (2 g twice over 1 day) shortens the duration of recurrent orolabial herpes by ~1 day (Elish et al., 2004). The FDA has approved an acyclovir/hydrocortisone combination (lipsovir) for early treatment of recurrent herpes cold sores. Topical acyclovir cream is modestly effective in recurrent labial (Spruance et al., 2002) and genital herpes simplex virus infections. Preexposure acyclovir prophylaxis (400 mg twice daily for 1 week) reduces the overall risk of recurrence by 73% in those with sun-induced recurrences of HSV infections. Acyclovir during the last month of pregnancy reduces the likelihood of viral shedding and the frequency of cesarean delivery in women with primary or recurrent genital herpes (Corey and Wald, 2009).

In immunocompromised patients with mucocutaneous HSV infection, intravenous acyclovir (250 mg/m² every 8 hours for 7 days) shortens healing time, duration of pain, and the period of virus shedding. Oral acyclovir (800 mg five times per day) and valacyclovir (1000 mg twice daily) for 5-10 days are also effective. Recurrences are common after cessation of therapy and may require long-term suppression. In those with very localized labial or facial HSV infections, topical acyclovir may provide some benefit. Intravenous acyclovir may be beneficial in viscerally disseminating HSV in immunocompromised patients and in patients with HSV-infected burn wounds.

Systemic acyclovir prophylaxis is highly effective in preventing mucocutaneous HSV infections in seropositive patients undergoing immunosuppression. Intravenous acyclovir (250 mg/m2 every 8-12 hours) begun prior to transplantation and continuing for several weeks prevents HSV disease in bone marrow transplant recipients. For patients who can tolerate oral medications, oral acyclovir (400 mg five times daily) is effective, and long-term oral acyclovir (200-400 mg three times daily for 6 months) also reduces the risk of VZV infection (Steer et al., 2000). In HSV encephalitis, acyclovir (10 mg/kg every 8 hours for a minimum of 10 days) reduces mortality by >50% and improves overall neurologic outcome compared with vidarabine. Higher doses (15-20 mg/kg every 8 hours) and prolonged treatment (up to 21 days) are recommended by many experts. Intravenous acyclovir (20 mg/kg every 8 hours for 21 days) is more effective than lower doses in viscerally invasive neonatal HSV infections (Kimberlin et al., 2001). In neonates and immunosuppressed patients and, rarely, in previously healthy persons, relapses of encephalitis following acyclovir may occur. The value of continuing long-term suppression with valacyclovir after completing intravenous acyclovir is under study.

An ophthalmic formulation of acyclovir (not available in the U.S.) is at least as effective as topical vidarabine or trifluridine in herpetic keratoconjunctivitis.

Infection owing to resistant HSV is rare in immunocompetent persons; however, in immunocompromised hosts, acyclovir-resistant HSV isolates can cause extensive mucocutaneous disease and, rarely, meningoencephalitis, pneumonitis, or visceral disease. Resistant HSV can be recovered from 6-17% of immunocompromised patients receiving acyclovir treatment (Bacon et al., 2003). Recurrences after cessation of acyclovir usually are due to sensitive virus but may be due to acyclovir-resistant virus in AIDS patients. In patients with progressive disease, intravenous foscarnet therapy is effective, but vidarabine is not (Chilukuri and Rosen, 2003).

Varicella-Zoster Virus Infections. If begun within 24 hours of rash onset, oral acyclovir has therapeutic effects in varicella of children and adults. In children weighing up to 40 kg, acyclovir (20 mg/kg, up to 800 mg per dose, four times daily for 5 days) reduces fever and new lesion formation by ~1 day. Routine use in uncomplicated pediatric varicella is not recommended but should be considered in those at risk of moderate-to-severe illness (persons >12 years of age, secondary household cases, those with chronic cutaneous or pulmonary disorders, or those receiving corticosteroids or long-term salicylates) (Committee on Infectious Diseases, American Academy of Pediatrics, 2003). In adults treated within 24 hours, oral acyclovir (800 mg five times daily for 7 days) reduces the time to crusting of lesions by ~2 days, the maximum number of lesions by one-half, and the duration of fever. Intravenous acyclovir appears to be effective in varicella pneumonia or encephalitis of previously healthy adults. Oral acyclovir (10 mg/kg four times daily) given between 7 and 14 days after exposure may reduce the risk of varicella.

In older adults with localized herpes zoster, oral acyclovir (800 mg five times daily for 7 days) reduces pain and healing times if treatment can be initiated within 72 hours of rash onset. A reduction in ocular complications, particularly keratitis and anterior uveitis, occurs with treatment of zoster ophthalmicus. Prolonged acyclovir and concurrent prednisone for 21 days speed zoster healing and improve quality-of-life measures compared with each therapy alone. Valacyclovir (1000 mg three times daily for 7 days) provides more prompt relief of zoster-associated pain than acyclovir in older adults (≥50 years) with zoster.

In immunocompromised patients with herpes zoster, intravenous acyclovir (500 mg/m² every 8 hours for 7 days) reduces viral shedding, healing time, and the risks of cutaneous dissemination and visceral complications, as well as the length of hospitalization, in disseminating zoster. In immunosuppressed children with varicella, intravenous acyclovir decreases healing time and the risk of visceral complications.

Acyclovir-resistant VZV isolates uncommonly have been recovered from HIV-infected children and adults who may manifest chronic hyperkeratotic or verrucous lesions and sometimes meningoradiculitis. Intravenous foscarnet also appears to be effective for acyclovir-resistant VZV infections.

Other Viruses. Acyclovir is ineffective therapeutically in established cytomegalovirus (CMV) infections but ganciclovir is effective for CMV prophylaxis in immunocompromised patients. High-dose intravenous acyclovir (500 mg/m² every 8 hours for 1 month) in CMV-seropositive bone marrow transplant recipients is associated with ~50% lower risk of CMV disease and, when combined with prolonged oral acyclovir (800 mg four times daily through 6 months), improves survival. Following engraftment, valacyclovir (2000 mg four times daily to day 100) appears as effective as intravenous ganciclovir prophylaxis in such patients (Winston et al., 2003). High-dose oral acyclovir or valacyclovir (2000 mg four times daily) suppression for 3 months may reduce the risk of CMV disease and its sequelae in certain solid-organ transplant recipients (Lowance et al., 1999), but oral valganciclovir is the preferred agent for mismatched graft recipients (Pereyra and Rubin, 2004). Compared with acyclovir, high-dose valacyclovir reduces CMV disease in advanced HIV infection but is associated with greater toxicity and possibly shorter survival.

In infectious mononucleosis, acyclovir is associated with transient antiviral effects but no clinical benefits. EBV-related oral hairy leukoplakia may improve with acyclovir. Oral acyclovir in conjunction with systemic corticosteroids appears beneficial in treating Bell's palsy, but valacyclovir is ineffective in acute vestibular neuritis.

In vitro inhibitory concentrations range from >0.2 to 0.7 μg/mL for CMV, 0.4 to 33 μg/mL for HSV, and 0.02-17 μg/mL for adenoviruses. Because cidofovir is a phosphonate that is phosphorylated by cellular but not virus 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.

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.

Absorption, Distribution, and Elimination. Cidofovir is dianionic at physiological pH and has very low oral bioavailability (Cundy, 1999). The plasma levels after intravenous dosing decline in a biphasic pattern with a terminal t_1/2 that averages 2.6 hours. The volume of distribution approximates total-body water. Penetration into the CNS or eye has not been well characterized, but CSF levels are low. Extemporaneously compounded topical cidofovir gel may result in low plasma concentrations (<0.5 μg/mL) in patients with large mucocutaneous lesions.

Cidofovir is cleared by the kidney via glomerular filtration and tubular secretion. Over 90% of the dose is recovered unchanged in the urine without significant metabolism in humans. The probenecid-sensitive organic anion transporter 1 mediates uptake of cidofovir into proximal renal tubular epithelial cells (Ho et al., 2000). High-dose probenecid (2 g three hours before and 1 g two and eight hours after each infusion) blocks tubular transport of cidofovir and reduces renal clearance and associated nephrotoxicity. At cidofovir doses of 5 mg/kg, peak plasma concentrations increase from 11.5-19.6 μg/mL with probenecid, and renal clearance is reduced to the level of glomerular filtration. Elimination relates linearly to creatinine clearance, and the t_1/2 increases to 32.5 hours in patients on chronic ambulatory peritoneal dialysis (CAPD). Hemodialysis removes >50% of the administered dose (Cundy, 1999).

Untoward Effects. Nephrotoxicity is the principal dose-limiting side effect of intravenous cidofovir. Proximal tubular dysfunction includes proteinuria, azotemia, glycosuria, metabolic acidosis, and uncommonly, Fanconi's syndrome. Concomitant oral probenecid and saline prehydration reduce the risk of renal toxicity. 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. Concurrent probenecid administration is associated with gastrointestinal (GI) upset, constitutional symptoms, and hypersensitivity reactions, including fever, rash, and uncommonly, anaphylactoid manifestations. Administration with food and pretreatment with antiemetics, antihistamines, and/or acetaminophen may improve tolerance.

Probenecid, but not cidofovir, 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). Concurrent nephrotoxic agents are contraindicated, and at least 7 days should elapse between the end of aminoglycoside therapy and initiation of cidofovir. The same interval should separate intravenous pentamidine, amphotericin B, foscarnet, NSAID, or contrast dye and cidofovir. 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. Intravitreal cidofovir may cause vitreitis, hypotony, and visual loss and is contraindicated.

Preclinical studies indicate that cidofovir has mutagenic, gonadotoxic, embryotoxic, and teratogenic effects. Because cidofovir is carcinogenic in rats, it is considered a potential human carcinogen. It may cause infertility and is classified as pregnancy Category C.

Therapeutic Uses. Intravenous cidofovir is approved for the treatment of CMV retinitis in HIV-infected patients.

Intravenous cidofovir (5 mg/kg once a week for 2 weeks followed by dosing every 2 weeks) increases the time to progression of CMV retinitis in previously untreated patients and in those failing or intolerant of ganciclovir and foscarnet therapy. CMV viremia may persist during cidofovir administration. Maintenance doses of 5 mg/kg are more effective but less well tolerated than 3 mg/kg doses. Intravenous cidofovir has been used for treating acyclovir-resistant mucocutaneous HSV infection, adenovirus disease in transplant recipients (Ljungman et al., 2003), and extensive molluscum contagiosum in HIV patients. Reduced doses (0.25-1 mg/kg every 2-3 weeks) without probenecid may be beneficial in BK virus nephropathy in renal transplant patients (Vats et al., 2003).

Extemporaneously compounded 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.

Penciclovir is similar to acyclovir in its spectrum of activity and potency against HSV and VZV. The inhibitory concentrations of penciclovir depend on cell type but are usually within 2-fold of those of acyclovir for HSV and VZV. It also is inhibitory for HBV.

Resistant variants owing to thymidine kinase or DNA polymerase mutations can be selected by passage in vitro, but the occurrence of resistance during clinical use is currently low (Bacon et al., 2003). Thymidine kinase–deficient, acyclovir-resistant herpes viruses are cross-resistant to penciclovir.

Absorption, Distribution, and Elimination. 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 from the intestine (Gill and Wood, 1996). Thus, the bioavailability of penciclovir is ~75% following oral administration of famciclovir.

Food slows absorption but does not reduce overall bioavailability. After single 250- or 500-mg doses of famciclovir, the peak plasma concentration of penciclovir averages 1.6 and 3.3 μg/mL, respectively. A small quantity of the 6-deoxy precursor but no famciclovir is detectable in plasma. After intravenous infusion of penciclovir at 10 mg/kg, peak plasma levels average 12 μg/mL. The volume of distribution is about twice the volume of total-body water. The plasma elimination t_1/2 of penciclovir averages ~2 hours, and >90% is excreted unchanged in the urine, probably by both filtration and active tubular secretion. 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 t_1/2 averages 9.9 hours in renal insufficiency (Cl_cr <30 mL/minute); hemodialysis efficiently removes penciclovir. Lower peak plasma concentrations of penciclovir, but no reduction in overall bioavailability of famciclovir, occur in compensated chronic hepatic insufficiency (Boike et al., 1994).

Untoward Effects. Oral famciclovir is well tolerated but may be associated with headache, diarrhea, and nausea. Urticaria, rash, and hallucinations or confusional states (predominantly in the elderly) have been reported. Topical penciclovir, which is formulated in 40% propylene glycol and a cetomacrogol base, is associated infrequently with application-site reactions (~1%). The short-term tolerance of famciclovir is comparable with that of acyclovir.

Penciclovir is mutagenic at high concentrations in vitro. Although studies in laboratory animals indicate that chronic famciclovir administration is tumorigenic and decreases spermatogenesis and fertility in rodents and dogs, long-term administration (1 year) does not affect spermatogenesis in men. No teratogenic effects have been observed in animals, but safety during pregnancy has not been established. No clinically important drug interactions have been identified to date with famciclovir or penciclovir (Gill and Wood, 1996).

Therapeutic Uses. Oral famciclovir, topical penciclovir, and intravenous penciclovir are approved for managing HSV and VZV infections (Sacks and Wilson, 1999).

Oral famciclovir (250 mg three times a day for 7-10 days) is as effective as acyclovir in treating first-episode genital herpes (Kimberlin and Rouse, 2004). In patients with recurrent genital HSV, patient-initiated famciclovir treatment (125 or 250 mg twice a day for 5 days) reduces healing time and symptoms by ~1 day. Famciclovir (250 mg twice a day for up to 1 year) is effective for suppression of recurrent genital HSV, but single daily doses are less effective. Higher doses (500 mg twice a day) reduce HSV recurrences in HIV-infected persons. Intravenous penciclovir (5 mg/kg every 8 or 12 hours for 7 days) (not available in the U.S.) is comparable to intravenous acyclovir for treating mucocutaneous HSV infections in immunocompromised hosts. In immunocompetent persons with recurrent orolabial HSV, topical 1% penciclovir cream (applied every 2 hours while awake for 4 days) shortens healing time and symptoms by ~1 day (Raborn et al., 2002).

In immunocompetent adults with herpes zoster of ≤3 days' duration, famciclovir (500 mg three times a day for 10 days) is at least as effective as acyclovir (800 mg five times daily) in reducing healing time and zoster-associated pain, particularly in those ≥50 years of age. Famciclovir is comparable with valacyclovir in treating zoster and reducing associated pain in older adults (Tyring et al., 2000). Famciclovir (500 mg three times a day for 7-10 days) also is comparable with high-dose oral acyclovir in treating zoster in immunocompromised patients and in those with ophthalmic zoster (Tyring et al., 2001).

Famciclovir is associated with dose-related reductions in HBV DNA and transaminase levels in patients with chronic HBV hepatitis but is less effective than lamivudine (Lai et al., 2002). Famciclovir is also ineffective in treating lamivudine-resistant HBV infections owing to emergence of multiply resistant variants.

Absorption, Distribution, and Elimination. Oral bioavailability of foscarnet is low. Following an intravenous infusion of 60 mg/kg every 8 hours, peak and trough plasma concentrations are ~450-575 and 80-150 μM, respectively. Vitreous levels approximate those in plasma, and CSF levels average 66% of those in plasma at steady state.

Over 80% of foscarnet is excreted unchanged in the urine by glomerular filtration and probably tubular secretion. Plasma clearance decreases proportionately with creatinine clearance, and dose adjustments are indicated for small decreases in renal function. Plasma elimination is complex, with initial bimodal half-lives totaling 4-8 hours and a prolonged terminal elimination t_1/2 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. Foscarnet's major dose-limiting toxicities are nephrotoxicity and symptomatic hypocalcemia. Increases in serum creatinine occur in up to one-half of patients but are reversible after cessation in most patients. High doses, rapid infusion, dehydration, prior renal insufficiency, and concurrent nephrotoxic drugs are risk factors. Acute tubular necrosis, crystalline glomerulopathy, nephrogenic diabetes insipidus, and interstitial nephritis have been described. 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. Decreased serum ionized Ca²⁺ may cause paresthesia, arrhythmias, tetany, seizures, and other CNS disturbances. Concomitant intravenous pentamidine administration increases the risk of symptomatic hypocalcemia. Parenteral magnesium sulfate does not alter foscarnet-induced hypocalcemia or symptoms (Huycke et al., 2000).

CNS side effects include headache in ~25% of patients, 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 and may cause tooth and skeletal abnormalities in developing laboratory animals. Safety in pregnancy or childhood is uncertain.

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.

In CMV retinitis in AIDS patients, foscarnet (60 mg/kg every 8 hours or 90 mg/kg every 12 hours for 14-21 days followed by chronic maintenance at 90 to 120 mg/kg every day in one dose) is associated with clinical stabilization in ~90% of patients. A comparative trial of foscarnet with ganciclovir found comparable control of CMV retinitis in AIDS patients but improved overall survival in the foscarnet-treated group (Studies of Ocular Complications of AIDS, 1992). This improved survival with foscarnet may be related to the drug's intrinsic anti-HIV activity, but patients stop taking foscarnet over three times as often as ganciclovir because of side effects. A combination of foscarnet and ganciclovir is more effective than either drug alone in refractory retinitis; combinations may be useful in treating ganciclovir-resistant CMV infections in solid-organ transplant patients. Foscarnet benefits other CMV syndromes in AIDS or transplant patients but is ineffective as monotherapy in treating CMV pneumonia in bone marrow transplant patients (possibly effective if started early). When used for preemptive therapy of CMV viremia in bone marrow transplant recipients, foscarnet (60 mg/kg every 12 hours for 2 weeks followed by 90 mg/kg daily for 2 weeks) is as effective as intravenous ganciclovir and causes less neutropenia (Reusser et al., 2002). When used for CMV infections, foscarnet may reduce the risk of Kaposi's sarcoma in HIV-infected patients. Intravitreal injections of foscarnet also have been used.

In acyclovir-resistant mucocutaneous HSV infections, lower doses of foscarnet (40 mg/kg every 8 hours for ≥7 days) are associated with cessation of viral shedding and with complete healing of lesions in about three-quarters of patients. Foscarnet also appears to be effective in acyclovir-resistant VZV infections. Topical foscarnet cream is ineffective in treating recurrent genital HSV in immunocompetent persons but appears to be useful in chronic acyclovir-resistant infections in immunocompromised patients.

Resistant clinical isolates of herpesviruses have emerged during therapeutic use and may be associated with poor clinical response to foscarnet treatment.

Intracellular ganciclovir triphosphate concentrations are 10-fold higher than those of acyclovir triphosphate and decline much more slowly with an intracellular elimination t_1/2 >24 hours. These differences may account in part for ganciclovir's greater anti-CMV activity and provide the rationale for single daily doses in suppressing human CMV infections.

CMV can become resistant to ganciclovir by one of two mechanisms: reduced intracellular ganciclovir phosphorylation owing to mutations in the viral phosphotransferase encoded by the UL97 gene and mutations in viral DNA polymerase (Schreiber et al., 2009). Resistant CMV clinical isolates have from 4- to >20-fold increases in inhibitory concentrations. Resistance has been associated primarily with impaired phosphorylation but sometimes only with DNA polymerase mutations. Highly resistant variants with dual UL97 and polymerase mutations are cross-resistant to cidofovir and variably to foscarnet. Ganciclovir also is much less active against acyclovir-resistant thymidine kinase–deficient HSV strains.

Absorption, Distribution, and Elimination. The oral bioavailability of ganciclovir averages 6-9% following ingestion with food. Peak and trough plasma levels are ~0.5-1.2 and 0.2-0.5 μg/mL, respectively, after 1000-mg doses every 8 hours. Oral valganciclovir is well absorbed and hydrolyzed rapidly to ganciclovir; the bioavailability of ganciclovir averages 61% following valganciclovir (Curran and Noble, 2001). Food increases the bioavailability of valganciclovir by ~25%, and peak ganciclovir concentrations average 6.1 μg/mL after 875-mg doses. High oral valganciclovir doses in the fed state provide ganciclovir exposures comparable with intravenous dosing (Brown et al., 1999). Following intravenous administration of 5 mg/kg doses of ganciclovir, peak and trough plasma concentrations average 8-11 and 0.6-1.2 μg/mL, respectively. Following intravenous dosing, vitreous fluid levels are similar to or higher than those in plasma and average ~1 μg/mL. Vitreous levels decline with a t_1/2 of 23-26 hours. Intraocular sustained-release ganciclovir implants provide vitreous levels of ~4.1 μg/mL.

The plasma elimination t_1/2 is ~2-4 hours in patients with normal renal function. Over 90% of ganciclovir is eliminated unchanged by renal excretion through glomerular filtration and tubular secretion. Consequently, the plasma t_1/2 increases almost linearly as creatinine clearance declines and may reach 28-40 hours 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 thrombocytopenia in 5-20%. Neutropenia 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. Oral valganciclovir is associated with headache and GI disturbance (i.e., nausea, pain, and diarrhea) in addition to the toxicities associated with intravenous ganciclovir, including neutropenia. Recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim, lenograstim) may be useful in treating ganciclovir-induced neutropenia (Chapter 37).

CNS side effects occur in 5-15% of patients and 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.

Teratogenicity, embryotoxicity, irreversible reproductive toxicity, and myelotoxicity have been observed in animals at ganciclovir dosages comparable with those used in humans. Ganciclovir is classified as pregnancy Category C.

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%.

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.

In CMV retinitis, initial induction treatment (5 mg/kg intravenously every 12 hours for 10-21 days) is associated with improvement or stabilization in ~85% of patients (Faulds and Heel, 1990). Reduced viral excretion is usually evident by 1 week, and funduscopic improvement is seen by 2 weeks. Because of the high risk of relapse, AIDS patients with retinitis require suppressive therapy with high doses of ganciclovir (5 mg/kg/day). Oral ganciclovir (1000 mg three times daily) is effective for suppression of retinitis after initial intravenous treatment but has been replaced in practice by oral valganciclovir. Oral valganciclovir (900 mg twice daily for 21 days initial treatment) is comparable with intravenous dosing for initial control and sustained suppression (900 mg daily) of CMV retinitis (Schreiber et al., 2009). Intravitreal ganciclovir injections have been used in some patients, and an intraocular sustained-release ganciclovir implant (vitrasert) is more effective than systemic dosing in suppressing retinitis progression.

Ganciclovir therapy (5 mg/kg every 12 hours for 14-21 days) may benefit other CMV syndromes in AIDS patients or solid-organ transplant recipients (Infectious Disease Community of Practice et al., 2004). Response rates of ≥67% have been found in combination with a decrease in immunosuppressive therapy. The duration of therapy depends on demonstrating clearance of viremia; early switch from intravenous ganciclovir to oral valganciclovir is feasible. Recurrent CMV disease occurs commonly after initial treatment. In bone marrow transplant recipients with CMV pneumonia, ganciclovir alone appears ineffective. However, ganciclovir combined with intravenous immunoglobulin or CMV immunoglobulin reduces the mortality of CMV pneumonia by about one-half. Ganciclovir treatment improved hearing outcomes in neonates with symptomatic congenital CMV infections involving the CNS (Kimberlin et al, 2003).

Ganciclovir has been used for both prophylaxis and preemptive therapy of CMV infections in transplant recipients (Schreiber et al., 2009). In bone marrow transplant recipients, preemptive ganciclovir treatment (5 mg/kg every 12 hours for 7-14 days followed by 5 mg/kg every day to days 100-120 after transplant) starting when CMV is isolated from bronchoalveolar lavage or from other sites is highly effective in preventing CMV pneumonia and appears to reduce mortality in these patients. Initiation of ganciclovir at the time of engraftment also reduces CMV disease rates but does not improve survival in part because of infections owing to ganciclovir-related neutropenia.

Intravenous ganciclovir, oral ganciclovir, and oral valganciclovir reduce the risk of CMV disease in solid-organ transplant recipients (Infectious Disease Community of Practice et al., 2004). Oral ganciclovir (1000 mg three times daily for 3 months) reduces CMV disease risk in liver transplant recipients, including high-risk patients with primary infection or those receiving antilymphocyte antibodies. Oral valganciclovir prophylaxis generally is more effective than high-dose oral acyclovir. Oral valganciclovir (900 mg once daily) provides somewhat greater antiviral effects and similar reductions in CMV disease as oral ganciclovir in mismatched solid-organ transplant recipients (Schreiber et al., 2009). Valganciclovir has recently been approved for prevention of CMV in pediatric transplant patients.

In advanced HIV disease, oral ganciclovir (1000 mg three times daily) may reduce the risk of CMV disease and possibly mortality in those not receiving didanosine (Brosgart et al., 1998) but has been replaced for prophylaxis by oral valganciclovir. The addition of oral high-dose ganciclovir (1500 mg three times daily) to the intraocular ganciclovir implant further delays the time to retinitis progression and reduces the risk of new CMV disease and possibly the risk of Kaposi's sarcoma.

Ganciclovir resistance emerges in a minority of transplant patients, especially mismatched solid-organ recipients (Limaye et al., 2000), and is associated with poorer prognosis. The use of antithymocyte globulin and prolonged ganciclovir exposure are risk factors. Recovery of ganciclovir-resistant CMV isolates has been associated with progressive CMV disease in AIDS and other immunocompromised patients. Over one-quarter of retinitis patients have resistant isolates by 9 months of therapy, and resistant CMV has been recovered from CSF, vitreous fluid, and visceral sites.

A ganciclovir ophthalmic gel formulation (zirgan) is effective in treating HSV keratitis (Colin et al., 1997). Oral ganciclovir also reduces HBV DNA levels and aminotransferase levels in chronic hepatitis B virus infection (Hadziyannis et al., 1999), but the drug is not approved for this indication.

Inhibitory concentrations of idoxuridine for HSV-1 are 2-10 μg/mL, at least 10-fold higher than those of acyclovir. 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. Such altered DNA is more susceptible to breakage and also leads to faulty transcription. Resistance to idoxuridine develops readily in vitro and occurs in viral isolates recovered from idoxuridine-treated patients with HSV keratitis.

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. In ocular HSV infections, topical idoxuridine is more effective in epithelial infections, especially initial episodes, than in stromal infections. Adverse reactions include pain, pruritus, inflammation, and edema involving the eye or lids; rarely do allergic reactions occur.

Concentrations of trifluridine of 0.2-10 μg/mL inhibit replication of herpesviruses, including acyclovir-resistant strains. Trifluridine 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 with altered thymidine kinase substrate specificity can be selected in vitro, and resistance in clinical isolates has been described.

Trifluridine currently is approved in the U.S. 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, irritation, and superficial punctate or epithelial keratopathy are uncommon. Topical trifluridine also appears to be effective in some patients with acyclovir-resistant HSV cutaneous infections.

Absorption, Distribution, and Elimination. Amantadine and rimantadine are well absorbed after oral administration (Schmidt, 2004) (Table 58–3). Peak plasma concentrations of amantadine average 0.5-0.8 μg/mL on a 100-mg twice-daily regimen in healthy young adults. Comparable doses of rimantadine give peak and trough plasma concentrations of ~0.4-0.5 and 0.2-0.4 μg/mL, respectively. The elderly require only one-half the weight-adjusted dose of amantadine needed for young adults to achieve equivalent trough plasma levels of 0.3 μg/mL. Both drugs have very large volumes of distribution. Nasal secretion and salivary levels of amantadine approximate those found in the serum. Amantadine is excreted in breast milk. Rimantadine concentrations in nasal mucus average 50% higher than those in plasma.

Amantadine is excreted largely unmetabolized in the urine through glomerular filtration and probably tubular secretion. The plasma t_1/2 of elimination is ~12-18 hours in young adults. Because amantadine's elimination is highly dependent on renal function, the elimination t_1/2 increases up to 2-fold in the elderly and even more in those with renal impairment. Dose adjustments are advisable in those with mild decrements in renal function. In contrast, rimantadine is metabolized extensively by hydroxylation, conjugation, and glucuronidation prior to renal excretion. Following oral administration, the elimination t_1/2 of rimantadine averages 24-36 hours, and 60-90% is excreted in the urine as metabolites. Renal clearance of unchanged rimantadine is similar to creatinine clearance.

Untoward Effects. The most common side effects related to amantadine and rimantadine are minor dose-related CNS and gastrointestinal (Schmidt, 2004). These include nervousness, light-headedness, difficulty concentrating, insomnia, and loss of appetite or nausea. CNS side effects occur in 5-33% of 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. Amantadine dose reductions are required in older adults (100 mg/day) because of decreased renal function, but 20-40% of infirm elderly will experience side effects even at this lower dose. At comparable doses of 100 mg/day, rimantadine is significantly better tolerated in nursing home residents than amantadine (Keyser et al., 2000).

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. Amantadine is teratogenic in animals. Both drugs are considered pregnancy Category C because safety has not been established in pregnancy.

Therapeutic Uses. Seasonal prophylaxis with either amantadine or rimantadine (a total of 200 mg/day in one or two divided doses in young adults) is ~70-90% protective against influenza A illness.

Efficacy has been shown during pandemic influenza, in preventing nosocomial influenza, and in curtailing nosocomial outbreaks. Doses of 100 mg/day are better tolerated and still appear to be protective against influenzal illness. Postexposure prophylaxis with either drug provides protection of exposed family contacts if ill young children are not concurrently treated (Schmidt, 2004).

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 in adults and children if treatment is initiated within 2 days of the onset of symptoms (Schmidt, 2004). Therapy reduces duration of viral excretion, fever, and other systemic complaints, but resistance has become more widespread with use. Duration of illness is shortened by ~1 day. 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 (Schmidt, 2004). In children, rimantadine treatment may be associated with less illness and lower viral titers during the first 2 days of treatment, but rimantadine-treated children have more prolonged shedding of virus. 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 (Schmidt, 2004). Resistant variants also arise commonly in immunocompromised patients (Englund et al., 1998). Illnesses owing to apparent transmission of resistant virus associated with failure of drug prophylaxis have been documented in contacts of drug-treated ill persons in households and in nursing homes (Schmidt, 2004). Resistant variants appear to be pathogenic and can cause typical disabling influenza.

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. The utility of the amantadines has been limited by the development of resistance. Amantadine and rimantadine are active only against susceptible influenza A viruses (not influenza B); rimantadine is 4- to 10-fold more active than amantadine. Currently, virtually all H3N2 strains of influenza circulating worldwide are resistant to these drugs. Resistance to these drugs results from a mutation in the RNA sequence encoding for the M2 protein transmembrane domain (Schmidt, 2004), and resistant isolates typically appears in the treated patient within 2-3 days of starting therapy.

Influenza variants selected in vitro for resistance to oseltamivir carboxylate contain hemagglutinin and/or neuraminidase mutations. The most commonly recognized variants (mutations at positions 292 in N2 and 274 in N1 neuraminidases) have reduced infectivity and virulence in animal models. Outpatient oseltamivir therapy has been associated with recovery of resistant variants in ~0.5% of adults and 5.5% of children; a higher frequency (~18%) occurs in hospitalized children. Seasonal influenza A (H1N1) has become virtually 100% resistant to oseltamivir worldwide (Moscona, 2009; Schirmer and Holodniy, 2009). Importantly, novel H1N1 (nH1N1 or swine influenza) remains susceptible to oseltamivir.

Absorption, Distribution, and Elimination. Oral oseltamivir phosphate is absorbed rapidly (Table 58–3) and cleaved by esterases in the GI tract and liver to the active carboxylate. Low blood levels of the phosphate are detectable, but exposure is only 3-5% of that of the metabolite. The bioavailability of the carboxylate is estimated to be ~80%. The time to maximum plasma concentrations of the carboxylate is ~2.5-5 hours. Food does not decrease bioavailability but reduces the risk of GI intolerance. After 75-mg doses, peak plasma concentrations average 0.07 μg/mL for oseltamivir phosphate and 0.35 μg/mL for the carboxylate. The carboxylate has a volume of distribution similar to extracellular water. Bronchoalveolar lavage levels in animals and middle ear fluid and sinus concentrations in humans are comparable with plasma levels. Following oral administration, the plasma t_1/2 of oseltamivir phosphate is 1-3 hours; that of the carboxylate is 6-10 hours. Both the prodrug and active metabolite are eliminated primarily unchanged through the kidney. Probenecid doubles the plasma t_1/2 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 (Kimberlin et al., 2009).

Untoward Effects. Oral oseltamivir is associated with nausea, abdominal discomfort, and, less often, emesis, probably owing to local irritation. GI complaints usually are mild to moderate in intensity, typically resolve in 1-2 days despite continued dosing, and are preventable by administration with food. The frequency of such complaints is ~10-15% when oseltamivir is used for the treatment of influenza illness and <5% when used for prophylaxis. An increased frequency of headache was reported in one prophylaxis study in elderly adults.

Oseltamivir phosphate and the carboxylate do not interact with CYPs in vitro. Their binding to protein is low. No clinically significant drug interactions have been recognized to date. Oseltamivir does not appear to impair fertility or to be teratogenic in animal studies, but safety in pregnancy is uncertain (pregnancy Category C). Very high doses have been associated with increased mortality, perhaps related to increased brain concentrations, in unweaned rats.

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% (Whitley et al., 2001). Treatment is associated with approximate halving of the risk of subsequent hospitalization in adults (Kaiser et al., 2003). 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 (7-10 days) protects against influenza in household contacts (Schirmer and Holodniy, 2009).

Because of the global development of resistance of H1N1 seasonal influenza, treatment recommendations issued by the CDC for the 2008–2009 influenza season required the co-administration of an adamantine and a neuraminidase inhibitor. An intravenous formulation of oseltamivir is being evaluated in adults and children under the 2009 EUA. Until recently, oseltamivir was only licensed for patients >2 years of age; however, with the introduction of 2009 nH1N1, an EUA allows for therapy for all ages (Centers for Disease Control and Prevention, 2009).

In vitro selection of viruses resistant to zanamivir is associated with mutations in the viral hemagglutinin and/or neuraminidase. Hemagglutinin variants generally have mutations in or near the receptor binding site that make them less dependent on neuraminidase action for release from cells in vitro, although they typically retain susceptibility in vivo. 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. Resistance has not been documented in immunocompetent hosts to date but has been seen rarely in highly immunocompromised patients (Eiland and Eiland, 2007).

Absorption, Distribution, and Elimination. The oral bioavailability of zanamivir is low (<5%) (Table 58–3), 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%, and plasma levels after 10-mg inhaled doses average ~35-100 ng/mL in adults and children. Median zanamivir concentrations in induced sputum samples are 1336 ng/mL at 6 hours and 47 ng/mL at 24 hours after a single 10-mg dose in healthy volunteers. The plasma t_1/2 of zanamivir averages 2.5-5 hours after oral inhalation but only 1.7 hours following intravenous dosing. Over 90% is eliminated in the urine as the parent compound (Eiland and Eiland, 2007).

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. Tolerability in more serious bronchopulmonary disorders or in intubated patients is uncertain. Zanamivir is not generally recommended for treatment of patients with underlying airway disease (e.g., asthma or chronic obstructive pulmonary 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.

Therapeutic Uses. Inhaled zanamivir is effective for the prevention and treatment of influenza A and B virus infections.

Early zanamivir treatment (10 mg [two 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 (Eiland and Eiland, 2007) and in adults reduces by 40% the risk of lower respiratory tract complications leading to antibiotic use (Kaiser et al., 2000). Once-daily inhaled, but not intranasal, zanamivir is highly protective against community-acquired influenza illness, and when given for 10 days, it protects against household transmission (Eiland and Eiland, 2007). Intravenous zanamivir is protective against experimental human influenza and is being evaluated for the 2009 nH1N1 EUA.

Inhibition of protein synthesis is the major inhibitory effect for many viruses. IFN-induced proteins include 2′-5′-oligoadenylate [2-5(A)] synthetase and a protein kinase, either of which can inhibit protein synthesis in the presence of double-stranded RNA. The 2-5(A) synthetase produces adenylate oligomers that activate a latent cellular endoribonuclease (RNase L) to cleave both cellular and viral single-stranded RNAs. The protein kinase selectively phosphorylates and inactivates a protein involved in protein synthesis, eukaryotic initiation factor 2 (eIF-2). IFN-induced protein kinase also may be an important effector of apoptosis. In addition, IFN induces a phosphodiesterase that cleaves a portion of transfer RNA and thus prevents peptide elongation. 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 hepatitis C virus 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 (Biron, 2001). 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.

Absorption, Distribution, and Elimination. Oral administration does not result in detectable IFN levels in serum or increases in 2-5(A) synthetase activity in peripheral blood mononuclear cells (used as a marker of IFN's biologic activity). After intramuscular or subcutaneous injection of IFN-α, absorption exceeds 80%. Plasma levels are dose related, peaking at 4-8 hours and returning to baseline by 18-36 hours. Levels of 2-5(A) synthetase in peripheral blood mononuclear cells show increases beginning at 6 hours and lasting through 4 days after a single injection. An antiviral state in peripheral blood mononuclear cells peaks at 24 hours and decreases slowly to baseline by 6 days after injection. Intramuscular or subcutaneous injections of IFN-β result in negligible plasma levels, although increases in 2-5(A) synthetase levels may occur. 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 (Bocci, 1992). With subcutaneous or intramuscular dosing, the plasma t_1/2 of IFN-α ranges is variable, 3-8 hours. Elimination from the blood relates 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-α2B is reduced by ~80% in hemodialysis patients (Uchiharaa et al., 1998).

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 (Bruno et al., 2004). Two pegylated IFNs are available commercially: peginterferon alfa-2a (pegasys) and peginterferon alfa-2B (pegintron). PegIFN alfa-2B has a straight-chain 12,000-Da type of PEG that increases the plasma t_1/2 from ~2-3 hours to ~30-54 hours (Glue et al., 2000). PegIFN alfa-2a consists of an ester derivative of a branched-chain 40,000-Da PEG bonded to IFN-α2A and has a plasma t_1/2 averaging ~80-90 hours. PegIFN alfa-2A is more stable and dispensed in solution, whereas pegIFN alfa-2B requires reconstitution prior to use. For pegIFN alfa-2A, peak serum concentrations occur up to 120 hours after dosing and remain detectable throughout the weekly dosing interval (Bruno et al., 2004); steady-state levels occur 5-8 weeks after initiation of weekly dosing (Keating and Curran, 2003). For pegIFN alfa-2A, dose-related maximum plasma concentrations occur at 15-44 hours after dosing and decline by 96-168 hours. These differences in pharmacokinetics may be associated with differences in antiviral effects (Bruno et al., 2004). Increasing PEG size is associated with longer t_1/2 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 to 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 hours. 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.

The principal dose-limiting toxicities of systemic IFN are depression, myelosuppression with granulocytopenia and thrombocytopenia; neurotoxicity manifested by somnolence, confusion, behavioral disturbance, and rarely, seizures; debilitating neurasthenia and depression; autoimmune disorders including thyroiditis and hypothroidism; and uncommonly, cardiovascular effects with hypotension and tachycardia. The risk of depression appears to be higher in chronically infected HCV than in HBV patients (Marcellin et al., 2004). 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 (Sokal et al., 1998). The development of serum neutralizing antibodies to exogenous IFNs may be associated infrequently with loss of clinical responsiveness. IFN may impair fertility, and 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 generally 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. Laboratory abnormalities, including severe neutropenia and the need for dose modifications, are higher in HIV-co-infected persons.

Therapeutic Uses. Recombinant, natural, and pegylated IFNs currently are approved in the U.S., depending on the specific IFN type, for treatment of condyloma acuminatum, chronic HCV infection, chronic HBV infection, Kaposi's 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 loss of HBV DNA, loss of HBeAg and development of anti-HBe antibody, and biochemical and histological improvement in ~25-50% of the patients.

Lasting responses require moderately high IFN doses and prolonged administration (typically 5 MU/day or 10 MU in adults and 6 MU/m² in children three times per week of IFNα-2B for 4 to 6 weeks) (Sokal et al., 1998). Plasma HBV DNA and polymerase activity decline promptly in most patients, but complete disappearance is sustained in only about one-third of patients or less. Low pretherapy serum HBV DNA levels and high aminotransferase levels are predictors of response. Sustained responses are infrequent in those with vertically acquired infection, anti-HBe positivity, or concurrent immunosuppression owing to HIV. PegIFN alfa-2A appears superior to conventional IFN alfa-2A in HbeAg-positive patients (Cooksley et al., 2003), and treatment (180 μg once weekly for 24-48 weeks) is associated with normalization of aminotransferases in ~60% and sustained viral suppression in ~20% of HBeAg-negative patients (Marcellin et al., 2004). Responses with seroconversion to anti-HBe usually are associated with aminotransferase elevations and often a hepatitis-like illness during the second or third month of therapy, likely related to immune clearance of infected hepatocytes. High-dose IFN can cause myelosuppression and clinical deterioration in those with decompensated liver disease.

Remissions in chronic hepatitis B induced by IFN are sustained in >80% of patients treated and frequently are followed by loss of HBV surface antigen (HbsAg), histological improvement or stabilization, and reduced risk of liver-related complications and mortality (Lau et al., 1997). IFN may benefit some patients with nephrotic syndrome and glomerulonephritis owing to chronic HBV infection. 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 three times a week) is associated with an approximate 50-70% rate of aminotransferase normalization and loss of plasma viral RNA, but relapse rates are high, and sustained virologic remission (absence of detectable HCV RNA) 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 (Coverdale et al., 2004). Viral genotype and pretreatment RNA level influence response to treatment, but early viral clearance is the best predictor of sustained response. Failure to achieve an early viral response (nondetectable HCV RNA or reduction ≥2 log₁₀ units compared with baseline at 12 weeks) predicts lack of sustained viral response with continued treatment (Seeff and Hoofnagle, 2002). 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 (Alberti et al., 2002).

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 (weight-adjusted doses of 1.5 μg/kg/week for 1 year) is associated with sustained response in 30-39%, including stable cirrhotic patients (Heathcote et al., 2000), and it is a treatment option in patients unable to take ribavirin. Studies of prolonged (4 years) maintenance monotherapy with pegylated IFNs are in progress for those not responding to IFN-ribavirin combinations. A large randomized comparison of pegIFN alfa-2A versus alfa-2B combined with ribavirin found no difference in response rates (McHutchison et al., 2009).

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 in previously untreated patients (Fried et al., 2002). A shorter duration of therapy (24 weeks) and lower ribavirin dose (800 mg/day) are effective in genotype 2 and 3 infections, but prolonged therapy and higher ribavirin doses are needed for genotype 1 and 4 infections (Hadziyannis et al., 2004). Approximately 15-20% of those failing to respond to combined IFN-ribavirin will have sustained responses to combined pegIFN-ribavirin. Histological improvement may occur in patients who do not achieve sustained viral responses. In patients with compensated cirrhosis, treatment may reverse cirrhotic changes and possibly reduce the risk of hepatocellular carcinoma (Poynard et al., 2002).

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 (Wiley et al., 2002). 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 three 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 in vitro. 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. Systemically administered IFN-α may be beneficial in early treatment of SARS (Loutfy et al., 2003).

Emergence of viral resistance to ribavirin has not been documented in most viruses but has been reported in Sindbis and HCV (Young et al., 2003); it has been possible to select cells that do not phosphorylate ribavirin to its active forms.

Absorption, Distribution, and Elimination. Ribavirin is actively taken up by nucleoside transporters in the proximal small bowel; oral bioavailability averages ~50% (Glue, 1999). Extensive accumulation occurs in plasma, and steady state is reached by ~4 weeks. Food increases plasma levels substantially (Glue, 1999). Following single or multiple oral doses of 600 mg, peak plasma concentrations average ~0.8 and 3.7 μg/mL, respectively. After intravenous doses of 1000 and 500 mg, plasma concentrations average ~24 and 17 μg/mL, respectively. With aerosol administration, plasma levels increase with the duration of exposure and range from 0.2 to 1.0 μg/mL after 5 days (Englund et al., 1990). Levels in respiratory secretions are much higher but vary up to 1000-fold.

The apparent volume of distribution for ribavirin is large (~10 L/kg) owing to its cellular uptake. Plasma protein binding is negligible. The elimination of ribavirin is complex. The plasma t_1/2 increases to ~200-300 hours at steady state. Erythrocytes concentrate ribavirin triphosphate; the drug exits red cells gradually, with a t_1/2 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 clearance decreases by two-thirds in those with advanced renal insufficiency (Cl_cr = 10-30 mL/minute); the drug should be used cautiously in patients with creatinine clearances of <50 mL/minute (Glue, 1999).

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.

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. High ribavirin triphosphate levels may cause oxidative damage to membranes, leading to erythrophagocytosis by the reticuloendothelial system. 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 (Glue, 1999). Bolus intravenous infusion may cause rigors.

Pregnant women should not directly care for patients receiving ribavirin aerosol (FDA pregnancy Category X).

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 (Chapter 59).

Therapeutic Uses. Oral ribavirin in combination with injected pegIFN alfa-2A or -2B has become standard treatment for chronic HCV infection (Reddy et al., 2009; Seeff and Hoofnagle, 2002).

Ribavirin monotherapy for 6-12 months reversibly decreases aminotransferase elevations to normal in ~30% of patients but does not affect HCV RNA levels. Combination therapy with pegIFN alfa-2A and oral ribavirin (500 mg, or 600 mg if weight is >75 kg, twice daily for 24-48 weeks) increases the likelihood of sustained biochemical and virologic responses to ~56% depending on genotype (Fried et al., 2002). The combination is superior to IFN or pegIFN monotherapy and combinations of pegIFN alfa-2 and ribavirin in both treatment-naive patients and those not responding to, or relapsing after, IFN monotherapy. A longer duration of therapy (48 weeks) appears necessary in those with genotype 1 infections, whereas 24 weeks' therapy is adequate in genotype 2 and 3 infections (Hadziyannis et al., 2004). Combined ribavirin and pegIFN alfa-2A or -2B is effective in achieving sustained viral responses in a minority of HCV/HIV co-infected patients (Reddy et al., 2009). Combined therapy has been used in the management of recurrent HCV infection after liver transplantation.

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 18 hours' exposure per day for 3-7 days) may reduce some illness measures, but its use generally is not recommended (Committee on Infectious Diseases, American Academy of Pediatrics, 2003). No consistent beneficial effects on duration of hospitalization, ventilatory support, mortality, or long-term pulmonary function have been found. High-dose, reduced-duration therapy (60 mg/mL in the drug reservoir of the small particle aerosol generator unit for 2 hours three times daily) has been used. Aerosol ribavirin combined with intravenous immunoglobulin appears to reduce mortality of RSV infection in bone marrow transplant and other highly immunocompromised patients (Ghosh et al., 2000).

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. Oral ribavirin has been used for the treatment and prevention of Crimean-Congo hemorrhagic fever and treatment of Nipah virus infections (Mardani et al., 2003). Intravenous ribavirin is investigational in the U.S.

Absorption, Distribution, and Elimination. The parent compound has low oral bioavailability (<12%), whereas the dipivoxil prodrug is absorbed rapidly and hydrolyzed by esterases in the intestine and blood to adefovir with liberation of pivalic acid, providing a bioavailability ~30-60%. After 10-mg doses of the pro-drug, peak serum concentrations of adefovir average 0.02 μg/mL, and the pro-drug is not detectable. Food does not affect bioavailability. Adefovir is scantily protein bound (<5%) and has a volume of distribution similar to body water (~0.4 L/kg).

Adefovir is eliminated unchanged by renal excretion through a combination of glomerular filtration and tubular secretion. After oral administration of adefovir dipivoxil, ~30-45% of the dose is recovered within 24 hours; the serum t_1/2 of elimination is 5-7.5 hours. Dose reductions are recommended for Cl_Cr values <50 mL/minute. Adefovir is removed by hemodialysis, but the effects of peritoneal dialysis or severe hepatic insufficiency on pharmacokinetics are unknown.

Pivalic acid is a product of adefovir dipivoxil metabolism that can cause reduced free carnitine levels. Although l-carnitine has been given in some investigational HIV studies of adefovir, supplementation generally is not recommended at the doses used in chronic HBV infection.

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 lower dose (10 mg/day) used in chronic HBV infection patients has been associated with few adverse events (e.g., headache, abdominal discomfort, diarrhea, and asthenia) and negligible renal toxicity compared with a 3-fold higher dose (Hadziyannis et al., 2003; Marcellin et al., 2003). Adverse events lead to premature discontinuation in ~2% of patients. After 2 years of dosing, the risk of serum creatinine levels rising above 0.5 mg/dL is ~2% but is higher in those with preexisting renal insufficiency. Acute, sometimes severe exacerbations of hepatitis can occur in patients stopping adefovir or other anti-HBV therapies. Close monitoring is necessary, and resumption of antiviral therapy may be required in some patients.

No clinically important drug interactions have been recognized to date, although drugs that reduce renal function or compete for active tubular secretion 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).

Adefovir is genotoxic, and high doses cause hepatotoxicity, lymphoid toxicity, and renal tubular nephropathy in animals. The diphosphate's inhibitory effects on renal adenylyl cyclase may contribute to nephrotoxicity. 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).

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 (Marcellin et al., 2003). Continued therapy is associated with increasing frequencies of aminotransferase normalization and HbeAg seroconversion (De Clercq, 2003). In patients with HbeAg-negative chronic HBV, adefovir is associated with similar biochemical and histological benefits (Hadziyannis et al., 2003). 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, but lamivudine alone or added to adefovir is not beneficial (Peters et al., 2004). In patients with dual HIV and lamivudine-resistant HBV infections, adefovir dipivoxil (10 mg/day) causes significant HBV DNA level reductions (Benhamou et al., 2001), and it also has been used successfully in patients with lamivudine-resistant HBV infections both before and following liver transplantation. The optimal duration of treatment in different populations, possible long-term effects on HBV complications, and combined use with other anti-HBV agents are under study.

Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ. The inhibitory concentration against HBV is 0.004 μM in transfected cells and ranges from 0.01 to 0.059 μM against lamivudine-resistant (L180M, M204V) HBV. Eight- to 30-fold reductions in entecavir susceptibility were observed for lamivudine-resistant strains in cell-based assays (Scott and Keating, 2009).

Entecavir selected for an M184I substitution in HIV reverse transcriptase at μM concentrations in cell culture, and HIV variants containing the M184V substitution showed loss of susceptibility to entecavir. In patients, entecavir decreased HIV-1 RNA in three persons with HIV-1 and HBV co-infection and led to HIV-1 variants with the M184V lamivudine-resistant mutation in one subject (McMahon et al., 2007). Lamivudine and telbivudine resistance confers decreased susceptibility to entecavir. In patients with preexisting lamivudine resistance, entecavir resistance emerged in 7% and 43% after 1 and 4 years, respectively (Dienstag, 2009).

Absorption, Distribution, and Elimination. Following multiple daily doses ranging from 0.1 to 1.0 mg, C_max and area under the concentration-time curve (AUC) at steady-state increased in proportion to dose. Time to peak occurs in 0.5-1.5 hours. Steady-state is reached after 6-10 days of once daily dosing. The tablet and oral solution can be used interchangeably. Administration with food decreases C_max by 44-46% and AUC by 18-20%; thus entecavir should be administered on an empty stomach.

Entecavir is extensively distributed in tissues and is 13% bound to serum proteins. It is primarily eliminated unchanged in the kidney. Renal clearance is independent of dose and ranges from 360 to 471 mL/minute, suggesting that entecavir undergoes both glomerular filtration and net tubular secretion. Entecavir exhibits biphasic elimination, with a terminal t_1/2 of 128-149 hours; the active triphosphate has an elimination t_1/2 of 15 hours. Dose reductions are needed for patients with Cl_Cr <50 mL/minute, typically by extension of the dosing interval (Scott and Keating, 2009).

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 at least 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 co-infection especially if HIV is not being treated. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported, mostly in women with some antiretroviral nucleoside analogs (Chapter 59), but not with entecavir. Other common adverse reactions include headache, fatigue, dizziness, and nausea (Scott and Keating, 2009).

The recommended dose for nucleoside-treatment-naive adults (>16 years of age) 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 (Dienstag, 2009). Durability of HBeAg responses is comparable to other oral agents. Entecavir had negligible resistance (≤1%) for up to 4 years and is active against adefovir-resistant HBV.

Oral lamivudine is active in animal models of hepadnavirus infection. Lamivudine shows enhanced antiviral activity in combination with adefovir or penciclovir against hepadnaviruses. Point mutations in the YMDD motif of HBV DNA polymerase result in a 40- to 104-fold reduction in in vitro susceptibility (Ono et al., 2001). Lamivudine resistance confers cross-resistance to related agents such as emtricitabine and the investigational agent, clevudine, 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 (Ono et al., 2001). Viruses bearing YMDD mutations are less replication competent in vitro 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 (Dienstag et al., 2003; Lai et al., 2002).

Absorption, Distribution, and Elimination. The pharmacokinetic properties of lamivudine are described in detail in Chapter 59. In HBV-infected children, doses of 3 mg/kg/day provide plasma exposure and trough plasma levels comparable with those in adults receiving 100 mg daily (Sokal et al., 2000). Dose reductions are indicated for moderate renal insufficiency (creatinine clearance <50 mL/minute). Trimethoprim decreases the renal clearance of lamivudine.

Untoward Effects. At the doses used for chronic HBV infection, lamivudine generally has been well tolerated. Aminotransferase rises after therapy occur more often in lamivudine recipients, and flares in post-treatment aminotransferase elevations (>500 IU/mL) occur in ~15% of patients after cessation.

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 in ≥41% of patients, and reductions in hepatic inflammation in >50% of patients (Dienstag et al., 1999; Lai et al., 2002). Seroconversion with antibody to HbeAg occurs in <20% of recipients at 1 year. In children 2-17 years of age, lamivudine (3 mg/kg/day to a maximum of 100 mg/day for 1 year) is associated with normalization of aminotransferase levels in about one-half and seroconversion to anti-Hbe in about one-fifth of cases (Jonas et al., 2002). In those without emergence of resistant variants, prolonged therapy is associated with sustained suppression of HBV DNA, continued histological improvement, and an increased proportion of patients experiencing a virological response (loss of HbeAg and undetectable HBV DNA). Prolonged therapy is associated with an approximate halving of the risk of clinical progression and development of hepatocellular carcinoma in those with advanced fibrosis or cirrhosis (Liaw et al., 2004). However, the frequency of lamivudine-resistant variants increases progressively with continued drug administration, reaching 67% after 4 years of treatment (Liaw et al., 2004). The risk of resistance development is higher after transplantation and in HIV/HBV co-infected patients.

Combined use of IFN or pegIFN alfa-2A with lamivudine has not improved responses in HBeAg-positive patients consistently. The addition of lamivudine to pegINF alfa-2A for 1 year of therapy does not improve post-treatment response rates in HBeAg-negative patients (Marcellin et al., 2004). In HIV and HBV co-infections, 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.

In cell-based assays, lamivudine-resistant HBV strains expressing either the M204I substitution or the L180M/M204V double substitution had ≥1000-fold reduced susceptibility. Telbivudine retained wild-type phenotypic activity against the lamivudine resistance– associated substitution M204V alone. HBV encoding the adefovir mutation A181V showed 3- to 5-fold reduced susceptibility, but N236T remained susceptible. The A181S and A181T substitutions conferred 2.7- and 3.5-fold reductions in susceptibility to telbivudine, respectively. The A181T substitution is associated with decreased clinical response in patients with HBV treated with adefovir and entecavir (Hadziyannis and Vassilopoulos, 2008).

In a cell culture model, the EC₅₀ for inhibition of viral DNA synthesis by telbivudine was 0.2 μM. The anti-HBV activity of telbivudine is additive with that of adefovir in cell culture, and it is not antagonized by the HIV-1 nucleoside analogs didanosine and stavudine (Hadziyannis and Vassilopoulos, 2008).

Absorption, Distribution, and Elimination. At 600 mg once daily, steady-state peak concentrations are ~3.7 μg/mL at a median of 2 hours post-dose. Steady state is achieved after ~5-7 days of once-daily administration with ~1.5-fold accumulation. In vitro protein binding is low (3.3%) and telbivudine is widely distributed into tissues. Telbivudine concentrations decline biexponentially with an elimination t_1/2 of 40-49 hours. The drug is eliminated unchanged in the urine. Patients with moderate-to-severe renal dysfunction and those undergoing hemodialysis 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. Elevations of creatine kinase activity, mostly asymptomatic grade 3-4, were more common in telbivudine-treated patients after 2 years of therapy than with lamivudine.

Therapeutic Uses. Similar to other oral HBV agents, 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. This dose is based on pharmacodynamic analyses showing a relationship between telbivudine dose and changes in HBV DNA from baseline to week 4 (Lai et al., 2004). The dose producing the maximum effect was between 400 and 800 mg/day. The drug has not been studied in patients with HBV/HIV co-infection. Telbivudine resistance is substantial (25%) after 2 years of treatment and higher than observed with other oral anti-HBV agents (Dienstag, 2009; Hadziyannis and Vassilopoulos, 2008). Cross-resistance and treatment-emergent resistance have limited the use of telbivudine for patients with chronic HBV, compared to alternative agents.

In in vitro cell cultures, the EC₅₀ for tenofovir against HBV ranged from 0.14 to 1.5 μM, with cytotoxicity concentrations >100 μM. No antagonistic activity was observed when combined with other oral anti-HBV agents. In cell-based assays, mutant HBV (V173L, L180M, and M204I/V) associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir of 0.7-3.4 times that of wild-type virus. Overall, tenofovir has a favorable resistance profile and has been effective in treating lamivudine-resistant HBV (Dienstag, 2009).

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 suppressed HBV DNA to <400 copies/mL in 93% of subjects at 48 weeks, compared to 63% for adefovir. Tenofovir resistance was not evident over 48 weeks of treatment. Due to the safety, efficacy, and resistance profile of tenofovir, it will likely supersede most adefovir use for the treatment of chronic HBV infection.

The tenofovir dose should be adjusted for impaired renal function: For Cl_cr of 30-49 mL/minute, 300 mg every 48 hours; 10-29 mL/minute, 300 mg every 72-96 hours. During hemodialysis the dose is 300 mg every 7 days or after 12 hours of dialysis.

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 shows antiviral activity in animal models after systemic or topical administration. When applied topically as a 5% cream to genital warts in humans, it induces local IFN-α, -β, and -γ and TNFα responses and causes reductions in viral load and wart size. When applied topically (three times weekly for up to 16 weeks), imiquimod cream is associated with complete clearance of treated genital and perianal warts in ~50% of patients, with response rates higher in women than in men (Skinner, 2003; Wiley et al., 2002). The median time to clearance is 8-10 weeks; relapses are not uncommon. Application is associated with local erythema in ~20% of patients, excoriation/flaking in 18-26%, itching in 10-20%, burning in 5-12%, and less often, erosions or ulcerations.