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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.

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Management of Antiretroviral Therapy – Case Presentations

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  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.

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