Protein complexes: two glycoproteins (extracellular GP120 + transmembrane GP41*) Attachment & Entry: GP120 binds to CD4 receptor o
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1 ANTIRETROVIRAL THERAPY HIV Intr & Life Cycle Infectin f CD4+ T-lymphcyte Entry requires cell surface receptrs: CD4 receptrs + c-receptrs (CCR5*, CXCR4) CD4 receptrs interact with prtein cmplexes embedded n surface f viral envelpe Prtein cmplexes: tw glycprteins (extracellular GP120 + transmembrane GP41*) Attachment & Entry: GP120 binds t CD4 receptr C-receptr CCR5* causes cnfrmatinal change in GP120 allws GP41 t unfld & insert its hydrphbic end int the cell membrane GP41 flds back n itself facilitates fusin f viral and cell membranes Viral nuclear capsid enters hst cell à breaks in Capsid releases tw viral RNA strands + 3 essential replicatin enzymes Replicatin enzymes: reverse transcriptase, integrase, & prtease Reverse transcriptase*: RNA RNA/DNA duble helix DNA duble helix Integrase*: cleaves dinucletide frm each 3 end f DNA creating tw sticky ends Facilitates integratin int hst cell genme Transcriptin f pr-viral DNA int mrna Viral mrna migrates int cell cytplasm Building blcks fr new virus are synthesized Prtease*: cleaves lng prteins int cre prteins (crucial t create infectius virus) Tw viral RNA strands + replicatin enzymes cme tgether à cre prteins assemble arund them à frms capsid f immature virus Leaves cell, acquiring new membrane and prteins Virus matures & becmes ready t infect new cells Very fast replicatin! trillins f virins/day High level f genetic diversity N effective vaccine r prtective antibdies Transmissin Risk Factrs: MSM & hetersexual cntact Male dminated disease IV drug use Needle stick Vertical transmissin (basically eliminated w/ mdern Tx) Bld transfusin (befre 1985 Nt a risk factr nw) HIV screening recmmended in all pts 13-64y/ Fluids that cntract HIV Bld Semen Vaginal fluids Breast milk AIDS Diagnsis HIV + test & CD4 cunt <200cells/ml -OR- has AIDS defining illness AIDS Defining Illnesses Opprtunistic infectins Candidiasis Kapsi s sarcma Histplasmsis Pneumcystis carinii pneumnia Etc. HIV Tx Guidelines Integrase Inhibitrs Fr mst pts w/ HIV; Crnerstne f HIV Tx NNRTI s Used as secnd line therapy regimens Bsted Prtease Inhibitrs Used when pts can t get integrase inhibitrs Reverse Transcriptase Inhibitrs Blck transcriptin frm RNA t DNA by binding t an allsteric site
2 NRTIs Nucleside reverse transcriptase inhibitrs PrEP: MOA: entry int cell metablized via kinases t triphsphrylated (active) frm Incrprated int viral DNA blcks attachment f next DNA building blck inhibits chain grwth HIV & Hep B activity: LET it B : Lamivudine, Emtricitabine, Tenfvir Class has structural similarities (exceptin: tenfvir) yet are NOT crss resistant Class characteristics: Mitchndrial txicity (lipatrphy, lactic acidsis, mypathy, neurpathy) Must be renally adjusted!! Cmb NRTIs: Descvy = TAF & FTC Truvada = TDF & FTC Epzicm = ABC & 3TC Descvy > Epzicm > Truvada Tenfvir disprxil (TDF): NucleTIDE analg already mnphsphrylated Still must be activated t triphsphate frm Mnphsphate des NOT increase efficacy Adensine analg Lng t½ & renally eliminated Dn t use in CrCL <70ml/min ADRs: Well tlerated Nephrtxicity Rare; likely caused by renal mitchndrial txicity f prximal tubule Decreased bne mineral density (BMD) Tenfvir alafenamide (TAF): Adensine analg Circulates as prdrug & activated INTRAcellularly high [ ] in target cells & lw plasma expsure Des nt accumulate in renal tubules n renal r bne txicity Dn t use in CrCL <30ml/min Abacavir (ABC): Guanine analg Hepatically metablized & lng t½ Des NOT need t be renally adjusted Hypersensitivity reactin Can be life-threatening if rechallenged! 1 st 4 week f Tx are critical! Mnitr clsely when initiating (fever, rash, chills, malaise) HLA-B*5701 Genetic Testing If (+), d NOT give abacavir! Requires multiple mutatins in virus t cnfer resistance Lamivudine (3TC) & emtricitabine (FTC): Cytsine analgs High incidence f resistance/resistance crss reactivity Gd absrptin, Vd, & lng t½ Renally eliminated N side effects (w)
3 Truvada ONLY drug FDA apprved frm PrEP PEP: pt expsed t HIV must get a full ART fr 1m Must be within <72hrs NNRTIs Nn-nucleside reverse transcriptase inhibitrs MOA: bind t allsteric site causing cnfrmatinal change reverse transcriptase cannt bind viral RNA N intracellular metablic activatin necessary Synergistic w/ NRTIs Class characteristics: Structurally diverse but similar txicities SE: rash, hepattxicity A LOT f crss resistance likely rules ut mst f class EXCEPTION: rilpivirine Efavirenz: C-frmulated w/ Truvada (TAF + emtricitabine) Lng t½ & hepatically eliminated Drug interactins: Is a CYP3A4 inducer increase [ ] s f ther drugs ADRs: CNS dizziness, sleep disturbances, vivid dreams, impaired cncentratin Elevated TGs Gives a false psitive fr THC in urine Etravirine: Fr resistance t efavirenz BID dsing (nly ne s far) Well tlerated (sme N/D) N CNS txicity Rilpivirine: Apprved fr Tx naïve pts Hepatically metablized Lw incidence f rash & minimal CNS effects OK in pregnancy!! Class Characteristics: Bictegravir: Must be taken w/ fd! Drug interactin w/ PPIs & H2RAs Integrase Inhibitrs Blcks integratin f viral DNA int human DNA Antacids w. divalent catins (Mg, Al, Al) must separate frm integrase inhibitrs Chelate integrase inhibitrs NOT ph dependent UGT1A1 & CYP3A4 substrates Resistance uncmmn Crss resistance between raltegravir & elvitegravir Biktarvy Cmplete ART regimen! Nt recmmended in hepatic impairment
4 OCT2 & MATE1 inhibitr Cntraindicated w/ dfetilide Well tlerated (N/D, headache, insmnia) Dlutegravir: Triumeq Cmplete ART regimen! Tivicay must be cmbined w/ Descvy (TAF/emtricitabine) r Truvada (TDF/emtricitabine) Daily r BID Juluca Only 2 drug cmplete ART regimen! cmbined w/ rilpivirine Switch Tx fr pts suppressed n current ART fr > 6m w/ n Hx r resistance NOT fr pts w/ baseline viral lad >100,000 cpies/ml r HepB cinfected Must be taken w/ fd! Well tlerated (headache, insmnia) Cntraindicated w/ dfetilide OCT & MATE1 inhibitr Insulin resistance & increased metfrmin [ ] in plasma max dse 1000mg daily Elvitegravir: Raltegravir: Stribild Cmplete ART regimen! & Genvya Cmplete ART regimen! Genvya > Stribild because TAF > TDF Must be taken with fd! ADRs: N/V/D, headache Crss resistant w/ raltegravir Resistance t ne = resistance t bth Must be bsted w/ cbicistat Isentress/Isentress HD must be cmbined w/ Descvy (TAF/emtricitabine) r Truvada (TDF/emtricitabine) Increased risk f rhabdmylysis w/ cncurrent statin Tx Atrvastatin,rsuvastatin, & pravastatin safer Taken 1 tab BID r 2 tabs daily (plus any cmbined meds) PK Bster Medicatins Inhibit hepatic metablism f prtease (& integrase) inhibitrs Prlng t½ f prtease inhibitrs Prtease inhibitrs are extensively metablized in the liver Allws fr nce daily dsing & mre time >MIC Used in cmb w/ ALL prtease inhibitrs & w/ elvitegravir Cbicistat: Strng CYP3A4 inhibitr Ritnavir Prtease Inhibitrs Inhibits maturatin f baby virin
5 Class Characteristics: Darunavir: Atazanavir: MOA: stps prtease frm cleaving new lng viral plyprtein int smaller essential prtein prducts new virin stays a baby and unable t infect ther cells ADRs: N/V/D, metablic disrders, liver txicity, fat redistributin (newer drugs have lwer incidence f this), avascular necrsis (jint replacements & sterid injectins) Must be cmbined w/ Descvy r Truvada PI + fluticasne = Cushing s Syndrme Take with fd Rash side effect Has sulfa sub grup Cautin in pts w/ sulfa allergy (Dn t use w/ anaphylaxis rxns) Prezista must take ritnavir separately (plus ther cmbined meds) Prezcbix cmb w/ cbicistat High barrier t resistance (PI f chice) ph dependent interactin w/ H2RAs, PPIs, & antacids Reyataz must be cmbined w/ ritnavir (plus ther cmbined meds) Evtaz cmb w/ cbicistat Causes indirect hyperbilirubinemia Pt needs t drink a lt f fluids Class Characteristics: Entry Inhibitrs Prevent viral entry int hst cell Indicated fr heavily Tx-experienced pts w/ MDR HIV & failing current regimen Must be cmbined w/ any ther drugs that may still nt have resistance cmbat resistance CCR5 Antagnist: Maravirc: MOA: Blcks the CCR5 c-receptr s that HIV cannt bind t hst cell ONLY wrks n CCR5 creceptr Mutatin in virus t bind CXCR4 = Resistance Must d Trpism testing Tests fr presence f CXCR4 mutatin Only indicated fr resistant HIV prir auth needed BID dsing Adjust w/ CYP3A4 drug interactins ½ w/ inhibitrs & Duble w/ inducers Fusin Inhibitr: Enfuvirtide: MOA: Blcks fusin t and entry int CD4 cell Injectable: 90mg SubQ BID Requires recnstitutin
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