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​The field of antiviral therapy—both the number of antiviral drugs and our understanding of their optimal use— continues to lag behind the field of antibacterial drug treatment, in which >70 years of experience have now been accumulated, but significant progress has been made in recent years on new drugs for several viral infections. The development of antiviral drugs poses several challenges.Viruses replicate intracellularly and often employ host cell enzymes, macromolecules, and organelles for synthesis of viral particles.Therefore, useful antiviral compounds must discriminate between host and viral functions with a high degree of specificity; agents without such selectivity are likely to be too toxic for clinical use. The development of laboratory assays to assist clinicians in the appropriate use of antiviral drugs is also in its early stages.


Phenotypic and genotypic assays for resistance to antiviral drugs are becoming more widely available, and correlations of laboratory results with clinical outcomes in various settings are beginning to be defined. Of particular note has been the development of highly sensitive and specific methods that measure the concentration of virus in blood (virus load) and permit direct assessment of the antiviral effect of a given drug regimen in that compartment in the host. Virus load measurements have been useful in recognizing the risk of disease progression in patients with certain viral infections and in identifying patients to whom antiviral chemotherapy might be of greatest benefit. Like any in vitro laboratory test, these tests yield results that are highly dependent on (and likely to vary with) the laboratory techniques employed. Information regarding the pharmacokinetics of some antiviral drugs, particularly in diverse clinical settings, is limited. Assays to measure the concentrations of these drugs, especially of their active moieties within cells, are primarily research procedures and are not widely available to clinicians.Thus there are relatively few guidelines for adjusting dosages of antiviral agents to maximize antiviral activity and minimize toxicity.


Consequently, clinical use of antiviral drugs must be accompanied by particular vigilance with regard to unanticipated adverse effects. Like that of other infections, the course of viral infections is profoundly affected by an interplay of the pathogen with a complex set of host defenses. The presence or absence of preexisting immunity, the ability to mount humoral and/or cell-mediated immune responses, and the stimulation of innate immunity are important determinants of the outcome of viral infections. The state of the host’s defenses needs to be considered when antiviral agents are used or evaluated. As with any therapy, the optimal use of antiviral compounds requires a specific and timely diagnosis. For some viral infections, such as herpes zoster, the clinical manifestations are so characteristic that a diagnosis can be made on clinical grounds alone. For other viral infections, such as influenza A, epidemiologic information (e.g., the documentation of a community-wide outbreak) can be used to make a presumptive diagnosis with a high degree of accuracy. However, for most other viral infections, including herpes simplex encephalitis, cytomegaloviral infections other than retinitis, and enteroviral infections, diagnosis on clinical grounds alone cannot be accomplished with certainty. For such infections, rapid viral diagnostic techniques are of great importance. Considerable progress has been made in recent years in the development of such tests, which are now widely available for a number of viral infections. Despite these complexities, the efficacy of a number of antiviral compounds has been clearly established in rigorously conducted and controlled studies. As summarized in Table 79-1, this chapter reviews the antiviral drugs that are currently approved or are likely to be considered for approval in the near future for use against viral infections other than those caused by HIV. Antiretroviral drugs are reviewed in Chap. 90.


ANTIVIRAL DRUGS ACTIVE AGAINST RESPIRATORY INFECTIONS ZANAMIVIR AND OSELTAMIVIR

Zanamivir and oseltamivir are inhibitors of the influenza viral neuraminidase enzyme, which is essential for release of the virus from infected cells and for its subsequent spread throughout the respiratory tract of the infected host. The enzyme cleaves terminal sialic acid residues and thus destroys the cellular receptors to which the viral hemagglutinin attaches. Zanamivir and oseltamivir are sialic acid transition-state analogues and are highly active and specific inhibitors of the neuraminidases of both influenza A and B viruses.The antineuraminidase activity of the two drugs is similar, although zanamivir has somewhat greater in vitro activity against influenza B. Both zanamivir and oseltamivir act through competitive and reversible inhibition of the active site of influenza A and B viral neuraminidases and have relatively little effect on mammalian cell enzymes. Oseltamivir phosphate is an ethyl ester prodrug that is converted to oseltamivir carboxylate by esterases in the liver. Orally administered oseltamivir has a bioavailability of >60% and a plasma half-life of 7–9 h. The drug is excreted unmetabolized, primarily by the kidneys.


Zanamivir has low oral bioavailability and is administered orally via a hand-held inhaler. By this route, ~15% of the dose is deposited in the lower respiratory tract, and low plasma levels of the drug are detected. Orally inhaled zanamivir is generally well tolerated, although exacerbations of asthma may occur.The toxicities most frequently encountered with orally administered oseltamivir are nausea, gastrointestinal discomfort, and (less commonly) vomiting. Gastrointestinal discomfort is usually transient and is less likely if the drug is administered with food. Recently, neuropsychiatric events (delirium, self-injury) have been reported in children who have been taking oseltamivir, primarily in Japan. Inhaled zanamivir and orally administered oseltamivir have been effective in the treatment of naturally occurring influenza A or B in otherwise-healthy adults. In placebo-controlled studies, illness has been shortened by 1.0–1.5 days of therapy with either of these drugs when treatment is administered within 2 days of onset.A recent meta-analysis of clinical studies of oseltamivir suggests that treatment may reduce the likelihood of certain respiratory tract complications of influenza. Once-daily inhaled zanamivir or once-daily orally administered oseltamivir provides effective prophylaxis against laboratory-documented influenza A– and influenza B–associated illness.


The emergence of viruses resistant to zanamivir or oseltamivir occurs but appears to be less frequent than the emergence of resistance to the adamantanes in clinical studies carried out thus far. In one pediatric study, 5.5% of patients treated with oseltamivir developed resistant isolates. A somewhat higher rate of resistance was noted in a recent pediatric study of oseltamivir from Japan. Resistance to the neuraminidase inhibitors may develop by changes in the viral neuraminidase enzyme, by changes in the hemagglutinin that make it more resistant to the actions of the neuraminidase, or by both mechanisms. Some isolates that are resistant to oseltamivir may remain sensitive to zanamivir. Since the mechanisms of action of the neuraminidase inhibitors differ from those of the adamantanes (see below), zanamivir and oseltamivir are active against strains of influenza A virus that are resistant to amantadine and rimantadine. Zanamivir and oseltamivir have been approved by the U.S.Food and Drug Administration (FDA) for treatment of influenza in adults and in children (those ≥7 years old for zanamivir and those ≥1 year old for oseltamivir) who have been symptomatic for ≤2 days. Oseltamivir is approved for prophylaxis of influenza in individuals ≥1 year of age and zanamivir for those ≥5 years of age (Table 79-1).


AMANTADINE AND RIMANTADINE

Amantadine and the closely related compound rimantadine are primary symmetric amines that display antiviral activity limited to influenza A viruses. Amantadine and rimantadine have been shown to be efficacious in the prophylaxis and treatment of influenza A infections in humans for >40 years. High frequencies of resistance to these drugs were noted among influenza A/H3N2 viruses in the 2005–2006 influenza season and continue to be seen up to the present (2006–2007). Therefore, these agents are no longer recommended unless the sensitivity of the individual influenza A isolate is known, in which case their use may be considered. Amantadine and rimantadine act through inhibition of the ion channel function of the influenza A M2 matrix protein, on which appropriate uncoating of the virus depends. A substitution of a single amino acid at critical sites in the M2 protein can result in a virus that is resistant to amantadine and rimantadine.


Amantadine and rimantadine have been shown to be effective in the prophylaxis of influenza A in large-scale studies of young adults and in less extensive studies of children and elderly persons. In such studies, efficacy rates of 55–80% in the prevention of influenza-like illness were noted, and even higher rates were reported when virus-specific attack rates were calculated. Amantadine and rimantadine have also been found to be effective in the treatment of influenza A infection in studies involving predominantly young adults and, to a lesser extent, children. Administration of these compounds within 24–72 h after the onset of illness has resulted in a reduction of the duration of signs and symptoms by ~50% from that in placebo recipients.The effect on signs and symptoms of illness is superior to that of commonly used antipyretic-analgesic agents. Only anecdotal reports are available concerning the efficacy of amantadine or rimantadine in the prevention or treatment of complications of influenza (e.g., pneumonia).


Amantadine and rimantadine are available only in oral formulations and are ordinarily administered to adults once or twice daily, with a dosage of 100–200 mg/d. Despite their structural similarities, the two compounds have different pharmacokinetics.Amantadine is not metabolized and is excreted almost entirely by the kidney, with a half-life of 12–17 h and peak plasma concentrations of 0.4 ìg/mL. In contrast, rimantadine is extensively metabolized to hydroxylated derivatives and has a half-life of 30 h. Only 30–40% of an orally administered dose of rimantadine is recovered in the urine. The peak plasma levels of rimantadine are approximately half those of amantadine, but rimantadine is concentrated in respiratory secretions to a greater extent than amantadine. For prophylaxis, the compounds must be administered daily for the period at risk (i.e., the peak duration of the outbreak). For therapy, amantadine or rimantadine is generally administered for 5–7 days.


Although these compounds are generally well tolerated, 5–10% of amantadine recipients experience mild central nervous system side effects consisting primarily of dizziness, anxiety, insomnia, and difficulty in concentrating. These effects are rapidly reversible upon cessation of the drug’s administration.At a dose of 200 mg/d, rimantadine is better tolerated than amantadine; in a large-scale study of young adults, adverse effects were no more frequent among rimantadine recipients than among placebo recipients. Seizures and worsening of congestive heart failure have also been reported in patients treated with amantadine, although a causal relationship has not been established. The dosage of amantadine should be reduced to 100 mg/d in patients with renal insufficiency [i.e., a creatinine clearance rate (CrCl) of <50 mL/min] and in the elderly.A rimantadine dose of 100 mg/d should be used for patients with a CrCl of <10 mL/min and in the elderly.


RIBAVIRIN

Ribavirin is a synthetic nucleoside analogue that inhibits a wide range of RNA and DNA viruses.The mechanism of action of ribavirin is not completely defined and may be different for different groups of viruses. Ribavirin- 5′-monophosphate blocks the conversion of inosine- 5′-monophosphate to xanthosine-5′-monophosphate and interferes with the synthesis of guanine nucleotides as well as that of both RNA and DNA. Ribavirin- 5′-monophosphate also inhibits capping of virus-specific messenger RNA in certain viral systems. In studies demonstrating the effectiveness of ribavirin in the treatment of respiratory syncytial virus (RSV) infection in infants, the compound was administered as a small-particle aerosol. In infants with RSV infection who were given ribavirin by continuous aerosol for 3–6 days, illness and lower respiratory tract signs resolved more rapidly and arterial oxygen desaturation was less pronounced than in placebo-treated groups. In addition, ribavirin has had a beneficial clinical effect in infants with RSV infection who require mechanical ventilation. Aerosolized ribavirin has also been administered to older children and adults with severe RSV and parainfluenza virus infections (including immunosuppressed patients) and to older children and adults with influenza A or B infection, but the benefit of this treatment, if any, is unclear. In RSV infections in immunosuppressed patients, ribavirin is often given in combination with immunoglobulins.


Orally administered ribavirin has not been effective in the treatment of influenza A virus infections. IV or oral ribavirin has reduced mortality rates among patients with Lassa fever; it has been particularly effective in this regard when given within the first 6 days of illness. IV ribavirin has been reported to be of clinical benefit in the treatment of hemorrhagic fever with renal syndrome caused by Hantaan virus and as therapy for Argentinian hemorrhagic fever. Moreover, oral ribavirin has been recommended for the treatment and prophylaxis of Congo-Crimean hemorrhagic fever. An open-label trial suggested that oral ribavirin may be beneficial in the treatment of Nipah virus encephalitis. Use of IV ribavirin in patients with hantavirus pulmonary syndrome in the United States has not been associated with clearcut benefits. Oral administration of ribavirin reduces serum aminotransferase levels in patients with chronic hepatitis C virus (HCV) infection; since it appears not to reduce serum HCV RNA levels, the mechanism of this effect is unclear. The drug provides added benefit when given by mouth in doses of 800–1200 mg/d in combination with interferon (IFN) á2b or á2a (see below), and the ribavirin/IFN combination has been approved for the treatment of patients with chronic HCV infection.


Large doses of ribavirin (800–1000 mg/d PO) have been associated with reversible hematopoietic toxicity.This effect has not been observed with aerosolized ribavirin, apparently because little drug is absorbed systemically. Aerosolized administration of ribavirin is generally well tolerated but occasionally is associated with bronchospasm, rash, or conjunctival irritation. Aerosolized ribavirin has been approved for treatment of RSV infection in infants and should be administered under close supervision— particularly in the setting of mechanical ventilation, where precipitation of the drug is possible. Health care workers exposed to the drug have experienced minor toxicity, including eye and respiratory tract irritation. Because ribavirin is mutagenic, teratogenic, and embryotoxic, its use is generally contraindicated in pregnancy. Its administration as an aerosol poses a risk to pregnant health care workers.


ANTIVIRAL DRUGS ACTIVE AGAINST HERPESVIRUS INFECTIONS ACYCLOVIR AND VALACYCLOVIR

Acyclovir is a highly potent and selective inhibitor of the replication of certain herpesviruses, including herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). It is relatively ineffective in the treatment of human cytomegalovirus (CMV) infections; however, some studies have indicated its effectiveness in the prevention of CMV-associated disease in immunosuppressed patients. Valacyclovir, the L-valyl ester of acyclovir, is converted almost entirely to acyclovir by intestinal and hepatic hydrolysis after oral administration.Valacyclovir has pharmacokinetic advantages over orally administered acyclovir: it exhibits significantly greater oral bioavailability, results in higher blood levels, and can be given less frequently than acyclovir (two or three rather than five times daily). The high degree of selectivity of acyclovir is related to its mechanism of action, which requires that the compound first be phosphorylated to acyclovir monophosphate. This phosphorylation occurs efficiently in herpesvirusinfected cells by means of a virus-coded thymidine kinase. In uninfected mammalian cells, little phosphorylation of acyclovir occurs, and the drug is therefore concentrated in herpesvirus-infected cells.Acyclovir monophosphate is subsequently converted by host cell kinases to a triphosphate that is a potent inhibitor of virus-induced DNA polymerase but has relatively little effect on host-cell DNA polymerase. Acyclovir triphosphate can also be incorporated into viral DNA,with early chain termination. Acyclovir is available in IV, oral, and topical forms, whereas valacyclovir is available in an oral formulation.


IV acyclovir is markedly effective in the treatment of mucocutaneous HSV infections in immunocompromised hosts, in whom it reduces time to healing, duration of pain, and virus shedding. When administered prophylactically during periods of intense immunosuppression (e.g., related to chemotherapy for leukemia or transplantation) and before the development of lesions, IV acyclovir reduces the frequency of HSV-associated disease.After prophylaxis is discontinued, HSV lesions recur. IV acyclovir is also effective in the treatment of HSV encephalitis; two comparative trials have indicated that acyclovir is more effective than vidarabine for this indication (see below). Because VZV is generally less sensitive to acyclovir than is HSV, higher doses of acyclovir must be used to treat VZV infections. In immunocompromised patients with herpes zoster, IV acyclovir reduces the frequency of cutaneous dissemination and visceral complications and—in one comparative trial—was more effective than vidarabine. Acyclovir, administered at doses of 800 mg PO five times a day, had a modest beneficial effect on localized herpes zoster lesions in both immunocompromised and immunocompetent patients. Combination of acyclovir with a tapering regimen of prednisone appeared to be more effective than acyclovir alone in terms of quality-of-life outcomes in immunocompetent patients over age 50 with herpes zoster. A comparative study of acyclovir (800 mg PO five times daily) and valacyclovir (1 g PO tid) in immunocompetent patients with herpes zoster indicated that the latter drug may be more effective in eliciting the resolution of zoster-associated pain.


Orally administered acyclovir (600 mg five times a day) reduced complications of herpes zoster ophthalmicus in a placebo-controlled trial. In chickenpox, a modest overall clinical benefit is attained when oral acyclovir therapy is begun within 24 h of the onset of rash in otherwise-healthy children (20 mg/kg, up to a maximum of 800 mg, four times a day) or adults (800 mg five times a day). IV acyclovir has also been reported to be effective in the treatment of immunocompromised children with chickenpox. The most widespread use of acyclovir is in the treatment of genital HSV infections. IV or oral acyclovir or oral valacyclovir has shortened the duration of symptoms, reduced virus shedding, and accelerated healing when employed for the treatment of primary genital HSV infections. Oral acyclovir and valacyclovir have also had a modest effect in treatment of recurrent genital HSV infections. However, the failure of treatment of either primary or recurrent disease to reduce the frequency of subsequent recurrences has indicated that acyclovir is ineffective in eliminating latent infection. Chronic oral administration of acyclovir for ≥1–6 years or of valacyclovir for ≥1 year has reduced the frequency of recurrences markedly during therapy; once the drug is discontinued, lesions recur. In one study, suppressive therapy with valacyclovir (500 mg once daily for 8 months) reduced transmission of HSV-2 genital infections among discordant couples by 50%. A modest effect on herpes labialis (i.e., a reduction of disease duration by 1 day) was seen when valacyclovir was administered upon detection of the first symptom of a lesion at a dose of 2 g every 12 h for 1 day.


In AIDS patients, chronic or intermittent administration of acyclovir has been associated with the development of HSV and VZV strains resistant to the action of the drug and with clinical failures.The most common mechanism of resistance is a deficiency of the virusinduced thymidine kinase. Patients with HSV or VZV infections resistant to acyclovir have frequently responded to foscarnet. With the availability of the oral and IV forms, there are few indications for topical acyclovir, although treatment with this formulation has been modestly beneficial in primary genital HSV infections and in mucocutaneous HSV infections in immunocompromised hosts. Overall, acyclovir is remarkably well tolerated and is generally free of toxicity. The most frequently encountered form of toxicity is renal dysfunction because of drug crystallization, particularly after rapid IV administration or with inadequate hydration. Central nervous system changes, including lethargy and tremors, are occasionally reported, primarily in immunosuppressed patients. However, whether these changes are related to acyclovir, to concurrent administration of other therapy, or to underlying infection remains unclear. Acyclovir is excreted primarily unmetabolized by the kidney via both glomerular filtration and tubular secretion.


Approximately 15% of a dose of acyclovir is metabolized to 9-[(carboxymethoxy) methyl]guanine or other minor metabolites. Reduction in dosage is indicated in patients with a CrCl of <50 mL/min. The half-life of acyclovir is ~3 h in normal adults, and the peak plasma concentration after a 1-h infusion of a dose of 5 mg/kg is 9.8 ìg/mL.Approximately 22% of an orally administered acyclovir dose is absorbed, and peak plasma concentrations of 0.3–0.9 ìg/mL are attained after administration of a 200-mg dose.Acyclovir penetrates relatively well into the cerebrospinal fluid (CSF), with concentrations approaching half of those found in plasma. Acyclovir causes chromosomal breakage at high doses, but its administration to pregnant women has not been associated with fetal abnormalities. Nonetheless, the potential risks and benefits of acyclovir should be carefully assessed before the drug is used in pregnancy. Valacyclovir exhibits three to five times greater bioavailability than acyclovir. The concentration-time curve for valacyclovir, given as 1 g PO three times daily, is similar to that for acyclovir, given as 5 mg/kg IV every 8 h. The safety profiles of valacyclovir and acyclovir are similar, although thrombotic thrombocytopenic purpura/ hemolytic-uremic syndrome has been reported in immunocompromised patients who have received high doses of valacyclovir (8 g/d).


Valacyclovir is approved for the treatment of herpes zoster, of initial and recurrent episodes of genital HSV infections in immunocompetent adults, and of herpes labialis, as well as for suppressive treatment of genital herpes. Although it has not been extensively studied in other clinical settings involving HSV or VZV infections, many consultants use valacyclovir rather than oral acyclovir in settings where the latter has been approved because of valacyclovir’s superior pharmacokinetics and more convenient dosing schedule.


CIDOFOVIR

Cidofovir is a phosphonate nucleotide analogue of cytosine. Its major use is in CMV infections, particularly retinitis, but it is active against a broad range of herpesviruses, including HSV, human herpesvirus (HHV) type 6, HHV- 8, and certain other DNA viruses such as polyomaviruses, papillomaviruses, adenoviruses, and poxviruses, including variola (smallpox) and vaccinia. Cidofovir does not require initial phosphorylation by virus-induced kinases; the drug is phosphorylated by host cell enzymes to cidofovir diphosphate, which is a competitive inhibitor of viral DNA polymerases and, to a lesser extent, of host cell DNA polymerases. Incorporation of cidofovir diphosphate slows or terminates nascent DNA chain elongation. Cidofovir is active against HSV isolates that are resistant to acyclovir because of absent or altered thymidine kinase and against CMV isolates that are resistant to ganciclovir because of UL97 phosphotransferase mutations.


Cidofovir is usually active against foscarnet-resistant CMV, although crossresistance to foscarnet as well as to ganciclovir has been described. Cidofovir has poor oral availability and is administered IV. It is excreted primarily by the kidney and has a plasma half-life of 2.6 h. Cidofovir diphosphate’s intracellular half-life of >48 h is the basis for the recommended dosing regimen of 5 mg/kg once a week for the initial 2 weeks and then 5 mg/kg every other week.The major toxic effect of cidofovir is proximal renal tubular injury, as manifested by elevated serum creatinine levels and proteinuria. The risk of nephrotoxicity can be reduced by vigorous saline hydration and by concomitant oral administration of probenecid. Neutropenia, rashes, and gastrointestinal tolerance may also occur. IV cidofovir has been approved for the treatment of CMV retinitis in AIDS patients who are intolerant of ganciclovir or foscarnet or in whom those drugs have failed. In a controlled study, a maintenance dosage of 5 mg/kg per week administered to AIDS patients reduced the progression of CMV retinitis from that seen at 3 mg/kg. IV cidofovir has been reported anecdotally to be effective for treatment of acyclovir-resistant mucocutaneous HSV infections.


Likewise, topically administered cidofovir is reportedly beneficial against these infections in HIV-infected patients; it is also being studied for the treatment of anogenital warts. Anecdotal use of IV cidofovir has been described in disseminated adenoviral infections in immunosuppressed patients, but its efficacy, if any, is not known.An ophthalmic formulation is being studied as treatment for adenoviral keratoconjunctivitis. Intravitreal cidofovir has been used to treat CMV retinitis but has been associated with significant toxicity.


FOMIVIRSEN

Fomivirsen is the first antisense oligonucleotide approved by the FDA for therapy in humans.This phosphorothioate oligonucleotide, 21 nucleotides in length, inhibits CMV replication through interaction with CMV messenger RNA. Fomivirsen is complementary to messenger transcripts of the major immediate early region 2 (IE2) of CMV, which codes for proteins regulating viral gene expression. In addition to its antisense mechanism of action, fomivirsen may exert activity against CMV through inhibition of viral adsorption to cells as well as direct inhibition of viral replication. Because of its different mechanism of action, fomivirsen is active against CMV isolates that are resistant to nucleoside or nucleotide analogues, such as ganciclovir, foscarnet, or cidofovir. Fomivirsen has been approved for intravitreal administration in the treatment of CMV retinitis in AIDS patients who have failed to respond to other treatments or cannot tolerate them. Injections of 330 mg for two doses 2 weeks apart, followed by maintenance doses of 330 mg monthly, significantly reduce the rate of progression of CMV retinitis. The major toxicity is ocular inflammation, including vitritis and iritis, which usually responds to topically administered glucocorticoids.


GANCICLOVIR AND VALGANCICLOVIR

An analogue of acyclovir, ganciclovir is active against HSV and VZV and is markedly more active than acyclovir against CMV. Ganciclovir triphosphate inhibits CMV DNA polymerase and can be incorporated into CMV DNA, whose elongation it eventually terminates. In HSVand VZV-infected cells, ganciclovir is phosphorylated by virus-encoded thymidine kinases; in CMV-infected cells, it is phosphorylated by a viral kinase encoded by the UL97 gene. Ganciclovir triphosphate is present in tenfold higher concentrations in CMV-infected cells than in uninfected cells. Ganciclovir is approved for the treatment of CMV retinitis in immunosuppressed patients and for the prevention of CMV disease in transplant recipients. It is widely used for the treatment of other CMV-associated syndromes, including pneumonia, esophagogastrointestinal infections, hepatitis, and “wasting” illness. Ganciclovir is available for IV or oral administration. Because its oral bioavailability is low (5–9%), relatively large doses (1 g three times daily) must be administered by this route. Oral ganciclovir has largely been supplanted by valganciclovir, which is the L-valyl ester of ganciclovir.Valganciclovir is well absorbed orally, with a bioavailability of 60%, and is rapidly hydrolyzed to ganciclovir in the intestine and liver. The area under the curve for a 900-mg dose of valganciclovir is equivalent to that for 5 mg/kg of ganciclovir given IV, although peak serum concentrations are ~40% lower for valganciclovir. The serum half-life is 3.5 h after IV administration of ganciclovir and 4.0 h after PO administration of valganciclovir. Ganciclovir is excreted primarily by the kidneys in an unmetabolized form, and its dosage should be reduced in cases of renal failure.The most commonly employed dosage for initial IV therapy is 5 mg/kg every 12 h for 14–21 days; this regimen is followed by an IV maintenance dose of 5 mg/kg per day or five times per week.


For oral therapy with valganciclovir, the dose is 900 mg twice daily for 21 days followed by 900 mg once a day for maintenance, with dose adjustment in patients with renal dysfunction. Intraocular ganciclovir, given by either intravitreal injection or intraocular implantation, has also been used to treat CMV retinitis. Ganciclovir is effective as prophylaxis against CMVassociated disease in organ and bone marrow transplant recipients. Oral ganciclovir administered prophylactically to AIDS patients with CD4+ T-cell counts of <100/ìL has provided protection against the development of CMV retinitis. However, the long-term benefits of this approach to prophylaxis in AIDS patients have not been established, and most experts do not recommend the use of oral ganciclovir for this purpose. As already mentioned, valganciclovir has supplanted oral ganciclovir in settings where oral prophylaxis or therapy is considered. The administration of ganciclovir has been associated with profound bone marrow suppression, particularly neutropenia, which significantly limits the drug’s use in many patients. Bone marrow toxicity is potentiated in the setting of renal dysfunction and when other bone marrow suppressants, such as zidovudine, are used concomitantly. Resistance has been noted in CMV isolates obtained after therapy with ganciclovir, especially in patients with AIDS. Such resistance may develop through a mutation in either the viral UL97 gene or the viral DNA polymerase. Ganciclovir-resistant isolates are usually sensitive to foscarnet (see below) or cidofovir (see above).


FAMCICLOVIR AND PENCICLOVIR

Famciclovir is the diacetyl 6-deoxyester of the guanosine analogue penciclovir. Famciclovir is well absorbed orally, has a bioavailability of 77%, and is rapidly converted to penciclovir by deacetylation and oxidation in the intestine and liver. Penciclovir’s spectrum of activity and mechanism of action are similar to those of acyclovir. Thus penciclovir is usually not active against acyclovir-resistant viruses. However, some acyclovir-resistant viruses with altered thymidine kinase or DNA polymerase substrate specificity may be sensitive to penciclovir.This drug is phosphorylated initially by a virus-encoded thymidine kinase and subsequently by cellular kinases to penciclovir triphosphate, which inhibits HSV-1, HSV-2,VZV, and EBV as well as hepatitis B virus (HBV). The serum half-life of penciclovir is 2 h, but the intracellular half-life of penciclovir triphosphate is 7–20 h—markedly longer than that of acyclovir triphosphate. The latter is the basis for the less frequent (twice-daily) dosing schedule for famciclovir than for acyclovir. Penciclovir is eliminated primarily in the urine by both glomerular filtration and tubular secretion.


The usually recommended dosage interval should be adjusted for renal insufficiency. Clinical trials involving immunocompetent adults with herpes zoster showed that famciclovir was superior to placebo in eliciting the resolution of skin lesions and virus shedding and in shortening the duration of postherpetic neuralgia; moreover, administered at 500 mg every 8 h, famciclovir was at least as effective as acyclovir administered at a dose of 800 mg PO five times daily. Famciclovir was also effective in the treatment of herpes zoster in immunosuppressed patients. Clinical trials have demonstrated its effectiveness in the suppression of genital HSV infections for up to 1 year and in the treatment of initial and recurrent episodes of genital herpes. Famciclovir is effective as therapy for mucocutaneous HSV infections in HIV-infected patients. Application of a 1% penciclovir cream reduces the duration of signs and symptoms of herpes labialis in immunocompetent patients (by 0.5–1.0 day) and has been approved for that purpose by the FDA. Famciclovir is generally well tolerated, with occasional headache, nausea, and diarrhea reported in frequencies similar to those among placebo recipients.The administration of high doses of famciclovir for 2 years was associated with an increased incidence of mammary adenocarcinomas in female rats, but the clinical significance of this effect is unknown.


FOSCARNET

Foscarnet (phosphonoformic acid) is a pyrophosphatecontaining compound that potently inhibits herpesviruses, including CMV.This drug inhibits DNA polymerases at the pyrophosphate binding site at concentrations that have relatively little effect on cellular polymerases. Foscarnet does not require phosphorylation to exert its antiviral activity and is therefore active against HSV and VZV isolates that are resistant to acyclovir because of deficiencies in thymidine kinase as well as against most ganciclovirresistant strains of CMV. Foscarnet also inhibits the reverse transcriptase of HIV and is active against HIV in vivo. Foscarnet is poorly soluble and must be administered IV via an infusion pump in a dilute solution over 1–2 h. The plasma half-life of foscarnet is 3–5 h and increases with decreasing renal function, since the drug is eliminated primarily by the kidneys. It has been estimated that 10–28% of a dose may be deposited in bone, where it can persist for months.The most common initial dosage of foscarnet—60 mg/kg every 8 h for 14–21 days—is followed by a maintenance dose of 90–120 mg/kg once a day.


Foscarnet is approved for the treatment of CMV retinitis in patients with AIDS and of acyclovir-resistant mucocutaneous HSV infections. In a comparative clinical trial, the drug appeared to be about as efficacious as ganciclovir against CMV retinitis but was associated with a longer survival period, possibly because of its activity against HIV. Intraocular foscarnet has been used to treat CMV retinitis. Foscarnet has also been employed to treat acyclovir-resistant HSV and VZV infections as well as ganciclovir-resistant CMV infections, although resistance to foscarnet has been reported in CMV isolates obtained during therapy. Foscarnet has also been used to treat HHV-6 infections in immunosuppressed patients. The major form of toxicity associated with foscarnet is renal impairment. Thus renal function should be monitored closely, particularly during the initial phase of therapy. Since foscarnet binds divalent metal ions, hypocalcemia, hypomagnesemia, hypokalemia, and hypo- or hyperphosphatemia can develop. Saline hydration and slow infusion appear to protect the patient against nephrotoxicity and electrolyte disturbances. Although hematologic abnormalities have been documented (most commonly anemia), foscarnet is not generally myelosuppressive and may be administered concomitantly with myelosuppressive medications such as zidovudine.


TRIFLURIDINE

Trifluridine is a pyrimidine nucleoside active against HSV-1, HSV-2, and CMV.Trifluridine monophosphate irreversibly inhibits thymidylate synthetase, and trifluridine triphosphate inhibits viral and, to a lesser extent, cellular DNA polymerases. Because of systemic toxicity, its use is limited to topical therapy.Trifluridine is approved for treatment of HSV keratitis, for which trials have shown that it is more effective than topical idoxuridine but similar in efficacy to topical vidarabine. The drug has benefited some patients with HSV keratitis who have failed to respond to idoxuridine or vidarabine. Topical application of trifluridine to sites of acyclovir-resistant HSV mucocutaneous infections has also been beneficial in some cases. VIDARABINE Vidarabine is a purine nucleoside analogue with activity against HSV-1, HSV-2,VZV, and EBV.Vidarabine inhibits viral DNA synthesis through its 5′-triphosphorylated metabolite, although its precise molecular mechanisms of action are not completely understood. IV-administered vidarabine has been shown to be effective in the treatment of herpes simplex encephalitis, mucocutaneous HSV infections, herpes zoster in immunocompromised patients, and neonatal HSV infections. Its use has been supplanted by that of IV acyclovir, which is more effective and easier to administer. Production of the IV preparation has been discontinued by the manufacturer, but vidarabine is available as an ophthalmic ointment, which is effective in the treatment of HSV keratitis.


ANTIVIRAL DRUGS ACTIVE AGAINST HEPATITIS VIRUSES LAMIVUDINE

Lamivudine is a pyrimidine nucleoside analogue that is used primarily in combination therapy against HIV infection (Chap. 90). It is also active against HBV through inhibition of the viral DNA polymerase and has been approved for the treatment of chronic HBV infection. At doses of 100 mg/d for 1 year, lamivudine is well tolerated and results in suppression of HBV DNA levels, normalization of serum aminotransferase levels in 50–70% of patients, and reduction of hepatic inflammation and fibrosis in 50–60% of patients. Loss of hepatitis B e antigen (HBeAg) occurs in 30% of patients. Resistance to lamivudine develops in 24% of patients treated for 1 year and is associated with changes in the YMDD motif of HBV DNA polymerase. This is an important limitation of monotherapy with the drug. Lamivudine is being evaluated as a component of combination regimens (with IFNs and other nucleoside or nucleotide analogues listed below) for the treatment of hepatitis B. Lamivudine appears to be useful in the prevention or suppression of HBV infection associated with liver transplantation. ADEFOVIR Adefovir dipivoxil is an acyclic nucleotide analogue of adenosine monophosphate that has activity against HBV, HIV, HSV, and CMV.


It is phosphorylated by cellular kinases to the active triphosphate moiety, which is a competitive inhibitor of HBV DNA polymerase and results in chain termination after incorporation into nascent viral DNA. Adefovir is administered orally and is eliminated primarily by the kidneys, with a plasma halflife of 7.5 h. In clinical studies, therapy with adefovir at a dose of 10 mg/d for 48 weeks resulted in normalization of alanine aminotransferase (ALT) levels in 48–72% of patients and improved liver histology in 53–64%; it also resulted in a 3.6-log10 reduction in the number of HBV DNA copies per milliliter of plasma. Adefovir was effective in treatment-naive patients as well as in those infected with lamivudine-resistant HBV. Resistance to adefovir appears to develop less readily than that to lamivudine, but adefovir resistance rates of 15–18% have been reported after 192 weeks of treatment.This agent is generally well tolerated. Significant nephrotoxicity attributable to adefovir is uncommon at the dose employed in the treatment of HBV infections (10 mg/d) but is a treatment-limiting adverse effect at the higher doses used in therapy for HIV infections (30–120 mg/d). In any case, renal function should be monitored in patients taking adefovir, even at the lower dose. Adefovir is approved only for treatment of chronic HBV infection.


TENOFOVIR

Tenofovir disoproxil fumarate is a nucleotide analogue of adenosine monophosphate with activity against both retroviruses and hepadnaviruses. In patients co-infected with HIV and HBV, tenofovir reduces HBV loads by 3–4 log10 copies/mL at 24 weeks and is effective against lamivudine-resistant HBV.The drug is approved only for treatment of HIV infection, but its use should be considered in patients co-infected with HIV and HBV. For a more detailed discussion of tenofovir, see Chap. 90. ENTECAVIR Entecavir is a cyclopentyl guanosine analogue that inhibits HBV through inhibition of HBV DNA polymerase by entecavir triphosphate and is also active against HIV. In vitro, entecavir is more potent than lamivudine or adefovir against HBV and is also effective against lamivudineresistant HBV. Administration of entecavir at a dose of 0.5 mg/d PO for 48 weeks results in a reduction of HBV DNA by 5.0–6.9 log10 copies/mL, normalization of ALT values in 68–78% of recipients, and loss of HBeAg in 21%. Entecavir is highly bioavailable but should be taken on an empty stomach since food interferes with its absorption.The drug is eliminated primarily in unchanged form by the kidneys, and its dosage should be adjusted for patients with CrCl values of <50 mg/min. Overall, entecavir is well tolerated. Resistance to entecavir has not been observed during the treatment of naïve patients; however, resistance was noted in 7–10% of lamivudinerefractory patients at 48 weeks of treatment with entecavir. Entecavir-resistant strains appear to be sensitive to adefovir. As with other anti-HBV treatments, exacerbation of hepatitis may occur when entecavir therapy is stopped. Entecavir is approved for treatment of chronic hepatitis B in adults.


TELBIVUDINE

Telbivudine is the â-L enantiomer of thymidine and is a potent inhibitor of HBV. Its active form is telbivudine triphosphate, which inhibits HBV DNA polymerase but has little or no activity against human DNA polymerase. Administration of telbivudine at a dose of 600 mg/d PO for 52 weeks to patients with chronic hepatitis B resulted in reduction of HBV DNA by >5 log10 copies/mL along with either loss of serum HBeAg or normalization of ALT in 75% of recipients. After 2 years of therapy, resistance to telbivudine was noted in isolates from 8.6–21.6% of patients.Telbivudine-resistant HBV is usually resistant to lamivudine as well but is generally susceptible to adefovir. Telbivudine is eliminated primarily by the kidneys, and the dosage should be reduced in patients with a ClCr value of <50 mL/min.Telbivudine is generally well tolerated, but increases in serum creatinine kinases and clinically evident myopathy have been observed. As with other anti-HBV drugs, hepatitis may be exacerbated in patients who have discontinued telbivudine therapy.Telbivudine has been approved for treatment of adults with chronic hepatitis B who have evidence of viral replication and either persistent elevation in serum aminotransferases or histologically active disease.


INTERFERONS

IFNs are cytokines that exhibit a broad spectrum of antiviral activities as well as immunomodulating and antiproliferative properties. IFNs are not available for oral administration but must be given IM, SC, or IV. Early studies with human leukocyte IFN demonstrated an effect in the prophylaxis of experimentally induced rhinovirus infections in humans and in the treatment of VZV infections in immunosuppressed patients. DNA recombinant technology has made available highly purified á, â, and ã IFNs that have been evaluated in a variety of viral infections. Results of such trials have confirmed the effectiveness of intranasally administered IFN in the prophylaxis of rhinovirus infections, although its use has been associated with nasal mucosal irritation. Studies have also demonstrated a beneficial effect of intralesionally or systemically administered IFNs on genital warts. The effect of systemic administration consists primarily of a reduction in the size of the warts, and this mode of therapy may be useful in persons who have numerous warts that cannot easily be treated by individual intralesional injections. However, lesions frequently recur after either intralesional or systemic IFN therapy is discontinued.


IFNs have undergone extensive study in the treatment of chronic HBV infection. The administration of IFN- á2b (5 million units daily or 10 million units three times a week for 16–24 weeks) to patients with stable chronic HBV infection resulted in loss of markers of HBV replication, such as HBeAg and HBV DNA, in 33–37% of cases; 8% of patients also became negative for hepatitis B surface antigen. In >80% of patients who lose HBeAg and HBV DNA markers, serum aminotransferases return to normal levels, and both short- and long-term improvements in liver histopathology have been described. Predictors of a favorable response to therapy include low pretherapy levels of HBV DNA, high pretherapy serum levels of ALT, a short duration of chronic HBV infection, and active inflammation in liver histopathology. Poor responses are seen in immunosuppressed patients, including those with HIV infection.A longer duration of therapy (12–24 months) is recommended for HBeAg-negative chronic hepatitis B.Adverse effects of the above doses of IFN are common and include fever, chills,myalgia, fatigue, neurotoxicity (primarily manifested as somnolence, depression, anxiety, and confusion), and leukopenia.


Approximately 25% of patients receiving a daily dose of 5 million units require dose reduction, but <5% require discontinuation of therapy. Pegylated IFNs, which are covalently linked with monomethoxy polyethylene glycol, have a markedly reduced clearance rate. Therefore, they can be administered less frequently, are better tolerated, and may be more effective in some settings than standard IFNs (see discussion of hepatitis C below). Pegylated IFN-á2a is approved for the treatment of patients with chronic hepatitis B who are either positive or negative for HBeAg (Table 79-1). Several IFN preparations, including IFN-á2a, IFN-á2b, IFN-alfacon-1, and IFN-ám1 (lymphoblastoid), have been studied as therapy for chronic HCV infections.A variety of monotherapy regimens have been employed, of which the most common is IFN-á2b or -á2a at 3 million units three times per week for 12–18 months.The addition of oral ribavirin to IFN-á2b—either as initial therapy or after failure of IFN therapy alone—results in significantly higher rates of sustained virologic and/or serum ALT responses (40–50%) than are obtained with monotherapy.


Comparative studies indicate that pegylated IFN-á2b or -á2a therapy is more effective than standard IFN treatment against chronic HCV infection. The combination of SC pegylated IFN and oral ribavirin is more convenient and appears to be the most effective regimen for treatment of chronic hepatitis C.With this combination regimen, sustained virologic responses were seen in 42– 46% of patients with genotype 1 infection and in 76–82% of patients with genotype 2 or 3 infection. Ribavirin appears to have a small antiviral effect in HCV infection, but may also be working through an immunomodulatory effect in combination with IFN. Optimal results with ribavirin appear to be associated with weight-based dosing. Prognostic factors for a favorable response include an age of <45 years, a short duration of infection, low levels of HCV RNA, and infection with HCV genotypes other than 1. IFN-alfacon, a synthetic “consensus” á interferon, appears to produce response rates similar to those elicited