Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: The SPARTAC Trial Investigators. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med 2013;368:207-17. DOI: 10.1056/NEJMoa1110039

1

Supplementary Materials

Table of Contents

S1. Further baseline characteristics of the 366 eligible participants enrolled into the SPARTAC trial. 2

S2. Serious adverse events (SAEs). 10

S3: reasons for initiating long-term ART for individuals initiating it without a confirmed CD4 <350 cells/mm3

18

S4: Hazard ratios (HR) and 95% confidence intervals for time to primary end-point for all eligible

participants and excluding those randomized under criterion 3* 19

SPARTAC Trial Investigators 20

Investigators and Staff at Participating Sites 20

2

S1. Further baseline characteristics of the 366 eligible participants enrolled into the SPARTAC trial.

SOC ART-12 ART-48 Total

Number of participants 123 (100%) 120 (100%) 123 (100%) 366 (100%)

Sex

Male

Female

74 (60%)

49 (40%)

71 (59%)

49 (41%)

74 (60%)

49 (40%)

219 (60%)

147 (40%)

Age (years)

Median (IQR) [range]

31 (25,39) [19,63]

32 (24,39) [19,61]

33 (26,41) [20,61]

32 (25,40) [19,63]

HIV infection risk group

Sex between men

72 (59%)

64 (53%)

69 (56%)

205 (56%)

3

Sex between men and women

Not known

50 (41%)

1 (1%)

55 (46%)

1 (1%)

53 (43%)

1 (1%)

158 (43%)

3 (1%)

Country of enrolment

Australia

Brazil

Ireland

Italy

South Africa

Spain

Uganda

13 (11%)

6 (5%)

1 (1%)

8 (7%)

39 (32%)

0 (0%)

6 (5%)

10 (8%)

6 (5%)

0 (0%)

8 (7%)

40 (33%)

0 (0%)

6 (5%)

13 (11%)

5 (4%)

1 (1%)

7 (6%)

39 (32%)

2 (2%)

7 (6%)

36 (10%)

17 (5%)

2 (1%)

23 (6%)

118 (32%)

2 (1%)

19 (5%)

4

UK 50 (41%) 50 (42%) 49 (40%) 149 (41%)

Evidence for seroconversion

Definitive

1. Positive HIV antibody test within 6

months of negative antibody test

2. HIV antibody negative with positive

RT- PCR

Presumptive

3. HIV antibody “incident” at low level

(OD<0.6) using a recent incidence

testing algorithm assay (subtype B only)

4. Equivocal HIV antibody test

85 (69%)

1 (1%)

25 (20%)

0 (0%)

81 (68%)

4 (3%)

26 (22%)

1 (1%)

80 (65%)

4 (3%)

21 (17%)

0 (0%)

246 (67%)

9 (2%)

72 (20%)

1 (0.3%)

5

repeated within 2 weeks showing rising

optical density

5. Clinical manifestations of

symptomatic HIV seroconversion illness

supported by antigen positivity <4 bands on

Western Blot

12 (10%)

8 (7%)

18 (15%)

38 (10%)

Time since seroconversion at randomization

(weeks)a

Median (IQR) [range]

11 (8,15) [2,24]

12 (9,15) [1,23]

12 (9,15) [1,22]

12 (9,15) [1,24]

CD4 cell count (cells/mm3)

b

≥750

500-749

22 (18%)

53 (43%)

17 (14%)

51 (43%)

31 (25%)

58 (47%)

70 (19%)

162 (44%)

6

300-499

<300

Median (IQR) [range]

33 (27%)

15 (12%)

543 (404,715)

[130,1226]

43 (36%)

9 (8%)

519 (433,638)

[95,1243]

29 (24%)

5 (4%)

605 (463,750)

[195,1399]

105 (29%)

29 (8%)

559 (435,700)

[95,1399]

HIV RNA (copies/ml)b

>1,000,000

>300,000-1,000,000

>100,000-300,000

>30,000-100,000

>10,000-30,000

5 (4%)

12 (10%)

25 (20%)

31 (25%)

14 (11%)

6 (5%)

9 (8%)

20 (17%)

21 (18%)

22 (18%)

8 (7%)

8 (7%)

23 (19%)

18 (15%)

28 (23%)

19 (5%)

29 (8%)

68 (19%)

70 (19%)

64 (17%)

7

>500-10,000

≤500

Median log10 (IQR) [range]

27 (22%)

9 (7%)

4.70 (3.68,5.24)

[1.70,6.22]

30 (25%)

12 (10%)

4.39 (3.59,5.18)

[1.40,6.22]

27 (22%)

11 (9%)

4.43 (3.81,5.13)

[2.22,6.47]

84 (23%)

32 (9%)

4.53 (3.67,5.18)

[1.40,6.47]

HIV subtype (REGA)a

Not knownb

B

C

Other

0

70 (57%)

40 (33%)

13 (11%)

1

67 (56%)

40 (34%)

12 (10%)

1

71 (58%)

40 (33%)

11 (9%)

2

208 (57%)

120 (33%)

36 (10%)

Number with resistance at Stanford levels 4-5c

Not knownd

0

1

1

2

8

Any

NRTI

NNRTI

PI

8 (7%)

5

5

1

5 (4%)

2

3

0

8 (7%)

6

3

1

21 (6%)

13

11

2

Reported an HIV seroconversion-type illness 81 (66%) 64 (53%) 70 (57%) 215 (59%)

a Time of seroconversion was estimated as the midpoint of last negative/equivocal and first positive tests for criteria 1 and 4, as the date of the test for

criteria 2, 3 (if OD≤0.01) and 5, and as the date of the test minus (OD*150/2) days for criteria 3 if OD>0.01.

b Mean of two values if available.

c Percentages are of non-missing values.

d No baseline value available: HIV RNA value too low (1), no sample available (1).

Characteristics compared across randomized groups using Kruskall-Wallis test to compare medians or Χ2 test for categorical variables; * indicates p<0.05

(but >0.01).

9

ART-12=12-week ART in PHI, ART-48=48-week ART in PHI, IQR=interquartile range, NNRTI=non-nucleoside reverse transcriptase inhibitor, NRTI=nucleoside

reverse transcriptase inhibitor, PHI=primary HIV infection, PI=protease inhibitor, RT-PCR=reverse transcriptase polymerase chain reaction, SOC=standard of

care (no treatment in PHI).

10

S2. Serious adverse events (SAEs).

SOC ART-12 ART-48 Total

Number of participants 123 (100%) 120 (100%) 123 (100%) 366 (100%)

Number of participants with at least

one SAE

34 (28%) 30 (25%) 29 (24%) 93 (25%)

Total number of SAEs

Including recurrences

Excluding recurrences

55

53

44

42

45

44

144

139

The following results exclude recurrences

Grade

Mild

Moderate

Severe

Very severe

Missing

2

6

31

14

0

1

6

28

6

1

3

9

23

9

0

6

21

82

29

1e

Fatal 3 3 2 8

Anaemia + Cardiac failure 1 0 0 1

Completed suicide 0 1 0 1

Deathf 1 0 1 2

Disseminated tuberculosis +

Pancytopenia 0 1 0 1

Fungal infection 0 0 1 1

Meningitis viral + Pneumonia

bacterial 0 1 0 1

11

SOC ART-12 ART-48 Total

Renal failure 1 0 0 1

Life-threatening 4 5 3 12

Accidental overdose 1 0 0 1

Anaphylactic reaction 0 1 0 1

Cardiac arrest + Myocardial

infarctiong 1 0 0 1

Hypokalaemia 0 0 1 1

Intestinal perforation 0 1 0 1

Major depression + Suicide attempt 1 0 0 1

Multiple drug overdose 0 0 1 1

Overdose 0 1 1 2

Skin laceration 0 1 0 1

Suicide attempt 1 1 0 2

Resulted in disability/incapacity 0 0 0 0

Caused/prolonged hospitalisation 43 33 33 109

Abdominal pain 1 1 0 2

Abdominal pain + Diarrhoea + Pelvic

fluid collection + Pyrexia 1 0 0 1

Abdominal pain lower 1 0 0 1

12

SOC ART-12 ART-48 Total

Abdominal pain upper +

Gastrooesophageal reflux disease +

Haematemesis 0 1 0 1

Abortion spontaneous 1 1 1 3

Abscess drainage 0 1 0 1

Acute tonsillitis + Oral herpes 0 0 1 1

Anaemia 0 1 0 1

Anaemia + Essential

thrombocythaemia 0 1 0 1

Angioedema + Soft tissue injury 0 0 1 1

Ankle fracture 0 1 0 1

Anxiety 1 0 0 1

Appendicectomy 0 0 1 1

Appendicitis 1 0 1 2

Appendicitis perforated 1 0 0 1

Arthralgia + Hypoaesthesia 1 0 0 1

Asthma + Measles + Rash generalised 0 1 0 1

Back pain + Dizziness + Headache 1 0 0 1

Caesarean section 2 1 0 3

Caesarean section + Wound sepsis 0 0 1 1

Castleman's disease 0 1 0 1

Cellulitis 0 1 0 1

Cellulitis of male external genital

organ 0 1 0 1

13

SOC ART-12 ART-48 Total

Chest pain 1 0 0 1

Chest pain + Dyspnoea 0 1 0 1

Chest pain + Dystonia + Pain 1 0 0 1

Convulsion 1 0 0 1

Convulsion + Cough +

Lymphadenopathy + Night sweats +

Pyrexia 1 0 0 1

Corneal abscess 0 0 1 1

Cytomegalovirus infection 0 1 0 1

Deep vein thrombosis 0 0 1 1

Dehydration 1 0 0 1

Dehydration + Gastroenteritis 1 0 0 1

Delivery 0 1 0 1

Demyelinating polyneuropathy 1 0 0 1

Diarrhoea 0 1 0 1

Diarrhoea + Vomiting 1 0 1 2

Eye infection syphilitic 1 0 0 1

Eye injury + Facial bones fracture 0 1 0 1

Foetal disorder 1 0 0 1

Gastritis alcoholic 1 0 0 1

Giardiasis 0 0 1 1

Hepatitis acute + Transaminases

increased 1 0 0 1

Herpes zoster 1 0 1 2

14

SOC ART-12 ART-48 Total

Impetigo 0 1 0 1

Influenza + Meningitis bacterial 0 0 1 1

Injury 2 0 0 2

Jaw fracture 1 0 0 1

Lethargy 1 0 0 1

Lobar pneumonia 1 0 0 1

Lymphadenopathy 1 0 0 1

Mania 0 1 0 1

Meningitis bacterial 0 0 1 1

Muscle spasms 0 0 1 1

Myocardial infarction 0 1 0 1

Nephrolithiasis 0 0 1 1

Oedema peripheral 2 0 0 2

Overdose 1 0 1 2

Parvovirus infection 0 0 1 1

Pelvic abscess 0 0 1 1

Pleural effusion + Pulmonary

tuberculosis + Upper respiratory

tract infection 0 0 1 1

Pneumonia 0 1 2 3

Pneumonia bacterial 2 0 0 2

Pneumonia primary atypical 0 1 0 1

Polycythaemia + Thrombocytopenia 1 0 0 1

Postoperative wound infection 1 0 0 1

15

SOC ART-12 ART-48 Total

Pregnancy 1 1 0 2

Proctitis herpes 0 1 0 1

Psychiatric symptom 0 0 1 1

Psychotic disorder 1 0 1 2

Pulmonary embolism 0 0 3 3

Pulmonary tuberculosis 0 2 1 3

Pyrexia 0 1 0 1

Rash 1 0 0 1

Rash generalised 0 1 0 1

Rectal fissure 2 0 0 2

Renal colic 0 0 1 1

Renal pelvis fistula 0 0 1 1

Road traffic accident 0 0 1 1

Serotonin syndrome 0 0 1 1

Suicidal behaviour 0 1 0 1

Thermal burn 0 1 0 1

Thrombocytopenia 0 1 0 1

Tonsillitis 0 1 0 1

Transurethral bladder resection 1 0 0 1

Upper respiratory tract infection 0 0 2 2

Wound infection 0 1 0 1

Non-AIDS defining cancers 0 0 3 3

16

SOC ART-12 ART-48 Total

Basal cell carcinoma 0 0 1 1

Orchidectomy + Testicular prosthesis

insertion 0 0 1 1

Testicular mass 0 0 1 1

Other medical conditions 3 1 3 7

Alanine aminotransferase increased 0 0 1 1

Alanine aminotransferase increased

+ Hepatitis C 0 1 0 1

Blood cholesterol increased + Blood

triglycerides increased 0 0 1 1

Hepatitis C 1 0 0 1

Lymphoma AIDS related 0 0 1 1

Pelvic inflammatory disease 1 0 0 1

Salpingitis 1 0 0 1

Total person years at risk

SAE rate (per 100 person years)

526

10.1

504

8.3

531

8.3

1561

8.9

One SAE had missing grade (caesarean section which caused or prolonged hospitalisation).

Events were classified by MedDRA® version 13 preferred terms and reviewed by an Endpoint

Review Committee. Events were considered to be a continuation of a previously reported

event (and therefore listed only once in the table) if the resolution date of the earlier event

was after the onset date of the later event; if the resolution date was missing then

subsequent events were considered to be continuations if the onset date was <6 months

after the earlier onset date. In all cases, the grade of the event included here was the highest

17

reached. Recurrences were those events which were reports of a previous event (after

excluding continuations).

18

S3: reasons for initiating long-term ART for individuals initiating it without a confirmed

CD4 <350 cells/mm3

Main reason for initiating long-term

ART

SOC

(n=27)

ART-12

(n=25)

ART-48

(n=27)

Total

(n=79)

High viral load 2 3 0 5

Low CD4 17 17 14 48

Clinical HIV progression 2 1 4 7

Dr/patient decision 3 3 3 9

Other 3 1 6 10

19

S4: Hazard ratios (HR) and 95% confidence intervals for time to primary end-point for all

eligible participants and excluding those randomized under criterion 3*

All eligible participants Excluding participants

enrolled under criterion 3

Total number 366 294

Number reaching primary

end-point

209 162

ART-12 vs. SOC 0.93 (0.67,1.29) 1.16 (0.80,1.68)

ART-48 vs. SOC 0.63 (0.45,0.90) 0.66 (0.44,0.99)

* HIV antibody “incident” at low level (optical density (OD) <0.6) using a recent incidence

testing algorithm assay (subtype B only)

20

SPARTAC Trial Investigators

Trial Steering Committee: Independent Members: A Breckenridge (Chair), P Clayden, C

Conlon, F Conradie, J Kaldor*, F Maggiolo, F Ssali. Country Principal Investigators: DA Cooper,

P Kaleebu, G Ramjee, M Schechter, G Tambussi, J Weber. Trial Physician: S Fidler. Trial

Statistician: A Babiker. Data and Safety Monitoring Committee (DSMC): T Peto (Chair), A

McLaren (in memoriam), V Beral, G Chene, J Hakim. Co-ordinating Trial Centre: Medical

Research Council 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, L Cook*, G Adcock*, P Ahmed*).

Clinical Endpoint Review Committee: N Paton, S Fidler.

Investigators and Staff at Participating Sites

Australia: 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, DA 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

21

Beppu Yoshida, JR Grangeiro da Silva, A Sampaio Amaral, D Fernandes de Aguiar, M de

Fátima Melo, R Quaresma Garrido).

Italy: Ospedale San Raffaele, Milan (G Tambussi, S Nozza, M Pogliaghi, S Chiappetta, L Della

Torre, E 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, LG 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: Medical Research Council/Uganda Virus Research Institute, Entebbe (H Grosskurth,

A Kamali, P Kaleebu, U Bahemuka, J Mugisha*, HF 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, London (M Johnson, S Kinloch, A Carroll, P Byrne, Z

22

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, Birmingham (S Taylor, G

Gilleran). Imperial College Trial Secretariat: S Keeling, A Becker. Imperial College DSMC

Secretariat: C Boocock.

* Left the study team before the trial ended