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When to start ART?

When to start ART?. Roy M. Gulick, MD, MPH Professor of Medicine Weill Medical College of Cornell University New York City. When to start ART?. EARLY RX: HIV disease is progressive. Rx decreases HIV RNA (and resistance) and increases CD 4 (and immune function).

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When to start ART?

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  1. When to start ART? Roy M. Gulick, MD, MPH Professor of Medicine Weill Medical College of Cornell University New York City

  2. When to start ART?

  3. EARLY RX: HIV disease is progressive. Rx decreases HIV RNA (and resistance) and increases CD4 (and immune function). 7+ years of virologic suppression demonstrated. Treatment reduces transmission. When to start ART?

  4. EARLY RX: HIV disease is progressive. Rx decreases HIV RNA (and resistance) and increases CD4 (and immune function). 7+ years of virologic suppression demonstrated. Treatment reduces transmission. DELAYED RX: Practical factors (inconvenience, toxicity outweigh benefits in earlier disease). Long term effects unknown. Risk of clinical progression appears low in earlier disease. Resistant virus can be transmitted. When to start ART?

  5. START EARLY WAIT

  6. Guidelines for Initiation of ART *except TB

  7. Guidelines for Initiation of ART *except TB

  8. Guidelines for Initiation of ART *except TB

  9. ACTG 5164: Immediate vs Delayed ART with an Acute OI • 282 pts with treatable OI diagnosed within 14 days randomized to start ART within 48 hrs vs. after 4 wks • most common OI: PCP (63%) • AIDS progression/death: immediate rx (14%) vs delayed rx (24%) • No differences in safety/toxicity, IRIS, or wk 48 responses Time to AIDS/death Zolopa A, et al. 15th CROI, Boston 2008, #142

  10. Guidelines for Initiation of ART *except TB

  11. Guidelines for Initiation of ART *except TB

  12. Guidelines for Initiation of ART *except TB

  13. ART 2008 Easier, less toxic, and more potent therapy

  14. ART 2008 Easier, less toxic, and more potent therapy

  15. ART Responses Improving: 1996-2002 • 4143 rx-naïve subjects from 5 clinic cohorts in Europe and Canada • Started ART from 1996-2002 • In recent years, most “failure” was due to loss to follow-up or rx 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 F, Arch Int Med 2006;166:521

  16. 150 Median CD4 increase 150 127 135 125 121 120 119 120 105 97 90 Median CD4 Increase 75 60 45 30 15 0 ART Responses Improving: 1996-2002 • 4143 rx-naïve subjects from 5 clinic cohorts in Europe and Canada • Started ART from 1996-2002 • In recent years, most “failure” was due to loss to follow-up or rx 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 F, Arch Int Med 2006;166:521

  17. Swiss Cohort Study • Case-control study • Over 1-2 yrs, 358 asymptomatic patients with CD4 >350/mm3 on ART had better survival than 358 matched patients not taking ART: • Deaths: • 1% (ART) vs. • 5% (no ART) (p=0.0006) Opravil, AIDS 2002;16:1371

  18. HIV Outpatient Study (HOPS) • Prospective observational cohort study • 596 pts started ART; 175 delayed ART • Mortality rates (deaths/1000 person-yrs): • CD4 201-350: 15 (ART) vs. 56 (delay) P<0.001 • CD4 351-500: 10 (ART) vs. 17 (delay) P=0.17 • CD4 501-750: 7.5 (ART) vs. 3 (delay) P>0.2 • Suppressed HIV RNA also more likely in those with CD4 201-350 and CD4 351-500 who started ART (P<0.04) Palella FJ, Ann Intern Med 2003;138:620

  19. When to start?:ART Cohort Collaboration 1.00 350 0.95 200-349 0.90 100-198 0.85 50-99 0.80 0-49 0.75 0 1 2 3 Years from starting ART • Time to AIDS defining events or death • 12,574 patients followed at 13 cohorts starting 3-drug ART Probability of AIDS-free survival CD4 cell count at baseline Egger, Lancet 2002;360:119.

  20. When to start?:ART Cohort Collaboration • Modeled data • 10,855 patients included, with >61,000 person-years of F/U (median 2.7 yrs) • 934 progressed to AIDS/ died • IDUs excluded from model Cumulative Probability of AIDS/Death by CD4 Count at Initiation of ART 101-200 cells/mm3201-350 cells/mm3351-500 cells/mm3 0.12 0.10 0.08 Probability of AIDS or Death 0.06 0.04 0.02 0.00 3 0 4 5 1 2 Years Since Initiation of HAART Antiretroviral Therapy (ART) Cohort Collaboration, AIDS 2007;21:1185-97.

  21. When to start?:ART Cohort Collaboration • Modeled data • 10,855 patients included, with >61,000 person-years of F/U (median 2.7 yrs) • 934 progressed to AIDS/ died • IDUs excluded from model Cumulative Probability of AIDS/Death by CD4 Count at Initiation of ART 101-200 cells/mm3201-350 cells/mm3351-500 cells/mm3 0.12 0.10 0.08 Probability of AIDS or Death 0.06 0.04 0.02 0.00 3 0 4 5 1 2 Years Since Initiation of HAART Antiretroviral Therapy (ART) Cohort Collaboration, AIDS 2007;21:1185-97.

  22. ALIVE study • Cohort study • Compared 920 HIV-negative IDU and 583 HIV+ IDU between 1997-2000 • Results: found survival rates comparable for HIV-negative and HIV+ with CD4 >350. • Mortality rate (/1000 pt-yrs): 19.9 (HIV-) vs. 24.1 (HIV+, CD4 >350, ART) (p=0.76) Wang, JID 2004;190:1046

  23. CASCADE: Cohort Study • N=9,858 • Median F/U 8 years post-seroconversion • 597 deaths, >50% non-AIDS-related • Current CD4, nadir CD4, and time with CD4 <350 cells/mm3 associated with: • AIDS deaths • Non-AIDS deaths: severe infections, liver disease, malignancy Marin IAS 2007 #WEPEB019

  24. Hopkins HIV Clinical Cohort Deaths (Kaplan-Meier estimated cumulative mortality rate) by year after ART start • CD4+ cell count of new pts (n=1617) at first presentation, 2000–2004: • 687 (42%) had CD4+ <200 • Estimated 2674 pt-yrs life lost caused by late presentation among patients in Maryland Moore R, 15th CROI, Boston 2008

  25. Death in Rx-Naive Patients with CD4 >350 24 developed country cohorts/collaborations Mortality in rx-naive pts with CD4 >350 ↑ than in matched general population controls 47474 pts, 4487 deaths recorded; 4.9/1000 patient-years HIV-related: 79 (16%) Non-HIV–related: 235 (48%) Unknown causes: 173 (36%) Despite higher counts, ↓CD4+ associated with death; Rate ratio: 0.95 per 100 cells ↑; (95% CI: 0.90-0.99; P= .018) Lodwick R, et al. CROI 2008. Abstract 141. SMR, sex-standardized mortality ratio

  26. BASELINE CD4 COUNT AND VIROLOGIC SUPPRESSION EUROSIDA COHORT Phillips AN, et al, JAMA 2001;286:2560

  27. ACTG 5142: Baseline characteristics and VF • Phase III, multicenter, open-label 96-week trial • 753 ART-naïve pts randomized to class-sparing regimens: • EFV + 2 NRTIs • LPV/r + 2 NRTIs • LPV/r + EFV *Multivariate HR stratified on screening HIV RNA, hepatitis, NRTI; number <1 signifies lower risk †<100, 100–199, 200–299, 300–500, >500 Riddler S, 15th CROI, Boston 2008, #776

  28. Subset of patients ART-naïve or not on ART at randomization Immediate ART: n=249 (131 naïve) Deferred ART: n=228 (118 naïve) Greater risk of OI, OI/death, serious non-AIDS event with deferred ART >5-fold increased composite risk with deferred ART Composite endpoint 25 HR=5.08 (95% CI: 1.91-13.5) p=0.001 20 Cum. probability (X100) 15 10 5 0 0 4 8 12 16 20 24 28 32 38 Months SMART Cohort Data Deferred ART Immediate ART Emery IAS 2007, #WEPEB018

  29. Changing Treatment Guidelines: DHHS: Asymptomatic patients <www.aidsinfo.nih.gov>

  30. HOPS update • Cohort study • 2304 patients (starting ART 1996-2005) developed renal insuff (n=124), PN (n=278), LA (n=168) • Less likely to develop complication (multivariate analysis): • Patients with higher preART CD4 cell counts (200-350, 350-500, >500) -- 30-40% reductions • Patients with >95% on ART after starting -- ~50% reduction Lichtenstein, CROI 2006, abstract #769

  31. Major mutations 50% less likely starting ART with CD4 >350 vs <200 p=0.076 p=0.007 p=0.051 p=0.103 60 50 Patients (%) 40 30 20 10 0 NNRTI mut. among NNRTI-exp (n=37) PI mut. among PI-exp (n=48) Any mutation (n=78) NRTI mut. among NRTI-exp (n=77) 0-199 cells/mm3 200-349 cells/mm3 >350 cells/mm3 HOPS Cohort Uy IAS 2007, #WEPEB017

  32. HIV-Associated Complications that are Less CD4-Dependent • Neurocognitive impairment • Non-Hodgkin’s lymphoma • Peripheral neuropathy • HPV-associated dysplasia/cancer • Kaposi’s sarcoma • HIV-associated nephropathy

  33. No GUD GUD 5 4.5 4 Probability of Transmission/1000 Coital Acts 3.5 3 2.5 2 1.5 1 0.5 0 <1700 1700- 12500- 38500+ Viral Load and HIV Transmission GUD = genital ulcer disease. GUD HIV RNA copies/mL) Gray R et al. Lancet. 2001;357:1149-1153.

  34. Cost-Effectiveness of Early vs. Deferred ART • Markov modeling approach • Johns Hopkins HIV clinic database Mauskopf JA, et al. JAIDS 2005;39:562-569.

  35. Cost-Effectiveness of Early vs. Deferred ART • Markov modeling approach • Johns Hopkins HIV clinic database • “Starting ART earlier … rather than later … is a cost-effective strategy (by the generally accepted benchmark in the US).” Mauskopf JA, et al. JAIDS 2005;39:562-569.

  36. WAIT START EARLIER

  37. When is ART Started?CD4 Count at Initiation, 2003-5 • 42 countries, 176 sites; n=33,008 Egger M, 14th CROI; 2007; Abstract 62.

  38. Rationale for Starting Early • Suppress HIV replication • Decrease HIV clinical progression and death • Decrease non-HIV related disease • Decrease risk of toxicity • More difficult to suppress HIV RNA later • Decrease risk of drug resistance • Decrease HIV transmission • Current ART regimens are convenient, well-tolerated and potent

  39. Rationale for Waiting • Risk of HIV clinical progression is low • Adherence • Toxicity – life-threatening, acute, chronic • Quality of life (?) • Durability of ART (?) • Number of approved drugs (?) • Newer drugs in development • Resistance and cross-resistance • Co$t

  40. START Study • INSIGHT Network • Study population: adults with CD4 >500 • Study treatment: • Immediate ART • CD4 <350 • Study endpoints: • Serious AIDS-defining illness, non-AIDS illness, death • Sample size: • N=1200 (pilot for feasibility) • N=3000 (definitive) Gordin, When to Start symposium, IAS 2007

  41. The Pros and Cons of a Randomized Trial

  42. PROS Clinical equipoise Could provide definitive answer Well-powered study would be convincing Change guidelines and clinical practice The Pros and Cons of a Randomized Trial

  43. PROS Clinical equipoise Could provide definitive answer Well-powered study would be convincing Change guidelines and clinical practice CONS Observational data already compelling Previous attempts to enroll such trials have failed Relevance? Expensive The Pros and Cons of a Randomized Trial

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