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Massimo Andreoni Azienda Ospedaliera Universitaria Policlinico Tor Vergata, Roma

Riflessioni su STR nella prospettiva dei farmaci generici in HIV. Massimo Andreoni Azienda Ospedaliera Universitaria Policlinico Tor Vergata, Roma. Registrational Treatment-Naive Clinical Trials: Cross-Study Comparison* HIV RNA <50 c/mL at Week 48. GS-103 QUAD (n=353) 12.

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Massimo Andreoni Azienda Ospedaliera Universitaria Policlinico Tor Vergata, Roma

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  1. Riflessioni su STR nella prospettiva dei farmaci generici in HIV Massimo Andreoni Azienda Ospedaliera Universitaria Policlinico Tor Vergata, Roma

  2. Registrational Treatment-Naive Clinical Trials: Cross-Study Comparison* HIV RNA <50 c/mL at Week 48 GS-103 QUAD (n=353)12 GS-102 QUAD (n=348)11 GS-103 ATV+RTV (n=355)12 STARTMRK RAL (n=281)8 GS-102 Atripla (n=352)11 ARTEMIS DRV+RTV (n=343)7 ECHO/THRIVE RPV (n=550)10 ECHO/THRIVE EFV (n=546)10 STARTMRK EFV (n=282)8 GS 934 EFV (n=244)4 ARTEMIS LPV/r (n=346)7 CASTLE ATV+RTV (n=440)6 ABT 730 LPV/r qd (n=333)5 NRTI backbone FTC/TDF3TC/ABC qd3TC+ABC bid3TC/ZDV3TC+TDF CASTLE LPV/r (n=443)6 ABT 730 LPV/r bid (n=331)5 GS-903 EFV (n=299)9 KLEAN FPV/r (n=434)14 KLEAN LPV/r (n=444)14 GS 934 EFV (n=243)4 CNA 30024 EFV (n=324)13 CNA 30024 EFV (n=325)13 SOLO FPV/r (n=322)2 MERIT ES MVC (n=311)3 MERIT ES EFV (n=303)3 SOLO NFV (n=327)2 CNA 30021 EFV (n=386)1 CNA 30021 EFV (n=384)1 % of Patients with HIV-1 RNA <50 copies/mL at Week 48 *This slide depicts data from multiple studies published from 2004-2012. Not all regimens have been compared head-to-head in a clinical trial

  3. STR: Strategie per ogni fase della terapia Switch per tossicità Naive NNRTI Eviplera NNRTI Atripla PI DRV/cob/FTC/7340 NI QUAD - DLT/ABC/3TC NNRTI Atripla PI DRV/cob/FTC/7340 NNRTI Eviplera NI QUAD NNRTI Atripla NI QUAD NNRTI Eviplera PI DRV/cob/FTC/7340 NI DLT/ABC/3TC

  4. STR: Strategie per ogni fase della terapia Switch per fallimento Naive PI DRV/cob/FTC/7340 NNRTI Atripla NI QUAD – DLT/ABC/3TC NNRTI Atripla PI DRV/cob/FTC/7340 NNRTI Eviplera NI QUAD – DLT/ABC/3TC NNRTI Atripla NI QUAD NNRTI Eviplera PI DRV/cob/FTC/7340 NI DLT/ABC/3TC ?

  5. EU Patent Expiry Dates

  6. DEFINIZIONE DI MEDICINALE GENERICO Un medicinale che ha la stessa composizione qualitativa e quantitativa di sostanze attive e la stessa forma farmaceutica del medicinale di riferimento nonché una bioequivalenza con il medicinale di riferimento dimostrata da studi appropriati di biodisponibilità art. 10, comma 5 DLvo n. 219/06; art. 10, comma 2 Direttiva europea 2001/83/CE e successive modificazioni.

  7. I Farmaci equivalenti in ItaliaDefinizione e normativa Legge n. 425 del 8 agosto 1996 Art. 1 comma 3 II medicinale generico è un medicinale a base di uno o più principi attivi, prodotto industrialmente, non protetto da brevetto, identificato dalla denominazione comune internazionale (DCI) del principio attivo o, in mancanza di questa, dalla denominazione scientifica del medicinale, seguita dal nome del titolare dell'AIC, che sia bioequivalente rispetto ad una specialità medicinale già autorizzata con la stessa composizione quali-quantitativa in principi attivi, la stessa forma farmaceutica e le stesse indicazioni terapeutiche.

  8. Bioequivalenza Due medicinali si definiscono bioequivalenti se contengono lo stesso principio attivo e, se dopo la somministrazione della stessa dose in identiche condizioni, i loro profili di concentrazione/tempo (biodisponibilità) sono così simili (da -20% a +25%) da non comportare differenze significative in termini di efficacia e sicurezza. Possono variare gli eccipienti e/o la dissoluzione e l’assorbimento.

  9. Equivalenza terapeutica Un medicinale è terapeuticamente equivalentedi un altro, se contiene lo stesso principio attivo e clinicamente dimostra lastessa efficacia e sicurezza del prodotto di riferimento la cui efficacia e sicurezza sono già state documentate con studi appropriati. In pratica, si accetta che uno studio di bioequivalenzasulla base dei profili plasmaticipossa costituire la dimostrazione indiretta dell’equivalenza terapeutica di due farmaci che sono farmaceuticamente equivalenti o alternative farmaceutiche.

  10. Farmaci Equivalenti

  11. Physicochemical Equivalence Biochemical Equivalence GENERIC EQUIVALENCE Clinical Equivalence Pharmacologic Equivalence

  12. Passato HAART Futuro?? Presente

  13. Poor adherence and viral rebound in suppressed patients Antinori, Antivir Ther 2004 Yasuda JM, Antivir Ther 2004

  14. Livelli di aderenza necessari per mantenere il successo virologico Paterson D. Ann Intern Med 2000

  15. Cosa preferisce il paziente?

  16. 100 All at once 90 Divided and taken twice-a-day 93 80 84 70 69 60 62 Percent patients preferring 59 50 40 41 38 30 31 20 7 16 10 0 3 pills 8 pills >8 pills 6 pills 4 pills Impact of number of pills per day on dose frequency preference N=504 across Europe Patients were asked if they had to take a certain number of pills each day how would they prefer them to be administered Moyle G et al. 6th ICDTHI, Glasgow, UK, 17-22 November 2002. Poster 99

  17. 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 (eg, BID should be taken 12  3 hours apart) P < .001 P = .008 P values not calculated 100 P = .001 80 79 74 71 69 60 65 Mean Dose-Taking Adherence (%) 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 AJ, et al. Clin Ther. 2001;23:1296-1310.

  18. AI455135: Patient Adherence to QD vs More Frequent Therapy Week 48 Adherence by MEMS Caps QD P < .01 100 BID+ 87 90 77 80 74 P < .01 70 60 Patients Achieving Compliance(%) 49 50 40 30 20 10 0 % Taken % Taken on Time* *Taken within 3 hours of prescribed interval. • AI455135: 320 patients with HIV-1 RNA < 50 copies/mL for ≥ 90 days on BID (or more frequent) HAART (BID+) • Randomized to switch to QD (d4T XR + 3TC + EFV) or continue BID+ • Week 48 virologic suppression noninferior with QD regimen • QD: 80.0% • BID+: 75.8% • Adherence monitored • ACTG Adherence Questionnaire • MEMS caps • Pill counts Boyle BA, et al. HIV Clin Trials. 2008;9:164-176.

  19. 1.00 0.75 0.50 0.25 Time to rebound among patients with virologic suppression 0.00 P = .028 QD group 0 5 10 15 20 25 30 Proportion Remaining Suppressed BID group Once-Daily vs Twice-Daily HAART in a Clinical Setting • Retrospective study of 218 patients on QD or BID antiretroviral therapy in an urban clinic (USA) Months Munsiff A, et al. IAS 2005. Abstract WePe12.2C14.

  20. Italian Cohort I C O N A Naive Antiretroviral Strategie di semplificazione e aderenza: studi di coorte • N° di pazienti: 3974 • Follow-up totale: 4998 PYFU • VR: 311 Incidenza cruda di VR x 100 PYFU (95%CI) Incidenza globale di VR: 6.2 X 100 PYFU (IC95% 5.6-7.0) QD BID 2-5 BID 6-8 BID 9-12 BID >12 Ammassari A et al. CROI 2007

  21. Association Between ARV Pill Burden and Hospitalization ART Experienced Patients ART Naïve Patients Number of Hospitalizations per 100 Patients Number of Hospitalizations per 100 Patients Diff: -14.1; P<0.001 Diff: -14.3; P<0.001 Single Tablet Per Day Regimen 2+ Pills Per Day Regimen Single Tablet Per Day Regimen 2+ Pills Per Day Regimen Conclusion: Patients on a single tablet per day regimen had consistently lower hospitalization risk than those on other regimens. Cohen C, et al. 51st ICAAC; Chicago, IL; Sept 17-20, 2011. Abst. H2-791.

  22. The relationship between patient persistence, regimen persistence, and adherence JW Bae, 2011 Adherence levels are shown as a solid line and HIV-1 RNA levels as a dashed line. The dotted line represents optimal HIV viral suppression. PNP, patient non persistence

  23. Switching to Atripla (EFV/FTC/TDF) from its components leads to improved treatment satisfaction:Results from the ONCE study Participants reported less treatment intrusiveness 48 weeks after switching to Atripla The proportion of people who reported their HAART regimen was “very easy” to follow increased after switching to Atripla P= 0.006* P< 0.0001* 1.75 100 IQR1.10, 1.80N=114 80 1.5 IQR1.00, 1.55N=97 60 Percentage (%) Median HIS score 40 1.25 20 1.4 1.2 70.2 91.8 1 0 Baseline Week 48 Baseline Week 48 *Wilcoxon signed rank test, n=97 *McNemar’s test, n=97 Cooper V, et al. EACS 2011;Belgrade. Poster PE7.5/6

  24. Adverse events after fixed-dose combinations of antiretrovirals disruption EACS 2011 Belgrado Francesc Homar1, Juan Martínez-Gómez1, Antonio Pareja2, Joaquín Serrano3, Carmen Carratalá1, Antoni Payeras1. 1. Departments of Internal Medicine, 2. Epidemiology 3. Pharmacy Hospital Son Llàtzer. Palma de Mallorca, Spain

  25. Methods The aim of this study was to describe adverse events in patients exposed to FDCAs disruption in a single center • We retrospectively compared adverse events reported by 75 patients exposed to FDCAs disruption and 150 non-exposed patients, matched by gender and type of FDCA, who did not changed the treatment • We collected adverse events at visit-1 (before FDCA disruption), baseline (at the time of FDCA disruption) and at the next two follow-up visits (visit+1 and visit+2) Homar F, et al. EACS 2011;Belgrade. Poster

  26. Median time (range) on treatment with FDCAs and EFV was 20 months (1–119) and 48.5 months (1–127) respectively, with no statistical differences between groups. Both cohorts were comparable at baseline in sex, age, HIV risk factors, HCV co-infection, previous history of AIDS, history of psychiatric conditions, use of methadone or psychotropic drugs, CD4 cell count and HIV-RNA levels. FDCAs were disrupted for a median time of 3 months. Atripla Truvada Kivexa Combivir Trizivir 29% 11% 8% 49% 3% Results:FDCA distribution of the exposed cohort FDCAs that were disrupted in the exposed cohort Homar F, et al. EACS 2011;Belgrade. Poster

  27. Exposed cohort(FDCAsdisruptioncohort) Non-exposedcohort(FDCAs cohort) Results: patient disposition Visit +2 (month 4) Visit +1 (month 2) • 21 patients • Remain FDCAs disruption, n=9 • FDCAs resumed, n=10 • Treatment change, n=0Treatment discontinuation, n=0 • Missing n=2 • 75 patients • Remain FDCAs disruption, n=21 • FDCAs resumed, n=47 • Treatment change, n=6 • Treatment discontinuation, n=1 • 146 patients • Remain FDCAs, n=132 • Treatment change, n=2 • Treatment discontinuation, n=0 • Missing, n=12 • 150 patients • Remain FDCAs, n=146 • Treatment change, n=4 • Treatment discontinuation, n=0 Homar F, et al. EACS 2011;Belgrade. Poster

  28. Adverse events (AEs) • At visit+1, 21 out of 75 exposed patients vs 7 out of 150 non-exposed patients experienced AEs (OR 8; 95%CI 3.3-20.1, p=0.0000). • Neuropsychiatric disorders related to efavirenz was the main AE reported (9 patients out of 14). • At visit+2, 2.7% of the exposed patients experienced probably HAART-related AE vs 1.3% of the non-exposed group, being this difference non statistically significant.

  29. Adverse eventsDescription of probably HAART-related AEs in the exposed group at visit +1 Homar F, et al. EACS 2011;Belgrade. Poster

  30. Severe adverse events probably relatedto HAART • Four patients experienced a total 10 severe AEs in the exposed group: • toxic hepatitis (n=2), • insomnia (n=2), • abnormal dreams (n=1), • anxiety (n=1), • nervousness (n=1) • concentration difficulties (n=2) • hallucinations (n=1). • No cases of severe HAART-related AEs were found in the non-exposed cohort

  31. Adverse eventsPatients with probably HAART-related AEs by study visit Homar F, et al. EACS 2011;Belgrade. Poster

  32. HIV RNA and CD4 cell count changes • There were no statistically significant differences in the rate of patients with HIV RNA>50 cop/mL at visit +1(7% of the exposed patient vs. 9% in the non-exposed group) and visit +2 (13% vs 8%) • No significant differences were found in changes from baseline in CD4 cell count

  33. Cost analysis • A post-hoc analysis was performed to calculate the implication in health care expenditures with this measure during 120 days (median of time with disrupted FDCA treatment) • When considering only the management of HAART-related AEs, an incremental cost of 148 €/patient (1.24 €/patient/day) was observed • When the cost of anticipating the follow-up visits is included in the analysis, the final cost increment reaches 494 €/patient (4.13 €/patient/day)

  34. Conclusions • In comparison with maintaining FDCAs, their disruption to include g3TC in the regimens were associated with higher risk of adverse events • Many of these adverse events were neuropsychiatric disorders probably related to efavirenz in stable patients previously tolerating this drug • Some of these adverse events were severe in intensity • Unlike the desired objective of cost-saving, FDCAs disruption led to an increase of health care expenditure

  35. 154 Patients taking Atripla for at least three months with an undetectable viral load were asked to complete an anonymous survey The majority of patients expressed an unwillingness to switch from Atripla and an individualized approach to such a strategy would appear to be needed

  36. The fixed-dose antiretroviral coformulations (FDACs) represent a significant advance in the simplification of antiretroviral therapy, facilitating adherence to complex and chronic treatments, and contributing to a quantifiable improvement in patient quality of life. AIDS 2011, 25:1683–169

  37. These drug coformulations reduce the risk of treatment error, are associated with a lower risk of hospitalization, and can lessen the possibility of covert monotherapy in situations of selective noncompliance. AIDS 2011, 25:1683–169

  38. With the exception of those cases requiring dose adjustments, the preferential use of FDACs should be recommended for the treatment of HIV-1 infection in those situations when the agents included in the coformulation are drugs of choice. AIDS 2011, 25:1683–169

  39. L’uso di STR di per sé può essere un elemento chiave per contribuire a migliorare la qualità di vita e l’aderenza dei pazienti [AII]

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