The effect of short-course ART in PHI

Final results from an international randomised controlled trial

SPARTAC

Sarah Fidlerfor SPARTAC Trial Investigators Imperial College, London, UK

www.imperial.ac.uk/medicine/spartac

Background

• HIV-induced immunological destruction begins early and despite later ART, is never completely reversed

• Observational studies: encouraging data suggest potential immunological benefit of early ART

• David Ho ‘HIT HIV HARD HIT EARLY’ [1995]

• Hypothesis: ART initiated as near to HIV transmission as possible may protect against HIV-induced immune damage

Currently no evidence from randomised trial to inform best clinical management of PHI

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

Trial Design

• Definition of PHI– laboratory evidence of infection within 6 months of a previous

negative test, <3 bands WB, RITA incident, antibody negative PCR+

• Randomisation 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 years

Secondary objectives

• Development of an AIDS defining illness or death

• HIV-specific CD4+ and CD8+ T-cell responses at week 60

• Slope of CD4 decline after intervention

• Development of new drug resistance by week 120

• Differences in blood pressure from randomisation at weeks 12 and 48

• Time to virological failure of first long-term ART regimen

Enrolment & Exclusions

SCREENED429

RANDOMISED371

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 randomisation error

International Sites

SitesParticipants

• Australia 10 36 (10%)• Brazil 1 17 (5%)• Ireland 1 2 (1%)• Italy 2 23 (6%)• South Africa 9 118 (32%)• Spain 1 2 (1%)• Uganda 1 19 (5%)• United Kingdom 11 149 (40%)

Total 35 366

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

7250

1

(59%)(41%)

(1%)

6455

1

(53%)(46%)

(1%)

6953

1

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

205158

3

(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%)

208120

36

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

Baseline ResistanceAny

NRTINNRTI

PI

8551

(7%) 5230

(4%) 8631

(7%) 211311

2

(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

abili

ty o

f not

reac

hing

prim

ary

endp

oint

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

ART48 HR 0.63 (0.45,0.90), p=0.01

ART12 HR 0.93 (0.67,1.29), p=0.67

SOC

Time to primary endpoint

Hazard ratio 95% CI p

ART12 vs. SOC 0.93 0.67 - 1.29 0.67

ART48 vs. SOC 0.63 0.45 - 0.90 0.01

ART48 vs. ART12 0.68 0.48 - 0.96 0.03

Time to primary endpoint SOC ART12 ART48

Median, weeks (95% CI)Difference vs. SOCDifference vs.

ART12

157

(114,213)--

184

(140,214)27(-

25,79)-

222

(189,270)65

(17,114)38(-

3,79)

59 58 57 54 50 46 42 31 21 8ART-48 ≤12 wks64 63 60 55 50 42 38 32 20 11ART-48 >12 wks70 62 51 41 39 34 30 22 16 10SOC ≤12 wks53 47 42 41 36 32 29 24 14 8SOC >12 wks

Time (years)

Prob

abili

ty o

f not

reac

hing

prim

ary

endp

oint

0.00

0.25

0.50

0.75

1.00

0 .5 1 1.5 2 2.5 3 3.5 4 4.5

ART-48 ≤12 wks

ART-48 >12 wks

SOC ≤12 wks SOC >12 wks

ART48 vs SOC < 12 w HR = 0.48 [0.30, 0.78] p=0.003

Duration of infection and time to Primary Endpoint

HIV RNA changes following ART interruption*

* Adjusted for baseline

99520ART-4818171043ART-12

9761SOC 14Number measurements censored due to long-term ART initiation

Chan

ge in

log1

0 H

IV R

NA

from

bas

elin

e

Weeks from ART interruption (ART-48 and ART-12) or randomisation (SOC)

.8

.6

.4

.2

0

.2

12 24 36 48 6012 24 36 48 60

ART-48

ART-12

SOC

Changes in CD4 values for ART-48 and SOC groups over entire study

Mea

n (p

oint

wis

e 95

% C

I)

Weeks from randomisation

-200

-100

0

100

200

0 12 24 36 48 60 72 84 96108

120132

144156

168180

192204

216228

240252

264276

288

ART-48

SOC

Average CD4 count over 4.5 years for ART-48 was 138 [90,185] cells/mm3 higher than SOC

Secondary end points

• No significant difference between the groups for AIDS, death or serious adverse events

• No difference in CD4 decline after ART interruption in treatment groups compared to decline from randomisation in SOC (p=0.92).

• In contrast to SMART there was no rebound in IL-6 and a drop in d-dimer compared with baseline levels 4 weeks after stopping ART.

• Virological failure on long-term ART was similar across groups

• Drug resistance by week 120: 6 had Stanford scores 4-5; 5 NNRTI-associated mutations and one PI-associated

• CD8+ & CD4+ HIV-specific responses: Analyses ongoing

Conclusions

• Spartac is the largest ever RCT in PHI enrolling men and women in both developed and developing world settings

• 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

THANKSAll The study participants

Trial Steering Committee (TSC): Independent TSC Members: A Breckenridge (Chair), P Clayden, C Conlon, F Conradie, J Kaldor*, F Maggiolo; F SsaliCountry Principal Investigators: D A Cooper, P Kaleebu, G Ramjee, M Schechter, G Tambussi, J.Miro J Weber Trial Physician: Sarah Fidler Trial Statistician: Abdel Babiker Data and Safety Monitoring Committee (DSMC): T Peto (Chair) A McLaren (in memoriam), V Beral, G Chene, J HakimCo-ordinating Trial Centre: MRC Clinical Trials Unit, London (A Babiker, K Porter, M Thomason, F Ewings, M Gabriel, D Johnson, K Thompson, A Cursley*, K Donegan*, E Fossey*, P Kelleher*, K Lee*, B Murphy*, D Nock*)Central Immunology Laboratories and Repositories: The Peter Medawar Building for Pathogen Research, University of Oxford, UK (R Phillips, J Frater, L Ohm Laursen*, N Robinson, P Goulder, H Brown)Central Virology Laboratories and Repositories: Jefferiss Trust Laboratories, Imperial College, London, UK (M McClure, D Bonsall*, O Erlwein*, A Helander*, S Kaye, M Robinson, Lisa Cook*, Gemma Adcock*)Clinical Endpoint Review Committee: N Paton, S FidlerImperial College Trial Secretariat: S Keeling, A BeckerImperial College DSMC Secretariat: C Boocock * Left the study team before the trial ended

Investigators and Staff at Participating SitesAustralia: St Vincent’s Hospital, Sydney (A Kelleher), Northside Clinic, Melbourne (R Moore), East Sydney Doctors, Sydney, (R McFarlane), Prahran Market Clinic, Melbourne (N Roth), Taylor Square Private Clinic, Sydney (R Finlayson), The Centre Clinic, Melbourne (B Kiem Tee), Sexual Health Centre, Melbourne (T Read), AIDS Medical Unit, Brisbane (M Kelly), Burwood Rd Practice, Sydney (N.Doong) Holdsworth House Medical Practice, Sydney ( M. Bloch) Aids Research Initiative, Sydney ( C. Workman). Coordinating centre in Australia: Kirby Institute University of New South Wales, Sydney (P Grey, D A Cooper, A Kelleher, M Law). Brazil: Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade federal do Rio de Janeiro, Rio de Janeiro (M Schechter, P Gama, M Mercon*, M Barbosa de Souza, C Beppu Yoshida, J R Grangeiro da Silva, A Sampaio Amaral, D Fernandes de Aguiar, M de Fátima Melo, R Quaresma GarridoItaly: Ospedale San Raffaele, Milan (G Tambussi, S Nozza, M Pogliaghi, S ChiappettaL Della Torre, Elisa Gasparotto,), Ospedale Lazzaro Spallanzani, Roma (G D’Offizi, C Vlassi, A Corpolongo) South Africa: Cape Town: Desmond Tutu HIV Centre, Institute of Infectious Diseases, Cape Town (R Wood, J Pitt, C Orrell, F Cilliers, R Croxford, K Middelkoop, L G Bekker, C Heiberg, J Aploon, N Killa, E Fielder, T Buhler) Johannesburg: The Wits Reproductive Health and HIV Institute, University of Witswatersrand, Hillbrow Health Precinct, Johannesburg. (H Rees, F Venter, T Palanee) Contract Laboratory Services, Johannesburg Hospital, Johannesburg (W Stevens, C Ingram, M Majam, M Papathanasopoulos) Kwazulu-Natal: HIV Prevention Unit, Medical Research Council, Durban (G Ramjee, S Gappoo, J Moodley, A Premrajh, L Zako) Uganda: MRC/Uganda Virus Research Institute, Entebbe (H Grosskurth, A Kamali, P Kaleebu, U Bahemuka, J Mugisha*, H F Njaj*)Spain: Hospital Clinic-IDIBAPS. University of Barcelona, Barcelona (JM Miro, M López-Dieguez*, C Manzardo, JA Arnaiz, T Pumarola, M Plana, M Tuset, MC Ligero, MT García, T Gallart, JM Gatell)UK and Ireland: Royal Sussex County Hospital, Brighton (M Fisher, K Hobbs, N Perry, D Pao, D Maitland, L Heald), St James’s Hospital, Dublin (F Mulcahy, G Courtney, S O’Dea, D Reidy), Regional Infectious Diseases Unit, Western General Hospital and Genitourinary Dept, Royal Infirmary of Edinburgh, Edinburgh (C Leen, G Scott, L Ellis, S Morris, P Simmonds), Chelsea and Westminster Hospital, London (B Gazzard, D Hawkins, C Higgs), Homerton Hospital, London (J Anderson, S Mguni), Mortimer Market Centre, London (I Williams, N De Esteban, P Pellegrino, A Arenas-Pinto, D Cornforth*, J Turner*) North Middlesex Hospital (J Ainsworth, A Waters), Royal Free Hospital (M Johnson, S Kinloch, A Carroll, P Byrne, Z Cuthbertson), Barts & the London NHS Trust, London (C Orkin, J Hand, C De Souza), St Mary’s Hospital, London (J Weber, S Fidler, E Hamlyn, E Thomson*, J Fox*, K Legg, S Mullaney*, A Winston, S Wilson, P Ambrose), Birmingham Heartlands Hospital (S Taylor, G Gilleran)

Next steps

• Explore the mechanisms• HIV-specific immune responses• Was there functional preservation?

• Viral reservoir and evolution• ART-12 was insufficient to suppress viral

reservoirs but ART-48 did alter the natural pattern- was it long enough?

• Preliminary data suggests there was an effect on reservoir size and limitation of viral evolution

• Is the next study continuous therapy?• Having shown that ART-48 is safe and may

confer individual benefit does this provide further support for UTT to limit transmission?

Baseline resistance

SOC ART-12 ART-48 TotalNumber with a resistance test 123 (100%) 119 (99%) 122 (99%) 364 (99%)

Number with resistance at Stanford level 4-5Any

NRTINNRTI

PI

8 (7%)551

5 (4%)230

8 (7%)631

21(6%)1311

2Number with new resistance by week 120

AnyNRTI

NNRTIPI

2020

1010

2020

1001

International trial sites

UK = 152

Italy = 19Spain = 2

Uganda = 20

South Africa = 118

Brazil = 17

Australia = 37

Ireland = 2

IL-6 and d-dimer levels at baseline and change 4 weeks after stopping ART

-1.5

-1

-.5

0

.5

1

log1

0 va

lue

of b

iom

arke

r

Baseline(randomisation)

-.15

-.1

-.05

0

.05

Mea

n ch

ange

(95%

CI)

in lo

g10

4 weeks after stopping ART (adjusted for baseline)

IL-6 0.00 (-0.07,0.06)

d-dimer -0.07 (-0.13,-0.01)

IL-6 0.15 (-0.08,0.36)

d-dimer -0.46 (-0.68,-0.29)

Enrolment by country

Country N Sites SOC (Site%)

ART-12 (Site%)

ART-48(Site%)

Total

Australia 10 13 (35%) 11 (30%) 13(35%) 37(10%)Brazil 1 6 (35%) 6 (35%) 5 (29%) 17 (5%)Ireland 1 1 (50%) 0 (0%) 1 (50%) 2 (1%)Italy 2 8 (35%) 8 (35%) 7 (30%) 23 (6%)South Africa 9 40 (34%) 40 (34%) 39 (33%) 118 (32%)Spain 1 0 (0%) 0 (0%) 2 (100%) 2 (1%)Uganda 1 6 (30%) 7 (35%) 7 (35%) 20 (5%)UK Pilot Main

110

10 (34%)41 (33%)

10 (34%)41 (33%)

9 (31%)41 (33%)

29 (8%)123 (33%)

Overall 35 124 (33%) 123 (33%) 124 (33%) 371 (100%)