Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 51 Antiviral Agents

MAJOR DRUG CLASSES

Nucleoside Analogs

Nucleoside Reverse Transcriptase

Inhibitors and Nucleotides

Non—Nucleoside Reverse

Transcriptase Inhibitors

Protease Inhibitors

Others

Virus Fusion Inhibitors

Inhibitors of Virus Uncoating

Neuraminidase Inhibitors

Immune Modulators

Therapeutic Overview

Viruses are responsible for significant morbidity and mortality in populations worldwide. These infectious agents consist of a core genome of nucleic acid (nucleoid) contained in a protein shell (capsid), which is sometimes surrounded by a lipoprotein membrane (envelope) (Fig. 51-1). Viruses cannot replicate independently. Rather, they must enter cells and use the energy-generating, deoxyribonucleic acid (DNA)-or ribonucleic acid (RNA)-replicating, and protein-synthesizing pathways of the host cell to replicate. Some viruses can integrate a copy of their genetic material into host chromosomes, achieving viral latency, in which clinical illness can recur without reexposure to the virus.

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FIGURE 51–1 Basic components of virus particles.

Some genera of viruses that cause human infections are listed in Table 51-1. Also listed is information about which genomic material—RNA or DNA—is present and examples of clinically important diseases attributed to each virus.

TABLE 51–1 Virus Groups of Clinical Importance

Virus Genera or Groupings

Nucleic Acid

Clinical Examples of Illnesses

Adenovirus

DNA

Upper respiratory tract and eye infections

Hepadnaviridae

DNA

Hepatitis B, cancer

Herpesvirus

DNA

Genital herpes, varicella, meningoencephalitis, mononucleosis, retinitis

Papillomavirus

DNA

Papillomas (warts), cancer

Parvovirus

DNA

Erythema infectiosum

Arenavirus

RNA

Lymphocytic choriomeningitis

Bunyavirus

RNA

Encephalitis

Coronavirus

RNA

Upper respiratory tract infections

Influenzavirus

RNA

Influenza

Paramyxovirus

RNA

Measles, upper respiratory tract infections

Picornavirus

RNA

Poliomyelitis, diarrhea, upper respiratory tract infections

Retrovirus

RNA

Leukemia, AIDS

Rhabdovirus

RNA

Rabies

Togavirus

RNA

Rubella, yellow fever

The way antiviral agents act is not always known. Most currently available antiviral drugs interfere with viral nucleic acid synthesis, regulation, or both; however, some agents work by interfering with virus cell binding, interrupting viral uncoating, or stimulating the host immune system. Because viruses generally take over host cell nucleic acid and protein replication pathways before clinical infection is discovered, antiviral drugs often must penetrate cells that are already infected to produce a response. Side effects to healthy cells can occur when the drug penetrates into them and disrupts normal nucleic acid or protein synthesis. This toxicity limits clinical utility of many drugs.

In vitro susceptibility testing of antiviral compounds differs significantly from antibacterial agents, because viruses require host cells to replicate. Generally greater than a 50% reduction in plaque-forming units at an achievable serum concentration qualifies a drug to be classified as active against a given virus. In recent years the polymerase chain reaction has provided the technology

Abbreviations

AIDS

Acquired immunodeficiency syndrome

AZT

Zidovudine (formerly known as azidothymidine)

CMV

Cytomegalovirus

CNS

Central nervous system

CSF

Cerebrospinal fluid

DNA

Deoxyribonucleic acid

GI

Gastrointestinal

HAART

Highly active antiretroviral therapy

HIV

Human immunodeficiency virus

HPV

Human papilloma virus

HSV

Herpes simplex virus

IM

Intramuscular

IV

Intravenous

NNRTIs

Non-nucleoside reverse transcriptase inhibitors

NRTIs

Nucleoside reverse transcriptase inhibitors

RNA

Ribonucleic acid

RSV

Respiratory syncytial virus

SC

Subcutaneous

to allow detection of individual virus mutations, allowing physicians to predict viral susceptibility to many antiviral agents.

Many antiviral agents inhibit single steps in the viral replication cycle. They are considered virustatic and do not destroy a given virus, but rather, temporarily halt replication. For an antiviral agent to be optimally effective, the patient must have a competent host immune system that can eliminate or effectively halt virus replication. Patients with immunosuppressive conditions are prone to frequent and often severe viral infections that may recur when antiviral drugs are stopped.

Prolonged suppressive therapy is often necessary. Currently there is no antiviral agent that eliminates viral

Therapeutic Overview

Approaches to treatment of viral infections include:

Block viral attachment to cells

Block uncoating of virus

Inhibit viral DNA/RNA synthesis

Inhibit viral protein synthesis

Inhibit specific viral enzymes

Inhibit viral assembly

Inhibit viral release

Stimulate host immune system

latency. Strains of viruses resistant to specific drugs can also develop.

Several agents are converted in the body to active compounds (acyclovir, ganciclovir) or must be present continuously to have an antiviral effect (amantadine). Other important considerations include drug distribution, duration of infection, and difficulty of administration. Approaches to the treatment of viral infections with drugs are summarized in the Therapeutic Overview Box.

Mechanisms of Action

Viral Replication Cycle

Understanding the steps involved in virus infection and replication has led to the development of drugs that interfere with this process at various sites. This replication cycle and sites of action for the major classes of antiviral drugs are illustrated for the human immunodeficiency virus (HIV) in Figure 51-2.

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FIGURE 51–2 Replication of the HIV virus and sites of action of antiviral drugs.

A virus first binds to an appropriate host cell to initiate an infection. It then penetrates the cell and promotes the synthesis of viral components by controlling host protein and nucleic acid synthesis. Virions are then formed and released to infect other cells. In the situation of HIV infection, infectious virions bind to appropriate host cell receptors. The viral genome crosses into the cell, uncoats, and disassembles. An HIV-specific reverse transcriptase converts viral RNA into DNA, and an integrase incorporates the DNA into the cell’s chromosomes. The host cell then produces a copy of the HIV genome for packaging into new virions and viral messenger RNA, which is the template for protein synthesis. An HIV-specific protease hydrolyzes a viral polyprotein into smaller subunits, which then assemble to form mature infectious virions.

Four classes of compounds have been used to interfere with the HIV reproductive cycle. These include fusion inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors. Anti-HIV therapy with multiple agents has been very effective in limiting the progression to acquired immunodeficiency syndrome (AIDS) in persons carrying HIV.

Other viruses also contain unique enzymes or metabolic pathways that make them susceptible to certain drugs. For example, herpes simplex virus (HSV) encodes a thymidine kinase that monophosphorylates acyclovir significantly better than does the host cell enzyme. Because acyclovir monophosphate is trapped in cells, it becomes highly concentrated. This causes significant inhibition of viral growth with few side effects on cells that do not contain the herpes simplex thymidine kinase. Because cytomegalovirus (CMV), another herpes family virus, does not encode such a thymidine kinase, it is inhibited only by concentrations of acyclovir that are not tolerated clinically; therefore acyclovir is not effective in treating CMV.

Inhibitors of Cell Penetration

Enfuvirtide

HIV entry into cells is accomplished by a complex series of virus host interactions. Initially, virus approximates the CD4 cell by interactions of HIV surface protein and the host CD4 receptor. After approximation, host coreceptors interact with HIV surface proteins, resulting in folding of the HIV protein gp41. This folding results in fusion of the HIV membrane with the host cell membrane and insertion of the HIV nucleoid into the cell. Enfuvirtide prevents entry of HIV into cells by lying along the gp41 coils, causing steric hindrance of protein folding. Resistance occurs when mutations of gp41 occur that alter conformation and folding.

Other antiviral drugs that work by inhibiting viral entry into cells include docosanol and palivizumab. Docosanol is a topical agent used to treat HSV. Sold over-the-counter for topical use, this compound prevents virus entry by inhibiting fusion of the HSV envelope with the plasma membrane of the host cell. Palivizumab is a human monoclonal antibody directed against an epitope in the A antigen site on the F surface protein of the HSV. Clinical resistance to palivizumab has not been observed, although it has been reported in in vitro studies.

Inhibitors of Viral Uncoating

Amantadine and Rimantadine

The structure of amantadine is shown in (Fig. 51-3). Its mechanism of action is not fully established but appears to involve blocking the ion channel activity of the M2 protein, thereby inhibiting late-stage uncoating of influenza A virions. This drug is not effective against influenza B, which lacks the M2 protein. A single amino acid change in the M2 protein results in amantadine resistance. Resistant virus is virulent and causes disease in exposed people. Rimantadine is a related compound with similar actions but an improved side effect profile.

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FIGURE 51–3 Structures of some antiviral drugs.

Inhibitors of Viral DNA and RNA Synthesis

Acyclovir

Acyclovir (see Fig. 51-3) is a synthetic guanosine analog and is the prototypical agent for this group of anti-HSV drugs. The group includes the related drugs valacyclovir and famciclovir, a prodrug for penciclovir. All of these drugs must be phosphorylated to be active and are initially monophosphorylated by viral thymidine kinase. Because the thymidine kinases of HSV types 1 and 2 are many times more active on acyclovir than host thymidine kinase, high concentrations of acyclovir monophosphate accumulate in infected cells. This is then further phosphorylated to the active compound acyclovir triphosphate. The triphosphate cannot cross cell membranes and accumulates further. The resulting concentration of acyclovir triphosphate is 50 to 100 times greater in infected cells than in uninfected cells.

Acyclovir triphosphate inhibits virus growth in three ways. First, it competitively inhibits DNA polymerases, with human DNA polymerases being significantly less susceptible than viral enzymes. Second, it terminates DNA elongation. Third, it produces irreversible binding between viral DNA polymerase and the interrupted chain, causing permanent inactivation.

The result is a several hundred-fold inhibition of HSV growth with minimal toxic effects on uninfected cells. However, HSVs with altered thymidine kinase (acyclovir-penciclovir resistant) have developed, although they occur primarily in patients receiving multiple courses of therapy. These mutants are susceptible to the antiviral drug, foscarnet. Changes in viral DNA polymerase structures can also mediate resistance to acyclovir.

Ganciclovir

The structure of ganciclovir is shown in Figure 51-3. It is also a synthetic guanosine analog active against many herpesviruses and must also be phosphorylated to be active. Infection-induced kinases, viral thymidine kinase, or deoxyguanosine kinase of various herpesviruses can catalyze this reaction. After monophosphorylation, cellular enzymes convert ganciclovir to the triphosphorylated form, and the triphosphate inhibits viral DNA polymerase rather than cellular DNA polymerase. Ganciclovir triphosphate competitively inhibits the incorporation of guanosine triphosphate into DNA. Because of its toxicity and the availability of acyclovir for treatment of many herpesvirus infections, its use is currently restricted to treatment of CMV retinitis.

Foscarnet

Foscarnet (see Fig. 51-3) inhibits DNA polymerases, RNA polymerases, and reverse transcriptases. In vitro it is active against herpesviruses, influenza virus, and HIV. Foscarnet is used primarily in treatment of CMV retinitis. Viral resistance is attributable to structural alterations in CMV DNA polymerase. Foscarnet inhibits CMV herpesviruses that are resistant to acyclovir and ganciclovir.

Ribavirin

Ribavirin is a synthetic purine nucleoside active against many viruses, including respiratory syncytial virus, Lassa fever virus, and influenza viruses (see Fig. 51-3). Ribavirin appears to be phosphorylated in host cells by host adenosine kinase. The 5’-monophosphate subsequently inhibits cellular inosine monophosphate formation, resulting in depletion of intracellular guanosine triphosphate. In some situations ribavirin triphosphate suppresses guanosine triphosphate-dependent capping of messenger RNA, thereby inhibiting viral protein synthesis. It also acts by suppressing the initiation or elongation of viral messenger RNA. Exogenous guanosine can reverse the antiviral effects of ribavirin with some viruses.

Nucleoside Reverse Transcriptase Inhibitors and Nucleotides

These drugs include zidovudine, didanosine, lamivudine, stavudine, and others (Box 51-1), and all work through a similar mechanism. Zidovudine (AZT) is the prototype for use in HIV infection. It is a thymidine analog that is phosphorylated to monophosphate, diphosphate, and triphosphate forms by cellular kinases in infected and uninfected cells. NRTIs have two primary methods of action. First, the triphosphate form acts as a competitive inhibitor of HIV reverse transcriptase. Second, after the nucleoside is incorporated into the elongating DNA chain, the forming sugar phosphate backbone of the DNA is blocked from further elongation by substitution at the 3 position. This results in chain termination. In the case of zidovudine, this substitution is an azido (N3) group. Zidovudine inhibits HIV reverse transcriptase at much lower concentrations than those needed to inhibit cellular DNA polymerases, leading to a more targeted effect against HIV.

BOX 51–1 Mechanism of Action of Antiviral Agents

Drug Inhibition of Specific Viral Enzymes

Human Immunodeficiency Virus

Reverse transcriptase

Zidovudine

Abacavir

Lamivudine

Zalcitabine

Didanosine

Stavudine

Tenofovir

Nevirapine

Efavirenz

Delavirdine

HIV protease

Ritonavir

Saquinavir

Nelfinavir

Lopinavir/Ritonavir

Amprenavir

Zanamivir

Influenza A and B

Neuraminidase inhibitors

Oseltamivir

Zanamivir

Tenofovir is the only nucleotide currently available for use. It is a monophosphate derivative of adenosine that is administered as the disoproxil salt. After ingestion, it is converted to triphosphates by cellular enzymes. Tenofovir acts as an adenosine analog to inhibit HIV reverse transcriptase and cause chain termination.

Differences in NRTIs and investigational nucleotides are primarily based on which nucleic acid is used and the type of substitution that causes chain termination. NRTIs have been produced for each of the four nucleic acids. Neither NRTIs nor nucleotides should be used as monotherapy.

Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine, Delavirdine, Efavirenz

As a class, NNRTIs bind to HIV reverse transcriptase at a site distant from the catalytic site. This binding causes a conformational change in the enzyme, disrupting enzyme activity. Because NRTIs and NNRTIs do not bind at the same site, they can be used effectively as combination therapy with significant inhibition of HIV reverse transcriptase. When resistance to NNRTIs occurs, all drugs currently available are affected, and this class of drugs is unavailable for therapy.

HIV Protease Inhibitors

Saquinavir, Ritonavir, Indinavir

Protease inhibitors inhibit an HIV-specific proteolytic enzyme necessary for the production of infectious HIV virions. Currently available protease inhibitors inhibit cleavage of the gag/pol HIV polyprotein, and act synergistically with NRTIs. Resistance to protease inhibitors can occur within weeks when they are used as single agents or intermittently. These drugs are therefore usually given in combination with other anti-HIV therapies. The possibility of cross-resistance between these agents is being investigated.

Inhibitors of Influenza Neuraminidase

Oseltamivir and Zanamivir

Influenza A and B possess a unique neuraminidase enzyme that is highly conserved in both viruses. The enzyme catalyzes removal of terminal sialic acid residues that are linked to glycoproteins and glycolipids. Oseltamivir and zanamivir are analogs of sialic acid and prevent release of new viruses. Proper neuraminidase activity seems to be necessary for such release.

Other Antiviral Agents

Idoxuridine

Idoxuridine is an iodinated thymidine nucleoside analog that is incorporated into DNA in place of thymidine and blocks further DNA chain elongation. In vitro it inhibits many DNA viruses, and exogenous thymidine eliminates its antiviral effect. Idoxuridine affects mammalian cells, and its teratogenic, mutagenic, and immunosuppressive effects limit its use to topical preparations. It is used especially for the treatment of HSV infections of the cornea. Herpesviruses resistant to idoxuridine do occur and generally have decreased thymidine kinase activity.

Trifluridine

Trifluridine, or trifluorothymidine, is a pyrimidine analog that inhibits viral DNA synthesis by being incorporated into viral DNA. It does not require thymidine kinase for it to become active and is active against thymidine kinase-deficient mutants of HSV that are resistant to acyclovir, idoxuridine, or both. It can only be administered topically.

Fluorouracil

Fluorouracil is an anticancer drug that blocks production of thymidylate and interrupts normal cellular DNA and RNA synthesis. Its primary action may be to cause thiamine deficiency and resultant cell death. The effect of fluorouracil is most pronounced on rapidly growing cells. Its antiviral activity stems primarily from its ability to kill cells infected with papillomavirus (warts), and it is applied topically for this purpose.

Interferons

Interferons are naturally occurring glycoproteins produced by lymphocytes, macrophages, fibroblasts, and other human cells (see Chapter 6). There are three distinct classes: α, β, and γ. They act as antiviral agents by inhibiting viral protein synthesis or assembly, or by stimulating the immune system. Interferons bind specific cell receptors and produce rapid changes in RNA. These effects may result in inhibition of viral penetration; uncoating, synthesis, or methylation of mRNA; translation of viral proteins; or assembly and release of virus. A 2’,5’-oligoadenylate synthetase and a protein kinase are usually produced that inhibit protein synthesis in the presence of double-stranded RNA. Interferons can also protect uninfected cells from infection by mechanisms that are as yet unclear. Interferons are used for the treatment of hepatitis B and C and papillomavirus infections.

Immunoglobulins

Immunoglobulins are used as antiviral agents, primarily to prevent infections. Some immunoglobulin preparations with high titers against specific viruses (e.g., hepatitis B, rabies) may be used for treatment or prophylaxis. Standard human immune globulin is used to prevent hepatitis A infection.

Pharmacokinetics

For most antiviral agents to be active, they must become concentrated within cells. Many compounds are nucleoside analogs and are rapidly metabolized to inactive compounds, which are then eliminated from the body. This necessitates frequent dosing to maintain adequate intracellular drug concentrations. Because of severe systemic toxicity, some agents can only be used topically.

Because these compounds often interfere with human DNA or RNA synthesis, any antiviral agent should be used with the utmost caution in pregnancy and only when the potential benefits of treatment clearly outweigh the potential risks. The pharmacokinetic parameters for some antiviral drugs are listed in Table 51-2.

TABLE 51–2 Pharmacokinetic Parameters of Some Commonly Used Drugs

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Inhibitors of Viral Uncoating

Amantadine is completely but slowly absorbed from the gastrointestinal (GI) tract, is 65% protein bound, and is distributed well throughout the body. Serum drug concentrations vary widely with the age of the patient, although peak drug concentrations occur 2 to 4 hours after ingestion. The plasma half-life of amantadine doubles in the elderly, necessitating dosage reductions. Amantadine is eliminated by kidney glomerular filtration and tubular secretion but is also metabolized to at least eight different compounds, although the biological activity of these metabolites is unknown.

Inhibitors of Viral DNA and RNA Synthesis

Acyclovir can be administered topically, orally, or by intravenous (IV) injection; valacyclovir and famciclovir are only available orally. Valacyclovir has a higher bioavailability than acyclovir. Acyclovir is minimally protein bound and well distributed throughout the body. Percutaneous absorption of topical acyclovir is very low. Because of poor absorption and the need for higher drug concentrations in the treatment of shingles, different dosage formulations of oral acyclovir are available.

Valacyclovir is rapidly metabolized in the liver to acyclovir. Because valacyclovir is better absorbed than acyclovir, serum concentrations of the active metabolite acyclovir are three to five times higher after valacyclovir administration. Famciclovir is also metabolized in the liver to its active compound, penciclovir. Most acyclovir is excreted unchanged. As a result, acyclovir may interfere with the renal excretion of drugs, such as methotrexate, that are eliminated through the renal tubules. Probenecid significantly decreases renal excretion of acyclovir. Penciclovir is eliminated in the same way as acyclovir.

Ganciclovir is primarily eliminated unchanged in urine, and therefore the plasma half-life can increase substantially in patients with severe renal insufficiency. It can also be administered intravitreally, in which setting it has a half-life of 50 hours.

Foscarnet has a low bioavailability and is only administered IV at this time. Because foscarnet can bind Ca++ and other divalent cations, it accumulates in bone and may be detectable for many months after treatment. It is mainly excreted unchanged in the urine, and therefore dosage must be adjusted for impaired renal function.

Ribavirin is approximately 45% bioavailable. Peak concentrations after IV administration are tenfold greater than those after oral administration. Ribavirin is administered by aerosol in treatment of severe respiratory syncytial virus (RSV) infections. Approximately 3% of ribavirin accumulates in red blood cells in the form of ribavirin triphosphate, to give a prolonged serum half-life of 40 days, during which the compound is slowly eliminated. Hepatic metabolism is the main route of elimination.

HIV Fusion Inhibitors

Enfuvirtide is a 36-amino acid polypeptide that is available only for subcutaneous (SC) injection. Peak concentrations of 5 µg/mL occur 4 to 6 hours after injection. Enfuvirtide is poorly water-soluble and is highly protein bound. Elimination of enfuvirtide is thought to be by catabolism of the polypeptide to constituent amino acids by a variety of tissue enzymes.

Nucleoside Reverse Transcriptase Inhibitors and Nucleotides

NRTIs and nucleotides are available for oral administration. Zidovudine is the only drug in this class available IV and can be helpful in managing pregnant women during labor. Peak serum concentrations for NRTIs and nucleotides generally occur within 30 to 90 minutes. Importantly, the intracellular half-life of the phosphorylated compounds is many hours. This can allow once- or twice-daily dosing for many of these agents, improving compliance and decreasing toxicity.

Drug absorption is unique for each of the drugs in this class, and food or stomach pH can affect absorption for some of these agents. Didanosine and tenofovir are most affected in this regard. Didanosine is extremely acid labile and is formulated with a buffer to neutralize stomach acid and maximize absorption. Food significantly improves tenofovir absorption. Penetration into the cerebrospinal fluid (CSF) varies widely for the drugs. NRTIs and nucleotides are eliminated by a combination of renal excretion and glucuronidation. Drugs that can interfere with hepatic glucuronidation (e.g., acetaminophen) or renal tubular transport (e.g., probenecid) may inhibit elimination of some agents and should be used with caution. Also, patients with renal insufficiency may need dosage adjustments. The improved dosing pattern of NRTIs and the need to use multiple NRTIs in management of HIV disease has allowed manufacture of fixed drug combinations, further improving patient compliance.

Non-Nucleoside Reverse Transcriptase Inhibitors

Bioavailability of NNRTIs is generally high. They are rapidly absorbed, with half-lives of 6 to 40 hours. No dietary restrictions are necessary for this class of drugs. Nevirapine induces and is extensively metabolized by the cytochrome P450 system, necessitating a modification in the doses of other drugs metabolized by this route. Efavirenz possesses the longest half-life and can be given once daily.

HIV Protease Inhibitors

Several protease inhibitors are now available for use. The absorption of these medications is usually improved with food; however, indinavir absorption is decreased with food. Peak serum concentrations of protease inhibitors are reached 1 to 3 hours after ingestion and are eliminated primarily by metabolism through cytochrome P4503A4. Inhibition of the P450 system can cause significant interactions with other medications. The elimination of protease inhibitors can be preferentially decreased by low-dose ritonavir, causing higher serum levels for longer periods of time. Lopinavir and ritonavir are available as a fixed-drug combination using this effect. Patients with liver disease who need protease inhibitor therapy need to be monitored carefully.

Other Antiviral Agents

Idoxuridine is used only topically, and systemic absorption is minimal. The small amount that is absorbed is metabolized to uracil and iodouracil. In vitro, resistance to idoxuridine develops easily, and resistant clinical isolates have been described that may be a source of treatment failure.

Trifluridine is available for topical use only, especially as an ophthalmic preparation. Minimal drug absorption occurs; no trifluridine has been detected in serum or aqueous humor from treated patients. Fluorouracil is also available as a topical preparation.

Because interferons are glycoproteins, their pharmacokinetics are difficult to assess. Simple detection of circulating interferon may not approximate clinical activity, because cellular binding is necessary, and an intact immune system is important to achieve a maximal response. Also, the biological activity may last days; even though the compound has been cleared from serum (see Chapter 6).

Interferons are administered by intramuscular (IM) or SC injection. Serum concentrations peak in 4 to 8 hours and decline steadily over 1 to 2 days. Biological activity of interferons begins within an hour of injection, peaks at 24 hours, and decreases over 4 to 6 days. Interferons are distributed throughout the body and are detectable in brain and CSF. The elimination of exogenous interferon is complex. Liver, lung, kidney, heart, and skeletal muscle are capable of inactivating the compounds. Negligible amounts are found in urine. Polyethylene glycol has been attached to some interferons, resulting in slower subcutaneous rates of absorption, longer serum half-lives, less-frequent dosing, and more-sustained antiviral activity. Interferons are injected three times per week in management of chronic hepatitis, whereas pegylated interferon is injected once per week. Interferons are also effective when injected directly into condylomas or given SC or IM in management of papillomavirus infections.

As antiviral therapies, immunoglobulins are given SC, IM, and IV. They are distributed throughout the body. After IM injection, immunoglobulin serum concentrations peak in 4 to 6 days and then decline, with half-lives of 20 to 30 days. Repeat immunization every 3 to 6 months is often recommended for people who are continually exposed to infectious agents such as hepatitis A. After exposure to rabies, it is recommended that the wound be infiltrated with high-titer immunoglobulin to neutralize virus, with the remaining immunoglobulin administered IM. IV gamma globulin is administered every 3 to 4 weeks to agammaglobulinemic patients. Clearance of immunoglobulins is variable, with a mean half-life of 20 days.

Relationship of Mechanisms of Action to Clinical Response

Many of the most effective antiviral agents target unique viral enzymes or life cycle pathways. Such specific inhibition is beneficial because uninfected cells experience minimal toxicity. As a result, many antiviral drugs only inhibit replication of specific viruses and are not useful against other viruses. Because antiviral drugs are used primarily after infection has occurred, they are most effective when given early. Viruses with latent characteristics may need chronic suppression. Many agents are limited in their use by their toxic effects on uninfected cells. Such compounds are primarily used topically.

Immunoglobulins and interferons have wide antiviral activity based on their mechanism of action. Interferons interfere with the replication of a large number of viruses (hence the origin of their name). They also broadly stimulate the immune system, further enhancing antiviral activity. Immune globulin has the ability to neutralize some viruses. The spectrum of immune globulin activity is dependent on the presence of neutralizing antibody and the capacity of the virus to be neutralized by antibody. Hepatitis C and HIV are not neutralized by currently available immune globulin preparations, so administration is not recommended after exposure to these viruses. All agents are significantly less effective in immunosuppressed patients.

Amantadine

Amantadine and rimantadine are both used for treatment and prophylaxis of influenza A infections but are ineffective against influenza B. They are most effective when given before exposure or within 48 hours of development of symptoms. It has been estimated that these drugs are 50% effective in protecting against infection and 60% to 70% effective in protecting against illness. These drugs do not inhibit antibody responses to influenza, and immunity develops during therapy in both immunized and infected patients. Protective effects of these medications are lost approximately 48 hours after therapy is stopped. Specific patients targeted for drug therapy include those who are unvaccinated and have greatest risk for complications of influenza infection. Such people should also be vaccinated, because resistant mutants may develop during therapy. The major advantage of rimantadine is that it carries a lower risk for causing central nervous system (CNS) effects than amantadine.

Zanamivir and oseltamivir are inhibitors of influenza A and B viral neuraminidase. Both agents effectively stop the release of virus and subsequent spread to healthy cells. These compounds improve symptoms and decrease duration of illness when started within 48 hours of symptoms. Zanamivir is administered via inhalation.

Acyclovir

Systemic acyclovir is effective in reducing viral shedding, alleviating local symptoms, and decreasing the severity and duration of HSV infections. Recurrences after termination of therapy are common because of viral latency. Acyclovir decreases mortality in patients with herpes encephalitis to approximately 20%. Approximately 50% of acyclovir-treated patients return to normal life. High-dose acyclovir is needed to treat encephalitis to improve penetration across the blood-brain barrier. Acyclovir should be administered as soon as possible after encephalitis is diagnosed to lessen patient morbidity and mortality.

IV or oral acyclovir should be used to treat primary genital HSV infection. Both treatments decrease viral shedding, local and systemic symptoms, and time to resolution. Neither form of therapy decreases the rate or severity of recurrences. Recurrent genital herpes is managed with orally administered acyclovir. Treatments begun when the first prodrome of clinical recurrence appears decrease symptoms and viral shedding. Patients with four to six recurrences of genital herpes infection per year are often given suppressive therapy. Approximately 75% of patients taking suppressive acyclovir will have no recurrences for 12 months, and the total number of recurrences decreases by 90%. After discontinuation of acyclovir, recurrence rates generally return to near pretreatment levels. Resistance has been noted in people with active lesions taking suppressive therapy. Patients must be informed that while taking acyclovir, they may shed virus even if no lesions are visible.

Oral acyclovir can be effective in suppressing recurrences of mucocutaneous HSV infections in immunosuppressed patients, and it is sometimes given after chemotherapy. It can also be used prophylactically in bone marrow and other transplant patients to prevent herpes recurrence. Therapy is most effective when begun before transplantation and continued for many weeks.

Acyclovir is also effective in the management of acute varicella. Acyclovir, valacyclovir, and famciclovir are effective in the treatment of herpes zoster (shingles). Patients whose treatment is begun within 72 hours of the onset of symptoms show decreased viral shedding and more-rapid healing. The total duration of illness is decreased by 2 days in healthy children with varicella who receive acyclovir.

Acyclovir is not effective in treating CMV pneumonia or visceral disease, Epstein-Barr virus, mononucleosis, or chronic fatigue syndrome. However, a condition in AIDS patients known as hairy leukoplakia (a proliferation of oral epithelium related to Epstein-Barr virus infection) is responsive to oral acyclovir.

Idoxuridine and trifluridine can be used topically to treat herpes simplex keratitis. Toxicity prevents systemic use of these agents.

Ganciclovir

Ganciclovir and valganciclovir are used in management of CMV disease in AIDS and transplant patients. In situations of CMV retinitis, ganciclovir implants or other ocular injections may be necessary. Retinitis recurs in patients when therapy is stopped. Approximately 65% of AIDS patients with visceral CMV infection have significant virological responses, but clinical improvement in response to ganciclovir is not as significant. Bone marrow transplant patients with CMV pneumonia also show virological responses, but there are no differences in overall mortality in patients receiving this antiviral agent.

Foscarnet

Foscarnet is approved only for IV administration in the treatment of CMV retinitis. It is equally as effective as ganciclovir; however, drug-related toxicity is more common.

Ribavirin

Ribavirin alters intracellular guanosine triphosphate (GTP) concentrations and has activity against RSV and Lassa fever virus; it is synergistic with interferon in treatment of chronic hepatitis C infection. When administered as an aerosol, special generators are required to generate the necessary particle sizes.

HUMAN IMMUNODEFICIENCY VIRUS

Initial studies with zidovudine monotherapy demonstrated that inhibition of HIV reverse transcriptase improved CD4 counts and clinical outcomes in patients. The effect was not sustained as reverse transcriptase mutations developed, viral replication progressed, CD4 counts fell, and clinical illnesses recurred. Other NRTIs were initially used as salvage therapy, and then in combination in an attempt to halt HIV replication. Because NRTIs all work in the same way at the same active site, inhibitors of other stages of the HIV replication cycle were actively sought.

NNRTIs and HIV protease inhibitors provided other mechanisms to inhibit viral replication, and combination therapy is now used as highly active antiretroviral therapy (HAART). With the agents currently available, it has become clear that HIV resistance occurs rapidly when medications are used as single agents or irregularly. Therefore medication compliance is crucial in achieving the best outcomes, which occur when viral replication is low. Improved understanding of cellular metabolism of NRTIs has shown intracellular half-lives to be significantly longer than serum half-lives, allowing less-frequent dosing of many medications and improving patient compliance. A further advance in management of HIV disease is the development of fusion inhibitors, which are still under active investigation.

The numerous agents currently available make good clinical outcomes possible for most HIV-infected patients when treated early in the disease process.

Papillomavirus

Fluorouracil

Fluorouracil has been used topically to treat condylomas (warts) caused by human papillomaviruses (HPV). It acts primarily as an ablative agent, destroying infected and uninfected cells, and can therefore be used only externally over relatively small areas.

Nonspecific Viral Inhibitors

Interferons

All three classes of human interferons (α, β, γ) are nonspecific immune stimulators that also have significant antiviral activity. As an antiviral agent, interferon is approved for the treatment of condyloma acuminata and chronic hepatitis B or C (often in combination with ribavirin). Adding polyethylene glycol to interferon has improved outcomes in chronic hepatitis C, presumably from greater sustained blood levels of interferon.

Immunoglobulins

Some human immunoglobulins have high titers against specific viruses such as hepatitis B and rabies and are more efficacious against these viruses than nonspecific immunoglobulins. Some viral infections amenable to immunoglobulin therapy are listed in Box 51-2. Immunoglobulins are usually given IM, as close as possible to the time of exposure to the virus. In some circumstances an immunoglobulin should also be given very close to the lesion (as in rabies) to provide high concentrations to lymphatic tissues. In most situations IM injection provides systemic immunoglobulin concentrations adequate to prevent the development of clinical infection. However, because immunoglobulins do not confer long-term immunity, they must often be given in a series of injections, together with vaccine therapy.

BOX 51–2 Viral Infections Amenable to Immunoglobulin Treatment

Cytomegalovirus

Hepatitis A

Hepatitis B

Rabies

Varicella*

Measles*

* Immunoglobulin treatment reserved for patients at high risk for complications.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Because many antiviral drugs are derivatives of nucleic acids, significant toxicities to uninfected cells can occur. Most toxicity involves bone marrow suppression with a loss of granulocytes, platelets, and erythrocytes. In many instances systemic toxicities are so severe that the drug can only be administered topically. Several of the clinical problems are summarized in the Clinical Problems Box.

Amantadine and Rimantadine

The most common side effects of amantadine therapy are GI upset and CNS side effects such as nervousness, insomnia, and headache. These develop within the first week of therapy and decrease with time, despite continued treatment. Side effects are reversible after discontinuation of the drug and are less frequent in patients receiving lower doses. Adverse effects occur in 5% to 33% of persons taking amantadine for influenza prophylaxis.

Amantadine also has anticholinergic properties that can cause urinary retention, ventricular arrhythmias, pupillary dilatation, and psychosis in some patients (see Chapter 28). The anticholinergic effects of amantadine are enhanced by antihistamines and anticholinergic drugs. Because its safety in pregnant and breast-feeding women is not established, caution should be exercised. Physostigmine given every 1 to 2 hours in adults may temporarily reverse serious neurological reactions. Overall, rimantadine is better tolerated than amantadine and does not appear to have significant anticholinergic effects.

Oseltamivir and Zanamivir

Side effects of oseltamivir include nausea, vomiting, and diarrhea, which occur in approximately 15% of patients. Zanamivir is administered by a disk inhalation device, and patients need to be instructed about proper use of the inhaler. Absorption of parent medication is minimal, and side effects in persons without underlying lung disease are less than 5%. Patients with a history of bronchospasm or sensitive airways should not receive zanamivir.

Acyclovir

Acyclovir is well tolerated with few side effects. Because the pH of IV-administered acyclovir is 9 to 11, phlebitis is the most common side effect, occurring in 15% of patients. Acyclovir is excreted renally, and crystalline nephropathy can occur. Transient elevated creatinine concentrations are more common in patients receiving rapid infusions, especially in those who are dehydrated. Approximately 1% of patients experience CNS effects sometimes associated with significant confusion. If probenecid is coadministered with the acyclovir, this can reduce renal clearance and prolong serum half-life. Valacyclovir and famciclovir are also well tolerated.

Acyclovir has not shown increased teratogenicity in animal models, but mutagenicity has been observed at extremely high doses. Because its safety in pregnancy is unknown, acyclovir should be given only after its potential benefits and risks are carefully evaluated. To date, no congenital syndromes have been identified in children of women who received acyclovir.

Ganciclovir

Most clinical experience with ganciclovir has been gained in the treatment of CMV retinitis in AIDS patients, in whom the most common side effects are bone marrow suppression (up to 40%) and CNS abnormalities (up to 15%). Neutropenia and thrombocytopenia are the most common manifestations of bone marrow suppression, usually observed in the second week of therapy. Effects are usually reversible, but significant infections during granulocytopenia can occur. Concurrent use of NRTIs increases bone marrow toxicity. Approximately 33% of AIDS patients developed CNS or bone marrow toxicities significant enough to interrupt therapy. AIDS patients who have received long-term ganciclovir therapy have significant increases in their follicle-stimulating hormone, luteinizing hormone, and testosterone concentrations. Side effects of oral therapy are less frequent. Because of significant side effects, some patients with CMV retinitis receive intraocular ganciclovir implants. Ganciclovir has proved to be teratogenic and mutagenic in several different experimental systems.

Foscarnet

Foscarnet is a strongly anionic compound and can chelate divalent cations. This has resulted in hypocalcemia and hypomagnesemia in up to 20% of patients receiving the drug. Seizures and cardiac dysrhythmias may occur, presumably as a result of hypocalcemia. Foscarnet causes renal insufficiency, and dosages must be adjusted in patients with decreased creatinine clearance. Up to 30% of AIDS patients receiving foscarnet therapy for CMV retinitis have increases in their serum creatinine. Foscarnet is less myelosuppressive than ganciclovir.

Ribavirin

Aerosolized ribavirin is generally well tolerated, but bronchospasm may occur. In adults with chronic obstructive pulmonary disease and asthmatics receiving aerosol therapy, significant deterioration of pulmonary function has been reported. Ribavirin may be passively absorbed by employees working with patients treated with aerosols. Pregnant women should not be exposed to the aerosol. The primary toxicity of oral ribavirin is that of hemolytic anemia and dyspnea. This occurs in approximately 10% of recipients and often begins 1 to 2 weeks after starting therapy. Patients should have serial measurement of hemoglobin while on ribavirin. Ribavirin is teratogenic or embryolethal at doses that are as low as 5% of the recommended human dose. It should never be started in women until a negative pregnancy test is obtained. Also, couples must use two effective forms of contraception while ribavirin is being given, and for 6 months after the drug is discontinued.

Fusion Inhibitors

The main side effects associated with enfuvirtide are reactions at the injection site and possible hypersensitivity reactions. Patients need to rotate injection sites to allow resolution of the problem. Analgesics are sometimes necessary. Hypersensitivity reactions have been rarely reported, but clinical experience with enfuvirtide has been limited to date. As the medication is more widely used, physicians need to be aware of the possibility of immune complex disease or acute hypersensitivity reactions, especially on reexposure to drug.

Nucleoside Reverse Transcriptase Inhibitors and Nucleotides

Side effects of NRTIs and nucleotides vary with clinical stage of HIV disease. Persons with CD4 counts above 200 generally tolerate these medications very well. The most common side effects in this group are GI upset, nausea, and headache. These effects occur in approximately 5% of patients and may decrease with time. Lamivudine is generally the best-tolerated NRTI. Patients with more advanced HIV disease often experience more frequent and more significant side effects to NRTIs and nucleotides. Bone marrow suppression and granulocytopenia have developed in up to 50% of NRTI recipients whose initial absolute CD4 count was less than 100 cells/mm3 but in only 20% of recipients whose initial CD4 count was greater than that. Megaloblastic erythrocyte changes occur within 2 weeks in most patients on zidovudine therapy. Black nail pigmentation may occur during therapy but is more common in people of African descent. All NRTIs and nucleotides inhibit mitochondrial DNA formation. Severe lactic acidosis and hepatic steatosis may occur. NRTIs have also been associated with lipodystrophy. The teratogenicity and mutagenicity of NRTIs has not been completely evaluated; however, zidovudine use in pregnancy to date has not been associated with abnormal birth patterns.

Didanosine’s major side effects are pancreatitis and peripheral neuropathy. Pancreatitis has been observed in 5% to 10% of all didanosine recipients. Peripheral neuropathy has been reported to occur in approximately 10% to 30% of patients on NRTIs and often improves upon discontinuation of the drug. Because didanosine is acid labile, stomach acid must be neutralized for proper absorption. In some situations buffer can interfere with the absorption of other medications. The main side effect of stavudine is peripheral neuropathy, which occurs in up to 20% of patients.

Non-Nucleoside Reverse Transcriptase Inhibitors

NNRTIs, although a single class of drugs, have widely varying side effects and treatment issues. One of the most significant side effects is rash. One third of patients taking nevirapine can develop significant rash, with life-threatening reactions occurring. Patients who experience the rash should not be rechallenged. Rash is less common in patients taking the other NRTIs. Efavirenz use can be associated with severe depression and sleep disturbances. A history of clinically significant depression is a relative contraindication for efavirenz use. Delavirdine appears to be the best-tolerated NNRTI. All NNRTIs can cause lipodystrophy.

Protease Inhibitors

Protease inhibitors are primarily metabolized by the P450 system and thus have the potential to alter the metabolism of other drugs. Ritonavir has the greatest capacity for drug-drug interactions, although this may occur with any protease inhibitor. Patients on protease inhibitor therapy need their medications routinely reviewed to check for significant drug-drug reactions. Lipodystrophy is common with all protease inhibitors, and glucose intolerance, dyslipidemia, may also occur. Patients on protease inhibitors have an increased risk of myocardial infarctions. Indinavir may precipitate in renal tubules and create clinically significant kidney stones. Adequate hydration is required for patients receiving indinavir. Other common side effects for protease inhibitors include GI upset and diarrhea.

CLINICAL PROBLEMS

Amantadine

GI upset, CNS effects (nervousness, insomnia), anticholinergic effects

Rimantadine

GI upset, CNS effects

Acyclovir

CNS effects (nervousness)

Valacyclovir

Headache

Famciclovir

Decreased renal famciclovir function

Ganciclovir

Bone marrow suppression, CNS effects, rash, fever

Ribavirin

Headache, GI upset, dyspnea, teratogenic

Zidovudine

Bone marrow suppression, granulocytopenia, myositis

Didanosine

Pancreatitis, neuropathy

Zalcitabine

Neuropathy

Lamivudine

Bone marrow suppression, neuropathy, malaise

Stavudine

Neuropathy, GI upset

Nevirapine

Rash

Saquinavir

Drug-drug interactions

Indinavir

Renal stones, drug-drug interactions

Ritonavir

Drug-drug interactions

Interferon

Systemic interferon use is associated with significant and frequent side effects. Common problems include severe malaise, myelosuppression, depression, and thyroid abnormalities. Patients on systemic interferon need to be closely monitored for signs of toxicity. Intralesional interferons produce pain at the injection site. Leukopenia, malaise, and fever also occur. The side effects are severe enough in approximately 10% to 20% of patients to warrant discontinuing therapy.

Immunoglobulins

Immunoglobulins are well tolerated, with pain at the injection site and brief low-grade fever the most commonly reported side effects. True allergic reactions with urticaria or angioedema rarely occur, but IV gamma globulin can activate the alternative complement pathway, producing an anaphylactoid reaction.

Others

Topical antivirals (idoxuridine, trifluorothymidine, trifluridine) are generally well tolerated. The most common side effects include mild local irritation, headaches, and nausea. Some topical agents include glucocorticoids to lessen this inflammation. The most common side effects of topical fluorouracil therapy are local pain, pruritus, and irritation. Contact dermatitis with scarring has also been reported.

New Horizons

Available antiviral agents have significantly increased since 1995. Research has been accelerated in large part by the need for effective therapies against HIV. Our ability to find, test, and produce new antivirals has been aided by our ability to clone specific viral enzymes and use computer-aided drug design to map possible target sites. Much work still needs to be done to optimize antiviral therapy

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Nucleoside Analogs

Acyclovir (Zovirax)

Famciclovir (Famvir)

Ganciclovir (Cytovene)

Ribavarin (Rebetol, Virazole)

Valacyclovir (Valtrex)

Nucleoside Reverse Transcriptase Inhibitors and Nucleotides

Abacavir (Epzicom, Trizivir, Ziagen)

Didanosine (Dideoxyinosine, ddi)

Emtricitabine (Emtriva, Truvada)

Lamivudine (Epivir)

Stavudine (Zerit)

Tenofovir (Viread)

Zalcitabine (Hivid)

Zidovudine (AZT, Retrovir)

Non-nucleoside Reverse Transcriptase Inhibitors

Delavirdine (Rescriptor)

Efavirenz (Sustiva)

Nevirapine (Viramune)

Protease Inhibitors

Amprenavir (Agenerase)

Lopinavir/Ritonavir (Kaletra)

Nelfinavir (Viracept)

Ritonavir (Norvir)

Saquinavir (Invirase, Fortovase)

Zanamivir (Relenza)

Neuraminidase Inhibitor

Oseltamivir (Tamiflu)

Fusion Inhibitors

Docosanol (Abreva)

Enfuvirtide (Fuzeon)

Palivizumab (Synagis)

Viral Uncoating Inhibitors

Amantadine (Symmetrel)

Rimantadine (Flumadine)

Immune Modulators

Immunoglobulins (H-Big, HyperHep, Hyperab, VZIG)

Interferon (Actimmune, IntronA, Alferon)

in both HIV and other chronic viral infections such as hepatitis. The utility of using mismatched RNA to inhibit viral growth is also being evaluated (see Chapter 5). Management of CMV infections in the immunocompromised patient continues to be problematic, and agents more effective against this infection are being sought.

FURTHER READING

Anonymous. Drugs for HIV infection. Treat Guidel Med Lett. 2006;4:67-76.

Anonymous. Drugs for non-HIV viral infections. Treat Guidel Med Lett. 2007;5:59-70.

Hammer et al 2006 Hammer SM, Saag MS, Schechter M, et al. International AIDS Society, USA Panel. Treatment for adult HIV infection. 2006 Recommendations of the International Aids Society-USA Panel. http://www.iasusa.org/pub/arv_2006.pdf.

Herrick TM, Million RP. Tapping the potential of fixed dose combinations. Nat Rev Drug Discov. 2007;6:513-514.

Johnson et al 2007 Johnson VA, Brun-Vezinet F, Clotet B, et al. International AIDS Society USA Panel. Update of the Drug Resistance Mutations in HIV-1:2007. http://www.iasusa.org/resistance_mutations/mutations_figures.pdf

SELF-ASSESSMENT QUESTIONS

1. A 78-year-old man presents for evaluation of a painful rash. He reports a sharp, burning pain radiating from his mid-back to his left side. He noticed a “rash” that spread “like a line” in the same area where he had pain. The rash has a dermatonal distribution from his spine around the left flank to the midline of the abdomen. It has erythematous patches with clusters of vesicles. He reports a history of chicken pox as a child. Among the following, which would be the most appropriate agent to prescribe?

A. Abacavir

B. Entecavir

C. Famciclovir

D. Oseltamivir

E. Ritonavir

2. An HIV-positive patient has been treated with zidovudine, didanosine, and nevirapine for the last 3 years, and plasma HIV RNA levels have been undetectable. However, recent plasma RT-PCR reveals that her HIV RNA levels are greater than 20,000 copies per mL. A new regimen was proposed that included abacavir, lamivudine, and efavirenz. One year later the patient’s HIV RNA level is again found to be elevated with 50,000 copies per mL. Which of the following most likely describes the reason for the failure of this second regimen?

A. The second regimen contained abacavir, which is not indicated for the treatment of HIV infections

B. The second regimen contained an NNRTI that was cross-resistant with nevirapine

C. The second regimen contained all protease inhibitors

D. The second regimen did not contain ritonavir

E. The second regimen included only three drugs, and four would be indicated when the RNA levels first increased

3. A 25-year-old man was recently diagnosed with genital herpes and was prescribed acyclovir. Although acyclovir is well distributed into most cells throughout the body, it is more active in herpesvirus (HSV)-infected cells. Which of the following mechanisms best accounts for the selective action of acyclovir in HSV-infected cells as compared with uninfected cells?

A. Competitive inhibition of viral thymidine kinase by acyclovir

B. Greater affinity of acyclovir triphosphate for cellular DNA polymerase

C. Greater inhibition of viral DNA repair enzymes

D. Inability to be converted to acyclovir triphosphate in virus-infected cells

E. Preferential conversion to acyclovir monophosphate in virus-infected cells

4. Which of the following drugs is indicated for the treatment of either influenza A or influenza B?

A. Amantadine

B. Foscarnet

C. Oseltamavir

D. Ribavarin

E. Rimantadine

5. Protease inhibitors are primarily metabolized by the P450 system, and the metabolism of other drugs can be altered in patients taking them. Which of the following drugs has the greatest potential for drug-drug interactions?

A. Oseltamavir

B. Ritonavir

C. Saquinavir

D. Stavudine

E. Zalcitabine