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When to start ART

When to start ART. Early success: Improving outcomes with ART, 1996 - 2002. 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018. Observational data, Johns Hopkins clinic. 350- 300. 500. When to start: Hit early.

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When to start ART

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  1. When to start ART

  2. Early success: Improving outcomes with ART, 1996 - 2002 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 Observational data, Johns Hopkins clinic

  3. 350-300 500 When to start: Hit early 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 Pre-HAART Era 1987-1996 Hit Early Era 1997-2000 DHHS[1] CD4 Count BHIVA[2-3] 200 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

  4. When to start ART? 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • 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 ClinEndocrinolMetab 2002;87:4845-4856

  5. When to start treatment? 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • 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

  6. 350-300 500 When to start ART: Delay ART Era 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 Pre-HAART Era 1987-1996 Hit Early Era 1997-2000 Delay Treatment Era 2001-2007 DHHS[1] DHHS[4] CD4 Count 350 BHIVA[2-3] 200 200 BHIVA[5]EACS (2005)[6] IAS-USA (2004)[7] Start treatmentwhen OIs occur PCP prophylaxis –Single drug therapy 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

  7. Delay ART Era: Reasons we were cautious 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • 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

  8. Delay ART Era: Reasons we were cautious 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • 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

  9. The rationale started to change 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • 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

  10. SMART study: HIV-related clinical events 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • 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[1] • 5,472 patients with a CD4 count of >350 were randomised to either stay on treatment* or take a treatment break[1] [1] The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-2296 accessed January 2018

  11. SMART: Non-HIV clinical events 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • 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 accessed January 2018

  12. 350-300 500 When to start: Control HIV Era 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 Pre-HAART Era 1987-1996 Hit Early Era 1997-2000 Delay Treatment Era 2001-2007 Control HIV Era 2007-2014 DHHS[1] WHO[7] 500 DHHS[4] CD4 Count 350 350 EACS[8] /BHIVA[9] BHIVA[2-3] 200 200 BHIVA[5]EACS (2005)[6] Start treatmentwhen OIs occur PCP prophylaxis –Single drug therapy Viral suppression Potent drugs Wait until needed Prevent HIV relatedco-morbidities like heart disease 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] WHO Consolidated ARV guidelines, June 2013. Available at: http://www.who.int/hiv/pub/guidelines/arv2013/art/statartadolescents/en/index.html Accessed Feb 2014 [8] 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 [9] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf Accessed Feb 2014

  13. The study on when to start ART 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 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 2015 2016 2017 2018 Over the past 5 years European and national guidelines have increasingly addressed 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

  15. Major ART Guidelines 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 [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. 350-300 500 When to start: Now – treat everyone 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 Pre-HAART Era 1987-1996 Hit Early Era 1997-2000 Delay Treatment Era 2001-2007 Control HIV Era 2007-2014 START Study 2014 DHHS[1] WHO[7] WHO[10] 500+ 500 DHHS[4] EACS[11] /BHIVA[12] CD4 Count 350 350 EACS[8] /BHIVA[9] BHIVA[2-3] 200 200 BHIVA[5]EACS (2005)[6] Start treatmentwhen OIs occur PCP prophylaxis –Single drug therapy Benefits of Treatment outweigh leaving HIV untreated Viral suppression Potent drugs Wait until needed Prevent HIV relatedco-morbidities like heart disease 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] WHO Consolidated ARV guidelines, June 2013. Available at: http://www.who.int/hiv/pub/guidelines/arv2013/art/statartadolescents/en/index.html Accessed Feb 2014 [8] 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 [9] BHIVA Guidelines Updtaed Nov 2013. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf Accessed Feb 2014 [10] http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ [11] http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html [12] http://www.bhiva.org/documents/Guidelines/Treatment/consultation/150621-BHIVA-Treatment-GL-Final-draft-for-consultation.pdf

  17. When to start ART: Conclusions 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2015 2016 2017 2018 • Now, British, European, World Health Organization and US guidelines have reached a consensus[1-4] • ART should be initiated in everyone living with HIV irrespective of CD4 cell count • ‘Evidence is accumulating that starting ART on the same day after establishing a diagnosis of HIV infection is feasible and acceptable to HIV-positive persons’[3] 1) WHO - http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ Guidelines 2016 accessd January 2018 https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0 accessed January 2018 2) BHIVA Guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy 2015 (2016 interim update) accessed January 2018 3) http://www.eacsociety.org/files/guidelines_9.0-english.pdf accessed January 2018 4) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection Recommendations for a public health approach - Second edition, World Health Organisation, June 2016 accessed January 2018

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