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AIDS: il ruolo del medico e le più attuali strategie terapeutiche Dott. Renato Maserati Coordinatore Servizi Ambulatoriali e Responsabile Ambulatorio AIDS,

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Presentation on theme: "AIDS: il ruolo del medico e le più attuali strategie terapeutiche Dott. Renato Maserati Coordinatore Servizi Ambulatoriali e Responsabile Ambulatorio AIDS,"— Presentation transcript:

1 AIDS: il ruolo del medico e le più attuali strategie terapeutiche Dott. Renato Maserati Coordinatore Servizi Ambulatoriali e Responsabile Ambulatorio AIDS, Fondazione IRCCS Policlinico San Matteo. Professore a Contratto Facoltà di Medicina Università di Pavia

2 Il principio di base della terapia antiretrovirale E il virus, stupido!!!

3 IMMUNE DESTRUCTION AND HIV: TWO DIFFERENT MODELS HIV CD4+ Cells INFECTION IMMUNE DESTRUCTION AIDS HIV CD4+ Cells INFECTION IMMUNE DESTRUCTION AIDS soluble factors cytokines apoptosis anti MHC Ab ????

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

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6 Il paradigma della ARV (1985 – 1996) VOGLIO VIVERE…. - mortalita elevata - alto livello di frustrazione nella lotta contro HIV - farmaci con una attivita antivirale deludente - basso livello di accettabilita della terapia da parte dei pazienti e delle loro associazioni

7 VOGLIO VIVERE… …BENE! VOGLIO VIVERE… …BENE! Il paradigma della ARV (1998 – oggi) - una buona attivita antiretrovirale e la norma - comodita di assunzione e bassa tossicita - emergono altre problematiche

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9 Lipodystrophy Syndrome No generally accepted case definition of syndrome(s) Initial reports suggested clustering of: – Central fat accumulation/adiposity – Lipoatrophy/fat wasting – Dyslipidemia – Insulin resistance/type 2 diabetes mellitus Recent cross-sectional epidemiological data question linkage of lipoatrophy and fat accumulation Fram J Acquir Immune Defic Syndr 2005;40:

10 Abdominal MRI Scans Control subjectIncreased Visceral Fat

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12 Non nucleosidic inhibitors NVP, EFV, DLV No need of activation in the cell Nucleotidic and nucleosidic inhibitors: AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTC Need phosphorilation before they become active Reverse transcriptase inhibitors

13 Guanosine ABC- MP CBV-MP CBV-DP CBV-TP ABC Adenosine Phosphotransferase Cytosolic Enzyme Kinase Thymidine ZDV-MP ZDV ZDV-DP d4T d4T-MP d4T-DP Thymidylate Kinase NDP Kinase Thymidine Kinase ZDV-TPd4T-TP Cytidine ddC 3TC FTC ddC-MP ddC-DP 3TC-MP 3TC-DP NDP Kinase CMP/dCMP Kinase Deoxycytidine Kinase ddC-TP3TC-TP Adenosine ddI - MP ddA-MP ddA-DP ddI 5 Nucleotidase Adenylate Synthetase & Adenylate Lyase Adenylate Kinase & PRPP Synthetase ddA-TP Tenofovir TFV-MP Tenofovir DF Diester Hydrolysis AMP Kinase NDP Kinase TFV-DP FTC-TP Phosphorylation of NRTIs and NtRTIs

14 Attivita antiretrovirale e farmacoresistenza probabilità di selezionare una mutazione aumento della soppressione della replicazione virale mono doppia tripla

15 Effects of common NRTI mutations MutationEffects M184V Selected by 3TC, FTC high-level resistance Also selected by ABC, rarely ddI and ddC Low-level resistance to ABC No major effect on ddI (? beneficial effect) Hypersusceptibility effects for ZDV, d4T and TDF TAMs Selected by ZDV and d4T (ddI) Resistance to ZDV, d4T, ddI, ddC, ABC, TDF number of TAMs = NRTI cross-resistance K65R Selected by TDF, ddI, ABC Resistance to TDF, ABC, 3TC, ddI, ddC Uncertain effects on susceptibility to d4T Hypersusceptibility to ZDV L74V Selected by ABC, ddI Resistance to ABC, ddI, ddC Uncertain effects on susceptibility to TDF Hypersusceptibility to ZDV

16 Protease Inhibitors Protease-substrate complex Saquinavir (SGC,HGC)* Nelfinavir Amprenavir* Lopinavir § Indinavir* Ritonavir Fos-Amprenavir* Tipranavir* * May be used with ritonavir as a booster § Available only in the boosted form

17 Is HAART so critical in HIV history? AIDS-related Mortality in the USA Year Deaths per 100 person-years Therapy with a PI (% of patient-days) Deaths Use of PIs Palella et al. 8th CROI,

18 Lopinavir/r 400/100mg BID Saquinavir/r 1000/100mg BID Indinavir/r 800/100mg BID Nelfinavir 1250mg BID Amprenavir/r 600/100mg BID Atazanavir 400mg QDQuestions over data What PI treatments do we now have?

19 Non nucleosidic inhibitors NVP, EFV, DLV No need of activation in the cell Nucleotidic and nucleosidic inhibitors: AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTC Need phosphorilation before they become active Reverse transcriptase inhibitors

20 % With VL < 50 at Week 48 Boosted PI NNRTI NRTI Unboosted PI HAART Studies Bartlett JA et al. Abstract 586, CROI 2005 Previous analysis emphasized relation b/w pill burden and response Updated analysis: pill burden less important Highlights efficacy of boosted-PI and NNRTI regimens

21 HAART Studies: which one?

22 Le scelte critiche nella HAART Quando e come iniziare Individuare i parametri che predicono il successo e linsuccesso nel singolo paziente a breve termine Nel medio-lungo periodo: tollerabilità, tossicità, sequenziabilità Nel paziente multi-trattato: introduzione di nuovi farmaci, terapie hold-on Co-morbidità: epatopatie croniche, diabete, altro Ruolo di farmacocinetica, genomica, immunologia

23 Considerations for Initial Regimen Initial Treatment Lifestyle Dosing Pill Burden Toxicity Short Term Long Term Drug Interactions Sequencing Underlying Conditions Hepatitis CV Disease

24 Perchè i pazienti interrompono la terapia? Tossicità 58.3% Non aderenza 19.6% Fallimento virologico 14.1% Altro 8.0% dArminio Monforte et al. AIDS 2000; 14:499–507 Cause di interruzione del primo schema HAART a 45 settimane nella coorte ICONA (n = 862)

25 Adattato da Munk. CPS Info Pack (suppl). POZ Gli eventi avversi come determinanti di non aderenza % di pazienti che hanno saltato una dose per un particolare evento avverso 0 60 Febbri Gastralgia Rash/psoriasi Variazione forma corpo Alterazioni gusto Neuropatia/ formicolio Diarrea Gas e gonfiore Fatigue Emicrania Nausea Vomito

26 Adverse Effects of NRTIs* Zidovudine (AZT)- headache, GI intolerance, bone marrow suppression Abacavir - hypersensitivity reaction Didanosine (ddI) - GI intolerance, pancreatitis, peripheral neuropathy Stavudine (d4T) - peripheral neuropathy, pancreatitis, lipoatrophy Zalcitabine (ddC) - peripheral neuropathy, oral ulcers Lamivudine (3TC) – rare side effects Emtricitabine (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 nevirapine Elevated liver enzymes (nevirapine > efavirenz, delavirdine) – Incidence of hepatotoxicity highest in women with pre-nevirapine CD4 counts >250 cells/mm 3 and men with >400 cells/mm 3 Efavirenz - neuropsychiatric, teratogenic in primates (FDA Pregnancy Class D)

28 Acute Adverse Effects of PIs GI intolerance, diarrhea Hyperbilirubinemia –atazanavir, indinavir Hepatotoxicity Increased bleeding in hemophiliacs Adverse metabolic effects – Dyslipidemia – Insulin resistance – ? Lipodystrophy/fat redistribution – Atazanavir has favorable metabolic profile

29 Adverse Effects of Entry Inhibitors Enfuvirtide (T-20) – Injection-site reactions – Hypersensitivity reaction – Increased incidence of bacterial pneumonia

30 Come si sta spostando il pendolo della terapia ?

31 Updated DHHS Guidelines: When to Start Treatment Clinical CategoryCD4+ Cell Count Plasma HIV-1 RNA General Guidelines AIDS-defining illness or severe symptoms* Any value Treat Asymptomatic< 200Any valueTreat Asymptomatic Any valueTreatment should be offered following full discussion of pros and cons of treatment. Asymptomatic> ,000Most clinicians recommend deferring therapy, but some clinicians will treat. Asymptomatic> 350< 100,000Defer therapy

32 CD4+ Count Prior to Therapy Predicts Progression to AIDS Johns Hopkins HIV Cohort Analysis 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 levels Rate of progression to AIDS or death was significantly higher over time in patients with CD4+ count 350 cells/mm³ Moore RD, et al. IAC Abstract THPE Yr 1Yr2Yr3Yr 4Yr 5Yr 6 CD4+ cells/mm³ 13% 12% 1.5% *% Over 6 years of study P <.05 compared with CD4+ < 200 % Developing AIDS* > 350 <

33 HAART and Survival Based on Initial CD4+ Cell Count Modeled data from ART Cohort Collaborative 10,855 patients included 934 progressed to AIDS or died IDUs excluded from model Sterne J, et al. CROI Abstract 525. Progression and Death According to CD4+ Cell Count (cells/mm 3 ) < 200 vs < 350 vs Hazard ratio for AIDS (95% CI) 3.68 ( ) 1.52 ( ) Hazard ratio for AIDS or death (95% CI) 2.93 ( ) 1.26 ( ) Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART Years Since Initiation of HAART Probability of AIDS or Death cells/mm cells/mm cells/mm 3

34 HOPS Cohort Prevalence of Mutations in Persons with Virologic Failure after HIV Suppression, by CD4 Cell Count at HAART Initiation Uy J, et al., IAS 2007; WEPEB017. * p-values are for comparisons between CD4 cell count ranges at HAART initiation Question: Does initiation of HAART at higher CD4 predispose to drug resistance? Study Eligibility: – achieved viral load (VL) <1,000suppression – later had rebound (>1,000) – had GT performed Conclusion: Less resistance observed in all ARV classes when therapy started earlier (CD4 >350)

35 HOPS: Lipoatrophy and CD4+ Nadir Lichtenstein K, et al. CROI Poster 684a (T) Min CD4+Max CD4+ > > 200 < 200 > < 200 Incidence of Lipoatrophy (%)

36 Factors Associated With Peripheral Neuropathy in HIV 1. Lichtenstein K, et al. IAS Abstract Lichtenstein K, et al. IAS Abstract 731. HIV Insight: Incidence of PNP by Nadir CD4 (N = 7980) [2] HOPS Cohort: PNP Associated With HAART (N = 2178) [1] Year Patients With PNP (%) Patients on HAART (%) % PNP % on HAART % 11.1% 7.7% 5.1% 4.3% Nadir CD4 Category P <.0001 Patients (%)

37 Increasing Prevalence of X4- or R5/X4- Tropic Virus at Lower CD4+ Cell Counts CCR5 – Patients with early-stage HIV disease tend to have pure R5- tropic virus CXCR4 – With advanced disease, X4- or dual-tropic virus emerges – Associated with more rapid clinical and immunologic progression Could CCR5 inhibition select for more virulent X4- tropic virus? 16.0% 14.8% 41.9% 40.0% > Prevalence of X4 or R5/X4 (%) < CD4+ Cell Count (cells/mm 3 ) n = Moyle G, et al. ICAAC Abstract 1135.

38 The Case for Earlier Initiation of Therapy Availability of more potent, easier, and less toxic regimens Cohort studies showing benefit with earlier therapy Better response to therapy Decreased transmission Preserve R5-tropic virus Cost-effectiveness

39 Come scegliere una combinazione HAART iniziale

40 2006 Guideline Recommendations for Initial HAART Regimen Recommended Initial Regimens for Antiretroviral-Naive Patients DHHS Guidelines (May 2006) [1] NNRTI-based regimenEFV + (3TC or FTC) + (TDF or ZDV) PI-based regimenLPV/RTV + (3TC or FTC) + ZDV IAS-USA Guidelines (August 2006) [2] NNRTI-based regimen EFV* (NVP*) PI-based regimen LPV/RTV* ATV/RTV* FPV/RTV* SQV/RTV* *Plus TDF/FTC, ABC/3TC, or ZDV/3TC. 1. DHHS Guidelines. Available at: Accessed Sept. 15, Hammer SM, et al. JAMA. 2006;296:

41 Study Follow- up, wks HIV-1 RNA < 50 c/mL, % VF, % Any Resistance*, % GS 934 [1] EFV + TDF/FTC EFV + ZDV/3TC ACTG 5142 [2] EFV + 2 NRTI LPV/RTV + 2 NRTI KLEAN [3] FPV/RTV + ABC/3TC LPV/RTV + ABC/3TC Durability of Response to HAART 1. 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. *Genotyped patients with virologic failure

42 % patients with VL<50 copies/mL at week 48 KLEAN: FPV/r vs LPV/r-Naive Virological response ITT-e: All patients exposed to >1 dose of randomized study medication 66% 65% 89% 88% n=434 n=444 n=328 n=341 Eron, et al. Lancet 2006; 368 (9534): ITT-e TLOVRObserved FPV/r LPV/r

43 KLEAN: FPV/r vs LPV/r-Naive Grade 3/4 lipid abnormalities Fasting cholesterol 300 mg/dL Fasting Triglycerides 751 mg/dL 11% 9% 8% Eron, et al. Lancet 2006; 368 (9534): ( 7.7mmol/l) ( 8.4mmol/l) FPV/r LPV/r Patients (%)

44 ALERT: FPV/r vs ATV/r-Naive Lipid results FPV/r Baseline FPV/r Week 24 ATV/r Baseline ATV/r Week 24 Smith K, et al. 46 th ICAAC 2006; abstract H-1670a p < Cholesterol LDLHDLTG n=48 n=38 n=39 n=48 n=38 n=45 n=39 n=38 n=39 n=48 n=38 n=46 n=39 Median level (mg/dL) n=46 n=48

45 1:1 randomization SQV/r 1000/100 mg bid + TDF/FTC Lopinavir/r 400/100 mg bid + TDF/FTC Prospective, Phase IIIb, randomized, multi-centre, open-label, 2-arm study N = 337 – 26 North American sites 8 Canada 1 Puerto Rico 17 United States – 11 French sites – 1 Thai site Duration 48 weeks Inclusion criteria – Treatment naive – CD4 350 – HIV RNA > 10,000 copies/ml Gemini SQV/r vs LPV/r-Naive

46 N = 882 – International, open-label trial Duration: 96 weeks Inclusion criteria: – HIV RNA 5,000 c/mL – Any CD4 count Primary efficacy endpoint: VL < 50 c/ml at 48 weeks Secondary outcomes: – VL < 50 c/mL at 96 weeks – VL < 400 c/mL at 48 & 96 weeks – Safety assessments Status – Study start: November 2005 – Fully enrolled Atazanavir/r 300/100 mg qd + TDF/FTC Lopinavir/r 400/100 mg bid + TDF/FTC BMS 138: ATV/r vs. LPV/r + TDF/FTC in ARV-naive patients 1:1 randomization

47 Metabolic Effects of PIs AgentLipidsGlucose RTV (full dose) TC/TG insulin resistance LPV/RTV TC/TG insulin resistance IDV/RTV TC/TG insulin resistance NFV LDL/TG, HDL(?)No insulin sensitivity APV/RTV or FPV/RTV TC/TGNo insulin sensitivity TPV/RTV TC/TG ? SQV/RTV Little No insulin sensitivity ATV No No insulin sensitivity ATV/RTV Little No insulin sensitivity DRV/RTV?? RTV associated with more pronounced effect on lipids than other PIs

48 BMS-045: randomized trial of patients with 2 HAART failures TCHDL-CLDL-C*TG* * Fasting values. P <.0001 vs LPV/RTV * Mean Change From Baseline to Wk 48 (%) ATV/RTVLPV/RTV Metabolic Effects of PIs: LPV/RTV vs ATV/RTV Johnson M, et al. AIDS. 2005;

49 Il paziente multi-experienced

50 HIV Transmission and the Establishment of HIV Reservoirs (A)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) The gp120 subunit binds the CD4 receptor Each subunit undergoes a conformational change exposing the region that will bind a transmembrane chemokine receptor CD4 +chemokine receptors Shifts away the steric hindrance of gp 120 Allows gp 41 to mediate the fusion and entry

52 DRV/r or TPV/r Versus cPI(s): Week 48: <50 copies/mL With First Use ENF 56% 11% 9% 36% DRV/r (n = 36) cPI(s) (n = 35) TPV/r (n = 123) cPI(s) (n = 97) First use of ENF Patients achieving response (%) POWERRESIST Hill A, et al. 46 th 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 De Meyer S, et al. 15 th International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Poster (94) 42 2 (113) 22 3 (58) 10 4 (41) 42 All (373) Number of TMC114 mutations (Number of patients) Patients with VL HIV RNA <50 copies/mL at Week 24 (%) 64 0 (67) V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V IAS-USA PI mutations

54 ITT analysis (non-completer = failure) Etravirine: Primary Endpoint Change in VL at 48 weeks Mean change in log 10 VL (±SE) Time (weeks) –0.5 –1.0 –1.5 –2.5 – –0.14 –0.88, P = –1.01, P = P values versus active control. SE, standard error. Active control (n = 40) 400 mg bid (n = 80) 800 mg bid (n = 79) Relevant NNRTI mutations: K101P, V179E, V179F, Y181I, Y181V, G190S, M230L Cohen C, et al. 16 th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

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58 Primary endpoint at 24 weeks: Mean change from baseline in HIV-1 RNA MOTIVATE 1 & 2: Trial Design 1076 ARV-experienced patients MVC 150 mg BID (n = 426) MVC 150 mg QD (n = 414) Placebo (n = 209) R5 HIV-1 infection (44% screen failures) HIV-1-RNA 5,000 copies/mL On stable regimen, or no ARVs for 4 weeks Resistance to and/or 6 months experience with 1 ARV from 3 classes (2 for PIs) 2 identical ongoing phase IIb/III studies Randomized (1:2:2), double-blind, placebo-controlled OBT = 3-6 ARVs* Stratified by ENF use and HIV-1 RNA < and 5 log *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. 14 th 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) Time (weeks) % 42.2% 24.6% Patients (%) Time (weeks) 60.4% 54.7% 31.4% <400 copies/mL<50 copies/mL P <0.0001* P = * 2 10 HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks. *Versus placebo + OBT. Nelson M, et al. 14 th 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 VL < 400 copies/mLVL < 50 copies/mL Patients, % Time (weeks) % 73.1% 69.3% 65.3% EFV (n = 361) MVC (n = 360) 00 Saag M, et al. IAS Abstract WESS104. 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/mm 3 )

61 Recently Approved New or Novel Antiretroviral Agents Mature virus Maraviroc Entry inhibitors Reverse transcriptase inhibitors Etravirine Integrase inhibitors Raltegravir PIs Darunavir Tipranavir

62 Percent <400 and <50 Copies/mL (ITT, NC=F) BENCHMRK 1 & 2

63 *Data from GS mg patients after addition of a PI were excluded. Zolopa A, et al. 14 th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 143LB. Elvitegravir (GS 9137) 125 mg: The Importance of the Regimen GS mg with no active drugs in OBT (n = 26) Mean change from baseline in HIV RNA log 10 copies/mL Week GS mg with 1 active NRTI or first use of T-20 (n = 47) P <0.001 –0.7 –

64 The E92Q IN Mutation Reduces Susceptibility to Multiple Integrase Inhibitors Drug Wild-type (HXB2) E92Q S147G E92Q S147G H51Y E92Q S147G H51Y E157Q S147GH51YE157Q GS-9137 EC 50, nM 1.3 ± ± 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-0518 EC 50, nM 5.9 ± ±10.5 (6.0) 45.6 ± 13.7 (7.7) 37.8 ± 6.0 (6.4) 33.7 ± 9.0 (5.7) N/D L-870,810 EC 50, nM 0.6 ± ± 1.1 (11.8) 16.6 ± 4.3 (27.7) 13.0 ± 1.5 (21.7) 20.0 ± 4.1 (33.3) N/D Fold changes: blue: FC 10. Mean EC 50 and standard deviation of n = 3 experiments; N/D, not determined. EC 50 and Fold Change (FC, Relative to Wild-type, HXB2) in Susceptibility to INIs and Control ARV Drugs of IN Site-directed Mutant HIV-1 Jones, et al. 14 th 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 Black n = 100 HLA-B*5701 test 2 positive 98 negative White n = 100 HLA-B*5701 test 94 negative 6 positive Do not treat with ABC Appropriate to treat with ABC Test 100 black patients: Treat 98 patients at low risk for ABC HSR Prevent 1 ABC HSR event Exclude ABC unnecessarily in 1 patient Test 100 white patients: Treat 94 patients at low risk for ABC HSR Prevent 4 ABC HSR events Exclude ABC unnecessarily in 2 patients Example shown is based on PPV derived from PREDICT-1 and SHAPE data. Saag M, et al. IAS Abstract WEAB305.

67 Linee guida sullimpiego della farmacocinetica in diverse nazioni CB recommendedconsider

68 Utilita del TDM (1) Spesso il dato che si ottiene dal TDM rientra nel range terapeutico indicato dal laboratorio e/o dalla letteratura Se il livello è normale.. – Vengono escluse interazioni significative – Bisogna cercare una spiegazione alternativa a fenomeni di tossicità o fallimento

69 Utilita del TDM (2) PROBLEMA / SITUAZIONE – Terapia efficace – Fallimento – Tossicità – Aderenza – Coinfezione HCV o HBV – Interazioni – Pz. speciali COSA AGGIUNGE TDM? livello ancora basso? spiega e/o previene previene? dose? misura oggettiva Individualizzazione; dose? accerta, ottimizza individualizza 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 concentration Time (hours) ?

71 ADERENZA

72 Factors Affecting Adherence Important to recognize factors that influence adherence However, physicians ability to identify patients who will or will not be adherent is limited Race, sex, and socioeconomic status are not independent risk factors for nonadherence Factors associated with increased adherence Patient belief in HAART Physician experience Social supports Regular office visits Factors associated with nonadherence Active injection-drug use Active alcohol abuse Active psychiatric disease (especially depression) Younger age Chaotic lifestyle Low functional literacy

73 Why Do Patients Miss Doses? Too busy/simply forgot 46 Away from home 45 Change in daily routine 27 Felt depressed/overwhelmed 20 Took drug holiday/medication break 20 Ran out of medication 19 Too many pills 19 Worried about becoming 'immune' 18 Felt drug was too toxic 17 Wanted to avoid side effects 17 Didn't want others to notice 16 Reminder of HIV infection 14 Confused about dosage direction 13 Didn't think it was improving health 10 To make it last longer 9 Were told the medicine is no good Reasons given for missing antiretroviral doses (structured questionnaire) POSSIBLE INTERVENTIONS Simplify dosing schedule Decrease pill burden Other % Gifford et al. JAIDS 2000;23:386–395.

74 Patient Preferences in Antiretroviral Regimens 4 most important regimen issues for patients – Total number of pills per day – Dosing frequency – Dietary restrictions – Side effects The ideal regimen from a patient perspective: – 2 or fewer small pills per day – Dosed all together, once daily – No dietary restrictions – No adverse effects

75 Moyle et al. 6 th Intl Congress on Drug Ther in HIV Inf Abstract 99. Fewer Patients Forget to Take QD Regimens 0 Patients Forgetting to Take HAART (%) TID+TIDBIDQD Forgetting rates reported by 438 of 504 patients in standardized interviews Patients answered the APPT-1 pan-European survey

76 Moyle G. Int J STD AIDS. 2003;14(Suppl 1): All at once Divided and taken twice-a-day Patients preferring schedule (%) > 8 pills 8 pills 6 pills 4 pills 3 pills 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?

77 You and your patient decided its time to start Initial treatment Clinical conditions at baseline Available drugs Drug drug interactions Co-morbidity Treatment schedule Future options Resistance pattern at baseline Patients expectations on the outcome Short term side effects Pill burden Long term side effects PK

78 General Principles of Client-Centered Counselling The focus of counselling should be clients concerns and interest explore the personal meaning that a client gives to issues Context is important assess the physical and emotional circumstances under which HIV risk behaviors take place Individualize sessions Impact of counselling will be enhanced when based on specific needs and unique situations of individual clients modified 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 issues Remember you limits information alone does not lead to behavior changes, that are a complex process requiring interventions based on clients 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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