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Starting Treatment: Early ART or Late, Safe Start?

Starting Treatment: Early ART or Late, Safe Start?. Is the Pendulum Swinging Back to Earlier Treatment?. 1500 and up 500 350 200 100 50 0. When to Start: Old Party Line. Normal Range Gray Zone Rx Range. Normal Range (>500 CD4 Cells)

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Starting Treatment: Early ART or Late, Safe Start?

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  1. Starting Treatment: Early ART or Late, Safe Start? Is the Pendulum Swinging Back to Earlier Treatment?

  2. 1500 and up 500 350 200 100 50 0 When to Start: OldParty Line Normal Range Gray Zone Rx Range • Normal Range (>500 CD4 Cells) • ARV not usually recommended in past • Exceptions in pregnancy and Acute HIV • Gray Zone (350-500 CD4 Cells) • Old guidelines suggest offering Tx • Treatment Range (<350 CD4) • Strong evidence of benefit at this range • Danger Range (< 200 CD4) • Increased risk for opportunistic infections • Everyone should be on Rx at this point

  3. DHHS and IAS-USA: Recommendations for Initiation of ART in Naïve Patients Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008; Hammer SM, et al. JAMA 2008;300:555-570.

  4. Early Antiretroviral Treatment:Rationale • Immune injury is permanent; lost CD4s don’t come all the way back with Rx. • Growing evidence of inflammation as a complication of HIV; worse if we wait! • Treatment is prevention: every person on treatment means the “community viral load” is lower. • Vulnerable communities are already starting late: there are justice issues here! Smart to Start

  5. Improved CD4 Recovery When Starting with Higher CD4 Count CD4-count increases on sustained suppressive (<400 c/mL) ARV treatment (n=655) by baseline count >350 cells/mm3: CD4 counts return to near-normal levels ≤350 cells/mm3: CD4 counts significantly increased but plateau after 4 years below normal range Differences in CD4 counts associated with differences in morbidity and mortality 900 800 700 CD4 Count (cells/mm3) 600 500 400 <200 201–350 >350 300 200 100 Years After Starting HAART 0 0 1 2 3 4 5 6 Median CD4 Counts Over 6 YearsStratified by Baseline CD4 Count Moore RD, Keruly JC. Clin Infect Dis 2007;44:441-446.

  6. Treatment as Prevention: Uganda Study to evaluate effect of ART on HIV transmission among HIV serodiscordant couples (N=2,993) ART only if clinically indicated Negative partner tested q3 months Sexual risk assessed by Self report Sperm on vaginal smear Pregnancy Combined variable using any of above Sullivan P, et al. 16th CROI, Montreal, Canada, 2009. Abst. 52bLB.

  7. Sexual risk behaviors lower in those on ART (19% vs. 25%, P<0.05) Both ART and change in behavior independently reduced HIV transmission Treatment as Prevention: Results 2,993 couples were followed for a median of 512 days HIV-free Survival of HIV-negative partners,by ARV status of HIV+ Partner 1.0 0.8 CensoredLogrank P<.0001 0.6 Survival Probability 0.4 On ARV Off ARV 0.2 0.0 0 500 1000 1500 2000 2500 Days * Includes 2 partners who seroconverted in the same 3-month interval when the HIV-infected partner initiated ARVs Sullivan P, et al. 16th CROI, Montreal, Canada, 2009. Abst. 52bLB.

  8. Main Reason to Start Early?It Works!

  9. NA-ACCORD: Improved Survival When ART is Started with ≥350 CD4 North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) Regional collaboration of 22 HIV research cohorts from United States and Canada Study of HIV+ patients with: CD4 count 351-500 cells/mm3 Active follow-up between 1996 and 2006 Outcome: All-cause mortality Groups compared from same CD4 count level: Immediate treatment: Initiate ART within 1.5 yrs after 1st CD4 count between 351-500 cells/mm3 Deferred treatment: Do not initiate ART in this time frame Patient data censored if treatment not initiated within the 1.5 year interval after the target CD4 count for ART initiation Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b

  10. NA-ACCORD: Improved Survival When ART is Started When CD4 Count ≥500 cells/mm3 ARV-naïve; CD4 count >500 cells/mm3, no prior H/O AIDS-defining illness, follow-up between 1996 and 2006 All-cause mortality compared between immediate vs. deferred ART Immediate Group: Start ART with > 500 cells/mm3 Deferred Group: Start ART within 1.5 years of CD4 <500 Statistical analysis adjusted for baseline population differences 0.20 Defer HAART > 500 CD4 cells (N=6,539) Initiate HAART > 500 CD4 cells (N= 2,616) 0.15 Mortality 0.10 0.05 Relative Hazard of Deferral 1.6 (1.3,1.9; p<0.001) 0.00 0 2 4 6 8 10 Years after 1996 Kitahata M, et al. 16th CROI, Montreal, Canada, 2009. Abst. 71.

  11. NA-ACCORD • 22 cohorts, US/Canada (n=8000) • Started ART within 18 mo of CD4 350-500 vs deferred • Death RR • 1.7 for deferral of ART • 1.6 for older age • 70% increased risk death for deferred ART Kitahata M, et al. 16th CROI, Montreal, Canada, 2009. Abst. 71.

  12. 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.

  13. Rebuttal…or what I call“Come on, Kathleen!” Sung to the tune of “Come on, Eileen!” Apologies to Dexy’s Midnight Runners… And all of you who will have this song in your head for the rest of the day!

  14. Much Ado About NA-ACCORD?Are we really going to change everything for one observational study…

  15. Observational Studies Can Be Wrong Numerous epidemiological studies demonstrated women on hormone replacement therapy (HRT) had decrease in risk of coronary heart disease (CHD) HCPs recommend HRT as protection against CHD Randomized controlled trials demonstrated HRT caused small, but significant, increase in CHD risk Women on HRT more likely to be from socio-economic groups with better than average diet and exercise HRT use and decreased CHD risk were coincident effects of a common cause, rather than cause and effect Lawlor DA, et al. Intl J Epidemiol 2004;33:464-467.

  16. Early starters may be different in some unmeasured way that improves survival Controlled for Hepatitis C and IVDU What about depression? Motorcycle enthusiasm? Different levels of adherence as shown by viral suppression 81% in early start 71% in deferred start Cause of death only known for 16% And we don’t have data on levels of resistance and toxicities of early treatment in these cohorts… Why NA-ACCORD May Not Be the End All-Be All

  17. Guess what? NA-ACCORD Wasn’t the Only Game at CROI! Antiretroviral Therapy Cohort Collaboration (ART-CC) Collaboration of HIV cohort studies to estimate risk of deferring ART at different CD4 Count levels ARV-naïve patients (N=24,444) starting ART after 1997 with <550 cells/mm3 Patients with H/O AIDS or IDU excluded Rates of AIDS and death with immediate vs. deferred ART compared in adjacent CD4 ranges of 100 cells/mm3 Adjusted for lead-time and unseen events in final analysis Sterne J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 72LB.

  18. ART-CC: When Should ART be Started? Hazard ratios for AIDS or death, adjusted for lead time/unseen events Delaying ART to <350 (but not <375) cells/mm3 is associated with an increased risk of AIDS or death 4 2 Hazard Ratio for AIDS or Death 1 .5 500 400 300 200 100 0 CD4 Threshold (cells/mm3) Sterne J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 72LB.

  19. Public health benefit may not be as robust as advertised Undetectable blood viral loads does not mean undetectable semen viral load Benefit may be offset by risk compensation? Most transmissions occur early in disease and we will still miss this window And As For Treatment as Prevention… Marcelin AG, et al. 16th CROI, Montreal, Canada, 2009. Abst. 51. Sheth P, et al. 16th CROI, Montreal, Canada, 2009. Abst. 50. Katz MH, et al, Am J Public Health. 2002 Mar;92(3):388-394.

  20. Rates of HIV Transmission by Stage of HIV InfectionRates per Coital Act in Rakai, Uganda, 1994-1999 Transmission by Stage of Infection Study Design • Background - N = 235 Couples - Monogamous, HIV-discordant couples - Number of Coital Acts estimated by reported coital acts per month Wawer M, et al. J Infect Dis 2005;191:1403-9.

  21. Early ART: Small Gains and Big Risks…. Benefits • Small reduction in morbidity & mortality? Drawbacks • May treat non-progresors • Toxicities, known and unknown…. • Lifestyle changes • Adherence challenges • Resistance risk • Losing meds we may need later • Cost of meds and labs

  22. Natural History of Untreated HIV Infection Even if we help this person… Acute HIV Year 1

  23. Not One-Size-Fits-All: Variable CD4 Progression Are we really helping this one? Or this one? 1000 Acute HIV Infection 800 600 CD4 Cell Count 400 200 0 0 2 4 6 8 10 12 14 Year 1 Years

  24. Big Risks: Toxicities Known and Unknown

  25. Emerging Data on Long-Term Toxicities ABACAVIR TENOFOVIR WHO KNOWS?

  26. Lifestyle Changes

  27. Adherence “Drugs don’t work if people don’t take them.” - C. Everett Koop

  28. Frequency of Non-Adherence • 30% ART non-adherence • In one study, only 6% of patients took >=95% of their medications “Adherence to HIV Antiretroviral Therapy.” HIV InSite. www.hivinsite.ucsf.edu. Content updated January 2006.

  29. Poor Adherence Leads to Virologic Failure N = 81 Patients on Protease Inhibitor-Based RX Paterson Dl et al. Ann Intern Med 2000;133:21-30.

  30. 0 And Poor Adherence Also Leads to Resistance

  31. Transmitted Drug Resistance:Prevalence Among Newly Diagnosed Patients Shet & Markowitz, JAIDS 2006, 41(4): 439.

  32. And Where Are the New Drugs? • The embarrassment of riches may be coming to an end… • What happens when we use up all our drugs? • Then what?!?!?!?!?

  33. Is the Benefit Worth the Cost? For one year: • Truvada: $10,850 • Kaletra: $9,343 • Atripla: $1,8661 • 4 CD4 counts: $800 • 4 viral loads: $400 TOTAL: $40,054 What CAN’T We Afford? • Adherence counseling • Prevention counseling • Family planning • Nutrition • Stress reduction training • Mental health • Smoking cessation • Substance abuse treatment www.drugstore.com and www.thebody.com. Prices will vary depending on supplier.

  34. Who Benefits the Most?

  35. Rebuttals: Early Start is Smart • Time from CD4 500 to CD4 350 in untreated patients is median <3 years…small additional period of risk when Rx goes on for decades…. • Toxicities are treatable. • Cost is coming down as generics become available in next 5-10 years • People living longer all the time – treatment extends life!

  36. It’s a Short Hop from 350-500 CD4 Cells. Is this period significant in terms of toxicity when therapy goes on for decades? Mellors, J. W. et. al. Ann Intern Med 1997;126:946-954

  37. Patients on HAART Deaths per 100 PY HIV Treatment Saves Lives Mortality and HAART Use Across Time HIV Outpatient Study, CDC, 1994-2003 Palella et al, JAIDS 2006; 43:27. Bureaucratic Busywork

  38. Condoms for Life? – No Thanks • Longer lifespan for PWHIV*: Tx Initiated: Average Survival Gain: CD4= 87 15 yrs CD4= 310 24 yrs • Possibility of condom-free sex; incentive for medication adherence? *Walensky, RP Survival Benefits of AIDS Tx in the US. JID 2006; 194: 11

  39. Audience Vote Early ART? Or Late Start?

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