Presentation on theme: "strategie terapeutiche"— Presentation transcript:
1 strategie terapeutiche AIDS: il ruolo del medico e le più attualistrategie terapeuticheDott. Renato MaseratiCoordinatore Servizi Ambulatoriali e Responsabile Ambulatorio AIDS, FondazioneIRCCS Policlinico “San Matteo”. Professore a Contratto Facoltà di MedicinaUniversità di Pavia
2 Il principio di base della terapia antiretrovirale E’ il virus, stupido!!!
3 IMMUNE DESTRUCTION AND HIV: TWO DIFFERENT MODELS CD4+ CellsINFECTIONIMMUNE DESTRUCTIONAIDSHIVsoluble factorscytokinesapoptosisanti MHC AbINFECTIONCD4+ Cells????IMMUNE DESTRUCTIONAIDS
4 Observational data: likelihood of developing AIDS by 3 years after becoming infected with HIV (untreated patients)Mellors jW, Munoz A, Gigorni JV et al Ann. Intern Med 1997
5 Raltegravir, an integrase inhibitor Etravirine, an NNRTI The accelerated pace of new drug approvals and novel ARV launches has made this a very exciting time to be practicing medicine in the field of HIV.Before 2007, the last launch of a new therapeutic class occurred with enfuvirtide, in Now, in just the last year, 3 important new ARVs have been launched, representing 2 new classes1,2:Maraviroc, a CCR5 antagonist and the first orally-dosed drug in a new class in over a decadeRaltegravir, an integrase inhibitorEtravirine, an NNRTIThese important advances have made it possible to achieve an undetectable viral load in even the most treatment-experienced patients.References1. U.S. Food and Drug Administration. HIV/AIDS historical time line: Accessed August 26, 2008.2. Intelence [package insert]. Yardley, PA: Tibotec, Inc; 2008.
6 Il paradigma della ARV (1985 – 1996) mortalita’ elevataalto livello di frustrazione nella lotta contro HIVfarmaci con una attivita’ antivirale deludentebasso livello di accettabilita’ della terapia da parte dei pazienti e delle loro associazioniVOGLIO VIVERE….
7 Il paradigma della ARV (1998 – oggi) una buona attivita’ antiretrovirale e’ la normacomodita’ di assunzione e bassa tossicita’emergono altre problematicheVOGLIO VIVERE… …BENE!
9 “Lipodystrophy Syndrome” No generally accepted case definition of syndrome(s)Initial reports suggested clustering of:Central fat accumulation/adiposityLipoatrophy/fat wastingDyslipidemiaInsulin resistance/type 2 diabetes mellitusRecent cross-sectional epidemiological data question linkage of lipoatrophy and fat accumulationFram J Acquir Immune Defic Syndr 2005;40:1. Lichtenstein. 13th International AIDS Conference; July 9-14, 2000; Durban, South Africa. Abstract ThOrB704.2. Martinez. AIDS ;13:3. Lilienfeld. 14th International Conference on Antiviral Research; April 8-14, 2001; Seattle, WA. Abstract 15.
11 The multiple steps in the viral replication cycle are the focus of current therapy research. Viral entry comprises 3 distinct processes/stages, each of which is being examined as a therapeutic target.1,2 Reverse transcriptase and protease continue to be examined as targets for newer improved agents, while additional research is focusing on integrase and maturation.1Protease inhibitors (PIs) and maturation inhibitors (MIs) both act on the gag protein. PIs act on the gag-pol, preventing polyproteins from being cleaved and forming infectious virions.3 MIs act on the gag protein, preventing P25 from becoming mature P24, thereby preventing maturation and the formation of mature particles that can emerge as mature infectious virions.4The viral entry pathway is the most upstream and only extracellular pathway necessary in the viral replication cycle.1 This pathway will be discussed in further detail.References1. Agrawal L, Lu X, Jin Q, Alkhatib G. Anti-HIV therapy: current and future directions. Curr Pharm Des. 2006;12:2. Markovic I. Advances in HIV-1 entry inhibitors: strategies to interfere with receptor and coreceptor engagement. Curr Pharm Des. 2006;12:3. Flexner C. HIV-protease inhibitors. N Engl J Med. 1998;338:4. Sakalian M, McMurtrey CP, Deeg FJ, et al. 3-O-(3',3'-dimethysuccinyl) betulinic acid inhibits maturation of the human immunodeficiency virus type 1 Gag precursor assembled in vitro. J Virol. 2006;80:
12 Reverse transcriptase inhibitors Non nucleosidicinhibitorsNVP, EFV, DLVNo need of activation in the cellNucleotidic and nucleosidic inhibitors:AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTCNeed phosphorilation before they become active
14 Attivita’ antiretrovirale e farmacoresistenza doppiamonotriplaprobabilità di selezionare una mutazioneaumento della soppressione della replicazione virale
15 Effects of common NRTI mutations M184VSelected by 3TC, FTC → high-level resistanceAlso selected by ABC, rarely ddI and ddCLow-level resistance to ABCNo major effect on ddI (? beneficial effect)Hypersusceptibility effects for ZDV, d4T and TDFTAMsSelected by ZDV and d4T (ddI)Resistance to ZDV, d4T, ddI, ddC, ABC, TDF↑ number of TAMs = ↑ NRTI cross-resistanceK65RSelected by TDF, ddI, ABCResistance to TDF, ABC, 3TC, ddI, ddCUncertain effects on susceptibility to d4THypersusceptibility to ZDVL74VSelected by ABC, ddIResistance to ABC, ddI, ddCUncertain effects on susceptibility to TDFPotential benefits of M184VSelected by ddI, ABCEmergence antagonised by ZDV or TAMsResistance to ddI and ddCLow-level resistance to ABCPartially suppresses ZDV resistance and possibly d4T and TDF resistance caused by T215Y
16 Protease Inhibitors Saquinavir (SGC,HGC)* Nelfinavir Amprenavir* Lopinavir §Indinavir*RitonavirFos-Amprenavir*Tipranavir** May be used with ritonavir as a booster§ Available only in the boosted formProtease-substrate complex
17 Is HAART so critical in HIV history? AIDS-related Mortality in the USA 403530252015105100755025DeathsDeaths per 100 person-yearsTherapy with a PI (% of patient-days)Use of PIsYearPalella et al. 8th CROI, 2001
18 What PI treatments do we now have? AtazanavirQuestions over data400mg QDLopinavir/r400/100mg BIDSaquinavir/r1000/100mg BIDIndinavir/r800/100mg BIDNelfinavir1250mg BIDAmprenavir/r600/100mg BID
19 Reverse transcriptase inhibitors Non nucleosidicinhibitorsNVP, EFV, DLVNo need of activation in the cellNucleotidic and nucleosidic inhibitors:AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTCNeed phosphorilation before they become active
20 HAART Studies 10 20 30 40 50 60 70 80 90 100 Unboosted PI NNRTI NRTI Previous analysis emphasized relation b/w pill burden and responseUpdated analysis: pill burden less importantHighlights efficacy of boosted-PI and NNRTI regimensUnboosted PINNRTINRTIDati piu’ recenti come quelli del CROI 2005 confermano che la HAART e’ stata e rimane uno degli interventi terapeutici di maggior successo della storia della medicina. Questo grafico ed il successivo portati da Bartlett che ha semplicemente aggiornato suoi grafici di qualche anno fa. Ognuna delle barre indica che percentuale nei vari regimi terapeutici (qui semplicemente classificati dal piu’ remoto a quello piu’ recente dall’alto al basso e con una chiave di colore a seconda della composizione principale del regime stesso) e Il successo non solo rimane ma e’ potenziato dagli ultimi regimi terapeutici disponibili.Boosted PI102030405060708090100% With VL < 50 at Week 48Bartlett JA et al. Abstract 586, CROI 2005
22 Le scelte critiche nella HAART Quando e come iniziareIndividuare i parametri che predicono il successo e l’insuccesso nel singolo paziente a breve termineNel medio-lungo periodo: tollerabilità, tossicità, sequenziabilitàNel paziente multi-trattato: introduzione di nuovi farmaci, terapie “hold-on”Co-morbidità: epatopatie croniche, diabete, altroRuolo di farmacocinetica, genomica, immunologia
23 Considerations for Initial Regimen UnderlyingConditionsHepatitisCV DiseaseLifestyleDosingPill BurdenInitialTreatmentDrugInteractionsSequencingToxicityShort TermLong Term
24 Perchè i pazienti interrompono la terapia? Cause di interruzione del primo schema HAART a 45 settimane nella coorte ICONA (n = 862)Fallimentovirologico 14.1%Tossicità 58.3%Non aderenza19.6%Altro 8.0%La causa maggiore di interruzione della terapia HAART è rappresentata da problemi di tossicità, pertanto deve essere sempre mantenuto un equilibrio tra lo stato generale del paziente e le sue condizioni viro-immunologiche.d’Arminio Monforte et al. AIDS 2000; 14:499–507
25 Gli eventi avversi come determinanti di non aderenza 5760503640262630% di pazienti che hanno saltato una dose per un particolare evento avverso1516172013141110DiarreaFatigueNauseaVomitoFebbriGastralgiaVariazioneforma corpoNeuropatia/ formicolioEmicraniaRash/psoriasiAlterazioni gustoGas e gonfioreAdattato da Munk. CPS Info Pack (suppl). POZ 1998.
26 Adverse Effects of NRTIs* Zidovudine (AZT)- headache, GI intolerance, bone marrow suppressionAbacavir - hypersensitivity reactionDidanosine (ddI) - GI intolerance, pancreatitis, peripheral neuropathyStavudine (d4T) - peripheral neuropathy, pancreatitis, lipoatrophyZalcitabine (ddC) - peripheral neuropathy, oral ulcersLamivudine (3TC) – rare side effectsEmtricitabine (FTC) – side effects uncommon; hyperpigmentation of palms/soles < 2% (non-Whites)Tenofovir - headache, GI intolerance, renal insufficiency*Lactic acidosis is a class effect, most strongly associated with d4T/ddI; 3TC, FTC, and tenofovir are active against HBV. Development of HBV resistance may lead to flare of hepatitis.
27 Adverse Effects of NNRTIs Rash, including Stevens-Johnson syndrome with nevirapineElevated liver enzymes (nevirapine > efavirenz, delavirdine)Incidence of hepatotoxicity highest in women with pre-nevirapine CD4 counts >250 cells/mm3 and men with >400 cells/mm3Efavirenz - neuropsychiatric, teratogenic in primates (FDA Pregnancy Class D)
28 Acute Adverse Effects of PIs GI intolerance, diarrheaHyperbilirubinemia –atazanavir, indinavirHepatotoxicityIncreased bleeding in hemophiliacsAdverse metabolic effectsDyslipidemiaInsulin resistance? Lipodystrophy/fat redistributionAtazanavir has favorable metabolic profile
29 Adverse Effects of Entry Inhibitors Enfuvirtide (T-20)Injection-site reactionsHypersensitivity reactionIncreased incidence of bacterial pneumonia
30 Come si sta spostando il “pendolo” della terapia ?
31 Updated DHHS Guidelines: When to Start Treatment Clinical CategoryCD4+ CellCountPlasmaHIV-1 RNAGeneral GuidelinesAIDS-defining illness or severe symptoms*Any valueTreatAsymptomatic< 200Treatment should be offered following full discussion of pros and cons of treatment.> 350≥ 100,000Most clinicians recommend deferring therapy, but some clinicians will treat.< 100,000Defer therapy
32 CD4+ Count Prior to Therapy Predicts Progression to AIDS % DevelopingAIDS*Johns Hopkins HIV CohortAnalysis of CD4+ cell count response and disease progression in patients who maintained sustained virologic suppression for up to 6 yrs (N = 280)Only patients with baseline CD4+ count > 350 cells/mm³ returned to near normal CD4+ cell count levelsRate of progression to AIDS or death was significantly higher over time in patients with CD4+ count < 200 and CD4+ count compared with CD4+ count > 350 cells/mm³900800> 3501.5%†70060012%500CD4+ cells/mm³13%400300< 200200100Yr 1Yr2Yr3Yr 4Yr 5Yr 6*% Over 6 years of study† P < .05 compared with CD4+ < 200Moore RD, et al. IAC Abstract THPE0109.
33 HAART and Survival Based on Initial CD4+ Cell Count Modeled data from ART Cohort Collaborative10,855 patients included934 progressed to AIDS or diedIDUs excluded from modelCumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAARTcells/mm cells/mm cells/mm3123450.000.020.040.060.080.100.12Progression and Death According to CD4+ Cell Count (cells/mm3)< 200 vs< 350 vsHazard ratio for AIDS (95% CI)( )1.52( )Hazard ratio for AIDS or death (95% CI)( )1.26( )Probability of AIDS or DeathFor more information, go to the Capsule Summary atYears Since Initiation of HAARTSterne J, et al. CROI Abstract 525.
34 HOPS Cohort Prevalence of Mutations in Persons with Virologic Failure after HIV Suppression, by CD4 Cell Count at HAART InitiationQuestion: Does initiation of HAART at higher CD4 predispose to drug resistance?Study Eligibility:achieved viral load (VL) <1,000suppressionlater had rebound (>1,000)had GT performedConclusion: Less resistance observed in all ARV classes when therapy started earlier (CD4 >350)One argument made against early initiation of HAART (eg with CD4 >350) is that if patients fail, they will likely develop drug resistance that will reduce therapeutic options later. However, patients who start therapy early, when viral loads are lower, immunologic function is more intact and general health is better may not develop resistance at the same rate as later stage patientsThe HIV Outpatient Study (HOPS), is a prospective observational cohort of HIV patients at ten HIV-specialty clinics in the USmajor drug resistance mutations as defined in IAS-USA guidelinesThe figure shows that rates of drug resistance decline with higher CD4 at time of HAART initiation. The reduction in resistance is especially striking for those initiating above 350.* p-values are for comparisons between CD4 cell countranges at HAART initiationUy J, et al., IAS 2007; WEPEB017.
35 HOPS: Lipoatrophy and CD4+ Nadir Min CD4+Max CD4+> 350> 3503.3> 20012.0< 200> 50013.2< 20017.0< 20018.2< 200< 20030.82550Incidence of Lipoatrophy (%)Lichtenstein K, et al. CROI Poster 684a (T).
36 Factors Associated With Peripheral Neuropathy in HIV HOPS Cohort: PNP Associated With HAART (N = 2178)HIV Insight: Incidence of PNP by Nadir CD4 (N = 7980)% PNP% on HAART1418P < .000115.5%12161001410801211.1%810Patients With PNP (%)Patients (%)607.7%Patients on HAART (%)684065.1%44.3%42202199119921993199419951996199719981999200020010-99≥ 500YearNadir CD4 Category1. Lichtenstein K, et al. IAS Abstract Lichtenstein K, et al. IAS Abstract 731.
37 Prevalence of X4 or R5/X4 (%) CD4+ Cell Count (cells/mm3) Increasing Prevalence of X4- or R5/X4-Tropic Virus at Lower CD4+ Cell CountsCCR5Patients with early-stage HIV disease tend to have pure R5- tropic virusCXCR4With advanced disease, X4- or dual-tropic virus emergesAssociated with more rapid clinical and immunologic progressionCould CCR5 inhibition select for more virulent X4-tropic virus?1008060Prevalence of X4 or R5/X4 (%)41.9%40.0%402016.0%16.0%14.8%> 3002481048151-10031< 5050CD4+ Cell Count (cells/mm3)n =Moyle G, et al. ICAAC Abstract 1135.
38 The Case for Earlier Initiation of Therapy Availability of more potent, easier, and less toxic regimensCohort studies showing benefit with earlier therapyBetter response to therapyDecreased transmissionPreserve R5-tropic virusCost-effectiveness
40 2006 Guideline Recommendations for Initial HAART Regimen Recommended Initial Regimens for Antiretroviral-Naive PatientsDHHS Guidelines (May 2006)NNRTI-based regimenEFV + (3TC or FTC) + (TDF or ZDV)PI-based regimenLPV/RTV + (3TC or FTC) + ZDVIAS-USA Guidelines (August 2006)EFV*(NVP*)LPV/RTV*ATV/RTV*FPV/RTV*SQV/RTV*The current standard of care of the treatment of HIV infection is a combination of 2 NRTIs and a third active agent.Of the various HAART combinations available, NNRTI-based regimens and ritonavir-boosted PI-based regimens have demonstrated superior efficacy and tolerability as initial treatment for HIV infection. For an NNRTI-based regimen, the May 2006 guidelines offered by the US Department of Health and Human Services (DHHS) recommended efavirenz with lamivudine or emtricitabine and tenofovir or zidovudine. In the same guideline, the preferred PI-based regimen was lopinavir/ritonavir with lamivudine or emtricitabine plus zidovudine.The International AIDS Society (IAS)-USA August 2006 guidelines recommended both efavirenz and nevirapine as initial NNRTIs for treatment-naive patients, noting the weight of evidence supporting the efficacy of efavirenz along with the fact that it is available as part of a 1-pill once-daily regimen. On the other hand, they note nevirapine’s similar efficacy as well as its role for women of childbearing age. With respect to PI initial regimens for antiretroviral-naive patients, the IAS-USA guidelines recommend 4 boosted-PI regimens as options for first-line therapy, noting that the largest cumulative data set exists for lopinavir/ritonavir–based regimens at this time.*Plus TDF/FTC, ABC/3TC, or ZDV/3TC.1. DHHS Guidelines. Available at: Accessed Sept. 15, Hammer SM, et al. JAMA. 2006;296:
41 Durability of Response to HAART StudyFollow-up, wksHIV-1 RNA < 50 c/mL, %VF, %Any Resistance*, %GS 934EFV + TDF/FTC144642968EFV + ZDV/3TC564276ACTG 5142EFV + 2 NRTI96892448LPV/RTV + 2 NRTI773721KLEANFPV/RTV + ABC/3TC666LPV/RTV + ABC/3TC65733*Genotyped patients with virologic failure1. Arribas JR, et al. IAS Abstract WEPEB Riddler S, et al. IAC Abstract THLB0204. Haubrich RH, et al. HIV Resistance Workshop Poster Eron J Jr, et al. Lancet. 2006;368:1238.
42 KLEAN: FPV/r vs LPV/r-Naive Virological response 100FPV/r89%88%80LPV/r66%6065%VL<50 copies/mL at week 48% patients with402043.35Klean presenta un’analisi tra FPV e kaletra: non c’è una differenza significativa per quanto riguarda la risposta virologica.n=434n=444n=328n=341ITT-e TLOVRObservedITT-e: All patients exposed to >1 dose of randomized study medicationEron, et al. Lancet 2006; 368 (9534):
43 KLEAN: FPV/r vs LPV/r-Naive Grade 3/4 lipid abnormalities 15FPV/rLPV/r1011%Patients (%)9%8%8%543.45Non c’è significativa differenza per quanto riguarda I livelli di trigliceridi. Si ha però un notevole incremento dei livelli di colesteroloFasting cholesterol ≥ 300 mg/dLFasting Triglycerides ≥ 751 mg/dL(≥ 7.7mmol/l)(≥ 8.4mmol/l)Eron, et al. Lancet 2006; 368 (9534):
44 ALERT: FPV/r vs ATV/r-Naive Lipid results 250200n=39p < 0.05n=48n=38n=38n=38150n=46n=39n=48Median level (mg/dL)n=48n=38n=45n=39100n=4650n=48n=38n=3944.08E anche I risultati relativi al metabolismo lipidico tra I due farmaci non differiscono significativamenteSono necessari altri trials per capire quale strategia sia migliore dal punto di vista del metabolismo lipidico.CholesterolLDLHDLTGFPV/r BaselineATV/r BaselineFPV/r Week 24ATV/r Week 24Smith K, et al. 46th ICAAC 2006; abstract H-1670a
45 Gemini SQV/r vs LPV/r-Naive Prospective, Phase IIIb, randomized, multi-centre, open-label, 2-arm studyN = 33726 North American sites8 Canada1 Puerto Rico17 United States11 French sites1 Thai siteDuration 48 weeksInclusion criteriaTreatment naiveCD4 ≤ 350HIV RNA > 10,000 copies/mlSQV/r 1000/100 mg bid+ TDF/FTC1:1 randomizationLopinavir/r 400/100 mg bid+ TDF/FTC……….- GEMINI: SQV/r + TDF/FTC vs LPV/r + TDF/FTC
46 BMS 138: ATV/r vs. LPV/r + TDF/FTC in ARV-naive patients International, open-label trialDuration: 96 weeksInclusion criteria:HIV RNA ≥ 5,000 c/mLAny CD4 countPrimary efficacy endpoint: VL < 50 c/ml at 48 weeksSecondary outcomes:VL < 50 c/mL at 96 weeksVL < 400 c/mL at 48 & 96 weeksSafety assessmentsStatusStudy start: November 2005Fully enrolledAtazanavir/r 300/100 mg qd+ TDF/FTC1:1 randomizationLopinavir/r 400/100 mg bid+ TDF/FTC44.22Le tre slides successive mostrano due studi ancora in corso che paragonano differenti regimi terapeutici:-Il BMS 138: ATV/r + TDF/FTC vs. LPV/r + TDF/FTC………
47 Metabolic Effects of PIs AgentLipidsGlucoseRTV (full dose) TC/TG insulin resistanceLPV/RTV TC/TGIDV/RTVNFV LDL/TG, HDL(?)No insulin sensitivityAPV/RTV or FPV/RTVTPV/RTV?SQV/RTVLittle ATVNo ATV/RTVDRV/RTVRTV associated with more pronounced effect on lipids than other PIs
48 Metabolic Effects of PIs: LPV/RTV vs ATV/RTV BMS-045: randomized trial of patients with 2 HAART failuresATV/RTVLPV/RTVTCLDL-C*HDL-CTG*35302515Mean Change From Baseline to Wk 48 (%)6251-5-4*-8†-7-15-10*Fasting values.†P < vs LPV/RTV.Johnson M, et al. AIDS. 2005;
50 HIV Transmission and the Establishment of HIV Reservoirs Interactions of HIV envelope glycoproteins, CD4, and CCR5 or CXCR4 coreceptors trigger fusion and entry of HIV.(B) Outline of the sequence and time course of events involved in viral dissemination.
51 Fusion inhibitors: T20, (T1249) CD4 +chemokine receptorsThe gp120 subunit binds the CD4 receptorEach subunit undergoes a conformational change exposing the region that will bind a transmembrane chemokine receptorFusion inhibitors bind to the gp41 envelope protein and block the structural changes required for the virus to fuse with the host CD4 cell. When the virus cannot penetrate the host cell membrane and infect the cell, HIV replication within that host cell is prevented.T-1249 binds to a region overlapping with, but different from, the T-20 binding region of gp-41. The two compounds show additive activity against wt virus in vitro, which may indicate synergistic activity in vivo. It was suggested that T-1249 may help answer questions about what drug to use with T-20 in highly experienced patients. (Abstract #14)Virus isolates show varying affinity for CCR5 or CXr4 receptorsShifts away the steric hindrance of gp 120Allows gp 41 to mediate the fusion and entry
52 Patients achieving response (%) DRV/r or TPV/r Versus cPI(s): Week 48: <50 copies/mL With First Use ENF80POWERRESIST6056%Patients achieving response (%)4036%2011%9%DRV/r(n = 36)cPI(s) (n = 35)TPV/r (n = 123)cPI(s) (n = 97)First use of ENFHill A, et al. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1386.
53 Virologic Response by Number of DRV-associated Mutations V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V1008040602064(67)Patients with VL HIV RNA <50 copies/mL at Week 24 (%)501(94)422(113)42All(373)223(58)10≥4(41)87910IAS-USA PI mutationsNumber of TMC114 mutations(Number of patients)De Meyer S, et al. 15th International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Poster 73.
54 Etravirine: Primary Endpoint Change in VL at 48 weeks 0.5ITT analysis (non-completer = failure)–0.14–0.5–0.88, P = 0.018–1.0–1.01, P = 0.002Mean change in log10 VL (±SE)P values versus active control.SE, standard error.–1.5Relevant NNRTI mutations:K101P, V179E, V179F, Y181I, Y181V, G190S, M230LActive control (n = 40)400 mg bid (n = 80)800 mg bid (n = 79)–2.0–2.524812162024324048Time (weeks)Cohen C, et al. 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.
55 Viral entry is the first pathway of the viral replication cycle Viral entry is the first pathway of the viral replication cycle. The most uniformly accepted stages of viral entry are virus attachment, co-receptor binding, and fusion. Viral attachment is the first step of viral entry. Attachment begins with the virus attaching to a susceptible target CD4+ T cell, through a specific interaction between a virus envelope glycoprotein known as gp120 and CD4, a primary receptor on the cell surface.1 The interaction leads to conformational changes of gp120, leading to exposure of the V3 loop, and relocation of the V1/V2 hypervariable loops of gp120.2Chemokines regulate leukocyte migration through interactions with 7-transmembrane, G-protein–coupled receptors.3 Two chemokines, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4), allow HIV to enter CD4+ T cells. CCR5 is mainly expressed on monocytes and T cells, while CXCR4 is expressed on T cells, B cells, monocytes, and neutrophils.3,4Co-receptor binding involves gp120 binding to 1 of 2 co-receptors on the cell’s surface, either CCR5 or CXCR4. CCR5 and CXCR4 belong to the 7-transmembrane, G-protein–coupled receptor family of proteins. The virus either chooses 1 co-receptor (CCR5/CXCR4) with which to bind, or the virus has the ability to use both receptors. Viruses are either classified as R5-, dual/mixed(D/M)-, or X4-tropic viruses, depending on which co-receptor they bind with to subsequently enter the cell.5,6 The exact mechanism by which fusion occurs is not well known, but a conformational change in gp41 is thought to result in the creation of an opening called a fusion pore, permitting exchange of viral material through the membrane of the target cell.1,7References1. Young JAT. The replication cycle of HIV type 1. In: Cohen PT, Sande MA, Volberding PA, eds. The AIDS Knowledge Base. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:2. Markovic I. Advances in HIV-1 entry inhibitors: strategies to interfere with receptor and coreceptor engagement. Curr Pharm Des. 2006;12:3. Deng HK, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature ;381:4. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven- transmembrane, G-protein–coupled receptor. Science. 1996;272:5. Westby M, van der Ryst E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother. 2005;16:6. Poveda E, Briz V, Quiñones-Mateu M, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS. 2006;20:7. Flint SJ, Enquist LW, Racaniello VR, Skalka AM. Attachment and entry. In: Principles of Virology: Molecular Biology, Pathogenesis, and Control of Animal Viruses. 2nd ed. Washington, DC: ASM Press; 2004:
56 The second stage of viral entry is co-receptor binding The second stage of viral entry is co-receptor binding. The prior binding of gp120 to the CD4 receptor leads to conformational changes in gp120, which in turn leads to exposure of the co-receptor site and then co-receptor binding.1,2References1. Westby M, van der Ryst E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother. 2005;16:2. Poveda E, Briz V, Quiñones-Mateu M, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS ;20:
57 As shown in the pictorial, the R5 HIV exclusively utilizes the CCR5 co-receptor to infect the CD4+ T cell, and X4 HIV exclusively utilizes the CXCR4 co-receptor. D/M virus can enter the cell via either of the 2 co-receptors.1-3References1. Westby M, van der Ryst E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother. 2005;16:2. Poveda E, Briz V, Quiñones-Mateu M, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS ;20:3. Berger EA, Doms RW, Fenyö E-M, et al. A new classification for HIV-1. Nature ;391:240.
58 MOTIVATE 1 & 2: Trial Design 2 identical ongoing phase IIb/III studiesRandomized (1:2:2), double-blind, placebo-controlled1076 ARV-experienced patientsR5 HIV-1 infection (44% screen failures)HIV-1-RNA ≥5,000 copies/mLOn stable regimen, or no ARVs for ≥4 weeksResistance to and/or ≥6 months’ experience with ≥1 ARV from 3 classes (≥2 for PIs)OBT = 3-6 ARVs*Stratified by ENF use and HIV-1 RNA < and ≥5 logPlacebo(n = 209)MVC 150 mg† QD (n = 414)MVC 150 mg† BID(n = 426)Primary endpoint at 24 weeks:Mean change from baseline in HIV-1 RNA*OBT, optimized background therapy (boosting doses of RTV not counted as an ARV).†Pts receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg of MVC, all others received 300 mg of MVC.Nelson M, Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 104aLB and 104bLB.
59 MOTIVATE: Percentage of Patients With Undetectable HIV-1 RNA MVC QD + OBT (n = 232)MVC BID + OBT (n = 235)Placebo + OBT (n = 118)1001009090<400 copies/mL<50 copies/mL808070P <0.0001*706060.4%6054.7%P <0.0001*50P <0.0001*5048.5%Patients (%)42.2%4040P = *31.4%303024.6%202010102481216202424812162024Time (weeks)Time (weeks)HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks. *Versus placebo + OBT.Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104aLB.
60 MERIT: 740 naïve patients randomized to Maraviroc (300 bid) vs EFV (600 OD), both with CBV EFV (n = 361)MVC (n = 360)100VL < 400 copies/mL100VL < 50 copies/mL73.1%808069.3%6070.6%6065.3%Patients, %Patients, %40402020For more information about this study, see the Capsule Summary at:24816243240482481624324048Time (weeks)Time (weeks)MVC was noninferior to EFV only for < 400 copies/mL endpoint (70.6% vs 73.1%)CD4+ cell count increases were higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm3)Saag M, et al. IAS Abstract WESS104.
61 Recently Approved New or Novel Antiretroviral Agents Mature virusPIsDarunavir TipranavirMaravirocEntry inhibitorsReverse transcriptase inhibitorsEtravirineThis is a summary of some of the recently approved new or novel antiretroviral agents, starting with the entry inhibitor maraviroc, a novel CCR5 antagonist; the next-generation NNRTI etravirine, which is active against most NNRTI-resistant viruses; and the integrase inhibitor raltegravir. Some newer PIs include darunavir and tipranavir, which were developed specifically for activity against PI-resistant virus.Integrase inhibitorsRaltegravir6161
62 Percent <400 and <50 Copies/mL (ITT, NC=F) BENCHMRK 1 & 2Percent <400 and <50 Copies/mL (ITT, NC=F)(P<0.001 at Week 16 for all parameters)Weeks% of Patients <400 Copies/mLBENCHMRK 1BENCHMRK 2RAL <400RAL <50Placebo <400Placebo <50Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, Absts. 105aLB and 105bLB.10080604020248121624
63 Elvitegravir (GS 9137) 125 mg: The Importance of the Regimen –0.7-1GS mgwith no activedrugs in OBT(n = 26)Mean change from baseline in HIV RNA log10 copies/mLP <0.001–2.1-2GS mgwith ≥1 active NRTI or first useof T-20 (n = 47)4812162024Week*Data from GS mg patients after addition of a PI were excluded.Zolopa A, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 143LB.
64 The E92Q IN Mutation Reduces Susceptibility to Multiple Integrase Inhibitors EC50 and Fold Change (FC, Relative to Wild-type, HXB2) in Susceptibility to INIs and Control ARV Drugs of IN Site-directed Mutant HIV-1DrugWild-type(HXB2)E92QS147GH51YE157QGS-9137EC50, nM1.3 ± 0.342.2 ± 11.2(32.5)98.6 ± 23.6(76.0)208 ± 32.4(160)237 ± 61.6(182)10.7 ± 1.1(8.0)5.1 ± 1.2(4.0)3.3 ± 0.4(2.5)MK-05185.9 ± 0.635.3 ±10.5(6.0)45.6 ± 13.7(7.7)37.8 ± 6.0(6.4)33.7 ± 9.0(5.7)N/DL-870,8100.6 ± 0.27.1 ± 1.1(11.8)16.6 ± 4.3(27.7)13.0 ± 1.5(21.7)20.0 ± 4.1(33.3)Fold changes: blue: FC <2.5; Yellow: FC ≥ ; Orange: FC >10.Mean EC50 and standard deviation of n = 3 experiments; N/D, not determined.Jones, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 627.
65 Ingresso di nuovi strumenti di diagnosi e monitoraggio
66 Potential HLA-B*5701 Screening Implications Example shown is based on PPV derived from PREDICT-1 and SHAPE data.Blackn = 100Whiten = 100HLA-B*5701 testHLA-B*5701 test2positive98negativeAppropriate totreat with ABC94negative6positiveDo not treat with ABCDo not treat with ABCTest 100 black patients:Treat 98 patients at low risk for ABC HSRPrevent 1 ABC HSR eventExclude ABC unnecessarily in 1 patientFor more information about this study, see the Capsule Summary at:Test 100 white patients:Treat 94 patients at low risk for ABC HSRPrevent 4 ABC HSR eventsExclude ABC unnecessarily in 2 patientsSaag M, et al. IAS Abstract WEAB305.66
67 Linee guida sull’impiego della farmacocinetica in diverse nazioni Brecommendedconsider
68 Utilita’ del TDM (1)Spesso il dato che si ottiene dal TDM rientra nel “range terapeutico indicato dal laboratorio e/o dalla letteraturaSe il livello è “normale”..Vengono escluse interazioni significativeBisogna cercare una spiegazione alternativa a fenomeni di tossicità o fallimento
69 Utilita’ del TDM (2) livello ancora basso? spiega e/o previene PROBLEMA / SITUAZIONETerapia efficaceFallimentoTossicitàAderenzaCoinfezione HCV o HBVInterazioniPz. specialiCOSA AGGIUNGE TDM?livello ancora basso?spiega e/o previenepreviene? dose?misura oggettivaIndividualizzazione; dose?accerta, ottimizzaindividualizza in gravide, bambini, insuff. organo
70 Final Consideration on PK and ARVs The management of HIV/AIDS patients is centered on optimizing their drug regimen. What do you think is a better correlate with clinical outcomes?Drug concentrationTime (hours)1224?
72 Factors Affecting Adherence Important to recognize factors that influence adherenceHowever, physicians’ ability to identify patients who will or will not be adherent is limitedRace, sex, and socioeconomic status are not independent risk factors for nonadherenceFactors associated withincreased adherencePatient belief in HAARTPhysician experienceSocial supportsRegular office visitsnonadherenceActive injection-drug useActive alcohol abuseActive psychiatric disease (especially depression)Younger ageChaotic lifestyleLow functional literacy
73 Why Do Patients Miss Doses? %102030405060Too busy/simply forgot52Away from home46Change in daily routine45Felt depressed/overwhelmed27Took drug holiday/medication break20Ran out of medication20Reasons given for missing antiretroviral doses (structured questionnaire)Too many pills19Worried about becoming 'immune'19Felt drug was too toxic18Wanted to avoid side effects17Didn't want others to notice17POSSIBLE INTERVENTIONSReminder of HIV infection16Confused about dosage direction14Simplify dosing scheduleDidn't think it was improving health13Decrease pill burdenTo make it last longer10OtherWere told the medicine is no good9Gifford et al. JAIDS 2000;23:386–395.
74 Patient Preferences in Antiretroviral Regimens 4 most important regimen issues for patientsTotal number of pills per dayDosing frequencyDietary restrictionsSide effectsThe ideal regimen from a patient perspective:2 or fewer small pills per dayDosed all together, once dailyNo dietary restrictionsNo adverse effects
75 Fewer Patients Forget to Take QD Regimens Patients Forgetting to Take HAART (%)7166634010203050607080TID+TIDBIDQDForgetting rates reported by 438 of 504 patients in standardized interviewsPatients answered the APPT-1 pan-European surveyMoyle et al. 6th Intl Congress on Drug Ther in HIV Inf Abstract 99.
76 Dosing Preferences By Pill Burden “If you were to take a certain number of pills each day, how would you prefer them to be administered?”All at once10093Divided and taken twice-a-day8490806970625960Patients preferring schedule (%)5041384031301620710> 8 pills8 pills6 pills4 pills3 pillsMoyle G. Int J STD AIDS. 2003;14(Suppl 1):34-36.
77 You and your patient decided “it’s time to start” Co-morbidityLong term side effectsShort term side effectsTreatment schedulePKInitial treatmentDrug drug interactionsAvailable drugsFuture optionsPatient’s expectations on the outcomeClinical conditions at baselineResistance pattern at baselinePill burden
78 General Principles of Client-Centered Counselling The focus of counselling should be client’s concerns and interest explore the personal meaning that a client gives to issuesContext is important assess the physical and emotional circumstances under which HIV risk behaviors take placeIndividualize sessions Impact of counselling will be enhanced when based on specific needs and unique situations of individual clientsmodified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003
79 General Principles of Client-Centered Counselling Take a neutral stance maintain a nonjudgmental manner when discussing sexual practices, substance abuse and other personal issuesRemember you limits information alone does not lead to behavior changes, that are a complex process requiring interventions based on client’s personal circumstances.modified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003
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