Approved Antiviral Drugs over the Past 50 Years

53 Pages·2016·9.06 MB·English

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Approved Antiviral Drugs over the Past 50 Years
ErikDeClercq,aGuangdiLia,b
KULeuven-UniversityofLeuven,RegaInstituteforMedicalResearch,DepartmentofMicrobiologyandImmunology,Leuven,Belgiuma;DepartmentofMetabolismand
Endocrinology,MetabolicSyndromeResearchCenter,KeyLaboratoryofDiabetesImmunology,MinistryofEducation,NationalClinicalResearchCenterforMetabolic
Diseases,TheSecondXiangyaHospital,CentralSouthUniversity,Changsha,Hunan,Chinab
SUMMARY..................................................................................................................................................696
INTRODUCTION............................................................................................................................................696
OVERVIEWOFNINEHUMANVIRUSES.....................................................................................................................698
HumanImmunodeficiencyVirus.........................................................................................................................698
HepatitisCVirus..........................................................................................................................................699
InfluenzaVirus............................................................................................................................................699
RespiratorySyncytialVirus................................................................................................................................699
HepatitisBVirus..........................................................................................................................................699
HumanPapillomavirus...................................................................................................................................699
HumanCytomegalovirus.................................................................................................................................705
HerpesSimplexVirus.....................................................................................................................................705
Varicella-ZosterVirus.....................................................................................................................................705
5-SUBSTITUTED2=-DEOXYURIDINEANALOGUES.........................................................................................................709
NUCLEOSIDEANALOGUES.................................................................................................................................709
PYROPHOSPHATEANALOGUES...........................................................................................................................711
NUCLEOSIDEREVERSETRANSCRIPTASEINHIBITORS.....................................................................................................711
NONNUCLEOSIDEREVERSETRANSCRIPTASEINHIBITORS................................................................................................713
PROTEASEINHIBITORS.....................................................................................................................................713
HIVProteaseInhibitors...................................................................................................................................713
HCVNS3/4AProteaseInhibitors..........................................................................................................................715
INTEGRASEINHIBITORS....................................................................................................................................715
Raltegravir................................................................................................................................................715
Elvitegravir................................................................................................................................................715
Dolutegravir..............................................................................................................................................715
ENTRYINHIBITORS.........................................................................................................................................717
EnfuvirtideandMaraviroc................................................................................................................................717
PalivizumabandRSV-IGIV................................................................................................................................719
VZIGandVariZIG.........................................................................................................................................719
Docosanol................................................................................................................................................719
ACYCLICGUANOSINEANALOGUES.......................................................................................................................719
ACYCLICNUCLEOSIDEPHOSPHONATEANALOGUES.....................................................................................................721
HCVNS5A/NS5BINHIBITORS..............................................................................................................................721
HCVNS5AInhibitors......................................................................................................................................721
HCVNS5BInhibitors......................................................................................................................................724
INFLUENZAVIRUSINHIBITORS.............................................................................................................................724
AmantadineandRimantadine...........................................................................................................................724
Zanamivir,Oseltamivir,Peramivir,andLaninamivirOctanoate...........................................................................................724
Ribavirin..................................................................................................................................................724
Favipiravir.................................................................................................................................................726
INTERFERONS,IMMUNOSTIMULATORS,OLIGONUCLEOTIDES,ANDANTIMITOTICINHIBITORS........................................................726
Interferons................................................................................................................................................726
ImmunostimulatoryandAntimitoticInhibitors..........................................................................................................726
AntisenseOligonucleotides..............................................................................................................................728
(continued)
Published8June2016
CitationDeClercqE,LiG.2016.Approvedantiviraldrugsoverthepast50years.
ClinMicrobiolRev29:695–747.doi:10.1128/CMR.00102-15.
AddresscorrespondencetoErikDeClercq,[email protected],or
GuangdiLi,[email protected].
Supplementalmaterialforthisarticlemaybefoundathttp://dx.doi.org/10.1128
/CMR.00102-15.
Copyright©2016,AmericanSocietyforMicrobiology.AllRightsReserved.
July2016 Volume29 Number3 ClinicalMicrobiologyReviews cmr.asm.org 695
DeClercqandLi
FORTHCOMINGANTIVIRALINHIBITORS...................................................................................................................728
SofosbuvirplusVelpatasvir...............................................................................................................................728
DaclatasvirplusAsunaprevirwithorwithoutBeclabuvir.................................................................................................728
FV100.....................................................................................................................................................728
Letermovir................................................................................................................................................729
ANTIVIRALSTRATEGIESAGAINSTCURRENTANDEMERGINGINFECTIOUSDISEASES...................................................................729
VirusesTargetedbybothAntiviralDrugsandVaccines..................................................................................................729
HBVvaccines...........................................................................................................................................729
VZVvaccines...........................................................................................................................................729
HPVvaccines...........................................................................................................................................729
Influenzavirusvaccines................................................................................................................................729
VirusesTargetedbyAntiviralDrugsbutNotbyVaccines.................................................................................................729
VirusesTargetedbyVaccinesbutNotbyAntiviralDrugs.................................................................................................730
VirusesTargetedbyneitherVaccinesnorAntiviralDrugs................................................................................................730
dsDNAviruses:EBV,humanpolyomavirus,andherpesvirus6.........................................................................................730
ssDNAvirus:humanparvovirusB19...................................................................................................................730
Positive-sensessRNAviruses:Zikavirus,norovirus,coronavirus,rhinovirus,astrovirus,sapovirus,denguevirus,chikungunyavirus,andWestNile
virus.................................................................................................................................................730
Negative-sensessRNAviruses:Ebola,Marburg,Hendra,Nipah,Lassa,Junin,andMachupoviruses...................................................731
CONCLUSIONSANDFUTUREPERSPECTIVES..............................................................................................................731
ACKNOWLEDGMENTS......................................................................................................................................733
REFERENCES................................................................................................................................................733
AUTHORBIOS..............................................................................................................................................747
SUMMARY treatmillionsofhumanbeingsworldwide.BetweenJune1963and
Sincethefirstantiviraldrug,idoxuridine,wasapprovedin1963, April 2016, 90 drugs were formally approved to treat 9 human
90antiviraldrugscategorizedinto13functionalgroupshavebeen infectious diseases (Table 1) despite the fact that thousands of
formally approved for the treatment of the following 9 human antiviral inhibitors have been proposed in the literature. Previ-
infectiousdiseases:(i)HIVinfections(proteaseinhibitors,inte- ously,wereviewedthehistoryof25approvedantiretroviraldrugs
graseinhibitors,entryinhibitors,nucleosidereversetranscriptase over25years(1984to2009)(4,5).Thepresentstudycommem-
inhibitors, nonnucleoside reverse transcriptase inhibitors, and orates90antiviraldrugsapprovedforthetreatmentof9human
acyclicnucleosidephosphonateanalogues),(ii)hepatitisBvirus infectiousdiseasesoverthepast5decades.
(HBV)infections(lamivudine,interferons,nucleosideanalogues, Approved antiviral drugs could be arbitrarily divided in 13
andacyclicnucleosidephosphonateanalogues),(iii)hepatitisC functional groups: (i) 5-substituted 2=-deoxyuridine analogues
virus (HCV) infections (ribavirin, interferons, NS3/4A protease (n(cid:2)3drugsanddrugcombinations);(ii)nucleosideanalogues
inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (n(cid:2)3);(iii)(nonnucleoside)pyrophosphateanalogues(n(cid:2)1);
(iv) herpesvirus infections (5-substituted 2=-deoxyuridine ana- (iv)nucleosidereversetranscriptase(RT)inhibitors(NRTIs)(n(cid:2)
logues,entryinhibitors,nucleosideanalogues,pyrophosphatean- 9);(v)nonnucleosidereversetranscriptaseinhibitors(NNRTIs)
alogues,andacyclicguanosineanalogues),(v)influenzavirusin- (n (cid:2) 5); (vi) protease inhibitors (PIs) (n (cid:2) 19); (vii) integrase
fections(ribavirin,matrix2proteininhibitors,RNApolymerase inhibitors (n (cid:2) 5); (viii) entry inhibitors (n (cid:2) 7); (ix) acyclic
inhibitors,andneuraminidaseinhibitors),(vi)humancytomega- guanosineanalogues(n(cid:2)6);(x)acyclicnucleosidephosphonate
lovirusinfections(acyclicguanosineanalogues,acyclicnucleoside (ANP)analogues(n(cid:2)10);(xi)hepatitisCvirus(HCV)NS5Aand
phosphonateanalogues,pyrophosphateanalogues,andoligonu- NS5Binhibitors(n(cid:2)8);(xii)influenzavirusinhibitors(n(cid:2)8);
cleotides),(vii)varicella-zostervirusinfections(acyclicguanosine and(xiii)immunostimulators,interferons,oligonucleotides,and
analogues, nucleoside analogues, 5-substituted 2=-deoxyuridine antimitoticinhibitors(n(cid:2)8).Theinhibitoryspectrumofthese
analogues,andantibodies),(viii)respiratorysyncytialvirusinfec- approveddrugsagainst9humaninfectiousdiseasescanbesum-
tions(ribavirinandantibodies),and(ix)externalanogenitalwarts marized as follows: human immunodeficiency virus (HIV)
causedbyhumanpapillomavirusinfections(imiquimod,sinecat- (groupsiv,v,vi,vii,viii,andx),humancytomegalovirus(HCMV)
echins,andpodofilox).Here,wepresentforthefirsttimeacom- (groupsiii,ix,x,andxiii),hepatitisBvirus(HBV)(groupsii,iv,x,
prehensiveoverviewofantiviraldrugsapprovedoverthepast50 andxiii),HCV(groupsvi,xi,xii,andxiii),herpessimplexvirus
years, shedding light on the development of effective antiviral (HSV)(groupsi,ii,iii,viii,andix),influenzavirus(groupxii),
treatments against current and emerging infectious diseases respiratorysyncytialvirus(RSV)(groupsviiiandxii),varicella-
worldwide. zostervirus(VZV)(groupsi,ii,viii,andix),andhumanpapillo-
mavirus(HPV)(groupxiii).Table2summarizestheinformation
INTRODUCTION
onantiviraldrugsregardingtheirapprovaldatesandmechanisms
Over the course of human civilization, viral infections have of drug action. Table S1 in the supplemental material provides
causedmillionsofhumancasualtiesworldwide,drivingthe detailsondrugdatabasesandchemicalformulas.
developmentofantiviraldrugsinapressingneed(1,2).Anewera NinehumanvirusescanbeclassifiedintoDNAviruses(HBV,
ofantiviraldrugdevelopmenthasbegunsincethefirstantiviral HCMV, HSV, HPV, and VZV), RNA viruses (HCV, RSV, and
drug,idoxuridine,wasapprovedinJune1963(3)(Fig.1).Since influenzavirus),andretroviruses(HIV)(Fig.2).Interestingly,11
then,manyantiviraldrugshavebeendevelopedforclinicaluseto of90antiviraldrugshavebeenapprovedforthetreatmentofmore
696 cmr.asm.org ClinicalMicrobiologyReviews July2016 Volume29 Number3
FIG1HistoryofantiviraldrugsapprovedbetweenJanuary1959andApril2016.(A)Approvedantiviraldrugsvisualizedinthezodiac.Thegrayarrowshows
thedatesofapprovalofantiviraldrugsfromJanuary1959toApril2016.Twelvesignsarepositionedinacircle.Eachsignindicatesadruggroupwhosenameis
annotatedoutsidethecircle.Inthedruggroup,eachredstarwithinasignrepresentsanapproveddrug,placedaccordingtotheyearofapproval.Yellowstars
indicateapproveddrugsthathavebeendiscontinuedorabandonedforclinicaluse.Atotalof90starsthusrepresentallapprovedantiviraldrugs,andeachdrug
starispositionedaccordingtoitsapprovaldate(Table2).Inthispicture,everyapproveddrugcouldbeconceivedasa“superstar,”anditscontributiontohuman
healthisworthyofbeingrememberedandrespected.Therefore,thiszodiac-basedfiguremetaphoricallyrecognizeseachantiviraldrugasastarintheuniverse,
commemoratingthesignificantcontributionsofantiviraldrugdiscoveryanddevelopmentoverthepast50years.AlistofdrugabbreviationsisavailableinTable
2.Moviesandlabelinformationforapproveddrugsareaccessibleonline(seehttp://www.virusface.com/).(B)Timelineofapprovalofdrugsagainst9human
infectiousdiseases(HIV,HBV,HCV,HSV,HCMV,HPV,RSV,VZV,andinfluenzavirus).ThexaxisindicatestheperiodfromJanuary1959toApril2016,and
theyaxisshowsthetotalnumberofapproveddrugs.Foreachvirus,acoloredlinedemonstratesthetotalnumberofapproveddrugs.Moreover,yearsofdiscovery
ofHBV(1963),HPV(1965),HIV(1983),andHCV(1989)areindicated,whiletheotherfiveviruseswerediscoveredbefore1959(Table1).
July2016 Volume29 Number3 ClinicalMicrobiologyReviews cmr.asm.org 697
DeClercqandLi
Proteintarget(s)ofapproveddrug(s) Protease,RT,integrase,GP41,CCR5NS3/4protease,NS5A,NS5BpolymeraseMatrixprotein2,neuraminidase,RNApolymeraseRNApolymerase,glycoproteinsDNApolymerase DNApolymeraseDNApolymerase,envelopeproteinsDNApolymerase,envelopeproteinsb— usedbyHPVinfections. cmsldiittiinnnhhiagrvsflheaesuhetenniugastbsrtasen,eosiomntmcvanfnzeviopeeaae,itrprwyhdiavrieseprnolitmureohrfdvufegeteaeefcespretdvgtngcls(eiriitotuaFcloniionuaavimuggptltespli.immiyovnad3snitgaefhir)rseanra.edaeciiltaMrzunatetdeiosrsomsoeritfsnuuriantmu(egslghTlolsdrttiiavamhlieipacpebseeorlpeplleevuRaimronisvolNrr2dehievtars)acAiela.,bbhndllTeiisavtiftualhnneioyurngefir,cusesgtrsyeaimcseevdcaentfsiliogssttreo:aiiaraonvns(eiHlfniFgs,dro.dCisaargfRttrlfuVhc.u-cidog4abl,ugastr)maRrbu.awvraeISpcgeinnilrVtsrnliitletonst,ifrhsvorn,eaahoeimfannrenotmatdddoer--l
ca emergingviralinfections.
cGenometype,length(kb) (cid:4)(cid:3)Linear()ssRNA,9.8 (cid:4)(cid:3)Linear()ssRNA,9.6 (cid:5)(cid:3)Linear()ssRNA,13.6 (cid:5)(cid:3)Linear()ssRNA,15(cid:3)CirculardsDNA,3.3 (cid:3)LineardsDNA,230LineardsDNA,152–155 (cid:3)LineardsDNA,125 (cid:3)CirculardsDNA,8 ntstotreatexternalgenitalwarts SdwmapgpiurrhveouebeicIumcgsnhahtesaiiqcstcnvaihuoniriariseemsgsamnpladprtesinelinrcysovtetfc,isfhievueacteidwsrhtcnoisate,oseiloindwtcvfhnos.eoeematl(yolofiriov)pehrtweoastHartrhuivvngoengeiegey?widtwvasIvte,ncwhiirntwaraieavneplerdeeeohd?ohrapit(visthhgieieeihooer)r3nslysvHiptcgi,edplehowiwcirntwsoetictictovhdomeafeeiovlnsa9teltrskarho?iheetaeef(dluyiassi,9mti(as)0aTpcuaWnhramnaodbiphegmlvvepaarieetg3arrsotuar)tshyh.ivsneToeeeorsisndor-tf.
ge antiviral drugs and vaccines against emerging infectious diseases.
a
6) 0) 39) otic Challengesinthefieldofantiviraldrugdiscoveryareenvisionedatthe
Meanviralparticlediam(nm)(range) (cid:3)145(95–16 (cid:3)68(45–86) (cid:3)120(84–17 100–1,00042–46 150–200(cid:3)225(209–2 150–200 65–120 54).ulatoryorantimit OefoonfVrdamEn.RTt(iVovhiItrsEtaupWlp:/dp/rOwourFwgtswNtha.IvniNsidrEruevsvHaficaUeccwiMen,.ceAwosN.emh/V)aIvtReoUauSlspEodSaetsetatbhleisthheedraapneountilcinaesppelactt-s
(d
ctiousdiseasestreatedbyapproveddrugs MeanincubationAnimalreservoir(s)Transmissionrouteperiod(range) Chimpanzee,gorilla,Bloodborne8–11yrsootymangabey(cid:3)UnclearBloodborne7wk(4–20wk) (cid:3)Birds,pigs,horsesRespiratory2days(1–4days) (cid:3)NoanimalreservoirRespiratory5days(3–8days)Unclear(bats?)Bloodborne90days(60–150days)NoanimalreservoirBloodborne3–12wk(cid:3)NoanimalreservoirSexualorskin4days(2–12days)contactNoanimalreservoirRespiratory10–21days (cid:3)aNoanimalreservoirSkin-to-skincontact2.9mo(0.5–8mo) nbirds,reptiles,marsupials,andmammals,whereascross-transferbetweenspeciesisrarethreeFDA-approveddrugs(podofilox,sinecatechins,andimiquimod)actasimmunomo(cid:5)RNA;()ssRNA,negative-sensesingle-strandedRNA;dsDNA,double-strandedDNA. spgt(geRAeAhRvHD(cid:3)itcH(lwhiH1anreriyruneSfsuriIio1e2tnor,cesgnmuVVIigmi4o)uceetooViaocgls.es,o5nfeparmn1eaagri-Iv-dnatVisns1Aens1ntsgihHee,ninn)stmhiZonpirsshe.nrdnIaoI(euafgrVmatAaV1nficsdmivh(btnsescl,0,adhr-tmehecotdiuhep)a1a2byaentinbe,lnulisea(0HgepnsamodgasTem1etgeh1netduhrutoIen9eea6so9oRioValnmors,v,8b,eis1dkuiNehn9g-ead3vtlga9dpi2espeen5ufleiinAnatt(5its)nnfis1ldhimsui7ggtet,0,mooci)coi(ea)ecr%ov.ooaHaiwnfs,nnsieae1HinsfnrvtgeHrchttzIRn6ioedseaebetoHVIavi6ocIrNhnfdVl(csemiVey1fH,IheervntpodAdVs4twue,tAibmnrrVehtIri.p)as,airuicV(e7aIueamineair6)Dgerrgi%lvtds,seietaoul)nesi).naaHySen.tnnfn,sctrhmfshbtBHte2Bituoa(adiecahae80fnvemirlVabiItotvobe)tltianiVwnourheh,.roleembufuomHw-sieeAnbaebctec1hgserese,enCnslehinmttitmeencaweeendcr(aVosHlnnsratfoeHsioae,toutt,vcad(disI-hbraHraerdIig9tVseeidneeVydpiniHe)avwCefive,d,pRt-ogpnrdedIewhtecM1rleeacoVd1orivaooathvrlvesi5iVrni-nvnitbnieWenunon2ieetwsn,rcmtgbviw,a2todeosHcleioitiei0rt3voraa,dnsythv,tSi0te7lttyesrpedosweuewVrexg.cleaC5davohyeratoobth,se%ieefnurelirmHeuiptnine(fnecmivwHnyatr1assPfhpticpbteammeit0rrIahVhlvoaeceraaVii)n9eer------sssfll.,
1Summaryof9humaninfe Yrofdiscovery/virusisolation 1983 1989 influenza1933 19571963 1956Before1900 1953 1965 maviruseshavebeenwidelyfoundioftargetingHPVproteinsdirectly,NA,positive-sensesingle-stranded tbrhstnDtihopieuecluerlee1materrddr1seiaaanlb(de(ynng1Hyessm1s,acmIhp,rhV(a1saai1rit3r-tn(o1ti1i)1eneln,.y7dnggiD1)crtt,f4.sohuriMb–nucore1loafmpotae6nuosonc)gbcmdtPyhihe(ocuFacitHnlmrnoliitag,nmIdipn.tVpihcasOel2-afeenc)iul)nzz.oi,csneofnioaAeeocontmcsusnnatd(bmseopaH,dastliioitonIbccwioVoraaltiottntr-tyimeoah1odpndmnHages-btsrrfabeIoelinhVrooorunagrsodpbv,anadHsyebloeeofMsbtIyevrrVHexasiebranuIin(usnoVsHaskdmdrl,ecIncyVNpiaHoosflno-snw)I2uir,Vtbont)aigeendcottdisstoo8-s.:,;
TABLE Human HIV HCV Humanvirus RSVHBV HCMVHSV VZV HPV aPapillobInstead(cid:4)c()ssR leyamsep,hluonmgac,apnscyecrh,ikaitdrniceydidsiosredaseer,s,ogstienogpivoirtioss,isc,aprdaipouvlaosscquulaarmdoius-s
698 cmr.asm.org ClinicalMicrobiologyReviews July2016 Volume29 Number3
ApprovedAntiviralDrugs
disorders,anddentalorsalivaryglanddiseases(forareview,see RespiratorySyncytialVirus
reference18).Inthepast3decades,HIVhascausedagreatburden Discoveredin1957(37),humanRSVbelongstothePneumovirus
toglobalwealthandhealth.AccordingtotheWHOglobalhealth genus in the Paramyxoviridae family (Fig. 2). An RSV particle,
survey,(cid:3)36.9million(range,34.3millionto41.4million)people which is (cid:3)100 to 1,000 nm in diameter (38), contains a linear,
wereinfectedwithHIV,causing1.2million(range,1.0millionto negative-sense, single-stranded RNA genome encoding 11 viral
1.5million)deathsin2014. proteins(39).RSVstrainscanbeclassifiedintotwoantigenicsub-
types,subtypesAandB,whicharefurtherdividedinto11RSV-A
HepatitisCVirus
and23RSV-Bgenotypes(40).Similartoinfluenzaviruses,RSV
Discoveredin1989(19),HCVisahepacivirusintheFlaviviridae takesrespiratoryroutesforitstransmission,mainlybydirectcon-
family(Fig.2).AnHCVparticle,whichis(cid:3)68nm(range,45to86 tactwithcontaminatedaerosolsordroplets.Nevertheless,thereis
nm) in diameter (20), contains a linear, positive-sense, single- no animal reservoir for human RSV (41). During human RSV
stranded RNA genome encoding 10 viral proteins (21). HCV infection,theincubationperiodis(cid:3)5days(range,3to8days)
strainscanbeclassifiedinto7majorgenotypes(genotypes1to7), (42),andmanyclinicalcomplications(e.g.,respiratorytractdis-
amongwhichgenotypes1and2causemostinfectionsworldwide eases, sinusitis, otitis bronchiolitis, and pneumonia) have been
(22).IthasbeenestimatedthatthenucleotidediversityofHCV observed (see http://www.cdc.gov/). Regarding the burden of
genomes is about 32.4% between HCV genotypes and 14.6% RSV,itcauses66,000to199,000deathseveryyear.In2005,RSV
withinHCVgenotypes(23).RegardingtheoriginofHCV,itre- infectionscaused33.8millioncasesofRSV-associatedacutelower
mains a mystery, but nonhuman primates (apes and monkeys) respiratoryinfectionsamongchildren(cid:6)5yearsofage(43).
andmammals(e.g.,horsesanddogs)mighthavebeenpotential
zoonoticreservoirs(24).Asablood-bornevirus,HCVistrans- HepatitisBVirus
mittedmainlybysexualcontact,needlesharing,bloodtransfu- Discoveredin1963(44),HBVbelongstotheOrthohepadnavirus
sions,ormaternaltransmissions.Duringacuteinfection,thein- genus in the Hepadnaviridae family (Fig. 2). An HBV particle,
cubationperiodofHCVis(cid:3)7weeks(range,4to20weeks)(25). whichis(cid:3)42to46nmindiameter(45),containsacirculardou-
Manyclinicalcomplicationshavebeenobserved,includingliver ble-stranded DNA (dsDNA) genome encoding 6 viral proteins.
cirrhosis,liverfailure,portalhypertension,orhepatocellularcar- HBVstrainshavebeenclassifiedinto8genotypes,furtherdivided
cinoma(26,27).HCVisalsoknowntocauselivercancerssuchas intomorethan24subtypes.Ithasbeenestimatedthatthenucle-
hepatocellular carcinoma (28). According to the WHO global otidediversityofHBVgenomesis(cid:3)14.5%betweenHBVgeno-
health survey, HCV causes 500,000 deaths every year, and 130 typesand2.8%withinHBVgenotypes(46).Regardingtheorigin
millionto150millionpeoplewerelivingwithHCVin2014. ofHBV,itremainsamysterytobeunveiled,butbatsmighthave
beentheancestralsourcesofprimatehepadnaviruses(47,48).As
InfluenzaVirus ablood-bornevirus,HBVcanbetransmittedbysexualcontact,
HumaninfluenzavirusesfromtheOrthomyxoviridaefamily(Fig. needle sharing, blood transfusions, or maternal transmissions.
2)causedthefirstrecognizableinfluenzapandemicinthesummer TheincubationperiodofHBVinfectionsis(cid:3)90days(range,60to
of1510(29,30),andtheywereisolatedforthefirsttimein1933 150 days) (49). Major clinical complications of HBV infections
(31).Aviralparticleofinfluenzavirus,whichis(cid:3)120nm(range, havebeenobserved,suchashepatitis,anorexia,abdominaldis-
84to170nm)indiameter(32),containsalinear,negative-sense, comfort, nausea, vomiting, arthralgia, rash, or liver cancer (see
single-strandedRNAgenomethatencodes11or12proteinsde- http://www.cdc.gov/).HBVisalsoknowntocauselivercancers
pendingonthevirusstrain(33).Influenzavirusescanbeclassified (e.g., hepatocellular carcinoma) (28). According to the WHO
intothreetypes:typesA,B,andC.InfluenzaAvirusesthatcause globalhealthsurvey,HBVcauses780,000deathseveryyear,and
humanepidemicsandpandemics(e.g.,Spanishfluin1918,Asian 240millionpeoplewereinfectedin2014.
fluin1957,andHongKongfluin1968)arefurtherdividedinto
extensivesubtypes(i.e.,H1N1,H1N2,orH3N2)basedonthese- HumanPapillomavirus
quencevariationofhemagglutinin(HA)andneuraminidase(NA), Discoveredin1965(50),HPVsfromthePapillomaviridaefamily
twoglycoproteinsoftheinfluenzavirusmembrane(34,35).Influ- arethecausativeagentsof(cid:7)90%ofcervicalcancers,thesecond
enzaBvirusesthatcausehumanepidemicsaredividedintostrains mostcommoncanceramongwomenworldwide(51).AnHPV
butnotsubtypes.InfluenzaCvirusescauseneitherepidemicsnor particle, which is (cid:3)65 to 120 nm in diameter (52), contains a
pandemics,becausetheyusuallyinfecthumanswithmildillnesses. closed,circular,double-strandedDNAgenomeencoding9viral
Ontheotherhand,influenzaviruseshavebeendiscoveredinabroad proteins(53).HPVstrainscanbeclassifiedinto(cid:7)200typesbased
spectrumofanimalreservoirs(36).InfluenzaAvirusescanbetrans- on the sequence variation of a late region encoding the capsid
mitted from animal reservoirs such as birds (e.g., H2N2, H5N1, proteinL1(54).HPVinfectionsareresponsiblefor(cid:3)5%ofhu-
H7N3,andH9N2),pigs(e.g.,H1N1andH3N2),orseals(H7N7)to mancancers(e.g.,cervicalcarcinoma,analcarcinoma,andpenile
humans (36). Using respiratory routes, influenza viruses spread carcinoma)(28,55).Particularly,high-riskHPVtype16(HPV-
mostlythroughdirectcontactwithcontaminatedaerosolsordrop- 16)andHPV-18areknowntocause70%ofcervicalcancers,while
lets.Duringinfluenzainfection,thetypicalincubationperiodis(cid:3)1to low-riskHPV-6andHPV-11cause90%ofexternalgenitalwarts
4days(average,2days),andmanyclinicalcomplications(e.g.,pneu- (56)aswellasmostcasesofrecurrentrespiratorypapillomatosis
monia,bronchitis,dehydration,encephalitis,sinusitis,andearinfec- (57).Papillomaviruseshavebeenwidelyfoundinbirds,reptiles,
tions)havebeenreported(seehttp://www.cdc.gov/).Accordingto marsupials,andmammals,butcross-transferbetweenspeciesis
theWHOglobalhealthsurvey,influenzavirusescause250,000to rare(54).TheincubationperiodfromHPVinfectiontoclinical
500,000deathseveryyear,and3millionto5millioncasesofsevere wartsvaries,andtheaveragetimeis(cid:3)2.9months(range,0.5to8
illnesseswerereportedin2014. months) (58). HPV infections are transmitted mainly through
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DeClercqandLi
ee
at
Approvald June1963 Apr.19802000 Nov.1976 Mar.2005 Oct.2006 Sept.1991 Mar.1987 Oct.1991 June1992 June1994 Nov.1995 Sept.1997 Dec.1998 Nov.2000 July2003 June1996 Apr.1997 Sept.1998
Mechanism(s)ofdrugaction SubstitutesforthymidineandtargetsHSVDNApolymerasetoinhibitviralDNAsynthesisInhibitsHSVDNAreplicationBrivudinetriphosphatetargetsVZVDNApolymerasetoinhibitviralDNAsynthesis VidarabinetriphosphatecompeteswithdATPtoinhibittheactivityofviralDNApolymeraseInhibitstheactivityofHBVDNApolymeraseInhibitstheactivityofHBVDNApolymerase InhibitstheactivityofviralDNApolymerase TargetsHIVRTandcompeteswithdTTPtoinhibitDNAsynthesisTargetsHIVRTandcompeteswithdATPtoinhibitDNAsynthesisTargetsHIVRTandcompeteswithdCTPtoinhibitDNAsynthesisTargetsHIVRTandcompeteswithdTTPtoinhibitDNAsynthesisTargetsviralpolymeraseandcompeteswithdCTPtoinhibitDNAsynthesisTwice-daily,fixed-dose,single-tabletdrugusedtoinhibittheactivityofHIVRTTargetsHIVRTandcompeteswithdGTPtoinhibitDNAsynthesisTwice-daily,fixed-dose,single-tabletdrugofabacavir,lamivudine,andzidovudineusedtoinhibittheactivityofHIVRTTargetsHIVRTandcompeteswithdCTPtoinhibitDNAsynthesis BindsdirectlytoHIVRTandinhibitsDNAsynthesisBindsdirectlytoHIVRTandinhibitsDNAsynthesisBindsdirectlytoHIVRTandinhibitsDNAsynthesis
vir
o
cl
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Approvedcliniuse(s) HSV-1 HSVHSV-1,VZV HSV,VZV HBV HBV HCMV,HSV(resistant) HIV HIV HIV HIV HIV,HBV HIV HIV HIV HIV HIV-1 HIV-1 HIV-1
dBrandname(s) Dendrid ViropticZostex(Europe) Vira-A Baraclude Tyzeka Foscavir Retrovir Videx Hivid Zerit Epivir Combivir Ziagen Trizivir Emtriva Viramune Rescriptor Sustiva
T
Z
A
cn (cid:4)
fuggroups Abbreviatio IDU TFTBVDU VDR ETV LdT PFA AZT ddI ddC d4T 3TC (cid:4)3TCAZT ABC (cid:4)ABC3TC (cid:5)()FTC NVP DLV EFV
r
d
ovedantiviraldrugsin13 Drugname Idoxuridine TrifluridineBrivudine aVidarabine Entecavir Telbivudine Foscarnet Zidovudine Didanosine aZalcitabine Stavudine Lamivudine (cid:4)Lamivudinezidovudine Abacavir (cid:4)(cid:4)Abacavirlamivudinezidovudine Emtricitabine Nevirapine aDelavirdine Efavirenz
r
p
p e
a n
0 di
TABLE2Summaryof9 Druggroup =5-substituted2-deoxyurianalogues Nucleosideanalogues Pyrophosphateanalogues NRTIs NNRTIs
700 cmr.asm.org ClinicalMicrobiologyReviews July2016 Volume29 Number3
ApprovedAntiviralDrugs
ge)
a
p
Jan.2008 Aug.2011 Dec.1995 Mar.1996 Mar.1996 Mar.1997 Apr.1999 Sept.2000 June2003 Oct.2003 June2005 June2006 Jan.2015 Jan.2015May2011 May2011Nov.2013July2014Sept.2014 nfollowing
o
d
BindsdirectlytoHIVRTandinhibitsDNAsynthesisBindsdirectlytoHIVRTandinhibitsDNAsynthesis BlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsBlockstheactivesiteofHIVproteasetopreventcleavageofviralprecursorproteinsHIVproteaseinhibitorscanbecombinedwithcobicistattoinhibittheactivityofHIVprotease HCVproteasedrugscaninhibittheproteolyticactivityofHCVNS3/4A(cid:8)protease;ribavirinandPegIFNcaninterferewithHCVreplication (Continue
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HIV- HIV- HIV HIV HIV HIV HIV- HIV HIV HIV- HIV- HIV HIV HIVHCV HCVHCVHCVHCV
Intelence Edurant Invirase Norvir Crixivan Viracept Agenerase Kaletra Reyataz Lexia Aptivus Prezista Prezcobix EvotazIncivek VictrelisOlysioSunvepra(Japan)Vanihep(Japan)
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C C R
ETR RPV SQV RTV IDV NFV APV LPV/r ATV FPV TPV DRV (cid:4)DRV (cid:4)ATVTVR BOCSMVASV(cid:4)VPV
(cid:4)
Etravirine Rilpivirine Saquinavir Ritonavir Indinavir Nelfinavir aAmprenavir Lopinavir-ritonavir Atazanavir Fosamprenavir Tipranavir Darunavir (cid:4)Darunavircobicistat (cid:4)AtazanavircobicistataTelaprevir aBoceprevirSimeprevirbAsunaprevir(cid:4)Vaniprevirribavirin(cid:8)PegIFN-2b
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July2016 Volume29 Number3 ClinicalMicrobiologyReviews cmr.asm.org 701
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ee
at
d
Approval Dec.2014July2015Jan.2016 Oct.2007 Aug.2012 Aug.2013 Aug.2014 Feb.2015 Jan.1996 June1998 July2000 Mar.2003Aug.2007 Feb.1981 Dec.2012 Mar.1982 June1989 June1994
Mechanism(s)ofdrugaction TargetsHIVintegrasetoinhibittheintegrationofviralDNAintohumanchromosomesTargetsHIVintegrasetoinhibittheintegrationofviralDNAintohumanchromosomesTargetsHIVintegrasetoinhibittheintegrationofviralDNAintohumanchromosomesFixed-dosecombinationswithdolutegravirandNRTIscantargetHIVintegraseandRTtointerruptviralreplication RSV-neutralizingantibodiesmaypreventbindingofRSVsurfaceglycoproteinsFandGMonoclonalantibodythattargetstheantigenicsiteofRSVglycoproteinFMayinterferewithbindingofviralenvelopeproteinstocellmembranereceptorsBlocksHIVGP41fusiontocellmembraneBlocksGP120-CCR5interactiontoinhibitHIVentryIgGantibodiesprotectpatientsfromVZVinfectionIgGantibodiesprotectpatientsfromVZVinfection AcyclovirtriphosphatecompeteswithdGTPtoinhibitviralDNApolymeraseactivityGanciclovirtriphosphatetargetsHCMVDNApolymerasetoinhibitviralDNAsynthesisFamciclovirtriphosphatecompeteswithdGTPtoinhibittheactivityofviralDNApolymerase
4
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ni pepepe
Approvedcliuse(s) HCVgenotyHCVgenotyHCVgenoty HIV HIV HIV HIV HIV RSV RSV HSV HIV-1HIV VZV VZV HSV,VZV HCMV HSV,VZV
dBrandname(s) ViekiraPakTechnivieZepatier Isentress Vitekta Tivicay Triumeq Dutrebis RespiGam Synagis Abreva FuzeonSelzentry VZIG VariZIG Zovirax Zirgan,Vitrasert Famvir
C
T
3
cn (cid:4)
o C C
Abbreviati PTV GZR RAL EVG DTG (cid:4)DTGAB (cid:4)DTG3T RSV-IGIV PZ C22 EFVMVC VZIG VariZIG ACV GCV FCV
(cid:4) ne
vir udi
a v
ac mi
ab la
(cid:4) (cid:4)
Drugname bParitaprevir bGrazoprevir Raltegravir Elvitegravir Dolutegravir Dolutegravirlamivudine Dolutegravir aRSV-IGIV Palivizumab Docosanol EnfuvirtideMaraviroc aVZIG VariZIG Acyclovir Ganciclovir Famciclovir
es
u
g
ued) nalo
TABLE2(Contin Druggroup Integraseinhibitors Entryinhibitors Acyclicguanosinea
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a
p
June1995 Sept.1996 Mar.2001 June1996 Oct.2001 Sept.2002 Aug.2004 July2006 Aug.2011 Aug.2012 Nov.2015 Mar.2016 Apr.2016 Dec.2013 Dec.2013 nfollowing
o
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ValacyclovirtriphosphatecompeteswithdGTPtoinhibittheactivityofviralDNApolymerasePenciclovirtriphosphatetargetsHSVDNApolymerasetoinhibitviralDNAsynthesisValganciclovirtriphosphatecompeteswithdGTPtoinhibittheactivityofviralDNApolymerase InhibitstheactivityofHCMVDNApolymeraseCompeteswithdATPtoinhibittheactivityofHIVRTandHBVDNApolymeraseAdefovirdiphosphatecompeteswithdATPtoinhibittheactivityofHBVDNApolymeraseTruvadaisaonce-dailyfixed-dosesingletabletcontaining2drugstoinhibitHIVreplicationAtriplaisaonce-dailyfixed-dosesingletabletcontaining3drugstoinhibitHIVreplicationCompleraisaonce-dailyfixed-dosesingletabletcontaining3drugstoinhibitHIVreplicationStribildisaonce-dailyfixed-dosesingletabletcontaining4drugstoinhibitHIVreplication Genvoyaisaonce-dailyfixed-dosesingletabletcontaining4drugstoinhibitHIVreplication Odefseyisaonce-dailyfixed-dosesingletabletcontaining3drugstoinhibitHIVreplicationDescovyisaonce-dailyfixed-dosesingletabletcontaining2drugstoinhibitHIVreplication(cid:4)2SofosbuvirbindstoMgionsinNS5BpolymeraseandinhibitsHCV(cid:8)replication;ribavirinandPegIFNcaninterferewithHCVreplication (Continue
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HSV,VZV HSV HCMV HCMVretipatients)HIV,HBV HBV HIV HIV HIV HIV HIV HIV HIV HCVgenot HCVgenot
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vi
E
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Valtrex Denavir Valcyte Vistide Viread Hepsera Truvada Atripla Compler Stribild Genvoya Odefsey Descovy Sovaldi Sovaldi
TC TC TC (cid:8)N
V V (cid:4)(cid:5)()FTC (cid:4)(cid:4)(cid:5)EFV()F (cid:4)(cid:4)(cid:5)RPV()F (cid:4)(cid:4)(cid:5)COBI()(cid:4)CEVG (cid:4)(cid:4)(cid:5)COBI()(cid:4)CEVG (cid:4)(cid:4)(cid:5)RPV()F (cid:4)(cid:5)()FTC (cid:4)RBV (cid:4)(cid:4)RBVPegIF
AC CV GC DV DF DV DF DF DF DFFT AFFT AF AF OF OF
V P V C T A T T T T T T T S S
(cid:4) (cid:4) (cid:4)
Valacyclovir Penciclovir Valganciclovir Cidofovir Tenofovirdisoproxilfumarate Adefovirdipivoxil Tenofovirdisoproxil(cid:4)fumarateemtricitabineTenofovirdisoproxil(cid:4)fumarateefavirenzemtricitabineTenofovirdisoproxil(cid:4)fumaraterilpivirineemtricitabineTenofovirdisoproxil(cid:4)fumaratecobicistat(cid:4)emtricitabineelvitegravir(cid:4)Tenofoviralafenamide(cid:4)cobicistat(cid:4)emtricitabineelvitegravir(cid:4)Tenofoviralafenamide(cid:4)rilpivirineemtricitabine(cid:4)Tenofoviralafenamideemtricitabine (cid:4)Sofosbuvirribavirin (cid:4)(cid:4)Sofosbuvirribavirin(cid:8)PegIFN
es
u
alog S5B
en N
da
Acyclicnucleosiphosphonate HCVNS5Aandinhibitors
July2016 Volume29 Number3 ClinicalMicrobiologyReviews cmr.asm.org 703
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at
Approvald July2014 Oct.2014 Nov.2014 Dec.2014 July2015 July2015 Jan.2016 Oct.1966 Dec.1985 Sept.1993 July1999 Oct.1999 Sept.2010 Dec.2014 Mar.2014 June1986 Oct.1997 June1998
Mechanism(s)ofdrugaction TargetsNS5AandNS3/4AproteasetopreventHCVreplicationHarvoniinhibitsHCVNS5AandNS5BpolymerasetopreventRNAreplicationSofosbuvirandsimeprevirtargetHCVNS5BandNS3/4protease,respectivelyViekiraPakisamulticlasscombinationdrugapprovedfortreatmentofHCVgenotype1infection;inhibitsactivitiesofHCVNS5A,NS5Bpolymerase,andNS3/4AproteaseTechnivieisusedwithribavirintotreatHCVgenotype4infection;inhibitsHCVNS5AandNS3/4AproteaseInhibitsactivitiesofHCVNS5AandNS5BpolymeraseElbasvirandgrazoprevirinhibitactivitiesofNS5AandNS3/4Aprotease,respectively Targetsviralmatrixprotein2toinhibitviraluncoatingRibavirintriphosphatetargetsviralRNApolymerasetoinhibitmRNAsynthesisTargetsmatrixprotein2toinhibitviraluncoatingTargetsviralneuraminidasetoinhibitvirusreleasefromhostcellsTargetsviralneuraminidasetoinhibitvirusreleasefromhostcellsTargetsviralneuraminidasetoinhibitvirusreleasefromhostcellsTargetsviralneuraminidasetoinhibitvirusreleasefromhostcells=Favipiravir-ribofuranosyl-5-triphosphateinhibitstheactivityofinfluenzaRNApolymerase (cid:8)PegIFN-2bisusedtotreatpatientswithHBVand/orHCVinfectionInterferonalfacon1canbeusedwithribavirintotreatHCVinfection(cid:8)PegIFN-2bisusedwithribavirintotreatpatientswithHCVinfection
Approvedclinicaluse(s) HCVgenotype1 HCVgenotype1 HCVgenotype1 HCVgenotype1 HCVgenotype4 HCVgenotype3 HCVgenotype1or4 InfluenzavirusA HCV,RSV,hemorrhagicfeverInfluenzavirusA InfluenzavirusesAandBInfluenzavirusesAandBInfluenzavirusesAandBInfluenzavirusesAandBInfluenzavirusesA,B,andC HBV,HCV HCVgenotype1 HCV
a
dBrandname(s) (cid:4)DaklinzaSunvepr(Japan)Harvoni (cid:4)SovaldiOlysio ViekiraPak Technivie (cid:4)DaklinzaSovaldi Zepatier Symmetrel Copegus,Rebetol,VirazoleFlumadine Relenza Tamiflu Inavir(Japan) Rapivab Avigan(Japan) Intron-A,PegIntron Infergen Rebetron
V
T
R
(cid:4)
cAbbreviation (cid:4)DCVASV (cid:4)LDVSOF (cid:4)SOFSMV (cid:4)(cid:4)OBVDASPTV (cid:4)(cid:4)OBVPTVRTV (cid:4)DCVSOF (cid:4)EBRGZR AMT RBV RIM ZAN OTV LO PRV FPV (cid:8)PegIFN-2b CIFN (cid:8)(cid:4)PegIFN-2bRBV
Drugname (cid:4)Daclatasvirasunaprevir (cid:4)Ledipasvirsofosbuvir (cid:4)Sofosbuvirsimeprevir (cid:4)(cid:4)Ombitasvirdasabuvir(cid:4)paritaprevirritonavir (cid:4)Ombitasvirparitaprevir(cid:4)ritonavir (cid:4)Daclatasvirsofosbuvir (cid:4)Elbasvirgrazoprevir aAmantadine Ribavirin Rimantadine Zanamivir Oseltamivir Laninamiviroctanoate Peramivir Favipiravir Pegylatedinterferonalfa2b aInterferonalfacon1 Pegylatedinterferonalfa2b(cid:4)ribavirin
TABLE2(Continued) Druggroup Influenzavirusinhibitors Interferons,immunostimulators,oligonucleotides,andantimitoticinhibitors
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