Simplifying Antiretroviral Therapy: The Way Forward

Transcription

1 Simplifying Antiretroviral Therapy: The Way Forward Calvin Cohen, MD, MSc Clinical Instructor Harvard Medical School Research Director Harvard Vanguard Medical Associates Director of Research Community Research Initiative of New England Boston, USA 1

2 Years lived How far have we Come? Current Life Expectancy of HIV-Positive Patients Comparison of life expectancy of Athena cohort patients (n=4,174) to general population Years of Life Remaining Age at time of death Remaining Life Years General Population Asymptomatic HIV+ Patients Age at 24 weeks (years) van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, Abst

3 What Have we done to Maximize Long term Medication Adherence? Reduce side effects Short and long term Use medications with longer half-lives Forgiveness factor Symmetry of components to avoid monotherapy with missed doses Reduce pill number Co-formulations 3

4 Patients with <50 copies/ml (TLOVR) at Week 96, % ARTEMIS: Confirmed Response at Week 96: Week 4 96 Mean Adherence P= P<.0001 >95% Adherent b <95% adherent c P< Darunavir/r LPV/r 0 Week 96 n/n: 221/269 42/55 196/252 37/70 a viral load <50 copies/ml, TLOVR; b Week 4-96 mean adherence >95%; c Week 4-96 mean adherence 95%; n, number of patients with <50 copies/ml; N, number of patients who completed the questionnaire Nelson M, et al. BHIVA Abstract P115 4

5 Drug concentration Symmetry of Half Life: The Principle Dose Missed dose Zone of potential HIV replication on monotherapy MEC Time (hours) Taylor et al

6 Fixed-Dose Combinations Improve Medication Compliance: A Meta-Analysis A meta-analysis of 9 studies to assess the risk of medication noncompliance using FDCs vs components given separately N=11,925 patients on FDC vs 8,317 on components given separately in multiple disease areas: TB (2) HTN (4) HIV (1) DM (2) DM, diabetes mellitus; FDC, fixed-dose combination; HTN, hypertension; TB, tuberculosis. Bangalore S, et al. Am J Med. 2007;120:

7 Decreased Risk of Nonadherence With FDCs FDC regimens reduce risk of nonadherence by 26% compared with non-fdc. Effect of FDCs versus non-fdc on risk of nonadherence Study # Pills/ Day Disease Risk Ratio (95% CI) Dezii CM et al, HTN 0.74 (0.65, 0.84) Dezii CM et al, HTN 0.71 (0.62, 0.80) Eron JJ et al, HIV 0.78 (0.55, 1.11) Geiter LJ et al, TB 0.88 (0.55, 1.42) Melikian C et al, DM 0.50 (0.35, 0.71) Melikian C et al, DM 0.47 (0.22, 1.01) NDC Dataset, HTN 0.81 (0.77, 0.86) Su WJ et al, TB 0.89 (0.51, 1.57) Taylor AA et al, HTN 0.74 (0.67, 0.81) Overall P < (0.69, 0.80) -1 1 Risk Ratio 10 Bangalore S, et al. Am J Med. 2007;120: Favors FDC Favors Free-Drug Combinations 7

8 Multicenter Study: AZT/3TC + PI vs AZT + 3TC + PI Patients recently started on separate tablet regimen for >10 weeks, VL<4 log Randomized, open-label study of: Combination AZT/3TC tablet (n=110) vs Continue AZT and 3TC separate tablets (n=113) Results: Observed success (<400 c/ml) AZT/3TC 96.4% vs AZT + 3TC 92.9% [CI 3.5%; -2.4, 9.3] Loss of suppression Week 8: 0% on AZT/3TC, 12% AZT + 3TC Adherence Questionnaire: Significantly fewer missed doses Weeks 8 (P =.007) and 16 (P =.046) Eron J, et al. AIDS. 2000;14:

9 Multicenter Study: AZT/3TC + PI vs. AZT + 3TC + PI Skipped NRTI Dose Never (%) Once or Twice (%) Adherence Questionnaire: % Missed Doses Separate Tablet Combination Tablet Baseline Week 4 Week 8 Baseline Week 4 Week a 68 b Skipped PI dose Never (%) Once or Twice (%) Eron J, et al. AIDS. 2000;14: a p <0.01; b p <.05. 9

10 Patients, % Study 073: Switching from multiple pills to a Single Tablet Regimen The proportion of patients describing EFV/FTC/TDF as much better * than their previous regimen *p<0.001 at all time points Percentage of patients who found their regimen very easy to take 97 p< EFV/FTC/TDF Previous Regimen Week 0 Week 48 DeJesus E, et al. JAIDS 2009;51:

11 REACH cohort adherence study Adherence and efficacy results Patients recruited from a cohort of HIV+ homeless and marginally housed individuals and from public health clinics in San Francisco % Adherence > 90% % P = EFV/FTC/TDF r-pi NNRTI HIV RNA < 50 c/ml P = n = n = Bangsberg DR et al. AIDS. 2010;24:

12 Patients at or Above Adherence Threshold, % LifeLink Database: Impact of Simplified Regimens on Adherence STR associated with 59% greater likelihood of 95% adherence vs 3 pills per day STR generally favorable significantly greater adherence vs more pills per day Single-pill-per-day regimen 2-pills-per-day regimen 3-pills-per-day regimen % 90% a P <0.05 for single-pill-per-day cohort vs 2- and 3-pills-per-day cohorts at all levels of adherence, except vs 2-pills-per-day cohort at 90% level of adherence. Adherence Threshold a Sax P, et al. HIV Glasgow. Oral #113.; Sax P, et al. PLoS ONE. 2012;7:e

13 LifeLink Database: Impact of Simplified Regimens on Hospitalization Patients receiving a single pill per day had a 24% lower risk of hospitalization compared with patients receiving 3 pills per day. P =.003 Not significant n=2365 n=411 n=4297 Sax P, et al. PLoS ONE. 2012;7:e

14 LifeLink Database: Impact of Adherence on Hospitalization 95% Adherence Patients who achieved a 95% adherence threshold had a significantly lower rate of hospitalization compared with those who did not, regardless of pill burden a P values for all cohorts were <.001 for adherence 95% versus adherence <95%. Sax P, et al. PLoS ONE. 2012;7:e

15 LifeLink Database: Impact of Adherence on Hospitalization 95% Adherence <95% Adherence Patients who achieved a 95% adherence threshold had a significantly lower rate of hospitalization compared with those who did not, regardless of pill burden a P values for all cohorts were <.001 for adherence 95% versus adherence <95%. Sax P, et al. PLoS ONE. 2012;7:e

16 Subjects with adherence 95%, by study medication, % Selective Adherence: Week 48 Randomized Trial Results Randomized, open-label, multicenter, 96 week study of subjects (N=115) taking ABC/3TC 600mg/300 mg + FPV 1400 mg mg vs 200 mg of RTV QD % % 48% 20 0 FPV RTV 3TC/ABC* *Fixed-dose combination Hicks C, et al. EACS Madrid. Poster P5.7/01 16

17 Partial / Complete non-adherence as a % of Days Partial and Complete Non-Adherence to ART Complete non-adherence Partial adherence 26% 23% p< p< % p< p< for each group vs. STR for the % of time with partial plus complete non-adherence 14% 14% 15% 14% 14% Raltegravir based HAART (n=729) Boosted PI based HAART (n=3,556) NNRTI based HAART (n=775) STR based HAART (n=1,878) C Cohen. HIV11, Glasgow, UK 2012 #P1 17

18 % Patients COMPACT Adherence in pts on an STR or multi-pill regimens Retrospective, observational cohort analysis in 1,604 HIV+ patients ( ) Non-Adherence to cart Regimens Viral Load and CD4 at 1 year Follow-Up STR PI NNRTI RAL Non-Adherence Selective Non-Adherence CD4 Cell count >500 HIV-1 RNA <50cpm SUM: Higher Adherence with the STR vs. multi-pill regimens STR associated with a higher rate of Virologic suppression (VL<50) CD4>500 cells/mm 3 Antinori, et al. HIV ; Glasgow. Poster 18

19 Antiretroviral medication errors during admissions: Johns Hopkins Hospital 2009 Day Day Admissions with >1 error Total # Errors Most common errors Incomplete regimen, incorrect dosage or schedule Protease inhibitors ~72% of dose / scheduling errors Admissions to surgical services at increased risk of errors OR 3.10; 95% CI Day 1: 380 admissions (with ART medication), 230 patients Day 2: 308 admissions (with ART medication), 188 patients Yehia BR et al. Clin Infect Dis. 2012; 55:

20 STaR: Study Design Multicenter, International, Randomized, Open-label, Phase 3b, 96-Week Study ARV-naive HIV-1 RNA >2500 c/ml Sensitivity to EFV, FTC, RPV, TDF (N=786) N=394 RPV/FTC/TDF STR 48 Week Primary Endpoint Stratified by HIV RNA ( or >100,000 c/ml) N=392 EFV/FTC/TDF STR Primary endpoint: % VL 50 c/ml at Wk 48 (FDA Snapshot); 12% non-inferiority Cohen C, et al. HIV11; Glasgow, Scotland; November 11-15, 2012; Abst. O

21 ECHO & THRIVE Double Blind Studies of RPV vs. EFV: Dosing of Study Drugs Drug Dosing Food Requirement Pill Count Dosing Times per Day Rilpivirine drug or placebo Efavirenz drug or placebo 1 pill qd 1 pill qd With food (breakfast) Empty stomach (ideally bedtime) PLUS Either: FTC/TDF (60%) or 3TC/AZT (30%) or 1 pill qd With or without food 1 pill bid With or without food 3-4 pills per day Dosing at least twice per day 3TC/ABC (10%) 1 pill qd With or without food 21

22 STaR & ECHO/THRIVE: Virologic Failure at Week 48 by Baseline HIV-1 RNA STaR ECHO/THRIVE TVD Subsets* FDA Snapshot Cohen C, et al. HIV11; Glasgow, Scotland; November 11-15, 2012; Abst. O

23 The Future: More ARVs, More FDCs and STRs Non-nucleoside RTIs RPV/TDF/FTC Protease Inhibitors DRV/COBI/FTC/7340 ATV/COBI DRV/COBI Integrase Inhibitors EVG/COBI/FTC/TDF EVG/COBI/FTC/TAF DOL/ABC/3TC 23

24 Conclusions Maintaining HIV suppression allows HIV+ patients to look forward to a normal life span Adherence is essential to this improved prognosis Multiple factors contribute to improved adherence Simplification / co-formulation are associated with: Improved adherence Increased patient satisfaction Fewer regimen errors Lower risk of viremia Lower risk of hospitalization Reduced medical costs of care 24