2. HIV Therapy Experience is the Best Teacher David K. Stein, M.D. Director, Adult HIV Research Activities Jacobi Medical Center Associate Professor of Clinical Medicine Albert Einstein College of Medicine

3. But, It’s a Humbling Way to Learn Lessons I’ve Learned the Hard Way!

4. Assumptions Most of you will never take the ID Boards or become Primary Care HIV Providers Most of you will not be the Primary manager of HIV infected patients Most of you don’t speak up when a question is asked of the audience in a lecture, even if you know the answer. o I have assurances that even if you answer incorrectly you will probably still have a job tomorrow (although I can’t say what that job will entail) My kids think I’m crazy, and they probably are right.

5. LS

6. What do all those letters and numbers mean? M184M/V Translation = High level resistance to Lamivudine and Emtricitibine

7. LS Genotypes June 2002 M41M/L D67N K70R K103N T215F K219E February 2005 K65K/R October 2007 D67N K70R K103N T215F K219E September 2006 None

9. Let’s Go Back to School

10. Y=mx + b

12. 10 10

13. 10 -5 Codon 184 Normally Methionine ATG to ATA [methionine to isoleucine] and ATG to GTA [methionine to valine]

14. HAART = Highly Active Anti-Retroviral Therapy HAART typically contains 3 or more ACTIVE drugs

15. 10 -5 X 10 -5 X 10 -5 = 10 -15 10 -5 X 10 -5 X 10 -5 = 10 -15

16. Genetic Barrier Different Drugs have different Genetic Barriers

17. OK, I’ve been sitting here for the last few minutes. What has this got to do with me?

18. HIVNET 012 Neviripine given for Maternal-Fetal HIV Transmission Prevention

19. I GOT IT – at least 3 DRUGS BUT 1 can equal 2 or 3 or 4

20. Drug Combinations Combivir 1=2 Epzicom 1=2 Truvada 1=2 Kaletra 2=1+ Trizivir 1=3 Atripla 1=3 Complera 1=3 o Complere 1=0 Stribild 1=3+

21. Nothing is Not always Nothing

22. What to do? Patient comes to ER complaining of stomach upset and nausea after starting a 3 drug combination of Efavirenz, Lamivudine and Zidovudine. He says he is miserable and looks uncomfortable, but not in need of admission. He was given Zofran and Omeprazole with no relief. He sees his PMD in 10 days but it is the weekend and he is not in the office today.

23. T 1/2

24. A Little Bit of Something can be Dangerous

25. What is wrong with this? A patient with HIV, Asthma, and a history of a prior UGI bleed comes to the ER with an acute Asthma attack. She is taking Atazanavir and Epzicom for the last 4 years. Nebs are given and the patient is somewhat better, but needs steroids before discharge. In addition to the Prednisone she is given Omeprazole which she received 3 years ago when she had an UGI bleed.

26. Click!

29. Giving a Prescription is not a Treatment 1 BID is not 2 pills a day 1 BID is not 1 at Breakfast, 1 at Lunch In This case 1 or 2 is less than 1

30. Time to Switch Gears

31. Sometimes the little things that don’t seem important at the time can save a person’s life A 27 year old female comes into the ER with burning on urination for the last week. She is otherwise healthy. Her exam is remarkable for some mild tenderness over the bladder. UA is abnormal and she is given some antibiotics for a UTI

32. clinicaloptions.com/hiv Improving Practical Skills for Primary Care of HIV-Infected Patients 2006 Recommendations From CDC: Routine Opt-Out Testing for HIV  Routine voluntary testing for patients aged 13- 64 yrs in healthcare settings—not based on patient risk Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

33. Improving Control of HIV Begins With Enhanced Detection and Linkage to Care Data from CDC and Prevention National HIV Surveillance System used to calculate HIV prevalence, undiagnosed HIV prevalence, and linkage to HIV care Hall HI, et al. AIDS 2012. Abstract FRLBX05. 100 80 60 40 20 0 Diagnosed Linked to Care Retained in Care Prescribed ART Viral Suppression 82% 56% 89% 25% Patients (%) N = 1,148,200 941,524 757,812 80% 424,834 378,906 287,050 75% 33% 37% 66% 82%

34. When to Start ART Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts Current recommendation: ART for all March 2012 www.aidsetc.org34

35. Potential Benefits of Early Therapy o 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 o Increasing evidence of direct HIV effects on various end organs and indirect effects via HIV-associated inflammation o End-organ damage occurs at all stages of infection March 2012 www.aidsetc.org35

36.  Drug toxicity  Preservation of limited Rx options  Risk of resistance (and transmission of resistant virus)  ↑ potency, durability, simplicity, safety of current regimens  ↓ emergence of resistance  ↓ toxicity with earlier therapy  Risk of uncontrolled viremia  Near normal survival if CD4+ count > 500  ↓ transmission Early ARTDelayed ART Risks and Benefits of Earlier Initiation of ART

37. Current ARV Medications NRTI  Abacavir (ABC)  Didanosine (ddI)  Emtricitabine (FTC)  Lamivudine (3TC)  Stavudine (d4T)  Tenofovir (TDF)  Zidovudine (AZT, ZDV) NNRTI  Delavirdine (DLV)  Efavirenz (EFV)  Etravirine (ETR)  Nevirapine (NVP)  Rilpivirine (RPV) PI  Atazanavir (ATV)  Darunavir (DRV)  Fosamprenavir (FPV)  Indinavir (IDV)  Lopinavir (LPV)  Nelfinavir (NFV)  Ritonavir (RTV)  Saquinavir (SQV)  Tipranavir (TPV) Integrase Inhibitor (II)  Raltegravir (RAL)  Elvitegravir* (EVG) Fusion Inhibitor  Enfuvirtide (ENF, T-20) CCR5 Antagonist  Maraviroc (MVC) 37www.aidsetc.org * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

38. Selected Complications Mitochondrial Toxicity Lactic Acidosis Lipoatrophy Metabolic Syndrome Cardiac Toxicity? Nephrotoxicity Other

39. Adverse Effects: NRTIs All NRTIs: o Lactic acidosis and hepatic steatosis (highest incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC) o Lipodystrophy (higher incidence with d4T) March 2012 www. aidset c.org 39

40. Adverse Effects: NNRTIs All NNRTIs: o Rash, including Stevens-Johnson syndrome o Hepatotoxicity (especially NVP) o Drug-drug interactions March 2012 www. aidset c.org 40

41. Adverse Effects: PIs All PIs: o Hyperlipidemia o Lipodystrophy o Hepatotoxicity o GI intolerance o Possibility of increased bleeding risk for hemophiliacs o Drug-drug interactions March 2012 www. aidset c.org 41

42. Adverse Effects: II RAL o Nausea o Headache o Diarrhea o CPK elevation, myopathy, rhabdomyolysis o Rash March 2012 www. aidset c.org 42

43. Adverse Effects: CCR5 Antagonist MVC o Drug-drug interactions o Rash o Abdominal pain o Upper respiratory tract infections o Cough o Hepatotoxicity o Musculoskeletal symptoms o Orthostatic hypotension, especially if severe renal disease March 2012 www. aidset c.org 43

44. Adverse Effects: Fusion Inhibitor ENF o Injection-site reactions o HSR o Increased risk of bacterial pneumonia March 2012 www. aidset c.org 44

45. Opportunistic Infections PJP Cryptococcal meningitis MAC Cryptosporidiosis Toxoplasmosis Esophageal Candidiasis Histoplasmosis CMV TB

46. Treatment-Experienced Patients: ART Failure Causes of treatment failure include: o Patient factors (eg, CD4 nadir, pretreatment HIV RNA, comorbidities) o Drug resistance o Suboptimal adherence o ARV toxicity and intolerance o Pharmacokinetic problems o Suboptimal drug potency o Provider experience March 2012 www. aidset c.org 46

47. A mere one pill once per day….but at what cost? $2253/month $2323.84/month $2810/month HIV Treatment 2013

48. Take Home Message Unless 1or 2 = 3 3