1. The HPTN 052 HIV Treatment as Prevention Trial: A case study of ethical considerations in human research conducted in low and middle income countries (LMIC) Dr. Philip Berger St. Michael’s Hospital, Toronto, Canada

2. CountryYearARV Initiation Recommendation During Trial Period June 2007- May 2010 Guideline Met for Delayed: CD4 < 250/AIDS ARV Coverage Rate 2009, % Botswana2008WHO Stage 3No83 (77-95) Brazil2008 Significant symptoms or CD4 200-350 when VL > 100,000 NoN/A India2007 WHO Stage 3 with no CD4; consider WHO Stage 3 & CD4 < 350 NoN/A Kenya2005WHO Stage 3 & CD4 < 350No50 (46-55) Malawi2008WHO 3 regardless of CD4No48 (44-54) South Africa2010CD4 < 350 + TB No for pulmonary TB 36 (35-37) Thailand 2008 2010 Symptomatic HIV, any CD4 value Asymptomatic with CD4 < 350 No61 (49-77) United States2009All patients with CD4 < 350NoN/A Zimbabwe 2005 2007 WHO Stage 3 WHO Stage 3 with no CD4; consider treatment with WHO Stage 3 & CD4 < 350 No34 (32-37)

3. International Guideline YearARV Initiation RecommendationGuideline Met? International AIDS Society (USA) 2008 2010 All patients CD4 < 350 All patients CD4 < 500 No WHO / UNAIDS 2003 2006 2009 WHO Stage 3 with consideration of CD4 < 350 For CD4 200-350, consider treatment All patients CD4 < 350 No Research Ethics Guideline Recommendation052 Compliant? WMA Declaration of Helsinki Research subject wellbeing takes precedenceNo UNAIDS/WHO Guidelines (2007, 2011) Treatment regimens must be accessible to subjects who become HIV-infected during a trial Research teams may need to modify their plans to meet updated national guidelines Cannot determine for participants who sero-converted Presidential Commission (2011, US) The “best-proven” intervention in not knownNo

4. The HPTN 052 HIV Treatment as Prevention Trial: a case study of the ethical considerations in human research conducted in low and middle income countries (LMIC) Discussion “Delayed therapy” group were not treated in accordance with existing country and international guidelines. Ethical guidelines -- current standard of treatment should be provided to clinical trial subjects. ARV coverage rates were sufficiently high (approaching or exceeding the 80% UNAIDS definition of universal coverage) The absence of treatment infrastructure was not a bone fide reason to withhold treatment The 052 descriptor “early” is inaccurate relative to standard ARV initiation guidelines in the USA.