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WHEN TO START TREATMENT

WHEN TO START TREATMENT. 1. Early success: Improving outcomes with ART, 1996 - 2002. 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014. Observational data, Johns Hopkins clinic. 2.

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WHEN TO START TREATMENT

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  1. WHEN TO START TREATMENT 1

  2. Early success: Improving outcomes with ART,1996 - 2002 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Observational data, Johns Hopkins clinic 2 Adapted from Moore R et al. 11th Conference on Retroviruses and Opportunistic Infections (CROI ), San Francisco, CA 2004; Abstract 558

  3. 300-350 500 When to start: Hit early 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2000 Hit Early Era 1997-2000 Pre-ART Era 1987-1996 DHHS[1] 200 CD4 Count BHIVA[2,3] Start treatmentwhen OIs occur* PCP prophylaxis –Single drug therapy Triple therapy Viral eradication? [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 2014 [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 3

  4. When to start treatment? 2002 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • Eradication proved impossible as we began to realise that HIVremained hidden in “viral reservoirs”…control of the virus wasthe best we could hope for[1,2] • And concerns were soon raised about the emergence ofresistance if the virus was not fully suppressed in an individualwho was taking therapy for 30-50 years or more[3-5] • The existing drugs were not thought to be as potent anddurable[6] • There were also concerns about side effects that may occurwith a lifetime on long term medication[6] • In particular, there were concerns with the increasing numbersof people being affected by lipodystrophy (body fat changes) which could showthrough very quickly with some of the early drug regimes used[7-9] [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 2014 [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 2014 [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.pdfAccessed Feb 2014 [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 4

  5. When to start treatment? 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • 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 [1] Time Magazine, 30th December 1996 [2] Ho DD, Time to Hit HIV, Early and Hard. N Engl J Med 1995, 333:450-451 5

  6. 300-350 200 500 350 When to start: Delay Treatment Era 2004 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Hit Early Era 1997-2000 Pre-HAART Era 1987-1996 Delay Treatment Era 2001-2007 DHHS[1] DHHS[4] 200 BHIVA[5]EACS (2005)[6]IAS-USA (2004)[7] Start treatmentwhen OIs occur PCP prophylaxis –Single drug therapy CD4 Count BHIVA[2,3] Viral suppression Potent drugs Wait until needed Triple therapy Viral eradication? [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 2014 [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 2014 [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 [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 6

  7. Delay Treatment Era:Reasons we were cautious 2005 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • 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! [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. [3] NAM. Adherence Booklet. Fourth edition, 2007 7

  8. Delay Treatment Era:Reasons we were cautious 2005 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • 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/mm3 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] [1] Expert opinion of author Brian West as well as the BEST Advisory Board and Review Committee; agreed on 24th September 2009 [2] European AIDS Clinical Society (EACS) European Guidelines for the Clinical Management and Treatment of HIV Infected Adults 2005 8

  9. The rationale started to change 2006 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • 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? [1] NAM Aids Treatment Update April 2006, issue 155. http://www.aidsmap.com/files/file1000631.pdf Accessed Feb 2014 [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 2014 9

  10. SMART: HIV-Related clinical events 2006 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • 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

  11. SMART: Non-HIV clinical events 2006 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • 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] [1] The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-2296 11

  12. When to start: Control HIV Era 2009 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Hit Early Era 1997-2000 Pre-HAART Era 1987-1996 Delay Treatment Era 2001-2007 Control HIV Era 2007-2014 SMART WHO[8] DHHS[1] DHHS[4] 500 500 350 300-350 350 200 200 EACS[9]/ BHIVA[10] BHIVA[5]EACS (2005)[6] CD4 Count Start treatmentwhen OIs occur PCP prophylaxis –Single drug therapy BHIVA[2,3] Prevent HIV relatedco-morbidities like heart disease Viral suppression Potent drugs Wait until needed Triple therapy Viral eradication? [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 2014 [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 2014 [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 [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 [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 [10] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdfAccessed Feb 2014 12

  13. The study on when to start ART 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 • 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 [1] http://www.aidsmap.com/START-trial-provides-definitive-evidence-of-the-benefits-of-early-HIV-treatment/page/2986272/

  14. ART and preventing HIV transmission 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 • European and national guidelines increasingly address the issue of the use of ART in preventing HIV transmission • . [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 2014 [2] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf Accessed Feb 2014 14

  15. Major ART Guidelines (1) https://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.pdf (3 ) http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html (4) http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/

  16. Conclusions 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2009 • 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. 16 [1] WHO - http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ guidellines September 2015

  17. When to start: Now – treat everyone 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 Hit Early Era 1997-2000 Pre-HAART Era 1987-1996 Delay Treatment Era 2001-2007 Control HIV Era 2007-2014 SMART 2014 START study 2011+ WHO[11] DHHS[1] WHO[8] 500+ DHHS[4] 500+ 500 500 350 300-350 EACS[12] /BHIVA[13] 350 200 200 CD4 Count EACS[9] /BHIVA[10] BHIVA[5] EACS (2005) [6] Start treatmentwhen OIs occur PCP prophylaxis –Single drug therapy BHIVA[2,3] Benefits of Treatment outweigh leaving HIV untreated Prevent HIV relatedco-morbidities like heart disease Viral suppression Potent drugs Wait until needed Triple therapy Viral eradication? [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 2014 [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 2014 [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 [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 [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 [10] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdfAccessed Feb 2014 (11) http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ (12 ) http://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 17 17 17

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