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HIV Infection: When to Start ART – Revisited…Again

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Susan J. Little, MD (UC San Diego Antiviral Research Center) presents "HIV Infection: When to Start ART – Revisited…Again"

Susan J. Little, MD (UC San Diego Antiviral Research Center) presents "HIV Infection: When to Start ART – Revisited…Again"

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  • 1. AIDS CLINICAL ROUNDSThe UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.
  • 2. HIV Infection:When to Start ART – Revisited…Again Susan Little, M.D. Professor of Medicine University of California San Diego 1/18/13
  • 3. Guidelines for Initiation of ART CD4  Panel AIDS/Sx CD4 350‐500 CD4 >500 AHI <350 DHHS ‘l2 YES YES YES YES Consider IAS‐USA ‘12 YES YES YES YES YES UK ‘12 YES  YES  Conditional Conditional Conditional EACS ‘11 YES YES Consider§ Defer§ Consider WHO ‘12 YES YES NO* NO* ND§Provide if symptomatic w/CDC B or C Conditions, HBV needing Tx 1/18/13*Yes for discordant couples (continue for life) and pregnant women    ND=No Data
  • 4. Guidelines for Initiation of ART CD4  Panel AIDS/Sx CD4 350‐500 CD4 >500 AHI <350 DHHS ‘l2 YES YES YES YES Consider IAS‐USA ‘12 YES YES YES YES YES UK ‘12 YES  YES  Conditional Conditional Conditional EACS ‘11 YES YES Consider§ Defer§ Consider WHO ‘12 YES YES NO* NO* ND§Provide if symptomatic w/CDC B or C Conditions, HBV needing Tx 1/18/13*Yes for discordant couples (continue for life) and pregnant women    ND=No Data
  • 5. When to Start ART: Issues Preserving Normalizing immunologic function Minimizing HIV-associated AE Reducing HIV Transmission Improving potential responses to “cure” strategies 1/18/13
  • 6. Data to Inform ART DecisionsThe Setpoint Study (ACTG 5217) ‐change in virologic setpoint Hogan et al, JID 2011Spartac: The effect of short‐course ART in PHI – time to CD4<350 Fidler et al, NEJM 2013Enhanced CD4 Recovery with Earlier ART – normalization of CD4 Le et al, NEJM 2013 1/18/13
  • 7. 1/18/13
  • 8. ACTG 5217 Hypothesis:  36 weeks of ART given to subjects within 6 months of acquiring HIV-1 infection will lower the virologic setpoint after treatment discontinuation as compared to subjects who do not receive ART Inclusion:  ART Naïve adults with early HIV infection (by detuned EIA or serial tests).  CD4+ T cell count > 350 cells/mm3 and > 14% Multi-site study:  Eligible patients randomized to immediate treatment (IT) for 36 wks or delayed treatment (DT) until specified criteria reached for treatment initiation.  CD4 (initially 350, then 500), VL (200k), or clinical disease progression 1/18/13
  • 9. Study Design Treatment (IT Arm) Off Treatment TDF + FTC + LPV/r*  week 36‐72ART‐naïve  through week 36 adults with  Step 1early HIV‐1  Eligible for Step 2 (ART)infection  N = 150randomized to  No TreatmentIT or DT (DT Arm) x 72 weeksPrimary Endpoints:  Log10HIV‐1 RNA at Wk 72 (IT/DT arms) and Wk 36 (DT arm) *88% chose provided regimen – alternatives allowed 1/18/13
  • 10. Baseline Characteristics All subjects IT  DT (n=130) (n=66)  (n=64) Sex Male 117 (90%) 58 (88%) 59 (92%)Age (years) Median (Q1, Q3) 33.0 (26.0, 42.0) 34.0 (25.0, 40.0) 33.0 (27.0, 42.0)Race White 105 (81%) 49 (74%) 56 (88%) Black/African American 13 (10%) 10 (15%) 3 (5%) Other/unknown 12 (9%) 7 (11%) 5 (8%)Ethnicity Hispanic or Latino 23 (18%) 14 (21%) 9 (14%) Not Hispanic or Latino 107 (82%) 52 (79%) 55 (86%) aCD4 Count  Median (Q1, Q3) 540 (435, 697) 514 (415, 671) 557 (441, 721) 201‐350 6 (5%) 4 (6%) 2 (3%) 351‐500 50 (38%) 26 (39%) 24 (38%) >500 74 (57%) 36 (55%) 38 (59%) aHIV‐1 RNA  Median (Q1, Q3) 4.4 (4.0, 4.7) 4.4 (3.9, 4.8) 4.4 (4.0, 4.7)a Baseline CD4 cell count (cells/mm3) and baseline HIV‐1 RNA (log10 c/mL) were the values at study entry 1/18/13
  • 11. Time to Meeting Criteria for Initiation/Reinitiation of ART 1/18/13
  • 12. Time to Meeting ART Eligibility Criteria Starting at Wk 36 (IT) vs. Wk 0 (DT) 16 wks delay 1/18/13
  • 13. Setpoint Change? RNA Values IT (26) DT (22) Change in RNA wk 0-36 NA 0.07 (0.09) Change in RNA wk 0-72 -0.29 (0.16) 0.01 (0.17 Higher VL in DT group than IT group (4.37 log10 copies/mL vs 3.99 log10 copies/mL) Interpret with caution, given overlapping confidence intervals 1/18/13
  • 14. Conclusions Progression to meeting criteria for initiation of ART occurred more rapidly than anticipated, limiting our ability to evaluate HIV-1 RNA levels at study endpoint Limited period of ART during early HIV-1 infection modestly delayed the need for subsequent initiation of ART Time between diagnosis of early HIV-1 infection and need for initiation of long-term ART was shorter than anticipated Future attempts to randomize recently infected patients to delayed therapy should consider the potential risk of early disease progression among untreated patients 1/18/13
  • 15. Acknowledgements A5217 Study Team Christine Hogan MD  Carlos Del Rio MD • Tia Frazier RN MS Susan Little MD  C. Bradley Hare MD • Beatrice Kallungal BS Victor DeGruttola ScD  Rick Hecht MD • Mark Byroads BA Xin Sun MS  Donna Mildvan MD • Kenneth Wood MEd Eric Daar MD  Karen Tashima MD • David Currin RN Martin Markowitz MD  Renard Descallar • Rob Camp Susan Fiscus PhD  Jim Rooney MD • Lori Kryspin BS MT • Ana I. Martinez RPh Charles Rinaldo PhD  Roula Qaqish PharmD • Lawrence Fox MD PhD A5217 Study SitesUniv of Colorado,  Aaron Diamond AIDS Research Ctr, Ohio State, UCSD, Miriam Hospital Rhode Island, Univ of Washington, Univ of WA Primary Infection,  Washington Univ, Univ of Pennsylvania, Univ of Miami, Northwestern Univ, Moses Cone Hospital Greensboro, Rush Presbyterian/St. Luke’s, Harbor‐UCLA, Univ of North Carolina, Investigaciones Medicas en Salud (INMENS), Univ of Rochester, Mass General Hospital, Columbia Univ, UCSF, Asociacion Civil Impacta Salud Y Educacion, Indiana Univ, Beth Israel Medical Center‐NY, Brigham and Women’s Hospital, Community Health Network Inc., Univ of Maryland, Emory Univ DAIDS Abbott Laboratories & Gilead Sciences Study Participants
  • 16. Sarah Fidlerfor SPARTAC Trial Investigators  Imperial College, London, UK 1/18/13
  • 17. Primary Objective• To determine the effect of two short course  ART schedules of different durations  compared with no immediate ART in Primary  HIV infection on time to CD4 <350 or initiation  of long‐term ART1/18/13
  • 18. Trial Design• Definition of PHI – laboratory evidence of infection within 6 months of a previous negative test, <3  bands WB, Recent Infection Testing Algorithm (RITA) incident, antibody negative  PCR+ • Randomization to one of three arms: – 48‐week short course ART (ART‐48) – 12‐week short course ART (ART‐12) – No therapy (Standard of Care SOC)• Primary end point  – time to CD4 <350 cells/mm3 or long‐term ART initiation• Sample size – 360 providing 90% power to detect relative reduction in risk of time to CD4  <350 cells/mm3 of 50% and 25% in ART‐48 and ART‐12 compared to SOC 1/18/13 respectively over an average follow‐up of 4 years
  • 19. Enrolment & Exclusions SCREENED 429 58 EXCLUDED 15 not PHI 19 protocol exclusions 24 other reasons RANDOMIZED 371 SOC ART-12 ART-48 124 123 124 5 EXCLUDED 2 not equivocal 1 HIV-neg>8 months 1 remained HIV-neg 1 randomization error SOC ART-12 ART-48 124 120 1231/18/13
  • 20. Baseline demographics SOC ART‐12 ART‐48 TotalSexmale 74 (60%) 71 (59%) 74 (60%) 219 (60%)female 49 (40%) 49  (41%) 49 (40%) 147 (40%)Age median (IQR) 31 (25,39) 32 (24,39) 33 (26,41) 32 (25,40)Predominant risk factorMSM 72 (59%) 64 (53%) 69 (56%) 205 (56%)WSM 50 (41%) 55 (46%) 53 (43%) 158 (43%)not known 1 (1%) 1 (1%) 1 (1%) 3 (1%)CD4 median (IQR) 543 (404,715) 519 (433,638) 605 (463,750) 559 (435,700)Viral Load mean log10 (IQR log10) 4.70 (3.68,5.24) 4.39 (3.59,5.18) 4.43 (3.81,5.13) 4.53 (3.67,5.18)Estimated duration of infection at  11 (8,15) 12 (9,15) 12 (9,15) 12 (9,15)randomisation (weeks) mean (IQR)Subtype B 70 (57%) 67 (56%) 71 (58%) 208 (57%)Subtype C 40 (33%) 40 (34%) 40 (33%) 120 (33%)Subtype Other 13 (11%) 12 (10%) 11 (9%) 36 (10%)Baseline Resistance Any 8 (7%) 5 (4%) 8 (7%) 21 (6%) NRTI 5 2 6 13 NNRTI 5 3 3 11 PI 1 0 1 2 Median (IQR) follow up 4.2 years (3.5‐7.2 years) with 13% lost to follow‐up  91% Combivir + Kaletra
  • 21. Time to primary endpoint 1.00 48‐wk ART HR 0.63  (0.45,0.90), p=0.01Probability of not reaching 0.75 primary endpoint SOC 0.50 12‐wk ART HR 0.93  (0.67,1.29), p=0.67 0.25 0.00 0 .5 1 1.5 2 2.5 3 3.5 4 4.5 Time (years) SOC 123 109 93 82 75 66 59 46 30 18 ART‐12 120 110 95 84 79 71 63 49 32 21 ART‐48 123 121 117 109 100 88 80 63 41 19
  • 22. Time to CD4<350• Relative to time between seroconversion and  randomization: ARM ≤12 Week Interval >12 Week Interval 48‐week ART 218 weeks 229 weeks* 12‐week ART 181 weeks 185 weeks SOC 126 weeks 213 weeks• 48‐wk ART vs. SOC ≤12 wk interval associated with HR=0.48  [0.30, 0.78] p=0.003• *Post hoc analyses showed greater benefit of 48‐week ART,  the sooner treatment started after seroconversion (P =  0.09)
  • 23. Conclusions • ART‐48 associated with a significant delay in time to CD4 <350 or  long‐term ART initiation, although the actual delay may not have  been any longer than the time spent on treatment – Overall this effect was greater when ART‐48 was started closer to the time of  HIV infection. (p=0.09) • Compared to standard of Care – ART‐48 associated with significant reduction in viral set point of HIV RNA of  0.44 (0.25,0.64) log10 copies/ml sustained to 60 weeks after stopping therapy  – ART‐48  conferred a higher average CD4 count of 138 cells over 4.5 years • Interruption of ART in PHI had no evidence of harm; development of  drug resistance, or CD4 recovery after starting long‐term ART • No evidence of a benefit of ART‐121/18/13
  • 24. 1/18/13
  • 25. 1/18/13
  • 26. HypothesisThere is a critical time period followingacute HIV infection during which ART iscapable of restoring ‘normal’ immunefunction. 1/18/13
  • 27. Evaluate and Define the Optimal “RestorativeWindow” for Immune Recovery Prospective, observational study (’96 -’10) in San Diego, California 468 ART-naïve, recently HIV-infected persons Evaluated CD4+ count trajectories x 48 mo.  Naïve and ART-Tx’d patients  “Normal” CD4 defined as 900 cells/mm3* ART generally unrestricted*Defined from analysis of 34 studies in HIV neg persons 1/18/13
  • 28. CD4+ Counts in Seronegative  Caucasians and African Americans Summary Statistics for CD4+ counts No. of study  CD4+ T‐Cell Counts (cells/mm3) Population groups (No.  Weighted  Median (IQR) Range of subjects) Mean (95% CI)European 17 (10937) 1012 (949‐ 940 (834‐ 796‐1109 1074) 1020)Mixed USA 6 (3175) 1014 (910‐ 1015 (839‐ 771‐1075 1118) 1036)African  2 (1006) 1077 (1059‐ 1078 (1055‐ 1055‐1100American 1095) 1100)Combo 25 (15118) 1017 (948‐ 993 (839‐ 771‐1109 1085) 1036)1/18/13
  • 29. Study Sets and Inclusion Criteria1/18/13
  • 30. Characteristics of Participants: Set 1 Variable Total P value*No. of subjects 384Male sex — no. (%) 373 (97.1)EU‐American — no. (%) 299 (77.9)Age at EDI — yr  33 (27‐40)Time from EDI to study entry — wk 10.0 (8.4‐13.2)Length of untreated follow‐up — mo 7.7 (3.5‐21.6)VL at study entry – log10 copies/ml 4.92 (4.12‐5.61)CD4+ count at study entry — cells/mm3 495 (383‐622)Time from EDI to peak CD4+ — mo 3.5 (2.6‐5.2)CD4+ count at peak — cells/mm3 763 (573‐987)CD4+ Δ between peak and study entry — 234 (95‐437) <0.001 cells/mm3 1/18/13
  • 31. Characteristics of Participants: Set 2Variable Total ≤4 Mo. of  >4 Mo. of  P  EDI EDI value*No. of subjects 213 97 116Male sex—no. (%)  202 (94.8) 93 (95.9) 109 (94.0) 0.53EU‐American—no. (%) 172 (80.8) 87 (89.7) 85 (73.3) 0.01Age at EDI—yrs 35 (29‐41) 36 (30‐42) 34 (27‐41) 0.08Time from EDI to study  10.0 (8.0‐ 10.0 (2.2‐ 12.7 (10.0‐ <0.001entry — wk 13.6) 10.0) 19.0)CD4+ count at ART‐start 451  504 (378‐ 386 (281‐ <0.001 (336‐612) 720) 554)VL at ART‐start 4.95 (4.55‐ 5.20 (4.67‐ 4.82 (4.45‐ <0.001 5.48) 5.82) 5.23)Time (mo) from ART‐start  3.9  4.0  3.7  0.44to VL suppression (2.3‐5.6) (2.3‐5.7) (2.4‐5.4) 1/18/13
  • 32. Trajectories of CD4+ T‐Cell Counts before and after Initiation of ART1/18/13
  • 33. Viral load trajectories in study sets 1 and 2
  • 34. Rate of Recovery of CD4+ T‐Cell Counts after Initiation of ART1/18/13
  • 35. Likelihood and Rate of CD4 Recovery to ≥900 cells/mm3  within 48 Months after Starting ARTPredictive Factor Odds Ratio P Value Rate Ratio P Value (95% CI) (95% CI)Model 1: CD4+ count — <500 vs.  0.07 (0.04–0.15)  <0.001 0.17 (0.11–0.26) <0.001≥500 cells/mm3 at ARTinitiationModel 2: Time from EDI to ART  0.90 (0.85–0.96) 0.001 0.92 (0.88–0.96) <0.001initiation — each increaseof 1 moModel 3: Time from EDI to ART  0.35 (0.17–0.71) 0.004 0.44 (0.29–0.67) <0.001initiation — >4 mo vs. ≤4 moModel 4: Initiation of ART ≤4 mo, >4–12 mo, or >12 moafter EDI >4–12 mo vs. ≤4 mo 0.48 (0.21–1.06) 0.07 0.52 (0.33–0.83) 0.007 >12 mo vs. ≤4 mo 0.21 (0.08–0.55) 0.002 0.32 (0.17–0.61) <0.0011/18/13
  • 36. Conclusions There is a critical time-window (i.e., a ‘restorative time window’) for CD4 recovery post-ART - that is independent of the CD4 at ART initiation. The probability of attaining a CD4 >900 on ART was greatest for those who started ART within 4 months of EDI. Each additional month delay in ART reduced probability of achieving a CD4 > 900 by approximately 10%. 94% Reduced likelihood of achieving CD4>900 if CD4<500 cells/mm3 at ART initiation, independent of EDI Less than 25 % of the ART-naïve patients maintained CD4≥500 beyond 12 months 1/18/13
  • 37. Summary All three studies support immediate therapy of recently infected persons All studies suggest a time-sensitive window during which maximal benefits of ART may be recognized.  Recovery of the immune system as measured by ‘normal CD4 cell counts’ is most likely if ART is started within months of AHI These studies highlight the importance of diagnostic screening methods that allow identification of acute HIV infection. Studies are needed to evaluate the public health implications of widespread, immediate ART provided to persons with AHI 1/18/13