Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 49. Antiviral Chemotherapy & Prophylaxis

Antiviral Chemotherapy & Prophylaxis: Introduction

As obligate intracellular parasites, the replication of viruses depends on synthetic processes of the host cell. Antiviral drugs can exert their actions at several stages of viral replication including viral entry, nucleic acid synthesis, late protein synthesis and processing, and in the final stages of viral packaging and virion release (Figure 49-1). Most of the drugs active against herpes viruses (HSV) and many agents active against human immunodeficiency virus (HIV) are antimetabolites, structurally similar to naturally occurring compounds. The selective toxicity of antiviral drugs usually depends on greater susceptibility of viral enzymes to their inhibitory actions than host cell enzymes.

FIGURE 49-1

The major sites of antiviral drug action. Note: interferon-alfas are speculated to have multiple sites of action on viral replication.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 49-1.)

One of the most important trends in viral chemotherapy, especially in the management of HIV infection, has been the introduction of combination drug therapy. This can result in greater clinical effectiveness in viral infections and can also prevent, or delay, the emergence of resistance.

Antiherpes Drugs

Most drugs active against herpes viruses are antimetabolites bioactivated via viral or host cell kinases to form compounds that inhibit viral DNA polymerases.

Acyclovir (Acycloguanosine)

Mechanisms

Acyclovir is a guanosine analog active against herpes simplex virus (HSV-1, HSV-2) and varicella-zoster virus (VZV). The drug is activated to form acyclovir triphosphate, which interferes with viral synthesis in 2 ways. It acts as a competitive substrate for DNA polymerase, and it leads to chain termination after its incorporation into viral DNA (Figure 49-2). Resistance of HSV can involve changes in viral DNA polymerase. However, many resistant strains of HSV (TK- strains) lack thymidine kinase, the enzyme involved in the initial viral-specific phosphorylation of acyclovir. Such strains are cross-resistant to famciclovir, ganciclovir, and valacyclovir.

FIGURE 49-2

Mechanism of action of antiherpes agents.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 49-3.)

Pharmacokinetics

Acyclovir can be administered by the topical, oral, and intravenous routes. Because of its short half-life, oral administration requires multiple daily doses of acyclovir. Renal excretion is the major route of elimination of acyclovir, and dosage should be reduced in patients with renal impairment.

Clinical Uses and Toxicity

Oral acyclovir is commonly used for the treatment of mucocutaneous and genital herpes lesions (Table 49-1) and for prophylaxis in AIDS and in other immunocompromised patients (eg, those undergoing organ transplantation). The oral drug is well tolerated but may cause gastrointestinal (GI) distress and headache. Intravenous administration is used for severe herpes disease, including encephalitis, and for neonatal HSV infection. Toxic effects with parenteral administration include delirium, tremor, seizures, hypotension, and nephrotoxicity. Acyclovir has no significant toxicity on the bone marrow.

TABLE 49-1 Important antiviral drugs.

Virus Primary Drugs Alternative or Adjunctive Drugs CMV Ganciclovir, valganciclovir Cidofovir, foscarnet, fomiversin HSV, VZV Acyclovira

Cidofovir, foscarnet, vidarabine HBV IFN-, lamivudine Adefovir dipivoxil, entacavir, lamivudine, telbivudine HCV IFN- Ribavirin Influenza A Oseltamivir Amantadine, rimantadine, zanamivir Influenza B Oseltamivir Zanamivir

aAnti-HSV drugs similar to acyclovir include famciclovir, penciclovir, and valacyclovir; IFN-, interferon-.

Other Drugs for HSV and VSV Infections

Several newer agents have characteristics similar to acyclovir. Valacyclovir is a prodrug converted to acyclovir by hepatic metabolism after oral administration and reaches plasma leveles 3-5 times greater than those achieved by acyclovir. Valcyclovir has a longer duration of action than acyclovir. Penciclovir undergoes activation by viral thymidine kinase, and the triphosphate form inhibits DNA polymerase but does not cause chain termination. Famciclovir is a prodrug converted to penciclovir by first-pass metabolism in the liver. Used orally in genital herpes and for herpes zoster, famciclovir is well tolerated and is similar to acyclovir in its pharmacokinetic properties. None of the acyclovir congeners has activity against TK- strains of HSV. Docosanol is an aliphatic alcohol that inhibits fusion between the HSV envelope and plasma membranes. It prevents viral entry and subsequent replication. Used topically docosanol shortens healing time.

Ganciclovir

Mechanisms

Ganciclovir, a guanine derivative, is triphosphorylated to form a nucleotide that inhibits DNA polymerases of cytomegalovirus (CMV), and HSV and causes chain termination. The first phosphorylation step is catalyzed by virus-specific enzymes in both CMV-infected and HSV-infected cells. CMV resistance mechanisms involve mutations in the genes that code for the activating viral phosphotransferase and the viral DNA polymerase. Thymidine kinase-deficient HSV strains are resistant to ganciclovir.

Pharmacokinetics

Ganciclovir is usually given intravenously and penetrates well into tissues, including the eye and the central nervous system (CNS). The drug undergoes renal elimination in direct proportion to creatinine clearance. Oral bioavailability is less than 10%. An intraocular implant form of ganciclovir can be used in CMV retinitis. Valganciclovir, a prodrug of ganciclovir, has high oral bioavailability and has decreased the use of intravenous forms of ganciclovir (and also of intravenous cidofovir and foscarnet) in end-organ CMV disease.

Clinical Uses and Toxicity

Ganciclovir is used for the prophylaxis and treatment of CMV retinitis and other CMV infections in immunocompromised patients. Systemic toxic effects include leukopenia, thrombocytopenia, mucositis, hepatic dysfunction, and seizures. The drug may cause severe neutropenia when used with zidovudine or other myelosuppressive agents.

Cidofovir

Mechanisms and Pharmacokinetics

Cidofovir is activated exclusively by host cell kinases and the active diphosphate, which inhibits DNA polymerases of HSV, CMV, adenovirus, and papillomavirus (HPV). Because phosphorylation does not require viral kinase, cidofovir is active against many acyclovir and ganciclovir-resistant strains. Resistance is due to mutations in the DNA polymerase gene. The drug is given intravenously and undergoes renal elimination. Dosage should be adjusted in proportion to creatinine clearance and full hydration maintained.

Clinical Uses and Toxicity

Cidofovir is effective in CMV retinitis, in mucocutaneous HSV infections, including those resistant to acyclovir, and in genital warts. Nephrotoxicity is the major dose-limiting toxicity of cidofovir, additive with other nephrotoxic drugs including amphotericin B and aminoglycoside antibiotics.

Foscarnet

Mechanisms

Foscarnet is a phosphonoformate derivative that does not require phosphorylation for antiviral activity. Although it is not an antimetabolite, foscarnet inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase. Resistance involves point mutations in the DNA polymerase gene.

Pharmacokinetics

Foscarnet is given intravenously and penetrates well into tissues, including the CNS. The drug undergoes renal elimination in direct proportion to creatinine clearance.

Clinical Uses and Toxicity

The drug is an alternative for prophylaxis and treatment of CMV infections, including CMV retinitis, and has activity against ganciclovir-resistant strains of this virus. Foscarnet inhibits herpes DNA polymerase in acyclovir-resistant strains that are thymidine kinase-deficient and may suppress such resistant herpetic infections in patients with AIDS. Adverse effects are severe and include nephrotoxicity (30% incidence) with disturbances in electrolyte balance (especially hypocalcemia), genitourinary ulceration, and CNS effects (headache, hallucinations, seizures).

Other Antiherpes Drugs

Vidarabine

Vidarabine is an adenine analog and has activity against HSV, VZV, and CMV. Its use for systemic infections is limited by rapid metabolic inactivation and marked toxic potential. Vidarabine is used topically for herpes keratitis but has no effect on genital lesions. Toxic effects with systemic use include GI irritation, paresthesias, tremor, convulsions, and hepatic dysfunction. Vidarabine is teratogenic in animals.

Idoxuridine and Trifluridine

These pyrimidine analogs are used topically in herpes keratitis (HSV-1). They are too toxic for systemic use.

Fomivirsen

Fomivirsen is an antisense oligonucleotide that binds to mRNA of CMV, inhibiting early protein synthesis. The drug is injected intravitreally for treatment of CMV retinitis.

Cross-resistance between fomivirsen and other anti-CMV agents has not been observed. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Fomiversin causes iritis, vitreitis, increased intraocular pressure and changes in vision.

Anti-HIV Drugs

The primary drugs effective against HIV are antimetabolite inhibitors of viral reverse transcriptase and inhibitors of viral aspartate protease (Table 49-2). The current approach to treatment of infection with HIV is the initiation of treatment with 3 or more antiretroviral drugs, if possible, before symptoms appear. Such combinations usually include nucleoside reverse transcriptase inhibitors (NRTIs) together with inhibitors of HIV protease (PI). Highly active antiretroviral therapy (HAART) involving drug combinations can slow or reverse the increases in viral RNA load that normally accompany progression of disease. In many AIDS patients, HAART slows or reverses the decline in CD4 cells and decreases the incidence of opportunistic infections.

TABLE 49-2 Major antiretroviral drugs.

Subclass Prototype Other Significant Agents Nucleoside reverse inhibitors Zidovudine Abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, zidovudine Nonnucleoside reverse transcriptase inhibitors Delavirdine Efavirenz, etravirine, nevirapine, tenofovir Protease inhibitors Indinavir Amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir CCR-5 antagonist Maraviroc Fusion inhibitor Enfuvirtide

Drug management of HIV infection is subject to change. Updated recommendations can be obtained at the following websites: ATIS, http://www.hivatis.org; and NPIN, http://www.cdcnpin.org.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

To convert their RNA into dsDNA, retroviruses require virally encoded RNA-dependent DNA polymerase (reverse transcriptase). Mammalian RNA and DNA polymerases are sufficiently distinct to permit a selective inhibition of the viral reverse transcriptase.

NRTIs are prodrugs converted by host cell kinases to triphosphates, which not only competitively inhibit binding of natural nucleotides to the dNTP-binding site of reverse transcriptase but also act as chain terminators via their insertion into the growing DNA chain. Because NRTIs lack a 3'-hydroxyl group on the ribose ring, attachment of the next nucleotide is impossible. Resistance emerges rapidly when NRTIs are used as single agents via mutations in the pol gene; cross-resistance occurs but is not complete.

Abacavir

A guanosine analog, abacavir has good oral bioavailability and an intracellular half-life of 12-24 h. HIV resistance requires several concomitant mutations and tends to develop slowly. Hypersensitivity reactions, occasionally fatal, occur in 5% of HIV patients.

Didanosine (ddI)

Oral bioavailability of ddI is reduced by food and by chelating agents. The drug is eliminated by the kidney, and the dose must be reduced in patients with renal dysfunction. Pancreatitis is dose-limiting and occurs more frequently in alcoholic patients and those with hypertriglyceridemia. Other adverse effects include peripheral neuropathy, diarrhea, hepatic dysfunction, hyperuricemia and CNS effects.

Emtricitabine

Good oral bioavailability and renal elimination with long half-life permits once-daily dosing of emtricitabine. Because of the propylene glycol in the oral solution, the drug is contraindicated in pregnancy and young children and in patients with hepatic or renal dysfunction. Common adverse effects of the drug include asthenia, GI distress, headache, and hyperpigmentation of the palms and/or the soles.

Lamivudine (3TC)

Lamivudine is 80% bioavailable by the oral route and is eliminated almost exclusively by the kidney. In addition to its use in HAART regimens for HIV, lamivudine is also effective in hepatitis B infections. Dosage adjustment is needed in patients with renal insufficiency. Adverse effects of lamivudine are usually mild and include GI distress, headache, insomnia, and fatigue.

Stavudine (d4T)

Stavudine has good oral bioavailability and penetrates most tissues, including the CNS. Dosage adjustment is needed in renal insufficiency. Peripheral neuropathy is dose-limiting and increased with coadministration of didanosine or zalcitabine. Lactic acidosis with hepatic steatosis occurs more frequently with stavudine than with other NRTIs.

Tenofovir

Although it is a nucleotide, tenofovir acts like NRTIs to competitively inhibit reverse transcript and cause chain termination after incorporation into DNA. Tenofovir also has activity against HBV (see below). Oral bioavailability of tenofovir is in the range 25-40%, the intracellular half-life is more than 60 h, and the drug undergoes renal elimination. Tenofovir may impede the renal elimination of acyclovir and ganciclovir. Adverse effects include GI distress, asthenia, and headache; rare cases of acute renal failure and Fanconi's syndrome have been reported.

Zalcitabine (ddC)

Zalcitabine has a high oral bioavailability. Dosage adjustment is needed in patients with renal insufficiency and nephrotoxic drugs (eg, amphotericin B, aminoglycosides) increase toxic potential. Dose-limiting peripheral neuropathy is the major adverse effect of ddC. Pancreatitis, esophageal ulceration, stomatitis, and arthralgias may also occur.

Zidovudine (ZDV)

Formerly called azidothymidine (AZT), zidovudine is active orally and is distributed to most tissues, including the CNS. Elimination of the drug involves both hepatic metabolism to glucuronides and renal excretion. Dosage reduction is necessary in uremic patients and those with cirrhosis. The primary toxicity of zidovudine is bone marrow suppression (additive with other immunosuppressive drugs) leading to anemia and neutropenia, which may require transfusions. GI distress, thrombocytopenia, headaches, myalgia, acute cholestatic hepatitis, agitation, and insomnia may also occur. Drugs that may increase plasma levels of zidovudine include azole antifungals and protease inhibitors. Rifampin increases the clearance of zidovudine.

NRTIs and Lactic Acidosis

NRTI agents, taken alone or in combination with other antiretroviral agents, may cause lactic acidemia and severe hepatomegaly with steatosis. Risk factors include obesity, prolonged treatment with NRTIs, and preexisting liver dysfunction. Consideration should be given to suspension of NRTI treatment in patients who develop elevated aminotransferase levels.

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

NNRTIs bind to a site on reverse transcriptase different from the binding site of NRTIs. Nonnucleoside drugs do not require phosphorylation to be active and do not compete with nucleoside triphosphates. There is no cross-resistance with NRTIs. Resistance from mutations in the pol gene occur very rapidly if these agents are used as monotherapy.

Delavirdine

Drug interactions are a major problem with delavirdine, which is metabolized by both CYP3A4 and CYP2D6. Its blood levels are decreased by antacids, ddI, phenytoin, rifampin, and nelfinavir. Conversely, the blood levels of delavirdine are increased by azole antifungals and macrolide antibiotics. Delaviridine increases plasma levels of several benzodiazepines, nifedipine, protease inhibitors, quinidine, and warfarin. Delavirdine cause skin rash in up to 20% of patients, and the drug should be avoided in pregnancy because it is teratogenic in animals.

Efavirenz

Efavirenz can be given once daily because of its long half-life. Fatty foods may enhance its oral bioavailability. Efavirenz is metabolized by hepatic cytochromes P450 and is frequently involved in drug interactions. Toxicity of efavirenz includes CNS dysfunction, skin rash, and elevations of plasma cholesterol. The drug should be avoided in pregnancy, particularly in the first trimester because fetal abnormalities have been reported in animals at doses similar to those used in humans.

Etravirine

Etravirine, the newest NNRTI approved for treatment-experienced HIV patients, may be effective against HIV strains resistant to other drugs in the group. The drug causes rash, nausea, and diarrhea. Elevations in serum cholesterol, triglycerides, and transaminase levels may occur. Etravirine is a substrate as well as an inducer of CYP3A4 and also inhibits CYP2C9 and CYP2C19 and may be involved in significant drug-drug interactions.

Nevirapine

Nevirapine has good oral bioavailability, penetrates most tissues including the CNS, has a half-life of more than 24 h and is metabolized by the hepatic CYP3A4 isoform. The drug is used in combination regimens and is effective in preventing HIV vertical transmission when given as single doses to mothers at the onset of labor and to the neonate. Hypersensitivity reactions with nevirapine include a rash, which occurs in 15-20% of patients, especially female. Stevens-Johnson syndrome and a life-threatening toxic epidermal necrolysis have also been reported. Nevirapine blood levels are increased by cimetidine and macrolide antibiotics and decreased by enzyme inducers such as rifampin.

Protease Inhibitors

The assembly of infectious HIV virions is dependent on an aspartate protease (HIV-1 protease) encoded by the pol gene. This viral enzyme cleaves precursor polyproteins to form the final structural proteins of the mature virion core. The HIV protease inhibitors are designer drugs based on molecular characterization of the active site of the viral enzyme. Resistance is mediated via multiple point mutations in the polgene; the extent of cross-resistance is variable depending on the specific protease inhibitor. Protease inhibitors (PIs) have important clinical use in AIDS, most commonly in combinations with reverse transcriptase inhibitors as components of HAART. All of the PIs are substrates and inhibitors of CYP3A4 with ritonavir having the most pronounced inhibitory effect. The PIs are implicated in many drug-drug interactions with other antiretroviral agents and with commonly used medications.

Atazanavir

This is a PI with a pharmacokinetic profile that permits once-daily dosing. Oral absorption of atazanavir requires an acidic environment—antacid ingestion should be separated by 12 h. The drug penetrates cerebrospinal and seminal fluids and undergoes biliary elimination. Adverse effects include GI distress, peripheral neuropathy, skin rash, and hyperbilirubinemia. Prolongation of the QTc interval may occur at high doses. Unlike most PIs, atazanvir does not appear to be associated with dyslipidemias, fat deposition, or a metabolic syndrome. However, it is a potent inhibitor of CYP3A4 and CYP2C9.

Darunavir

This is a newer drug used in combination with ritonavir in treatment-experienced patients with resistance to other PIs. The drug is a substrate of CYP3A4. GI adverse effects and rash occur, and liver toxicity has been reported. Darunavir contains a sulfonamide moiety and should be used with caution in sulfonamide allergy.

Fosamprenavir

Fosamprenavir is a prodrug forming amprenavir via its hydrolysis in the GI tract. The drug formulation includes propylene glycol and should not be used in children or in pregnant women. Fosamprenavir is often used in combination with low-dose ritonavir. The absorption of amprenavir is impeded by fatty foods. Amprenavir undergoes hepatic metabolism and is both an inhibitor and an inducer of CYP3A4. The drug causes GI distress, paresthesias, and rash, the latter sometimes severe enough to warrant drug discontinuation. Cross-allergenicity may occur with sulfonamides.

Indinavir

Oral bioavailability of indinavir is good except in the presence of food. Clearance is mainly via the liver, with about 10% renal excretion. Adverse effects include nausea, diarrhea, thrombocytopenia, hyperbilirubinemia, and nephrolithiasis. To reduce renal damage, it is important to maintain good hydration. Insulin resistance may be more common with indinavir than other PIs. Indinavir is a substrate for and an inhibitor of the cytochrome P450 isoform CYP3A4 and is implicated in drug interactions. Serum levels of indinavir are increased by azole antifungals and decreased by rifamycins. Indinavir increases the serum levels of antihistamines, benzodiazepines, and rifampin.

Lopinavir/Ritonavir

In this combination, a subtherapeutic dose of ritonavir acts as a pharmacokinetic enhancer by inhibiting the CYP3A4-mediated metabolism of lopinavir. Patient compliance is improved owing to lower pill burden and the combination is usually well tolerated.

Nelfinavir

This PI is characterized by increased oral absorption in the presence of food, hepatic metabolism via CYP3A4 and a short half-life. As an inhibitor of drug metabolism, nelfinavir has been involved in many drug interactions. Adverse effects include diarrhea, which can be dose-limiting. The drug has the most favorable safety profile of the PIs in pregnancy.

Ritonavir

Oral bioavailability is good, and the drug should be taken with meals. Clearance is mainly via the liver, and dosage reduction is necessary in patients with hepatic impairment. The most common adverse effects of ritonavir are GI irritation and a bitter taste. Paresthesias and elevations of hepatic aminotransferases and triglycerides in the plasma also occur. Drugs that increase the activity of the cytochrome P450 isoform CYP3A4 (anticonvulsants, rifamycins) reduce serum levels of ritonavir, and drugs that inhibit this enzyme (azole antifungals, cimetidine, erythromycin) elevate serum levels of the antiviral drug. Ritonavir inhibits the metabolism of a wide range of drugs, including erythromycin, dronabinol, ketoconazole, prednisone, rifampin, and saquinavir.

Subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of other protease inhibitors (eg, indinavir, lopinavir, saquinavir); this is the rationale for PI combinations that include ritonavir because it permits the use of lower doses of the other protease inhibitor.

Saquinavir

Original formulations of saquinavir had low and erratic oral bioavailability. Reformulation for once-daily dosing in combination with low-dose ritonavir has improved efficacy with decreased GI side effects. The drug undergoes extensive first-pass metabolism and functions as both a substrate and inhibitor of CYP3A4. Adverse effects of saquinavir include nausea, diarrhea, dyspepsia, and rhinitis. Saquinavir plasma levels are increased by azole antifungals, clarithromycin, grapefruit juice, indinavir, and ritonavir. Drugs that induce CYP3A4 decrease plasma levels of saquinavir.

Tipranavir

This is a newer drug used in combination with ritonavir in treatment-experienced patients with resistance to other PIs. The drug is a substrate and inducer of CYP3A4 and also induces P-glycoprotein transporters, possibly altering GI absorption of other drugs. For example, increased blood levels of the HMG-CoA reductase inhibitors (eg, lovastatin) may occur, thus increasing the risk for myopathy and rhabdomyolysis. GI adverse effects, rash, and liver toxicity have been reported.

Effects on Carbohydrate and Lipid Metabolism

The use of PIs in HAART drug combinations has led to the development of disorders in carbohydrate and lipid metabolism. It has been suggested that this is due to the inhibition of lipid-regulating proteins, which have active sites with structural homology to that of HIV protease. The syndrome includes hyperglycemia and insulin resistance or hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy. The syndrome has been observed with PIs used in HAART regimens, with an incidence of 30-50% and a median onset time of approximately 1 yr duration of treatment.

Entry Inhibitors

Maraviroc

HIV-1 infection begins with attachment of an HIV envelope protein called gp120 to CD4 molecules on surfaces of helper T cells and other antigen-presenting cells such as macrophages and dendritic cells. The attachment of many HIV strains involves a transmembrane chemokine receptor CCR5. This receptor, a human protein, is the target for maraviroc, which blocks viral attachment. Although resistance has occurred, there is minimal cross-resistance with other antiretroviral drugs.

Maraviroc is used orally and has good tissue penetration. It is a substrate for CYP3A4, and dosage adjustments may be needed in the presence of drugs that induce or inhibit this enzyme. Adverse effects of maraviroc include cough, diarrhea, muscle and joint pain, and increases in hepatic transaminases.

Enfuvirtide

Enfuvirtide is a synthetic 36-amino-acid peptide. The drug binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes. There is no cross-resistance with other anti-HIV drugs, but resistance may occur via mutations in the env gene. Enfuvirtide is administered subcutaneously in combination with other anti-HIV agents in previously drug-treated patients with persistent HIV-1 replication despite ongoing therapy. Its metabolism via hydrolysis does not involve the cytochrome P450 system. Injection site reactions and hypersensitivity may occur. An increased incidence of bacterial pneumonia has been reported.

Anti-Influenza Agents

Amantadine and Rimantadine

Mechanisms

Amantadine and rimantadine inhibit an early step in replication of the influenza A (but not influenza B) virus (Figure 49-1). They prevent "uncoating" by binding to a protein M2. This protein functions as a proton ion channel required at the onset of infection to permit acidification of the virus core, which in turn activates viral RNA transcriptase. Adamantine-resistant influenza A virus mutants are now common.

Clinical Uses and Toxicity

These drugs are prophylactic against influenza A virus infection and can reduce the duration of symptoms if given within 48 h after contact. However, adamantine-resistant influenza A virus mutants including H3N2 strains causing seasonal influenza in the United States have increased drammatically in the last 2-3 yr. The H1N1 strain responsible for the recent pandemic that contain genes derived from both avian and porcine influenza viruses is also resistant to the adamantines. Fortunately, there is minimal cross-resistance to the neuraminidase inhibitors. Toxic effects of these agents include GI irritation, dizziness, ataxia, and slurred speech. Rimantadine's activity is no greater than that of amantadine, but it has a longer half-life and requires no dosage adjustment in renal failure.

Oseltamivir and Zanamivir

Mechanisms

These drugs are inhibitors of neuraminidases produced by influenza A and B and are currently active against both H3N2 and H1N1 strains. These viral enzymes cleave sialic acid residues from viral proteins and surface proteins of infected cells. They function to promote virion release and to prevent clumping of newly released virions. By interfering with these actions, neuraminidase inhibitors impede viral spread. Decreased susceptibility to the drugs is associated with mutations in viral neuraminidase, but worldwide resistance remains rare.

Clinical Use and Toxicity

Oseltamivir is a prodrug used orally, activated in the gut and the liver. Zanamivir is administered intranasally. Both drugs decrease the time to alleviation of influenza symptoms and are more effective if used within 24 h after onset of symptoms. Taken prophylactically, oseltamivir significantly decreases the incidence of influenza. GI symptoms may occur with oseltamivir; zanamivir may cause cough and throat discomfort and has induced bronchospasm in asthmatic patients.

Agents Used in Viral Hepatitis

The agents available for use in the treatment of infections caused by hepatitis B virus (HBV) are suppressive rather than curative. The primary goal of drugs used for infections caused by hepatitis C virus (HCV) is viral eradication.The drugs available include interferon- (IFN-), lamivudine, adefovir dipivoxil, entacavir, telbivudine, tenofovir, and ribavirin.

IFN-

Mechanisms

IFN- is a cytokine that acts through host cell surface receptors increasing the activity of Janus kinases (JAKS). These enzymes phosphorylate signal transducers and activators of transcription (STATS) to increase the formation of antiviral proteins. The selective antiviral action of IFN- is primarily due to activation of a host cell ribonuclease that preferentially degrades viral mRNA. IFN- also promotes formation of natural killer cells that destroy infected liver cells.

Pharmacokinetics

There are several forms of IFN- with minor differences in amino acid composition. Absorption from intramuscular or subcutaneous injection is slow; elimination of IFN- is mainly via proteolytic hydrolysis in the kidney. Conventional forms of IFN- are usually administered daily or 3 times a week. Pegylated forms of IFN- conjugated to polyethylene glycol can be administered once a week.

Clinical Uses

Interferon- is used in chronic HBV as an individual agent or in combination with other drugs. When used in combinations with ribavirin, the progression of acute HCV infection to chronic HCV is reduced. Pegylated IFN-together with ribavirin is superior to standard forms of IFN- in chronic HCV. Other uses of IFN- include treatment of Kaposi's sarcoma, papillomatosis, and topically for genital warts. Interferons also prevent dissemination of herpes zoster in cancer patients and reduce CMV shedding after renal transplantation.

Toxicity

Toxic effects of IFN- include GI irritation, a flu-like syndrome, neutropenia, profound fatigue and myalgia, alopecia, reversible hearing loss, thyroid dysfunction, mental confusion, and severe depression. Contraindications include autoimmune disease, a history of cardiac arrhythmias, and pregnancy.

Adefovir Dipivoxil

Mechanisms

Adefovir dipivoxil is the prodrug of adefovir, which following its phosphorylation by cellular kinases, competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into the viral DNA. HBV resistance to adefovir—though uncommon—has recently been reported.

Pharmacokinetics and Clinical Use

Adefovir has good oral bioavailability unaffected by foods. The drug is eliminated by the kidney, and dose reductions are required in renal dysfunction.

Adefovir suppresses HBV replication and improves liver histology and fibrosis. However, serum HBV DNA reappears after cessation of therapy. Adefovir has activity against lamivudine-resistant strains of HBV.

Toxicity

Nephrotoxicity is dose-limiting. Lactic acidosis and severe hepatomegaly with steatosis may also occur.

Entecavir

Entecavir is a guanosine nucleoside that inhibits HBV DNA polymerase. Effective orally, the drug has an intracellular half-life of more than 12 h and undergoes renal elimination in part via active tubular secretion. Clinical efficacy is similar to that of lamivudine and there is cross-resistance between the 2 drugs. The drug causes headache, dizziness, fatigue, and nausea.

Lamivudine

This nucleoside inhibitor of HIV reverse transcriptase (see prior discussion) is active in chronic HBV infection. Lamivudine has a longer intracellular half-life in HBV-infected cells than in HIV-infected cells (see prior discussion) and thus can be used in lower doses for hepatitis than for HIV infection. Used as monotherapy, lamivudine rapidly suppresses HBV replication and is remarkably nontoxic. However, coinfection with HIV may increase the risk of pancreatitis. Lamivudine-resistant HBV mutants emerge at a rate of about 20% per year if the drug is used alone. On reappearance of detectable levels of HBV DNA, patients should be switched to IFN- or adefovir.

Ribavirin

Mechanisms

Ribavirin inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, respiratory syncytial virus (RSV), paramyxoviruses, HCV, and HIV. Although the precise antiviral mechanism of ribavirin is not known, the drug inhibits guanosine triphosphate formation, prevents capping of viral mRNA, and can block RNA-dependent RNA polymerases.

Pharmacokinetics and Clinical Uses

Ribavirin is effective orally (avoid antacids) and is also available in intravenous and aerosolic forms. It is eliminated by the kidney, necessitating dose reductions in renal dysfunction. Ribavirin is used adjunctively with IFN- in chronic HCV infection in patients with compensated liver disease. Monotherapy with ribavirin alone is not effective. Early intravenous administration of ribavirin decreases mortality in viral hemorrhagic fevers. Despite its alleged activity against RSV, ribavirin has been shown to have no benefit in treatment of RSV infections, although it is still recommended by some authorities in immunocompromised children.

Toxicity

Systemic use results in dose-dependent hemolytic anemia. Aerosolic ribavirin may cause conjunctival and bronchial irritation. Ribavirin is a known human teratogen, absolutely contraindicated in pregnancy.

Newer Drugs for HBV

Telbivudine, a nucleoside analog, is phosphorylated by cellular kinases to the triphosphate form, which inhibits HBV DNA polymerase. The drug is at least as effective as lamivudine in chronic HBV infections and is similar in terms of its safety profile. However, like lamivudine, HBV mutants emerge at a rate of about 20% per year if the drug is used alone. Tenofovir , an antiretroviral drug, is also approved for chronic HBV infection and is active against lamivudine- and entacavir-resistant strains.

Checklist

When you complete this chapter, you should be able to:

 Identify the main steps in viral replication that are targets for antiviral drug action.

 Describe the mechanisms of action of antiherpes drugs and the mechanisms of HSV and CMV resistance.

 List the characteristic pharmacokinetic properties and toxic effects of acyclovir, ganciclovir, cidofovir, and foscarnet.

 Describe the mechanisms of anti-HIV action of zidovudine, indinavir, and enfuvirtide.

Match a specific antiretroviral drug with each of the following, to be avoided in pregnancy: hyperpigmentation, neutropenia, pancreatitis, peripheral neuropathy, inhibition of P450, severe hypersensitivity reaction, injection site reactions.

 Identify the significant characteristics of 4 drugs active against HBV and HCV.

Identify the significant characteristics of an anti-influenza drug acting at the stage of viral uncoating and another acting at the stage of viral release

Drug Summary Table: Antivirals and Antiretrovirals

Drug Class Mechanism of Action Clinical Applications Pharmacokinetics & Interactions Toxicities ANTIVIRAL DRUGS Antiherpes drugs Acyclovir Valacyclovir (prodrug) Penciclovir Famciclovir (prodrug) Activated by viral thymidine kinase (TK) to forms that inhibit viral DNA polymerase Treatment and prophylaxis for HSV-I, HSV-2, and VZV None of these drugs is active against TK- strains Acyclovir: Topical, oral, and IV Penciclovir: Topical Famciclovir and valcyclovir: Oral Oral forms cause nausea, diarrhea, and headache IV acyclovir may cause renal and CNS toxicity Drugs for cytomegalovirus Ganciclovir Valganciclovir Cidofovir Foscarnet Viral activation of ganciclovir to form inhibiting DNA polymerase; no viral bioactivation of cidofovir and foscarnet Treatment of CMV infections in immunosuppression (eg, AIDS) and organ transplantation Ganciclovir: Oral, IV, intraocular forms Valganciclovir: Oral Cidofovir and foscarnet (IV) Ganciclovir: Bone marrow suppression, hepatic and neurologic dysfunction Cidofovir and foscarnet: Nephrotoxicity Foscarnet: CNS effects and electrolyte imbalance Antihepatitis drugs Interferon- (IFN-) Adefovir-dipivoxil Entecavir Lamivudine Ribavirin Degrades viral RNA via activation of host cell RNAase (IFN-); inhibition of HBV polymerase (others); multiple antiviral actions (ribavirin) Suppressive treatment of HBV (all drugs except ribavirin); treatment of HCV (ribavirin +/- IFN-) IFN-: Parenteral Adefovir, entacavir, lamivudine, and ribavirin: Oral Ribavirin: Inhalational IFN-: Alopecia, myalgia, depression, flu-like syndrome Adefovir: lactic acidosis, renal and hepatic toxicity Ribavirin: Anemia, teratogen Anti-influenza drugs Amantadine Rimantadine Oseltamivir Zanamivir Amantadine and rimantidine: block of M2 proton channels Oseletamivir and zanamivir inhibit neuraminidase M2 blockers virtually obsolete; others prophylaxis vs most current flu strains and shorten symptoms Oral forms except zanamivir (inhalational) Oseltamivir: Gastrointestinal effects Zanamivir: Bronchospasm in asthmatics ANTIRETROVIRAL DRUGS Nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs)a Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zalcitabine Zidovudine Inhibit HIV reverse transcriptase after phosphorylation by cellular enzymes; cross-resistance common, but incomplete Duration of action usually longer than half-life; most undergo renal elimination especially, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine Zidovudine: Bone marrow suppression Abacavir: Hypersensitivity Didanosine: Pancreatitis Stavudine, zalcitabine: Peripheral neuropathy Most NRTIs are not extensively metabolized by hepatic enzymes such as the CYP450 isoforms, so they have few interactions that concern their pharmacokinetic characteristics Nonnucleoside reverse transcriptase inhibitors (NNRTIs)Delavirdine Efavirenz Etravirine Nevirapine Inhibit HIV reverse transcriptase; no phosphorylation required; cross-resistance between NNRTIs but not with NRTIs All current NNRTIs are metabolized via CYP450 isozymes; etravirine may induce formation of CYP3A4, but inhibits other CYP450s Delavirdine, nevirapine: Rash, increased liver enzymes Efavirenz: Teratogenicity Inducers of CYP450 isozymes (eg, phenytoin, rifampin) and inhibitors (eg, azoles, PIs) alter NNRTI duration of action; note etravirine Protease inhibitors (PIs)b Atazanavir Darunavir Fosamprenavir Indinavir Nelfinavir Ritonavir Saquinavir Tipranavir Inhibit viral protein processing; cross-resistance between PIs common Elimination mainly via metabolism by CYP450 isozymes; they act as substrates and inhibitors of P450 Fosamprenavir is a prodrug forming amprenavir, a substrate and inducer of CYP450 Atazanavir, fosamprenavir, lopinavir, nelfinavir, saquinavir: GI distress and diarrhea Atazanavir: Peripheral neuropathy Amprenavir: Rash Indinavir: Hyperbilirubinemia and nephrolithiasis Ritonavirc and other PIs can inhibit CYP450 metabolism of many drugs including antihistamines, antiarrhythmics, HMG-CoA reductase inhibitors, oral contraceptives and sedative-hypnotics Drugs known to induce or inhibit CYP450 isoforms may alter the plasma levels of PIs

Entry inhibitors Enfuvirtide Maraviroc Block fusion between viral and cellular membranes (enfuvirtide); CCR5 receptor antagonist (maraviroc) Extrahepatic hydrolysis of enfuvirtide (subcutaneous injection); P450 metabolism (maraviroc) Enfuvirtide: Hypersensitivity Maraviroc: Muscle/joint pain, diarrhea, and increased liver enzymes Inducers and inhibitors of CYP450 alter elimination of maraviroc; no effects on enfuvirtide

aNRTIs, nucleoside/nucleotide reverse transcriptase inhibitors: Risk of lactic acidosis with hepatic steatosis is characteristic of the group.

bPIs, inhibitors: Risk of hyperlipidemia, fat maldistribution, hyperglycemia, and insulin resistance is characteristic of the group, with possible exception of fosamprenavir.

cRitonavir is a potent inhibitor of the 3A4 isoform of CYP450, an action used to advantage in "boosting" effects of other PIs. Drug-drug interactions between PIs and many other medications occur commonly.



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