When to Start When to Stop? What to Start?

1. When to StartWhen to Stop?What to Start? Joseph J. Eron, Jr, MD Professor of Medicine Principal Investigator AIDS Clinical Trials Unit School of Medicine University of North Carolina at Chapel Hill Chapel Hill, NC

2. Benefits and Risks of Deferred ARV Therapy • Potential risks of deferred therapy • Potential for irreversible immune damage • Is immune recovery the same as immune preservation • Increased possibility of clinical progression • HIV related • Malignancy and cognitive disorder • Non-HIV clinical events. • Increased risk for HIV transmission • Potential benefits of deferred therapy • Avoidance of toxicity, improved quality of life • Preservation of future treatment options • Delayed development of drug resistance • Decreased total time on drug therapy • Increased time for patient education • More time for development of more potent, less toxic, and better studied combinations Adapted from DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006.

3. The Case for Earlier Initiation of Therapy • Availability of more potent, easier, and less toxic regimens • Cohort studies showing benefit with earlier therapy • Better response to therapy • Decreased transmission • Cost-effectiveness

4. The Case for Earlier Initiation of Therapy • Easier, more potent, and less toxic therapy

5. 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, Fath MJ, Demasi R, et al.  An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults. AIDS 2006;20:2051-64.

6. 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 count increase in later years • Most “failure” now 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 F, et al. CROI 2005. Abstract 593

7. Unadjusted and adjusted risk ratios of virological failure by year of starting cART 1999 is reference category. Unadjusted*=adjusted for cohort only; Adjusted 1#=adjusted for cohort, age, risk group, pre-HAART VL and CD4 count, previous AIDS; Adjusted 2$ =adjusted for all above factors plus starting regimen as defined by 3rd drug and nucleoside combination. Lampe et al, Arch Intern Med 2006;166:521-528

8. Cohort Data Improved outcomes with earlier antiretroviral therapy HIV and non-HIV clinical events associated with CD4 cell counts above 200

9. HAART and Survival Based on Initial CD4 Cell Count Cumulative Probability of AIDS/Death by CD4 Count at Initiation of ART • Modeled data from ART Cohort Collaborative • 10,855 pts, >61,000 person-years of F/U • 934 progressed to AIDS or died • IDUs excluded from model 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.

10. 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 HOPS Cohort: Early, Uninterrupted ARTAssociated with Improved Outcomes Incidence per 1,000 patient years by pre-HAART CD4 count and % time on HAART (n = 4,421) Opportunistic Infections Mortality 71.5 HAART < 95% of time HAART > 95% of time HAART < 95% of time HAART > 95% of time * 55.9 * P = 0.05 for difference by % HAART use * P = 0.05 for difference by % HAART use 47.8 37.8 38.5 Incidence per 1,000 Person-Years Incidence per 1,000 Person-Years * * * 26.1 25.5 22.3 21.4 20.1 16.2 15.9 14.2 * 11.5 10.4 * 7.5 7.3 7.2 5.4 2.4 0-49 50-199 200-349 350-499 500+ 0-49 50-199 200-349 350-499 500+ CD4 category CD4 category CD4 Cell Count Category Lichtenstein K, et al. CROI 2006. Abstract 769.

11. 900 800 700 600 CD4 cells/mm³ 500 400 300 200 100 0 0 Yr 1 Yr2 Yr3 Yr 4 Yr 5 Yr 6 Pre-HAART CD4 Predicts Progression to AIDS: Johns Hopkins Cohort • Johns Hopkins HIV Cohort • Patients with virologic suppression for up to 6 yrs (N=280) • Only patients with baseline CD4 >350 returned to near normal CD4 count levels • Rate of progression to AIDS or death significantly higher over time in patients with CD4 <200 and 201-350 vs. >350 1.5%*† 12%* 13%* *% developing AIDS over 6 years of study † P < .05 compared with CD4+ < 200 Moore RD, et al. IAC 2006. Abstract THPE0109.

12. Caveat • Remember Bias of Cohort Studies • Complex or non adherent patient may have therapy delayed • Bias by indication • Lead time bias

13. 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

14. RR of death according to immune function and specific cause 100 Overall HIV Malignancy Liver Heart RR 10 1.0 >500 <50 50–99 100–199 200–349 350–499 CD4 count 0.1 D:A:D Study: CD4 Count Associated with Risk of Non-HIV Related Death • >23,000 pts in Europe, Australia, USA • 1248 (5.3%) deaths 2000–2004 (1.6/100 person-years) • Of these, 82% on ART • Both HIV- and non–HIV-related mortality* associated with CD4 depletion *Liver-related: Chronic viral hepatitis, liver failure (other); malignancy-related: malignancy, non-AIDS hepatitis; heart-related: MI, other CVD, other heart disease Weber R et al. 12th CROI; 2005; Boston. Abstract 595.

15. CD4+T-cell Count Associated with Risk of AIDS and Non-AIDS-related Malignancies • Risk factors for fatal AIDS-defining malignancies (ADM) and non-ADM in the D:A:D study • Of 1246 deaths, 112 ADM and 193 non-ADM related • 4 most common non-ADM: lung, GI, hematologic, anal • Risk of ADM and non-ADM increased as CD4 cells decrease • Additional risk factors • ADM: Prior AIDS event (RR 2.43, P<0.0001) • Non-ADM: Older age (RR 1.53/5 years older, P<0.0001), current smoking (RR 2.42, P<0.0001), active HBV (RR 1.89, P=0.008) D’Arminio Monforte A et al. 14th CROI; 2007; Los Angeles. Abstract 84.

16. Malignancies and CD4+ T-cell Count D’Arminio Monforte A et al. 14th CROI; 2007; Los Angeles. Abstract 84.

17. CD4+ T-Cell and Risk of Clinical events Multivariate HR/100 CD4 Cell Increase* • Evaluation of impact of CD4+ count on OI and non-OI events • Compared latest CD4 count in FIRST study (n=1397) with risk • Median BL CD4 163 cells/uL, mean increase of 238 cells/uL • Median F/U 5 years • Higher latest CD4 associated with lower risk of OI and non-OIs • Tx strategies should minimize time spent at lower CD4 counts 1.2 1 1 0.92 0.83 0.81 0.78 0.76 0.8 0.58 Hazard Ratio 0.6 0.4 0.2 0 OI CV Liver Renal Non-OI Reference Malignancy P value <0.01 <0.01 0.06 0.40 0.08 <0.01 Baker J et al. 14th CROI; 2007; Los Angeles. Abstract 37. *Adjusted for: age, sex, race, prior AIDS, hepatitis B and C, baseline CD4 & RNA, and latest RNA

18. CASCADE: Sero-conversion Cohort • N=9,858; med. F/U 8 yrs post-seroconversion • 597 deaths, >50% non-AIDS-related • Current & nadir CD4 and time with CD4 <350 assoc. with: • AIDS deaths • Non-AIDS deaths: Infections, liver disease, malignancy Marin B, et al.Sydney 2007, #WEPEB019

19. Randomized Studies There are none!

20. SMART1 Subset: 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 ARV >5-fold increased risk with deferred ARV 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 Clinical Trial Data Supporting Earlier Therapy Composite endpoint1 Deferred ART Immediate ART 1. Emery S, et al.4th IAS, Sydney 2007, #WEPEB018;

21. Early Therapy Greater Toxicity? Greater Resistance?

22. Risk of Fat Loss/Accumulation with NRTIs + PIs Increases with Time on ARVs Kaplan-Meier Curve Showing Progression to Any Lipodystrophy • Prospective study of 494 ARV-naïve patients starting HAART (Oct ’96-Sept ’99) • 85 subjects (17%) developed fat changes after median of 18 mo. • 21% central obesity • 34% subcutaneous lipoatrophy • 45% mixed • 11.7 cases per 100 person-years • Associated laboratory changes* • CD4 cell count  • Plasma HIV RNA  • Triglyceride level  • Cholesterol level  Any lipodystrophy Lipodystrophy with subcutaneous lipoatrophy Lipodystrophy with central obesity 25 20 15 % of patients 10 5 0 0 6 12 18 24 Time since starting HAART (months) Numbers at risk494 433 333 246136 Martinez E et al. Lancet. 2001;357:592-598. *All P values 0.001.

23. Incidence of Myocardial Infarction Increases with Duration of Combination ART (D:A:D Study) 8 7 6 5 Incidence per 1000 Person-Years 4 3 2 1 0 Exposure (y):None<1 1-22-33-4 >4 Relative Risk:0.24 1.0 1.341.731.982.55 No. of events3914223147 No. of person-y 571441404801584772208477 Friis-Møller N et al. N Engl J Med. 2003;349:1993-2003.

24. Relative Rate of MI according to NNRTIExposure(adjusted for PI exposure) Adjusted RR* per year of NNRTI: 1.05 [0.98-1.13] • : Adjusted for sex, age, cohort, calendar year, prior CVD, family history of CVD, smoking, body-mass index, PI exposure Friis-Moller et al, CROI 2006, oral 144

25. HOPS: More Toxicity with Later Initiation of Therapy • More NRTI toxicity (anemia, neuropathy, renal insufficiency) with initiation of ART at lower CD4 counts Lichtenstein CROI 2005

26. UNC CFAR DB Triple Class Resistance

27. Triple-class antiretroviral drug resistance (TC-DR) incidence rates (cases/1000 person-years) stratified by first HAART regimen TCDR=4 N=34 PY=176 TCDR=15 N=184 PY=756 Incidence rate of TC-DR (cases/1000 PY) TCDR=2 N=65 PY=316 TCDR=2 N=110 PY=659 TCDR=1 N=227 PY=713 TCDR=0 N=53 PY=244 TCDR=0 N=116 PY=258 EFV PI/r NFV PI/NNRTI NVP DLV IDV PI First HAART regimen

28. Major mutations 50% less likely in pts starting with CD4 >350 vs <200, despite greater treatment exposure p=0.076 p=0.007 p=0.051 p=0.103 60 50 Patients (%) 40 30 20 10 0 Any mutation (n=78) NRTI mut. among NRTI-exp (n=77) NNRTI mut. among NNRTI-exp (n=37) PI mut. among PI-exp (n=48) 0-199 cells/mm3 200-349 cells/mm3 >350 cells/mm3 HOPS: More Resistance with Later Initiation of Therapy GT mutations and virologic failure Uy JP, et al. 4th IAS, Sydney 2007, #WEPEB017

29. Transmission

30. HIV RNA Level Affects Probabilityof HIV Transmission 5 No GUD GUD 4.5 4 3.5 3 Probability of Transmission/1000 Coital Acts 2.5 2 1.5 1 .5 0 <1700 1700- 12,500- 38,500+ GUD Log Viral Load (c/mL) GUD = genital ulcer disease. Gray R, et al. Lancet. 2001;357:1149-1153.

31. ART-Induced Reduction in Plasma HIV RNA Associated with Decreased Levels in Semen Controls (drug naive) n=55 Effective ART n=114 100 P<0.0001 80 60 P=0.01 detectable HIV in semen Patients (%) with 40 20 0 HIV-RNA HIV-DNA Vernazza PL et al. AIDS. 2000;14:117-121.

32. The Impact of ART on HIV Transmission Among HIV Serodiscordant Couples • ART offered in Kigali, Rwanda since 2003 • 1034 serodiscordant couples followed • 248 “index cases” receiving ART (CD4<200) • In spite of counseling, 42 seroconversions • Only 2/42 seroconversions with partner on ART • HIV-negative individuals whose partners are on ART are less likely to seroconvert compared with those whose partners are not on ART(OR = 0.19; 95% CI:0.05-0.80) Kayitenkore K et al. XVI IAC; 2006; Toronto. Abstract MOKC101.

33. Current DHHS Guidelines for Initiating ART: Chronic Infection

34. Indications for HAARTRegardless of CD4 Cell count • HBV co-infection that requires therapy • Entecavir not longer an option • HIV Associated Nephropathy • Pregnancy • Discordant couples? • Perhaps if fully informed

35. DHHS Guidelines

36. Maintain higher CD4; prevent irreversible immune system damage Decrease risk of HIV-associated complications eg, TB, NHL, KS, peripheral neuropathy, HPV-associated malignancies, HIV-associated cognitive impairment Decrease risk of nonopportunistic conditions and non-AIDS associated conditions eg, CV, renal, and liver disease; malignancies; infections Decrease risk of HIV transmission Potential Benefits of Early Therapy (CD4 >350 cells/mm³)

37. ARV-related side effects and toxicities Drug resistance (due to ART failure) Inadequate time to learn about HIV, treatment, and adherence Increase in total time on ART; greater chance of treatment fatigue Current ART may be less effective or more toxic than future therapies Transmission of ARV-resistant virus, if incomplete virologic suppression Potential Risks of Early Therapy (CD4 >350 cells/mm³)

38. Once Treatment is Started, Can We Stop?

39. Continuous antiretroviral therapy throughout follow-up* (n = 2752) ART stopped/deferred† until CD4+ <250 cells/mm3 then started to increase CD4+ to >350 cells/mm3 (n = 2720) Consequences of Stopping ART: SMART Trial HIV-1-infected patients with CD4+ cell count > 350 cells/mm3 (N = 5472) 95.4% treatment experienced El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296. *Mean follow-up 16 months †The protocol also permitted antiretroviral therapy to be initiated/reinitiated if symptoms of disease from HIV infection developed or the percentage of CD4+ lymphocytes (CD4+ percentage) was less than 15%.

40. SMART: Primary Endpoint and Components #Pts w/ Events Relative Risk (95% CI) Endpoints Death from any cause or Opportunistic Disease 167 2.6 1.8 Death from any cause 85 6.6 Serious opportunistic disease 15 1.7 Severe Complications* 104 0.1 1 10 Favors VS ► (viral suppression) ► Favors DC (drug conservation) *CVD, Renal, Hepatic Events (fatal/nonfatal) El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.

41. N= 5472; randomized trial comparing continuous treatment (VS) to “STI” arm (DC): Stop meds CD4 >350 Restart CD4 <250 Trial halted Jan 2006 2.63 greater risk of OI/death in DC versus VS arm Greater risk of DC strategy explained by: Lower CD4 count Higher viral load at higher CD4 counts Implications for “When to Start?” SMART: Why Did the “STI” Arm Have More Clinical Progression? Event Risk by Time Updated CD4 Count1 OI/Death by Arm During Study (%) Time Spent at Different CD4 Strata2 31.7 Follow-Up Time (%) 8.2 7.2 1.7 3.1 0.8 VS Group DC Group 1. Lundgren J, et al. Presented at: XVI IAC; August 13-18, 2006;Toronto, Canada. Abstract WEAB 0203; 2. El Sadr W, et al. Presented at: XVI IAC; August 13-18, 2006;Toronto, Canada. Abstract WEAB0204.

42. Trivacan Study • Treatment Naïve patients in Abidjan • Randomized to continuous ARV treatment or CD4 guided interruption or timed interruption of therapy • Therapy held for CD4 > 350 and resumed when CD4 < 250 • CD4 guided arm stopped on DSMB review • 110 received continuous treatment • 216 received CD4 guided therapy Lancet. 2006 Jun 17;367(9527):1981-9

43. Trivacan: Time to severe Morbidity or Death

44. Trivacan Study Continuous CD4 guided

45. What to Start With?

46. Initial Treatment: Preferred Components *Avoid in pregnant women and women with significant pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa. NNRTI Option NRTI Options • Tenofovir + emtricitabine** • Zidovudine + lamivudine** OR + PI Options

47. Initial Treatment: Alternative Components *Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts >400 cells/mm³ **Atazanavir must be boosted with ritonavir if used in combination with tenofovir NNRTI Option NRTI Options • Abacavir + lamivudine • Didanosine + (emtricitabine or lamivudine) OR PI Options

48. Initial Treatment: Other Possible Options ARV drugs or regimens Rationale These are considered acceptable but inferior to preferred or alternative components. They may be used in special circumstances. *Should not be given to pregnant women.

49. ARVs Not Recommended in Initial Treatment (1)

50. ARVs Not Recommended in Initial Treatment (2)