This document summarizes evidence from several studies on testing for acute HIV infection and initiating antiretroviral therapy (ART) on the same day as diagnosis. It discusses the optimal window for initiating ART after infection to restore immune function based on a study showing greater probability of achieving CD4 counts over 900 if starting ART within 4 months of infection. It also summarizes results from randomized controlled trials and observational studies demonstrating that rapid/same-day ART initiation improves linkage to care, ART initiation rates, and viral suppression compared to standard of care with initiation delayed by weeks or months.

1. Testing for Acute HIV and
Early Initiation of ART
Susan Little, MD
Professor of Medicine
University of California San Diego

2. Financial Disclosures
• Dr. Little has served as a member of data monitoring committees for
GlaxoSmithKline – sponsored clinical trials
• Dr. Little received research grants awarded to her institution from
Gilead Sciences, Inc.
05/14/2018 1

3. AHI Testing and Same Day Treatment
• AHI Detection
• Same Day Treatment
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4. 05/14/2018 3
NOTE: For laboratories in which instrumented Ag/Ab testing is not feasible, Determine can be used with serum/plasma
as the first step in the laboratory algorithm. It may not detect infection as early as the instrumented tests. Laboratories
using Determine are advised to acknowledge the limitations of the testing procedure when reporting results.
Laboratory Testing for Diagnosis of HIV (serum/plasma)
CDC/APHL (Association of Public Health Laboratories); June 2014

5. • Abbott Architect HIV Ag/Ab
Combo chemiluminescent
assay (CIA), June 2010
• BioRad HIV Combo Ag/Ab
EIA, July 2011
Note: neither assay will distinguish between the detection
of HIV-1 p24 antigen, HIV-1 antibody, or HIV-2 antibody
4th Generation Immunoassays
Simultaneous qualitative detection of HIV-1 p24
antigen (Ag) and antibodies (Ab) to HIV-1 (Groups M
and O) and HIV-2 in human serum or plasma
405/14/2018

6. 05/14/2018 5

7. HIV Infection and Laboratory Markers
05/14/2018 6
Modified after Busch et al. Am J Med. 1997
Viral
detection

8. Fiebig Stages of Primary HIV Infection
05/14/2018 7Fiebig et al. AIDS 2003

9. Recent Infection Testing Algorithm (RITA) Assays
RITA Assay Proposed Cutoff
Index
False Recent Rate
(95% CI)
Mean Duration Recent
Infection (MDRI)
OPTIMAL ASSAY1 <1% 1 year
Architect HIV Ag/Ab Combo 200 S/CO 0.6% (N/A)* 186 days (165 – 208)
Geenius HIV-1/2 1.5 Index 4.1% (2.2 – 7.0) 179 days (155 – 201)
Limiting Antigen Avidity (LAg) 1.5 ODn 1.3 % (0.3 – 3.2) 188 days (165 – 211)
Genome Similarity Index (GSI)⍑ 0.67 0.33% (0 – 0.98) 420 days (361 – 467)
05/14/2018 8
Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA)
Kassanjee R, et al. AIDS 2014; Keating S, et al. JAIDS 2016; Grebe E, et al. JAIDS 2017
Park SY, et al. Scientific Reports 2017
FRR=False Recent Rate, ODn=Optical density, S/CO=signal-to-cutoff ratio
1 Incidence Assay Critical Path Working Group. PLoS Med. 2011
*FRR context-specific, estimated for specific subtype B epidemiological scenario, ⍑Utilized Env sequencing
Even state-of-the-art recency staging algorithms perform poorly in
surveillance applications

10. UCSD Early Test: Screening for AHI
05/14/2018 9
Morris S, et al. Ann Intern Med. 2010

11. Comparison: HIV Ag/Ab combo vs. ID-NAT
• 2,744 HIV Ab negative samples
• Dual testing:
• 14 positive by ID-NAT
• 9 positive by HIV Combo
• 5 false negative – all during
exponential increase HIV RNA
• 5 false positive (negative by NAT)
• HIV Combo: Sensitivity 73.7%,
Specificity 99.8%
05/14/2018 10Karris M, et al. JCM. 2012

12. Detection of Acute HIV Infection
Importance:
• To estimate HIV incidence
• To find HIV unaware persons
• To offer immediate treatment and risk reduction
• To identify HIV transmission “hot spots”
• high transmission and high burden zones
• To tailor prevention services to actual behaviors and risks
associated with AHI
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13. AHI Testing and Same Day Treatment
• AHI Detection
• Same Day Treatment
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14. Early Therapy Beneficial
05/14/2018 13
Time to First Primary Event
INSIGHT START Trial, NEJM 2015 TEMPRANO ANRS 12136 Study, NEJM 2015
Primary Outcome

15. How early is early enough??
We hypothesized: There is a critical time period
following acute HIV infection during which ART is
capable of restoring ‘normal’ immune function.
05/14/2018 14
Le T, et al. NEJM 2013

16. Optimal “Restorative Window” for Immune Recovery
Study Design:
• 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
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*Defined from analysis of 34 studies in HIV neg persons
Le T, et al. NEJM 2013

17. Study Sets and Inclusion Criteria

18. 05/14/2018 17
Rate of Recovery of CD4+ T-Cell Counts after Initiation of ART
Le T, et al. NEJM 2013

19. 05/14/2018 18
CD4+ Recovery to ≥900 cells/mm3
CD4+≥900cells/mm3
(%ofparticipants)
Months since Initiation of ART

20. Conclusions
• The probability of attaining a CD4 >900 on ART was
greatest for those who started ART within 4 months of EDI.
• Each month delay in ART reduced probability of achieving
a CD4 > 900 by approximately 10%.
• Chance of achieving CD4>900 reduced by 94% if CD4<500
at ART start, independent of EDI.
• <25 % of ART-naïve patients maintained CD4≥500 beyond
12 months.
05/14/2018 19Le T, et al. NEJM 2013

21. ART Guidelines
• 2017 WHO Guidelines1: On the basis of international randomized
trials, immediate (within 7 days of diagnosis) ART initiation
recommended for willing persons.
• 2017 UNAIDS2: Adoption of same-day initiation of ART is one of the
most crucial cornerstones of successfully achieving the 90-90-90
targets.
• 2017 US Treatment guidelines3: Same-day ART – still an
investigational approach
05/14/2018 20
1 World Health Organization (2017). HIV Treatment Guidelines
2 Joint UNAIDS (2017). ENDING AIDS: Progress Towards the 90-90-90 Targets
3 DHHS Guidelines (2018): https://aidsinfo.nih.gov/guidelines

22. Same Day/Rapid ART
• Two RCT – individual level
• RapIT in South Africa (Rosen SR, et al. PLoS Med 2015)
• Same Day ART study in Haiti (Koenig S.P., et al. PLoS Med 2017
• Two RCT – clinic level
• START-ART in Uganda (Amanyire G, et al. Lancet HIV 2016)
• CASCADE in Lesotho (Labhardt ND, et al. JAMA 2018)
• Two Clinic-Based Cohort Studies
• RAPID protocol in San Francisco (Pilcher CD, et al. JAIDS 2017)
• Modified RAPID protocol in San Diego (Hoenigl M, et al. Scientific Reports 2016)
• One Citywide Implementation Study
• RAPID ART Initiative in San Francisco (Bacon O, et al. CROI 2018, Abs 93)
05/14/2018 21

23. RapIT in South Africa (RCT-Individual)
• Rapid Initiation of Treatment (RapIT) – unblinded RCT of single-visit
ART initiation in two clinics (one primary care/one hosp HIV clinic)
• Eligibility: ≥18 yrs, non-pregnant, receiving pos HIV test or first eligible
CD4 count (≤350 cells/mm3)
05/14/2018 22
Rosen SR, et al. PLoS Med 2015
• Primary outcome:
Viral suppression (VL
≤400 c/ml) in those
retained in care by 10
mo after study
enrollment
(N=377 eligible)

24. ART Initiation, Retention and Suppression
Outcome Standard Arm (%)
N=190
Rapid Arm (%)
N=187
Crude risk
difference
(95% CI)
Crude relative risk
(95% CI)
ART≤ 90d, VL≤400 by
10 mo
96 (51%) 119 (64%) 13% (3%-23%) 1.26 (1.05-1.50)
Initiated ≤ 90 d 136 (72%) 182 (97%) 25% (19%-33%) 1.36 (1.24-1.49)
ART> 90d, VL≤400 by
10 mo
94 (49%) 68 (36%)
ART≤ 90d, NOT
suppressed by 10 mo
40 (21%) 63 (34%)
ART≤ 90d and
retained at 10 mo
121 (64%) 151 (81%) 17% (5%-23%) 1.27 (1.12-1.44)
RT≤ 90d and NOT
retained at 10 mo
15 (8%) 31 (17%)
05/14/2018 23
Rosen SR, et al. PLoS Med 2015

25. Summary & Conclusions
• High acceptance rate: 79% accepted Rapid ART same day/next day
• Overall, uptake of ART increased by 36% and viral suppression
increased by 26%
• Two sites (one public clinic, one HIV hospital clinic)
• 47% were enrolled at visit to get their CD4 results, so already partly
linked; 41% enrolled on day of diagnosis
• All physically at the clinic at recruitment
• More pts in the rapid initiation group dropped out of care after
starting treatment than standard group.
• Though rapid group still had better health outcomes overall
05/14/2018 24
Rosen SR, et al. PLoS Med 2015

26. Same Day ART study in Haiti (RCT-Individual)
• RCT trial of standard ART vs. same day HIV testing and ART
• Eligibility: ≥ 18 yrs, WHO Stage 1 or 2 disease and CD4 ≤500 cells/mm3
• Site: outpatients at GHESKIO Clinic in Port-au-Prince, Haiti
• Randomized (n=703 eligible):
• Same day: initiated ART on the day of testing
• Standard group: initiated ART 3 wks after HIV testing
• Primary endpoint: retention in care 12 months after testing with
RNA<50 copies/mL
05/14/2018 25Koenig S.P., et al. PLoS Med 2017

27. Same Day ART study in Haiti (RCT-Individual)
05/14/2018 26Koenig S.P., et al. PLoS Med 2017
*
* No deaths for those in care were attributed to IRIS or an OI that was missed at ART initiation

28. Retention in Care by Study Group
05/14/2018 27
P=0.028
80%
72%

29. Summary & Limitations
• Demonstrated feasibility of initiating ART on day of HIV diagnosis
• Same-day ART vs. ART initiated 21 days after HIV diagnosis:
• 100% vs. 92% initiated ART
• At 12 months after HIV testing (same-day vs. 21 day)
• 80% vs. 72% were retained in care
• 53% vs. 44% were retained in care and suppressed (VL<50 copies/mL)
• Further interventions still needed to improve retention in care
(overall LTFU 24.2%) and viral suppression (overall 48.4%)
• Conducted at a single clinic in Haiti
05/14/2018 28Koenig S.P., et al. PLoS Med 2017

30. START-ART in Uganda (RCT-clinic level)
• Location: 20 Clinics in Uganda (n=11,813 enrolled & eligible)
• Health facilities (clinics) were the unit of randomization.
• Groups of clinics were randomly assigned to receive the intervention at
intervals of about 6 months until all clinics had entered the intervention.
• Intervention: START-ART strategy targeted health-care worker
behavior – eliminated multiple pre-ART counseling sessions.
• Eligibility: ≥ 18 yrs, ART-naïve, eligible for ART (CD4 ≤350 [changed to
≤ 500 during study], any WHO stage 3 or 4 condition, pregnancy)
• Primary outcome: ART initiation 14 days after first eligibility
05/14/2018 29Amanyire G, et al. Lancet HIV 2016

31. Results: START-ART
05/14/2018 30Amanyire G, et al. Lancet HIV 2016
Outcome Control Group (%)
N=7066
Intervention
Group (%)
N=4747
Risk difference
(95% CI)
Risk ratio
(95% CI)
START ART in 14 d 2585 (38%) 3753 (80%) 41.9% (40.1-43.8) 2.11 (2.03-2.20)
START ART same-day 1313 (18%) 3358 (71%) 52.5% (50.7-54.3) 3.87 (3.64-4.11)
START ART in 90 d 4004 (70%) 4349 (90%) 19.3% (17.6-21.0) 1.27 (1.25-1.30)
• Results consistent across sub-groups (sex, age, clinic size, CD4 count at eligibility, WHO stage,
pregnancy, and TB at eligibility)
• HIV RNA measured on subset of 335:
• 85% virologic suppression in the intervention vs. 75% in control group (RR 1.13, 95% CI
1.02–1.27; p=0.024) using inverse probability weighting to address missing outcomes
• Retention in care did not vary by group.
• Mortality at 1 year not different (2% vs. 3%)

32. Summary & Conclusions
• Multicomponent intervention targeting health-care worker behavior
• Increased likelihood of ART-START within 14 days.
• Large study with consistent effects
• Demonstrates that rapid treatment is feasible and sustainable
• Overall, improved suppression
• No difference in mortality or retention in care
• All pts were at the clinic at recruitment
05/14/2018 31Amanyire G, et al. Lancet HIV 2016

33. CASCADE in Lesotho (RCT-clinic level)
• RCT of 6 healthcare facilities in Lesotho
• During home-based HIV testing in 6655 households from 60 rural
villages and 17 urban areas, 278 people tested positive
• Randomized:
• Same-day home-based ART initiation with f/u at health facility (n=138)
• Usual care with referral for ART and care (n=140)
• Co-primary end points: rates of linkage to care within 90 days and VL
suppression(<100 copies/mL) at 12 months
05/14/2018 32Labhardt ND, et al. JAMA 2018

34. Primary and Secondary End Points
05/14/2018 33
Allowing for linkage after 90 days, linkage rates were still higher in the same day group
(same-day, 100 of 137 vs usual care, 83 of 137, absolute diff, 12.4%; 95%CI, 1.3%-23.2%; P = .03)
Labhardt ND, et al. JAMA 2018

35. Summary & Conclusions
• First trial to assess same-day ART initiation as a strategy for patients
tested at home.
• First trial of same-day ART initiation irrespective of CD4 cell count
(55.6% had CD4≥350 cells/mm3)
• Linkage within 90 days and VL suppression by 12 months were both
superior in the same-day ART group compared to the usual care
group.
• Virologic suppression rates by 12 months overall were low (42.3%)
• Loss to follow-up rates similar
• These findings support the practice of offering same-day ART
initiation during home-based HIV testing
05/14/2018 34Labhardt ND, et al. JAMA 2018

36. RAPID protocol in San Francisco (Cohort)
• Clinic-based cohort of consecutive patients with newly diagnosed HIV
and Acute/Early HIV or CD4<200.
• Intervention: Rapid ART Program for Individuals with an HIV
Diagnosis (RAPID)
1) Same-day access to HIV provider – on the day of HIV diagnosis
2) Same-day medical visit (3-4 hours)
3) Accelerated insurance approval process
4) Pre-approved regimens: generally DTV+TDF/FTC
5) 5-day starter packs
6) Observed administration of first dose
7) Telephone f/u within 7 days to review labs, review adherence, etc.
05/14/2018 35Pilcher CD, et al. JAIDS 2017

37. Newly HIV Diagnosed Pts: Clinical Milestones
Group RAPID Non-RAPID Universal ART CD4-guided Between-group
comparisons
Years 2013-1014 2013-2014 2010-2013 2006-2009 RAPID vs.
non-RAPID
RAPID vs.
Universal ART
ART recommended All All All CD4<500 P-values
N 39 47 69 25
Time (d) from referral to:
Clinic intake 1 (0-5) 10 (7-17) 13 (7-26) 9 (2-44) <0.001 <0.001
Primary provider visit 14 (3-30) 26 (13-105) 31 (17-60) 30 (7-65) 0.13 0.089
VL <200 56 (40-87) 79 (53-174) 132 (91-210) 218 (116-777) 0.009 <0.001
Time (d) from diagnosis to:
VL <200 65 (52-119) 170 (79-363) 190 (113-302) 580 (138-971) <0.001 <0.001
05/14/2018 36Pilcher CD, et al. JAIDS 2017

38. Summary & Conclusions: RAPID SF
• 86 patients: 39 eligible for RAPID, 47 received clinic standard of care
• 75% of RAPID had acute or recent infection
• 37/39 (94.9%) in RAPID began ART within 24 hrs
• Loss to f/u was similar in RAPID (10.3%) and non-RAPID (14.9%) pts
• Time to VL suppression (<200 copies/mL) was significantly faster for
RAPID vs. non-RAPID pts (median 1.8 mo vs. 4.3 mo, respectively;
p=0.0001).
05/14/2018 37Pilcher CD, et al. JAIDS 2017

39. Modified RAPID protocol in San Diego
• Clinic-based cohort of consecutive patients with newly diagnosed HIV
• Including AHI, Early HIV, and chronic HIV (any CD4)
• Intervention: Modified RAPID Program:
1) Access to HIV provider within 48 hrs of HIV diagnosis
2) Same-day medical visit (3-4 hours)
3) ART Provided: elvitegravir, cobicistat, emtricitabine & tenofovir alafenamide
4) Observed administration of first dose
5) Telephone f/u within 14 days to review labs, review adherence, etc.
• Case Management: insurance assessment and linkage to care
• Chronically infected persons followed 12 wks
• Acute and early infected persons followed up to 5 years
05/14/2018 38
Hoenigl M, et al. Scientific Reports 2016

40. I-ART Participant Characteristics
Characteristic N (%)
Enrolled 162
Male 156 (96.3)
Stage of HIV infection
Acute (Ab neg) 36 (22.2)
Early (LAg c/w infection <70 days) 42 (25.9)
Chronic 84 (51.9)
Laboratory (at presentation)
CD4 cells/µl, median (IQR) 480 (332 – 662)
HIV RNA log10 copies/ml, median (IQR) 4.6 (4.1 – 5.2)
ART Data
Initiated ART 131 (95)
Time from EDI to ART for AEH, median days (IQR) 34 (19-81)
Time from presentation to ART, median days (IQR) 5.0 (0 – 9)
05/14/2018 39*AEH=Acute and Early HIV infection

41. ART Outcomes in AEH Participants
Variable Universal ART
(2009-2013)
Modified RAPID
(2014-2016)
Started ART, % 69% 95%
Study entry to ART (mean days) 37 days 5 days
EDI to ART (mean days) 78 days 43 days
ART to VL suppression (mean
time, days)
110 days 56 days
05/14/2018 40

42. Citywide RAPID ART Initiative: San Francisco
• New confirmed HIV diagnoses linked to care ≤ 5 working days
• 1st visit: baseline labs, counseling, med/psychosocial assessment, ART
started unless risk for fatal IRIS
• [TFV+FTC] + [INSTI or DRV/r] with option for 4 drug regimen if infection on
PrEP
• Outcomes
• Time (median days) from Dx to VL <200 c/ml
• ART to VL < 200 c/ml
• Diagnosis to 1st care visit
• 1st care visit to ART start
05/14/2018 41Bacon O, et al. CROI 2018, Abs 93

43. Linkage to Care and ART Initiation Following HIV Diagnosis
Metric 2013 2014 2015 2016
Diagnosed 399 329 295 265
In Care (%) 372 (93) 318 (97) 282 (96) 258 (97)
Started ART (%) 311 (78) 276 (84) 244 (83) 215 (81)
Met RAPID definition (%)* 23 (6) 45 (14) 50 (17) 80 (30)
05/14/2018 42
*Both diagnosis to care w/in 5 days and ART w/in 1 day
Bacon O, et al. CROI 2018, Abs 93

44. Linkage to Care and ART Initiation Following HIV Diagnosis
Metric 2013 2014 2015 2016
Diagnosed 399 329 295 265
In Care (%) 372 (93) 318 (97) 282 (96) 258 (97)
Started ART (%) 311 (78) 276 (84) 244 (83) 215 (81)
Met RAPID definition (%)* 23 (6) 45 (14) 50 (17) 80 (30)
05/14/2018 43
*Both diagnosis to care w/in 5 days and ART w/in 1 day
Bacon O, et al. CROI 2018, Abs 93

45. Median Time to Care, ART and Virologic Suppression
Metric 2013 2014 2015 2016 % 2013-16
In care within 1 yr (%) 372 (93) 318 (97) 282 (96) 258 (97)
1st care visit to ART (d) 27 17 6 1 -96%
Diagnosis to VL<200 c/mL (d) 134 92 77 61 -54%
Diagnosis to care (d) 8 7 7 5 -38%
ART to VL<200 c/mL (d) 70 53 50 38 -46%
05/14/2018 44
• Time from first care visit to ART decreased significantly in all groups
• Time from diagnosis to VL<200 decreased significantly in all groups
• Time from diagnosis to first care visit decreased significantly for males, whites, Latinos, youth (13-29) and the housed
• Time from ART to VL<200 decreased significantly for males, under 40 yrs, whites, Latinos, Asian/Pacific Islanders, and the
housed
Bacon O, et al. CROI 2018, Abs 93

46. Summary and Limitations
• 30% of new HIV diagnoses in 2016 met strictest RAPID start
definition vs. 6% in 2013
• Median time from care to ART cut 96%, from 27 days to 1 day
• Time to virologic suppression cut by >50%, from 134 days to 61 days
• Including traditionally vulnerable populations, though disparities remain
• Durability of virologic suppression not addressed
05/14/2018 45Bacon O, et al. CROI 2018, Abs 93

47. Overall Summary and Conclusions
• The current CDC/APHL algorithm will reliably diagnose AHI
• Diagnostic strategies are available to differentiate recent from
chronic infection
• Initiation of ART within days of HIV diagnosis improves:
• Uptake of ART
• Linkage to care
• Time to virologic suppression (incl. vulnerable pop)
• Feasible for patients tested at home, at the clinic and referred to the clinic
• Long-term safety (resistance), engagement, durability of suppression
unknown
05/14/2018 46