Antiviral Agents

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Chapter 51 Antiviral Agents

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

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.

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

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.

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 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.

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.

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.

Other Antiviral Agents

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.

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.

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.

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.

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.

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.

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.

Nonspecific Viral Inhibitors

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.

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.

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.

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

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

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.

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