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

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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 Decisions
The Setpoint Study (ACTG 5217)
‐change in virologic setpoint
Hogan et al, JID 2011
Spartac: The effect of short‐course ART in PHI
– time to CD4<350
Fidler et al, NEJM 2013
Enhanced 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 36‐72
ART‐naïve through week 36
adults with Step 1
early HIV‐1 Eligible for Step 2 (ART)
infection N = 150
randomized to No Treatment
IT or DT
(DT Arm) x 72 weeks
Primary 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%)
a
CD4 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%)
a
HIV‐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 Sites
Univ 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 Fidler
for 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 ART
1/18/13

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
124 120 123
1/18/13

20. Baseline demographics
SOC ART‐12 ART‐48 Total
Sex
male 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 factor
MSM 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=0.01
Probability 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‐12
1/18/13

24. 1/18/13

25. 1/18/13

26. Hypothesis
There is a critical time period following
acute HIV infection during which ART is
capable of restoring ‘normal’ immune
function.
1/18/13

27. Evaluate and Define the Optimal “Restorative
Window” 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‐ 1055‐1100
American 1095) 1100)
Combo 25 (15118) 1017 (948‐ 993 (839‐ 771‐1109
1085) 1036)
1/18/13

29. Study Sets and Inclusion Criteria
1/18/13

30. Characteristics of Participants: Set 1
Variable Total P value*
No. of subjects 384
Male 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 2
Variable Total ≤4 Mo. of >4 Mo. of P
EDI EDI value*
No. of subjects 213 97 116
Male sex—no. (%) 202 (94.8) 93 (95.9) 109 (94.0) 0.53
EU‐American—no. (%) 172 (80.8) 87 (89.7) 85 (73.3) 0.01
Age at EDI—yrs 35 (29‐41) 36 (30‐42) 34 (27‐41) 0.08
Time from EDI to study 10.0 (8.0‐ 10.0 (2.2‐ 12.7 (10.0‐ <0.001
entry — 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 0.44
to 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 ART
1/18/13

33. Viral load trajectories in study sets 1 and 2

34. Rate of Recovery of CD4+ T‐Cell Counts after Initiation of ART
1/18/13

35. Likelihood and Rate of CD4 Recovery to ≥900 cells/mm3
within 48 Months after Starting ART
Predictive 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 ART
initiation
Model 2: Time from EDI to ART 0.90 (0.85–0.96) 0.001 0.92 (0.88–0.96) <0.001
initiation — each increase
of 1 mo
Model 3: Time from EDI to ART 0.35 (0.17–0.71) 0.004 0.44 (0.29–0.67) <0.001
initiation — >4 mo vs. ≤4 mo
Model 4: Initiation of ART ≤4 mo,
>4–12 mo, or >12 mo
after 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) <0.001
1/18/13

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