1. 439CHAPTER43Antiviral Drugscompounds have been developed for the treatment of someviral infections.These include herpesvirus infections, humanimmunodeﬁciency virus (HIV) infection, inﬂuenza, andhepatitis.Most antiviral drugs are antimetabolites of endogenousnucleosides and prevent the replication of viral nucleic acid.Other antiviral drugs inhibit the entry, uncoating, or releaseand spread of the virus. Other targets for antiviral therapyare currently being investigated.DRUGS FOR HERPESVIRUS INFECTIONSAll herpesviruses are DNA viruses. The most commonexamples are herpes simplex virus (HSV), varicella-zostervirus (VZV), and cytomegalovirus (CMV).HSV frequently causes herpes genitalis (genital herpesinfection), herpes labialis (infection of the lips and mouth),or herpetic keratoconjunctivitis (infection of the corneaand conjunctiva).Less commonly,it causes herpeticenceph-alitis, a potentially fatal disease.VZV is the cause of chickenpox (varicella) and shingles(herpes zoster). Chickenpox occurs primarily in young chil-dren. Shingles, which is reported more frequently in theelderly, results from activation of latent VZV in dorsal rootganglia. In patients with shingles, pain and skin lesions occurin areas where the virus travels peripherally along sensorynerves to the corresponding cutaneous or mucosal surfaces.The skin lesions eventually heal but can leave residual scars.Postherpetic neuralgia is a common and disabling complica-tion of shingles.CMV infections in immunocompetent individuals areusually asymptomatic. Symptomatic CMV diseases, such asretinitis, esophagitis, and colitis, are seen most often inimmunocompromised patients, including those with HIVinfection or acquired immunodeﬁciency syndrome (AIDS).Numerous drugs are available to treat herpesvirus infec-tions. With the exception of foscarnet, all of the drugs arenucleoside analogues.Nucleoside AnaloguesDrug PropertiesChemistry and Mechanisms. Most of the nucleosideanalogues used to treat herpesvirus infections contain anaturally occurring purine or pyrimidine base combinedwith a synthetic carbohydrate moiety.The nucleoside analogues are prodrugs that are phos-phorylated by viral and host cell kinases to form activetriphosphate metabolites (Fig. 43-1). In this process, thenucleoside analogues are initially converted to monophos-phate metabolites by a virus-encoded thymidine kinase.The conversion occurs only in infected host cells, therebycontributing to the selective toxicity of the analogues. Hostcell kinases subsequently convert the monophosphates toactive triphosphate metabolites. The active metabolites thencompete with endogenous nucleoside triphosphates andcompetitively inhibit viral DNA polymerase, which in turnDrugs for Herpesvirus InfectionsNucleoside Analogues• Acyclovir (ZOVIRAX)a• Ganciclovir (CYTOVENE)• Triﬂuridine (VIROPTIC)Other Drugs• Foscarnet (FOSCAVIR)Drugs for Human ImmunodeﬁciencyVirus InfectionNucleoside and Nucleotide ReverseTranscriptase Inhibitors• Zidovudine (RETROVIR)• Lamivudine (EPIVIR)• Emtricitabine (EMTRIVA)b• Tenofovir disoproxil (VIREAD)Nonnucleoside Reverse Transcriptase Inhibitors• Efavirenz (SUSTIVA)• Nevirapine (VIRAMUNE)Protease Inhibitor• Atazanavir (REYATAZ)cFusion and Entry Inhibitors• Enfuvirtide (FUZEON)• Maraviroc (SELZENTRY)Integrase Strand Transfer Inhibitor• Raltegravir (ISENTRESS)Drugs for Inﬂuenza• Oseltamivir (TAMIFLU)• Zanamivir (RELENZA)dDrugs for Hepatitis and Other ViralInfections• Ribavirin (VIRAZOLE)• Interferon alfa-2b (INTRON A)e• Telaprevir (INCIVEK)• Boceprevir (VICTRELIS)CLASSIFICATION OF ANTIVIRAL DRUGSeAlso peginterferon alfa-2b (PEGINTRON), interferon alfa-2a (ROFERON-A), andinterferon alfacon-1 (INFERGEN).dAlso amantadine (SYMMETREL) and rimantadine (FLUMADINE).cAlso darunavir (PREZISTA), fosamprenavir (LEXIVA), ritonavir (NORVIR),saquinavir (INVIRASE), and lopinavir with ritonavir (KALETRA).bAlso abacavir (ZIAGEN), didanosine (VIDEX), and stavudine (ZERIT).aAlso famciclovir (FAMVIR), penciclovir (DENAVIR), valacyclovir (VALTREX),cidofovir (VISTIDE), and valganciclovir (VALCYTE).OVERVIEWViruses are obligate intracellular parasites that use thehost cell’s metabolic pathways for reproduction. This limitsthe number of potential sites for antiviral drug action. Fur-thermore, antibacterial and antifungal drugs have little or noeffect on viruses. Despite these obstacles, effective antiviral
2. 440 Section VII ❙ ChemotherapyHSV and VZV strains are not resistant to other nucleosideanalogues or to foscarnet. Most acyclovir-resistant strainshave been recovered from immunocompromised patients.Loss of thymidine kinase activity is the major cause ofinnate and acquired resistance to acyclovir.Resistance of CMV to ganciclovir is a more serious clini-cal problem than is HSV resistance, but most ganciclovir-resistant CMV strains are sensitive to cidofovir and foscarnet.Loss of a virus-speciﬁc protein kinase is the major cause ofresistance to ganciclovir.Acyclovir, Famciclovir, and ValacyclovirAcyclovir,famciclovir, and valacyclovir are nucleoside ana-logues that are effective in the treatment of various HSVand VZV infections (see Table 43-2). These drugs are notprevents the synthesis of viral DNA. Some nucleoside ana-logues (e.g., acyclovir) are incorporated into nascent viralDNA and cause DNA chain termination because they lackthe 3-hydroxyl group required for attachment of the nextnucleoside (see Fig. 43-1). Other analogues (e.g., ganciclovirand penciclovir) inhibit viral DNA polymerase but do notcause DNA chain termination.Pharmacokinetics and Indications. The properties andclinical uses of individual drugs for herpesvirus infectionsare compared in Tables 43-1 and 43-2.Viral Resistance. The incidence of resistance to thenucleoside analogues varies with the drug and viral patho-gen. Resistance of HSV and VZV to acyclovir is notcommon, and resistant strains are usually less infective thanare sensitive strains. Furthermore, most acyclovir-resistantFIGURE 43-1. Mechanisms of action of nucleoside analogues used in the treatment of viral infections. Acyclovir and other nucleoside analogues are con-verted to active nucleoside triphosphates by viral and host cell kinases. These active nucleoside triphosphates compete with the corresponding endogenousnucleoside triphosphates and competitively inhibit viral DNA polymerase. Acyclovir and the nucleoside reverse transcriptase inhibitors (NRTIs) are incor-porated into viral DNA and cause chain termination because they lack the 3-hydroxyl group required to attach the next nucleoside. Ganciclovir andpenciclovir do not cause chain termination.OOH2NHOHNNNNOOPGGuanine (G)Acyclovir(acycloguanosine)Acycloguanosinemonophosphate(acyclo-GMP)Viral kinaseOOPGPPAcycloguanosinetriphosphate(acyclo-GTP)Host cell kinaseViral DNApolymeraseOH2NNNNNHOH2COHO1´2´3´OGuanosinePTOPCOPCOPGOPAOOPPCGOPTOPCOPGViral DNAGrowingstrandTemplate
3. Chapter 43 ❙ Antiviral Drugs 441sufﬁciently active against CMV to be effective in treatingCMV infections, but acyclovir and valacyclovir can be usedfor prophylaxis of CMV infections, such as in bone marrowand organ transplant recipients and in persons with HIVinfection. All three drugs are available for oral use. In addi-tion, acyclovir is available for intravenous and topical use.The intravenous form of acyclovir is the most effectivetreatment for serious herpesvirus infections, including her-petic encephalitis and severe HSV and VZV infections inimmunocompromised patients.The topical form of acyclovir can be used to treatherpes genitalis and mild mucocutaneous infections inimmunocompromised patients. In cases of herpes genitalis,however, the topical form is less effective than the oral formof acyclovir.In its oral form, acyclovir has a relatively low bioavail-ability (22%). Valacyclovir, which was developed later thanacyclovir, is a prodrug that is rapidly converted to acyclovirby intestinal and hepatic enzymes and is more completelyabsorbed than acyclovir. Because of its greater bioavailability(55%), valacyclovir requires less frequent administrationthan acyclovir. Famciclovir has the greatest bioavailability(80%) and is rapidly hydrolyzed to penciclovir after itsabsorption.TABLE 43-1 Pharmacokinetic Properties of Antiviral Drugs*DRUGROUTES OFADMINISTRATIONORALBIOAVAILABILITY (%)ELIMINATIONHALF-LIFE (HOURS) ROUTES OF ELIMINATIONDrugs for Herpesvirus InfectionsAcyclovir Oral, IV, or topical 22 3 Renal excretionCidofovir IV NA 2.5 Renal excretionFamciclovir Oral 80 2 Metabolism; renal and fecal excretionGanciclovir Oral or IV 8 4 Renal excretionPenciclovir Topical NA NA NATriﬂuridine Topical ocular NA NA NAValacyclovir Oral 55 3 Renal excretionFoscarnet IV NA 5 Renal excretionDrugs for HIV InfectionNRTIsDidanosine Oral 30 2 Metabolism; renal excretionLamivudine Oral 85 6 Renal excretionStavudine Oral 85 3.5 Renal excretionTenofovir disoproxilfumarateOral 25 (active metabolite) 17 Renal excretionZidovudine Oral or IV 65 1 Metabolism; renal excretionNNRTIsEfavirenz Oral 50 65 Metabolism; fecal excretionNevirapine Oral 92 30 Metabolism; fecal excretionProtease InhibitorsAtazanavir Oral Dose dependent 7 MetabolismDarunavir Oral 37 (alone)82 (with ritonavir)15 Metabolism; fecal excretionRitonavir Oral 80 4 Metabolism; fecal excretionSaquinavir Oral 12 12 Metabolism; fecal excretionLopinavir Oral 80 6 Metabolism; fecal excretionOther DrugsEnfuvirtide Subcutaneous NA 3 MetabolismMaraviroc Oral 25 16 MetabolismRaltegravir Oral Unknown 9 Fecal and renal excretion ofglucuronide metaboliteDrugs for InﬂuenzaOseltamivir Oral 75 8 Metabolism; renal excretionZanamivir Nasal NA U Metabolism; renal excretionDrugs for Other Viral InfectionsInterferon alfa-2b Subcutaneous NA 7 MetabolismPeginterferon alfa-2b Subcutaneous NA 40 MetabolismRibavirin Inhalation or IV NA 9.5 Metabolism; renal excretion*Values shown are the mean of values reported in the literature.HIV, Human immunodeﬁciency virus; IV, intravenous; NA, not applicable; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTIs, nucleoside reverse transcriptaseinhibitor; U, unknown.
4. 442 Section VII ❙ ChemotherapyTABLE 43-2 Use of Drugs for Treating Herpesvirus InfectionsDRUGHERPESGENITALISHERPESLABIALISHERPETICKERATOCONJUNCTIVITISHERPETICENCEPHALITIS CHICKENPOX SHINGLESCYTOMEGALOVIRUSDISEASESAcyclovir Yes Yes No Yes Yes Yes No*Cidofovir No No No No No No Yes†Famciclovir Yes Yes No No No Yes NoFoscarnet Yes†No No No No Yes†Yes†Ganciclovir No No Yes No No No YesPenciclovir No Yes No No No No NoTriﬂuridine No No Yes No No No NoValacyclovir Yes Yes No No No Yes No*Valganciclovir No No No No No No Yes*Can be used for prophylaxis but not for treatment.†For treating patients with intolerance of or resistance to other drugs.When acyclovir, famciclovir, or valacyclovir is given orallyfor the treatment of herpes genitalis, it prevents the replica-tion of HSV and thereby reduces pain and other symptomsof acute infection. It also shortens the time to healing oflesions and reduces the amount of viral shedding. It does noteliminate the virus, and recurrent episodes of infection arecommon. Shorter courses of therapy are usually sufﬁcientfor these episodes, because recurrent infections are usuallymilder than the initial infection. Severe herpes genitalis mayrequire intravenous acyclovir therapy.When acyclovir, famciclovir, or valacyclovir is given orallyfor the treatment of shingles, it shortens the duration ofacute illness, acute pain, and postherpetic pain (neuralgia).In patients with shingles, famciclovir and valacyclovir appearto be more effective than acyclovir. The newer drugs allowfor less-frequent administration and provide higher serumdrug levels because of their greater oral bioavailability. Anew vaccine has been shown to reduce the incidence andseverity of herpes zoster infections in older adults.Acyclovir is available in an oral suspension for the treat-ment of children with chickenpox. The drug has a goodsafety record in this setting.Acyclovir, famciclovir, and valacyclovir are well toleratedwhen given orally, and they do not have signiﬁcant interac-tions with other drugs. Gastrointestinal disturbances, head-ache, and rash are the most common side effects. Intravenousadministration of acyclovir can produce phlebitis and revers-ible renal dysfunction. Resistance to these drugs is rare inimmunocompetent patients, but drug-resistant strains havebeen recovered from immunocompromised subjects.PenciclovirPenciclovir, the active metabolite of famciclovir, is nowavailable in a topical cream formulation for the treatment ofherpes labialis. In a study of patients with a history of fre-quent herpes labialis episodes, use of penciclovir was foundto shorten the time to healing and the duration of pain byabout a day. It also was found to decrease the duration ofviral shedding.Ganciclovir, Valganciclovir, and CidofovirGanciclovir and cidofovir are nucleoside analogues that havebeen primarily used to prevent and treat CMV diseases,including retinitis, esophagitis, and colitis. Ganciclovir isabout 100 times more active against CMV than is acyclovir.Both ganciclovir and cidofovir are available for intravenoususe, and ganciclovir is also available for oral use. Ganciclovirhas a relatively low oral bioavailability, so oral administrationis used only for long-term suppression of CMV retinitis.Ganciclovir is also active against herpes simplex and is avail-able as an ophthalmic gel to treat acute epithelial keratitis(infection of the corneal epithelium) caused by HSV-1 andHSV-2. Other treatments for this ocular infection includetriﬂuridine.Valganciclovir is a prodrug that has better oral bioavail-ability than ganciclovir and is converted to ganciclovir in thebody. It is approved for prevention and treatment of CMVinfections, including those occurring in renal and hearttransplant patients.Ganciclovir produces a much higher incidence of adverseeffects than do acyclovir and famciclovir. The most commonserious adverse effects are leukopenia and thrombocy-topenia. Severe myelosuppression is more likely if thedrug is given concurrently with zidovudine (ZDV). Otheradverse effects of ganciclovir include retinal detachment,liver and renal dysfunction, rash, fever, and gastrointestinaldisturbances.Cidofovir is generally reserved for infections that areresistant to ganciclovir or other drugs, because it can causenephrotoxicity, neutropenia, metabolic acidosis, and otherserious adverse effects. About 25% of patients have discon-tinued cidofovir because of adverse reactions. The drug iscontraindicated in patients who are taking other nephrotoxicdrugs, such as aminoglycosides or amphotericin B.TriﬂuridineTriﬂuridine is administered topically to treat ocular herpes-virus infections, primarily herpetic epithelial keratitis andkeratoconjunctivitis. Herpetic keratitis typically manifestsas a characteristic dendritic (branching) lesion in the cornea.The drug is generally well tolerated but can cause superﬁcialocular irritation and hyperemia.Other Drugs for Herpesvirus InfectionsFoscarnet is a pyrophosphate derivative that blocks thepyrophosphate-binding sites on viral DNA polymeraseand prevents attachment of nucleotide precursors to DNA.Unlike the nucleoside analogues used to treat herpesvirusinfections, foscarnet does not require activation by viral orhost cell kinases.
5. Chapter 43 ❙ Antiviral Drugs 443The drugs now available for treatment of HIV infectioninclude those that inhibit fusion and entry, reverse transcrip-tase, integrase strand transfer, and protease.Reverse Transcriptase InhibitorsThe two most important types of reverse transcriptaseinhibitors are the nucleoside reverse transcriptase inhibi-tors (NRTIs) and the nonnucleoside reverse transcriptaseinhibitors (NNRTIs). Small amounts of the NRTIs areconverted to their active triphosphate metabolites by hostcell kinases. The triphosphate metabolites (nucleotides)compete with the corresponding endogenous nucleoside tri-phosphates for incorporation into viral DNA in the reactioncatalyzed by reverse transcriptase. Once incorporated intoDNA, the NRTIs cause DNA chain termination in thesame manner as described earlier for acyclovir (see Fig.43-1). The NRTIs also inhibit host cell DNA polymeraseto varying degrees, and this may account for some of theirtoxic effects (e.g., anemia).Unlike the NRTIs, the nonnucleoside drugs bind directlyto reverse transcriptase and disrupt the catalytic site. Hencethe NNRTIs do not require phosphorylation for activity.Because they act by different mechanisms, the NRTIs andNNRTIs exhibit synergistic inhibition of HIV replicationwhen they are given concurrently.Tenofovir disoproxil fumarate (TDF), a diphosphonatediester of a nucleoside drug, is classiﬁed as a nucleotidereverse transcriptase inhibitor (a nucleotide being a phos-phate ester of a nucleoside). As a nucleotide prodrug, TDFis hydrolyzed in the body to form tenofovir, and thenTABLE 43-3 Regimens for Initial Treatmentof Human ImmunodeﬁciencyVirus Infection in Adultsand Adolescents*Preferred RegimensNonnucleoside Reverse Transcriptase Inhibitor–BasedRegimen• Efavirenz + tenofovir + emtricitabine or lamivudineProtease Inhibitor–Based Regimens• Atazanavir/ritonavir + tenofovir + emtricitabine or lamivudine• Darunavir/ritonavir + tenofovir + emtricitabine or lamivudineIntegrase Strand Transfer Inhibitor–Based Regimen• Raltegravir + tenofovir + emtricitabine or lamivudineRegimen for Pregnant Women• Lopinavir/ritonavir + zidovudine + lamivudine or emtricitabineAlternative RegimensNonnucleoside Reverse Transcriptase Inhibitor–BasedRegimens• Efavirenz + abacavir or zidovudine + lamivudine or emtricitabine• Nevirapine + zidovudine + lamivudine or emtricitabineProtease Inhibitor–Based Regimens• Atazanavir/ritonavir + abacavir or zidovudine + lamivudine oremtricitabine• Fosamprenavir/ritonavir + abacavir or zidovudine + lamivudine oremtricitabine†• Lopinavir/ritonavir + abacavir or zidovudine + lamivudine oremtricitabine†*Updated January 10, 2011. For details and updates, see http://aidsinfo.nih.gov.†Can substitute tenofovir + emtricitabine in place of listed nucleoside reversetranscriptase inhibitors.Foscarnet is active against CMV, VZV, and HSV. It mustbe administered intravenously and is used to treat CMVretinitis in patients with AIDS and to treat acyclovir-resistant HSV infections and shingles. Foscarnet can becombined with ganciclovir to treat infections that are resis-tant to either drug alone.Adverse reactions to foscarnet include renal impairmentand acute renal failure, hematologic deﬁciencies, cardiacarrhythmias and heart failure, seizures, and pancreatitis.Renal toxicity can be minimized by administering intrave-nous ﬂuids to induce diuresis before and during foscarnettreatment.DRUGS FOR HUMAN IMMUNODEFICIENCYVIRUS INFECTIONRemarkable advances have been made in the treatment ofHIV infection and AIDS as new drugs and drug classes aredeveloped and used.The combined use of two or more drugsfrom different classes has been shown to markedly reduceviral loads and improve survival in HIV-positive individuals.This type of multidrug treatment has been called highlyactive antiretroviral therapy (HAART). Initially, HAARTregimens were complicated and required multiple doses ofseveral drugs every day. In recent years, emphasis has beenplaced on developing drug regimens that require only a fewdoses each day, or even a single pill. This has been accom-plished by developing longer-acting drugs and combinationdrug products. The guidelines for treating HIV infectioncontinue to evolve as new drug regimens are developedand tested. The current recommendations for previouslyuntreated (therapy-naïve) adult HIV patients are listed inTable 43-3.Sites of Drug ActionHIV is an RNA retrovirus. Its replication and sites of drugaction are depicted in Figure 43-2. Viral replication beginswhen glycoprotein 120 on the surface of HIV-1 binds tothe CD4 (cell differentiation–4) antigen on the surface ofHIV-speciﬁc helper lymphocytes (CD4 cells). Binding ofglycoprotein 120 to CD4 causes a conformational change inglycoprotein 120, enabling it to interact with the chemokineco-receptor (CCR5 or CXCR4) on the lymphocyte surface.These events expose a virus fusion protein, glycoprotein 41,which undergoes a conformational change so it can inserta hydrophobic tail into the host cell membrane and bindhost cell integrins, leading to fusion of the viral and hostcell membranes and transfer of the viral genome into thecytoplasm.Once HIV enters the CD4 cell, viral RNA serves as atemplate to produce a complementary doubled-strandedDNA in a reaction catalyzed by viral reverse transcriptase(RNA-dependent DNA polymerase). The viral DNA thenenters the host cell nucleus and is incorporated into the hostgenome in a reaction catalyzed by HIV integrase. Eventu-ally the viral DNA is transcribed and translated to producelarge, nonfunctional polypeptides called polyproteins.These polyproteins are packaged into immature virions atthe cell surface. An enzyme called HIV protease cleaves thepolyproteins into smaller, functional proteins in a processcalled viral maturation as the virions are released into theplasma.
6. 444 Section VII ❙ ChemotherapyViral Resistance. Resistance to NRTIs can developduring therapy and is more likely to occur in persons receiv-ing single-drug therapy for 6 months or longer. Studies ofZDV indicate that HIV type 1 (HIV-1) acquires resistanceto the drug in a stepwise manner involving four or ﬁve spe-ciﬁc mutations in the gene that encodes the reverse tran-scriptase enzyme. Because the virus undergoes frequentmutations, the only way to prevent resistance is to preventHIV replication by using combination drug therapy. Resis-tance to lamivudine is associated with a mutation in the HIVreverse transcriptase gene. Reduced sensitivity of hepatitis Bvirus to lamivudine is related to mutations in the catalyticdomain of hepatitis B virus DNA polymerase.Adverse Effects and Interactions. As shown in Table43-4, the NRTIs differ in their major toxicities and in theirinteractions with other drugs. ZDV produces bone marrowsuppression and can cause anemia and neutropenia. Didano-sine and stavudine can cause pancreatitis, and didanosinecan also cause peripheral neuropathy. Abacavir (ABC) ismore likely to cause a hypersensitivity reaction, whereastenofovir produces renal impairment in some patients.Speciﬁc DrugsZDV was the ﬁrst NRTI to be developed, and it is still oneof the more widely used drugs in this class. ZDV is alwayscombined with other drugs and is available in productscontaining ZDV with lamivudine or emtricitabine, and aformulation containing ZDV,lamivudine, and ABC. Com-bination therapy produces a greater reduction in viral loadthan is obtained with a single drug, and decreases the riskof emergence of drug resistance.Early studies found that ZDV treatment signiﬁcantlyreduced in utero transmission of HIV from infected preg-nant women to their offspring when administered from the14th to the 34th weeks of gestation. Combination drugtenofovir is converted to tenofovir diphosphate by CD4cell kinases. Tenofovir diphosphate competes with deoxy-adenosine 5´-triphosphate and is incorporated into viralDNA by reverse transcriptase, causing DNA chain termina-tion. Hence tenofovir is similar to the NRTIs in its mannerof activation and mechanism of action.Nucleoside Reverse Transcriptase InhibitorsThe NRTIs were the ﬁrst class of drugs developed for thetreatment of HIV-positive individuals, and they are includedin almost all HIV treatment regimens. Although all NRTIshave the same basic mechanism of action, different drugs inthe class serve as antimetabolites of different purine andpyrimidine bases of DNA. For this reason, an NRTI is oftenmore effective when it is given in combination with anotherNRTI than when it is given alone. As shown in Table 43-3,two NRTIs are usually combined with either an NNRTI ora protease inhibitor (PI).Drug PropertiesChemistry and Pharmacokinetics. The NRTIs are syn-thetic derivatives of naturally occurring nucleosides. Did-anosine is a purine base congener, whereas lamivudine,stavudine, emtricitabine, and ZDV are pyrimidine base con-geners. All of the NRTIs can be given orally, and ZDV canalso be given intravenously. The NRTIs cross the blood-brain barrier and are distributed to the cerebrospinal ﬂuid.The drugs are eliminated primarily by renal excretion, andrenal impairment will prolong their plasma elimination half-life and may necessitate a reduction in dosage.Spectrum and Indications. The NRTIs are the founda-tion of chemotherapy for HIV infection. In addition toinhibiting the replication of human and animal retroviruses,some of the NRTIs have demonstrated activity against hep-atitis B virus and Epstein-Barr virus.FIGURE 43-2. Sites of action of drugs for human immunodeﬁciency virus (HIV) infection. Enfuvirtide inhibits the fusion of HIV with host CD4 cellmembranes. After the virus penetrates the host cell and becomes uncoated, the viral RNA is transcribed by reverse transcriptase to form viral DNA. ViralDNA is incorporated into the host genome in the cell nucleus by HIV integrase. The viral DNA is then transcribed to RNA. Viral RNA is incorporatedinto new virions and is translated to synthesize polyproteins. The polyproteins are cleaved into viral proteins by HIV protease as the new virions are releasedfrom the cell.Viral RNAViral RNAViral DNA PolyproteinsProteaseCell nucleusReversetranscriptaseIntegraseSite of action ofprotease inhibitorsSite of action of reversetranscriptase inhibitorsSite of actionof enfuvirtideandmaravirocSite of actionof raltegravir
7. Chapter 43 ❙ Antiviral Drugs 445therapy is now recommended for most pregnant womenwith HIV infection (see Table 43-3).Newer NRTIs are now recommended for the initial treat-ment of HIV infection, including TDF and emtricitabine(ﬂuorothiacytidine [FTC]), as shown in Table 43-3. A com-bination drug product containing tenofovir, emtricitabine,and efavirenz (Atripla) is now available and enables once-a-day therapy with a single pill for many HIV patients.Lamivudine, or 3-thiacytosine (3TC), causes relativelyfew adverse effects and is often used in combination withZDV. Lamivudine is also used in the treatment of hepatitisB virus. Stavudine and didanosine are used as alternativesto ﬁrst-line drugs, for example, in cases in which a ﬁrst-linedrug is not tolerated or when viral resistance occurs. Forexample, stavudine is used as a substitute for ZDV in personswho cannot tolerate ZDV or who fail to respond to it. ZDVand stavudine are not used together because they appear tobe antagonistic. Didanosine, or dideoxyinosine (ddI), ismainly used in combination with lamivudine or emtric-itabine plus a PI.Nonnucleoside Reverse Transcriptase InhibitorsThe NNRTIs include efavirenz, nevirapine, and delavirdine.These drugs directly inhibit reverse transcriptase. UnlikeNRTIs, NNRTIs do not require metabolic activation, andthey are not incorporated into viral DNA. Efavirenz is themost potent NNRTI currently available and is the preferredNNRTI for the initial treatment of patients with HIV infec-tion. Unlike other NNRTIs, efavirenz can be taken once aTABLE 43-4 Most Important Adverse Effects and Interactions of Drugs for Human ImmunodeﬁciencyVirus InfectionDRUG ADVERSE EFFECTS AND INTERACTIONSNRTIsAll NRTIs Lactic acidosis, hepatic steatosis, and lipodystrophy (all higher with stavudine)Abacavir Hypersensitivity reactionsDidanosine Pancreatitis, peripheral neuropathy, gastrointestinal intoleranceEmtricitabine Headache, nausea, diarrhea, fatigue, depression, insomniaStavudine Pancreatitis, peripheral neuropathyTenofovir Headache, gastrointestinal intolerance, renal impairmentZidovudine Headache, gastrointestinal intolerance, bone marrow suppressionNNRTIsAll NNRTIs Rash, drug interactionsEfavirenz Neuropsychiatric reactions, teratogenic effectsNevirapine Hepatotoxicity, rash including Stevens-Johnson syndrome; increases metabolism of protease inhibitors,contraceptive steroids, and other drugsProtease InhibitorsAll protease inhibitors Lipodystrophy (fat accumulation), hyperlipidemia, insulin resistance and diabetes, liver dysfunction andhepatitis; inhibit metabolism of other drugs including protease inhibitors, antiarrhythmic agents, opioids,and tricyclic antidepressantsAtazanavir PR interval prolongationFosamprenavir Gastrointestinal intolerance, rashLopinavir, ritonavir Gastrointestinal intoleranceOther DrugsEnfuvirtide Injection site reactions, hypersensitivity reactionsMaraviroc Upper respiratory symptoms, possible hepatotoxicityRaltegravir Headache, diarrhea, nausea, vomitingNNRTI, Nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor.day. Nevirapine is most often used in combination with twoNRTIs (see Table 43-3). Delavirdine is not recommendedfor most patients with HIV infection because of its lowerantiviral activity compared with other drugs in its class.Drug PropertiesPharmacokinetics. The NNRTIs are administered orallyand have good oral bioavailability (see Table 43-1). They arehighly lipophilic, and the concentrations that they reach inthe central nervous system are adequate for antiviral activity.The drugs are extensively metabolized before undergoingfecal and renal excretion.Activity, Indications, and Viral Resistance. In vitrostudies show that NNRTIs act synergistically with NRTIsand PIs against HIV. The NNRTIs are never used alone totreat patients with HIV infection, because viral resistancedevelops rapidly unless they are combined with other drugs.Preferred regimens for previously untreated (therapy-naïve) adult HIV patients are listed in Table 43-3.Adverse Effects and Interactions. NNRTIs are moder-ately well tolerated. Rash is the most common side effect ofthese drugs. In patients with a mild rash, the drugs canusually be continued or restarted. Patients should be moni-tored, however, because the rash can progress to Stevens-Johnson syndrome. Efavirenz is teratogenic in primates andshould be avoided in pregnant women and women who maybecome pregnant. Efavirenz can also cause neuropsychiatricreactions. Nevirapine induces CYP3A4 and CYP2B6 andaccelerates the metabolism of certain drugs (see Table 43-4).
8. 446 Section VII ❙ ChemotherapyFusion and Entry InhibitorsMaraviroc and enfuvirtide are newer drugs that inhibit thefusion and entry of HIV. They are active against HIVstrains that are resistant to reverse transcriptase and PIs, andthey are approved for treatment of HIV infection causedby drug-resistant strains. In this setting, these drugs havebeen shown to decrease viral loads, increase CD4 cells, andimprove symptoms.Maraviroc is an antagonist of chemokine co-receptor 5(CCR5). Maraviroc binds to CCR5 and prevents interactionwith HIV-1 glycoprotein 120 (see earlier), which is neces-sary for CCR5-tropic HIV-1 to enter cells. The drug doesnot bind CXCR4 and is active only against CCR5-tropicHIV strains. It has been shown to have a synergistic effectwith enfuvirtide.Enfuvirtide (T-20) is a large peptide that binds to HIVglycoprotein 41 and thereby blocks the fusion process.Because of its peptide structure,enfuvirtide is not active whengiven orally and must be injected subcutaneously twice daily.This injection often causes injection site reactions, which canbe minimized by rotating injection sites. Enfuvirtide is oth-erwise well tolerated and is approved for use in both adultsand children. In clinical trials called TORO-1 and TORO-2(T-20 versus Optimized Regimen Only, trials 1 and 2), enfu-virtide was given to patients who had developed resistance toother antiretroviral drugs. In these studies, enfuvirtide—incombination with an optimized regimen of antiretroviralagents—caused a signiﬁcantly greater decrease in viral loadsand a signiﬁcantly greater increase in CD4 cell counts thandid the other antiretroviral agents given alone. Enfuvirtideappears to represent a valuable alternative to other anti-HIVdrugs when drug resistance or intolerance occurs.Integrase Strand Transfer InhibitorIntegrase incorporates the viral DNA formed by reversetranscriptase into the DNA of CD4 cells through a multi-step process. First, integrase removes the last nucleotidefrom both 3´ ends of the viral DNA strand to enable forma-tion of a preintegration complex of viral DNA, integrase,and other viral and host cell proteins. This complex is ableto pass from the cell cytoplasm into the nucleus, whereintegrase randomly incorporates viral DNA into the hostchromosome by DNA strand transfer.Raltegravir is the ﬁrst integrase strand inhibitor to beapproved for treating HIV infections. It appears that ralte-gravir prevents DNA strand transfer by binding divalentcations in the catalytic core of integrase that are requiredfor interaction of the enzyme with host cell DNA.Raltegravir has potent in vitro activity against wild-typeand multidrug-resistant HIV strains. Clinical trials foundthat raltegravir, when used in combination with other anti-retroviral agents, decreased viral loads and increased CD4cells, and the drug has been shown to effectively treat infec-tions caused by resistant strains. Recent recommendationsfor the initial treatment of HIV infections include a regimencontaining raltegravir (see Table 43-3).Raltegravir is given orally twice daily without regard tofood, and its terminal half-life is about 9 hours. Headache,diarrhea, nausea, and vomiting were the most commonadverse effects in clinical trials. The drug is not a substratefor cytochrome P450 enzymes and does not appear to inhibitor induce these enzymes.In addition to skin rash, it can also cause hepatotoxicity andshould not be used in patients with hepatic impairment.Drug interactions and other common adverse effects ofNNRTIs are listed in Table 43-4.Protease InhibitorsHIV protease cleaves the gag-pol (group-speciﬁc antigen-polymerase) polyprotein to provide functional viral proteinsand is essential for the maturation of the virus. PIs bind theactive site of the enzyme and inhibit proteolytic activity,resulting in production of immature, noninfectious viralparticles.Saquinavir, the ﬁrst HIV PI, was approved in 1995, ush-ering in a new era in the treatment of HIV infection andAIDS. Other PIs were subsequently developed, includinglopinavir and ritonavir. More recently, PIs that are bettertolerated and have improved pharmacokinetic propertieswere introduced, including atazanavir, darunavir, andfosamprenavir. Atazanavir and darunavir are currentlythe preferred PIs for treating most HIV patients (seeTable 43-3).Because ritonavir inhibits the metabolism of other PIs, itis usually combined with other PIs to increase their plasmalevels and duration, and this is known as boosted therapy.Combination drug products containing ritonavir and anotherPI are available and have become the standard mode of PIadministration in HIV therapy (see Table 43-3).Tables 43-1 and 43-4 compare information on the prop-erties, effects, and interactions of selected PIs. Figure 43-2shows the site of action of these drugs.Drug PropertiesPharmacokinetics. PIs are given orally and are exten-sively metabolized by cytochrome P450 enzymes beforeundergoing fecal excretion.Activity, Indications, and Viral Resistance. PIs are syn-ergistic with NRTIs and are often combined in treatmentregimens. Administration of a PI and two NRTIs signiﬁ-cantly reduces viral load, increases CD4 cells, and slows theclinical progression of disease and the emergence of drugresistance. Resistance to PIs is associated with the accumu-lation of mutations resulting in amino acid substitutionsin the viral protease structure. Varying degrees of cross-resistance occur between different PIs, but cross-resistancebetween PIs and reverse transcriptase inhibitors is rare.The preferred PI and NRTI combinations are listed inTable 43-3.Adverse Effects and Interactions. All PIs can causelipid accumulation in tissues (lipodystrophy) and hyperlip-idemia, insulin resistance and diabetes, elevated liver func-tion test results, and drug interactions. Ritonavir appears toproduce the highest incidence of adverse effects, whereasatazanavir is better tolerated that most other PIs and hasa lower propensity to cause diarrhea, lipodystrophy, andhyperlipidemia.PIs interact with a number of other drugs (see Table 43-4)via inhibition of cytochrome P450 enzymes. They have thegreatest effect on drugs metabolized by the CYP3A4isozyme, and they can cause a severalfold increase in theplasma concentration of these drugs and other PIs. TheNNRTI nevirapine increases the metabolism and decreasesthe therapeutic effect of PIs.
9. Chapter 43 ❙ Antiviral Drugs 447replication. Second, it inactivates respiratory tract mucusthat would otherwise prevent spreading of virions throughthe respiratory tract. Neuraminidase accomplishes this bycleaving sialic acid residues attached to mucus proteins.Oseltamivir and zanamivir are active against most currentinﬂuenza strains, including inﬂuenza A 2009 H1N1, 2009H3N2, and the H5N1 avian inﬂuenza strain. Oseltamiviris given orally and can be used for both prophylaxis andtreatment of inﬂuenza in patients who are at least 1 year ofage. For treatment of inﬂuenza, oseltamivir is administeredorally twice a day for 5 days, and it is given once daily forprophylaxis. Zanamivir is administered as a nasal spraytwice daily for treatment of inﬂuenza in persons who are atleast 7 years of age, and for prophylaxis in persons at least 5years of age. Because it is administered intranasally, zanami-vir should not be used by patients with underlying airwaydisease, such as asthma or emphysema.Evidence gained during the 2010-2011 inﬂuenza seasonshows that the neuraminidase inhibitors are most beneﬁcialin reducing symptom severity and duration of illness ifadministered less than 3 days after the onset of symptoms,preferably within the ﬁrst 48 hours. However, the drugs stillprovide beneﬁt in reducing respiratory failure and death inTreatment ConsiderationsThe decision to initiate therapy for HIV infection is basedon several considerations, including the patient’s CD4 count(expressed in terms of the number of T cells per microliter[μL]), the patient’s viral load (expressed in terms of thenumber of HIV RNA copies per milliliter), and whetherthe patient has clinical symptoms of disease. It is now rec-ommended that antiretroviral therapy be initiated in symp-tomatic patients with an AIDS-deﬁning illness and inpatients with less than 350 CD4 cells/μL. Therapy shouldbe strongly considered for patients with CD4 counts between350 and 500, and about half of the consultants developingthe latest guidelines favor therapy for patients with morethan 500 CD4 cells/μL.The patient’s viral load can be usefulin deciding when to initiate therapy, and those with morethan 100,000 viral RNA copies per milliliter should betreated, regardless of their CD4 cell count.Drug regimens for treating HIV infection in adults andadolescents are listed in Table 43-3. The preferred regimensfor initial drug therapy consist of two NRTIs and either anNNRTI or a PI. The NNRTI-based regimens are the sim-plest for patients to take, and the formulation containingtenofovir, emtricitabine, and efavirenz allows for once-daily administration with a single pill. PI-based regimensusually include ritonavir, involve once- or twice-dailyadministration, and generally require more pills in theregimen, although the pill burden associated with PI-basedregimens has decreased over the years.To determine the response to therapy, viral loads shouldbe measured 2 to 8 weeks after therapy is begun and every3 to 4 months thereafter. The time course of the response ishighly variable. Viral suppression can take many months inpatients with high viral loads.The main reasons for changing medication after initiatingtherapy are treatment failure and drug toxicity. Treatmentfailure is indicated by increased viral loads and decreasedCD4 cells. If the patient fails to respond to a drug regimen,the new regimen should include at least two new drugs.Drug resistance testing can provide useful information con-cerning the selection of alternative therapy. Alternative drugcombinations are listed in Table 43-3. If dose-limiting orintolerable toxicity occurs, the clinician should choose alter-native drugs that cause a lower incidence of the adverseeffects experienced by the patient.DRUGS FOR INFLUENZABecause inﬂuenza is one of the most common causes ofinfectious disease–related deaths, efforts have been made todevelop methods to prevent and treat illness caused by thisRNA virus. Vaccines are the primary means of prevention,but neuraminidase inhibitors are useful for prophylaxisduring outbreaks and can shorten the duration of illness ininfected persons and prevent complications (Box 43-1).Neuraminidase InhibitorsOseltamivir and zanamivir inhibit the enzyme neuramini-dase (sialidase) in inﬂuenza A and B viruses. These drugswere designed to bind to the active site of neuraminidasebased on studies of the enzyme’s crystalline structure.Neuraminidase catalyzes reactions that promote viralspreading and infection. First, it enables the release ofvirions from the surface of infected cells after viralCASE PRESENTATIONA 20-year-old student visits the university health clinicbecause of chills, fever, sore throat, cough, chest discom-fort, severe myalgia, and extreme tiredness that beganabout 12 hours ago. Examination reveals a temperature of102° F, nonexudative pharyngitis, nasal discharge, and scat-tered rhonchi on chest auscultation. A nasal aspirate issubjected to a rapid test for inﬂuenza nucleoproteins and isfound to be positive. The patient is started on oseltamivirand acetaminophen and is sent to the clinic inﬁrmary forbed rest. She is instructed to use an ear-loop face mask inthe presence of others. Her symptoms improve over the next48 hours, and she has an uneventful recovery.CASE DISCUSSIONInﬂuenza is a seasonal respiratory infection caused by inﬂu-enza type A and type B viruses. Hand washing and inﬂuenzavaccines are the primary means of prevention, but the vac-cines often fail to include strains that cause inﬂuenza out-breaks because vaccine strains must be selected manymonths before the next ﬂu season begins. The presentationof inﬂuenza varies considerably, and it may be difﬁcultto distinguish it from other upper respiratory infections.However, patients with inﬂuenza usually have a higher feverand more severe constitutional symptoms, such as myalgia,than patients with other infections. The availability of rapidtests has improved diagnostic accuracy. These tests can beperformed in as little as 10 minutes and usually cost lessthan $20 (US). The rapid diagnostic tests are highly speciﬁc,but their sensitivity, typically 70% to 80%, is less than thatof viral culture methods that require more time and expense.Hence, clinical judgment is still important in diagnosinginﬂuenza. Treatment of inﬂuenza includes antipyretic agentssuch as acetaminophen, antiviral agents, and bed rest. Osel-tamivir and zanamivir are the only drugs that are effectiveagainst current strains of inﬂuenza, and they are useful forboth prophylaxis and treatment.BOX 43-1. A CASE OF COUGH, FEVER,AND MYALGIA
10. 448 Section VII ❙ ChemotherapyRibavirinMechanism of ActionRibavirin is a synthetic guanosine (purine) analogue thatacts by several mechanisms to inhibit the synthesis of viralnucleic acid. Ribavirin is activated by kinases that phos-phorylate the drug. The active metabolites inhibit purinemetabolism by inhibiting inosine monophosphate dehydro-genase, thereby causing a deﬁciency of guanosine triphos-phate, which is a precursor to nucleic acids. Hence ribavirincan block the synthesis of viral DNA and RNA. Unlikeacyclovir and some reverse transcriptase inhibitors, ribavirinalso inhibits the synthesis of host cell nucleic acid, whichaccounts for some of its toxicity.Pharmacokinetics, Spectrum, and IndicationsTable 43-1 outlines the pharmacokinetic properties ofribavirin.The drug is a broad-spectrum antiviral drug that isactive in vitro against a wide range of RNA and DNAviruses. These include adenovirus, Colorado tick fever virus,Crimean-Congo hemorrhagic fever virus, Hantaan virus,hepatitis A and C viruses, herpesviruses, inﬂuenza A andB viruses, Lassa virus, measles virus, Muerto Canyon virus,mumps virus, respiratory syncytial virus (RSV), Rift Valleyfever virus, and yellow fever virus. Although ribavirin hasbeen successfully used to treat infections caused by severalof these viruses, the drug is speciﬁcally approved for thetreatment of severe RSV infection and chronic hepatitis C(HCV). The monoclonal antibody palivizumab is also usedto treat RSV (see Chapter 45).For the treatment of hospitalized infants and young chil-dren with severe RSV infection, ribavirin is administeredby aerosol, using a small-particle aerosol generator, whichserves to localize drug concentrations at the site of infection.In the treatment of HCV, orally administered ribavirin iscombined with subcutaneously injected interferon alfa (seelater). Studies showed that this drug combination achievesundetectable hepatitis C RNA levels during a 24- or 48-weektreatment period (depending on viral serotype) and main-tains a so-called sustained virologic response for 24 weeks afterthe last dose.Adverse Effects and InteractionsWhen ribavirin is given by inhalation, it can cause seriouspulmonary and cardiovascular effects, including apnea,pneumothorax, worsening of respiratory status, and cardiacarrest. When the drug is given orally it may cause hemolyticanemia, which can worsen cardiac disease and lead to myo-cardial infarction. Ribavirin is teratogenic in animals, and itsuse is contraindicated in pregnant or lactating women. Riba-virin antagonizes the antiviral effect of ZDV, and the twodrugs should not be used concurrently.InterferonsChemistry and PharmacokineticsInterferons are a large group of glycoprotein cytokinesproduced by host cell leukocytes in response to viral andbacterial infections. They were named for their ability tointerfere with viral replication. The natural interferonsinclude interferon-alfa-2a and interferon-alfa-2b. These areproduced by recombinant DNA technology for clinicaluse and designated as interferons alfa-2a (Roferon-A)pregnant women with inﬂuenza when started 3 to 4 daysafter symptom onset. Neuraminidase inhibitors also reducethe complications of inﬂuenza, such as otitis media andpneumonia. Drug therapy should be started as early as pos-sible for any patient with conﬁrmed or suspected inﬂuenzawho is hospitalized; has a severe, complicated, or progressiveillness; or is at a higher risk of inﬂuenza complications.Neuraminidase inhibitors are 70% to 90% effective inpreventing inﬂuenza and are useful adjuncts to vaccination.However, the U.S. Centers for Disease Control and Preven-tion (CDC) does not recommend routine chemoprophylaxisof inﬂuenza because of the risk of promoting viral resistance.Instead, the CDC recommends prophylaxis for populationsat increased risk of inﬂuenza complications and to controloutbreaks in institutional settings such as nursing homes.Prophylaxis is appropriate for persons with severe immuno-deﬁciencies who may not respond to vaccination. It is alsobeneﬁcial to persons at high risk of complications duringthe ﬁrst 2 weeks after vaccination who are exposed to aninfectious person. To be most effective, prophylaxis mustcontinue throughout the period of potential exposure toinﬂuenza, and for 7 days afterward.The adverse effects of neuraminidase inhibitors areusually mild and transient, mostly consisting of minor respi-ratory and gastrointestinal reactions.Amantadine and RimantadineThe adamantanes, amantadine and rimantadine, are syn-thetic tricyclic amine compounds that block the M2 proton-selective ion channel and prevent acidiﬁcation of inﬂuenzatype A virus and the fusion of viral membranes and endo-somes required for uncoating and transfer of viral nucleicacid into the host cell cytoplasm.Adamantanes have been used for prevention and treat-ment of inﬂuenza A but not inﬂuenza B. However, theemergence of resistant strains has rendered these agents lesseffective, and they are not currently recommended for treat-ing inﬂuenza A. Interestingly, amantadine is also used fortreatment of Parkinson disease, in which it increases therelease of dopamine (see Chapter 24).DRUGS FOR HEPATITIS AND OTHERVIRAL INFECTIONSThe primary drugs used to treat hepatitis are ribavirin,interferon alfa, and nucleoside and nucleotide analoguessuch as lamivudine and tenofovir. Lamivudine and tenofovirare reverse transcriptase inhibitors, described earlier. Thesedrugs are active against hepatitis B, a DNA virus, becausethe replication of this virus depends on reverse transcriptionof a messenger RNA intermediate formed during viral rep-lication. RNA transcription produces a negative-sense strandof DNA, which then serves as a template for synthesis ofpositive-sense viral DNA. These orally administered drugsare useful in the treatment of chronic hepatitis B, but theuse of lamivudine is limited by the development of viralresistance in 76% of cases after 5 years of use, whereas resis-tance to tenofovir has not been reported after 3 years of use.Hence tenofovir is the current choice of treatment forchronic hepatitis B. The drug achieves long-term viral sup-pression and has the potential to reverse hepatic cirrhosisand achieve viral seroconversion (loss of detectable viralsurface antigen).
11. Chapter 43 ❙ Antiviral Drugs 449SUMMARY OF IMPORTANT POINTS• Acyclovir, famciclovir, penciclovir, and valacyclovir arenucleoside analogues used to treat HSV and VZVinfections.• Triﬂuridine is a nucleoside analogue used to treat her-petic keratoconjunctivitis.• Cidofovir and ganciclovir are nucleoside analoguesused for the prevention and treatment of CMV dis-eases (e.g., retinitis, esophagitis, and colitis).• Valacyclovir is a prodrug that is converted to acyclovirin vivo. It has better oral bioavailability than acyclovir.• Acyclovir, ganciclovir, and penciclovir are selectivelyphosphorylated to their monophosphate metabolitesby viral kinases, and then host cell kinases convertthem to triphosphates. Other nucleoside analogues,including those for treating HIV infection, are phos-phorylated only by host cell kinases.• Acyclovir and most NRTIs cause chain terminationwhen they are incorporated into viral DNA. Ganciclovirand penciclovir inhibit viral DNA polymerase but arenot incorporated into viral DNA.• Foscarnet is a nonnucleoside drug used to treatCMV retinitis and acyclovir-resistant HSV and VZVinfections.• Drugs for HIV infection include agents that inhibitreverse transcriptase, HIV protease, integrase strandtransfer (raltegravir), and HIV fusion (maraviroc andenfuvirtide). Drug combinations act synergistically toreduce viral loads, increase CD4 cells, and amelioratesymptoms. The most commonly used combinationsconsist of two NRTIs plus either a protease inhibitor oran NNRTI.• Frequently used NRTIs include zidovudine, tenofovir,emtricitabine, and lamivudine. Zidovudine can causeanemia and neutropenia.• Examples of PIs include lopinavir and ritonavir. Efavi-renz is the most frequently used NNRTI.• Some PIs and NNRTIs interact with other drugs viainhibition or induction of cytochrome P450 isozymes.• Oseltamivir and zanamivir, neuraminidase inhibitorsthat inhibit the release and spreading of inﬂuenza Aand B virions, are used in prophylaxis and treatmentof inﬂuenza.• Ribavirin is a broad-spectrum antiviral drug used totreat respiratory syncytial virus infection in neonates,and hepatitis C in combination with interferon-alfa.• Interferon-alfa is used to treat hepatitis B, hepatitis C,and anogenital warts. Lamivudine, an NRTI, is alsoused to treat hepatitis B.REVIEW QUESTIONS1. A man with HIV infection is taking an agent that pre-vents viral maturation. Which adverse effect is typicallyassociated with this type of drug?(A) anemia(B) pancreatitis(C) neuropsychiatric reactions(D) peripheral neuropathy(E) lipodystrophyand alfa-2b (Intron-A). A pegylated derivative calledpeginterferon alfa-2b is also available in which poly-ethylene glycol (PEG) molecules have been covalentlyconjugated with the interferon protein. Pegylation signiﬁ-cantly increases the half-life and duration of action of theinterferon. Hence the peginterferon is given only once aweek, rather than three times a week as are other inter-feron preparations. Interferons must be administeredsubcutaneously because they are not absorbed after oraladministration.Mechanism of ActionInterferons bind to cell surface receptors on target cells andsignal these cells to increase host defenses through a varietyof mechanisms, including activation of gene transcription,inhibition of protein synthesis, degradation of viral RNA,and activation of cytotoxic T lymphocytes and natural killercells.These effects often lead to destruction of both the virusand infected host cells.Spectrum and IndicationsThe interferon alfa preparations are active against hepatitisviruses and against some papillomaviruses. They are usedin the treatment of hepatitis B, hepatitis C, genital warts(condyloma acuminatum), hairy cell leukemia, chronicmyelocytic leukemia, Kaposi sarcoma, renal carcinoma,malignant melanoma, and multiple myeloma.Several interferon preparations are used in treating hepa-titis B and C, including alfa-2a, alfa-2b, and pegylated alfa-2b. These are usually administered for at least 12 monthsand produce clinical remission in many patients. For hepa-titis C, combination therapy with interferon and ribavirinachieves a higher response rate than therapy with either drugalone, and some studies found that pegylated interferonalfa-2b produced better results than conventional alfa-2b. Inclinical studies of chronic hepatitis B, interferon treatmentwas found to result in loss of hepatitis B antigens, normal-ization of serum aminotransferase activity, sustained histo-logic improvement, and a lower risk of progression of liverdisease.Interferon alfa is also effective in the treatment of ano-genital warts (condylomata acuminata), which are causedby several types of papillomavirus. For this infection theinterferon is injected directly into the lesions three times aweek for 3 weeks, with a repeated course of treatment after12 to 16 weeks.The U.S. Food and Drug Administration (FDA) hasrecently approved two new hepatitis C PIs, boceprevir andtelaprevir, for use in combination with ribavirin andpeginterferon alfa for the treatment of HCV, genotype 1strains. These agents increased the percentage of patientsachieving a sustained virologic response to treatment anddecreased the percentage who relapsed during or after treat-ment. The long-term efﬁcacy of these drugs has not beenfully established.Adverse EffectsInterferons can cause many serious and unpleasant adverseeffects, including hematologic toxicity, cardiac arrhythmias,changes in blood pressure, central nervous system dysfunc-tion, gastrointestinal distress, chills, fatigue, headache, andmyalgia.
12. 450 Section VII ❙ ChemotherapyANSWERS AND EXPLANATIONS1. The answer is E: lipodystrophy. Protease inhibitorsprevent viral maturation by preventing cleavage of poly-proteins into functional proteins such as reverse trans-criptase. Anemia (A) is most often caused by zidovudine.Pancreatitis (B) and peripheral neuropathy (D) are asso-ciated with didanosine and stavudine. Neuropsychiatricreactions (C) may be caused by efavirenz.2. The answer is B: inhibition of DNA polymerase. Thepatient received famciclovir, which is converted to penci-clovir in the body. The active triphosphate metabolite ofpenciclovir inhibits viral DNA polymerase, but it is notincorporated into nascent DNA to cause chain termina-tion (D). Penciclovir has no direct effect on purine bio-synthesis (A), viral entry (C), or viral maturation (E).3. The answer is E: release of progeny virions. The womanmost likely has inﬂuenza and was treated with zanamivirnasal spray. Zanamivir and oseltamivir inhibit viral neur-aminidase and the release and spread of progeny virions.They do not affect entry into host cells (A), uncoating orreplication of viral nucleic acid (B and C), or maturationof viral proteins (D).4. The answer is A: foscarnet. Foscarnet is an alternativedrug for treating herpesvirus infections caused by strainsthat are resistant to nucleoside analogues such as acyclovirand ganciclovir. Foscarnet may cause renal failure, cardiacarrhythmias, hematologic deﬁciencies, and other adverseeffects. Nucleoside analogues (B, C, D, and E) do notcause these adverse effects.2. A patient with shingles receives a drug that is convertedto penciclovir in the body. Which antiviral action isexerted by this agent?(A) blockade of purine biosynthesis(B) inhibition of DNA polymerase(C) inhibition of viral entry(D) DNA chain termination(E) prevention of viral maturation3. A woman with an upper respiratory infection is treatedwith an agent that is administered by nasal inhalation.Which step in viral replication is prevented by this drug?(A) entry into host cells(B) uncoating of viral nucleic acid(C) replication of viral nucleic acid(D) maturation of viral proteins(E) release of progeny virions4. A man with immunodeﬁciency syndrome being treatedfor a severe herpesvirus infection develops acute renalinsufﬁciency and tachycardia. Which drug is he mostlikely receiving?(A) foscarnet(B) triﬂuridine(C) acyclovir(D) famciclovir(E) ganciclovir