HIVTransmissionRoutes,Pathology,TreatmentandPreventionDamianKellyFeb2017

HIVTransmissionRoutes• Factorsnecessaryfortransmission

• HIVpresenceinbodyfluids

• Commonroutesoftransmission

• Lesscommonroutesoftransmission

• HIVpresentininfectiousquantitiesinblood,semenandvaginalfluids,breastmilkofanHIVpositiveperson

• Entersbodythroughsexualorgans,bloodstream,mouth

• Presenceofvirusinbodyfluid

• Quantityofvirusinbodyfluid

• Qualityofvirusinbodyfluid

• Routeintothebody/bloodstream

Quality

Quantity

Routeoftransmission

CommonRoutesofTransmission

• Unprotectedanalorvaginalsex

• Bloodtobloodcontact– e.g.sharingneedles

• Mothertobaby– duringpregnancy,birthorthroughbreastfeeding

LessCommonRoutesofTransmission• Oralsexwithoutacondom

• Sharingsextoys

• Needlestickinjuries

• Eyesplashes

• Skinpiercing/tattooing(unsterilised equipment)

• Donatedbloodandtissueincountrieswithinadequatescreening

WhenshouldyougetanHIV test?Youhavesexwithoutacondom,withotherpeopleotherthanyourpartner– *oral,vaginaloranalsex

Youhaveunprotectedsex(withoutcondomorimpropercondomuse)withyourpartnerwhoinjectsdrugsorhassexwithothers

Youinjectdrugsandshareneedleswithotherpeople

Watch:https://www.youtube.com/watch?v=Kw_e_O6MdM4

Allpregnantwoman

Sexualassault/rape

HIVTestingAntibodytest

• Antibodytests• Rapidtestsandhometests

• Antibodiesareproducedbytheimmunesystemwhichiswhatthetestlooksfor.Canbeusedinbloodandoralfluid

• 3– 12weeksafterinfectionbeforedetection

• Rapidantibodyscreeningtesttakes30minutes• OraQuick HIVtestswabfromthemouthtakesabout20minutes• Hometestingkitsinvolvesafingerprickbloodsamplecantake7– 10daysforresults

• Allpositivetestresultswillrequireasecondconformationtest

FourthGenerationTests

• Fourthgenerationtestslookfor• HIVantibodiesandantigens• Antigensareforeignsubstancesthatcauseyourimmunesystemtoactivate• Antigenispartofthevirusandpresentduringacuteinfection• Antigenp24isproducedbeforeantibodiesareproduced

• 2– 6weeksforthebodytomakeenoughantigensandantibodiesforthetesttodetectHIV

NucleicAcidTest(NAT)

• Nucleicacidtest• Doesnotlookforantigensorantibodies

• Itlooksforthevirus• Givesapositiveornegativeresult• Andtheactualamountofthevirus

Takes7– 28daysforNATtodetectthevirus

Veryexpensiveandrarelyused

HIVTypes• Type1• 4strainsclassedintofourgroups• M,N,O,P.M(major)groupglobalinfections• WithingroupMatleast9subtypesA-K• Baccountsformostclinicaltrials

• Type2• ConcentratedinWestAfrica

• Lessinfectious• Progressesslower• Fewclinicaltrials• Optimumtreatmentpoorlyunderstood

HIVlifecycle

https://www.youtube.com/watch?v=fBPicJ-AZAk

HIVDrugs• ThereareseveralcategoriesofdrugsusedtotreatHIV

• Acombinationofcategoriesshouldbeused• Monotherapy1980’sx• Dualtherapy1980’s– 1990’sx• Tripletherapy1990’sonwards

• Untilrecentlywhendualtherapyandevenmonotherapyarebeinginvestigatedagainwiththenewdrugs.

WhyStartTreatment?• Topreventinjury/damagetotheimmunesystem

• Torepairdamagedone

• Topreventonwardtransmission

• Toremainhealthy

• Tobeincontrol

KeyTerms• Viralload• CD4count• Resistancetests• Druglevels• Viraltropism• Renalfunctiontest• Liverfunctiontests• Fullbloodcount

ViralLoad• Themostimportanttestoncestartedontreatment!

• Showshowmuchvirusisintheblood

• Resultmaylooklike100000copies/mLforsomeonenotonART• ForsomeoneonARTitmaylooklike3copies/mL(undetectable)

• ViralloadsshowiftheARVtherapyisworkingornot

CD4Count• Thismeasureshowyourimmunesystemisfunctioning-

• AhighCD4countmeansitsgood• AlowCD4countisnot

• Anythingunder250isdangerous• ThemostimportanttestbeforecommencingARVtherapy

• CD4cellsarelymphocytecells(whitebloodcells)sometimeknownasT-cells

• TwotypesofT-cells– CD4arehelpercellsandleadagainstinfectionandCD8cells“suppressor”cells.Thesearealsokillercells

• AnormalCD4countrangewouldbe400– 1600cellspercubicmillimeter

• CD4%isthetotallymphocytes(whitebloodcells)thatareCD4cells

• StartingARVwillincreasetheCD4countastheimmunesystemrecovers

WhentoStartTreatmentAIDS /symptoms

CD4<200

CD4200- 350

CD4350- 500

CD4>500

USDHHS2016 RECOMMENDED

IAS/USA2016 RECOMMENDED

EACS2016 RECOMMENDED

BHIVA2016 RECOMMENDED

WHO2016 StronglyrecommendedPRIORITY

Stronglyrecommended

ResistanceTesting• ThisshowsiftheHIVvirusisresistanttoHIVdrugs• Itshowsifthechosendrugwillwork

• Avirusthathasmutatedmaycausedrugresistancetooccur• K103NwillstopEFVandNVPfromworking• M184Vwillstop3TCandFTCworking

• Missingmedicationcancauseresistancetodevelop

• Andetectableviralloadwhileontreatmentcancauseamutationtooccur

TherapeuticDrugMonitoring• Drugleveltesting

• ThisshouldbedoneoncecommencedonARV

• Detectshowmuchdrugthebodyisabsorbing• ForARV’stoworkproperlytherehastobeasetlevelofdruginthebody

• Sometimesadoseadjustmentmaybeneededorachangeoftherapyifthebodydoesnotabsorbthedrugcorrectly• Manyreasonswhydrugsarenotabsorbed• Adherencelevelisthebiggestreasonwhydruglevelsmaybelow….

RenalFunctionTests(TX&PrEP)• HIVAssociatedNephropathy(HIVAN)

damagecausedbyHIVtokidneys

• NephrotoxicitytoxicityorinjurytothekidneyssideeffectsofARV’s

• Upto30%ofHIV+peoplehavekidneydisease

• Measuresthelevelsofurea,creatinineandsaltsdipstickurinetestsoftenpickupincreasedproteinlevelswhichindicatepotentialkidney

damage

DrugClasses• Fixeddosecombination(STR)singletabletregime

• Nukes;nucleosideornucleotidereversetranscriptaseinhibitors(NRTIs)

• Non-nucleosidereversetranscriptaseinhibitors(NNRTIs)

• Integraseinhibitors(INIs)

• CCR5Inhibitors(entryinhibitor)

• ProteaseInhibitor(PIs)

• PK(pharmacokinetic)booster

• AttachmentInhibitor

Fixed Dose Combination (STR) single tablet regime

NAME Restrictions and recommended dose

Ammount of Tablets

Atripla Efavirenz 600mg + emtricitabine 200mg +Tenofovir DF 300mg

Take at night and not with high fat meal

1 tablet a day

Eviplera Rilpivirine 25mg + emtricitabine 200mg + Tenofovir DF 300mg

Take with food 1 tablet a day

Odefsey Rilpivirine 25mg + emtricitabine 200mg + TAF 25mg

With food 1 tablet a day

Triumeq Dolutegravir 50mg + Abacavir 600mg + lamivudine 300mg

With or without food 1 tablet

Genvoya Elvitegravir 150mg + cobicistat 150mg + emtricitabine 200mg + TAF 10mg

Take with food 1 tablet a day

Stirbald Elvitegravir 150mg + cobicistat 150mg + emtricitabine 200mg + Tenofovir DF 300mg

Take with food 1 tablet a day

Nukes;nucleosideornucleotidereversetranscriptinhibitors(NRTIs)

SingleNukes

lamivudine(3TC)

1x300mgor2x

150mgtakenasonce

dailyortwicedaily

dose

1if300mg

2if150mg

Abacavir

(Ziagen,Epzicom

2x300mgtablets

takenasoncedailyor

twicedailydose

2Tablets

Emtricitabine(FTC)

(Emtriva)

1x200mgonceaday 1Tabletaday

TenofovirDF

(Viread)

1X300MGtabletonce

aday

1Tabletaday

Zidovudine(AZT) 1x250mgtwicedaily 2tablets

ddi

(Videx,Didanosine)

1tabletadayeither;

125,200,250or

400mg)takeonempty

stomach2hrsbefore

eating

1tabletaday

DualNukes

Truvada(Tenofovirand

FTC)

TenofovirDF300mg+

emtricitabine200mg

1Tabletaday

Descovy(TAF) TAF25mg+

Emtricitabine200mg

1tabletaday

Kivexa(Abacavirand

3tc)

Abacavir600mg+

lamivudine300mg

1Tabletaday

Combivir(AZTand3T) Onetablettwiceaday 2Tabletsaday

TripleNukes

Trizivir

(AZT+3TC+abacavir)

Onetablettwiceaday 2tabletsaday

Non-nucleosidereversetranscriptaseinhibitors(NNRTI’s)

Efavirenz Notwithhighfatmeal.1x600mgtabletor3x200mgtabletsatnight

1Tabletor3tabletsdependingondose

Nevirapine200mg(Viramune)Nevirapine400mg(Viramunepr)

200mgoncedailyforfirst14days.Then1x200mgtablettwiceadayor2x200mgonceadayOR1x400mgprolongedreleasetabletonceaday

1or2Tabletsdependingwhether200mg0r400mg

Etravirine (Intelence)

1x200mgtablettwiceadaytakewithfood

2Tabletsaday

Rilpivirine(Edurant)

1x25mgtabletonceadaywith500kcal)

1Tabletaday

NottobeusedtotreatHIVtype2infections

Integraseinhibitors(INIs)

Raltegravir(Isentress)

1x400mgtablettwiceadaywithorwithoutfood

2Tabletsaday

Elvitegravir(Vitekta)

1x85mgtabletonceaday(or1x50mgtablettwiceadayifdrugresistance)Withorwithoutfood

1Tabletaday

Dolutegravir(Ticicay) 1x50mgtabletonceadayor1x50mgtwiceadayifdrugresistanceWithorwithoutfood

1or2Tabletsaday

EntryInhibitor(CCR5inhibitors)

Maraviroc 150mg300mgor600mgasdirectedanddependingonwhichotherdrugsareused

1or2or4tabletsaday

T20(Fuzeon,enfuvirtide)

90mginjectionundertheskintwiceaday

2injectionsaday

ProteaseInhibitors(PIs)

Atazanavir(Reyataz)

1x300mgtablet+aboosteronceadaywithfood.150mgand200mgarealsoavailable

1Tabletplusabooster

Darunavir(Prezista)

1x800mgplusboosteronceadayor1x600mgplus100mgboostertwiceadayifresistance.Takewithfood

1or2tablets(basedondose)plusboosters

Atazanavir/cobicistat(Evotaz)

Takewithfood 1tabletaday

Darunavir/cobicistat(Prezcobix)

Takewithfood 1tabletaday

Lopinavir(Kaletra)200/50or100/25mg

2x200/50mgtwicedailyOR4x100/25mgwithorwithoutfood

4TablestusingthelargerdoseOR8Tabletsusingthesmallerdose

Foasamrenavir(Telzir)

1x700mg+100mgRitonavirtwiceadayTakewithorwithoutfood

2Tabletsadayplusbooster

Saquinavir(Invirase)

2x500mgtwiceadayTakewithfood

4tabletsadayplusbooster

Tripranavir(Aptivus)

2x250mgtwiceadaytakewithfood

4Tabletsadayplusbooster

Pharmacokineticboosters(PK)

Cobicistat(Tybost)

150mgtabletonceadayusedetoboostAtazanavir,DarunavirandElvitegravir

Dependsonboosteddrug

Ritonavir(RTV)Norvir

100mgtabletsusedatdifferentdoses

DependsonPIdrugs

WarningofDrugDrugInteractionsespeciallyEcstasyandViagra

WhattoStartNRTI NNRTI PI INS

USDHHS2016 TAF/FTCTDF/FTCABC/3TC

DRV/r DTGEVGRAL

IAS2016 TAF/FTCABC/3TC

DTGEVGRAL

EACS TAF/FTCTDF/FTCABC/3TC

RPV DRV/r or/c DTGEVGRAL

BHIVA2016 TAF/FTCTDF/FTC

RPV ATV/rDRV/r

DTGEVGRAL

WHO2015 TDF+3TCorFTC EFV

ARTin2017• 29approveddrugs• 5broadmechanisticclassesNRTI,NNRTI,PI,INI’s,entryinhibitor

• 10recommendedfirstlinechoices• 1standardstrategy:2NRTI’s+1NNRTIorPIorINSTI

• Properties• virologic activity• safetyandtolerability• convenience• Accessandcost• Lifeexpectancy

Undetectable – Whatdoesitmean?Undetectablemeanshavingaviralloadbelow50copies.

Undetectable doesNOT meancuredofHIV.HIVinfectionisstillpresentwithinthebodybutcannotbepickeduponastandardHIVtest.

Undetectable meansthevirushasbeen“switchedoff”andisnolongerreplicatingathighlevelswithinthebody.

Undetectable meanstheriskofonwardtransmissionisvirtually0%chanceoftransmittingthevirus.

Adherence

• Whatisadherence?

• Howmuchisenough?

• Howcanadherencebeimproved?

• Whataboutmissedorforgottentablets?

Andsoto….

PreExposureProphylaxis

PrEPPreExposureProphylaxis

PrEPISNOTNEW….

“The reduction in mother-to-child transmission of humanimmunodeficiency virus (HIV) is regarded as one of the mosteffective public health initiatives.

In the absence of treatment, the risk of vertical transmission of HIV is as high as 25-30%. With the implementation of HIV testing, counseling, antiretroviral medication,delivery by cesarean section prior to onset of labor, and discouraging breastfeeding, themother-to-infant transmission has decreased to less than 2%”

PrEPPreExposureProphylaxis

Oct2009:RV144HIVvaccine

July2010:Tenofovirmicrobicide

Oct2013:Firstrectalmicrobicidetrial• MTN017:• PhaseIItrial• Reducedglycerineformulationoftenofovirgel

• Daily• Beforeandaftersex

• Truvadaoraldaily• Enrolling186MSM/TSWinPeru,SouthAfrica,ThailandandtheUnitedStates

Howaretheantiretrovirals used? • Oralpill• Topicalgel(microbicide)

•Rectal•Vaginal

• Injection• Intravaginalring

Howoftenaretheantiretroviralsused? • Daily• Intermittently• Coitally(before/sex)

Howmanyantiretroviralsareused? • Single• Combination

Whatantiretroviralsareused? • MostlyTRUVADA• Over25available

Adherence

PrEPPreExposureProphylaxis

PrEPPreExposureProphylaxis

PrEPPreExposureProphylaxis

PrEPPreExposureProphylaxis

Adherence

Adherence

Adherence

Adherence

Adherence