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AIDS CLINICAL ROUNDS

Susan Little, M.D.Professor of Medicine

University of California San Diego

HIV Infection: When to Start ART – Revisited…Again

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Guidelines for Initiation of ART

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Panel AIDS/Sx CD4 <350 CD4 350‐500 CD4 >500 AHI

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*Yes for discordant couples (continue for life) and pregnant women    ND=No Data

Guidelines for Initiation of ART

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Panel AIDS/Sx CD4 <350 CD4 350‐500 CD4 >500 AHI

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*Yes for discordant couples (continue for life) and pregnant women    ND=No Data

When to Start ART: Issues

Preserving Normalizing immunologic functionMinimizing HIV-associated AEReducing HIV TransmissionImproving potential responses to “cure”

strategies

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Data to Inform ART Decisions

TheSetpointStudy(ACTG5217)‐changeinvirologicsetpoint

Hoganetal,JID2011

Spartac:Theeffectofshort‐courseARTinPHI– timetoCD4<350

Fidler etal,NEJM2013

EnhancedCD4RecoverywithEarlierART– normalizationofCD4

Leetal,NEJM2013

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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

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Step 1

N = 150

TreatmentTDF + FTC + LPV/r* 

through week 36 

No Treatmentx 72 weeks

*88% chose provided regimen – alternatives allowed

(IT Arm)

(DT Arm)

Study Design

Primary Endpoints:  Log10HIV‐1 RNA at Wk 72 (IT/DT arms) and Wk 36 (DT arm)

Eligible for Step 2 (ART)

ART‐naïve adults with early HIV‐1 infection randomized to IT or DT

Off Treatmentweek 36‐72

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Baseline Characteristics

All subjects(n=130)

IT 

(n=66) 

DT

(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%)

CD4 Count a 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%)

HIV‐1 RNA a 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

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Time to Meeting Criteria for Initiation/Reinitiation of ART

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Time to Meeting ART Eligibility Criteria Starting at Wk 36 (IT) vs. Wk 0 (DT)16 wks delay

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Setpoint Change?

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

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

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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

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Acknowledgements

Christine Hogan MD

Susan Little MD

Victor DeGruttola ScD

Xin Sun MS

Eric Daar MD

Martin Markowitz MD

Susan Fiscus PhD

Charles Rinaldo PhD

Carlos Del Rio MD

C. Bradley Hare MD

Rick Hecht MD

Donna Mildvan MD

Karen Tashima MD

Renard Descallar

Jim Rooney MD

Roula Qaqish PharmD

Abbott Laboratories & Gilead Sciences

Study Participants

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

• Tia Frazier RN MS• Beatrice Kallungal BS• Mark Byroads BA• Kenneth Wood MEd• David Currin RN• Rob Camp• Lori Kryspin BS MT• Ana I. Martinez RPh• Lawrence Fox MD PhD

A5217 Study Team

A5217 Study Sites

DAIDS

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Sarah Fidlerfor SPARTAC Trial Investigators Imperial College, London, UK

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

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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 respectively over an average follow‐up of 4 years1/18/13

Enrolment & Exclusions

SCREENED429

RANDOMIZED371

SOC124

ART-12123

ART-48124

SOC124

ART-12120

ART-48123

58 EXCLUDED15 not PHI

19 protocol exclusions24 other reasons

5 EXCLUDED2 not equivocal

1 HIV-neg>8 months1 remained HIV-neg

1 randomization error

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Baseline demographics

SOC ART‐12 ART‐48 TotalSexmalefemale

7449

(60%)(40%)

7149 

(59%)(41%)

7449

(60%)(40%)

219147

(60%)(40%)

Age median (IQR) 31 (25,39) 32 (24,39) 33 (26,41) 32 (25,40)Predominant risk factorMSMWSMnot known

72501

(59%)(41%)(1%)

64551

(53%)(46%)(1%)

69531

(56%)(43%)(1%)

2051583

(56%)(43%)(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 randomisation (weeks) mean (IQR) 11 (8,15) 12 (9,15) 12 (9,15) 12 (9,15)

Subtype BSubtype CSubtype Other

704013

(57%)(33%)(11%)

674012

(56%)(34%)(10%)

714011

(58%)(33%)(9%)

20812036

(57%)(33%)(10%)

Baseline ResistanceAnyNRTI

NNRTIPI

8551

(7%) 5230

(4%) 8631

(7%) 2113112

(6%)

Median (IQR) follow up 4.2 years (3.5‐7.2 years) with 13% lost to follow‐up 91% Combivir + Kaletra

Time to primary endpoint

123 121 117 109 100 88 80 63 41 19ART‐48120 110 95 84 79 71 63 49 32 21ART‐12123 109 93 82 75 66 59 46 30 18SOC

0.00

0.25

0.50

0.75

1.00

Prob

ability of n

ot re

aching

prim

ary en

dpoint

0 .5 1 1.5 2 2.5 3 3.5 4 4.5Time (years)

48‐wk ART HR 0.63 (0.45,0.90), p=0.01

12‐wk ART HR 0.93 (0.67,1.29), p=0.67

SOC

Time to CD4<350

• Relative to time between seroconversion and randomization:

• 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)

ARM ≤12 Week Interval >12 Week Interval48‐week ART 218 weeks 229 weeks*12‐week ART 181 weeks 185 weeksSOC 126 weeks 213 weeks

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

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Hypothesis

There is a critical time period following acute HIV infection during which ART is capable of restoring ‘normal’ immune function.

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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 personsEvaluated 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 persons1/18/13

CD4+ Counts in Seronegative Caucasians and African Americans 

Summary Statistics for CD4+ counts

PopulationNo. of study groups (No. of subjects)

CD4+ T‐Cell Counts (cells/mm3)Weighted 

Mean (95% CI) Median (IQR) Range

European 17 (10937) 1012 (949‐1074)

940 (834‐1020)

796‐1109

Mixed USA 6 (3175) 1014 (910‐1118)

1015 (839‐1036)

771‐1075

African American

2 (1006) 1077 (1059‐1095)

1078 (1055‐1100)

1055‐1100

Combo 25 (15118) 1017 (948‐1085)

993 (839‐1036)

771‐1109

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Study Sets and Inclusion Criteria

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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 —cells/mm3

234 (95‐437) <0.001 

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Characteristics of Participants: Set 2

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Variable Total ≤4 Mo. of EDI

>4 Mo. of EDI

P 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 entry —wk

10.0 (8.0‐13.6)

10.0 (2.2‐10.0)

12.7 (10.0‐19.0)

<0.001

CD4+ count at ART‐start 451 (336‐612)

504 (378‐720)

386 (281‐554)

<0.001

VL at ART‐start 4.95 (4.55‐5.48)

5.20 (4.67‐5.82)

4.82 (4.45‐5.23)

<0.001

Time (mo) from ART‐start to VL suppression

3.9 (2.3‐5.6)

4.0 (2.3‐5.7)

3.7 (2.4‐5.4)

0.44

Trajectories of CD4+ T‐Cell Counts before and after Initiation of ART

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Viral load trajectories in study sets 1 and 2

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Rate of Recovery of CD4+ T‐Cell Counts after Initiation of ART

Likelihood and Rate of CD4 Recovery to ≥900 cells/mm3 

within 48 Months after Starting ART

Predictive Factor Odds Ratio(95% CI)

P Value Rate Ratio(95% CI)

P Value

Model 1: CD4+ count — <500 vs. ≥500 cells/mm3 at ARTinitiation

0.07 (0.04–0.15)  <0.001 0.17 (0.11–0.26) <0.001

Model 2: Time from EDI to ART initiation — each increaseof 1 mo

0.90 (0.85–0.96) 0.001 0.92 (0.88–0.96) <0.001

Model 3: Time from EDI to ART initiation — >4 mo vs. ≤4 mo

0.35 (0.17–0.71) 0.004 0.44 (0.29–0.67) <0.001

Model 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

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

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

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