1 / 50

Management of Antiretroviral Therapy – Case Presentations

Management of Antiretroviral Therapy – Case Presentations. Roy M. Gulick, MD, MPH Weill Medical College of Cornell University. Antiretroviral Therapy: Continuing Questions. When to start? What to start? When to switch? What to switch to? Can you stop therapy?. When to Start? Case 1.

thuy
Télécharger la présentation

Management of Antiretroviral Therapy – Case Presentations

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. Management of Antiretroviral Therapy – Case Presentations Roy M. Gulick, MD, MPH Weill Medical College of Cornell University

  2. Antiretroviral Therapy: Continuing Questions • When to start? • What to start? • When to switch? • What to switch to? • Can you stop therapy?

  3. When to Start? Case 1 • 35 year old woman • Recently diagnosed • History of oral thrush and zoster • Never on treatment • HIV RNA 20,000 • CD4 120 • Do you recommend treatment?

  4. When to Start? Case 2 • 35 year old woman • Recently diagnosed • Asymptomatic • Never on treatment • HIV RNA 20,000 • CD4 120 • Do you recommend treatment?

  5. When to Start? Case 3 • 35 year old woman • Recently diagnosed • Asymptomatic • Never on treatment • HIV RNA 20,000 • CD4 420 • Do you recommend treatment?

  6. Goal of Antiretroviral Therapy • to suppress HIV RNA (viral load level) as low as possible, for as long as possible • to preserve or enhance immune function • to delay clinical progression of HIV disease

  7. symptomatic asymptomatic, HIV RNA >10-20K or CD4 <500 asymptomatic, HIV RNA <10-20K and CD4 >500 treat offer treatment delay or treat When To Start Treatment? -- DHHS DHHS Guidelines, 1/28/00

  8. EARLY RX: HIV disease is progressive. Rx decreases VL (and resistance) and increases CD4 (and immune function). 3+ years of virologic suppression demonstrated. DELAYED RX: Risk of clinical progression low in early disease. Practical factors (adherence, toxicity outweigh benefits in early disease). Long term effects unknown. Early vs. Late Treatment DHHS Guidelines, 1/28/00

  9. What to Start? Case 1 • 35 year old woman • Recently diagnosed • History of oral thrush and zoster • Never on treatment • HIV RNA 20,000 • CD4 120

  10. What to start?Case 1 (cont.) • What would you recommend? • Indinavir + 2 nucs • Nelfinavir + 2 nucs • Efavirenz + 2 nucs • Nevirapine + 2 nucs • Something else

  11. What to Start? Case 2 • 35 year old woman • Recently diagnosed • History of oral thrush and zoster • Never on treatment • HIV RNA 20,000 • CD4 120 • Concerned about her ability to adhere to therapy

  12. What to start?Case 2 (continued) • What would you recommend? • Indinavir + 2 nucs • Nelfinavir + 2 nucs • Efavirenz + 2 nucs • Nevirapine + 2 nucs • Something else

  13. What to Start? Case 3 • 35 year old woman • Recently diagnosed • History of oral thrush and zoster • Never on treatment • HIV RNA 20,000 • CD4 120 • Recently diagnosed with pulmonary TB, taking INH, RIF, PZA, ETH

  14. What to start?Case 3 (cont.) • What would you recommend? • Indinavir + 2 nucs • Nelfinavir + 2 nucs • Efavirenz + 2 nucs • Nevirapine + 2 nucs • Something else

  15. nucleoside RTIs zidovudine (AZT, ZDV) didanosine (ddI) zalcitabine (ddC) stavudine (d4T) lamivudine (3TC) abacavir (ABC) NNRTIs nevirapine delavirdine efavirenz nucleotide RTIs *tenofovir (PMPA) protease inhibitors saquinavir ritonavir indinavir nelfinavir amprenavir lopinavir (ABT-378/r) ANTIRETROVIRAL DRUGS -- 2000

  16. Column A efavirenz indinavir nelfinavir ritonavir + saquinavir Column B d4T + 3TC d4T + ddI ZDV + 3TC ZDV + ddI DHHS Treatment Guidelines:Strongly Recommended DHHS Guidelines, 1/28/00

  17. Study Regimen Results (48 wk f/u) Dupont 006 (N=450) NEJM1999 ZDV/3TC/EFV, EFV/IDV, ZDV/3TC/IDV EFV regimen superior (?due to excess drop out with IDV) Glaxo 3005 + 3014 ICAAC 1999 + 2000 ZDV/3TC/ABC, ZDV/3TC/IDV comparable VL response (?concern of baseline VL >100K) Atlantic (N=298) Durban 2000 d4T/ddI/NVP, d4T/ddI/IDV, d4T/ddI/3TC comparable VL responses Combination Rx: 3-Drug Regimens

  18. Column A abacavir amprenavir delavirdine nelfinavir + saquinavir nevirapine ritonavir saquinavir sgc Column B ddI + 3TC AZT + ddC DHHS Treatment Guidelines:Recommended Alternatives DHHS Guidelines, 1/28/00

  19. DHHS Treatment Guidelines:Other NO RECOMMENDATION; INSUFFICIENT DATA • hydroxyurea in combination regimens • ritonavir + indinavir • ritonavir + nelfinavir NOT RECOMMENDED; SHOULD NOT BE OFFERED • all monotherapies • saquinavir HGC • other 2 NRTIs: d4T + AZT, ddC + 3TC, ddC + d4T, ddC + ddI DHHS Guidelines, 1/28/00

  20. When to change?Case • 35 year old woman • Recently diagnosed • History of oral thrush and zoster • HIV RNA 20,000 • CD4 120 • Tolerating her current regimen (ZDV/3TC/EFV) reasonably well

  21. When to change?Case • Which of the following would be the STRONGEST reason to change therapy? • HIV RNA 600 cps/ml by 6 months. • CD4 increase of only +10 by 6 months. • Recurrence of zoster by 6 months. • Persistent mild nausea at 6 months.

  22. Clinical Cohort N Failure rate (% above LD, time) Amsterdam 271 40% , 48 wks Cleveland 310 53%, 1 yr Hopkins 273 63%, 1 yr Swiss 1517 exp 1157 naïve 38%, 2 yrs 20%, 2 yrs UCSF 337 50%, 48 wks Treatment Failure: Clinical Cohort Studies

  23. When to Change Therapy? • <0.5-0.75 log reduction in HIV RNA by 4 weeks or <1.0 log reduction by 8 weeks • failure to suppress HIV RNA BLD by 4-6 months • repeated detection of HIV RNA after suppression BLD • any reproducible significant increase of HIV RNA • undetectable viremia in pts taking dual nucs • persistently declining CD4 cell counts • clinical deterioration DHHS Guidelines, 1/28/00

  24. Why Does Treatment Fail Patients? • adherence • side effects – acute and longer-term • baseline resistance or cross-resistance • use of less potent antiretroviral regimens • sequential monotherapy • drug levels and drug interactions • tissue reservoir penetration • other, unknown reasons

  25. What to change to?Case (f/u) • At 6 months, you substituted d4T for ZDV, with resolution of nausea. • At 9 months of therapy with d4T/3TC/EFV, patient has HIV RNA 12,000 cps/ml.

  26. What to change to?Case (f/u) • You recommend all of the following EXCEPT: • Review adherence and tolerability • Confirm HIV RNA level • Check CD4 count • Substitute 3TC with ddI • Order genotype

  27. What to Change To? • very few clinical data to support specific strategies • use resistance testing • change at least two new drugs, and preferably at least three drugs • may be prudent to delay change in anticipation of new drugs • clinical expertise required DHHS Guidelines, 1/28/00

  28. Study Intervention Results VIRADAPT (N=108) Lancet 1999 genotype vs. none; 6 month f/u genotype group had superior VL response GART (N=153) AIDS 2000 genotype (with expert opinion) vs. none; 12 wk f/u genotype group had superior VL response VIRA 3001 (N=118) Durban 2000 phenotype vs. none; 16 wk f/u phenotype group had superior VL response Prospective Studies ofResistance Testing in Salvage Rx

  29. DHHS Monitoring Guidelines • Use of drug resistance assays • Recommended • virologic failure on HAART • suboptimal HIV RNA suppression after starting rx • Consider • acute HIV infection • Not generally recommended • chronic HIV infection, prior to rx • after discontinuation of drugs • HIV RNA <1000 copies/ml DHHS Guidelines, 1/28/00

  30. Investigational Drugs: 2000 • nucleoside RTI: DAPD/DXG, FTC • NNRTI: emivirine, capravirine, calanolide A, DPC 083 and 983 • nucleotide RTI: tenofovir • protease inhibitors: tipranavir, BMS 232,632, Ag 1776, PD 178390, DPC 681 and 689 • entry inhibitors: • fusion inhibitors: T-20, T-1249 • chemokine receptor inhibitors: AMD-3100, TAK-799, Schering-C • CD4 attachment inhibitors: PRO 542 • TAT inhibitors: CG 137053 • integrase inhibitors:

  31. Current Approach to Salvage Rx • Review antiretroviral hx; assess adherence and tolerability • Distinguish first, second, multiple failures • Perform resistance testing while on drugs • Identify susceptible drugs/drug classes • Consider PK enhancement (RTV, DLV, HU) • Consider novel strategies (mega-HAART; STI) • Consider newer agents through expanded access or clinical trials • Design a regimen with >3 active drugs (if possible)

  32. STI’s: CASE • 43 yo man, HIV+ • Originally evaluated in 6/96 with CD4 52, HIV RNA 325K • Started d4T/3TC/IDV • HIV RNA <400 ever since (and in 8/00, <50) • Last CD4: 304 (5/00), 362 (8/00) • Calls Friday late afternoon from London to say that he’s flying to Katmandu tomorrow for a two week trek in the Himalayas and has lost his IDV

  33. QUESTION #1 • What do you advise? 1. cancel the trip and obtain meds in London ASAP 2. take d4T and 3TC on the trip, resume 3 drugs on return 3. take d4T only on the trip, resume 3 drugs on return 4. take nothing on the trip, resume 3 drugs on return 5. discontinue meds, check labs on return

  34. Common Reasons for Stopping Antiretrovirals • access • intercurrent illness • toxicities • surgery • first trimester of pregnancy • futility (virologic) in late-stage disease • non-adherence

  35. Comet Study • Ten antiretroviral naïve patients (baseline VL 63K, CD4 414) • Rx with ZDV/3TC/IDV X 28 days • Interrupted antiretrovirals X 28 days, VL rebound observed, then restarted meds • Viral load decline rate the same, no resistance-conferring mutations observed • With 4-12 months follow-up, VL <200 maintained

  36. Treatment Interruption (1) • 837 subjects took 2 nucs + EFV or IDV on Dupont 006 • 170 had d/c >2d for adverse event, then restarted later • for 82 with VL <400, ~70% reached <50 • for 88 with VL >400, ~40% reached <50

  37. Treatment Interruption (2) • 78 of 1246 clinic patients UAB had treatment interruption >30d, then resumed for >30d • prior to interruption, VL 9K, CD4 230 • after interruption, VL 400, CD4 230 (best response) • 59% reached 90% of prior CD4 • 77% reached within 0.3 logs of prior VL

  38. CASE #1 FOLLOW-UP • Patient decides to proceed with the trip, and not to take any antiretrovirals. • 3 weeks later, he present with no complaints and asks about “doing an STI.”

  39. QUESTION #1 • Have you had a patient ask to “do an STI”? • Yes • No

  40. QUESTION #2 • Have you used an STI as part of the management of an HIV-infected patient (to effect virologic/immunologic status)? 1. Yes 2. No

  41. Clinical Rationale for STI • Issues with antiretroviral regimens • adherence • toxicity • quality of life • cost • viral eradication not possible

  42. STI: The Hypothesis In patients with virologic suppression on therapy: • Discontinuing therapy with viral rebound will re-stimulate HIV specific immune responses. • These immune responses will be able to control viremia without antiretroviral therapy.

  43. Clinical Settings for STI • Acute infection with virologic suppression on antiretrovirals • Preserve/stimulate HIV-specific cellular responses • Chronic infection with virologic suppression on antiretrovirals • stimulate HIV-specific cellular responses and/or provide a break from therapy • Virologic failure • promote reversion to wild type virus; improve activity of subsequent regimen

  44. STI in Acute HIV Infection • 8 patients with acute/recent HIV infection treated with antiretrovirals (VL <50 X >8 months) • All underwent STI and all experienced viral rebound; 3 pts had VL <5000 and remained off rx • Other 5 underwent second STI after resuppression and 2 maintained VL <500 X 5-6 months off meds • HIV-specific CD4 responses maintained/augmented and CTL responses augmented/broadened Rosenberg, Nature 2000

  45. STI in Chronic HIV Suppression • SSITT study: The Swiss-Spanish Intermittent Trial • 122 subjects on HAART, VL <50 and CD4 >300 • STI cycles: d/c X 2 wks, rx X 8 wks (4 cycles) • 9 of 54 (17%) had VL <5K, 3 of 54 (6%) VL <50 • No clear changes in VL rebound levels, p24 specific CD4 IR increased, one subject developed 3TC and PI resistance, 2 had acute retroviral syndrome Hirschel, Durban 2000

  46. STI: Risks • repopulate reservoirs • virologic rebound and resistance • CD4 decline • clinical • acute antiretroviral syndrome • AIDS-defining illness

  47. Antiretroviral Therapy: Conclusions (1) • The optimal time to start rx is not clear. • The optimal initial rx regimen is not clear. • There are many effective combination regimens available. • First line rx fails in 10-60% of patients.

  48. Antiretroviral Therapy: Conclusions (2) • Better “salvage therapy” regimens are needed. • Resistance testing demonstrates benefits in selecting antiretroviral therapy. • There are a number of new drugs in development, both in existing classes and drugs with new mechanisms of action.

  49. Antiretroviral Therapy: Conclusions (3) • It is too early to recommend the routine use of STI in any clinical setting. • Prospective, randomized, controlled studies are needed to establish the risks and benefits of STI’s. • Further research is needed.

  50. For more HIV-related resources, please visit www.hivguidelines.org

More Related