A Randomised Open-label Study Comparing the Safety and Efficacy of Ritonavir Boosted Lopinavir and 2-3N(t)RTI Backbone Versus Ritonavir Boosted Lopinavir and Raltegravir in Participants Virologically Failing First-line NNRTI/2N(t)RTI Therapy
Phase: PHASE4
Conditions: HIV Infections
Sponsor: Kirby Institute

SECOND-LINE STUDY 
5th November 2009 
Page 1 of 92 
 
Clinical Protocol: 
A randomised open-label study comparing the safety and efficacy of ritonavir boosted 
lopinavir and 2-3N(t)RTI backbone versus ritonavir boosted lopinavir and raltegravir in 
participants virologically failing first-line NNRTI/2N(t)RTI therapy: the SECOND-LINE 
study 
Original protocol date: 14th May 2008 
Protocol version: Version 2.0 
Amendment date: 5th November 2009 
Name and address of sponsor: 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
University of New South Wales (UNSW) 
Sydney, Australia 
Telephone: +61 2 9385 0900 
Facsimile: +61 2 9385 0910  
Email:SECONDLINE@nchecr.unsw.edu.au 
 
Name and address of Protocol Steering Committee (PSC): 
Prof David A Cooper 
Principal Investigator 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
University of New South Wales (UNSW) 
Sydney, AUSTRALIA 
Telephone: +61 2 9385 0900 
Facsimile: +61 2 9385 0920  
Email: dcooper@nchecr.unsw.edu.au 
 
Prof Brian Gazzard 
Principal Investigator 
Chelsea & Westminster Hospital 
St Stephen's AIDS Trust, 1st Floor, St Stephen's Centre 
369 Fulham Road 
Fulham, London, SW10 9NH 
UNITED KINGDOM 
Telephone: + 44 208 746 8239 
Facsimile: + 44 208 746 5611 
Email: Yvonne.Stupple@chelwest.nhs.uk 

SECOND-LINE STUDY 
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Dr Mark Boyd  
Principal Clinical Advisor and Project Leader 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 2, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Telephone: +61 2 9385 0900 
Facsimile: +61 2 9385 0910  
Email: mboyd@nchecr.unsw.edu.au 
 
Prof Sean Emery 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 2, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0910  
Email: semery@nchecr.unsw.edu.au 
 
Dr Hedy Teppler 
Merck Research Laboratories  
Merck Clinical Research - Infectious Diseases  
Mail stop: UG3D-56 USA 
Telephone: +1 267-305-7403  
Facsimile: +1 267-305-6545 
Email: hedy_teppler@merck.com 
 
Chris Woodward 
Medical Affairs, Virology 
Global Pharmaceutical Research and Development Abbott 
21 Pacific Ave, Sinking Spring 
Pennsylvania PA 19608 USA 
Telephone: +1 847 951 3249 
Facsimile: +1 610 670 8569 
Email: chris.woodward@abbott.com 
 
In addition there will be one investigator from each participating country nominated as a member on the PSC (indicated 
below with an *). 
 
Name and addresses of the SECOND-LINE study team 
 
Alli Humphries 
Senior Clinical Project Coordinator 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 2, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0910  
Email: ahumphries@nchecr.unsw.edu.au 
 
Jialun Zhou 
Project Statistician 
St Vincent’s Centre for Applied Medical Research 
Level 4, Lowy Packer Building 
405 Liverpool Street 
Darlinghurst NSW 2010 Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0920  
Email: jzhou@nchecr.unsw.edu.au 
Maria Arriaga 
Clinical Project Coordinator 

SECOND-LINE STUDY 
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National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 2, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0910  
Email: marriaga@nchecr.unsw.edu.au 
 
Nisha Seneviratne 
Clinical Project Coordinator 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 2, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0910  
Email: nseneviratne@nchecr.unsw.edu.au 
 
Natalie Espinosa 
Clinical Project Coordinator 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 2, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0910  
Email:  
 
Wendy Lee 
Project Data Manager 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 1, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0910  
Email: wlee@nchecr.unsw.edu.au 
 
Rossitza Chevkenova 
Project Database Programmer 
St Vincent’s Centre for Applied Medical Research 
Level 4, Lowy Packer Building 
405 Liverpool Street 
Darlinghurst NSW 2010 Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0920  
Email: rchevkenova@nchecr.unsw.edu.au 
 
Rosemary Robson 
Project Administrative Assistant 
National Centre in HIV Epidemiology and Clinical Research (NCHECR) 
Level 2, CC4 East Wing, UNSW Cliffbrook Campus 
45 Beach Street | Coogee NSW 2034 | Australia 
Phone: (+ 61 2) 9385 0900 
Facsimile: +61 2 9385 0910  
Email: rrobson@nchecr.unsw.edu.au 

SECOND-LINE STUDY 
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Page 4 of 92 
 
Investigational Sites and Principal Investigators 
AUSTRALIA 
NEW SOUTH WALES 
 
ALBION STREET CENTRE 
Don Smith 
150-154 Albion St 
Surry Hills, NSW, 2010 
Telephone: +61 2 9332 9611 
Facsimile: + 61 2 9332 6519 
Email: don.smith@sesiahs.health.nsw.gov.au 
 
 
 
ST VINCENT’S HOSPITAL 
David Cooper 
Immunology B Clinic 
Level 4, Xavier Building 
Darlinghurst, NSW, 2010 
Telephone: + 61 2 8382 4903 
Facsimile: + 61 2 8382 4964 
Email: dcooper@nchecr.unsw.edu.au 
 
LIVERPOOL HOSPITAL 
John Quin 
Liverpool Health Service 
Immunology HIV Department 
Ground Floor, Bigge Park Centre 
13 Elizabeth Street 
Cnr Bigge & Elizabeth Streets 
Liverpool, NSW, 2170 
Telephone: + 61 2 9827 8022 
Facsimile: + 61 2 9602 4352 
Email: john.quin@swsahs.nsw.gov.au 
 
 
 
VICTORIA 
 
THE ALFRED HOSPITAL 
*Julian Elliott 
Infectious Diseases Unit 
Level 2, Burnet Institute 
85 Commercial Road 
Melbourne, Victoria, 3004 
Telephone: + 61 3 9076 6077 
Facsimile: + 61 3 9076 2431 
Email: Julian.elliott@alfred.org.au 
 
NEW ZEALAND 
AUCKLAND HOSPITAL 
*Mark Thomas 
Infectious Diseases Unit 
Park Road, Grafton 
Auckland, New Zealand 
Telephone: + 64 9 379 7440 
Facsimile: +64 9 307 4940 
Email: mg.thomas@auckland.ac.nz 
 
 
 
 
CENTRE CLINIC 
Ban Kiem Tee 
Rear 77 Fitzroy Street 
St Kilda, Victoria, 3182 
Telephone: + 61 3 9525 5866 
Facsimile: + 61 3 9525 3673 
Email: bk_tee@vicaids.asn.au 
 
 
 
 
 
 

SECOND-LINE STUDY 
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ARGENTINA 
CAICI 
Sergio Lupo  
Rodriguez 1215 
2000 Rosario Provincia de Santa Fe 
ARGENTINA 
Telephone: + 54 (341) 424 8045 
Facsimile: + 54 (341) 449 6326 
Email: sergiolupo@arnet.com.ar 
Hospital Central 
Victor Bittar  
Immunology Service 
Alem and Salta - Ground Floor West Wing 
5500 Mendoza 
ARGENTINA 
Telephone: + 54 (261) 420 1920 
Facsimile: + 54 (261) 420 2624 
Email: victorbittar@ciudad.com.ar 
 
Hospital Italiano 
*Waldo Belloso 
Gascon 450 
C1181ACH, CABA 
ARGENTINA 
Telephone: + 54 (11) 4959 0393 
Facsimile: + 54 (11) 4959 0393 
Email: waldo.belloso@hospitalitaliano.org.ar 
 
 
Eurosistemas S.A. 
Arnaldo Casiro 
Gorriti 4001 
1406 Buenos Aires 
ARGENTINA 
Telephone: + 54 (11) 4611 6666  
Facsimile: + 54 (11) 4612 2805 
Email: casiroa@fibertel.com.ar 
 
 
 
Hospital J.M. Ramos Mejía 
*Marcelo Losso 
Servicio de Immunocomprometidos 
Urquiza 609 
Pabellon de Clinica, 2 Piso 
C1221 ADC Buenos Aires 
ARGENTINA 
Telephone: + 54 (11) 4931 5252 
Facsimile: + 54 (11) 4956 1522 
Email: mlosso@hivramos.org.ar 
 
Hospital Prof. Alejandro Posadas 
Hector Laplume 
Av. Presidente Illia y Av. Marconi 
El Palomar, Haedo 
1706 Provincia de Buenos Aires 
ARGENTINA 
Telephone: + 54 (11) 4469 9300 
Facsimile: + 54 (11) 4469 9279 
Email: hlaplume@speedy.com.ar 
 
Hospital Rawson 
Norma del Carmen Luna 
Bajada Pucará 2025 
5000 Córdoba 
ARGENTINA 
Telephone: +54 (351) 4348754 
Facsimile: +54 (351) 422 7452 
Email: danielo.david@gmail.com 
 
FUNCEI 
Gustavo Lopardo 
French 3085, 
C1425AWK, CABA 
ARGENTINA 
Telephone: +54 (11) 5236 7772 
Facsimile: +54 (11) 5236 7706 
Email: glopardo@intramed.net.ar 
 
Centro de Estudio y Tratamiento Infectológico 
(CETI)  
Jorge Contarelli 
Calle 53 #1082 (between 16 and 17) 
La Plata, Provincia de Buenos Aires 
ARGENTINA 
Telephone: +54 (221) 4518082 
Facsimile: +54 (221) 4539462 
Email:infectologiaceti@gmail.com 
Centros de Estudios y Atencion De Infectologia 
(CEADI) 
Oscar Garcia Messina 
Guayaquil 866, 
C1424CAV - CABA 
ARGENTINA 
Telephone: +54 (11) 32430151  
Email:garciamessina@gmail.com 

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CHILE 
Hospital San Borja-Arriaran 
*Marcelo Wolff 
University of Chile 
Santa Elvira 629 
Santiago 
CHILE 
Telephone: + 56 (2) 551 6738 
Facsimile: + 56 (2) 556 5025 
Email: marcewolff@yahoo.com 
 
Hospital de la Universidad Católica Pontificia 
Carlos Perez 
Direccion Medica P8 
Marcoleta 367 
Santiago 
CHILE 
Telephone: +56 (2) 354 3103 
Email: caperezco@gmail.com 
 
PERU 
Instituto de Medicina Tropical Alexander von 
Humboldt, Universidad Peruana Cayetano 
Heredia 
*Eduardo Gotuzzo 
Av Honorio Delgado 430 
Urbanizacion Ingenieria 
San Martin de Porres 
PERU 
Telephone: +51 (1) 482 3910 
Email: eduardogotuzzo@yahoo.es 
 
IMPACTA 
Jorge Sanchez 
Av Grau 1010 
Barranco 
Lima 
PERU 
Telephone: +51 (1) 242 3072 
Email: jsanchez@inmensa.org 
 
Hospital Almenara 
Raul Salazar 
Av Grau 800 Piso 1B Oeste 
Urbanizacion Ingenieria 
La Victoria 
Lima 
PERU 
Telephone: +51 (1) 473 0956/475 6378 
Email: salazarraul@speedy.com.pe 
 
Via Libre 
Robinson Cabello 
Jr Paraguay 478 
Carcado de Lima 
Lima 
PERU 
Telephone: +51 (1) 203 9900 
Email: robinsoncabello@yahoo.com 
 
MEXICO 
Instituto Nacional de Ciencias Medicas y 
Nutricion “Salvador Zubirán” 
*Juan Sierra-Madero 
Department of Infectious Diseases  
Vasco de Quiroga 15, Tlalpan 
Mexico D.F. 
MEXICO  
Telephone: + 52 (5) 655 9675 
Facsimile: + 52 (5) 513 8106 
Email: jsmadero2@terra.com.mx 
Hospital General de Guadalajara 
Jaime Andrade Villanueva 
Calle Hospital 278 SH 
Colonia Alcalde Barranquitas 
Guadalajara 44280 
Estado de Jalisco 
MEXICO  
Telephone: +33 (3658) 2848 
Facsimile:  
Email: jandradev@msn.com 
 
 
 
 
 

SECOND-LINE STUDY 
5th November 2009 
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ENGLAND 
Chelsea & Westminster Hospital 
*Brian Gazzard 
369 Fulham Road 
Fulham, London 
SW10 9NH 
UNITED KINGDOM 
Telephone: + 44 208 746 8239 
Facsimile: + 44 208 746 5611 
Email: Yvonne.Stupple@chelwest.nhs.uk 
 
 
IRELAND 
Mater Misericordiae University Hospital 
*Paddy Mallon 
Catherine McAuley Education and Research 
Centre 
Nelson Street 
Dublin 7 
IRELAND 
Telephone: +353 1 716 6311 
Facsimile: +353 1 716 6335 
Email: Paddy.Mallon@ucd.ie 
 
 
FRANCE 
Hopital Saint-Louis 
*Jean-Michel Molina 
Department of Clinical Infectious Diseases 
1 Avenue Claude 
Vellefaux 75010 
Paris 
FRANCE 
Telephone: +33 (1) 4249 9066 
Facsimile: +33 (1) 4249 9067 
Email: jean-michel.molina@sls.aphp.fr 
 
 
GERMANY 
Johann Wolfgang Goethe-University Hospital 
*Christoph Stephan 
HIVCENTER Building No. 68  
Theodor-Stern-Kai 7 
60590  Frankfurt 
GERMANY 
Telephone: +49 (69) 6301 7680 
Facsimile: +49 (69) 6301 5712 
Email: Christoph.Stephan@hivcenter.de 
Medical Group Practice 
Heiko Jessen 
Medical Group Practice - General Medicine and 
HIV 
Motzstr 19 
Berlin 10777 
GERMANY 
Telephone: +49 (30) 235 10 70 
Facsimile: +49 (30) 235 10 722 
Email: heiko.jessen@gmx.de 
 
 
 

SECOND-LINE STUDY 
5th November 2009 
Page 8 of 92 
ISRAEL 
Rambam Medical Center
*Eynat Kedem 
Immunology Allergy & AIDS Institute 
B. Rappaport Faculty of Medicine, Technion 
Haifa 31096 
ISRAEL 
Telephone: +972 4 854 3581 
Facsimile: +972 4 854 3327 
Email: e_kedem@rambam.health.gov.il 
 
 
MALAYSIA 
University of Malaya Medical Centre 
*Adeeba Kamarulzaman 
Clinical Investigations Centre (CIC) 
13th Floor, Menara Utama 
Lembah Pantai 
Kuala Lumpur 50603 
MALAYSIA 
Telephone: + 60 (3) 7950 2168 
Facsimile: + 60 (3) 7955 7740 
Email: adeeba@ummc.edu.my 
 
Hospital Sungai Buloh  
Christopher Lee 
Department of Medicine 
Jalan Hospital 
47000, Sungai Buloh 
Selangor 
MALAYSIA 
Telephone: +60 (3) 6145 4333 
Facsimile: +60 (3) 6157 1703 
Email: chrislee@hkl.gov.my 
 
Hospital Pulau Pinang 
Chow Ting Soo 
Jalan Residens 
10990 Georgetown 
Pulau Pinang  
MALAYSIA 
Email: tingsoochow@yahoo.com 
 
HONG KONG 
Queen Elizabeth Hospital 
*Patrick Li 
30 Gascoigne Road 
Kowloon 
HONG KONG 
Telephone: + 852-295-86731 
Facsimile: + 852-238-44698 
Email: lickp@ha.org.hk 
 
 
TAIWAN 
National Taiwan University Hospital 
*Chien-Ching Hung 
Section of Infectious Diseases Department of 
Internal Medicine 
No. 7 Chung-Shan South Road 
Taipei, TAIWAN 
Telephone: +886 02 397 0800 Ext 2743 or 3726 
Facsimile: + 886 02 397 1412 
Email: hcc0401@ntu.edu.tw 
 

SECOND-LINE STUDY 
5th November 2009 
Page 9 of 92 
SINGAPORE 
Tan Tock Seng Hospital 
*Poh-Lian Lim 
Infectious Diseases Research Centre 
11 Jalan Tan Tock Seng 
Singapore 308433 
SiNGAPORE 
Telephone: + 65 6357 7924 
Facsimile: +65 (6252) 3540 
Email: poh_lian_lim@ttsh.com.sg 
 
 
THAILAND 
 
HIV-NAT Program on AIDS - Thai Red Cross  
AIDS Research Centre 
*Praphan Phanuphak 
HIV-NAT Research Collaboration 
104 Ratchadamri Road 
Pathumwan 
Bangkok 10330  
THAILAND 
Telephone: +66 2 252 7888 
Facsimile: +66 2 252 5779 
Email: praphan.p@chula.ac.th 
 
 
Research Institute for Health Sciences (RIHES), 
Chiang Mai University 
Khuanchai Supparatpinyo 
110 Intavaroros Road 
Sriphum, Muang  
Chiang Mai 50200  
THAILAND 
Telephone: +66 5394 5055-8 
Facsimile: +66 5322 1849 
Email: khuanchai@idthai.org 
 
Chiang Rai Prachanukroh Hospital 
Pacharee Kantipong 
1039 Sathanpayaban Road 
Muang District 
Chiang Rai 57000 
THAILAND  
Telephone: +66 53 711300 ext 1784 
Email: pachareek@hotmail.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Khon Kaen University 
Ploenchan Chetchotisakd 
Division of Infectious Disease and Tropical 
Medicine 
Department of Medicine 
The Srinagarind Hospital, Khon Kaen University 
123 Mitraparb Highway 
Khon Kaen 4002 
THAILAND 
Telephone: +66 43 363 654 
Facsimile: +66 43 203 772 
Email: ploencha@kku.ac.th 
 
Chonburi Hospital,  
Chureeratana Bowonwatanuwong  
Chonburi 20000  
THAILAND  
Telephone: +66 38-931395 
Email: c.bowon@gmail.com 
 
 
 
 
 
 
Khon Kaen Hospital 
Niramon Leerattanapecth 
56 Srichan road, Amphor Muang 
Khon Kaen 40000 
THAILAND 
Phone: + 66 81 876-8566 
Email : niram02@yahoo.com 
 
 
CHINA 
DiTan Hospital 
Hongxin Zhao 
No8 Jingshun Dongjie 
Chaoyang District 
Beijing 
China 
Telephone: +86 (10) 8432 2581 
Email: zhao_hongxin66@yahoo.com.cn 
 
PUMCH 
Taisheng Li 
1 Shuaifuyuan Wangfujing 
Beijing 
China, 100730 
Telephone: +(8610) 6529 5086 
Facsimile: + (8610) 6529 5046 
Email: litsh@263.net 
 

SECOND-LINE STUDY 
5th November 2009 
Page 10 of 92 
Beijing You An Hospital 
Hao Wu 
No. 8 Xi Tou Tiao 
You’an Men Wai 
Fent Tai District 
Beijing 
China 
Tel: +86 (10) 6305 3963 
Facsimile: +86 (10) 6329 4417 
Email: wuhd@public.bta.net.cn 
 
Shanghai Public Health Clinical Centre (Fudan 
University) 
Hongzhou Lu 
2901 Caolang Road 
Jinshan District 
Shanghai 
China, 201508 
Telephone: +(8621) 5724 8758 
Facsimile: + (8621) 5724 8758 
Email: luhongzhou@fudan.edu.cn 
 
Guangzhou No 8 People’s Hospital 
Cai Weiping 
627 Dongfeng Dong Road 
Guangzhou 
P.R. China 510060 
Telephone: +(8620) 83710422 
Email: caiwp@163.net 
 
 
 
INDIA 
YRGCARE Medical Center VHS 
*Nagalingeswaran Kumarasamy 
Y.R.Gaitonde Medical, Educational & Research 
Foundation 
Voluntary Health Services  
Rajiv Gandhi Salai 
Taramani  
Chennai 600 113  
INDIA 
Telephone: +91 (44) 39106818 
Email: kumarasamy@yrgcare.org 
 
Institute of Infectious Diseases 
Sanjay Pujari 
Kumar Business court, D wing 
1st Floor, Kumar Business Court, D wing 
Mukundnagar, Pune 411037 
India
Telephone: +91 20 24274950 
Email: sanjaypujari@gmail.com 
 
 
 
 
NIGERIA 
Plateau State Specialist Hospital 
*Chidi Nwizu 
Institute Of Human Virology 
North East Regional Office 
No 11 Niven Close off 
Ibrahim Taiwo Road GRA 
Jos 
Plateau State 
Nigeria 
Telephone: +2348086435943 
Facsimile: 
Email: canwiz@pol.net 
 
Evangel Hospital (ECWA) 
Chidi Nwizu 
P.M.B. 2238 
Jos 
Plateau State  
NIGERIA 
Email: canwiz@pol.net 
 
Jos University Teaching Hospital (JUTH) 
Oche Agbaji 
2 Murtala Mohammed Way 
Jos 
Plateau State 
NIGERIA 
Tel: +234 803 349 1857 
Email: oagbaji@yahoo.com 
 
 
 
 
 
 
 
 
 
 
 
 
 

SECOND-LINE STUDY 
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SOUTH AFRICA 
 
JOSHA Research Bloemfontein 
Sharne Foulkes 
1st Floor, Rubins Building 
28 East Burger Street 
Bloemfontein 
SOUTH AFRICA 
Telephone: + 27 514 128 160 
Facsimile: + 27 514 128 190 
Email: sharne.foulkes@josha.co.za  
 
Desmond Tutu HIV Foundation 
Robin Wood 
Wernher Beit Building North 
UCT Medical School 
Anzio Road 
Observatory 7925 
Cape Town, South Africa 
Phone: +27 21 650 6726 
Fax: +27 21 650 6963 
Email: Robin.Wood@hiv-research.org.za 
 
 
 
Chris Hani Baragwanath Hospital 
*Lerato Mohapi 
University of Witwatersrand 
Soweto 
South Africa 
Email: mohapil@hivsa.com 
 

SECOND-LINE STUDY 
5th November 2009 
Page 12 of 92 
SECOND-LINE PROTOCOL AMENDMENT LIST 
Original protocol date: 14th May 2008 
Previous protocol version: Version 1.0 (2nd July 2009) 
Current protocol version: Version 2.0 
Amendment date: 28th October 2009 
 
Please find below the list of amendments that have been made to the SECOND-LINE protocol Version 1.0 (2nd 
July 2009) to create the current version Version 2.0 (28th October 2009) 
Chapter/Section Page # 
Issues/Comments 
Cover page 
1 
Update date and protocol number. 
PSC Committee 
2 
Add details for Hedy Teppler from Merck. 
PSC Committee 
2 
Add details for Chris Woodward from Abbott. 
PSC Committee 
3-10 
Added in an * for those site PIs on the PSC committee. 
Site list 
3-10 
Removed Vietnam from site list and updated some contact details. 
Protocol 
synopsis 
19 
Add details of dose, mode of administration, and duration of treatment of 
ritonavir boosted lopinavir soft gelatin capsules: 133.3mg/33.3mg 6 capsules 
once daily or 3 capsules twice daily. 
Protocol 
synopsis 
19 
Add details of ritonavir boosted lopinavir availability both tablet and soft 
gelatin capsule formulations. 
Protocol 
synopsis 
20 
Added a sentence to clarify that the third year of drug supply will only be to 
those sites/countries where the drugs are not available via the local health 
care system 
Schedule of 
assessments 
23 
Superscripts h and i were inserted incorrectly in the table.  These were 
switched back around to be sequential. 
Schedule of 
assessments 
23 
Made the X grey for plasma HIV drug resistance test at screening as this is only 
required if the site is a “genotypic site”.  Plus, added an X at week 0 for the 
central drug resistance test.  This has also been updated under subscript k 
Schedule of 
assessments 
23 
Removed the “x” from dispense study medication at the week 96 visit. 
Schedule of 
assessments 
23 
Under subscript e we have changed the wording to indicate that Hep B should 
be done at screening if the previous tests have been negative or there is no 
report to verify a previous positive test. 
4.1 
30 
Changed the number of sites from 30 to approximately 50, and added New 
Zealand to the country list. 
5.1 
32 
Add details of dose, mode of administration, and duration of treatment of 
ritonavir boosted lopinavir soft gelatin capsules: 133.3mg/33.3mg 6 capsules 
once daily or 3 capsules twice daily. 
5.2.2 
32 
Added in additional language about the Kaletra soft gel capsules that will be 
available for use by sites. 
5.2.2 
33 
Added in language about Kaletra not being sent to Australian sites.  In Australia 
the costs associated with provision of Kaletra will be reimbursed via NCHECR. 
5.2.3 
33 
Updated the information on the ALMAC depots that will be used for a central 
repository and shipment. 
5.4 
34 
Additional language added to the selection on NRTIs regarding mandatory 
selection of innovator or FDA/WHO approved generic formulations. 
5.13 
41 
Add more detail about prohibited drugs. 
6.1.2 
43 
Clarified that Hep C antibody need only be done if previous test results have 
been negative or if there is no report available to confirm a positive result. 
8.2 & 8.5 
48 & 
49 
Updated the information on how to report a pregnancy on study.  It needs to 
be an expedited report and therefore will be completed on the SAE form 
8.5 
50 
Highlighted in bold the 24hour reporting time requirement for SAE reporting.  
Also stated that 24 hours equals one working day. 
9.2 
51 
Updated the number of labels that are on the booklet label from 8 to 13.  Also 
indicated that some labels are single-panel English labels. 

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Page 13 of 92 
9.2 AND 9.3 
52 
Drug packaging, labelling and dispensing sections have been updated to 
include Kaletra soft-gel capsules. 
10.1 
53 
Remove information about SydPath blood packs being provided for collection 
on spare serum and plasma samples.  Blood tubes will be sourced locally and 
reimbursed via the study budget. 
10.7 
54 
Removed the statement that the first interim analysis will be conducted on 
locally measured HIV-RNA. 
APPENDIX 2 
81 
Update the template for the patient information and consent form with the 
changed blood volumes collected at each visit.  
APPENDIX 2 
81 
Updated the side effects profile of raltegravir 
APPENDIX 2 
82 
 Updated the table of adverse events to include those for Kaletra and Aluvia in 
the template for the patient information and consent form. 
APPENDIX 2 
83 
Updated the patient information and consent form in regards to compensation 
in case of injury to make the template generic for ALL sites, not just Australia 

SECOND-LINE STUDY 
5th November 2009 
Page 14 of 92 
Investigator agreement and signature page 
between the NCHECR and the study investigator (s) 
 
Principal Investigator: __________________________________________ 
 
Co-investigators (please list, if applicable): __________________________ 
 
 
This study will compare two SECOND-LINE regimens of combination antiretroviral therapy in people living with HIV 
infection (PLHIV) experiencing confirmed virological failure of a first-line NNRTI/2N(t)RTI regimen.  The trial will 
enrol participants across a range of high-middle income sites in Australia, Asia, Latin America, Europe and low 
income sites in sub-Saharan Africa.  Participants will be randomised to receive either boosted lopinavir + 2-
3N(t)RTIs or boosted lopinavir + raltegravir.  The study will be conducted for 96 weeks and is expected to involve 
550 eligible participants. 
Clinical work is expected to start in the second half of 2009.  This trial protocol, ICH Guidelines on Good Clinical 
Practice, the NCHECR standard operating procedures, the Therapeutic Goods Administration Access to Unapproved 
Therapeutic Goods – Clinical Trials in Australia regulations and the Declaration of Helsinki will be adhered to in all 
cases. 
All patient data will be completely and accurately recorded in the patient case record forms.  Case record forms will 
be completed by the site following study visits.  Patient medical records will also be kept up-to-date regarding study 
information.  The trial monitor will be allowed to review the patient case record forms, the source medical records, 
the trial progress and the consent forms.  In addition, the sponsor’s auditors and regulatory authority auditors will 
be allowed access to all study documents, including source documents, if necessary. 
Before entering this study, all participants, or in special cases, their legal representative or guardian will give their 
written informed consent.  The signed consent forms will be retained by the investigator(s)/co-investigator(s) listed 
below. 
 
I/We accept responsibility for the conduct of the research detailed in the proposal including all protocol-specific 
assessments, and I/we agree to abide by all decisions made by our Ethics Committee. 
 
I/We agree to the above, which, in conjunction with the NHMRC Statement on Ethical Conduct in Research 
Involving Humans, will serve as the basis for co-operation in this study. 
RESPONSIBLE INVESTIGATOR 
 
             CO-INVESTIGATORS 
(signature and date) 
 
 
 
 
(signature and date) 
 
_________________________________ 
 
___________________________________ 
 
SPONSOR’S REPRESENTATIVE 
(signature and date) 
__________________________________ 
 
NCHECR MONITOR(S)/COORDINATOR (S) 
__________________________________ 
 

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TABLE OF CONTENTS 
Name and address of sponsor: ............................................................................................................................................ 1 
Name and address of Protocol Steering Committee (PSC) : ................................................................................................. 1 
Investigational Sites and Principal Investigators .................................................................................................................. 4 
Investigator agreement and signature page ...................................................................................................................... 12 
PROTOCOL SYNOPSIS......................................................................................................................................................... 19 
Flow chart/time and events schedule ................................................................................................................................ 18 
1 
INTRODUCTION .......................................................................................................................................................... 25 
1.1 
Background and rationale ...................................................................................................................................... 25 
1.2 
Rationale for investigation of a dual therapy, N(t)RTI sparing regimen .................................................................. 27 
1.3 
Research hypothesis .............................................................................................................................................. 28 
2 
STUDY OBJECTIVES ..................................................................................................................................................... 29 
2.1 
Primary objective ................................................................................................................................................... 29 
2.2 
Secondary objectives.............................................................................................................................................. 29 
2.3 
Exploratory objectives ............................................................................................................................................ 29 
3 
STUDY POPULATION .................................................................................................................................................. 29 
3.1 
Eligibility criteria .................................................................................................................................................... 29 
3.2 
Inclusion criteria ..................................................................................................................................................... 29 
3.3 
Exclusion criteria .................................................................................................................................................... 29 
3.4 
Withdrawal of subjects from study ........................................................................................................................ 30 
4 
TRIAL DESIGN ............................................................................................................................................................. 30 
4.1 
Study design ........................................................................................................................................................... 30 
4.2 
Criteria for evaluation ............................................................................................................................................ 31 
5 
TREATMENT OF SUBJECTS .......................................................................................................................................... 33 
5.1 
Treatment group assignment ................................................................................................................................. 33 
5.2 
Study drugs ............................................................................................................................................................ 33 
5.3 
Genotypic resistance testing .................................................................................................................................. 34 

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5.4 
Backbone N(t)RTI selection .................................................................................................................................... 34 
5.5 
Clinical management of ART regimen failure .......................................................................................................... 36 
5.6 
Management of ART intolerance ............................................................................................................................ 37 
5.7 
Dose modifications ................................................................................................................................................. 37 
5.8 
Toxicity management ............................................................................................................................................. 37 
5.9 
Protocol-specific toxicity management guidelines ................................................................................................. 39 
5.10 
Management of AIDS Defining Illnesses (ADI) and Immune Restoration Disease (IRD) .......................................... 41 
5.11 
Discontinuation of therapy..................................................................................................................................... 41 
5.12 
Treatment adherence ............................................................................................................................................. 42 
5.13 
Prohibited and restricted therapies during the study ............................................................................................. 42 
 
5.14 
Concomitant medication  
 
 
 
 
 
 
 
 
            35 
6 
STUDY PROCEDURES .................................................................................................................................................. 43 
6.1 
Initial screening period ........................................................................................................................................... 43 
6.2 
Randomisation visit ................................................................................................................................................ 45 
6.3 
Follow-up visits ...................................................................................................................................................... 46 
7 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................................................................. 47 
8 
ADVERSE EVENT REPORTING ..................................................................................................................................... 48 
8.1 
Definition and reporting of an overdose ................................................................................................................ 49 
8.2 
Reporting of pregnancy .......................................................................................................................................... 49 
8.3 
Adverse events ....................................................................................................................................................... 49 
8.4 
Serious non-AIDS events (SNAEs) ........................................................................................................................... 49 
8.5 
Serious adverse events (SAEs) ................................................................................................................................ 50 
8.6 
Laboratory test abnormalities ................................................................................................................................ 51 
8.7 
Other safety considerations ................................................................................................................................... 52 
9 
PACKAGING, LABELLING and ACCOUNTABILITY of TRIAL SUPPLIES ............................................................................ 52 
9.1 
Study drugs ............................................................................................................................................................ 52 
9.2 
Packaging and labeling ........................................................................................................................................... 52 
9.3 
Handling and dispensing of study drugs ................................................................................................................. 53 
9.4 
Study drug records at investigational site(s) ........................................................................................................... 53 
10 
BIOLOGICAL SAMPLES ............................................................................................................................................ 54 

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10.1 
Blood collection ..................................................................................................................................................... 54 
10.2 
Labeling of specimen tubes .................................................................................................................................... 54 
10.3 
Transportation of samples to pathology ................................................................................................................ 54 
10.4 
Storage of samples ................................................................................................................................................. 55 
10.5 
Processing of samples ............................................................................................................................................ 55 
10.6 
Reporting of results ................................................................................................................................................ 55 
10.7 
Plasma HIV RNA determination .............................................................................................................................. 55 
11 
STATISTICAL METHODOLOGY ................................................................................................................................. 55 
11.1 
Sample size determination and statistical analysis ................................................................................................. 55 
11.2 
Supplementary sample size assessments for exploratory analysis………………….…………………………………………………..47 
11.3  
Analysis plan……………………………………………………………………………………………………………………………………………….………48 
11.4  
Schedule of analyses…………………………………………………………………………………………………………………………………………..49 
11.5  
Demographics and baseline characteristics…………………………………………………………………………………………………………51 
11.6  
Efficacy analyses…………………………………………………………………………………………………………………………………………………51 
11.7  
Subgroup analyses……………………………………………………………………………………………………………………………………………..51 
11.8  
Safety analyses……………………………………………………………………………………………………………………………………………………52 
12 
DATA COLLECTION, SOURCE DOCUMENTS AND RECORD RETENTION .................................................................... 60 
12.1 
Data collection and source documents ................................................................................................................... 60 
12.2 
Records retention................................................................................................................................................... 61 
12.3 
Monitoring for protocol compliance....................................................................................................................... 61 
12.4 
Auditing ................................................................................................................................................................. 62 
13 
ETHICS COMMITTEE/REGULATORY APPROVAL AND INFORMED CONSENT ............................................................ 62 
13.1 
Ethics...................................................................................................................................................................... 62 
13.2 
Institutional review board/independent ethics committee (IRB/IEC) ..................................................................... 62 
13.3 
Compliance with the protocol and protocol revisions ............................................................................................ 63 
13.4 
Informed consent ................................................................................................................................................... 63 
13.5 
Informed consent procedures ................................................................................................................................ 63 
14 
CONFIDENTIALITY OF DATA .................................................................................................................................... 65 
14.1 
Confidentiality of participant records ..................................................................................................................... 65 

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14.2 
Confidentiality of study data .................................................................................................................................. 65 
15 
FINANCING AND INSURANCE ................................................................................................................................. 65 
16 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................................................... 66 
17 
PUBLICATION POLICY ............................................................................................................................................. 66 
References ......................................................................................................................................................................... 67 
Appendix 1: Definitions and Criteria For HIV Disease and AIDS Events .............................................................................. 71 
Appendix 2: Template Patient Information Statement and Consent Form ......................................................................... 71 
Appendix 3: Diagnostic Criteria for Serious Non-AIDS Events ............................................................................................ 80 

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PROTOCOL SYNOPSIS 
Title of Study: 
A randomised open-label study comparing the safety and efficacy of a ritonavir-boosted lopinavir and 2-
3N(t)RTI backbone versus ritonavir-boosted lopinavir and raltegravir in participants virologically failing first-
line NNRTI/2N(t)RTI therapy: the SECOND-LINE study. 
Estimated Number of Study Centres and Countries/Regions: 
Approximately 50 selected centres in Australia, Africa, Asia, Latin America, and Europe. 
Primary Objective 
The primary objective of this study is to compare the virological efficacy of the two strategies as measured 
by the proportion of participants with HIV RNA <200 copies/mL 48 weeks after randomisation.  
Research Hypothesis 
In HIV-infected subjects who have virologically failed first-line antiretroviral therapy comprising 2N(t)RTI + 
NNRTI a regimen of second-line therapy incorporating ritonavir-boosted lopinavir and raltegravir provides 
comparable (i.e. non-inferior) antiretroviral efficacy over 48 weeks to a regimen containing ritonavir-
boosted lopinavir and 2-3N(t)RTIs. 
Study Design: 
This is a Phase IIIb/IV, international, randomised, open label study comparing two regimens of combination 
antiretroviral therapy in people living with HIV with confirmed virological failure of first-line NNRTI/2N(t)RTI 
regimens.  The study will run for 96-weeks but the primary analysis will take place at the week 48 time 
point. 
Eligible participants will be randomised in equal proportions to one of two regimens of combination ART as 
follows: 
I. 
ritonavir boosted lopinavir (LPV/r) + 2-3N(t)RTIs 
II. 
ritonavir boosted lopinavir (LPV/r) + raltegravir  
Randomisation will be stratified for the following variables: 
1. Clinical site 
2. Plasma HIV-1 RNA viral load < or ≥ 100,000 copies/mL 
Number of Subjects per Group: 
Approximately 275 eligible subjects will be randomly allocated to each of the two treatment arms giving a 
study total of 550 participants. 
 

SECOND-LINE STUDY 
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Study Population: 
Eligible participants will satisfy all of the following criteria within 45 days prior to randomisation. 
Inclusion criteria: 
1. HIV-1 positive by licensed diagnostic test 
2. Aged 16 years or older (or minimum age as determined by local regulations or as legal 
requirements dictate) 
3. Have received first antiretroviral regimen consisting of an NNRTI plus 2N(t)RTIs for ≥ 24 weeks 
4. No change in antiretroviral therapy within 12 weeks prior to screening 
5. Failed first-line NNRTI + 2N(t)RTI combination therapy according to virological criteria defined by 
two consecutive (≥7 days apart) HIV RNA results of >500 copies/mL 
6. No prior or current exposure to HIV protease inhibitors and/or HIV integrase inhibitors 
7. Able to provide written informed consent 
Exclusion criteria: 
1. 
The following laboratory variables: 
a)      
absolute neutrophil count (ANC) <500 cells/µL 
b)      
hemoglobin <7.0 g/dL 
c)      
platelet count <50,000 cells/µL 
d)     
ALT >5 x ULN 
2. 
Pregnant or nursing mothers 
3.    Participants with active viral hepatitis B infection defined by the presence in serum of hepatitis B 
surface antigen  
4.     Use of immunomodulators within 30 days prior to screening 
5.  Use of any prohibited medications (rifampicin, midazolam, triazolam, cisapride, pimozide, 
amiodarone, 
dihydroergotamine, 
ergotamine, 
ergonovine, 
methylergonovine, 
astemizole, 
terfenadine, vardenafil, and St. John’s wort) 
6.    Intercurrent illness requiring hospitalisation 
7.  Active opportunistic disease not under adequate control in the opinion of the site Principal 
Investigator 
8.    Participants with current alcohol or illicit substance abuse that in the opinion of the site Principal 
Investigator might adversely affect participation in the study 
9.    Participants deemed by the site Principal Investigator unlikely to be able to remain in follow-up for 
the protocol-defined period 
Study Drugs, Dose and Mode of Administration, Duration of Treatment: 
I. 
ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tablets once daily or 2 tablets twice 
daily (OR 133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules 
twice daily) + 2-3N(t)RTIs  
II. 
ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily (OR 
133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules twice daily) + 

SECOND-LINE STUDY 
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raltegravir 400mg twice daily 
A maximum of 3 years drug supply (2 years of trial and one year post study) will be provided to study 
participants. If the study drugs are available via the local healthcare system at the end of the two years, the 
3rd year supply will not be provided. Raltegravir will be in tablet form and should be taken orally. Ritonavir 
boosted lopinavir will be available in both soft gelatin and tablet formulations. Selection of the N(t)RTI 
component of study arm I will be at the discretion of the treating physician according to local drug 
availability. Recommendations about the composition of the N(t)RTI backbone are made in section 5.4 of 
this protocol. For each combination ART regimen, section 5.5 of this protocol recommends options for 
episodes of drug intolerance that preserve the SECOND-LINE composition of the regimen where possible. 
Primary endpoint (week 48 and 96) 
The proportion of participants with HIV RNA <200 copies/mL. 
Secondary endpoints (week 48 and 96) 
A number of secondary endpoints will be examined in this protocol by randomised treatment arm.  These 
will include, but not be limited to the following: 
Virological 
 
an analysis of the time to loss of virological response (TLOVR) 
 
proportions of participants with <50 and <400 HIV RNA copies /mL 
 
time to plasma HIV RNA <200 copies/mL 
Immunological 
 
mean change in CD4+ cell count from baseline 
Safety 
 
total number of participants with any serious adverse events (SAEs), and the cumulative incidence 
of SAEs 
 
total number of participants with any adverse event(s) (AEs) and the cumulative incidence of all 
AEs  
 
total number of participants with any adverse event (AE), and cumulative incidence of all AEs 
associated with cessation of randomly assigned therapy 
Antiretroviral treatment 
 
analyses in which participants who change ART for any reason are classified as having failed 
randomised treatment 
 
time to change in randomly assigned therapy (all reasons individually and on aggregate) 
Exploratory Endpoints (week 48 and 96) 
A number of exploratory endpoints will be examined in this protocol by randomised treatment arm.  These 
will include, but not be limited to the following: 
Clinical 

SECOND-LINE STUDY 
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 
total number of AIDS events and deaths  
 
total number of serious non-AIDS events 
Metabolic and anthropometric 
 
mean/median changes from baseline in fasted lipids (TC, LDL-c, HDL-c, and TG), insulin and blood 
glucose 
 
changes in body morphology as determined by waist and hip measurements 
Resistance 
 
patterns of genotypic HIV resistance associated with virological failure 
Adherence 
 
adherence and virological outcomes (using the CPCRA instrument) 
Quality of Life 
 
quality of life assessment using the SF-12 instrument 
Statistical Methods: 
The primary endpoint is the comparison of proportions of participants in each arm whose plasma HIV RNA 
is <200 copies/mL after 48 weeks.  Under the assumption that there is no difference between randomised 
treatment policies, to have 90% power to demonstrate non-inferiority in the intention to treat (ITT) analysis 
using a 12% margin will require 248 participants per arm to be randomised (2-sided alpha=5%) making a 
total of 496 participants.  
 
To ensure that the per protocol (PP) analysis also has 90% power to demonstrate non-inferiority, the 
sample size needs to be increased for participants who switch ART due to treatment toxicity over the course 
of the first 48 weeks of study. In this population this is estimated to be no more than 10% of randomised 
participants. Therefore, to ensure 90% power to demonstrate non-inferiority on the ITT and subsequently 
on the PP analyses, a total of 550 (i.e. 273 per arm, round to 550) participants will be randomised.  The 
power of the study for the ITT analysis in this case is 92.9%. 
Schedule of Analyses: 
There will be four formal analyses conducted within this protocol: two interim analyses of week 24 data 
(one when 125 participants in each arm reach week 24; a second when all participants reach week 24), a 
primary analysis at week 48 (all participants complete week 48) and a follow up confirmatory analysis at 
week 96 (all participants complete week 96).  
Both interim analyses will be reviewed by an independent Data Safety Monitoring Board (DSMB) which will 
recommend to the Protocol Steering Committee (PSC) that the study should continue unchanged or be 
amended in light of observed differences between treatment arms or aspects of study conduct that warrant 
modification (e.g. poor recruitment, safety concerns, and substantial losses to follow-up).  Their review of 
treatment regimens will be coded as A and B.  The DSMB, in agreement with the PSC, may require stopping 
rules to be implemented that require changes in the conduct of the study should concerns about the safety 

SECOND-LINE STUDY 
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of participants arise from review of the week 24 results.  A conservative Peto-Prentice type stopping rule 
(p<0.001) will be used to judge whether one arm should be ceased for inferiority at each of the two interim 
analyses.  

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Flow chart/time and events schedule 
 
 
 
Study week numbera 
Procedure 
SCRb 
0 
4 
12 
24 
36 
48 
60 
72 
84 
96 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anthropometric studiesd 
 
X 
 
 
 
 
X 
 
 
 
X 
Quality of life 
 
X 
 
 
 
 
X 
 
 
 
X 
Adherence 
 
 
X 
 
 
 
X 
 
 
 
X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis C antibodye 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematologyh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma HIV-1 RNAi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CD4+ and CD8+ T cell (absolute and %) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasted metabolic parametersj 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Plasma HIV drug resistance testk 
X 
X 
 
 
 
 
 
 
 
 
 
Plasma and serum preparation for storage 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for central HIV-RNA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC preparation and storage 
 
X 
 
 
 
 
 
 
 
 
 
Clinical Drug Supplies 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a All efforts should be made to schedule visits in keeping with the proposed week numbers.  Visit windows are: week 4 (from week 2 to week 6),  week 
12-96 (actual visit can be 6 weeks either side of the scheduled visit date) 
b All screening assessments must be completed within 45 days prior to the date of randomisation 
c Vital signs include blood pressure, temperature, pulse, weight, height (baseline only) 
d Anthropometric studies include umbilical waist and maximum hip measurement 
e Hepatitis C antibody results need only be done at screening if previous test results were negative or there is no report available to confirm a positive 
result 
f If female and of child bearing potential 
g Biochemistry includes: electrolytes (sodium, potassium, bicarbonate, chloride, phosphate), creatinine, urea, ALT, creatinine kinase and total bilirubin. 
(aniona gap, creatinine clearance and glomerular filtration rate will be automatically calculated on the eCRF) 
h Haematology includes: haemoglobin, white cells, neutrophils, lymphocytes, platelets 
i All HIV-1 RNA assays will be run by a laboratory using an assay with a lower limit of detection of 50 copies/mL in plasma 
j Fasting parameters includes: glucose, total cholesterol, HDL cholesterol, calculated LDL cholesterol, triglycerides and insulin (homeostasis model 
assessment-insulin resistance (HOMA-IR) will be automatically calculated on the eCRF) 
k If a site elects to conduct genotypic resistance testing, testing on all participants at that site must be conducted at screening.  However, ALL 
participants will have plasma stored at week 0 for HIV resistance genotype testing which will be centrally analysed 

SECOND-LINE STUDY 
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INTRODUCTION 
1.1 Background and rationale 
The emergence of the new antiretroviral therapy (ART) class of HIV-integrase strand transfer inhibitors (InSTIs) 
and data suggesting that the first-in-class drug raltegravir offers substantial and rapid anti-HIV potency means 
that the current paradigms of ART management may be revolutionised in the near future [1-3]. 
Current treatment guidelines recommend the construction of initial combination regimens derived from three 
classes – nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI), non-nucleoside reverse transcriptase 
inhibitors (NNRTI) and protease inhibitors (PI) [4,5].  The selection of the component drugs for inclusion in a 
regimen of combination antiretroviral therapy includes consideration of the following factors: potency; pill 
burden, dosing frequency, food restrictions, overlapping toxicities, genetic barrier to HIV drug resistance; and 
overall impact on activities of daily living and quality of life.  The availability of potent new agents increases the 
possible combinations of antiretroviral therapy. 
While the evidence base for the use of NNRTI+2N(t)RTI (2N(t)RTI defined as two drugs from the N(t)RTI class) as 
first-line therapy is reasonably well established, what should be done when first-line therapy fails is not [6].  The 
majority of the evidence that informs our current decision making regarding the management of antiretroviral 
regimens is based on studies conducted in antiretroviral naïve participants, or in those who have been exposed 
to and failed numerous N(t)RTI, NNRTI and PI containing regimens (‘deep salvage’).  In the case of first-line 
failure (i.e. defined as ‘virological failure’ and not simply intolerance of one or more components of the first-line 
regimen), current guidelines generally recommend the introduction of a ritonavir pharmaco-enhanced or 
‘boosted’ PI (PI/r) and the use of new or recycled N(t)RTIs.  Guidelines also allow for the maintenance of 
lamivudine (or emtricitabine) with a new N(t)RTI in a second line regimen because of evidence that the presence 
of the typical lamivudine/emtricitabine mutation (M184V) reduces viral fitness, confers residual antiviral activity, 
and improves viral sensitivity to zidovudine or tenofovir [4,5].  However, as compared to the case of first-line 
therapy, none of these recommendations are based on evidence gathered from optimal study designs, and the 
strength of evidence is therefore considered no more than moderate [6]. 
Guidelines generally recommend the use of an HIV resistance genotype assay if available to guide decision 
making in selection of second-line therapy.  There is however no conclusive proof that HIV resistance genotype 
testing contributes significantly to virological response after failure of first-line therapy [7,8]. 
The need for a better, evidence based understanding of the optimal therapy to follow first-line NNRTI+2N(t)RTI 
failure is made more urgent by the ART roll-out efforts in the developing world. WHO/UNAIDS announced in 
April 2007 that its ‘Three by Five’ campaign had registered two million HIV-infected people in developing 
countries receiving ART [9].  This, in combination with the efforts of The United States President's Emergency 

SECOND-LINE STUDY 
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Page 26 of 92 
Plan for AIDS Relief (PEPFAR), Médicins Sans Frontières (MSF) and other non-governmental organisations and 
developing world governments means that many HIV-infected individuals are likely to need second-line therapy 
in the near future after the inevitable failure of first-line ART [10].  To compound the problem, most of those 
accessing combination ART in resource-limited settings do not receive regular monitoring of plasma HIV RNA, 
and therefore, may remain on failing first-line regimens for far longer than those receiving the same drug 
combinations in settings in which both routine HIV RNA monitoring and alternative ART combinations are readily 
available [11,12]. It is likely in this latter situation that individuals will accumulate substantial resistance to the 
N(t)RTI (and NNRTI) class, and therefore the response to second-line combination therapy may be attenuated 
compared to that seen in developed countries (i.e. those placed on standard PI/r+2-3N(t)RTI second-line 
regimens may effectively be receiving PI/r monotherapy as a result of multi-N(t)RTI resistance) [13-15]. A 
computer simulation model suggests that in ART programs in which only clinical criteria are used for monitoring 
of standard first-line combination ART consisting of nevirapine (NVP) plus stavudine (d4T) and lamivudine (3TC), 
at least half will have selected at least 3 or more thymidine-analogue mutations at the time of switch [16].  
Finally, evidence suggests that resistance to the NNRTIs is associated with a greater risk of death compared to 
resistance to PIs [17,18]. 
The availability of raltegravir, coupled with a lack of robust evidence supporting the use of a PI/r+2-3N(t)RTI as 
an effective second-line strategy following the failure of a first-line combination consisting of an NNRTI+2N(t)RTI 
provides an opportunity to investigate a new SECOND-LINE approach.  The experimental arm of this study will 
consist of raltegravir coupled with a ritonavir-boosted PI versus a control arm comprising a ritonavir-boosted-
PI+2N(t)RTI (the current guideline recommended standard of care) in participants with documented failure of 
conventional first-line NNRTI+2N(t)RTI combination therapy.  
The PI/r to be used in both the experimental and control arms is heat stable ritonavir-boosted lopinavir (LPV/r).  
Heat stable LPV/r is an attractive option for a number of reasons.  Firstly, it is co-formulated product that does 
not require refrigeration, a distinct advantage in middle- and low-income countries which are located in tropical 
and sub-tropical zones.  Secondly it has acted as the ‘gold-standard’ boosted-PI since it was proven to be 
superior to nelfinavir in 2002 [19].  Since that time a substantial evidence base including data from a number of 
randomised trials in both treatment-naïve and -experienced participants has accumulated which has repeatedly 
demonstrated its efficacy and safety [20-22]. More recently it has been demonstrated in a randomised, 
controlled trial that LPV/r administered at 800/200 mg once daily provides a non-inferior virological response 
compared to that achieved with administration of LPV/r 400/100 mg twice daily, with similar rates of study 
discontinuation and adverse events [23]. Therefore this study protocol will allow prescription of LPV/r once daily 
or twice daily depending upon the preference of the investigator in discussion with study participants. 
This randomised study will permit the development of a stronger evidence base for second-line therapy while at 
the same time testing an innovative, attractive and compact regimen against the currently recommended 
standard(s) of care.  The study is SECOND-LINE in nature as it aims to not only test a novel dual ART combination 
but also a new management strategy.  The new management strategy aims to prove that drugs selected from 

SECOND-LINE STUDY 
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two drug classes to which a patient is naïve is non-inferior to the currently accepted standard-of-care strategy in 
which an agent from a new class (PI) is combined with two drugs from a class to which the patient has previously 
been exposed (N(t)RTIs).  Furthermore, the experimental dual combination arm of this study represents an 
antiretroviral management strategy consistent with the ‘public health approach’ recommended for use in 
resource-limited settings [24].  If this approach is proven effective it would open up a simplified ART 
management pathway consisting of first line ART incorporating two ART drug classes (NNRTI+2N(t)RTI) followed 
by second-line therapy incorporating two independent ART drug classes, PI (ritonavir-boosted PI) + InSTI 
(raltegravir)) 
1.2 
Rationale for investigation of a dual therapy, N(t)RTI sparing regimen 
The era of combination antiretroviral therapy has been characterised by the use of ‘triple-therapy’ and a 
proposal to use only 2 agents from 2 new classes to construct a second-line therapy might be viewed as 
inadequate.  However, there is evidence that the use of two potent antiretroviral drugs in combination is 
sufficient to confer powerful and durable antiretroviral activity.  The Merck 006 study suggested that a 
combination of unboosted indinavir and efavirenz conferred similar antiretroviral efficacy to a standard 
combination of unboosted indinavir plus 2N(t)RTIs [25].  This experience was repeated in the ACTG 5142 study in 
which a combination of boosted-lopinavir and efavirenz was comparable to that of boosted-lopinavir and 
2N(t)RTIs [26].  A single arm study in Thailand took 61 participants failing combination N(t)RTIs and enrolled 
them in a study of boosted indinavir 800/100 mg tid and efavirenz 600 mg qd.  Four year follow-up of the study 
demonstrated that 80% of all enrolled participants were maintaining a viral load <50 copies/ml on the same ART 
combination [27,28].  One recent study investigated and reported the efficacy of dual therapy with ritonavir-
boosted lopinavir and tenofovir with conventional triple therapy consisting of boosted-lopinavir used with 
various combinations of 2N(t)RTIs.  The study, while small, demonstrated very similar outcomes in both arms for 
virological control at 400 and 50 copies/ml.  CD4 count increase from baseline was significantly better in the dual 
therapy arm [29]. 
Evidence derived from antiretroviral salvage trials conducted in multi-class experienced participants provides 
indirect supporting evidence for the concept of the use of 2 potent agents as effective combination ART.  Most 
late salvage trials have demonstrated the best virological responses in those receiving the greatest number of 
fully active agents [30-34].  For instance, the addition of enfuvirtide in those naïve to the drug, improved 
virological responses in both the RESIST and POWER studies.  In these studies, participants who received the 
active protease inhibitor and enfuvirtide as a novel agent received at most two fully active agents.  More recent 
salvage studies have been able to examine the benefit of three fully active agents over two fully active agents.  In 
most cases there are numerically greater virological responses in persons who received three versus two fully 
active agents.  However, the differences are small and in some cases not statistically significant.  Seventy-three 
percent of those who received three active novel agents (enfuvirtide, etravirine and darunavir) achieved a viral 

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load of < 50 copies/ml at 24 weeks compared with 68% of participants who received two active novel agents 
(enfuvirtide and darunavir).  This difference was not statistically significant [32]. 
Similarly, the BENCHMRK studies demonstrated that 98% of 44 participants who received enfuvirtide, darunavir 
and raltegravir achieved a viral load of <400 copies/ml at 24 weeks compared with 87% of the 23 individuals who 
received enfuvirtide and darunavir but not raltegravir as novel agents [33].  Given the small numbers who 
received three fully active drugs it is impossible to draw firm conclusions from these studies relating to the 
benefit of three versus two fully active agents.  In addition, we propose in this study to provide two agents 
drawn from separate ARV classes to which people have not been previously exposed, which differs from the 
situation described in the late salvage studies described above in which participants received various mixtures of 
new classes in addition to new agents from classes to which the patient had previously been exposed. 
A separate reason for examining a dual combination of drugs from two new classes of ART in second-line therapy 
is that it is consistent with the simplified public health approach for the use of antiretroviral therapy. This 
strategy is generally agreed to be the only feasible option for the antiretroviral roll-out effort across resource-
limited settings worldwide [24]. The currently recommended approach for second-line ART is inconsistent with 
public health principles in that the advice about optimising the N(t)RTI combination is vague and complicated.  In 
response to this concern WHO has published a document which prioritises two 2N(t)RTI combinations according 
to whether thymidine-analogues (two high priority dual combinations) or non thymidine analogues (two high 
priority dual combinations) were used in the first-line combination regimen. The document also allows for the 
use of two specific 3N(t)RTI combinations as support for the boosted-PI in second-line ART based on theoretical 
considerations for which there is however no clinical efficacy data [35].  If this proposed study were to 
demonstrate non-inferiority with a regimen consisting of ritonavir boosted lopinavir plus raltegravir, then it 
would be possible to recommend simplified guidelines for both first- and second-line therapy in resource-limited 
settings. 
A final reason that studying a dual combination of drugs from two new classes of ART is attractive is that this 
strategy spares the continued use of N(t)RTIs in second-line regimens.  The N(t)RTIs have been associated with a 
range of toxicities which are most likely related to the mitochondrial toxicity of N(t)RTIs as a class, albeit with 
various manifestations depending upon the particular drug(s) administered.  The toxicities are many and include 
myelosuppression, peripheral neuropathy, lactic acidosis, pancreatitis, myopathy, peripheral lipoatrophy, 
impairment of renal function and metabolic derangements. 
1.3 Research hypothesis 
In HIV-infected subjects who have virologically failed first-line antiretroviral therapy, treatment with second-line 
antiretroviral therapy comprising ritonavir-boosted lopinavir and raltegravir provides comparable (i.e. non-
inferior) antiretroviral efficacy over 48 weeks to treatment with a regimen comprising ritonavir-boosted-
lopinavir and 2-3N(t)RTIs. 

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2 STUDY OBJECTIVES 
2.1 Primary objective 
To compare the virological efficacy of the two regimens. 
2.2 Secondary objectives 
A number of secondary outcomes will be assessed which are of relevance and interest in the assessment of the 
performance of the two study treatment regimens. These will include (but will not necessarily be limited to) 
virological, immunological, safety and antiretroviral treatment change. 
2.3 Exploratory objectives 
Some exploratory objectives will also be examined including clinical, metabolic, anthropometric, medication 
adherence and quality of life. 
3 STUDY POPULATION 
3.1 Eligibility criteria 
Eligible participants will satisfy all the following inclusion and exclusion criteria within 45 days prior to 
randomisation, unless otherwise stated.  No waivers will be issued.  Those with mild to moderate laboratory 
abnormalities can be re-screened (within the 45 day period) for the abnormal variable if appropriate in the 
opinion of the Principal Investigator at the site. 
3.2 Inclusion criteria 
1. HIV-1 positive by licensed diagnostic test 
2. Aged 16 years or older (or minimum age as determined by local regulations or as legal requirements 
dictate) 
3. Have received first antiretroviral regimen consisting of an NNRTI plus 2N(t)RTIs for ≥ 24 weeks 
4. No change in antiretroviral therapy within 12 weeks prior to screening 
5. Failed first-line NNRTI + 2N(t)RTI combination therapy according to virological criteria defined by two 
consecutive (≥7 days apart) HIV RNA results of >500 copies/mL 
6. No prior or current exposure to HIV protease inhibitors and/or HIV integrase inhibitors 
7. Able to provide written informed consent 
3.3 Exclusion criteria 
1. The following laboratory variables 
a)      
absolute neutrophil count (ANC) <500 cells/µL. 

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b)      
hemoglobin <7.0 g/dL 
c)      
platelet count <50,000 cells/µL 
d)     
ALT >5 x ULN  
2. Pregnant or nursing mothers 
3. Participants with active viral hepatitis B infection defined by the presence in serum of hepatitis B 
surface antigen  
4. Use of immunomodulators within 30 days prior to screening 
5. Use of any prohibited medications (rifampicin, midazolam, triazolam, cisapride, pimozide, 
amiodarone, 
dihydroergotamine, 
ergotamine, 
ergonovine, 
methylergonovine, 
astemizole, 
terfenadine, vardenafil, St. John’s wort) 
6. Intercurrent illness requiring hospitalisation 
7. Active opportunistic disease not under adequate control in the opinion of the investigator 
8. Participants with current alcohol or illicit substance abuse that in the opinion of the investigator 
might adversely affect participation in the study 
9. Participants deemed by the investigator unlikely to be able to remain in follow-up for the protocol 
defined period 
3.4 Withdrawal of subjects from study 
In general terms, all randomised study subjects should remain in follow-up for the duration of the trial, 
regardless of whether or not they continue to take randomly assigned therapy.  All study subjects should 
continue to attend all study visits and complete all study-mandated assessments. 
Subjects MUST be discontinued from study therapy AND withdrawn from the study for the following reasons: 
 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
 
Termination of the study by the Protocol Steering Committee. 
 
4 TRIAL DESIGN 
4.1 Study design 
This study is a Phase IIIB/IV, randomised, open label comparison of two independent regimens of combination 
antiretrovirals as second-line therapy following confirmed virological failure of a first-line NNRTI/2N(t)RTI 
combination ART regimen.  Eligible participants will be randomly allocated to receive one of the two study 
regimens. 

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The study will continue for 96-weeks but the primary analysis will take place using the week 48 time point.  A 
total of 550 subjects will be recruited over approximately 50 selected sites in Australia, New Zealand, Africa, 
Asia, Latin America and Europe. 
4.2 Criteria for evaluation 
4.2.1 Primary endpoint 
To compare the virological efficacy of the two regimens as measured by the proportion of participants with HIV 
RNA <200 copies/mL 48-weeks and 96 weeks after randomisation in the intention-to-treat (ITT) population*. 
*See definition of the ITT and other analysis populations in the analysis plan (Section 11.3) 
(note: all sites will have plasma stored at each visit (except screening visit) that will be analysed retrospectively 
by a central laboratory for HIV-RNA testing). 
4.2.2 Secondary endpoints 
A number of secondary endpoints will be examined at week 48 and 96 in this protocol by randomised treatment 
arm.  These will include, but not be limited to the following: 
Virological endpoints 
 
an analysis of the time to loss of virological response (TLOVR) 
 
proportions of participants with <50 and <400 HIV RNA copies /mL 
 
time to plasma HIV RNA <200 copies/mL 
 
time to treatment failure (>200 copies/mL) 
Immunological endpoints 
 
mean change in CD4+ cell count from baseline 
Safety 
 
total number of participants with any serious adverse events (SAEs), and the cumulative incidence of 
SAEs  
 
total number of participants with any adverse event(s) (AEs) and the cumulative incidence of all AEs  
 
total number of participants with any adverse event (AE), and cumulative incidence of all AEs associated 
with cessation of randomly assigned therapy 
Antiretroviral treatment 
 
analyses in which participants who change ART for any reason are classified as having failed randomised 
treatment 
 
time to change in randomly assigned therapy (all reasons individually and on aggregate) 
 

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4.2.3 Exploratory endpoints 
Clinical  
 
total number of AIDS events and deaths  
 
total number of serious non-AIDS events* 
Metabolic and anthropometric 
 
mean/median changes from baseline in fasted lipids (TC, LDL-c, HDL-c, and TG), insulin and blood glucose 
 
changes in body morphology as determined by waist and hip measurements 
Resistance 
 
patterns of genotypic resistance associated with virological failure 
Adherence 
 
adherence and virological outcomes (using the CPCRA instrument) 
Quality of Life 
 
quality of life assessment using the SF-12 instrument 
 
*Serious non-AIDS defining events will be defined as follows (refer to Appendix 4 for details on diagnostic 
criteria): 
 
acute myocardial infarction 
 
coronary artery disease requiring drug treatment 
 
coronary revascularisation  
 
congestive heart failure 
 
deep vein thrombosis 
 
peripheral arterial disease 
 
pulmonary embolism 
 
stroke 
 
end-stage renal disease (ESRD)  
 
decompensated liver disease  
 
non-AIDS-defining cancers  
 
diabetes mellitus 
 
For all endpoints (primary, secondary and exploratory), plans describing all proposed analyses will be prepared in 
advance of database lock for each defined interim and final evaluation. 

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5 TREATMENT OF SUBJECTS 
5.1 Treatment group assignment 
Eligible participants will be randomised in equal proportions to one of two regimens of combination ART: 
I. 
ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily (OR 
133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules twice daily) + 2-3N(t)RTIs 
II. 
ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily (OR 
133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules twice daily) + raltegravir 400 
mg 1 tablet twice daily 
Randomisation will be conducted via the electronic case report form.  Specific details regarding randomisation 
will be provided in the study Manual of Operations (MOOP). Randomisation will be stratified for the following 
variables: 
1. 
Clinical site 
2. 
Plasma HIV-1 RNA viral load < or ≥100,000 copies/mL 
5.2 Study drugs 
5.2.1 Raltegravir 
Raltegravir is an HIV integrase strand-transfer inhibitor licensed for use as part of combination ART in HIV-
infected subjects. Tablets are pink, oval-shaped, film-coated tablets with "227" on one side.  One 400mg tablet is 
taken orally, twice daily with or without food.  Tablets will be dispensed from local pharmacies in bottles 
containing 60 tablets.  The bottles must be stored at 20-25°C (68-77°F). 
 
5.2.2 Ritonavir boosted lopinavir 
Ritonavir boosted lopinavir is a co-formulation of one protease inhibitor and a pharmaco-enhancer licensed for 
use as part of combination ART in HIV infected subjects. Ritonavir boosted lopinavir is available in two different 
forms (‘Kaletra’ and ‘Aluvia’) depending upon the country in which it is marketed. The ‘Kaletra’ form comes as 
two formulations: (1) yellow, film-coated, ovaloid tablets embossed with the Abbott logo on one side and ‘KA” 
on the other, (2) orange, soft gelatin, liquid filled capsules.  The ‘Aluvia’ form comes as red, ovaloid, film-coated 
tablets embossed with the Abbott logo on one side and ‘AL’ on the other. Two 200 mg lopinavir/50 mg ritonavir 
tablets (i.e. 400 mg lopinavir/100 mg ritonavir) should be taken twice daily or four 200 mg lopinavir/50 mg 
ritonavir tablets (i.e. 800 mg lopinavir/200 mg ritonavir) should be taken once daily with or without food.  Three 
133.3 mg lopinavir/33.3 mg ritonavir capsules should be taken twice daily or six 133.3 mg lopinavir/33.3 mg 
ritonavir capsules should be taken once daily with or without food.  The tablets and capsules should be 
swallowed whole and not chewed, broken, or crushed.  The choice of once or twice daily dosing is the decision of 
the treating physician in discussion with the participant. As described in the background section of this protocol, 

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once daily dosing has now been shown to be virologically equivalent to twice daily. Tablets and capsules will be 
dispensed from local pharmacies in bottles containing 120 tablets and 180 capsules.  The tablet bottles must be 
stored at 20-25°C (68-77°F) and capsule bottles at 2-8°C (36°F - 46°F). Ritonavir boosted lopinavir will not be 
provided to Australian sites, as it is ready available via the local healthcare system.  In Australia the cost 
associated with provision of the drug will be covered by NCHECR. 
 
5.2.3 Drug distribution  
Drug will be distributed through central ALMAC depots in the following countries:  
 
USA - will ship directly to one clinical site in  Australia, New Zealand, and Mexico.  Drugs will be internally 
transported if there are more than one clinical site within the country 
 
Ireland-  will ship directly to sites in England, Ireland, France, Israel, Germany, Nigeria,  South Africa, and 
India 
 
Singapore - will ship directly to sites in Singapore, Malaysia, Hong Kong, Taiwan and Thailand 
 
Argentina 
 
Peru 
 
Chile 
 
5.3 Genotypic resistance testing 
This trial will be conducted in high, medium, and low income settings, in which genotyping will be variably 
available.  As such, the approach to HIV drug resistance testing during screening will be as follows: genotyping 
will be allowed but will be optional.  Sites wishing to guide the selection of the N(t)RTI backbone according to 
genotypic resistance testing must have local access to the technology and specify its use to construct the N(t)RTI 
backbone before the study is implemented.  Once a site elects to conduct genotypic HIV drug resistance testing, 
it must do so for all participants enrolled.  However, regardless of this specification, all participants will have a 
baseline (week 0) sample collected and stored for retrospective analysis of HIV resistance genotype which will be 
analysed at a single centralised site.  This information will then be used in a pre-specified analysis of responses 
according to genotype. 
5.4 Backbone N(t)RTI selection 
At sites in which genotypic HIV drug resistance testing is performed, N(t)RTI selection will be the decision of the 
treating clinician based upon the result.  At sites in which such testing is not available or at sites which have 
access to genotyping but elect not to use this option for selection of the N(t)RTI backbone, the following 
recommendations are made with regard to selection of N(t)RTIs in the control arm (arm I): 
 
If first-line N(t)RTIs included zidovudine (AZT) or stavudine (d4T) with lamivudine (3TC) or emtricitabine 
(FTC), the two second line N(t)RTIs should consist of: 

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1. 
tenofovir disoproxil fumerate (TDF) and 
2. 
3TC or FTC with or without 
3. 
zidovudine (AZT) 
 
If first-line N(t)RTIs consisted of didanosine (ddI), tenofovir disoproxil fumerate (TDF), or abacavir (ABC) 
with lamivudine (3TC) or emtricitabine (FTC), the two second line N(t)RTIs should consist of: 
1. 
zidovudine (AZT) or stavudine (d4T) and 
2. 
3TC or FTC with or without 
3. 
abacavir (ABC) 
If uncertainty exists about the selection of the most appropriate N(t)RTI backbone, investigators are advised to 
refer to the WHO recommendations on antiretroviral therapy for HIV-infection in adults and adolescents in 
resource-limited settings (http://www.who.int/hiv/pub/guidelines/adult/en/index.html). 
The decision of whether to incorporate either two or three N(t)RTIs into the nucleoside/nucleotide backbone of 
the control arm is up to the investigator. The use of 3N(t)RTIs in the backbone of the second line regimen is 
based mainly on theoretical considerations; the clinical efficacy of this strategy is unproven [5]. 
The WHO recommendations on antiretroviral therapy for HIV-infection in adults and adolescents in resource-
limited settings states that the combination of TDF and ddI should be used with caution and, with an adjustment 
of ddI dose according to body weight [5]. From the point of view of the SECOND-LINE protocol the combination 
of TDF with ddI is considered not recommended, based on data that has suggested unsatisfactory immune 
reconstitution, comparatively high rates of virological failure and a suggestion of an increased risk of N(t)RTI-
associated toxicity using this backbone N(t)RTI combination [36-38]. 
The use of AZT combined with d4T and 3TC combined with FTC is absolutely contraindicated.  
The regimen of raltegravir and 2NRTIs is not permitted in this study. 
In the SECOND-LINE protocol the research sites will locally procure nucleoside/nucleotide reverse transcriptase 
inhibitor (N(t)RTI) antiviral agents for use as components of the combination antiretroviral regimen used in the 
control arm of the study.  NCHECR will reimburse the costs of the N(t)RTIs used in the study. 
For all participating research sites NCHECR mandates the use of innovator nucleoside/nucleotide reverse 
transcriptase inhibitor agents if locally available. 
In situations in which innovator nucleoside/nucleotide reverse transcriptase inhibitor agent are not locally 
available or are in short supply, the use of alternative generic products will be allowed. However, the generic 
alternatives will be limited to only those products which have received pre-approval through the agency of the 
World Health Organization (WHO) and/or the US Federal Drug Authority (FDA).  

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Research sites in which generic formulations may be used will be asked to specify before study commencement 
the WHO and/or FDA approved generic formulations of choice. This list will be updated on an annual basis.  
The pre-approved nucleoside/nucleotide reverse transcriptase inhibitor products can be found at the respective 
WHO and FDA websites: 
WHO: http://apps.who.int/prequal 
FDA: http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm 
5.5 Guidelines for clinical management of ART regimen failure on study 
This section deals with the clinical management of a series of clinical scenarios which may arise during the 
course of the study and which require a clinical response. 
 
It is emphasised that these scenarios and suggested responses relate to clinical management issues and ARE 
INDEPENDENT of the analyses of the primary and secondary study endpoints. 
Failure of the regimens in this study from the perspective of clinical management (independent of the study 
endpoints) will be defined as any (one or more) of the following: 
1. failure to attain a plasma HIV RNA level <500 copies/mL within the first 24-weeks following 
commencement of randomised therapy 
2. recrudescence of plasma HIV RNA to >500 copies/mL on 2 consecutive occasions ≥7 days apart 
3. WHO stage IV HIV diseases progression event (not deemed by the investigator to be a result of immune 
restoration disease [IRD]) – see section 5.10 for IRD definition 
4. Failure of the absolute CD4 T-cell count to rise from baseline value following 24-weeks of continuous 
randomised therapy 
5. Adverse events experienced that result in discontinuation of study drug (see section 5.6 for further 
details).  
Participants failing the regimen according to the above criteria should be managed as considered clinically 
appropriate. Participants will be encouraged to remain in clinical follow-up and have blood drawn according to 
the study protocol schedule.  
 
From the point of view of individual patient management investigators may elect to continue participants on the 
same regimen if, in their judgement the patient continues to benefit on virological, and/or immunological and/or 
clinical grounds. 
 

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In the case of virological failure of the control regimen (LPV/r + 2-3N(t)RTI) it is likely that the boosted-lopinavir 
will retain activity and therefore participants will be allowed to replace the 2-3N(t)RTI component with 
raltegravir and continue the LPV/r component. It is emphasised that under this clinical scenario (virological 
failure of the control regimen) participants should NOT switch the LPV/r to raltegravir and continue on N(t)RTIs 
as this is associated with an increased risk of virological failure [39].  
 
In the case of virological failure of the experimental arm, management will be at the discretion of the 
investigator but may include continuation of the same regimen, partial or complete regimen change (e.g. ceasing 
raltegravir and replacing with 2-3(t)RTIs) or simplification to LPV/r monotherapy.  The use of resistance 
genotypic testing is advised if local testing is available, as well as reference to the results of the screening 
resistance test.  For sites not using resistance testing at screening, reference to Section 5.4 of this protocol 
(Backbone N(t)RTI selection) is recommended for selection of a suitable N(t)RTI combination. 
 
5.6 Management of ART intolerance 
Management of intolerance to one or more of the antiretrovirals will be at the discretion of the investigator and 
will depend upon the local availability of alternatives.  In the case of intolerance attributed to LPV/r a switch to 
an alternative boosted-PI is advised.  If intolerance is thought to be due to one of the N(t)RTIs, an alternative 
N(t)RTI is recommended (e.g. AZT to d4T for anaemia, TDF to ddI for renal toxicity, d4T to AZT for peripheral 
neuropathy, ddI to TDF for peripheral neuropathy or pancreatitis). 
 
In all such situations the study will provide material support for switch to alternative agents sourced locally at 
each site. 
5.7 Dose modifications 
It is recommended that no dose modifications be employed in response to observed toxicities or failure to 
achieve or maintain a clinical response.  Toxicities and unacceptable treatment responses should be managed as 
guided in Sections 5.10 and 5.11. 
5.8 Toxicity management 
Limited pathology will be collected for analysis as part of this Protocol.  Each investigator must ensure that safety 
pathology is collected and reviewed, in keeping with local standards of care. 
Clinical events and clinically significant laboratory abnormalities will be graded according to the DAIDS Common 
Toxicity Grading Scale (please refer to Appendix B of the Manual of Operations [MOOP]). 

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5.8.1 Grade 1 or 2 toxicity 
Subjects who develop a Grade 1 or 2 adverse event or toxicity may continue study drugs without modification.  
Subjects experiencing Grade 1 or 2 adverse events who choose to discontinue the study drugs should remain on 
study and continue to undergo protocol-mandated evaluations and assessments. 
5.8.2 Grade 3 
If the investigator has compelling evidence that the adverse event has NOT been caused by the study drug(s), 
dosing may continue. 
Subjects who develop a Grade 3 adverse event or toxicity, except for elevated triglycerides (Section 5.10.1), 
glucose (Section 5.10.2) and AST/ALT (Section 5.10.3) should have their antiretroviral study drugs withheld, at 
the investigator’s discretion. 
The subject should be re-evaluated regularly until the adverse event returns to Grade <2, at which time the 
study drugs may be reintroduced at the discretion of the investigator or according to standard practice. 
If the same Grade 3 adverse event recurs within four weeks, study drug(s) must be permanently discontinued if 
the investigator considers the adverse event related to study drug(s).  However, if the same Grade 3 adverse 
event recurs after four weeks, the management scheme outlined above may be repeated. 
Subjects experiencing Grade 3 adverse events requiring permanent discontinuation of study drug therapy should 
be followed regularly (weekly is suggested) until resolution of the adverse event. Participants should remain in 
follow-up and continue to attend for protocol-mandated assessments and evaluations.  See Section 5.4 for 
permitted drug substitutions. 
5.8.3 Grade 4 adverse events 
Subjects who develop a Grade 4 adverse event or toxicity will have all study drug(s) temporarily discontinued 
(except for those abnormalities described in Sections 5.10.1 – 5.10.4 inclusive).  The AE should be resolved 
before any decision is made to rechallenge the subject with study drugs.  Subjects experiencing Grade 4 AEs 
requiring permanent discontinuation of study drug therapy should be followed regularly (weekly is suggested) 
until resolution of the adverse event.  The patient should remain on study and continue to undergo protocol-
specified evaluations and assessments. 
Subjects with Grade 4 asymptomatic or non-significant laboratory abnormalities may continue study drug 
therapy if the investigator has compelling evidence that the toxicity is NOT related to the study drug(s).  

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5.9 Protocol-specific toxicity management guidelines  
Certain clinical and laboratory abnormalities will be subject to the following guidelines under this protocol.  
These guidelines are provided to encourage uniformity of patient management in light of observed clinical 
and/or laboratory abnormalities that are well documented as expected adverse experiences following 
administration of study drugs.  Departure from these guidelines is discouraged. 
5.9.1 Hypertriglyceridaemia/Hyperlipidaemia 
If elevated triglyceride or lipid levels are from a non-fasting blood draw, the test should be repeated on a 
specimen drawn after a minimum eight hour fast. Only levels done in a fasting state (8-hour minimum) should be 
graded for toxicity. 
Subjects with asymptomatic Grade >3 triglyceride, total cholesterol, or LDL elevations may continue study 
medications at the discretion of the investigator.  Appropriate dietary modification and lipid lowering therapy 
should be considered.  Thought should also be given to modification of other existent cardiovascular disease 
(CVD) risk factors (e.g. sedentariness, overweight/obese, tobacco smoking). The preferred first line 
pharmaceutical intervention is gemfibrozil 600 mg q 12 hours, taken 30 minutes prior to the morning and 
evening meals.  Fasting triglycerides should be rechecked at regular (suggest at least monthly) intervals. For 
persistent uncontrolled hypertriglyceridaemia and/or hypercholesterolemia, the addition of niacin and/or an 
HMG-CoA reductase inhibitor (i.e. ‘statin’) may be considered.  These medications should be introduced with 
caution (see Section 6.3).  Niacin has the propensity to worsen the control of blood sugar in subjects with 
diabetes mellitus or a history of hyperglycaemia. Several HMG-CoA reductase inhibitors have substantial 
interactions with the PI class. The use of pravastatin or atorvastatin is advised.  Rosuvastatin should be used with 
care (please refer to table 5.1 under section 5.13 in this protocol for further details). 
5.9.2 Hyperglycaemia 
Subjects with Grade >3 hyperglycaemia may continue study medications at the discretion of the investigator and 
be managed with oral hypoglycaemic medications or insulin, with referral to endocrinologists as appropriate. 
5.9.3 Hepatitis/Hepatotoxicity 
For Grade 3 elevation in AST or ALT (5.1-10.0 x ULN), study medications may be continued at the discretion of 
the site investigator.  Careful assessments should be performed to rule out alcohol-related hepatitis, non-study 
medication-related drug toxicity, or viral hepatitis (e.g. flare of disease activity, acute infection, super-infection 
or IRD) as the cause of the Grade 3 elevation.  The possibility of mitochondrial toxicity/hepatic steatosis/lactic 
acidosis syndrome should also be explored in participants in the control arm receiving N(t)RTIs. 

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For Grade 4 elevations (>10 x ULN) in AST or ALT, all study medications should be withheld until the toxicity 
grade returns to Grade <2. 
5.9.4 Lactic acidosis 
The relevance of asymptomatic lactic acid elevations is unclear, and routine collection of lactates is not 
recommended and will not form part of the routine safety evaluations for this study.  Routine lactate monitoring 
is not currently recommended. 
The syndrome of lactic acidosis is sometimes fatal (particularly if recognised late) and is often associated with 
evidence of hepatic steatosis. It is a recognised but nevertheless uncommon complication of N(t)RTI therapy.  
This syndrome is thought to be secondary to mitochondrial toxicity induced by the inhibitory effect of N(t)RTIs 
on DNA polymerase gamma, a key enzyme needed for mitochondrial DNA synthesis.  Current knowledge 
regarding this syndrome is not complete, although female sex, obesity and prolonged N(t)RTI exposure may be 
risk factors.  The clinical features of lactic acidosis frequently involve non-specific symptoms such as fatigue, 
weakness, and fever; the majority of cases also involve symptoms suggestive of hepatic dysfunction such as 
nausea, vomiting, abdominal or epigastric discomfort, abdominal distension, hepatomegaly, and elevation of 
liver enzymes (often to only mild to moderate levels).  A high index of suspicion is required to diagnose this 
condition. Alternatively, unwarranted concern may be raised by over interpretation of lactate levels, particularly 
if the participant is asymptomatic.  N(t)RTI toxicity is only one cause of lactic acidosis.  Type “B” lactate 
elevations or those without clinically apparent tissue hypoxia are also seen in the context of diabetes mellitus, 
uraemia, liver disease, infections, malignancies, alkaloses, drug and/or toxin ingestion of such substances as 
ethanol, methanol, ethylene glycol and salicylates. 
5.9.5 Renal toxicity 
Routine assessment of renal function is required with derivation of creatinine clearance (CLcr) using the 
Cockcroft-Gault equation.  Dosing of all medications in a patient’s regimen should be critically reviewed if the 
estimated creatinine clearance falls below 50mls/minute.  
Glomerular filtration rate will also be estimated using the abbreviated MDRD equation.  Estimated GFR = 186 x 
([SCR/88.4]-1.154) x age-0.203 x (0.742 if female) x (1.210 if African-American).  Dosing of all medications in a patient’s 
regimen should be critically reviewed if the eGFR falls below 60ml/min/1.73m2. 
 
It is important to note that recommendations regarding dose adjustments in the presence of renal impairment 
are based on calculations of renal function using the Cockcroft-Gault equation. 
 

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5.10 
Management of AIDS Defining Illnesses (ADI) and Immune Restoration Disease 
(IRD) 
In general, management will follow relevant local and international guidelines.  Any episode of an ADI on study 
will be regarded as a study failure according to CDC criteria (Appendix 1), unless the episode is thought to 
represent immune restoration disease (IRD).  The protocol and Manual of Operations will contain guidelines for 
the differentiation of ADI and IRD.  
 
For the purposes of this study the definition of IRD will follow a modification of the proposed criteria suggested 
by French, Price and Stone as follows [40]: 
A. Atypical presentation of opportunistic infections or tumours in participants responding to antiretroviral 
therapy (ART) 
I 
Localised disease 
II 
Exaggerated inflammatory reaction 
III 
Atypical inflammatory response in affected tissues 
IV 
Progression of organ dysfunction or pre-existing lesions after definite clinical improvement with 
pathogen-specific therapy prior to commencement of ART and exclusion of treatment toxicity and new 
diagnoses. 
 
B. Decrease in plasma HIV RNA level by >1log10copies/mL 
 
To qualify for a diagnosis of IRD participants would be required to demonstrate at least one of criterion  
A (AI – AIV) and criterion B [40]. 
 
In the case of an episode of new or recurrent pulmonary tuberculosis (PTB) this will not be counted as evidence 
of HIV disease progression.  In the case of PTB, treatment will be according to standard recommendations with 
the caveat that participants will have access to rifabutin under the auspices of the study in place of rifampicin as 
the rifamycin for inclusion in combination anti-TB therapy.  Rifabutin will be dose-reduced in the presence of a 
protease inhibitor according to guidelines.  In this instance, participants may remain on their randomised 
regimen. 
 
5.11 
Discontinuation of therapy 
Study therapy MUST be immediately discontinued for the following reasons: 
 
any clinical adverse event, laboratory abnormality or intercurrent illness that, in the opinion of 
the investigator, indicates that continued treatment with study therapy is not in the best interest 
of the subject 

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 termination of the study by the Protocol Steering Committee 
 withdrawal of consent by the participant 
Women found to be pregnant should be managed in keeping with the provisions in Section 8.2. 
Subjects discontinuing their study drugs should remain in follow-up and be encouraged to continue protocol-
mandated evaluations and assessments.  
5.12 
Treatment adherence 
Study drug adherence will be assessed using the CPCRA (Community Programs for Clinical Research on AIDS) 
questionnaire.  For full details on this adherence tool please refer to the Manual of Operations (MOOP).  All 
participants should be counselled regularly on the need for maintaining strict adherence with the allocated study 
regimens.  The objective should be 100% adherence at all times during follow-up.  The site Principal Investigator 
is responsible for assessing adherence with all aspects of the study including use of study drugs and attendance 
at protocol-mandated clinical visits and assessments. 
5.13 
Prohibited and restricted therapies during the study 
The following medications are prohibited during the study: rifampicin, midazolam, triazolam, cisapride, 
pimozide, 
amiodarone, 
dihydroergotamine, 
ergotamine, 
ergonovine, 
methylergonovine, 
astemizole, 
terfenadine, vardenafil, St. John’s wort and immunomodulators. 
 
Investigational drugs other than those included in the assigned regimens are prohibited in this protocol. 
 
Systemic cytotoxic chemotherapy is prohibited in this protocol.  If a participant requires chemotherapy whilst on 
study follow-up, please contact NCHECR.  
Caution should be used when coadministering Raltegravir with strong inducers of uridine diphosphate 
glucuronosyltransferase (UGT) 1A1 (e.g. rifampicin which is prohibited in this protocol) due to reduced plasma 
concentrations of raltegravir. Other less stronger inducers (e.g., rifabutin) may be used. 
Drugs known to interact with HIV protease inhibitors in ways that may require therapeutic drug monitoring 
and/or adjustment of concomitant medication are listed in Table 5.1 below.  
Table 5.1 Significant drug interactions requiring dosage alteration or alterative drugs (LPV) 
  
LIPID-LOWERING AGENTS 
Avoid simvastatin, lovastatin with LPV. Use pravastatin, fluvastatin or 
rosuvastatin instead. 
  
  
IMMUNOSUPPRESSANTS 
Caution when using cyclosporine, sirolimus and tacrolimus with LPV, as they 
may increase levels of immunosuppressants. 
  
 

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STEROIDS 
Caution when using steroids like dexamethasone, fluticasone, propionate and 
ethinyl oestradiol. 
 
 
HEART MEDICINE 
Caution using calcium channel antagonistas like felodipine, nifedipine and 
nicardipine with LPV. 
Caution using bepridil, systemic lidocaine and quinidine with LPV. 
Caution using digoxin with LPV. 
 
 
ANTI-INFECTIVES 
Caution using certain antibiotics like rifabutin and clarithromycin with LPV 
  
 
ANTI-CONVULSANTS 
Caution using anti-convulsants like carbamazepine, phenytoin and 
phenobarbital with LPV 
  
 
ANTI-DEPRESSANTS 
Caution using antidepressants like trazodone with LPV 
  
  
ANTI-FUNGALS 
Caution using antifungals like ketoconazole and itraconazol with LPV 
  
  
MORPHINE LIKE MEDICINE 
Caution using drugs like methadone with LPV. 
  
  
ERECTILE DYSFUNCTION 
Caution with erectile dysfunction drugs (sildenafil and tadalafil) with LPV as 
dose of ED drug can be increased and may need dose reduction. 
 
 
SEX STEROIDS 
Caution using oral contraceptives with LPV as sole method of contraception; 
unreliable. 
 
For further information on HIV drug interactions please refer to the website:  
http://www.hiv-druginteractions.org 
5.14 
Concomitant Medication 
For this study we will only be collecting information on concomitant medications that are prescribed by a 
physician. 
6 STUDY PROCEDURES 
6.1 Initial screening period 
Potentially eligible individuals can be screened within 45 days before the randomisation visit and all results from 
screening must be available for randomisation.  All subjects should be given adequate information about the trial 
including the Participant Information Sheet and be given an opportunity to ask questions about the trial.  
Written consent for the trial should be obtained at the screening visit before any protocol specified assessments 
are performed.  The following evaluations will be performed within 45 days prior to randomisation: 
6.1.1 Clinical assessments 
 
Complete medical history to include 

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o non-HIV related diagnosis including liver disease, renal disease, cardiovascular disease, diabetes, 
hypertension, pancreatitis, bone disorders, rheumatoid arthritis, non-AIDS defining cancer, non-
traumatic fracture and substance abuse 
o smoking history 
 
family history of diabetes or hip fracture 
 
race and gender at birth 
 
measure weight, sitting blood pressure and pulse 
 
informed consent 
6.1.2 Laboratory assessments 
 
If the patient is female and is of child bearing potential, she must have a urine or blood sample pregnancy 
test 
 
serum chemistries and liver function tests: electrolytes (sodium, potassium, bicarbonate, chloride, 
phosphate), urea, creatinine, LFTs (total bilirubin and ALT), anion gap (automatically calculated on the 
eCRF) and creatinine kinase 
 
Haematology: full blood count (haemoglobin, white cells, neutrophils, lymphocytes, platelets) 
 
creatinine clearance will be calculated by the Cockcroft-Gault equation 
Male: (140 - age in years) x (wt in kg) = CLCr (mL/min) 
 0.814 x (serum creatinine in µmol/L) 
Female:(140 - age in years) x (wt in kg) x 0.85 = CLCr (mL/min) 
 0.814 x (serum creatinine in µmol/L). 
 
glomerular filtration rate (GFR) will be calculated by the abbreviated MDRD (Modification of Diet in Renal 
Disease)  equation. 
Estimated GFR = 186 x ([SCR/88.4]-1.154) x age-0.203 x (0.742 if female) x (1.210 if African-American) 
 
real time plasma HIV-RNA analysis at local laboratory 
 
Immunology: CD4 and CD8 (% and absolute) 
 
Hepatitis B surface antigen 
 
Hepatitis C antibody results need only be done if status is unknown, or previous tests were negative or 
reports for positive results are not available to verify the result 
 
HLA-B*5701 testing can be conducted if locally available (costs will be reimbursed) 
 
For those sites which have nominated as sites performing genotype testing as part of the study a local 
genotype should be collected at screening to assist with N(t)RTI selection at randomisation if participant is 
randomised to that arm* 
 
*The site must advise NCHECR if they wish to guide the N(t)RTI backbone by conducting genotypic resistance 
testing prior to the randomisation visit.  Once the site elects this option it must be followed for all enrolled 
participants. 

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6.2 Randomisation visit 
To proceed, all subjects must have fulfilled the eligibility criteria by the results of evaluations at screening.  All 
randomisation evaluations must be completed prior to the commencement of study drug. 
 
Trial entry procedures will include: 
6.2.1 Clinical assessments 
 
targeted physical examination (symptom directed) 
 
height, weight, sitting blood pressure and pulse 
 
symptoms reported by the subject will be reviewed by the clinician at each visit and recorded on the CRFs as 
adverse events 
 
full HIV history to include: mode of transmission, duration of HIV infection, antiretroviral treatment history, 
nadir CD4+ cell count, highest recorded HIV RNA, and current stage of HIV disease and any prior AIDS events 
(CDC classification – refer Appendix 1)  
 
anthropometric assessments: umbilical waist and maximum hip measurement (refer to MOOP for 
instructions on how to perform this measurement) 
 
updated medical history including changes or additions to diagnoses, diseases, or any change in 
antiretroviral drugs, concomitant medications 
 
complete Short Form 12 (SF12) quality of life questionnaire 
 
collection of current prescribed concomitant medications 
6.2.2 Laboratory assessments 
 
If the patient is female and is of child bearing potential, they must have a urine or blood sample pregnancy 
test 
 
serum chemistries and liver function tests: electrolytes (sodium, potassium, bicarbonate, chloride, 
phosphate), urea, creatinine, LFTs (total bilirubin and ALT), anion gap (automatically calculated on eCRF) 
and creatinine kinase 
 
Fasting metabolic parameters (minimum 8 hours): total cholesterol, HDL cholesterol, LDL cholesterol, 
triglycerides, glucose, HOMA and insulin. 
 
Haematology: full blood count (haemoglobin, white cells, neutrophils, lymphocytes, platelets) 
 
creatinine clearance will be calculated by the Cockcroft-Gault equation, as above 
 
estimated glomerular filtration rate will be calculated by the MDRD equation, as above 
 
real time plasma HIV-RNA analysis at local laboratory 
 
Immunology: CD4 and CD8 (% and absolute) 
 
storage plasma, serum and PBMC for possible future investigations related to HIV disease 
 
Plasma storage for central HIV RNA and genotype analysis 

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6.2.3 Drug supply and randomisation 
After completion of all randomisation study visit assessments the participant will be randomised online via the 
web based CRF.  Eligibility must be confirmed and the participant will then be automatically randomised to 
commence either: 
I. 
ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily (OR 
133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules twice daily) + 2-3N(t)RTIs 
II.  ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily (OR 
133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules twice daily) + raltegravir 400 
mg 1 tablet twice daily 
 
The treatment assignment will be stratified according to: 
1. Clinical site 
2. Plasma HIV-1 RNA viral load < or >100,000 copies/mL 
 
The investigator should complete a prescription for the randomised regimen and the participant should fill the 
prescription that same day or the next.  Therefore, the study drug should be commenced as soon as possible 
after randomisation. 
6.3 Follow-up visits 
The scheduled date of study visits will be calculated from the date of randomisation (day 0, week 0).  A schedule 
of the dates for study visits will be automatically provided for each participant on the eCRF, once randomisation 
has been completed.  For study visit week 4, the actual visit can be from week 2 to week 6.  For study visits week 
12 and onwards the actual visit can be 6 weeks either side of the scheduled visit date.   
NOTE: Subjects must be in a fasting state, but encouraged to take free fluids at weeks 4, 12, 24, 48, 72, and 96. 
6.3.1 Clinical assessments 
 
targeted physical examination (symptom directed) [all visits] 
 
symptoms reported by the subject or symptoms identified after examination will be reviewed by the 
clinician at each visit and recorded on the CRFs as adverse events [all visits] 
 
updated medical history including changes or additions to diagnoses, diseases, or any change in 
antiretroviral drugs, prescribed concomitant medications [all visits] 
 
measure vital signs: weight, sitting blood pressure and pulse [all visits] 
 
anthropometric measurements including waist and hip measurements [week 48 and 96] (refer to MOOP for 
instructions on how to perform this measurement) 
 
complete the CPCRA adherence questionnaire [weeks 4, 48, 96] 
 
complete SF12 quality of life questionnaire [week 48 and 96] 

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6.3.2 Laboratory assessments 
 
Pregnancy test if the patient is female and of child bearing potential [all visits] 
 
haematology - full blood count (haemoglobin, white cells, neutrophils, lymphocytes, platelets) [all visits] 
 
serum chemistries and liver function tests: electrolytes (sodium, potassium, bicarbonate, chloride, 
phosphate), urea, creatinine, LFTs (total bilirubin and ALT), anion gap (automatically calculated on the 
eCRF and creatinine kinase [all visits]. 
 
creatinine clearance will be calculated by the Cockcroft-Gault equation as above [all visits] 
 
estimated glomerular filtration rate will be calculated by the abbreviated MDRD equation as above [all 
visits] 
 
fasting parameters (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose, HOMA and 
insulin) [all weeks with the exception of weeks 36, 60 and 84] 
 
Immunology: CD4 and CD8 (% and absolute) [all visits] 
 
real time plasma HIV-RNA analysis [all visits], tested at local laboratory. 
 
plasma storage for central HIV RNA analysis [all visits] 
 
storage plasma and serum [all weeks]. 
 
General comments 
 
The window period for each study visit is continuous so that all collected results may be utilised. 
 
If a scheduled visit is conducted after the window period has ceased for that specific visit, it will be 
counted as the next visit, and the previous visit should be documented as “missed”.  DO NOT conduct a 
second routine visit in the same window period. 
 
7 DATA SAFETY MONITORING BOARD (DSMB) 
An independent DSMB will be established.  Clinicians or investigators responsible for the clinical care of study 
subjects or representatives of Pharmaceutical Companies are not permitted to be members of the DSMB.  
 
The DSMB will monitor the trial and will review efficacy and safety data by blinded treatment allocation (A and 
B).  Safety monitoring will be carried out on two occasions, firstly when 250 (125 in each arm) participants 
complete the week 24 visit and secondly when all participants complete the week 24 visit. The first analysis will 
assess virological response data between arms; the second analysis will include laboratory data, Grade 3 and 
Grade 4 adverse events, viral load data, serious adverse events (SAEs) and adverse events leading to cessation of 
study medication.   
 
The DSMB will develop a formal stopping rule for early evidence of regimen failure or success.  They will make 
their recommendations to the Protocol Steering Committee who will decide whether to amend the trial.  

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Separate procedures will be developed to assist the DSMB in these tasks.  All data will be reviewed blind to 
treatment allocation. 
 
8 ADVERSE EVENT REPORTING 
In this study we will be collecting all grade (grade 1-4) clinical adverse events.  Laboratory abnormalities that 
occur without related clinical symptoms and signs should not be recorded as an adverse event.  If the laboratory 
event becomes clinically significant, then the resulting clinical event should be reported as an adverse event (e.g. 
a low haemoglobin should be reported as anaemia). 
An AE can be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal (investigational or 
marketed) product, whether or not considered related to that product.  AEs include any illness, sign, symptom, 
or clinically significant laboratory test abnormality that has appeared or worsened during the course of the 
clinical trial, regardless of causal relationship to the drug(s) under study.  Changes resulting from normal growth 
and development which do not vary significantly in frequency or severity from expected levels are not to be 
considered adverse experiences.  Examples of this may include, but are not limited to, onset of menses or 
menopause occurring at a physiologically appropriate time. 
Adverse experiences may occur in the course of the use of a drug in clinical studies or within the follow-up 
period specified by the protocol, or prescribed in clinical practice, from overdose (whether accidental or 
intentional), from abuse and from withdrawal. 
Adverse experiences may also occur in screened subjects/participants during any pre-allocation baseline period 
as a result of a protocol-specified intervention including washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
Timely and complete reporting of all AEs assists in identifying any untoward medical occurrence, thereby 
allowing:  (1) protection of safety of study subjects; (2) a greater understanding of the overall safety profile of 
the study drugs; (3) recognition of dose-related study drug toxicity; (4) appropriate modification of study 
protocols; (5) improvements in study design or procedures; and (6) adherence to worldwide regulatory 
requirements. 
AEs may be either spontaneously reported or elicited during questioning and examination of a subject. All 
identified AEs must be recorded and described on the appropriate Non-serious or Serious AE (SAE) page of the 
CRF.  If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual 
symptoms. 

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Subjects experiencing AEs that cause interruption or discontinuation of study drugs, or those experiencing AEs 
that are present at the end of their participation in the study should receive follow-up as appropriate.  If 
possible, report the outcome of any AE that caused permanent discontinuation or that was present at the end of 
the study particularly if the AE was considered by the investigator to be certainly, probably, or possibly related to 
the study drugs. 
8.1 Definition and reporting of an overdose 
Any overdose, whether or not associated with an adverse experience, must be reported within 24 hours to the 
NCHECR.  An overdose of raltegravir would be an excess of 1200 mg per day (raltegravir).  
8.2 Reporting of pregnancy 
Sexually active women of childbearing potential must use an effective method of birth control during the course 
of the study, in a manner such that risk of failure is minimised. 
Women found to be pregnant during follow-up should be managed in keeping with prevailing national or 
international guidelines. If a patient on raltegravir becomes pregnant during the study and there are other 
appropriate treatment options, it is suggested that they discontinue raltegravir and use an alternative. 
All pregnancies on study are subject to expedited reporting on the study, and therefore the serious advise event 
form will need to be completed and submitted to NCHECR within 24 hours (one working day) of becoming aware 
of the pregnancy. It is the responsibility of investigators or their designees to report any pregnancy in a 
subject/patient (spontaneously reported to them) which occurs during the study or within 30 days of completing 
the study.  All subjects/participants who become pregnant must be followed to the completion/termination of 
the pregnancy.  If the pregnancy continues to term, the outcome (health of infant) must also be reported to the 
NCHECR. 
8.3 Adverse events 
All adverse events must be recorded on the AE page of the CRF.  These should be followed to resolution or 
stabilisation, and reported as an SAE if they become serious or as an SNAE if they meet the criteria. 
Laboratory abnormalities that occur without related clinical symptoms and signs should not be recorded as AEs 
unless of themselves they represent a clinically significant event.  
8.4 Serious non-AIDS events (SNAEs) 
Serious non-AIDS defining events will be defined as follows (refer to Appendix 4 for details on diagnostic 
criteria): 
 
acute myocardial infarction 

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 
coronary artery disease requiring drug treatment 
 
stroke 
 
coronary revascularisation 
 
congestive heart failure 
 
deep vein thrombosis 
 
peripheral arterial disease 
 
pulmonary embolism 
 
end-stage renal disease (ESRD) 
 
decompensated liver disease 
 
non-AIDS-defining cancers  
 
diabetes mellitus 
 
Please note that most of the SNAEs will also be reported as a serious adverse event (SAE) and whether or not a 
serious adverse event, all SNAEs will require expeditious reporting as outlined in the next section.  There is only 
one paper-based serious event form that needs to be completed if the event is either an SNAE or SAE. 
8.5 Serious adverse events (SAEs) 
An event that is serious must be recorded on the paper SAE (SAE) form as well as on the AE eCRF and requires 
expeditious handling to comply with regulatory requirements.  
A Serious Adverse Event or reaction is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life threatening - 
(Defined as an event in which the subject or patient was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a cancer (a pre-existing cancer need only be reported if after study entry it has worsened) 
 
Is an overdose (whether accidental or intentional) 
 
Pregnancy 
 
Is an important medical event - 
 
(Defined as a medical event(s) that may not be immediately life-threatening or result in death or 
hospitalisation but, based upon appropriate medical and scientific judgement, may jeopardise the 
patient/subject or may require intervention (e.g., medical, surgical) to prevent one of the other 
serious outcomes listed in the definition above).  Examples of such events include, but are not limited 

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to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalisation. 
Adverse events classified as ‘serious‘ require expeditious handling and reporting to NCHECR to comply with 
regulatory requirements.  Any SAE that, in the opinion of the Investigator, is certainly, probably, possibly, not 
likely related or unrelated to the study drugs must be immediately reported by telephone, if feasible.  
Regardless, all SAEs whether related or unrelated to study drugs, must be immediately reported by confirmed 
facsimile transmission and mailing of the completed SAE page.  A facsimile transmission does not preclude 
mailing of the SAE page.  Overnight express mail may be used in lieu of facsimile.  If only limited information is 
initially available, follow-up reports are required. 
Any serious adverse experience, including death due to any cause, which occurs to any subject/patient entered 
into this study or within 30 days following cessation of study drug, whether or not related to the drug product, 
must be reported within 24 hours (or one working day) to the NCHECR.  
If the participant is prescribed abacavir and subsequently experiences an “Abacavir Hypersensitivity Reaction” 
this will need to be reported as a serious adverse event. 
Additionally, any serious adverse experience considered by an investigator who is a qualified physician to be 
possibly, probably, or definitely related to the study drug that is brought to the attention of the investigator, at 
any time outside of the time period specified in the previous paragraph, also must be reported immediately to 
the NCHECR.  Should the investigator become aware of an SAE (regardless of its relationship to investigational 
product) that occurs within 30 days after stopping the study drugs, the SAE must be reported in accordance with 
procedures specified in this protocol.  In the event of death, if an autopsy is performed, a copy of the report 
should be sent to NCHECR. 
Upon receiving such notices, the Investigator must review and retain the notice with the Investigator Brochure 
and immediately submit a copy of this information to the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) according to local regulations.  The Investigator and IRB/IEC will determine if the informed 
consent requires revision.  The Investigator should also comply with the IRB/IEC procedures for reporting any 
other safety information.  
Updates by the Investigator to Health Authorities should be handled according to local regulations. 
Contact information for Safety Reporting will be provided by the suppliers of the clinical trial material and will be 
outlined in the Manual of Operations. 
8.6 Laboratory test abnormalities 
Laboratory test abnormalities will not be recorded as AEs unless there is an associated clinical manifestation, in 
which case only the clinical sign and symptoms should be recorded on the AE form. 

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8.7 Other safety considerations 
Any clinically significant changes noted during physical examinations, electrocardiograms, x-rays, and any other 
potential safety assessments, whether or not these procedures are required by the protocol, should also be 
recorded on the appropriate AE page of the CRF (i.e., NON-SERIOUS or SERIOUS) in order for NCHECR to collect 
additional information about that abnormality, including information regarding relationship to investigational 
product or other causes, any action taken and resolution. 
 
9 PACKAGING, LABELLING and ACCOUNTABILITY of TRIAL SUPPLIES 
9.1 Study drugs 
Study materials will be dispensed in accordance with the random allocation following receipt of prescriptions 
from recognised study investigators.  Study drugs will be dispensed at weeks 0, 4, 12, 24, 36, 48, 60, 72, and 84 
plus one more year after that. 
There will be no drug accountability in this study so no returned bottles or destruction required. 
At each dispensing, participants should be counselled on the importance of adherence. 
Raltegravir and LPV/r will be the only study drugs which will be provided centrally in this protocol.  As such the 
study requires that management of raltegravir and LPV/r supplies be subject to a number of important 
provisions (as shown in the following sections). 
Mechanisms will be implemented to secure adequate supplies of all other study drugs in countries where access 
is constrained by cost.  Continued supply of required study drugs will be ensured to the study participants in 
these countries for a period of no less than one year after completion of the 2 year study (i.e. a minimum of 3 
year drug supply will be provided to all study participants).  Material support for the cost of the N(t)RTI 
component of arm I of the randomisation will be provided to the clinical site. 
All other study drugs should be handled in keeping with normal procedures for licensed products. 
9.2 Packaging and labeling 
The raltegravir and ritonavir boosted lopinavir will be packaged and labeled by ALMAC clinical services based in 
the USA and UK.  Each bottle will be labeled either with a single-panel English label or a booklet label containing 
13 languages.   
 
Raltegravir will be packaged in bottles containing 60 pink tablets with “227” image, which will be sufficient for 30 
days supply. 

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Ritonavir boosted lopinavir is available in two different forms (‘Kaletra’ and ‘Aluvia’) depending upon the country 
in which it is marketed. The ‘Kaletra’ form comes as two formulations: (1) yellow, film-coated, ovaloid tablets 
embossed with the Abbott logo on one side and ‘KA” on the other, (2) orange, soft gelatin, liquid filled capsules. 
The ‘Aluvia’ form comes as red, ovaloid, film-coated tablets embossed with the Abbott logo on one side and ‘AL’ 
on the other. Tablets and capsules will be dispensed from local pharmacies in bottles containing 120 tablets and 
180 capsules. The tablet bottles must be stored at 20-25°C (68-77°F) and capsule bottles at 2-8°C (36°F - 46°F).  
 
9.3 Handling and dispensing of study drugs 
Raltegravir (400 mg tablets) and LPV/r (200mg/50mg tablets or 133.3 mg lopinavir/33.3 mg soft gel capsules) 
should be stored in a secure area according to local regulations. It is the responsibility of the Investigator to 
ensure that the study drugs are only dispensed to study participants.  The study drugs must be dispensed only 
from official study sites by authorised personnel according to local regulations. 
Once the subject has received a treatment assignment, a 30-day supply will be dispensed to the subject from 
clinical supplies stored at the study site.  A 60- to 90-day supply will be dispensed at the week 4 and subsequent 
visits.  The subject must be instructed to take the tablets whole and to store all medication out of sight and reach 
of children. 
9.4 Study drug records at investigational site(s) 
It is the responsibility of the Investigator to ensure that a current record of raltegravir disposition is maintained 
at each study site where it is inventoried and disposed.  Records or logs must comply with applicable regulations 
and guidelines and should include: 
 
amount received and placed in storage area 
 
amount currently in storage area 
 
label ID number or batch number 
 
dates and initials of person responsible for each investigational product inventory entry/movement 
 
amount dispensed to each subject, including unique subject identifiers 
 
amount transferred to another area for dispensing or storage 
 
non-study disposition (e.g., lost, wasted, broken) 
The Sponsor will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements. 

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10 BIOLOGICAL SAMPLES 
10.1 Blood collection 
It is important that the handling of blood samples is undertaken according to local guidelines and regulations for 
handling infectious substances.  The blood tubes required to be used for each test should be as per your local 
laboratory guidelines.  Please check requirements with your local laboratory. Storage samples for HIV RNA, spare 
plasma and PBMC will be collected. Information on the types of blood tubes required for these specimens are 
detailed in the Manual of Operations.  These samples will be processed locally and then shipped to a central 
laboratory. 
It is preferred that the blood is collected within 14 days of the planned visit date (except the screening visit). 
All lipid and glycaemic parameters must be collected in the fasting state defined as no intake of food or beverage 
for at least 8 hours prior to blood collection (although plain water can be taken ad libitum).  Prior to blood 
collection, subjects must have: 
 
Followed a regular diet for 3 days 
 
Undertaken normal physical activity for 3 days but no strenuous physical activity within the previous 24 
hours 
When blood is taken, subjects must have been sitting for at least 5 minutes.  A tourniquet may be applied, but 
for no longer than 2 minutes. 
Ensure all tubes are filled to capacity.  Invert all the tubes 5-10 times after filling, DO NOT SHAKE. 
All samples should be kept at ROOM temperature until delivered to the laboratory. 
10.2 Labeling of specimen tubes 
It is important that the blood tubes are labelled accurately and legibly.  If your normal procedure is to write 
directly onto the tube then please ensure you use a permanent marker and all required sections are completed.  
NCHECR will provide you with specimen labels for you to use if you prefer.  These labels are only to be used on 
the blood tubes to be sent to the laboratory, not to be placed on the aliquot tubes for frozen storage. 
10.3 Transportation of samples to pathology 
It is important that during the transportation of blood samples precaution is taken according to local guidelines 
and regulations for handling infectious substances. 

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You will be required to set up the procedures for transporting the blood tubes to your local laboratory.  It is 
important that the samples arrive at the laboratory within 2-3 hours of blood collection (this time frame is 
determined by the chemistry, lipids and glucose).   
10.4 Storage of samples 
Serum and plasma samples will be collected and processed at the local pathology provider.  The samples will be 
stored in the interim at local laboratories and then sent for central storage in Sydney at regular intervals 
throughout the study. Transport to the central laboratory will be organised by NCHECR.  The cost of processing 
and storage of bloods will be provided to the sites as per the financial agreements.  For more detailed 
information on the types of tubes and processing requirements please refer to the Manual of Operations. 
10.5 Processing of samples 
All samples will be analysed at the local laboratory.  It is important that the handling of blood samples is 
undertaken according to local guidelines and regulations for handling infectious substances.  The investigator 
may be contacted should the technical condition of the sample, absence of information or inconsistencies on the 
request form be such that the samples cannot be processed.  Demographic errors (i.e. incomplete or 
inconsistent participant information) will be called through to the site and a faxed confirmation of correct 
information requested.  Where such errors are noted after a report has been sent to the site, then a second 
corrected report will be reissued by the local laboratory. 
10.6 Reporting of results 
The results will be reported to you as per your local standard procedure.  It is important that once these results 
are received they are entered into the eCRF and a hardcopy of the results are kept in the medical notes.  If you 
receive the laboratory results electronically, the electronic format is adequate for source data verification. 
10.7 Plasma HIV RNA determination 
Plasma HIV RNA will be measured at your local laboratory for assessment of eligibility and clinical decisions.  
Plasma will be stored and sent to a central laboratory for central assessment of HIV RNA.  These central results 
will be used for the analysis of the study at week 24, 48 and 96.   
 
11 STATISTICAL METHODOLOGY 
11.1 Sample size determination and statistical analysis 
Approximately 550 participants will be enrolled. 

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The primary endpoint is the comparison of proportions of people in each arm whose plasma HIV RNA is <200 
copies/mL after 48 weeks. A virological threshold of 200 copies/mL was chosen because of recent work 
suggesting that this viral load threshold is sufficiently sensitive, while avoiding unreliable very low level viral load 
failures (‘blips’) that on subsequent measurement are not confirmed [41]. Contemporary studies of the use of a 
boosted-PI with background N(t)RTIs in ART naïve participants suggest that ~80% will return a plasma HIV RNA 
result <200 copies/mL after 48 weeks.  In this study we would expect a similar response in a standard WHO 
recommended control arm of PI/r + 2-3N(t)RTIs.  Non-inferiority will be defined as the lower 95% confidence 
limit of the difference in proportions with undetectable viral load lying above -12% (i.e. a non-inferiority margin 
of 12%).  
 
Under the assumption that there is no difference between randomised treatment arms, to have 90% power to 
demonstrate non-inferiority in the ITT analysis using a 12% margin will require 248 participants per arm to be 
randomised (2-sided alpha=5%) making a total of 496 participants.  
 
To ensure that the PP analysis also has 90% power to demonstrate non-inferiority, the sample size needs to be 
increased to compensate for participants who switch ART due to treatment toxicity over the course of the first 
48 weeks of study. In this population this is estimated to be no more than 10% of randomised participants. 
Therefore, to ensure 90% power to demonstrate non-inferiority on the ITT and subsequently on the PP analyses, 
a total of 546 (i.e. 273 per arm) participants need to be randomised. We therefore aim to recruit a total of 550 
participants to the study. The power of the study for the ITT analysis in this case is 92.9%. 
 
11.2 Supplementary sample size assessments for exploratory analyses 
Estimates of variability (standard deviations for changes from baseline) to detect differences in fasted lipid 
measures with an 80% power for pair-wise comparisons between arms I and II were obtained from the Gilead 
903 and 934 studies [42,43]. Standard deviations were estimated based on mean changes and p-values quoted in 
the text. 
1. Total cholesterol (mg/dl): 201 participants per arm has 80% power to detect a mean difference between 
study arms of 21 mg/dl (SD = 75 mg/dl) 
2. LDL-cholesterol (mg/dl): 221 participants per arm has 80% power to detect a mean difference between study 
arms of 8 mg/dl (SD = 30 mg/dl) 
3. HDL-cholesterol: 185 participants per arm has 80% power to detect a mean difference between study arms 
of 3.5 mg/dl (SD = 12 mg/dl) 
4. Triglycerides mg/dl): 215 participants per arm has 80% power to detect a mean difference between study 
arms of 100 mg/dl (SD = 370 mg/dl) 
 
11.3 Analysis plan 

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The criteria by which the experimental regimen of ritonavir-boosted lopinavir and raltegravir will be judged non-
inferior to the control regimen will be if the lower limit of the 95% confidence interval for the difference in 
virological response between the two groups does not exceed -12%. Tests for non-inferiority will be primarily 
performed in analyses of the intention-to-treat (ITT) study population. If non-inferiority is demonstrated in the 
ITT population a supportive analysis of the PP population will be undertaken. 
 
For secondary and exploratory efficacy endpoints the ITT population will be primary, although analyses of the PP 
population will also be performed. Safety endpoints will all be analysed according to ART received. 
 
11.3.1 The intention to treat (ITT) population 
The ITT population is defined as all participants who undergo randomisation and who receive at least one dose 
of study medication. Participants will be compared as randomised regardless of the treatment received. 
 
During follow-up it is anticipated that a proportion of participants will experience various events which may 
result in different exposures to ART.  
 
The following describes a framework for the analysis of the primary endpoint based on a particular handling of 
anticipated events: 
 
I. in the event of the patient dying or becoming lost to follow-up the patient will be considered to have failed 
randomised treatment 
II. in the event that ART is changed because of plasma HIV RNA ≥200 copies/mL the patient will be considered to 
have failed randomised treatment 
III. ART changes for any other reason (other than II) do not constitute failure in the ITT population 
IV. if the week 48 data are missing, a last observation carried forward (LOCF) imputation will be made for all 
participants, except for those who are missing week 36 data, who are dead, lost to follow-up, or have 
experienced virological failure (HIV RNA ≥200 copies/mL) that resulted in a change of ART. 
 
This analysis corresponds to a comparison of the randomised treatment strategies, including all changes to ART 
regimens that occur subsequent to randomisation and will constitute the primary analysis. 
 
A secondary analysis of this population but using a virological threshold of 50 and 400 copies/mL will also be 
undertaken 
 
The following describes a framework for a secondary analysis of the ITT based on a different handling of the 
same anticipated events. This analysis will constitute a secondary endpoint of the study. 
 

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I. in the event of the patient dying or becoming lost to follow-up the patient will be considered to have failed 
randomised treatment 
II. in the event that ART is changed because of plasma HIV RNA ≥200 copies/mL the patient will be considered to 
have failed randomised treatment 
III. ART changes for any other reason (other than II), are considered failures  
IV. if the week 48 data are missing, a last observation carried forward (LOCF) imputation  will be made for all 
participants, except for those with week 36 data missing,  who are dead, lost to follow-up, have experienced 
virological failure (HIV RNA ≥200 copies/mL) or have changed randomised ART for any other reason. 
 
This analysis corresponds to a non-completer=failure (NC=F) analysis, making this secondary endpoint directly 
comparable with other trials. 
 
11.3.2 The per protocol (PP) population 
The PP population is defined as all participants included in the ITT population excluding those who changed 
randomly assigned ART for any reason other than plasma HIV RNA ≥200 copies/mL. 
 
Analyses will be based on available data. 
 
This approach corresponds to a comparison of the effectiveness of the two randomised ART regimens as if 
participants had adhered to their randomly allocated ART. 
 
11.4 Schedule of analyses 
There will be four formal analyses to be conducted within this protocol: two interim analyses of week 24 data 
(one when 125 participants each arm reach week 24; second when all participants reach week 24), a primary 
analysis at week 48 (all participants complete week 48) and a follow up confirmatory analysis at week 96 (all 
participants complete week 96). 
 
The first interim analysis will occur after 125 participants in each arm (a total of 250 participants) have reached 
24 weeks and will assess the rate of viral decline from baseline between the two groups.  The aim of the analysis 
is to ensure that there is no evidence of a substantially different performance between regimens in virological 
suppression as judged by a difference between groups of >0.5 log10.  Assuming that between-patient variability 
of time-weighted change in plasma HIV-1 RNA corresponds to a standard deviation of 1.0 log10, and adopting a 
significance level of 0.05, 125 participants per arm will confer >98% power to determine that the two-sided 95% 
confidence has an upper limit below 0.5 log10. A recommendation to stop the study at this analysis would only 
be made in the event that the experimental arm was considered inferior (i.e. if the control arm (arm I) is found 
to have provided a ≥ 0.5 log10 difference in virological suppression from baseline, using a ONE-sided significance 
level of 0.01).  In the event that the experimental arm (arm II) appeared to be superior, the recommendation 

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would be to continue study until at least the second scheduled interim analysis in order to allow accumulation of 
sufficient data to make a reasonable judgement of the primary endpoint. 
 
The second interim analysis will summarise study variables once all enrolled participants have completed 24 
weeks of follow-up and will include all stated primary and key secondary measures of interest.  The proportions 
of participants in each study arm at weeks 36 and 48 will also be compared at this time.  The trial may be 
stopped if one arm is found to be inferior on the endpoint of percentage of participants with detectable plasma 
HIV RNA at week 24, using a two-sided significance level of 0.001.  A recommendation of this sort could only be 
made if the finding for the week 24 data was consistent with the observations made at weeks 36 and 48 (in the 
sense that observations at all time points consistently suggest that one arm is inferior to the other).  
 
Both interim analyses will be reviewed by an independent Data Safety Monitoring Board (DSMB) which will 
recommend to the Protocol Steering Committee that the study should continue unchanged or be amended in 
light of observed differences between treatment arms or aspects of study conduct that warrant modification 
(e.g. poor recruitment, safety concerns, and/or substantial losses to follow-up). Their review of treatment 
regimens will be coded as A and B.  The DSMB, in agreement with Protocol Steering Committee, may require 
stopping rules to be implemented that require changes in the conduct of the study should concerns surrounding 
the safety of participants arise from review of the week 24 results.  
 
In addition, the DSMB will be provided with information relating to the conduct and management of the study.  
Un-blinded datasets will not be made available for review outside of the DSMB and relevant project statistician. 
 
The primary analysis will summarise study variables when the last patient randomised has completed 48 weeks 
of follow-up.  This analysis will be reviewed firstly by the Protocol Steering Committee and then presented 
publicly with treatment arms identified.  Since this constitutes the final analysis of week 48 data (the primary 
analysis point), decisions regarding the future conduct of the trial will be made based on statistical significance at 
the conventional p<0.05 level. 
 
It is explicitly recognised that publication of the week 48 data may affect conduct of the trial between weeks 48 
and 96, and so may affect final results between those time points.  The 96-week analysis will provide longer term 
durability and safety data. 
 
11.5 Demographics and baseline characteristics 
Demographic and baseline characteristics will be summarised by randomised treatment group.  There will be no 
formal comparisons of randomised treatments for demographic and baseline characteristics (i.e. no p-values), as 
any imbalance will by definition have occurred by chance. 
 

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11.6 Efficacy analyses 
Treatment estimates and 95% confidence intervals will be calculated and used to assess primary and secondary 
efficacy endpoints.  If non-inferiority is established for the primary comparison (ITT and secondary PP analyses) 
further analyses to assess for superiority will be undertaken. 
 
Binary endpoints will be analysed using chi-square tests or logistic regression.  Continuous endpoints will be 
analysed using ANOVA methods or non-parametric equivalents.  Time to event endpoints will be analysed using 
survival analysis methods. 
 
For all endpoints and analysis populations, the primary treatment comparisons will be simple, unadjusted, two-
group comparisons.  If there are important imbalances in baseline characteristics, then adjusted analyses will 
also be performed and presented in addition to unadjusted analyses.  
 
11.7 Subgroup analyses 
There will be four pre-specified stratified analyses performed.  Outcomes of the primary and key secondary 
efficacy variables will be compared in strata defined by baseline plasma HIV-1 RNA viral load < or ≥100,000 
copies/mL.  There will also be a pre-specified analysis according to whether sites used HIV genotyping at baseline 
for construction of the N(t)RTI backbone in the control arm and an analysis of outcomes according to World Bank 
defined income criteria (high, middle and low) [43].  It is accepted that the reduced power of these comparisons 
will make establishing non-inferiority within each strata unlikely (i.e. increase the probability of making a Type II 
error).  The consistency of treatment comparisons across strata will be assessed using formal statistical tests for 
interaction between treatment group and strata. 
 
11.8 Safety analyses 
The proportion of participants with all grade adverse events and grade 3/4 adverse events will be summarised by 
randomised treatment group, by severity and by relation to study drug for all subjects treated with study drug.  
Serious adverse events will be summarised for all enrolled subjects.  The incidence rate of adverse events will 
also be calculated. The analysis of safety variables will be done according to a per protocol (see 11.3.2) approach.  
 
 
12 DATA COLLECTION, SOURCE DOCUMENTS AND RECORD RETENTION 
12.1 Data collection and source documents 
An Investigator is required to prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the investigation on each individual treated with the investigational 

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product or entered as a control in the investigation.  Data reported on the CRF that are derived from source 
documents must be consistent with the source documents or the discrepancies must be explained. 
The CRF for this study will be an Electronic Data Capture (EDC) system using a web-enabled password protected 
platform. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy and 
confidentiality rules in accordance with the applicable regulatory requirement(s). 
Corrections to CRFs will only be possible by study personnel with sufficient authorisation to make changes.  All 
changes will record time, date, computer ID and the name of the authorised person’s access code. 
12.2 Records retention 
The Investigator must retain investigational product disposition records, copies of CRFs (or electronic files), and 
source documents for the maximum period required by applicable regulations and guidelines, or Institution 
procedures, or for the period specified by the NCHECR, whichever is longer.  The Investigator must contact the 
Sponsor prior to destroying any records associated with the study. 
If the Investigator withdraws from the study (e.g. relocation, retirement), the records shall be transferred to a 
mutually agreed upon designee (i.e. another Investigator, IRB).  Notice of such transfer will be given in writing to 
the NCHECR. 
12.3 Monitoring for protocol compliance 
Representatives of the Sponsor must be allowed to visit all study site locations periodically to assess the data, 
quality and study integrity.  On site they will review study records and directly compare them with source 
documents and discuss the conduct of the study with the Investigator, and verify that the facilities remain 
acceptable.  Such visits will be scheduled in advance and with sufficient warning to allow arrangements of diaries 
and personnel as appropriate. 
There will be a total of 5 visits throughout the 2 year study.  The first will be an initiation visit prior to study 
commencement.  The 4 monitoring visits will be conducted firstly within a couple of months of the first 
participant being randomised, then when all participants have completed week 24, 48 and 96. 
In addition, the study may be evaluated by the regulatory authorities.  Audit reports will be kept confidential. 
THE INVESTIGATOR MUST NOTIFY THE SPONSOR PROMPTLY OF ANY INSPECTIONS SCHEDULED BY REGULATORY 
AUTHORITIES, AND PROMPTLY FORWARD COPIES OF INSPECTION REPORTS TO NCHECR. 

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12.4 Auditing 
The study may be subject to audit by properly authorised individuals but such information will be treated as 
strictly confidential and will in no circumstances be made publicly available.  Under such circumstances, the 
investigator must agree to allow access to study documents and relevant hospital/clinic records. 
 
13 ETHICS COMMITTEE/REGULATORY APPROVAL AND INFORMED CONSENT 
13.1 Ethics 
This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki and will be consistent with Good Clinical Practice (GCP) and applicable regulatory requirements. 
The study will be conducted in compliance with the protocol. The protocol, any Amendments and the Participant 
Informed Consent (PIC) will receive Institutional Review Board (IRB)/Human Research Ethics Committee (HREC) 
approval prior to initiation of the study. 
Freely given written informed consent must be obtained from every research subject or his or her legally 
acceptable representative prior to clinical trial participation, including informed consent for any screening 
procedures conducted to establish eligibility for the trial. 
For further details on informed consent, see Section 13.5 
The rights, safety and wellbeing of the trial subjects are the most important considerations and should prevail 
over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training, and experience to 
perform their respective task(s). 
This trial will not use the services of study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g. loss of medical licensure, debarment).  
Systems with procedures that assure the quality of every aspect of the study will be implemented. 
13.2 Institutional review board/independent ethics committee (IRB/IEC) 
Before study initiation, the Investigator must have written and dated approval/favourable opinion from the 
IRB/IEC for the protocol, consent form, subject recruitment materials/process (e.g. advertisements) and any 
other written information to be provided to subjects.  The Investigator should also provide the IRB/IEC with a 
copy of the product labelling and information to be provided to subjects and any updates. 

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The Investigator should provide the IRB/IEC with reports, updates, and other information (e.g., Safety Updates, 
Amendments, and Administrative Letters) according to regulatory requirements or Institution procedures. 
13.3 Compliance with the protocol and protocol revisions 
The study shall be conducted as described in this approved protocol.  The Investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favourable opinion from the 
Institutional Review Boards/Human Research Ethics Committees (IRB/HREC) of an Amendment, except where 
necessary to eliminate an immediate hazard(s) to study subjects.  Any significant deviation must be documented 
in the CRF. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to obtaining 
IRB/IEC approval/favourable opinion, as soon as possible the deviation or change will be submitted to: 
 
IRB/IEC for review and approval/favourable opinion; 
 
The Sponsor 
 
Regulatory Authority(ies), if required by local regulations. 
Documentation of approval signed by the chairperson or designee of the IRB(s)/HREC(s) must be sent to NCHECR 
along with other required documentation as outlined in the Manual of Operations. 
If the revision is an Administrative Letter, Investigators must inform their IRB(s)/HREC(s). 
If an Amendment substantially alters the study design or increases the potential risk to the subject: (1) the 
consent form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favourable opinion; (2) 
the revised form must be used to obtain consent from subjects currently enrolled in the study if they are 
affected by the Amendment; and (3) the new form must be used to obtain consent from new subjects prior to 
enrolment. 
13.4 Informed consent 
Investigators must ensure that subjects or their legally acceptable representative are clearly and fully informed 
about the purpose, potential risks and other critical issues regarding clinical trials in which they volunteer to 
participate. 
13.5 Informed consent procedures 
Preparation of the consent form is the responsibility of the Investigator and must include all elements required 
by ICH GCP and applicable regulatory requirements, and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The consent form must also include a statement that study 

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sponsors and regulatory authorities will have direct access to subject records.  Prior to the beginning of the 
study, the Investigator must have the IRB/IEC’s written approval/favourable opinion of the written informed 
consent form and any other information to be provided to the subjects. 
The Investigator must provide the subject or legally acceptable representative with a copy of the consent form 
and written information about the study in the language in which the subject is most proficient. The language 
must be non-technical and easily understood.  The Investigator should allow time necessary for subject or 
subject's legally acceptable representative to inquire about the details of the study, then informed consent must 
be personally signed and dated by the subject or the subject's legally acceptable representative and by the 
person who conducted the informed consent discussion. The subject or legally acceptable representative should 
receive a copy of the signed informed consent and any other written information provided to study subjects 
prior to subject's participation in the trial. 
13.5.1 Other circumstances 
Imprisonment or the compulsory detention for treatment of either a psychiatric or physical (e.g. infectious 
disease) illness precludes enrolment in clinical trials. 
When a subject may be in a dependent relationship with the investigator, a well-informed physician who is not 
engaged in the clinical trial and is completely independent of the relationship between the subject and 
investigator should obtain the subject’s informed consent. 
13.5.2 Update of informed consent 
The informed consent and any other information provided to subjects or the subject's legally acceptable 
representative, should be revised whenever important new information becomes available that is relevant to the 
subject's consent, and should receive IRB/IEC approval/favourable opinion prior to use. The Investigator, or a 
person designated by the Investigator should fully inform the subject or the subject's legally acceptable 
representative of all pertinent aspects of the study and of any new information relevant to the subject's 
willingness to continue participation in the study.  This communication should be documented. 
During a subject's participation in the trial, any updates to the consent form and any updates to the written 
information will be provided to the subject. 
 

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14 CONFIDENTIALITY OF DATA 
14.1 Confidentiality of participant records 
By signing of the protocol, the investigator agrees that the sponsor, ethics committee or regulatory authorities 
may consult and/or copy study documents to verify information in the case record form.  By signing of the 
consent form the participant agrees to this process. 
Participant confidentiality will be maintained at all times and no documents containing the participant’s name or 
other identifying information will be collected by the sponsor.  It may be necessary for the sponsor’s 
representatives, the ethics committee and regulatory authority representatives to have direct access to the 
subject/participant’s medical records.  If study documents need to be photocopied during the process of 
verifying case record form data, the subject/participant will be identified by a unique code only; full names and 
other identifying information will be masked.  
14.2 Confidentiality of study data 
By signing this protocol, the investigator affirms to the sponsor that information provided to the investigator by 
the sponsor will be maintained in confidence and will be divulged only as necessary to the ethics committee and 
institution employees directly involved in the study.  Both ethics committee members and employees must also 
understand the confidentiality requirements for any information divulged to them.  The data generated by this 
study will be considered confidential by the investigator, except to the extent that it is included in a publication 
as agreed in the publication policy of this protocol. 
 
15 FINANCING AND INSURANCE 
Investigators will be paid according to the separate financial agreement document that must be signed and 
dated prior to study commencement.   
It is the investigators responsibility to provide details of the study budget to the ethics committee, as required by 
each individual ethics committee.  Unless the clinical site comes under the St Vincent’s Hospital ethics 
application, in which case NCHECR will do this on behalf of the investigator. 
Indemnification for site personnel, investigators and institutions will be provided as required in keeping with the 
provisions as determined by the Medicines Australia guidelines through the University of New South Wales.  
Details of this provision will be documented in separate agreements. 

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No fault compensation is available to study participants who experience injury as a result of their participation in 
this study.  Details of the method of compensation will be provided in separate agreements between 
institutions. 
 
16 QUALITY CONTROL AND QUALITY ASSURANCE 
By signing of this protocol, the sponsor agrees to be responsible for implementing and maintaining quality 
control and quality assurance systems with written standard operating procedures.  These procedures will 
ensure that trials are conducted and data are generated, documented and reported in compliance with the 
protocol, Good Clinical Practice standards and all applicable local laws and regulations relating to the conduct of 
a clinical trial. 
 
17 PUBLICATION POLICY  
In the interests of collegiality and recognising that completion of this trial will have resulted from the 
contribution of many people the masthead authorship for the manuscript will be “The SECOND-LINE Study 
Group”.  The protocol steering committee (PSC) will constitute the writing committee for the primary 
manuscript.  In addition, one person from each investigational site will be listed in a separate appendix as being 
part of the SECOND-LINE Study Group.  The PSC will determine if there is a need for other appendices in which to 
identify others who have contributed in a significant way to the design AND conduct AND reporting of resultant 
trial data.  If the journal will not accept group authorship the writing committee will be listed as authors and be 
completed with the phrase ‘on behalf of the SECOND-LINE Study Group’. 
Additional manuscripts that are expected to report on the findings of any subsequent sub-studies should have 
named investigators and be completed with the phrase ‘on behalf of the SECOND-LINE Study Group’.  In these 
circumstances an appendix should contain the names of the PSC.   
All proposed manuscripts should be submitted to the PSC 45 days before they are to be submitted to a journal 
for peer review. 
Conference presentations should identify an authorship group consistent with those who have contributed to 
the data to be reported.  All proposed conference presentations should be submitted to the PSC at least 20 days 
before submission of an abstract. 

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References 
[1] 
Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir 
(MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomized controlled 
trial. Lancet 2007;369:1261-9. 
[2] 
Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 integrase 
inhibitor raltegravir as part of combination therapy in treatment naïve patients with HIV-1 coinfection. J Acquir 
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The World Bank. Data and Statistics. Available at: http://web.worldbank.org 

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Appendix 1: Definitions and Criteria For HIV Disease and AIDS Events 
 
The following list encompass the CDC's 1993 surveillance case definition of AIDS (without the CD4+ criterion), 
with the addition of several diagnoses increasingly felt to be associated with severe immunosuppression in 
participants infected with HIV.  
 
Modified CDC Category C 1993 Definition 
• Candidiasis of bronchi, trachea or lungs 
• Candidiasis, esophageal 
• Cervical cancer, invasive 
• Coccidioidomycosis, disseminated or extrapulmonary 
• Cryptococcosis, extrapulmonary 
• Cryptosporidiosis, chronic intestinal (> 1 month’s duration) 
• CMV disease (other than liver, spleen, or nodes) 
• CMV retinitis (with loss of vision) 
• Encephalopathy, HIV-related (including AIDS Dementia Complex) 
• Herpes simplex, chronic ulcers (> 1 month’s duration); or bronchitis, pneumonitis or 
esophagitis 
• Histoplasmosis, disseminated or extrapulmonary 
• Isosporiasis, chronic intestinal (> 1 month’s duration) 
• Kaposi’s sarcoma (mucocutaneous or visceral) 
• Lymphoma, Burkitt’s (or equivalent term) 
• Lymphoma, primary, of brain 
• Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary 
• M. tuberculosis, any site (pulmonary or extrapulmonary) 
• Mycobacterium, other species or unidentified species, disseminated or extrapulmonary 
• Pneumocystis carinii pneumonia (pneumocystic jiroveci) 
• Pneumonia, recurrent bacterial (2 documented episodes within 1 year of each other 
following randomization) 
• Progressive multifocal leukoencephalopathy 
• Salmonella septicemia, recurrent (2 documented episodes within 1 year of each other 
following randomization) 
• Toxoplasmosis of brain 
• Wasting syndrome due to HIV 
 
Additions to CDC Definition 
• Aspergillosis, invasive 
• Bartonellosis 
• Chagas disease (American trypanosomiasis) of the CNS 
• Herpes zoster, multi-dermatomal (≥10 lesions in a non-contiguous site) 
• Leishmaniasis, visceral (kala-azar) 
• Lymphoma, Hodgkin’s 
• Lymphoma, non-Hodgkin's, all cell types 
• Microsporidiosis (> 1 month’s duration) 
• Nocardiosis 
• Penicillium marneffii, disseminated 
• Pneumocystis carinii, extrapulmonary 
• Rhodococcus equi disease 

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CONFIRMED  
PROBABLE  
CONSTITUTIONAL DISEASE 
 
 
HIV wasting syndrome 
None 
A plus B plus C: (A) unexplained, 
involuntary weight loss >10% from 
baseline, (B) persistent diarrhoea with  
>2 liquid stools/d for >1 month or 
weakness for >1 month or fever for >1 
month, (C) tests for alternate causes of 
weight loss, such as cancer, TB, MAC, 
cryptosporidiosis or other specific 
causes of weight loss, if obtained, should 
be negative 
INFECTIONS 
 
 
Aspergillosis, invasive pulmonary 
A plus B plus C: (A) CXR abnormality 
compatible with aspergillosis, (B) 
invasive mycelia consistent with 
Aspergillus on lung biopsy, (C) positive 
culture from lung biopsy or sputum 
collected by any method 
A plus B: (A) CXR abnormality 
compatible with aspergillosis, (B) 
invasive mycelia consistent with 
Aspergillus on lung biopsy or positive 
culture of lung tissue or positive culture 
of sputum collected by any method 
Aspergillosis, other invasive 
A plus B plus C: (A) compatible clinical 
course, (B) invasive mycelia consistent 
with Aspergillus on tissue biopsy or 
clinical evidence of infection, (C) 
positive culture from the affected 
tissue 
A plus B: (A) clinical evidence of invasive 
infection, (B) invasive mycelia consistent 
with Aspergillus on tissue biopsy or 
positive culture at a normally sterile site 
(e.g., blood) apart from the involved 
tissue 
Bartonellosis 
A plus B: (A) Clinical or histologic 
evidence of bacillary angiomatosis or 
bacillary peliosis, (B) a positive culture 
or PCR for B. quintana or B. henselae 
A plus B: (A) Clinical evidence of bacillary 
angiomatosis or bacillary peliosis, (B) 
positive silver stain for bacilli from a skin 
lesion or an affected organ 
Candidiasis of bronchi, trachea or 
lungs 
Macroscopic appearance at 
bronchoscopy or autopsy plus 
microscopic evidence of yeasts or 
pseudo hyphae 
None 
Candidiasis, esophageal 
A plus B: (A) Macroscopic appearance 
at esophagoscopy or autopsy, (B) 
microscopic evidence of yeasts or 
pseudo hyphae 
A plus B plus C: (A) Recent onset of 
retrosternal pain or difficulty on 
swallowing, (B) a clinical diagnosis of 
oral candidiasis plus microscopic 
evidence of yeasts or pseudo hyphae 
from oropharyngeal mucosa, (C) clinical 
response to treatment 

SECOND-LINE STUDY 
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CONFIRMED 
PROBABLE 
INFECTIONS 
(CONTINUED) 
 
 
Chagas disease (American 
trypanosomiasis) of the CNS 
Histologic evidence obtained by brain 
tissue biopsy or autopsy 
A plus B plus C plus D: (A) Focal, typically 
hemispheral neurological dysfunction with 
onset over several days or weeks; (B) 
enhancing focal lesion(s) with mass effect, 
and surrounding edema and contrast 
enhancement, typically located in grey 
matter; (C) serum antibodies to T. cruzi, 
(D) response to standard therapy with 
documented clinical or radiographic 
improvement (if radiography was done, it 
must be improved), or peripheral blood 
smear or CSF smear positive for T. cruzi 
Coccidioidomycosis, disseminated or 
extrapulmonary 
From tissue other than lung or hilum, 
A or B or C: (A) Microscopic 
demonstration of spherules, (B) 
positive culture, (C) antigen detection   
None 
Cryptococcosis, meningitis or 
extrapulmonary 
From tissue other than lung or hilum, 
A or B or C or D: (A) microscopic 
demonstration of narrow based 
budding yeast, (B) for meningitis, if 
done, a positive CSF India ink test, (C) 
positive culture, (D) antigen detention  
None 
Cryptosporidiosis 
Diarrhea for >1 month and positive 
microscopy  
None 
CMV retinitis 
Autopsy demonstration 
Typical appearance on fundoscopy of 
discrete patches of retinal whitening, 
spreading along blood vessels, associated 
with vasculitis, hemorrhage and necrosis, 
confirmed by ophthalmologist  
CMV radiculomyelitis 
Autopsy demonstration 
A plus B plus C plus D plus E plus F: (A) 
Loss of sensation, leg weakness, or 
decreased reflexes, (B) presentation over 
3 days to 3 weeks, (C) CT, MRI or 
myelogram must be done and all imaging 
studies must not show a mass lesion, (D) 
CSF shows >10 WBC with >50% 
polymorphs, (E) CSF shows no other 
pathogen, (F) persistence of symptoms in 
the absence of CMV treatment, or 
elevated quantitative CMV in the CSF by 
PCR  

SECOND-LINE STUDY 
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CONFIRMED 
PROBABLE 
INFECTIONS 
(CONTINUED) 
 
 
CMV meningoencephalitis 
Autopsy or brain biopsy demonstration 
A plus B: (A) Rapid <4 weeks syndrome 
with progressive delirium, cognitive 
impairment and fever, (B) CT/MRI 
demonstration of periventricular 
abnormalities or elevated quantitative 
CMV DNA in the CSF by PCR 
CMV, other disease 
A plus B plus C plus D: (A) compatible 
illness, (B) histologic demonstration of 
inclusion bodies from affected tissue, 
(C) if done, detectible CMV antibodies, 
(D) if done, detectible CMV DNA or 
CMV antigen in blood  
A plus B plus C plus D: (A) Compatible 
illness, (B) moderate to markedly high 
CMV antigen or CMV DNA in blood, (C) 
response to therapy, (D) if done, 
detectible CMV antibodies  
HSV mucocutaneous ulceration 
A plus B: (A) Ulceration for >1 month, 
(B) histology or culture or detection of 
antigen from affected tissue 
A plus B: (A) Typical HSV ulceration for >1 
month, (B) response to an antiviral active 
against HZV unless resistance is 
demonstrated 
HSV, bronchitis, pneumonitis, 
esophagitis or other visceral disease 
A plus B: (A) Compatible symptoms, (B) 
histology or culture or detection of 
antigen from affected tissue 
None 
HZV, disseminated 
A plus B: (A) multiple ulcerated lesions 
affecting at least 2 non-contiguous 
dermatomes, or with genralised 
cutaneous dissemination: or HZV 
involvement of the lung, liver, brain, or 
other internal organs (B) positive 
culture, PCR, or antigen asssay from 
from affected tissue 
A plus B: (A) multiple typical ulcerated 
lesions affecting at least 2 non-contiguous 
dermatomes, or with generalised 
cutaneous dissemination (B) response to 
an antiviral active against HZV unless 
resistance is demonstrated 
Histoplasmosis, disseminated or 
extrapulmonary 
A plus B: (A) Compatible symptoms, (B) 
histology or culture or elevated blood 
or urine antigen levels 
None 
Isosporiasis 
Diarrhea for >1 month, plus 
microscopic identification of Isospora 
belli  
None 
Leishmaniasis, visceral 
Compatible symptoms, plus 
microscopic identification of 
Leishmania 
None 
Microsporidiosis 
Diarrhea for >1 month plus 
Microscopic identification of 
Microsporidia 
None 
MAC and other mycobacterial 
disseminated disease  
A plus B: (A) Fever, fatigue, anemia or 
diarrhea, (B) positive culture from 
blood, body fluids or tissue other than 
pulmonary, hilar or stool 
A plus B plus C: (A) Fever, fatigue, anemia 
or diarrhea, (B) AFB or positive direct MAC 
PCR in blood, body fluids or tissue other 
than pulmonary, hilar or stool (C) no 
concurrent non-pulmonary TB 

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CONFIRMED  
PROBABLE  
INFECTIONS 
(CONTINUED) 
 
 
M. tuberculosis disease, pulmonary 
A plus B: (A) Compatible symptoms of 
fever, dyspnea, cough, weight loss or 
fatigue, (B) culture or PCR from 
sputum or bronchial lavage or lung 
tissue  
A plus B plus C plus D: (A) Symptoms of 
fever, dyspnea, cough, weight loss or 
fatigue, (B) abnormal chest X-ray, (C) AFBs 
seen in sputum or lavage or lung tissue 
but not grown in culture, (D) responds to 
treatment  
M. tuberculosis disease, 
extrapulmonary 
A plus B: (A) Compatible symptoms, (B) 
culture or PCR from blood or affected 
tissue  
A plus B plus C: (A) Compatible symptoms, 
(B) AFBs seen from affected tissue or 
blood (C) concurrent diagnosis of 
pulmonary TB or responds to treatment  
Nocardiosis 
Clinical evidence of invasive infection 
plus a positive culture from the 
affected tissue or blood  
Clinical evidence of invasive infection plus 
microscopic evidence of bronchial weakly 
acid fast organisms from the affected 
tissue 
Penicillium marneffei, disseminated 
Culture from a non-pulmonary site  
Known presence in a P. marneffei endemic 
area plus characteristic skin lesions plus 
response to antifungal therapy for 
penicillosis  
PCP 
A plus B: (A) compatible clinical 
syndrome, (B) microscopic or 
histoloical demonstration of P. carinii 
cysts in a pulmonary specimen 
A plus B plus C plus D plus E: (A) dyspnea 
or cough, or fever progressive over >1 
week, (B) diffuse chest x-ray abnormality 
or, if on inhalational pentamidine, diffuse 
upper lung field abnormality, (C) evidence 
of hypoxia, (D) not suggestive of bacterial 
pneumonia (i.e., not purulent sputum or 
hemoptysis, no bacterial pathogen 
identified in blood or bronchial wash), (E) 
response to PCP treatment 
Pneumocystis jirovecii, 
extrapulmonary 
Compatible symptoms, plus 
microscopy  
None 

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CONFIRMED  
PROBABLE  
INFECTIONS 
(CONTINUED) 
 
 
Pneumonia, recurrent bacterial 
excludes, (a) post-obstructive 
pneumonias, including in those with 
intrapulmonary/bronchial lesions, 
(b) aspiration pneumonia, including 
in those with decreased 
consciousness levels, (c) nosocomial 
ventilator-associated pneumonias 
Both pneumonia episodes must occur 
after enrolment and satisfy criteria (A) 
plus (B) plus (C).  The recurrent 
pneumonia must also satisfy criteria 
(D) plus (E): (A) Signs and symptoms 
suggestive of bacterial pneumonia, (B) 
focal CXR abnormality compatible with 
bacterial pneumonia, (C) identification 
of a bacterial pathogen by positive 
blood culture, positive bronchoscopic 
sputum culture, detection of 
Legionella or pneumococcal antigen in 
urine or blood or diagnostic serologic 
findings, (D) the second pneumonia 
had onset of symptoms <365 days 
after the first episode, (E) there is 
strong evidence that the first episode 
was cured such as an intervening clear 
CXR or absence of symptoms after >1 
month off antibacterials effective 
against pathogens commonly 
producing pneumonia 
Both pneumonia episodes must occur 
after enrollment and satisfy criteria (A) 
plus (B) plus (C).  The recurrent 
pneumonia must also satisfy criteria (D) 
plus (E): (A) Signs and symptoms 
suggestive of bacterial pneumonia, (B) 
focal CXR abnormality compatible with 
bacterial pneumonia, (C) diagnosed by a 
doctor, physicians’ assistant or nurse 
practitioner, (D) the second pneumonia 
had onset of symptoms <365 days after 
the first episode, (E) there is strong 
evidence that the first episode was cured 
such as an intervening clear CXR or 
absence of symptoms after >1 month off 
antibacterials effective against pathogens 
commonly producing pneumonia 
PML (progressive multifocal 
leukoencephalopathy) 
A or B: (A) positive histology, (B) 
compatible clinical and radiologic 
course and positive CSF PCR for JK 
virus 
A plus B plus C: (A) Consistent symptoms, 
(B) brain image consistent with PML, (C) 
no response to toxo treatment or 
toxoplasma seronegative 
Rhodococcus equi disease 
Clinical evidence of invasive infection 
plus microbiologic identification of the 
organism in the affected tissue or 
blood  
None 
Salmonella septicemia, recurrent 
Both episodes must occur after 
enrollment and met criterion (A).  The 
second episode must meet criteria (B) 
and C: (A) Positive blood or tissue 
culture, (B) the second septicemia had 
onset of symptoms <365 days after the 
first episode, (C) the second 
septicemia must be due to a different 
Salmonella serotype or there must be 
strong evidence that the first episode 
was cured such as a negative blood 
culture off effective antibacterials for 
>1 week or absence of symptoms off 
antibacterials for >1 month 
None 

SECOND-LINE STUDY 
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Page 77 of 92 
 
CONFIRMED  
PROBABLE  
INFECTIONS 
(CONTINUED) 
 
 
Toxoplasmosis of brain 
Microscopy 
A plus B plus C: (A) Symptoms of focal 
intracranial abnormality or decreased 
consciousness, (B) brain image consistent 
with lesion(s) enhanced by contrast, (C) 
positive toxoplasma serology or responds 
to treatment clinically or by scan  
NEOPLASMS 
 
 
Cervical carcinoma, invasive 
Histology (NOT carcinoma-in-situ) 
None 
Kaposi sarcoma, (mucocutaneous or 
visceral) 
Histology 
Highly typical appearance and persistence 
for >1 month 
Lymphoma, primary, of brain 
Histology 
Symptoms consistent with lymphoma plus 
at least one CNS lesion with mass effect 
plus lack of clinical and radiographic 
response to at least 2 weeks of treatment 
for toxoplasmosis  
Lymphoma, Hodgkin's 
Histology 
None 
Lymphoma, non-Hodgkin's, all cell 
types 
Histology 
None 
NEUROLOGICAL 
 
 
HIV encephalopathy (including AIDS 
Dementia Complex) 
None 
Cognitive or motor dysfunction interfering 
with usual activity, progressive over weeks 
or months plus no other condition to 
explain the findings plus brain image 
obtained and suggests no other causes 
plus grade 2 or worse impairment in at 
least 2 domains by NARS (see below) 
excluding abnormal domains at trial entry.  
(For persons with abnormal domains at 
entry worsening by at least two grades 
meets criteria.) 
 
 

SECOND-LINE STUDY 
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Page 78 of 92 
 
 
Abbreviated NARS (Neuropsychiatric AIDS Rating Scale) Grading for HIV Encephalopathy 
Adapted from: Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis 1988; 158 (5): 1079-83, and 
Hughes CP, Berg L, Danziger WL. A new clinical scale for the staging of dementia. Brit J Psych 1982; 140: 566-
92. 
 
NARS 
stage 
Cognitive-Behavioral Domains 
 
Orientation 
Memory 
Motor 
Behavior 
Problem solving 
Activities of 
daily living 
0.5 
fully oriented 
complains of 
memory 
problems 
fully 
ambulatory 
slightly 
slowed 
movements 
normal 
has slight 
mental slowing 
slight 
impairment 
in business 
dealings 
1 
fully oriented, 
may have 
brief periods 
of “spaciness" 
mild memory 
problems 
balance, co-
ordination 
and 
handwriting 
difficulties 
more irritable, 
labile or 
apathetic, 
withdrawn 
difficulty 
planning and 
completing 
work 
can do 
simple daily 
tasks, may 
need 
prompting 
2 
some 
disorientation 
memory 
moderately 
impaired, new 
learning 
impaired 
ambulatory 
but may 
require 
walking aid 
some 
impulsivity or 
agitated 
behaviour 
severe 
impairment, 
poor social 
judgement, gets 
lost easily 
needs 
assistance 
with ADLs 
3 
frequent 
disorientation 
severe 
memory loss, 
only 
fragments of 
memory 
remain 
ambulatory 
with 
assistance 
may have 
organic 
psychosis 
judgement very 
poor 
cannot live 
independent
ly 
4 
confused and 
disoriented 
virtually no 
memory 
bedridden 
mute and 
unresponsive 
no problem 
solving ability 
nearly 
vegetative 
 
 

SECOND-LINE STUDY 
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Appendix 2: Template Patient Information Statement and Consent Form 
 
Patient Information Statement and Consent Form 
 
[Insert institutional letterhead] 
[name of local institution/s where research is being conducted] 
 
A randomised open-label study comparing the safety and efficacy of ritonavir boosted 
lopinavir and 2-3N(t)RTI backbone versus ritonavir boosted lopinavir and raltegravir in 
participants virologically failing first-line NNRTI/2N(t)RTI therapy: the SECOND-LINE study 
Invitation 
 
You are invited to participate in a research study to investigate the use of a new antiretroviral drug 
(Raltegravir) as a key component of therapy following the failure of the first-line anti-HIV regimen (so called 
‘second-line HIV therapy’). Current guidelines to treat HIV recommend the first types of drugs to be 
prescribed include drugs from 3 different classes.  These classes are called nucleoside reverse transcriptase 
inhibitors (N(t)RTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). In 
your case your first set of antiretroviral drugs has included two (2) drugs from the N(t)RTI class and one (1) 
drug from the NNRTI class. We know from experience that over time these combinations of antiretroviral 
drugs begin to lose effect in a proportion of people taking them. Eventually in such cases patients need to 
change to a different set of drugs in order to continue to keep the HIV under control and maintain their 
health. In general, guidelines recommend that once a person fails treatment with a drug combination with an 
NNRTI and 2 N(t)RTIs, they should switch therapy to three drugs with a PI combined once again with 2 
N(t)RTIs. However, the strength of this recommendation is poor because little research has been done to 
make sure that this strategy works well. One of the reasons that so little research has been done on that 
question is that up until recently there haven’t been much in the way of alternatives. However, there is now a 
new anti-HIV drug called raltegravir which is in a new class called the integrase strand-transfer inhibitor (InSTI) 
class. The evidence to date suggests that raltegravir is powerful and relatively free of unwanted side effects. 
The availability of this new drug means that we now have an opportunity to see how well it works in patients 
for whom the ‘first-line’ therapy is failing. 
 
Raltegravir is the first in class integrase strand-transfer inhibitor licensed for use as part of a combined anti-
HIV regimen.  At this point in time it is not currently licensed in every country involved in this study. 
 
The study is being conducted by the National Centre in HIV Epidemiology and Clinical Research, University of 
New South Wales in Australia. The study is part of an international collaborative study.  
 
Before you decide whether or not you wish to participate in this study, it is important for you to understand 
why the research is being done and what it will involve. Please take the time to read the following information 
carefully and discuss it with others if you wish. 
 
1. What is the purpose of the study? 
 
The objective of this study is to compare the safety and effectiveness over 96 weeks of two combinations of 
anti HIV drugs in controlling HIV-infection. Patients enrolled in the study will have been prescribed their first 
anti-HIV regimen consisting of an NNRTI plus 2N(t)RTIs for a minimum period of 24 weeks, however this 
treatment is no longer working to control the HIV infection.  Participants in the study will change their 
treatment to either what is currently recommended (LPV/r + 2-3N(t)RTIs) or the new treatment of raltegravir 
+ LPV/r. 

SECOND-LINE STUDY 
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2. Why have I been invited to participate in this study? 
 
You have been invited to participate in this study because you have been receiving antiretroviral regimen 
consisting of an NNRTI plus 2N(t)RTIs for at least 24 weeks and have: 
 
Failed this therapy according to virological criteria defined by two consecutive (≥7 days apart) HIV 
RNA results of >500 copies/mL. 
 
No prior or current exposure to HIV protease inhibitors and/or raltegravir. 
 
3. ‘What if I don’t want to take part in this study or if I want to withdraw later?’ 
 
Participation in this study is voluntary. It is completely up to you whether or not you participate. If you decide 
not to participate, it will not affect the other treatment you receive now or in the future. Whatever your 
decision, it will not affect your relationship with the staff caring for you. 
 
New information about the treatment being studied may become available during the course of the study. 
You will be kept informed of any significant new findings that may affect your willingness to continue in the 
study. 
 
If you wish to withdraw from the study once it has started, you can do so at any time without having to give a 
reason. 
 
However, it may not be possible to return your samples to you or withdraw your data from the study results if 
these have already had your identifying details removed. 
 
4. ‘What does this study involve?’ 
 
If you agree to participate in this study, you will be asked to sign the Participant Consent Form.  
This study will be conducted over 96 weeks. 
The treatment being investigated in this study differs from the standard treatment offered in this institution 
because raltegravir is not currently indicated for this use. However this drug is licensed for the treatment of 
HIV infection. 
This is an open-label study so you will be aware of which treatment you are prescribed. 
To ensure you are familiar with the meaning of this terminology and the design of the study the following 
information may be useful to consider.  
The underlying principle for conducting a randomised study is that sometimes the best way of treating 
patients with a particular condition is not known and so comparisons need to be made between different 
treatments. To do this, study participants are put into groups and given different treatments, and the results 
are compared to see whether one treatment is better. To ensure the groups are similar to start with, a 
computer allocates each study participant into a group randomly, like the flip of a coin. Neither the doctor nor 
the study participant can decide which treatment the participant receives.  
 
The study aims to enrol 550 subjects from approved sites in Australia, Argentina, Chile, Peru, Mexico, England, 
Ireland, France, Germany, Malaysia, Singapore, Thailand, Hong Kong, India, New Zealand, South Africa, Israel, 
and Nigeria. 
 
If you are eligible to enter the study, you will be randomised to receive either: 
 
I. 
ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily (OR 
133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules twice daily) + 2-3N(t)RTIs 
 
II. 
ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily (OR 
133.3mg/33.3mg 6 soft gelatin capsules once daily or 3 soft gelatin capsules twice daily) + raltegravir 
400 mg 1 tablet twice daily 
 
You will be required to attend the clinic on 11 occasions over the 96 weeks of the study. 

SECOND-LINE STUDY 
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If you agree to participate in this trial, you will be asked to undergo the following procedures:  
 
Initial Visit (to screen for eligibility for study) 
 
Medical history 
 
Laboratory blood tests to screen for eligibility and gain a picture of your current state of health. Total 
amount of blood drawn at this visit will be approximately 30mL (1.5 tablespoons) 
 
Physical examination by your doctor 
 
Pregnancy test, if required 
 
Randomisation Visit (on commencement of study drugs) 
 
Physical examination by your doctor 
 
Laboratory blood tests for safety and efficacy (fasting). Total amount of blood drawn at this visit will 
be approximately 75 ml (about 4 tablespoons) 
 
Pregnancy test, if required 
 
Measurement of waist and hip circumference, and weight and height 
 
Questionnaire about your quality of life 
 
Visit at Week 4, 12, 24, 36, 48, 60, 72, 84 and 96 
 
Physical examination by your doctor 
 
Laboratory blood tests for safety and efficacy (fasting week 4, 12, 24, 48, 72, 96 and non-fasting 
weeks 36, 60 and 84). Total amount of blood drawn at this visit will be approximately 70-75mL ml 
(about 3.5 to 4 tablespoons). 
 
Pregnancy test, if required 
 
Assessment for any adverse side-effects of the study drugs 
 
Measurement of waist and hip circumference, and weight (week 48 and 96 only) 
 
Questionnaire about your ability to take study medication (week 4, 48 and 96 only) 
 
Questionnaire about your quality of life (week 48 and 96 only) 
 
Some of the blood collected at all visits will be stored for future testing.  It is possible that some of the stored 
blood may be used as a source of DNA for genetic testing to be done at a later date, but such testing is not so 
far planned.  Prior to any genetic test being undertaken, approval will be sought from your local Research 
Ethics Committee.  In these studies, your DNA may be analysed to see if you have certain types of genes that 
are responsible for influencing how your body reacts to HIV, the drugs used to treat HIV or infections that can 
occur in HIV-infected persons.  This means the study will only evaluate those genes that have a role in 
responding to HIV or related infections.  If samples are selected for genetic testing, they will not contain any 
of your personal details such as your name, but only a study ID code.  Genetic testing is an optional part of this 
study.  You may refuse genetic testing, which will not affect your participation in this study.  If you agree to 
participate in this part of the study, you have the option of discontinuing at any time.  If you change your 
mind, you must contact research staff and let them know that you do not want your samples used for genetic 
testing.  The results of these genetic tests will be used for research purposes only.  Neither you nor your 
doctor will be given the results from these tests. 
 
At any time during the study, if you have a bad effect from the study medications, you will need to advise your 
doctor.  You may be asked to stop the study medication and be required to come to the clinic for an additional 
visit(s) for additional exams or lab tests. 
 
Interaction with Concurrent Medications 
There can be a risk of serious and/or life threatening side effects when non-study medications are taken with 
the study drug.  For your safety, you must tell the study doctor or nurse about all medications you are taking 
before you start the study.  You must tell any doctor you see during the study about all of the medications you 
are taking, especially before starting any new medications. This includes any other prescribed medicines, 
over-the-counter medicines, herbal medicines or supplements.  In addition, you must tell the study doctor or 
nurse before enrolling in any other clinical trials while on this study. 

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5. 
‘How is this study being paid for?’ 
 
This study is being funded by the National Centre in HIV Epidemiology and Clinical Research (NCHECR), 
University of New South Wales (UNSW), Merck Sharp & Dohme and Abbott. There is no conflict of interest 
declared by any of the investigators.  
 
The drugs being used are being provided by their manufacturers: raltegravir by Merck Sharp & Dohme and 
ritonavir boosted lopinavir by Abbot. All of the money being paid by NCHECR, UNSW to run the trial at your 
site will be deposited into an account managed by [insert hospital/Area Health Service]. No money is paid 
directly to individual researchers. 
 
6. 
‘Are there risks to me in taking part in this study?’ 
 
All medical procedures involve some risk of injury. In addition, there may be risks associated with this study 
that are presently unknown or unforeseeable.  
As part of this study, you will have your blood drawn. This procedure may be uncomfortable but rarely results 
in any significant problems. Side effects that have been noted with drawing blood include feeling light-headed 
or faint, fainting, pain and bruising at the needle stick site. 
Some of the side effects of the drugs in the study are listed below. Please note that this list does not include 
all the side effects seen with these drugs. This list includes the more common or serious side effects. If you 
have questions concerning any additional side effects, please ask the study doctor or nurse at your site. 
 
Frequency 
Raltegravir 
Kaletra/Aluvia 
Very Rare 
(<1%) 
Irritation of the stomach lining, liver 
problems, herpes simplex, decrease in kidney 
function, low blood counts, increase in blood 
glucose 
Decreased sex drive  
Rare# 
(≥1% <2%) 
Weakness, tiredness, nausea, diarrhoea 
Anorexia, muscular pain, 
abnormal sensations such 
as burning or tingling, 
depression, rash 
Uncommon# 
(≥2%<10%) 
 
Headache, diarrhoea 
Abdominal pain, 
weakness, headache, 
nausea, vomiting, upset 
stomach, flatulence, 
insomnia 
Common* 
(>10%) 
Headache, nausea, diarrhoea, fever, 
tiredness, vomiting, illness caused by an 
infection involving the nose or throat 
Diarrhoea  
# moderate intensity (discomfort enough to cause interference with usual activity) to severe intensity 
(incapacitating with inability to work or do usual activity) 
* all intensities 
 
Some adverse events have been reported but it remains unknown if they were related to raltegravir and are 
considered rare, these include: creatinine kinase elevations and muscle disease. 
 
Pregnancy 
Because of the unknown effects of raltegravir on the unborn child, women should avoid becoming pregnant 
during the course of this trial. If you do become pregnant during the study you should tell your study doctor 
immediately. Your study doctor will discuss the options with you at that time and will follow your progress 
until your baby is born. 
 
You should speak to the study doctor about the need to avoid pregnancy during this study. 

SECOND-LINE STUDY 
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7. 
What happens if I suffer injury or complications as a result of the study?’ 
 
If you suffer any injuries or complications as a result of this study, you should contact the study doctor as soon 
as possible, who will assist you in arranging appropriate medical treatment. 
 
If you suffer any adverse experience resulting directly from the study drug/procedure, compensation will be 
provided for the reasonable costs of medical treatment to the extent such costs are not covered by your 
medical insurance or government health schemes. Compensation will be provided in accordance with the 
principles of the national compensation scheme of the country in which the study is performed and the 
incident occurs will be adhered to. If no national scheme exists the Clinical Trial Compensation Guidelines 
issued by Medicines Australia will be adhered to. 
 
8. 
‘Will I benefit from the study?’ 
 
Information learned from this study may improve future treatments of HIV infection however it may not 
directly benefit you. 
 
9. 
‘Will taking part in this study cost me anything, and will I be paid? 
 
The only specific cost in this study will be the travel costs for attending the clinic on the 11 occasions for study 
specific visits.  It is hoped you can arrange for most of these visits to tie in with your normal three monthly 
visits with your doctor.   
 
The NCHECR, UNSW will cover any cost associated with provision of the study drugs. 
 
10. 
‘What will happen to my blood sample after it has been used?’ 
 
This blood will be stored for current and future medical research that relates to the treatment of HIV. Not all 
potentially beneficial future research can be known at any one time, as the need for future research is 
determined by ongoing developments in the field indefinitely for future research. The Human Research Ethics 
Committee will determine whether, or not, your consent should be obtained at that time for a particular 
research project. 
 
11. 
‘How will my confidentiality be protected?’ 
 
Of the people treating you, only the study doctor and research team involved in your care will know whether 
or not you are participating in this study. Any identifiable information that is collected about you in 
connection with this study will remain confidential and will be disclosed only with your permission, or except 
as required by law. Only the researchers at your site will have access to your details and results that will be 
held securely at [insert name of institution]. 
 
12. 
‘What happens with the results?’ 
 
If you give us your permission by signing the consent document, we may discuss/publish the results e.g. with 
the sponsor for monitoring purposes, the HREC for monitoring purposes, peer-reviewed medical and scientific 
journals, presentation at conferences or other professional forums. 
In any publication, information will be provided in such a way that you cannot be identified. Results of the 
study will be provided to you, if you wish. 
 
13. 
‘What happens to my treatment when the study is finished?’ 
 
Study drug will be provided for a maximum of 3 years as part of the protocol.  If the study drugs are not 
available locally after that time then the decision will be made in consultation between you and your treating 
doctor about the most appropriate treatment. 
 
 
 

SECOND-LINE STUDY 
5th November 2009 
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14. ‘What should I do if I want to discuss this study further before I decide?’ 
 
When you have read this information, the researcher [insert name] will discuss it with you and any queries 
you may have. If you would like to know more at any stage, please do not hesitate to contact him/her on 
[insert number – or other if different]. 
 
15. 
‘Who should I contact if I have concerns about the conduct of this study?’ 
 
This study has been approved by [insert HREC name]. If you have any questions about your rights as a 
research participant, please contact [insert HREC contact details] and quote [insert HREC project number]. 
 
 
Thank you for taking the time to consider this study. 
If you wish to take part in it, please sign the attached consent form. 
This information sheet is for you to keep. 

SECOND-LINE STUDY 
5th November 2009 
Page 85 of 92 
[Insert institutional letterhead] 
[name of local institution/s where research is being conducted] 
 
A randomised open-label study comparing the safety and efficacy of ritonavir boosted 
lopinavir and 2-3N(t)RTI backbone versus ritonavir boosted lopinavir and raltegravir in 
participants virologically failing first-line NNRTI/2N(t)RTI therapy: the SECOND-LINE study 
1.   
I,.................................................................................................................  
of................................................................................................................ 
agree to participate as a subject in the study described in the participant information statement 
attached to this form. 
 
2. 
 
I acknowledge that I have read the participant information statement, which explains why I have been 
selected, the aims of the study and the nature and the possible risks of the investigation, and the 
statement has been explained to me to my satisfaction. 
 
3. 
 
Before signing this consent form, I have been given the opportunity of asking any questions relating to 
any possible physical and mental harm I might suffer as a result of my participation and I have received 
satisfactory answers. 
 
4. 
 
I understand that I can withdraw from the study at any time without prejudice to my relationship to 
the ([insert or delete as necessary] University [name] and the ......Hospital, Research Institute). 
 
5. 
 
I agree that research data gathered from the results of the study may be published, provided that I 
cannot be identified. 
 
6. 
 
I understand that if I have any questions relating to my participation in this research, I may contact Dr 
............................on telephone................., who will be happy to answer them. 
 
7. 
 
I agree to have my blood samples used for genetic testing  ________(Patient initials) 
I do not agree to have my blood samples used for genetic testing______(Patient initials) 
8. 
 
I acknowledge receipt of a copy of this Consent Form and the Participant Information Statement. 
 
Complaints may be directed to the, Research Governance Officer, [insert local details] 
 
Signature of subject  
 
Please PRINT name  
 
 
Date 
 
_______________________________________________________________________________________ 
 
Signature of witness  
 
Please PRINT name 
 
 
Date 
 
 
Signature of investigator  
Please PRINT name 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
__________________________________________________________________________________________ 

SECOND-LINE STUDY 
5th November 2009 
Page 86 of 92 
 
[Insert institutional letterhead] 
[name of local institution/s where research is being conducted] 
 
A randomised open-label study comparing the safety and efficacy of ritonavir boosted 
lopinavir and 2-3N(t)RTI backbone versus ritonavir boosted lopinavir and raltegravir in 
participants virologically failing first-line NNRTI/2N(t)RTI therapy: the SECOND-LINE study 
 
REVOCATION OF CONSENT 
 
 
I hereby wish to WITHDRAW my consent to participate in the study described above and understand that such 
withdrawal WILL NOT jeopardise any treatment or my relationship with the (University...[insert name of 
university], Hospital or my medical attendants). 
 
 
Signature________________________________________Date_____________ 
 
Please PRINT Name________________________________ 
 
The section for Revocation of Consent should be forwarded to (INSERT name and address of Principle 
Investigator).  
 
 
 
 

SECOND-LINE STUDY 
5th November 2009 
Page 87 of 92 
 
Appendix 3: Diagnostic Criteria for Serious Non-AIDS Events 
 
ACUTE MYOCARDIAL INFARCTION  
A. Rise and/or fall of cardiac biomarkers (preferably troponin), with at least one value above 99th 
percentile of upper reference limit (URL)  
B. Occurrence of a compatible clinical syndrome, including symptoms (such as chest pain) consistent 
with myocardial ischemia  
C. ECG changes indicative of new ischemia (new ST-changes or new left bundle branch block 
[LBBB]), or development of pathological Q waves on the ECG  
D. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality  
E. Sudden unexpected cardiac death involving cardiac arrest before biomarkers are obtained or 
before a time when biomarkers appear, along with (1) new ST-changes or new LBB, or (2) 
evidence of fresh thrombus on coronary angiography or at autopsy  
F. In participants with percutaneous coronary interventions and normal baseline troponin, increases 
in troponin of three times the 99th percentile of URL  
G. In participants with coronary artery bypass grafting and normal baseline troponin, increases in 
troponin of five times the 99th percentile of URL PLUS at least one of the following: (1) new 
pathological Q-waves or new LBBB, (2) angiographically documented new graft or native artery 
occlusion, or (3) imaging evidence of new loss of viable myocardium  
H. Pathologic findings of acute myocardial infarction (including acute MI demonstrated as the cause 
of death on autopsy)  
I. Development of 1) evolving new Q waves, or 2) evolving ST elevation, preferably based on at least 
2 ECGs taken during the same hospital admission  
J. In participants with coronary artery bypass grafting and normal baseline troponin, increases in 
troponin of five times the 99th percentile of URL  
Confirmed: One of the following 5 criteria (adapted from 2007 Universal Definition of Myocardial 
Infarction):  
1. A + (B or C or D)  
2. E  
3. F  
4. G  
5. H  
Probable: B+I or J 

 
 
Page 88 of 92 
CONGESTIVE HEART FAILURE  
A. Clinical signs and symptoms compatible with left or right sided heart failure (e.g., paroxysmal 
nocturnal dyspnea, rales or S3 on auscultation, jugular venous distention) without an alternative 
explanation  
B. Hemodynamic measurements, radionucleotide ventriculography, echocardiogram, cardiac 
catheterization, or multiple gated acquisition scan showing a decreased ejection fraction of < 45%  
C. Echocardiogram, cardiac catheterization or other studies showing evidence of increased left 
atrial pressure or right heart failure  
D. Elevated levels of Brain Natriuretic Peptide (BNP) or pro-BNP  
E. Chest x-ray or other imaging study showing evidence of congestive heart failure, including 
cardiac enlargement  
F. Documentation of treatment for congestive heart failure  
 
Confirmed: (A+B) or (A+C) or (A+D)  
Probable: A+E+F  
 
CORONARY ARTERY DISEASE REQUIRING REQUIRING DRUG TREATMENT  
Confirmed: A written report in the medical record documenting: (A) myocardial ischemia and/or 
coronary artery disease, AND (B) use of medications given to treat or prevent angina (e.g., 
nitrates, beta blockers, calcium channel blockers)  
Probable: Not applicable  
 
CORONARY REVASCULARISATION  
Confirmed: A written report in the medical record or hospital discharge summary from the 
hospitalization during which the procedure was performed for treatment of coronary artery 
disease, including: coronary artery bypass graft, coronary artery stent implant, coronary 
artherectomy, and percutaneous transluminal angioplasty  
Probable: Not applicable  
 
DECOMPENSATED LIVER DISEASE  
A. Histologic, radiographic, or ultrasound evidence of cirrhosis, as documented by one of the 
following:  
 
1. Histologic evidence of cirrhosis obtained by liver biopsy or autopsy  
 
2. MRI or CT consistent with cirrhosis  

 
 
Page 89 of 92 
 
3. A positive result on transient elastography (FibroScan) or other ultrasound imaging 
consistent with cirrhosis  
B. Clinical evidence of decompensation, as documented by one of the following, and without an 
alternative explanation:  
 
1. Ascites  
 
2. Hepatic encephalopathy  
 
3. Bleeding from gastric or esophageal varices  
4. Spontaneous bacterial peritonitis  
 
 
Confirmed: A+B  
Probable: B  
  
DEEP VEIN THROMBOSIS  
A. Diagnosis of deep vein thrombosis (DVT) by contrast venography, helical computed 
tomography, MRI, or ultrasonography other comparable imaging techniques  
B. An elevated D-dimer test OR abnormal plethysmography  
C. A score on the Wells Clinical Prediction Rule for DVT of >=3 points  
D. Absence of alternative diagnosis as likely or greater than that of deep venous thrombosis  
Wells Clinical Prediction Rule for DVT  
One point for each of the following:  
• Active cancer (treatment ongoing or within previous 6 months, or palliative)  
• Paralysis, paresis, or plaster immobilization of lower extremities  
• Recently bedridden for more than 3 days, or major surgery, within 4 weeks  
• Localized tenderness along distribution of the deep venous system  
• Entire leg swollen  
• Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured     10 cm 
below tibial tuberosity)  
• Pitting edema (greater in the symptomatic leg)  
• Collateral superficial veins (non-varicose)  
(Adapted from: Wells PS et al. Lancet 1997;350:1796)  
 
Confirmed: A  
Probable: B+C+D  

 
 
Page 90 of 92 
 
DIABETES MELLITUS  
A. Symptoms of diabetes plus casual plasma glucose concentration >= 200 mg/dL (11.1 mmol/L). 
(Casual is defined as anytime of day without regard to time since last meal. The classic symptoms 
of diabetes include polyuria and polydipsia).  
B. Fasting plasma glucose >= 126 mg/dL (7.0 mmol/L). (Fasting is defined as no caloric intake for at 
least 8 hours).  
C. 2-hour post-load glucose >= 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. 
(The test should be performed as described by WHO, using glucose load containing the 
equivalent of 75 g anhydrous glucose dissolved in water).  
 
Confirmed: A or B or C  
Probable: none  
 
END-STAGE RENAL DISEASE  
A. Hemodialysis or peritoneal dialysis for a period of at least one month, documented in a clinical 
note  
B. A kidney transplant, documented in a clinical note  
 
Confirmed: A or B  
Probable: Not applicable   
 
NON-AIDS-DEFINING CANCER  
A. Diagnosis of cancer other than lymphoma, Kaposi's sarcoma (KS), or invasive cervical cancer in 
an autopsy report  
B. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a pathology report 
that established the diagnosis  
C. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a hospital discharge 
summary or consultation note from the hospitalization or clinic visit during which the diagnosis 
was established  
 
Confirmed: A or B  
Probable: C  

 
 
Page 91 of 92 
PERIPHERAL ARTERIAL DISEASE  
A. Compatible clinical signs and symptoms (e.g., intermittent claudication, femoral bruit, 
decreased peripheral pulses, change in color or temperature of limb suggesting peripheral arterial 
disease)  
B. Positive results on diagnostic imaging studies (e.g., Doppler ultrasound, contrast arteriography, 
MRI arteriography)  
C. Ankle Brachial Pressure Index < 0.90 in non-diabetics  
D. A procedure report, hospital discharge summary, or other medical record from the 
hospitalization during which the procedure was performed documenting an invasive procedure 
for treatment of peripheral arterial disease (e.g. percutaneous transluminal angioplasty, 
endovascular procedures, or vascular surgery), or a consultation note documenting the 
occurrence of the procedure 
Confirmed: (A+B) or (A+C) or D  
Probable: A  
 
PULMONARY EMBOLISM  
A. Symptoms compatible with pulmonary embolism, such as shortness of breath, chest pain, or 
hemoptysis  
B. Results consistent with a diagnosis of pulmonary embolism on pulmonary angiography, helical 
CT, ventilation-perfusion scan or other comparable imaging studies  
C. A diagnosis of pulmonary embolism on autopsy  
D. Results consistent with a diagnosis of deep venous thrombosis on venography, ultrasound, or 
other comparable imaging studies  
E. A chest x-ray which, if performed, does not suggest an alternative etiology for the symptoms 
described in criteria A  
Confirmed: (A+B) or C  
Probable: A+D+E  
 
STROKE  
A. Acute onset with a clinically compatible course, including unequivocal objective findings of a 
localizing neurologic deficit  
B. CT or MRI compatible with diagnosis of stroke and current neurologic signs and symptoms  
C. Stroke diagnosed as cause of death at autopsy  
D. Positive lumbar puncture compatible with subarachnoid hemorrhage  

 
 
Page 92 of 92 
E. Death certificate or death note from medical record listing stroke as cause of death  
Confirmed: (A+B) or C  
Probable: (A+D) or (A+E)