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Approccio terapeutico nel paziente “naive”

Approccio terapeutico nel paziente “naive”. Ivano Mezzaroma Dipartimento di Medicina Clinica UOC Immunologia Clinica Università di Roma “La Sapienza”. Roma, 24 marzo 2006. Initiation of Therapy. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents October 2005.

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Approccio terapeutico nel paziente “naive”

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  1. Approccio terapeutico nel paziente “naive” Ivano Mezzaroma Dipartimento di Medicina Clinica UOC Immunologia Clinica Università di Roma “La Sapienza” Roma, 24 marzo 2006

  2. Initiation of Therapy Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents October 2005

  3. Goals of Antiretroviral Therapy (ART) • Eradication of HIV? Not possible with currently available antiretroviral medications

  4. Improvement of quality of life Reduction of HIV-related morbidity and mortality Restoration and/or preservation of immunologic function Maximal and durable suppression of viral load Selection of ARV regimen Preservation of future treatment options Rational sequencing of therapy Maximizing adherence Use of resistance testing in selected clinical settings ART Goals & Tools to Achieve Them

  5. Before Initiating ART • Confirm HIV results • Complete H&P • CBC, chemistry profile • CD4 cell count • Plasma HIV RNA measurement • Consider resistance testing • Assess “readiness” for treatment and adherence

  6. RPR or VDRL PPD Chest X ray Hepatitis A,B,C serology Toxoplasma IgG Fasting glucose and lipids Gynecologic exam with pap smear Testing for chlamydia and gonorrhea Ophthalmology exam (CD4+ T cell count <100 cells/µL) Before Initiating ART: Additional Tests

  7. Considerations in Initiating ART: Asymptomatic HIV • Willingness of patient to begin and the likelihood of adherence • Degree of immunodeficiency (CD4+ T cell count) • Plasma HIV RNA • Risk of disease progression • Potential benefits and risks of therapy

  8. Considerations in Initiating ART: Chronically HIV-Infected Patient, Asymptomatic • Strong evidence of decreased mortality and morbidity with ART if CD4 <200 cells/µLor symptomatic • Theoretical benefit of treatment at higher CD4 • Few data establish clinical benefit for treatment if CD4 >200 cells/µL; optimal point to initiate ART is unknown • Individualize treatment decisions

  9. Indications for ART in the Chronically HIV-Infected Patient Treat all (regardless of viral load): • Symptomatic (AIDS, severe symptoms) • Asymptomatic, CD4 count <200 cells/µL

  10. Indications for ART in the Chronically HIV-Infected Patient Offer treatment, after discussion of pros and cons: • Asymptomatic, CD4 count 200-350 cells/µL

  11. Indications for ART in the Chronically HIV-Infected Patient Defer Treatment: Asymptomatic, CD4 count >350 cells/µL • If HIV RNA >100,000 copies/mL, may consider treatment

  12. BENEFITS Avoid negative effects on quality of life Avoid drug-related toxicity Preserve future drug options Delay development of drug resistance Decrease total time on medications RISKS Possibility of irreversible immune system depletion Increased possibility of progression to AIDS Possible increased risk of HIV transmission Benefits and Risks of Deferred Therapy

  13. NRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Zalcitabine DDC Tenofovir TDF NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP PI Amprenavir APV Atazanavir ATV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV soft gel SGC hard gel HGC tablet INV Tipranavir TPV Fusion Inhibitor Enfuvirtide T-20 Current Antiretroviral Medications

  14. 1996Zerit/Epivir/Crixivan • 10 pills, Q8H • 1998Retrovir/Epivir/Sustiva • 5 pills, BID • 2002Combivir (AZT/3TC)/EFV • 3 pils, BID • 2003Viread/Emtriva/Sustiva • 3 pills, QD • 2004Truvada/Sustiva • 2004Kivexa/Sustiva • 2 pills, QD • 2 pills, QD • Daily pill burden • Regimen • Dosing The Move Toward Lower Pill Burdens

  15. HAART Studies with >65% Response (VL<50) COMBINE (NVP+ZDV/3TC) 2NN (NVP BID+d4T+3TC) ZODIAC (EFV+ABC QD+3TC) M98-863 (LPV/r+d4T+3TC) ZODIAC (EFV+ABC+3TC) CNA30024 (EFV+ZDV+3TC) 2NN (NVP QD+d4T+3TC) 2NN (EFV+d4T+3TC) CNA30024 (EFV+ABC+3TC) M02-418 (LPV/r+FTC+TDF QD) FTC301 (EFV+FTC+ddI QD) DMP266-043 (EFV+D4T+3TC) CLASS (EFV+ABC+3TC) ANRS 12-04 (EFV+ddI+3TC) M97-720 (LPV/r+d4T+3TC) Dart 1 (EFV+ddI-EC+3TC) GS903 (EFV+d4T+3TC) GS903 (EFV+TDF+3TC) ANRS 091 (EFV+ddI+FTC) 0 40 50 60 70 80 90 100 % with VL < 50 at week 48 Bartlett JA, et al. CROI, 2005, Abstract 586.

  16. Fattori importanti nella monosomministrazione • Fattori farmaco-correlati (caratteristiche intrinseche): - concentrazione plasmatica - legame alle proteine - concentrazione nel sito di azione • Fattori estrinseci: - tempo di assorbimento - velocità di eliminazione

  17. Cmax • maximum concentration • correlates with some short-term side effects, e.g. nausea • AUC • area under the curve • overall drug exposure 12 2 6 10 4 8 Pharmacokinetics Principles

  18. 12 2 6 10 4 8 Pharmacokinetics Principles • Cmin • minimum, or trough concentration • occurs at the end of the dosing interval • correlates with anti-HIV effect

  19. Half-lives of HIV Drugs * * * * * * * * * 24h t½ (h) 12h Intracellular Plasma Moore at al. AIDS. 1999;13:2239. Kewn. AAC. 2002;136:45; Hawkins.2004; Rome, Italy.

  20. Missed Dose MONOTHERAPY Missing Drug Doses With Different Half-lives (“Unbalanced”) Day 1 Day 2 Hypothetical and not representative of specific agents. Drug concentration IC90 Zone of potential replication IC50 12 0 24 36 48 Time (h)

  21. “Balanced” ART: PK Symmetry Missed Dose Day 1 Day 2 Window for replication vs synergy/additive activity Drug Concentration IC90 IC50 12 24 36 48 0 Time (hours)

  22. From in vitro to in vivo? Accumulation Synergy Active metabolites Protein binding Viral diversity P-glycoprotein What else? Sanctuaries

  23. Initial Treatment for Previously Untreated Patients: Choosing Regimens • Three categories: • 1 NNRTI + 2 NRTIs • 1 PI + 2 NRTIs • 3 NRTIs • Few clinical endpoints to guide choices • Advantages and disadvantages to each type of regimen • Individualize regimen choice

  24. ADVANTAGES Less fat maldistribution and dyslipidemia than in PI-based regimens PI options preserved for future use DISADVANTAGES Resistance - single mutation Cross-resistance among NNRTIs Rash; hepatotoxicity Potential drug interactions (CYP450) Antiretroviral Components in Initial Therapy: NNRTIs

  25. ADVANTAGES Longest prospective data NNRTI options preserved for future use DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) Greater potential for drug interactions (CYP450), especially with ritonavir Antiretroviral Components in Initial Therapy: PIs

  26. ADVANTAGES Established backbone of combination therapy Minimal drug interactions PI & NNRTI preserved for future use DISADVANTAGES Lactic acidosis and hepatic steatosis reported with most NRTIs (rare) Triple NRTI regimens show inferior virologic response compared with EFV- and IDV-based regimens* Antiretroviral Components in Initial Therapy: NRTIs * Triple NRTI regimen of abacavir + lamivudine + zidovudineto be used only when a preferred or alternative NNRTI- or PI-based regimen cannot or should not be used as first-line therapy.

  27. Initial Treatment: Preferred Regimens *Avoid in pregnant women and women with high pregnancy potential. NNRTI-Based # pills/day PI-Based

  28. Initial Treatment: Alternative Regimens (1) NNRTI-Based pills/day *Avoid in pregnant women and women with high pregnancy potential. **Because of higher rates of hepatotoxicity, nevirapine should not be initiated in women with pre-nevirapine CD4 counts >250cells/mm3 or men with CD4+ T cell counts >400 cells/mm3, unless the benefit clearly outweighs the risk.

  29. Initial Treatment: Alternative Regimens (2) # pills/day PI-Based

  30. Initial Treatment: Alternative Regimens (3) # pills/day PI-Based

  31. Initial Treatment: Alternative Regimens (4) # pills /day NRTI-Based * To be used only when a preferred or alternative NNRTI- or PI-based regimen cannot or should not be used as first-line therapy.

  32. Antiretroviral Medications: Not Recommended in Initial Treatment (1)

  33. Antiretroviral Medications: Not Recommended in Initial Treatment (2)

  34. Antiretroviral Medications: Should not be offered at any time • Regimens not recommended: • Monotherapy (except possibly in prevention of perinatal HIV transmission) • Dual NRTI therapy • 3-NRTI regimen of abacavir + tenofovir + lamivudine • 3-NRTI regimen of didanosine + tenofovir + lamivudine

  35. Antiretroviral Medications: Should not be offered at any time • Antiretroviral components not recommended: • Didanosine + stavudine • Stavudine + zidovudine • Emtricitabine + lamivudine • Zalcitabine + stavudine; zalcitabine + didanosine; zalcitabine + lamivudine

  36. Antiretroviral Medications: Should not be offered at any time • Antiretroviral components not recommended: • Efavirenz in pregnancy and in women with high potential for pregnancy* • Nevirapine initiation in women with CD4 >250 cells/mm3 or men with CD4 >400 cells/mm3 * Women with high pregnancy potential are those who are trying to conceive or who are not using effective and consistent contraception.

  37. Antiretroviral Medications: Should not be offered at any time • Antiretroviral components not recommended: • Atazanavir + indinavir • Amprenavir + fosamprenavir • Amprenavir oral solution in pregnancy, in children <4 years, in renal or hepatic failure, or in patients treated with metronidazole or disulfiram • Amprenavir oral solution + ritonavir oral solution • Saquinavir hard-gel capsule (Invirase) as single PI

  38. Sequenziamento NRTI/NtRTI • Potenza • Dosaggio once-daily • Tossicità • Convenienza • Coinfezioni • Resistenza al baseline • Profilo di resistenza dopo fallimento virologico

  39. Mutazioni in HIV-1 RT comunemente associate con resistenza agli NRTIs

  40. Dicotomia nella evoluzione delle TAMs Zidovudina o Stavudina 70R 215Y TAM pathway II TAM pathway I 41L 215Y 210W 67N 70R 219Q/E Elevato livello di resistenza ad AZT e d4T Più cross-resistenza tra NRTI Comune nella duplice terapia con NRTI ( AZT/ddC o AZT/ddI) Più basso livello di resistenza ad AZT e d4T Meno cross-resistenza agli NRTI Comune con la monoterapia con AZT

  41. Resistenza multinucleosidica (MNR) • 5 distinti mutazioni: A62V, V75I, F77L, F116Y e Q151M • Il complesso Q151 MNR conferisce ampia cross-resistenza a molteplici NRTI (ma non a TDF) • L’inserzione T69 (in combinazione con le TAM) conferisce resistenza a NRTIs + TDF

  42. The Choice of the NRTI Backbone2004 Prediction By the end of the year, virtually all dual-NRTIbackbones prescribed for initialtherapy will consist of 1 of 3 fixed-dose coformulations: AZT/3TCABC/3TC TDF/FTC Gallant, Bangkok 2004

  43. Choice of NRTI Backbone • AZT/3TC • Years of clinical experience • Prevention of K65R or L74V • Gradual and sequential emergence of TAMs • BID dosing, 2 pills/day • TAMs broad→ cross-resistance • GI side effects • Hematologic toxicity • Mitochondrial toxicity • TDF/FTC • Longest intracellular half-lives • Well tolerated • 1 pill QD, no food restrictions • No mitochondrial toxicity • M184V →↑ susceptibility to TDF • TDF: nephrotoxicity? • FTC: hyperpigmentation • K65R: cross-resistance to ABC, ddI • ABC/3TC • Well tolerated • 1 pill QD, no food restrictions • No mitochondrial toxicity • L74V>K65R: no TDF cross-resistance • Better CD4+ cell count response than AZT/3TC • ABC HSR, with potential confusion when combined with NNRTI • More patient education required • Failure with M184V →↓ susceptibility ABC & 3TC

  44. NRTI sequencing option resistance 3TC/FTC (AZT, All NRTIs) selection 184V TAMs AZT+3TC options ddI, d4T? TDF? ABC? resistance ABC, ddI, 3TC/FTC selection 184V 74V ABC+3TC options TDF, AZT (d4T) resistance 3TC/FTC, ABC, ddI (TDF) selection 184V 65R TDF+3TC/FTC options AZT, d4T? TDF? very low risk if with PI/r

  45. Sequenziamento degli NNRTI • Impiego degli NNRTI in combinazione con altri agenti attivi, all’interno di regimi la cui efficacia antivirale è stata stabilita • Opzione realistica con gli NNRTIs di seconda generazione (TMC125, ecc.) • Opzioni terapeutiche dopo fallimento con NNRTI: • Regimi a base di PI • Regimi con più NRTI (pochi dati clinici)

  46. Sequenziamento dei regimi con PI • Obiettivi dei regimi iniziali con PI • Elevata potenza antivirale • Ridurre la probabilità di un fallimento • Ridurre la possibilità di emergenza di resistenza • Mantenimento della suscettibilità ai successivi regimi di salvataggio con PI • Altre considerazioni per la terapia sequenziale con PI • Convenienza • Tolerabilità • Numero di compresse • Facilità di aderenza • Profilo di tossicità

  47. Regimi sequenziali con PI • Il clinico deve essere prudente quando vengono pianificati regimi di salvataggio con PI dopo fallimento con PI boosting • Il fallimento ad un regime basato sui PI dovrebbe essere trattato aggressivamente per evitare l’accumulo di mutazioni secondarie che possono ulteriormente aumentare la cross-resistenza. • TPV/RTV o TMC114/RTV + ENF: risultati incoraggianti

  48. Potential Advantages of Fixed-Dose Formulations • Reduced pill burden • Increased adherence • Improved patient satisfaction • Reduced risk of dosing errors

  49. Approved Fixed-Dose NRTIs • Zidovudine/lamivudine BID • Abacavir/lamivudine QD • Tenofovir/emtricitabine QD • Zidovudine/lamivudine/abacavir BID

  50. Fixed-Dose Antiretrovirals: Future Developments • Tenofovir/emtricitabine/efavirenz • First formulation to combine treatment in 2 different antiretroviral drug classes • Will be the first 1 pill/day combination regimen • Expected in 2006

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