Rational & Goals of Antiretroviral Therapy

1. Hyman M. Scott, MD, MPH University of California, San Francisco Division of Infectious Diseases & Center for AIDS Prevention Studies Rational & Goals of Antiretroviral Therapy

2. Disclosures • I have no financial disclosures or conflicts of interest.

3. Antiretroviral Timeline 2003: Fusion Inhibitor 1984: HIV Identified 1995: 1st PI approved 1996: HAART Era Begins 2006: CDC recommends routine HIV screening in US 1987: AZT Approved 1980 1990 2000 2010 1996: HAART Era “Hit Early & Hit Hard” 2013: Guidelines to offer treatment to everyone with HIV 1981: 1st AIDS Case Reported

4. 1996: The beginning of the HAART Era “For helping lift a death sentence — for a few years at least, and perhaps longer — on tens of thousands of AIDS sufferers, and for pioneering the treatment that just might lead to a cure, David Da-i Ho, M.D., is TIME's Man of the Year”

5. Nature Reviews Drug Discovery 6, 951-952 (December 2007)

6. Higher Mortality at lower CD4 Ann Intern Med. 2012 September 4; 157(5): 325–335

7. Higher mortality at lower CD4 Ann Intern Med. 2012 September 4; 157(5): 325–335

8. Mortality is higher at lower CD4 Ann Intern Med. 2012 September 4; 157(5): 325–335

9. 1000 1000 800 800 600 600 400 400 200 200 0 0 0 5 3 1 2 4 6 7 0 1 2 3 4 5 Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start Johns Hopkins HIV Clinical Cohort ATHENA National Cohort Mean CD4 Cell Count (cells/mm3) Years on ART Years on ART Keruly J, et al. Clin Infect Dis. 2007;44(3):441-446. Gras L, et al. J Acquir Immune DeficSyndr. 2007;45(2):183-192.

10. Nadir CD4 Count Predicts … • Increased cardiovascular disease1 • Higher risk of neurocognitive disorders2 • Increased risk of fracture3 • Chronic kidney disease4 1 – Ho J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 707. 2 – Ellis, et al. ibid. Abst. 429.3 – Dao C, et al. ibid. Abst. 128. 4 – Kirk O, et al. ibid. Abst. 107LB.

11. HIV causes damage even if “asymptomatic.”

12. Ongoing inflammation • Chronic inflammation • Replication of the virus in the body can cause damage by: • Scarring in lymph nodes • Infection of internal organs • Changes in lipid metabolism • Higher risk of cardiovascular disease

13. Used large database of patients in care in US and Canada. • Among patients with range of CD4 counts, greatest risk of death was deferring ARV • 94% higher risk if CD4 > 500 • 69% higher risk if CD4 350-500

14. San Francisco, 2010

15. New York City, 2011

16. Benefits to Starting Early • Keep CD4 count high and reduce inflammation. • Decrease risk of certain HIV-related health problems that can sometimes occur in people with high CD4 counts, including tuberculosis, non-Hodgkin's lymphoma, Kaposi's sarcoma, peripheral neuropathy, cancers and pre-cancers caused by human papillomavirus (HPV), and mental deficits seen in some people with HIV such as difficulty thinking and reasoning (neurocognitive problems). • Immediate Treatment: Reduce the viral reservoir (? role in cure). • Decrease risk of serious health problems that occur more frequently in HIV-positive people, such as cardiovascular disease, kidney disease, liver disease, neurological complications and various non-AIDS-related cancers and infections. • Reduce risk of transmitting HIV to others— TasP

17. Downsides to Starting Early • Potential treatment-related side effects. • Risk developing HIV drug resistance, resulting in loss of future treatment options. • For immediate treatment: less time to learn about HIV and its treatment, and less time to prepare for adherence to therapy. • Premature use of treatment before the development of more effective, less toxic and/or better studied combinations of HIV drugs. • Increased risk of transmitting drug-resistant HIV to others if detectable viral load while on treatment.

18. Important for the individual …

19. Treatment as Treatment (TasT) • Goals of antiretroviral treatment • Suppress HIV viral replication • Restore immune system • Increase CD4 count to as close to normal as possible

20. Optimal Response to ARVs • Steep drop in HIV viral load to undetectable levels. • Anticipate undetectable level within 4-6 months • Durable, complete suppression. • Rise in CD4 count and percentage. • Immune restoration. 40 Copies

21. Important the community…

22. Treatment as Prevention (TasP) HPTN 052 Trial of immediate vs delayed treatment of HIV in serodiscordant couples. 96% reduction in linked HIV transmissions among serodiscordant couples. Cohen et al N Engl J Med. 2011

23. Treatment as Prevention (TasP) Das et al. PLoS One 2010 Jun 10;5(6)

24. When to Start: 2013 DHHS Guidelines Updated 2/2013: ART is recommended for all HIV-infected individuals. DHHS. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

25. 2013 DHHS Guidelines: Conditions Where Deferral of Therapy Might be Considered • Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner. Therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners (AI [heterosexuals] or AIII [other transmission risk groups]). • Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). • Deferring therapy may be considered for: • Adherence barriers • Comorbidities that complicate or prohibit ART • Elite controllers/Long-term nonprogressors Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf..

26. 6 fold increase in rate of viral load suppression among patients entering clinic after SF 2010 recommendations. Geng et al CID 2012:55(12):1690-7

27. The Treatment Cliff CDC Fact Sheet HIV in the United States: The Stages of Care. July 2012

28. The HIV/AIDS National Strategy • Four Priorities: • ↓New HIV Infections • ↑Access & Outcomes • ↓ Disparities • Coordinate Response

29. Thank You! • Questions