1 / 60

Selected Controversies in Antiretroviral Therapy

Selected Controversies in Antiretroviral Therapy. Joel E. Gallant, MD, MPH Johns Hopkins University School of Medicine. When to Start Therapy?. Will We Return to Earlier Therapy?. Availability of more potent, easier, and less toxic regimens. 1996: ddI + d4T + SQV

presencia-queiro
Télécharger la présentation

Selected Controversies in Antiretroviral Therapy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Selected Controversies in Antiretroviral Therapy Joel E. Gallant, MD, MPH Johns Hopkins University School of Medicine

  2. When to Start Therapy?

  3. Will We Return to Earlier Therapy? • Availability of more potent, easier, and less toxic regimens

  4. 1996: ddI + d4T + SQV -SQV: 6 q8h with fatty food -ddI: 2 bid ½ hr ac or 2 hrs pc -d4T: 1 pill bid -24 pills/d, 5 doses -significant long-term toxicity 2005: TDF/FTC or ABC/3TC + EFV -2 pills qd -no food restrictions -no long-term toxicity anticipated The Move Toward Simpler Regimens3-drug regimens: 1996 and 2005

  5. One Pill, Once Daily Triple Combination Regimen? tenofovir + emtricitabine + efavirenz

  6. Collated Results of HAART Studies • Previous analysis emphasized relation b/w pill burden and response • Updated analysis: pill burden less important • Highlights efficacy of boosted-PI and NNRTI regimens Unboosted PI NNRTI NRTI Boosted PI 0 10 20 30 40 50 60 70 80 90 100 % With VL < 50 at Week 48 Bartlett JA et al. Abstract 586.

  7. 150 Median CD4+ increase 150 127 135 125 121 120 119 120 105 97 90 Median CD4+ Increase 75 60 45 30 15 0 Treatment Responses in 1st Year of HAARTImproving Over Time • 4143 subjects from 5 clinic cohorts in Europe and Canada • Treatment-naive; started HAART from 1996-2002 • ↓ risk of virologic failure, ↑ med. CD4 increase in later years • In recent years, most “failure” due to loss to follow-up or treatment discontinuation % with > 500 copies/mL 100 90 80 70 60 % With VL > 500 on ART 50 40 30 24.8 23.0 17.3 20 12.4 10 8.4 8 10 0 1996 1997 1998 1999 2000 2001 2002 Lampe S, et al. 12th CROI, 2005, Abstract 593

  8. What Degree of Adherence is Needed? Data From Unboosted PIs Adherence to a PI-containing regimen correlates with HIV RNA response at 3 months 100 80 60 % VL < 400 copies/mL 40 20 0 < 70 70–80 80-90 90–95 > 95 PI Adherence, % (MEMS caps) Paterson DL, et al. Ann Intern Med. 2000;133:21-30.

  9. Adherence and Virologic Suppression:NNRTIs vs. unboosted PIs • 109 indigent patients in San Francisco: 56 on unboosted PIs, 53 on NNRTIs • VL < 400 reliably seen with NNRTI if adherence > 54%, but with unboosted PI, only with very high adherence • Predictors of VL < 400: NNRTI use, adherence, high CD4 nadir, time on Rx 100 100 PI NNRTI 80 80 60 60 % VL < 400 copies/mL 40 40 20 20 0 0 0-53 54-73 74-93 94-100 0-53 54-73 74-93 94-100 % Adherence (Electronic Measurement) % Adherence (Pill Count) Bangsberg DR et al. 12th CROI, 2005. Abstract 616.

  10. Will We Return to Earlier Therapy? • Availability of better, easier, and less toxic regimens • Conflicting cohort data: some studies show benefit with earlier therapy

  11. Cohort Studies Supporting Earlier Therapy • Swiss Cohort: Better prognosis with initiation of HAART at CD4 >3501 • HOPS: Trend toward lower mortality in pts treated with CD4 351-5002 • ALIVE: Survival of HIV+ IDUs only approximated that of HIV- IDUs when HAART initiated at CD4 >3503 1. Opravil M, et al. AIDS 2002; 2. Palella FJ, et al. Ann Intern Med 2003; 3. Wang C, et al. J Infect Dis 2004

  12. Will We Return to Earlier Therapy? • Availability of more potent, easier, and less toxic regimens • Conflicting cohort data: some studies show benefit with earlier therapy • Risk of prolonged HIV exposure independent of CD4? (dementia, NHL, PML, KS)

  13. Will We Return to Earlier Therapy? • Availability of more potent, easier, and less toxic regimens • Conflicting cohort data: some studies show benefit with earlier therapy • Risk of prolonged HIV exposure independent of CD4? (dementia, NHL, PML) • Maintain options for intermittent therapy

  14. Characteristics: 3.2 prior ARV regimens 57 mo of prior ARV Pre-ARV RNA: ~100,000 c/mL Continuous therapy (n=38) 114 patients: CD4 >800 cells/mm3 HIV RNA <50 c/mL Restart therapy when CD4 <400 cells/mm3 (n=76) Intermittent CD4-Guided TherapyThe BASTA Study • 18/76 (24%) restarted HAART at least once • 95% in STI group have maintained CD4 >400 at 20 months of follow-up • Better lipid profiles in STI group: • Only nadir CD4 <350 cells/mm3 predicted time to restart HAART • Cost of care in STI group decreased by ~€300/month Maggiolo F, et al. 43rd ICAAC, Chicago, September 2003, H-448

  15. The BASTA Study:Maggiolo’s Conclusion “…therefore, we should start therapy earlier so we can stop.”

  16. CD4-Guided Intermittent Therapy Treatment interruption (years) CD4 Count CD4 Treatment threshold CD4 nadir = strongest predictor of time off therapy = on HAART Time

  17. Will We Return to Earlier Therapy? • Availability of more potent, easier, and less toxic regimens • Conflicting cohort data: some studies show benefit with earlier therapy • Risk of prolonged HIV exposure independent of CD4? (dementia, NHL, PML) • Maintain options for intermittent therapy • Preserve R5-tropic status

  18. How Will We Use New Agents?

  19. Targets for Antiretroviral Therapy Attachment Inhibitors, Coreceptor Antagonists Fusion Inhibitor NRTIs, NNRTIs EntryInhibitors PIs Reverse Transcriptase Inhibitors Integrase Inhibitors Protease Inhibitors Maturation Inhibitors

  20. New Antiretrovirals in Development • NRTIs/NtRTIs • SPD 754 (DOTC) • Amdoxovir (DAPD) • D-D4FC • Alovudine (MIV 310) • Racivir (+/–FTC) • SN1212 • Compound X • Entry inhibitors • Aplaviroc • Maraviroc • Vicriviroc • BMS-488043 • TNX-355 • NB-2, NB-64 • T-649 • NNRTIs • TMC125 • GW678248 (prodrug = GW695634) • TMC278 • BILR 355 BS • CSIC • DAPY/DATA • UC781 • TMC120 (as microbicide) • Protease inhibitors • TMC114 • GW0385 • P-1946

  21. CCR5 Inhibitors in Development Vicriviroc (SCH-417690) Aplaviroc (GW873140) HIV-infected volunteers (N = 48) 0.4 0.5 Placebo Dosing Period Washout Period 0.2 200 QD Placebo 0 200 BID 0.0 10 mg BID -0.2 400 QD 25 mg BID -0.4 600 BID Median VL Change From BL (log10 copies/mL) Median VL Change From BL (log10 copies/mL) 50 mg BID -0.6 -0.5 -0.8 -1 Most common AE: minor, self-limiting GI events -1.0 -1.2 -1.4 -1.6 Dosing -1.5 -1.8 0 5 10 15 20 25 30 0 15 5 10 20 25 30 Day Days Maraviroc (UK-427857) 0.5 Greater risk of postural hypotension 0 Median VL Change From BL (log10 copies/mL) 100 mg BID Placebo 15 -0.5 150 mg Fast Placebo 07 150 mg Fed 25 mg QD 50 mg BID 300 mg QD -1.0 -1.5 100 mg QD 300 mg BID Dosing -2.0 0 5 10 15 20 25 30 35 40 OaLb0203 Time (days)

  22. 100 90 80 70 60 Prevalence of X4 or R5/X4, % 50 41.9 40 40 30 16 16 14.8 20 10 0 > 300 248 > 201-300 104 > 101-200 81 > 51-100 31 < 50 50 CD4 count n = Increasing Prevalence of X4- or R5/X4-Tropic Virus At Lower CD4 Counts CCR5: • Pts with early stage HIV-disease tend to have pure R5-tropic virus CXCR4: • With advanced disease, X4- or dual-tropic virus emerges • Associated with more rapid clinical and immunologic progression CCR5 inhibition: could select for more virulent X4-tropic virus Moyle G, et al. Abstract 1135, 44th ICAAC, Washington, 2004

  23. Emergence of R5/X4 Virus During Maraviroc Monotherapy: Selection of Baseline Variants • Tropism assay threshold ~ 10% • Treatment selects for preexisting minority variants Patient A R5 100 R5/X4 n = 97 80 n = 68 n = 91 % of Envelope Clones 60 40 20 0 Day 1 Day 11 Day 40 Patient B R5 100 n = 67 X4 R5/X4 80 n = 118 60 % of Envelope Clones n = 63 n = 52 40 n = 49 n = 46 n = 48 n = 44 20 0 Prescreen Day 1 Day 11 Day 40 Day 203 Day 251 Day 308 Day 373 Lewis ME, et al. ICAAC 2004. Abstract 584b.

  24. CCR5 Inhibitors for Initial Therapy PROs: • Naïve patients less likely to have X4- or R5/X4-tropic virus • Well tolerated and convenient in early trials CONs: • Tough competition (e.g. 1 pill qd, well tolerated, with minimal long-term toxicity) • May require tropism screening: more expensive if used up-front before initial therapy in all patients Which agent(s) would it replace?

  25. CCR5 Inhibitors for Experienced Patients PROs: • Effective against NRTI-, NNRTI-, and PI-resistant virus • May be synergistic with other entry inhibitors (e.g. ENF) • Cost of tropism assay easier to justify in subset of patients failing therapy CONs: • Greater likelihood of X4- or R5/X4-tropic virus with more treatment experience or more advanced disease • Efficacy with dual-tropic virus depends on activity of other drugs in regimen, which decreases with greater treatment experience.

  26. 2 2 Post therapy On therapy 1 1 0 0 Δ from baseline HIV RNA log10 c/mL –1 –1 –2 –2 10 8 17 1 3 24 Days since randomization L-000870810 200 mg L-000870810 400 mg Placebo Integrase Inhibitors: Short-term Monotherapy with L-870,810 • Randomized, double-blind, placebo-controlled, 10-day dose-finding study • 200 mg BID (n=7) vs 400 mg BID (n=17) vs placebo (n=6) • Development stopped due to preclinical toxicity, but proof of concept demonstrated • Other candidate being evaluated Little S, et al. 12th CROI, # 161

  27. How Will We Use Integrase Inhibitors? • Too soon to tell… • Depends on potency, convenience, tolerability, toxicity • Unlike CCR5 inhibitors, there appear to be no other specific considerations that argue for earlier or later use

  28. Can “2nd Generation” Agents Move to the Head of the Line? Yes: • LPV/r started out as a “salvage drug” but became a 1st-line PI because of greater potency, durability, and lack of resistance with failure • Other examples: TDF, ABC What does it take to become 1st-line in a class? • Advantages with respect to tolerability, toxicity, convenience, durability, and/or resistance profile

  29. The Potential for Earlier Use of 2nd Generation Agents • PIs • Tipranavir: unlikely because of higher RTV dose, greater PI toxicity, pill burden, bid dosing • TMC 114: more likely than TPV, though still bid with higher pill burden than current standards • NNRTIs • TMC 125: unlikely because of higher pill burden vs. EFV • TMC 278: low pill burden, potential for earlier use if better tolerated than EFV • NRTIs • D-d4FC: qd dosing, but need data on resistance profile with failure

  30. Tipranavir/Ritonavir Superior to Lopinavir/Ritonavir in RESIST Studies • TPV/r superior to LPV/r at Week 24 in PI-experienced patients • In subgroups in each arm receiving same total number of active drugs, TPV/r arm remained superior % With VL ≥1 log10 c/mL 100 100 TPV/r LPV/r 80 80 P < .05 P < .0001 P < .05 P < .0001 60 60 45.3 45.7 39.6 39.6 39.6 36.1 35.2 40 35.8 40 21.4 21.4 20 20 13.1 10.7 0 0 LPV/rNaive LPV/r Experienced Overall LPV/r Susceptible LPV/rResistant Overall Cooper D, et al. ICAAC 2005, Abstract 560.

  31. L I K L E M K M I I Q H T V N I TPV 10 13 20 33 35 36 43 46 47 54 58 69 74 82 83 84 Score V V M F G I T L V A E K P L D V R M T V V L K L D V L M M I G I F I L A C V V I N L IAS-USA 10 20 24 30 32 33 36 46 47 48 50 53 54 63 71 73 77 82 84 88 90 F R I N I I I I V V L L V p V C I A V D M I M F L L A V L T S F S R I V V A T T V M A S C S TPV Mutation Score vs IAS-USA Protease Gene Resistance Mutations • Many mutations (13, 35, 43, 58, 74, 83) have not been associated with resistance to other PIs • Major mutations (D30N, G48V, N88D, L90M) associated with other PIs do not contribute to TPV mutation score

  32. 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.

  33. 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) POWER1: Virologic Response to TMC114/r 100 P < .001 for all doses 80 60 53% Patients with HIV-1 RNA < 50 copies/mL (%) 49% 48% 43% 40 20 18% 0 24 20 16 12 8 4 1 2 Time (weeks) LB0102

  34. New Trends in Resistance and Drug Sequencing

  35. Sequencing therapy in 2006 and beyond: how many tries do you get? • One of many plausible scenarios: 2 NRTIs + 1 NNRTI → 3 NRTIs + 1 PI/r → 1 PI/r + CCR5 inhibitor +/- NRTIs → integrase inhibitor + ENF + other CCR5 inhibitor +/-PI/r → maturation inhibitor + other entry inhibitor(s) + ? • Problems: • People who fail initial therapy today were probably non-adherent with simple regimens • The “first shot’ may always be the “best shot” • Infection with resistant virus can eliminate many sequences

  36. Resistance Mutations:What’s “In” and What’s “Out” in 2005 OUT • TAMs • Selected by ZDV and d4T, which will be used less frequently in initial therapy • Usually absent with initial failure • Impact of generic ZDV? • PI mutations • Typically absent with early failure of boosted PIs

  37. Resistance Mutations:What’s “In” and What’s “Out” in 2005 IN • M184V • 3TC and FTC are used in all initial regimens • M184V emerges quickly with failure • NNRTI mutations • NNRTIs used widely for initial therapy • NNRTI resistance emerges quickly with failure • K65R, L74V • Still not widely seen, but more likely to be selected by today’s regimens • May not be preventable with early modification • ENF mutations • Emerge rapidly with non-suppressive ENF-containing therapy

  38. Differences in efficacy primarily due to differences in discontinuation due to AEs GS934: Efficacy and Tolerability48-week data P = .034 100 77% 80 68% 60 Patients with HIV-1 RNA < 400 copies/mL [TLOVR] (%) 40 FTC + TDF + EFVAZT/3TC + EFV 20 (ITT n = 509) 0 BL 8 16 24 32 40 48 Weeks Excluding pts with baseline NNRTI resistance FTC + TDF 80%vsAZT/3TC 70% (P = .021) * P = .016 Pozniak AL, et al. IAS 2005. Abstract WeOa0202.

  39. GS934: Resistance Analysis • BL NNRTI resistance mutations ↓ response, whereas BL NRTI resistance mutations had little impact • 2/22 (9%) with BL NNRTI-R had VL < 400 at Wk 48 • 12/13 (92%) with BL NRTI-R had VL < 400 at Wk 48 % mITT, % of patients in modified intent-to-treat analysis; % RAP, % in patients with resistance testing McColl D, et al. IAS 2005. Abstract TuPp0305.

  40. “Nuke-Sparing Regimens”: The Latest Thing or Old News? • Rationale was based on concerns about inevitable mitochondrial toxicity with NRTIs

  41. N=156; analysis by intent to treat AZT/3TC ddI+d4T 20 † † 10 † † IQR 0 Median % change from baseline * † -10 † * * -20 -30 Entry 16 32 48 64 80 Study Week Role of NRTIs on Change in Limb Fat (ACTG 5005) *P<0.05 between groups; †P<0.05 within groups. Dube M, et al. 2002; 4th Lipo Wkshp. Abstract 27.

  42. “Nuke-Sparing Regimens”: The Latest Thing or Old News? • Rationale was based on concerns about inevitable mitochondrial toxicity with NRTIs • These concerns have subsided with greater use of “mitochondria-friendly” NRTIs (TDF, ABC, 3TC, FTC)

  43. Suppressed patients with self-defined lipoatrophy on thymidine analog (TA) 105 pts randomized to replace TA with TDF or ABC Total limb fat increased to similar extent in both arms over 48 weeks RAVE Study: Switch Thymidine Analog to ABC or TDF 1200 TDF 1061 1046 ABC 1000 791 800 Change in fat mass (g) by DEXA, Wk 48 522 600 393 316 400 200 0 Limb Trunk Total Fat Within-group change in limb fat from baseline: TDF P = .01, ABC P = .001 Moyle G, et al. 12th CROI, 2005, Abstract 44LB.

  44. TGs TC LDL HDL 0 -1 -16 -20 -40 -38 -60 -72 -80 GS 903E: Impact of Switching off d4T on Lipids and Limb Fat • 96-week open-label extension phase of 903 study • Data from subgroup of pts given d4T for 144 weeks who switched to open-label TDF for 48 weeks p = 0.005 5.02 (n = 74) 5.0 4.8 P < .001 4.6 Mean Total Limb Fat (kg) 4.60 (n = 74) Mean Change in Fasting Lipids at Week 48 (mg/dL) 4.4 d4T TDF 4.2 0 Wk 96 Wk 144 Wk 48post-switch Madruga JVR, et al. IAS 2005. Abstract TuPe2.2b12.

  45. “Nuke-Sparing Regimens”: The Latest Thing or Old News? • Rationale was based on concerns about inevitable mitochondrial toxicity with NRTIs • These concerns have subsided with greater use of “mitochondria-friendly” NRTIs (TDF, ABC, 3TC, FTC) • Recent data show greater toxicity with PI/NNRTI regimens (e.g. LPV/r + EFV) • Could new classes (e.g. CCR5 inhibitors) replace NRTIs? • Depends in part on long-term safety of TDF and ABC

  46. ‡ Study 934Serum Creatinine: week 48 a. Confirmed toxicity grade = 2 consecutive visits Arribas, J, et al. 18th International Conference on Antiviral Research, April 10, 2005. Barcelona, Spain

  47. The Hopkins Cohort: TDF and Renal Function * 120 * 100 80 GFR (ml/min/1.732) TDF 60 NRTI 40 20 0 0 90 180 270 360 450 540 Days # on TDF 335 304 247 185 # on NRTI 403 369 297 172 Gallant JE, et al. 3rd IAS, Rio de Janeiro, 2005

  48. Johns Hopkins Cohort Conclusions • Decline in ClCr independently associated with TDF use, baseline CD4<50, and duration of therapy • No association with age, race, sex, HIV transmission group, HTN, diabetes, HIV RNA, use of LPV/r or other specific ARV agents, or prior use of adefovir • Although statistically significant, clinical significance unclear: no difference in discontinuation • Majority of TDF-treated subjects remain on TDF and will continue to be followed Gallant JE, et al. 3rd IAS, Rio de Janeiro, 2005

  49. When to Use the New Agent • Too soon: • New drug used in combination with partially active drugs despite relatively preserved CD4

  50. Case 1 • 45-year-old man with multi-class resistance • Phenotype shows partial susceptibility to: • TPV (FC 3.8) • TDF (FC 1.3) • ddI (FC 1.4) • CD4 326, VL 52,000 • He is switched to TPV/r + TDF + ddI + ENF

More Related