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Approccio terapeutico nel paziente pre-trattato

Ivano Mezzaroma Dipartimento di Medicina Clinica UOC Immunologia Clinica Università di Roma “La Sapienza”. Approccio terapeutico nel paziente pre-trattato. Roma, 24 marzo 2006. Reasons for Failure of Initial HAART.

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Approccio terapeutico nel paziente pre-trattato

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

  2. Reasons for Failure of Initial HAART • Inability to take regimen (or nonadherence) is one primary reason for failure of initial therapy • Other causes have become more rare in current practice • Inadequate potency • Interindividual pharmacologic variability → inadequate levels in some patients) • Drug-drug interactions now very rare causes

  3. ICoNA Study: Reasons for Failure of Initial HAART 8% Toxicity n = 25 Failure Nonadherence 20% Other n = 61 58% n = 182 14% n = 44 d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.

  4. Reasons for Failure: Toxicity • Adverse effects are most common reason for discontinuation • Develop a plan to help patients deal with side effects • “Minor” common side effects may be as important to the patient as major grade 3/4 events • Nausea, vomiting, abdominal discomfort or cramping, and diarrhea are common reasons why patients stop their medications • Most patients are asymptomatic when treatment is started • Development of even minor symptoms can therefore be distressing • Remind patients not to “self-diagnose” by stopping one of their medications

  5. Adherence • A major determinant of degree and duration of viral suppression • Poor adherence associated with virologic failure • Optimal suppression requires 90-95% adherence • Suboptimal adherence is common

  6. Predictors of Inadequate Adherence • Regimen complexity and pill burden • Poor clinician-patient relationship • Active drug use or alcoholism • Unstable housing • Mental illness (especially depression) • Lack of patient education • Medication adverse effects • Fear of medication adverse effects

  7. Predictors of Good Adherence • Emotional and practical supports • Convenience of regimen • Understanding of the importance of adherence • Belief in efficacy of medications • Feeling comfortable taking medications in front of others • Keeping clinic appointments • Severity of symptoms or illness

  8. Improving Adherence • Establish readiness to start therapy • Provide education on medication dosing • Review potential side effects • Anticipate and treat side effects • Utilize educational aids including pictures, pillboxes, and calendars

  9. Improving Adherence • Simplify regimens, dosing, and food requirements • Engage family, friends • Utilize team approach with nurses, pharmacists, and peer counselors • Provide accessible, trusting health care team

  10. Adherence is Inversely Related to the Number of Doses Per Day Dose-taking adherence rates Dose-timing adherence rates • Dose-taking adherence: appropriate number of doses taken during the day (optimal adherence variously defined as 70%, 80%, 90%) • Dose-timing adherence: doses taken at appropriate time intervals, within 25% of the dosing interval (e.g. BID should be taken 12  3 hours apart) P < .001 P = .008 P values not calculated 100 P = .001 80 79 74 71 Mean dose-taking adherence (%) 69 60 65 58 59 51 40 46 40 20 0 Overall QD BID TID QID Overall QD BID TID QID Studies of electronic monitoring of adherence Claxton et al., Clin Ther .2001;23:1296–1310.

  11. 80 60 70 50 30 40 20 10 0 Patients Prefer QD Regimensto BID Regimens 68% % of Patients ever forgetting to take HIV medication Patients (%) 24% 5% 4 pills QD 1 morning, 1 evening 1 morning, 4 evening Bass D, et al. XIV IAC, July 7-12, Barcelona, 2002, Abstract MoPe3290.

  12. Changing Therapy:Considerations • Clinical status • HIV RNA level on 2 tests • CD4+ T cell count • Remaining treatment options • Potential viral resistance • Medication adherence • Patient education

  13. Changing Therapy: Treatment Regimen Failure • Virologic failure: • Incomplete virologic response: HIV RNA >400 copies/mL after 24 wks, >50 after 48 wks • Virologic rebound: repeated detection of HIV RNA after viral suppression • Immunologic failure: • CD4 increase of <25-50 cells/µL in first year of therapy • CD4 decrease below baseline, on therapy • Clinical failure: • occurrence of HIV-related events (after >3 months on therapy; excludes immune reconstitution syndromes)

  14. Treatment Regimen Failure: Assessment • Review antiretroviral history • Physical exam for signs of clinical progression • Assess adherence, tolerability, pharmacokinetic issues • Resistance testing (while patient is on therapy) • Identify treatment options

  15. Treatment Regimen Failure: Assessment • Possible causes: • Suboptimal adherence • Medication intolerance • Pharmacokinetic issues • Suboptimal drug potency • Viral resistance • Approach depends on cause of regimen failure and remaining antiretroviral options

  16. Treatment Regimen Failure: Assessment Therapeutic options: • Clarify goals: If extensive resistance, viral suppression may not be possible, but aim to reestablish maximal virologic suppression • Remaining ARV options • Base treatment choices on expected efficacy, tolerability, adherence, future treatment options, past medication history, and resistance testing

  17. Virologic Failure: Changing an ARV Regimen (1) General principles: • Prefer at least 2 fully active agents to design a new regimen • Determined by ARV history and resistance testing • If 2 active agents are not available, consider ritonavir-boosted PI plus optimized ARV background, and/or reusing prior ARVs to provide partial activity • Consider potent ritonavir-boosted PI and a drug with a new mechanism of action (e.g., entry inhibitor) plus an optimized ARV background: may have significant activity

  18. Virologic Failure: Changing an ARV Regimen (2) General principles (2): • In general, 1 active drug should not be added to a failing regimen because drug resistance is likely to develop quickly. In some patients with advanced HIV and few treatment options, this may be considered to reduce the risk of immediate clinical progression. • Consult with experts

  19. Treatment-Experienced Patients: Goals of Therapy Limited prior treatment: • Maximum viral suppression • Consider early change to prevent further resistance mutations Extensive prior treatment: • Preservation of immune function • Prevention of clinical progression • Balance benefits of partial viral suppression with risk of additional resistance mutations

  20. Changing Therapy: Treatment Options Limited prior treatment with low HIV RNA: • Intensification (e.g., tenofovir) • Pharmacokinetic (PK) enhancement • Change to new regimen

  21. Changing Therapy: Treatment Options Limited prior treatment with single drug resistance: • Change 1 drug • PK enhancement • Change to new regimen

  22. Changing Therapy: Treatment Options Limited prior treatment with >1 drug resistance: • Change drug classes and/or add new active drugs

  23. Changing Therapy: Treatment Options Prior treatment with no resistance identified: • Consider nonadherence or possibility that patient was off medications at time of resistance test • Consider resuming same regimen or starting new regimen and repeat resistance testing early (2-4 wks)

  24. Changing Therapy: Treatment Options Extensive prior treatment with resistance: • Avoid adding single active drug • Seek expert advice • If few or no treatment options, consider continuing same regimen. Other possible strategies: • PK enhancement • Therapeutic drug monitoring • Retreatment with prior medications • Multidrug regimens (limited by complexity, tolerability) • New ARV drugs, e.g., enfuvirtide, investigational drugs • Treatment interruptions not recommended

  25. Current Guidelines for Resistance Testing * Only if mother is viremic ** Only if mother was viremic and on treatment at time of birth 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. March 23, 2004. 2. Hirsch MS, et al. Clin Infect Dis. 2003;37:113-128. 3. Miller V, et al. AIDS. 2001;15:309-320.

  26. Testing for Drug Resistance • Recommended in case of virologic failure, to determine role of resistance and maximize the number of active drugs in a new regimen • Combine with obtaining a drug history and maximizing drug adherence • Research supports use in certain settings • Perform while patient is taking ART (or within 4 weeks of regimen discontinuation)

  27. Drug Resistance Testing: Limitations • Lack of uniform quality assurance • Relatively high cost • Insensitivity for minor viral species (<10-20%)

  28. Interruption of Antiretroviral Therapy • Intolerable side effects • Drug interactions • First trimester pregnancy • Poor adherence • Unavailability of drugs • Many other possible causes

  29. Interruption of Antiretroviral Therapy: Planned Structured (supervised) treatment interruption (STI) • Insufficient data to recommend STI; research ongoing • Possible risks: decline in CD4 count, disease progression, increase in HIV transmission, development of resistance • Possible benefits: reduction in drug toxicities, preservation of future treatment options

  30. Interruption of Antiretroviral Therapy: Planned Several scenarios: • Patients who started ART during acute HIV infection • Optimal duration of treatment is unknown; studies ongoing • Women who started ART during pregnancy to decrease risk of mother-to-child transmission • If pretreatment CD4 is above currently recommended ART starting levels and patient wishes to stop therapy after delivery

  31. Interruption of Antiretroviral Therapy: Planned • Patients with chronic infection with viral suppression and CD4 above levels recommended for starting therapy: • Started ART with CD4 above currently recommended starting levels • Started ART at lower CD4 but now with stable CD4 above recommended starting levels • Small short-term prospective clinical trials suggest safety; long-term studies ongoing • CD4 decline after treatment interruption is related to pretreatment CD4 nadir

  32. Interruption of Antiretroviral Therapy: Planned • Patients with treatment failure, extensive ARV resistance, and few available treatment options • Partial virologic suppression from ART has clinical benefit • Not recommended outside clinical trial setting

  33. Interruption of Antiretroviral Therapy • Stop all antiretroviral medications at once • efavirenz and nevirapine have long half-lives; consider stopping these before other agents • In patients with hepatitis B who are treated with emtricitabine, lamivudine, or tenofovir, discontinuation of these may cause hepatitis exacerbation • Monitor closely

  34. Optimal Use of Boosted PIs in Treatment-Experienced Patients

  35. Goals of Therapy With MDR HIV • Patients with access to ≥ 2 active agents • Complete viral suppression • Patients with access to < 2 active agents • Reduce viral load by 1 log10 copies/mL • Stabilize CD4+ cell counts • Minimize drug toxicity • Minimize mortality • Minimize accumulation of additional mutations that could cause resistance to drugs in development

  36. Saquinavir/Ritonavir • MaxCmin studies • Large, multinational, randomized trials comparing boosted SQV with other boosted PIs in drug-naive and drug-experienced patients also receiving ≥ 2 NRTIs and/or NNRTIs • MaxCmin 1: IDV/RTV 800/100 mg BID vs SQV/RTV 1000/100 mg BID[1] • Similar rate of virologic failure between treatments at Week 48 (27% vs 25%) • Adverse events more frequent in IDV/RTV arm • When switching from randomized treatment because of toxicity considered as failure, SQV/RTV superior (49% vs 34%, P = .009) • MaxCmin 2: LPV/RTV 400/100 mg BID vs SQV/RTV 1000/100 mg BID[2] • Found LPV/RTV superior at Week 48 • Risk of virologic failure and treatment discontinuation greater in SQV/RTV arm 1. Dragsted UB, et al. J Infect Dis. 2003;188:635-642. 2. Youle M, et al. IAS; 2003. Abstract LB23.

  37. < 50 copies/mL < 400 copies/mL CONTEXT: FPV/RTV vs LPV/RTV in PI-Experienced Patients • Greater number of virologic failures in FPV/RTV arms compared with LPV/RTV arm • Once-daily arm underperformed compared with twice-daily arms • Twice-daily FPV/RTV failed to meet protocol-defined threshold for noninferiority to LPV/RTV 70 61 58 60 50 50 46 50 37 40 Viral Suppression (%) 30 20 10 0 LPV/RTV Twice Daily FPV/RTV Once Daily FPV/RTV Twice Daily Intent-to-treat, missing equals failure analysis Elston RC, et al. IAC; 2004. Abstract MoOrB1055.

  38. Lopinavir/Ritonavir • LPV/RTV vs NFV, plus d4T/3TC, in treatment-naive patients[1] • 67% vs 52% of patients had viral load < 50 copies/mL at Week 48 (P < .001) • In patients with viral load > 400 copies/mL, frequency of emergent PI-associated mutations significantly lower with boosted PI • Supports theory that boosted PIs offer greater genetic barrier to emergent resistance than unboosted PIs • BMS 043: LPV/RTV vs ATV, plus NRTIs, in PI-experienced patients[2] • LPV/RTV showed -0.3 log10 copies/mL greater reduction in viral load than unboosted ATV at Week 24 (P = .0032) 1. Walmsley S, et al. N Engl J Med. 2002;346:2039-2046. 2. Nieto-Cisneros L, et al. Antivir Ther. 2003;8(suppl1):S212. Abstract 117.

  39. In Combination Therapy, Only The Active Drugs Count • Early “HAART” in NRTI-experienced patients often amounted to “serial monotherapy” • New drugs (eg, PIs) added to a failing NRTI-based regimen • Less sustained responses with only 1 active drug • TORO results demonstrated applicability of this principle to the use of enfuvirtide (ENF) • Several recent studies demonstrate that in triple-class-experienced patients, combining ENF + an active boosted PI improves response rate

  40. (n = 661) ENF + OB 100 ITT: DC or SW = F (n = 334) OB 90 80 70 60 Patients With HIV-1 RNA < 400 Copies/mL (%) 50 34% 40 26% 30 13% 20 10 0 0 16 32 48 64 80 96 Study Week TORO: Virologic Response to Enfuvirtide + OB Regimen Arastéh K, et al. IAC 2004. Abstract MoOrB1058.

  41. 100 ENF +OB (n = 661) OB (n = 334) 80 * 60 55% * Patients With HIV-1 RNA < 400 Copies/mL at Week 48 (%) *P < .05 38% 40 * * 24% 18% 18% 20 10% 4% 2% 0 n = 158 57 171 77 93 58 239 42 No LPV/r LPV/r No LPV/r LPV/r LPV/r Naive LPV/r Experienced TORO: Importance of Combining ENF With an Active Boosted PI Miralles GD, et al. IDSA 2004. Abstract 921.

  42. Number of Active Antiretrovirals in OB Regimen (Genotypic Sensitivity Score) ³ 5 0 1-2 3-4 0 ENF + OB OB -1.0 MeanChange in HIV-1 RNA at Week 24 (ITT) (log10 copies/mL) -2.0 -3.0 TORO: Impact of Number of Active Agents on Response Henry K, et al. IAS 2002. Abstract LbOr19B.

  43. 100 100 TPV/r (n = 311) TPV/r (n = 311) CPI/r (n = 309) CPI/r (n = 309) 80 80 ITT: NC=F ITT: NC=F 60 60 Patients With HIV- 1 RNA < 50 copies/mL(%) Patients With HIV- 1 RNA < 400 copies/mL(%) 34.7% 40 40 25.1% 16.5% 20 20 10.0% < .001 < .001 P P 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Week Week RESIST-1: Response to TPV/r vs CPI/r Hicks C, et al. ICAAC 2004. Abstract 1137a.

  44. ENF use comparable in both arms 27.1% TPV/r 22.2% CPI/r ENF use improved treatment response in both arms However, TPV/r superior to CPI/r with or without ENF No ENF ENF 100 80 60 53.9 Patients With HIV-1 RNA < 400 Copies/mL at Week 24 (%) 40 30.2 21.3 20 13.4 0 TPV/r CPI/r RESIST: Impact of Enfuvirtide on Virologic Response Deeks S, et al. IAS 2005. Abstract WeFo0201.

  45. TPV Score 0-1 2-3 4-5 6-7 8-9 Median FC: 0.7-0.9 1.1-1.4 2.0-3.1 3.3-3.9 14.7-52.5 0 -0.08 (n = 4) -0.45 (n = 260) -0.49 (n = 68) -1 -0.89 (n = 242) Median Change in VL at Wk 24* (log10 copies/mL) -2 -2.10 (n = 144) *24-week data from patients in RESIST-1 and -2 given TPV/r -3 Relationship of TPV Score to TPV Phenotype Results and Response Valdez H, et al. Resistance Workshop 2005. Abstract 27.

  46. 100 TMC114/r 400 QD (n = 64) TMC114/r 800 QD (n = 63) TMC114/r 400 BID (n = 63) TMC114/r 600 BID (n = 65) Comparator PIs (n = 63) 80 P < .001 for all dosesvs control 60 53% Patients with HIV-1 RNA < 50 copies/mL (%) 49% 48% 43% 40 20 18% 0 1 2 4 8 12 16 20 24 Time (weeks) POWER 1: Virologic Response to TMC114/r Katlama C, et al. IAS 2005. Abstract WeOaLB0102.

  47. 53% (n = 60) Overall 18% (n = 60) 63% (n = 19) ENF Used (Naive) 22% (n = 18) 56% (n = 34) ENF Not Used 19% (n = 36) 59% (n = 29)  3 Primary PI Mut 9% (n = 35) 46% (n = 28) TMC114 FC > 4 16% (n = 25) TMC114/r 600/100 BID 17% (n = 12) No Sensitive ARV in OBR Control 0% (n = 9) 0 20 40 60 80 100 % with HIV-1 RNA < 50 at Week 24 (ITT NC=F) POWER 1: Subgroup Analyses of Response to TMC114/r 600/100 BID Katlama C, et al. IAS 2005. Abstract WeOaLB0102.

  48. Days 2 4 6 8 0 * - 0.2 1 RNA ) - 0.4 - mL - 0.35 - 0.6 * copies/ - 0.64 - 0.8 Median Change in HIV * 10 - 1.0 - 0.89 (log * - 1.2 P * < .001 vs baseline - 1.4 TMC125 in Treatment-Experienced Patients • Open, phase 2a study • 16 HIV-infected men • Failing efavirenz or nevirapine • Resistance to efavirenz • CD4+ cell count: 389 cells/mm3 • Viral load: 10,753 copies/mL • TMC125 900 mg BID + continue NRTIs for 7 days • After 7 days, median 0.9-log decrease in viral load Gazzard BG, et al. AIDS. 2003;17:F49-F54.

  49. Aplaviroc (GW873140)[1] Vicriviroc (SCH-417690)[2] 0.4 Placebo 0.5 200 QD 0 200 BID 0.0 400 QD -0.4 600 BID Median VL Change From BL (log10 copies/mL) Median VL Change From BL (log10 copies/mL) -0.5 -0.8 Placebo 10 mg BID -1.0 -1.2 25 mg BID -1.6 Dosing 50 mg BID -1.5 Dosing 0 5 10 15 20 25 30 0 15 5 10 20 25 30 Day Days Maraviroc (UK-427857)[3] 0.5 0 -0.5 Median VL Change From BL (log10 copies/mL) Placebo 15 100 mg BID Placebo 07 150 mg Fast -1.0 -1.5 25 mg QD 150 mg Fed 50 mg BID 300 mg QD -1.5 100 mg QD 300 mg BID Dosing -2.0 0 5 10 15 20 25 30 35 40 Days CCR5 Inhibitors in Development 1. Lalezari J, et al. ICAAC 2004. Abstract H-1137b. 2. Schurmann D, et al. CROI 2004. Abstract 140LB. 3. Pozniak AL, et al. ICAAC 2003. Abstract H-443.

  50. Treatment Strategies in Experienced Patients: Role of NRTIs • Evidence for partial activity of NRTIs even with key resistance mutations present, eg, 3TC and d4T • M184V can confer improved phenotypic susceptibility to TDF and ZDV in viruses with TAMs and K65R • TDF and D-d4FC active against virus strains with TAMs • Both can select for K65R; ZDV shows hypersusceptibility • Strategic use of NRTI combinations possible • TDF - FTC - ZDV • TDF - ZDV - D-d4FC 1. Walmsley S, et al. CROI 2005. Abstract 580. 2. Ruiz L, et al. CROI 2005. Abstract 679.

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