1. Meg Sullivan, MD Section of Infectious Disease

2.  L.M. is a 26-year old man who has sex with men  Last unprotected sexual contact 3 weeks ago  He presents with a 1 week history of fever, rash, headache, sore throat, and diarrhea  HIV EIA reactive, HIV Western blot indeterminate, HIV RNA > 10 million copies/ml; CD4+ lymphocyte count 880/ml February 2013www.aidsetc.org2

3.  C.A. is a 56-year-old Haitian woman  Presented to PCP with dysphagia  EGD demonstrated esophageal candidiasis  HIV EIA and WB reactive  CD4+ lymphocyte count 7/ml February 2013www.aidsetc.org3

4.  N.C. is a 35-year-old homeless man  No regular shelter use  Recent IV heroin relapse  HIV test performed by OBOT provider  HIV EIA and WB reactive  CD+ lymphocyte count 418/ml February 2013www.aidsetc.org4

5.  For which of these patients is antiretroviral therapy indicated?  What benefit would accrue to each?  For which might ART be postponed? Why? February 2013www.aidsetc.org5

6. February 2013www.aidsetc.org6 Developed by the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC)

7.  Reduce HIV-related morbidity; prolong duration and quality of survival  Restore and/or preserve immunologic function  Maximally and durably suppress HIV viral load  Prevent HIV transmission February 2013www.aidsetc.org7

8.  Effective ART with virologic suppression improves and preserves immune function, regardless of baseline CD4 count ◦ Earlier ART may result in better immunologic responses and clinical outcomes  Reduction in AIDS- and non-AIDS-associated morbidity and mortality  Reduction in HIV-associated inflammation and associated complications  ART can significantly reduce risk of HIV transmission- ”Treatment as Prevention”  Recommended ARV combinations are effective and well tolerated February 2013www.aidsetc.org8

9.  Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts  Current recommendation: ART for all February 2013www.aidsetc.org9

10. ART is recommended for treatment:  “ART is recommended for all HIV- infected individuals to reduce the risk of disease progression.” ◦ The strength of this recommendation varies on the basis of pretreatment CD4 count (stronger at lower CD4 levels) February 2013www.aidsetc.org10

11.  Strength of recommendation: ◦ A: Strong ◦ B: Moderate ◦ C: Optional  Quality of evidence: ◦ I: ≥1 randomized controlled trials ◦ II: ≥1 well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes ◦ III: Expert opinion February 2013www.aidsetc.org11

12.  Recommended for all CD4 counts:  CD4 count <350 cells/µL (AI)  CD4 count 350-500 cells/µL (AII)  CD4 count >500 cells/µL (BIII) February 201312www.aidsetc.org

13.  CD4 count  350 cells/µL or history of AIDS- defining illness: ◦ Randomized control trial (RCT) data show decreased morbidity and mortality with ART  CD4 count 350-500 cells/µL: ◦ RCT data as well as nonrandomized trials and cohort data support morbidity and perhaps mortality benefit of ART February 2013www.aidsetc.org13

14.  CD4 count >500 cells/µL ◦ Cohort study data are not consistent; some show survival benefit if ART initiated ◦ Other considerations (eg, potential benefit of ART on non-AIDS complications, HIV transmission risk) support recommendation for ART February 2013www.aidsetc.org14

15. ◦ Untreated HIV may be associated with development of AIDS and non-AIDS- defining conditions  Earlier ART may prevent HIV-related end- organ damage; deferred ART may not reliably repair damage acquired earlier ◦ Increasing evidence of direct HIV effects on various end organs and indirect effects via HIV- associated inflammation ◦ End-organ damage occurs at all stages of infection February 2013www.aidsetc.org15

16.  Potential decrease in risk of many complications, including: ◦ HIV-associated nephropathy ◦ Liver disease progression from hepatitis B or C ◦ Cardiovascular disease ◦ Malignancies (AIDS defining and non-AIDS defining) ◦ Neurocognitive decline ◦ Blunted immunological response owing to ART initiation at older age ◦ Persistent T-cell activation and inflammation February 2013www.aidsetc.org16

17.  Pregnancy  AIDS-defining condition  Acute opportunistic infection  Lower CD4 count (eg, <200 cells/µL)  Acute/recent infection  Rapid decline in CD4  Higher viral load (eg, >100,000 copies/mL)  HIVAN  HBV coinfection  HCV coinfection February 2013www.aidsetc.org17

18.  ARV-related toxicities  Nonadherence to ART  Drug resistance  Cost February 2013www.aidsetc.org18

19. ART is recommended for Prevention:  “ART also is recommended for HIV- infected individuals for the prevention of transmission of HIV.”  “Treatment as Prevention” February 2013www.aidsetc.org19

20. Stable, healthy, serodiscordant couples, sexually active CD4+ count: 350 to 550 cells/mm 3 Primary Transmission Endpoint Virologically-linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death HPTN 052 Study Design Immediate ART CD4 350-550 Delayed ART CD4 <250 Randomization

21. Total HIV-1 Transmission Events: 39 HPTN 052: HIV-1 Transmission Breakdown Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 (p < 0.001) 96% efficacy Immediat e Arm: 1 Delayed Arm: 27 23/28 (82%) transmissions in sub-Saharan Africa 18/28 (64%) transmissions from female to male partners

22.  Perinatal transmission  Recommended for all HIV-infected pregnant women (AI)  Sexual transmission  Recommended for all who are at risk of transmitting HIV to sexual partners (AI for heterosexuals, AIII for other transmission risk groups) February 201322www.aidsetc.org

23.  Young MSM  Acute HIV infection  CD4 count preserved  Very high viral load  Should we treat him?  Why? February 2013www.aidsetc.org23

24.  Preservation of CD4 count in normal range  ? Prevention of CV risk, HAND, malignancy  ? Prevention of transmission ◦ High viral load associated with increased infectiousness ◦ Prevention by ART not as well established for MSM as for heterosexual couples February 2013www.aidsetc.org24

25.  “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.”  Patients may choose to postpone ART  Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors February 201325www.aidsetc.org

26. February 2013www.aidsetc.org26

27.  Clinical or personal factors may support deferral of ART ◦ If CD4 count is low, deferral should be considered only in unusual situations, and with close follow-up  When there are significant barriers to adherence  If comorbidities complicate or prohibit ART  “Elite controllers” and long-term nonprogressors February 2013www.aidsetc.org27

28.  A major determinant of degree and duration of viral suppression  Poor adherence associated with virologic failure  Optimal suppression requires 90-95% adherence  Suboptimal adherence is common 10/06

29.  Regimen complexity and pill burden  Poor clinician-patient relationship  Active drug use or alcoholism  Unstable housing  Mental illness (especially depression)  Lack of patient education  Medication adverse effects  Fear of medication adverse effects 10/06

30.  Age, race, sex, educational level, socioeconomic status, and a past history of alcoholism or drug use do NOT reliably predict suboptimal adherence.  Higher SES and education levels and lack of history of drug use do NOT reliably predict optimal adherence. 10/06

31.  Emotional and practical supports  Convenience of regimen  Understanding of the importance of adherence  Belief in efficacy of medications  Feeling comfortable taking medications in front of others  Keeping clinic appointments  Severity of symptoms or illness 10/06

32.  Establish readiness to start therapy  Provide education on medication dosing  Review potential side effects  Anticipate and treat side effects  Utilize educational aids including pictures, pillboxes, and calendars 10/06

33.  Simplify regimens, dosing, and food requirements  Engage family, friends  Utilize team approach with nurses, pharmacists, and peer counselors  Provide accessible, trusting health care team 10/06

34.  Older Haitian woman with OI  CD4 very low  Should we treat her?  Why? February 2013www.aidsetc.org34

35.  Immunologic recovery ◦ Likely somewhat blunted secondary to AIDS and low nadir count  Decreased risk for further OI  Decreased AIDS-related mortality  Except for tuberculous and cryptococcal meningitis, early ART reduces M/M especially if CD4 <50 February 2013www.aidsetc.org35

36.  Young middle-aged homeless man  Irregular housing  Recent IDU relapse  CD4 low, but > 350  Should we treat him?  Why? February 2013www.aidsetc.org36

37.  Benefits ◦ Decreased HIV morbidity ◦ ? Decreased mortality  But NC is at high risk for nonadherence  How can we help him with that? February 2013www.aidsetc.org37

38. February 2013www.aidsetc.org38

39.  Allows effective, durable viral suppression  3 standard combinations ◦ 2 NRTI + 1 NNRTI ◦ 2 NRTI+ 1 PI ◦ 2 NRTI+ 1 II February 2013www.aidsetc.org39

40.  Preferred ◦ Randomized controlled trials show optimal efficacy and durability ◦ Favorable tolerability and toxicity profiles  Alternative ◦ Effective but have potential disadvantages ◦ May be the preferred regimen for individual patients  Other ◦ May be selected for some patients but are less satisfactory than preferred or alternative regimens February 2013www.aidsetc.org40

41.  TDF/FTC preferred ◦ What coinfection is also treated by this combination? ◦ What cormorbidities might make this combination a suboptimal choice?  ABC/3TC alternative ◦ What test should be performed prior to using abacavir? Why? February 2013www.aidsetc.org41

42.  EFV preferred ◦ In what population should EFV NOT be used?  RPV alternative ◦ Is RPV an optimal choice if VL > 100K? ◦ What class of drugs is contraindicated in combination with RPV? February 2013www.aidsetc.org42

43.  ATV/r and DRV/r preferred ◦ What drug class must be used with caution in combination with ATV?  FPV/r and LPV/r alternative  Which comorbidities might make PI a suboptimal choice?  What drug classes interact with PIs? February 2013www.aidsetc.org43

44.  RAL preferred  EVG alternative ◦ What comorbidity contraindicates EVG? February 2013www.aidsetc.org44

45.  http://www.aidsetc.org  http://aidsinfo.nih.gov February 2013www.aidsetc.org45