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Effects of Switching From Fixed Dose Zidovudine/Lamivudine (CBV) to Fixed Dose Tenofovir DF/Emtricitabine (TVD): Maintenance of Virologic Suppression and Other Benefits.

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  1. Effects of Switching From Fixed Dose Zidovudine/Lamivudine (CBV) to Fixed Dose Tenofovir DF/Emtricitabine (TVD): Maintenance of Virologic Suppression and Other Benefits E. DeJesus1, P. Ruane2, C. McDonald3, F. Garcia4, J. Ecker5, R. Ebrahimi5, J. Flaherty5, and A. Fisher5for the COMET Team 1Orlando Immunology Center, Orlando, FL, 2Lifesource Medical, Los Angeles, CA, 3Tarrant County ID Associates, Fort Worth, TX, 4Valley AIDS Council, Harlingen, TX, and 5Gilead Sciences, Foster City, CA, USA

  2. Introduction • Fixed-dose ZDV/3TC (CBV) is widely used, but can be associated with nausea, headache, malaise/fatigue, and anemia • Superior outcomes (HIV RNA % <400 c/mL, CD4 counts, and discontinuations for AEs) were recently reported at 48 weeks in naïve patients randomized to TDF + FTC + EFV vs. CBV + EFV (Gallant et al. NEJM 2006;354:251-260) • The COMET study evaluated the impact of switching virologically-controlled patients from a BID regimen of CBV + EFV to a simpler, 2-pill QD regimen of TVD + EFV • First study to utilize the FDC formulation of TDF/FTC (TVD)

  3. COMET STUDY(Combination of Efavirenz and Truvada) • Prospective, multi-center, single arm, phase IV study • 411 patients were enrolled (Oct ’04 to Aug ’05) from 83 U.S. sites • All patients were switched from twice daily CBV + EFV to a once daily regimen of TVD + EFV • Key inclusion criteria: • HIV+ patients with HIV RNA < 400 copies/mL (Amplicor v1.5) on a regimen of CBV + EFV for ≥ 8 weeks • Evidence of CBV-related adverse event(s) and/or a desire to switch to a simplified QD regimen • Calculated CLCr by Cockcroft-Gault method ≥ 50 mL/min

  4. Methods • Assessments were performed at the screening/baseline visit, and at weeks 4, 12, and 24 post-switch • Efficacy • HIV RNA: % of pts < 400 copies/mL and < 50 copies/mLa • CD4 count: change from BL • Safety and tolerability • CBC (Hb, ANC, MCV), serum chemistries, and treatment-emergent AEs • Protocol later amended to include fasting lipid profile at each visit (n = 160) • Quality of life / treatment satisfaction / adherence • Validated questionnaire of symptoms, adherence, and treatment satisfaction (SATS) • SF-36 QoL Survey (BL and 24 wks) • Adherence also assessed by pill count • Or < 75 c/mL by bDNA

  5. SATS Questionnaire 3 part questionnaire completed by the patient at each visit • Part 1: Adherence • # missed doses in the past week, month, and reasons (14 items) • Part 2: Satisfaction with the Treatment Regimen • 4 items regarding treatment satisfaction(4 point scale: “very dissatisfied” → “very satisfied”) • 1 item regarding how bothered the pt is by side effects (SE) of regimen(4 point scale: “SE do not bother me” to “SE bother me terribly”) • Part 3: Symptoms Experienced During the Past 4 Weeks • 20 items regarding common symptoms experienced by HIV+ pts(5 point scale: “I don’t have this symptom” → “I have this symptom, and it bothers me terribly”)

  6. Baseline Demographics • N = 411 enrolled; 9 pts were not evaluable (8 pts enrolled at a single site did not have data entered; 1 pt was not dosed) • 1 pt with VL >1000 c/mL (major protocol violation) was included in safety, but not efficacy analysis • Or < 75 c/mL by bDNA (n = 28)

  7. Baseline Treatment Characteristics

  8. Early Discontinuations • a. AE’s: 5 pts with GI sx (dry mouth, diarrhea, nausea/vomiting, cramps, bloating) • 3 pts with CNS sx (EFV-related mental status change, HA, dizziness) • 1 pt with asthenia • 1 pt with abnormal LFTs • b. Defined as two HIV RNA values ≥ 400 c/mL separated by ≥ 4 weeks

  9. HIV RNA Results: % < 400 copies/mL 95% 87% % of Patients Weeks N = 401 389 386 366

  10. HIV RNA Results: % < 50 copies/mLa P < 0.001 Wk 24 vs. BLb 81% P = 0.38 Wk 24 vs. BL 74% % of Patients Weeks N = 401 389 386 366 • Or < 75 c/mL by bDNA • McNemar test HIV RNA < 50 (or <75 by bDNA) copies/mL at BL = 71%

  11. Change from Baseline (BL) in Selected Hematological Parameters at Week 24 • Hb = hemoglobin; ANC = absolute neutrophil count; MCV = mean corpuscular volume • Results expressed as median (IQR) • Wilcoxon Sign-Rank test

  12. Hb – Change from BL at Week 24 (n = 364) • % with  Hb change from BL of >1 g/dL: 31% • % with  Hb change from BL of >1 g/dL: 2%

  13. Fasting Lipids at BL (Median, IQR) and Changefrom BL at Week 24a 194 (169, 227) 112 (88, 133) 46 (38, 55) 163 (104, 240) P = 0.033 P = 0.024 Median Change from BL (mg/dL) P < 0.001b P < 0.001 • The protocol was amended to collect fasting lipid data. N = 160 pts were enrolled post-amendment. • Wilcoxon Sign-Rank test

  14. Symptoms and Treatment Satisfaction (SATS) Questionnaire Self-Reported by Patients (n=352) % of Patients Reporting “Very Satisfied” * * * * * P < 0.001a • McNemar test

  15. SATS Questionnaire Self-Reported byPatients (n= 352) % of Patients Reporting Absence of the Symptom * * * * P < 0.001a • McNemar test

  16. Adherence Results • Pill Count • 87% of patients achieved ≥ 95% adherence to the study regimen • SATS Questionnaire • % pts with full (100%) adherence on ≥ 95% of days by questionnaire recall: P = 0.002a P = 0.002 % pts with full adherence on ≥ 95% of days Recall • McNemar test

  17. Safety Results (N = 402) • Treatment emergent AEs reported in > 2% of patients: • nausea 5%; diarrhea 5%; headache 3%, insomnia 3% • Grade 3/4 laboratory abnormalities: • neutropenia (2 pts), thrombocytopenia (1 pt),  triglycerides (2 pts) • Renal results: • Confirmed  in Scr (1 pt; grade 2 ) - returned to normal range during study • Median (IQR) BL CLCr: 102 (87, 121) mL/min • Median (IQR) change from BL at Wk 24: -8 (-15, 0.0) mL/min (p <0.001)

  18. COMET: Conclusions Switching from CBV/EFV to TVD/EFV (comparison from BL to wk 24): • Virologic suppression was maintained • The regimen was well tolerated • Increases in CD4, Hb, and ANC • Normalization of MCV • Modest decreases in fasting lipids • Slight decreases in CLCr • Fewer patients reported being bothered by regimen side effects • More patients reported being “very satisfied” with the regimen • Improved adherence was observed by patient recall

  19. Backup Slides

  20. Change from Baseline in Lipid Parameters at Week 24 (n = 160) • TC = total cholesterol; LDL = low density lipoprotein chol; HDL = high density lipoprotein chol; Tg = triglycerides • Results expressed as median (IQR) • Wilcoxon Sign-Rank test

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