1. 1 WHEN TO START TREATMENT

2. Early success: Improving outcomes with ART, 1996 - 2002 Adapted from Moore R et al. 11 th Conference on Retroviruses and Opportunistic Infections (CROI ), San Francisco, CA 2004; Abstract 558 Observational data, Johns Hopkins clinic 1996 n = 238 1997-1998 n = 591 1999-2000 n = 365 2001-2002 n = 132 Regimens used NNRTI-based 0%5%65%59% Boosted PI 7%18%15%13% Single PI 85%72%26%7% All NRTI 0% 6%16% Outcomes (all regimens) Undetectable VL, 6 months 45%54%68%73% Undetectable VL, 12 months 43%47%60%68% CD4+ increase (cells/mm 3 ), 6 months 72769690 CD4+ increase (cells/mm 3 ), 12 months 100120148139 AIDS-defining illness during 1st year of treatment 21%25%9%10% Death during 1st year of treatment 18%19%2%1% 2 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

3. When to start: Hit early [1] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. December1, 1998. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf. Accessed Jan 2014http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf [2] British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1997;349:1086-1092 [3] British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2000;1:76-101 CD4 Count Hit Early Era 1997-2000 Pre-ART Era 1987-1996 500 Start treatment when OIs occur* PCP prophylaxis – Single drug therapy Triple therapy Viral eradication? 300- 350 DHHS [1] BHIVA [2,3] 200 3 2000 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

4. When to start treatment? Eradication proved impossible as we began to realise that HIV remained hidden in “viral reservoirs”…control of the virus was the best we could hope for [1,2] And concerns were soon raised about the emergence of resistance if the virus was not fully suppressed in an individual who was taking therapy for 30-50 years or more [3-5] The existing drugs were not thought to be as potent and durable [6] There were also concerns about side effects that may occur with a lifetime on long term medication [6] In particular, there were concerns with the increasing numbers of people being affected by lipodystrophy (body fat changes) which could show through very quickly with some of the early drug regimes used [7-9] 4 [1] Flexner C. N Engl J Med 1998;338:1281-1293 [2] Blankson et al. Annu Rev Med 2002;53:557-593 [3] Campaign for Access to Essential Medicines. Médecins Sans Frontières, July 2009. HIV/AIDS treatment in developing countries: The battle for long-term survival has just begun. http://doctorswithoutborders.org/publications/reports/2009/msf_hiv-aids-treatment_battle-for-long-term-survival.pdf Accessed Feb 2014http://doctorswithoutborders.org/publications/reports/2009/msf_hiv-aids-treatment_battle-for-long-term-survival.pdf [4] Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2002; 1-161. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL04232001006.pdf Accessed Feb 2014http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL04232001006.pdf [5] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. August 13, 2001. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf Accessed Feb 2014http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf [6] Expert opinion of author Brian West as well as the BEST Advisory Board and Review Committee; agreed on 24th September 2009 [7] Hengel RL et al. Lancet 1997;350:1596 [8] Carr et al. Aids 1998;12:F51-F58 [9] Chen, et al. J Clin Endocrinol Metab 2002;87:4845-4856 2002 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

5. When to start treatment? The goalposts have moved back and forth over the years since Time magazine named Dr. David Ho, Man of the Year on Dec. 30, 1996 [1] “Hit early hit hard,” was initially the American strategy [2] Perhaps, according to this approach, the virus could be completely eradicated 5 [1] Time Magazine, 30th December 1996 [2] Ho DD, Time to Hit HIV, Early and Hard. N Engl J Med 1995, 333:450-451 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

6. When to start: Delay Treatment Era CD4 Count Hit Early Era 1997-2000 Pre-HAART Era 1987-1996 500 Triple therapy Viral eradication? 300- 350 DHHS [1] BHIVA [2,3] 200 Delay Treatment Era 2001-2007 350 Viral suppression Potent drugs Wait until needed 200 BHIVA [5] EACS (2005) [6] IAS-USA (2004) [7] 6 [1] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. December 1, 1998. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf Accessed Feb 2014http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf [2] British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1997;349:1086-1092 [3] British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2000;1:76-101 [4] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. August 13, 2001. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf. Accessed Feb 2014http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf [5] British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy July 2003. http://www.bhiva.org/documents/Guidelines/Treatment%20Guidelines/Archive/2003/Treatment%20Guidelines%202003.pdf Accessed Feb 2014http://www.bhiva.org/documents/Guidelines/Treatment%20Guidelines/Archive/2003/Treatment%20Guidelines%202003.pdf [6] European AIDS Clinical Society (EACS) European Guidelines for the Clinical Management and Treatment of HIV Infected Adults 2005 [7] Treatment for Adult HIV Infection 2004. Recommendations of the International AIDS Society-USA Panel. JAMA 2004;292:251-265 Start treatment when OIs occur PCP prophylaxis – Single drug therapy DHHS [4] 2004 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

7. Delay Treatment Era: Reasons we were cautious If we had perfect drugs with no cost issues, no side effects, no resistance concerns and no issues with adherence we might treat everyone from the day of diagnosis [1] But early drugs were complex combinations – there were high pill counts, sometimes to be taken three times daily, so they could be difficult to adhere to [2,3] – and difficult to stomach! 7 [1] Expert opinion of author Brian West as well as the BEST Advisory Board and Review Committee; agreed on 24th September 2009 [2] Smith M. The Changing Face of Medicine, 1984-2009. HIV/AIDS - Much Progress, No Cure. Medpage Today, December 23, 2009. http://www.medpagetoday.com/HIVAIDS/HIVAIDS/17665 Accessed Feb 2014. http://www.medpagetoday.com/HIVAIDS/HIVAIDS/17665 [3] NAM. Adherence Booklet. Fourth edition, 2007 2005 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

8. Delay Treatment Era: Reasons we were cautious So we delayed starting treatment until the risk of HIV/AIDS complications became significant [1] We put off taking drugs until the CD4 count went below 200 cells/mm 3 or until the viral load went too high – above 100,000 copies/ml [2] More evidence based guidelines were needed on when to start [1] 8 [1] Expert opinion of author Brian West as well as the BEST Advisory Board and Review Committee; agreed on 24 th September 2009 [2] European AIDS Clinical Society (EACS) European Guidelines for the Clinical Management and Treatment of HIV Infected Adults 2005 2005 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

9. The rationale started to change Over time the drugs became easier to take and less toxic [1] Living long term with HIV meant it wasn’t just about the ART [1] We soon became concerned about other serious illnesses – more people were beginning to die of diseases not thought to be HIV-related than were dying of AIDS [2] So what damage was untreated HIV doing to us ? 9 [1] NAM Aids Treatment Update April 2006, issue 155. http://www.aidsmap.com/files/file1000631.pdf Accessed Feb 2014http://www.aidsmap.com/files/file1000631.pdf [2] Multicohort D:A:D Study Pinpoints Non-HIV Death Risk Factors People Can Change. http://www.natap.org/2009/CROI/croi_28.htm Accessed Feb 2014http://www.natap.org/2009/CROI/croi_28.htm 2006 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

10. SMART: HIV-Related clinical events Then SMART came along and surprised us [1] The SMART study was designed to examine a strategy of limiting time on ART with the hope of reducing the rates of treatment associated complications [2] 5,472 patients with a CD4 count of >350 were randomised to either stay on treatment * or take a treatment break [2] [1] HIV Positive! Magazine, January 18, 2006. Continuous HIV therapy proves its value [2] The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-2296 10 2006 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

11. SMART: Non-HIV clinical events [1] The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-2296 The study showed the importance of other serious non-AIDS events such as heart attack and stroke among patients interrupting HIV treatment [1] Significantly more (1.7 times more) * individuals in the treatment interruption arm developed major heart disease and stroke, kidney or liver disease than those who stayed on treatment [1] 11 2006 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

12. When to start: Control HIV Era CD4 Count [1] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. December 1, 1998. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf. Accessed Feb 2014http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf. [2] British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1997;349:1086-1092 [3] British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2000;1:76-101 [4] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. August 13, 2001. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf. Accessed Feb 2014http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf [5] British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy July 2003. http://www.bhiva.org/documents/Guidelines/Treatment%20Guidelines/Archive/2003/Treatment%20Guidelines%202003.pdf Accessed Feb 2014 http://www.bhiva.org/documents/Guidelines/Treatment%20Guidelines/Archive/2003/Treatment%20Guidelines%202003.pdf 12 Hit Early Era 1997-2000 Pre-HAART Era 1987-1996 500 Triple therapy Viral eradication? 300- 350 DHHS [1] BHIVA [2,3] 200 Delay Treatment Era 2001-2007 350 Viral suppression Potent drugs Wait until needed 200 BHIVA [5] EACS (2005) [6] Control HIV Era 2007-2014 SMART Prevent HIV related co-morbidities like heart disease 350 WHO [8] DHHS [4] Start treatment when OIs occur PCP prophylaxis – Single drug therapy EACS [9] / BHIVA [10] 2009 500 [6] European AIDS Clinical Society (EACS) European Guidelines for the Clinical Management and Treatment of HIV Infected Adults 2005 [7] Deleted entry [8] WHO Consolidated ARV guidelines, June 2013. Available at: http://www.who.int/hiv/pub/guidelines/arv2013/art/statartadolescents/en/index.html Accessed Feb 2014 http://www.who.int/hiv/pub/guidelines/arv2013/art/statartadolescents/en/index.html [9] European AIDS Clinical Society (EACS). Guidelines. Version 7 – October 2013 Available at http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf Accessed Feb 2014 http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf [10] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf Accessed Feb 2014 http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

13. The study on when to start ART The best way to decide when to start is through a randomised trial – the START study did this [1]  People living with HIV and a CD4 over 500 were randomised to immediate or deferred treatment(CD4 count 350-500)  First results were expected in 2016  The START DSMB stopped the randomised portion of the trial ahead of schedule in May 2015  START found that people living with HIV have a considerably lower risk of developing AIDS or other serious illnesses if they start taking ART sooner, when their CD4 cell count is above 500 cells/mm3, instead of waiting until their CD4 cell count drops below 350 cells/mm3 1996 1998 2000 2002 2004 2006 2008 2010 2012 20142015 [1] http://www.aidsmap.com/START-trial-provides-definitive-evidence-of-the-benefits-of-early-HIV-treatment/page/2986272/ http://www.aidsmap.com/START-trial-provides-definitive-evidence-of-the-benefits-of-early-HIV-treatment/page/2986272/

14. ART and preventing HIV transmission European and national guidelines increasingly address the issue of the use of ART in preventing HIV transmission. 14 [1] European AIDS Clinical Society (EACS). Guidelines. Version 7 – October 2013 Available at http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf Accessed Feb 2014http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf [2] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf Accessed Feb 2014http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf EACS states: [1] BHIVA states: [2] In serodiscordant couples, early initiation of ART as one aspect of the overall strategy to reduce HIV transmission to the seronegative partner should be considered and actively discussed. We recommend the evidence that treatment with ART lowers the risk of transmission is discussed with all patients, and an assessment of the current risk of transmission to others is made at the time of this discussion. We recommend following discussion, if a patient with a CD4 count above 350 cells/mm 3 wishes to start ART to reduce the risk of transmission to partners, this decision is respected and ART is started. 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

15. Guideline AIDS or HIV- Related Symptoms CD4+ Cell Count < 200/mm 3 CD4+ Cell Count 200- 350/mm 3 CD4+ Cell Count 350- 500/mm 3 CD4+ Cell Count > 500 cells/mm 3 DHHS-USA, 2014 Yes British HIV Association, 2015 Yes European AIDS Clinical Society, 2015 Yes World Health Organization, 2015 Yes (1) https://aidsinfo.nih.gov/contentfiles/lvguidelines/AA_Recommendations.pdfhttps://aidsinfo.nih.gov/contentfiles/lvguidelines/AA_Recommendations.pdf (2) http://www.bhiva.org/documents/Guidelines/Treatment/consultation/150621-BHIVA-Treatment-GL-Final-draft-for-consultation.pdfhttp://www.bhiva.org/documents/Guidelines/Treatment/consultation/150621-BHIVA-Treatment-GL-Final-draft-for-consultation.pdf (3 ) http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.htmlhttp://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html (4) http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ Major ART Guidelines

16. Now, European, WHO and US guidelines have reached a consensus [1] That ART should be initiated in everyone living with HIV irrespective of CD4 cell count. [1] WHO - http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ guidellines September 2015 http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ 16 2009 Conclusions 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

17. Hit Early Era 1997-2000 Pre-HAART Era 1987-1996 Start treatment when OIs occur PCP prophylaxis – Single drug therapy Triple therapy Viral eradication? 300- 350 DHHS [1] BHIVA [2,3] 200 Delay Treatment Era 2001-2007 Viral suppression Potent drugs Wait until needed 200 BHIVA [5] EACS (2005) [6] Control HIV Era 2007-2014 SMART Prevent HIV related co-morbidities like heart disease EACS [9] /BHIVA [10] WHO [8] 2014 START study 500+ Benefits of Treatment outweigh leaving HIV untreated 500 350 500+ DHHS [4] When to start: Now – treat everyone CD4 Count 17 2011+ 500 350 17 [1] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. December 1, 1998. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf. Accessed Feb 2014http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL12011998012.pdf. [2] British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1997;349:1086-1092 [3] British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2000;1:76-101 [4] Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services. August 13, 2001. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf. Accessed Feb 2014http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL08132001007.pdf [5] British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy July 2003. http://www.bhiva.org/documents/Guidelines/Treatment%20Guidelines/Archive/2003/Treatment%20Guidelines%202003.pdf Accessed Feb 2014 http://www.bhiva.org/documents/Guidelines/Treatment%20Guidelines/Archive/2003/Treatment%20Guidelines%202003.pdf 17 [6] European AIDS Clinical Society (EACS) European Guidelines for the Clinical Management and Treatment of HIV Infected Adults 2005 [7] deleted entry [ [8] WHO Consolidated ARV guidelines, June 2013. Available at: http://www.who.int/hiv/pub/guidelines/arv2013/art/statartadolescents/en/index.html Accessed Feb 2014 http://www.who.int/hiv/pub/guidelines/arv2013/art/statartadolescents/en/index.html [9] European AIDS Clinical Society (EACS). Guidelines. Version 7 – October 2013 Available at http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf Accessed Feb 2014 http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf [10] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf Accessed Feb 2014 http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf (11) http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ (12 ) http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.htmlhttp://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html (13) http://www.bhiva.org/documents/Guidelines/Treatment/consultation/150621-BHIVA-Treatment-GL-Final-draft-for- consultation.pdf 2014 1996 1998 2000 2002 2004 2006 2008 2010 20122015 EACS [12] /BHIVA [13] WHO [11]