ARV Management Selecting the Right Regimen

1. ARV ManagementSelecting the Right Regimen Jeffrey A. Beal, M.D. Clinical Director Florida/Caribbean AETC

2. Disclosure of Financial Relationships Dr. Beal has no significant financial relationships with commercial entities to disclose, and wishes to acknowledge and thank Dr. Behrens (NW AETC) and Dr. Susa Coffey (AETC National Resource Center) for slides shared on the AETC NRC site.

3. Initial Office Visit Patient LM 54 y/o white female crack cocaine addict returns to the office after being lost to follow-up for over 2 years. 8th grade education Unemployed, lives with her mother and cares for her ill father in-law and elderly mother HIV positive since 1996, ARV na�ve Presents stating she is ready to begin ARV therapy

4. Initial Office Visit2 Record review: Last CD4 560 and VL 199,526 (log 5.3) Hepatitis C positive with VL > 1 million Toxo IgG and CMV IgG positive HAV Ab + and HBsAb + (HBsAg -) Past RPR and PPD negative Prior CBC/Chemistry unremarkable

5. Initial Office Visit3 Weight is down 10 pounds otherwise VSS LM admits to drinking 6 beers per week and is taking 2 or more hits of cocaine per day Not sexually active at present and states understands importance of and uses condoms She wants meds now - DISCUSSION

6. When Should Patients with HIV be Treated with ART? Benefits reduced morbidity & mortality immune system recovery Drawbacks toxicities lifestyle changes potential for developing resistance

7. Initial Office Visit4 Limited exam: patient agitated, difficulty with train of thought, oral thrush � mild, otherwise ENT/Lungs/Hrt/abdomen/nodes unremakable CBC, CMP, CD4, VL, Hepatitis C VL, RPR, fasting lipid profile, urinalysis Genotype resistance test PPD placed H & P with PAP scheduled in 2-3 weeks

8. Initial Office Visit5 Discussed issues of compliance with OV and meds Negotiated decrease in crack to 1 hit/day Negotiated alcohol to 5 beer/week Contracted that if OV kept, will consider treating her Dispensed condoms

9. Patient LM6 Return Visit-1 LM returns � admits to controlling crack to a hit every other day and has stopped drinking beer Wt. ? 2 lb.; BP 140/90, otherwise VSS. Exam Pos. findings: Thrush, liver edge 3 fb below RCM, multiple ecchymosis, vaginal candidiasis Domestic violence screen negative, PHQ 9 consistent with mild depression, PTSD negative

10. Patient LM7 Return Visit-1 CD4 260 (12%), VL 125,893 (log 5.1) Hgb. 10.0, Hct. 28.0 indices normal Creat. 1.0, Est. CrCl 64, ALT and AST 2XULN, UA unremarkable, RPR negative, Lipid profile Nl., Cholesterol 80 Hep C VL 2.5 million PPD was negative Pelvic/PAP-candidiasis, result returned normal except inflammation and candida Geno: L210W, M46I

11. Patient LM8 Return Visit-1 Assessment: AIDS Oral Candidiasis; Vaginal Candidiasis Anemia, normocytic, normochromic Low normal renal function CAH C Depression, mild

13. HIV Infection is characterized by a steady decline in the number of CD4 cells

14. mm�

15. When Should ART be Initiated?An analysis of prospective studies 13 cohort studies from Europe & North America 12,574 patients initiating ART Median age 38; mostly men Median baseline CD4 count 250; VL 74,000 Median month of ART initiation: 12/1997 Mostly PI-based regimens 24,310 person-years of follow-up

16. Analysis of 13 cohort studies: effect of baseline CD4 count on response to initial ART

17. Findings: effects of clinical stage on clinical progression

18. Findings: effect of baseline HIV Viral Load on response to ART

19. Initiation of ART after HIV-related symptoms had developed was associated with a less durable response to ART For the asymptomatic patient, CD4 count at initiation of ART carried strongest prognostic significance, corroborating findings from other studies1-4 Age, infection via IDU, history of AIDS-related illness also appeared to affect durability of clinical response to ART Cohort studies: conclusions

20. Caveats High VL (>100,000 copies/mL) also carried prognostic significance, but few patients initiated on efavirenz or ritonavir-boosted regimens other recent studies have not demonstrated a clear correlation between baseline viral load and efficacy of ART1,2 Observational study: other potential confounding factors (e.g., adherence, hemoglobin) could have affected results

21. Implications for Clinical Practice � CD4 Cell Count Ideally, initiate ART before CD4 count drops below 200 cells/mm� and before clinical symptoms develop A benefit for treatment before CD4 count falls below 350 may exist, but the small risk of clinical progression if therapy is deferred must be balanced against drawbacks of ART If CD4 already less than 200 or clinical progression has occurred, ART is clearly indicated as soon as patient is ready to start

22. Implications for Clinical Practice -Baseline Viral Load Initiation of ART before VL >100,000 copies/mL may allow for more therapeutic options and greater clinical success However, highly potent efavirenz- or boosted PI-based regimens may be equally effective in patients with high baseline viral loads1-3 VL is a marker for rate of CD4 decline: more frequent monitoring in patients with high VL?

23. When Should ART be Initiated? DHHS Guidelines

24. Considerations pre-HAART Symptoms & OI/AIDS defining diagnosis CD4 Cell Count Viral Load Anticipated Adherence

25. Considerations for ARV Initiation Symptoms & Opportunistic Infections LM with candida and AIDS by %CD4 CD4 count LM below 350 cells/mm3 Viral Load > 100,000 Anticipated Adherence - patient �readiness� LM stating wants to start ARV

26. Patient LM9 Still substance abusing but keeping appointments States willing to start ARV Hep C co-infected Likely to have virus with NRTI/PI resistance yet to be defined Anemia confers poor prognosis Borderline renal status Low CD4 and High VL and statistically at high risk of disease progression

27. Patient LM10 She has only kept one appointment She has just learned she has AIDS She has untreated mild depression We have only one VL and CD4 � no trend data Will she be 95% adherent if ARV treatment started?

28. Adherence 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

29. Adherence 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.

30. Predictors of Inadequate Adherence 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

31. Predictors of Good Adherence 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

32. Patient LM10 Informed needed to confirm VL/CD4 and would draw in 2 wks. Nutrition counseling given Prozac 20 mg qd started Bactrim DS 1 qd started Diflucan 100 mg qd Asked what she could do to control cocaine � negotiated 2 hits per week Negotiated continued alcohol abstinence

33. Patient LM11 Provided information on simplicity and potency of current ARV Openly admitted some patients get sicker once ARV started in response to a good ARV regimen Discussed complexity of need to treat HIV before considering Hepatitis C treatment Discussed importance of adherence and discussed abstinence as means to protect from obtaining HIV resistance or STD�s

34. Patient LM12 Outlined side effects that could be occur with Prozac and Bactrim Discussed expectation that current ARV therapy should confer long life expectancy Asked her to identify what she wanted to be doing 20-30 years from now Offered possibility she could become a certified aid to her ailing parents or pursue other employment options in the future

35. Patient LM13 Return in 2-3 weeks for Lab CD4, VL, CMP, CBC, TSH Multivitamin one per day Begin a walking program Discussed informing partners of HIV status and importance of condoms Introduced concept of 95% adherence Think about formal drug/alcohol rehab.

36. Patient LM14 Return Visit 3 Patient returns in two weeks for lab 100% compliance on medication therapy Does not feel she has a drug or alcohol problem Has not used crack in the past one week Still has not used alcohol Lab drawn, behaviors praised Introduced class side effects of RTI/NNRTI/PI Return in one week

37. Patient LM15 Return Visit 4 Patient returns on appointment She �partied� over weekend with > 6 pack alcohol and cocaine use > 2 hits per week She is angry she has not been able to start ARV therapy and stresses the urgency that she must stay well to be the caregiver of her parents 100% compliance with Diflucan, Bactrim, Prozac and MVI

38. Patient LM16 Return Visit 4 No thrush on exam Weight is the same, BP normal Still refuses consideration of counseling and drug treatment. CD4 301 (12.2%), VL 251,189 (log 5.4) Anemia no change ALT/AST between 1-2 X ULN TSH normal No other significant lab findings PHQ9 still mild depression but patient reports increased energy, better sleep pattern and less sadness

40. Selecting the Initial ART Regimen

41. Combination Antiretroviral Therapy (ART) Combination of at least 3 drugs, usually: 2 NRTIs (the �NRTI backbone�), plus: 1 NNRTI or 1-2 PIs Therapy with only one or two agents allows HIV to overcome therapy through resistance mutations

44. Current Antiretroviral Medications NRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Tenofovir TDF NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP Combinations Combivir; Epzicom; Trizivir; Atripla Truvada PI Amprenavir APV Atazanavir ATV Darunavir DRV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV hard gel HGC tablet INV Tipranavir TPV Fusion Inhibitor Enfuvirtide T-20

45. Antiretroviral Components in Initial Therapy: NNRTIs ADVANTAGES Less fat maldistribution and dyslipidemia than in PI-based regimens PI options preserved for future use DISADVANTAGES Resistance - single mutation Cross-resistance among NNRTIs Rash; hepatotoxicity Potential drug interactions (CYP450)

46. Antiretroviral Components in Initial Therapy: PIs ADVANTAGES Longest prospective data NNRTI options preserved for future use DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) Greater potential for drug interactions (CYP450), especially with ritonavir

47. Antiretroviral Components in Initial Therapy: NRTIs ADVANTAGES Established backbone of combination therapy Minimal drug interactions PI & NNRTI preserved for future use DISADVANTAGES Lactic acidosis and hepatic steatosis reported with most NRTIs (rare) Triple NRTI regimens show inferior virologic response compared with EFV- and IDV-based regimens*

48. Components of Initial ART: DHHS Categories Preferred Clinical data show optimal efficacy and durability Acceptable tolerability and ease of use Alternative Clinical trial data show efficacy but also show disadvantages in ARV activity, durability, tolerability, or ease of use (compared to �preferred� components) may be the best option in select individual patients Other possible options Inferior efficacy or greater or more serious toxicities

49. Initial Treatment: Preferred Components *Avoid in pregnant women and women with significant pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa.

50. Initial Treatment: Alternative Components *Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts >400 cells/mm3 **Atazanavir must be boosted with ritonavir if used in combination with tenofovir

51. Initial Treatment: Other Possible Options

52. Choosing an Initial NRTI Backbone: Resistance Little difference between 3 dual-NRTI FDCs with respect to resistance consequences at failure All likely to select M184V at failure ZDV/3TC Thymidine analogue mutations (TAMs) emerge gradually but result in multi-NRTI resistance ABC/3TC L74V more likely to emerge than K65R, leaving ZDV and TDF available for later use TDF/FTC Emergence of K65R appears unusual Patients with M184V and K65R may be hypersusceptible to ZDV, susceptible to d4T, partially susceptible to TDF Strategic Use and Sequencing of Fixed-dose NNRTI�s; clinicaloptions.com/hiv

53. Co-infected Hepatitis B Emtricitabine, lamivudine, and tenofovir Adefovir dipivoxil or entecavir Cessation of anti-Hepatitis B therapy can result in hepatitis flares Use of PI or NNRTI likely will result in worsening LFT (5-10 times ULN) that will stabilize over time.

54. Antiretroviral Medications: Not Recommended in Initial Treatment (1)

55. Antiretroviral Medications: Not Recommended in Initial Treatment (2)

56. Antiretroviral Medications: Not Recommended in Initial Treatment (3)

57. Antiretroviral Medications: Should not be offered at any time Regimens not recommended: Monotherapy (except possibly zidovudine used to prevent perinatal HIV transmission) Dual NRTI therapy 3-NRTI regimen (except abacavir/lamivudine/ zidovudine and possibly lamivudine/zidovudine + tenofovir NRTI-sparing regimens

58. Antiretroviral Medications: Should not be offered at any time Antiretroviral components not recommended: Didanosine + stavudine Stavudine + zidovudine Emtricitabine + lamivudine

59. Antiretroviral Medications: Should not be offered at any time Antiretroviral components not recommended: Efavirenz in pregnancy and in women with significant potential for pregnancy* Nevirapine initiation in women with CD4 >250 cells/mm3 or men with CD4 >400 cells/mm3

60. Antiretroviral Medications: Should not be offered at any time Antiretroviral components not recommended: Atazanavir + indinavir Amprenavir + fosamprenavir Amprenavir oral solution in pregnancy, in children <4 years, in renal or hepatic failure, or in patients treated with metronidazole or disulfiram Amprenavir oral solution + ritonavir oral solution Saquinavir as single PI (unboosted)

61. Results from Comparable Trials:ITT analysis of VL <400 c/mL at Week 48

62. ARV Options for Patient LM17 Efavirenz 600 mg/d (1 cap) OR Atazanavir/r 300 mg/100 mg/d (2 caps) Fosamprenavir/r 700 mg +100 mg (1 tab + 1 cap) bid Lopinavir/r 400/100 mg/d (2 tabs) bid

63. ARV Options for Patient LM18 Tenofovir + (emtricitabine or lamivudine) Zidovudine + (lamivudine or emtricitabine) LM factors: Baseline L210W Anemia Low normal renal function

64. ARV Options for Patient LM19 Discussing options, patient felt 1/d dosing would be important EFV + Epzicom (2 pills hs) Patient informed deviation from 1st choice guidelines for Nucleoside/tide backbone because? Potential drug side effects outlined

65. Safety and Tolerability of Nucleoside and Nucleotide Reverse Transcriptase inhibitors; http://clinicaloptions.com/hiv Lamivudine Generally well tolerated, with a rare occurrence of serious events Most frequently reported serious adverse events Blood and lymphatic events (0.2%) Gastrointestinal events (0.1%) Hepatic/pancreas events (0.1%) Neuropathy (0.1%) Serious laboratory abnormalities Anemia/pancytopenia (0.4%) Neutropenia (0.4%) Thrombocytopenia (0.2%)

66. Hypersensitivity to Abacavir  Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate, contained in TRIZIVIR Symptoms usually appear within the first 6 weeks of treatment Median onset = 9 days (may occur at any time) Symptoms worsen during continued therapy with abacavir and usually resolve upon discontinuation

67. Hypersensitivity to Abacavir  In an analysis of 9 clinical trials, suspected hypersensitivity was reported in approximately 8% of 2,670�patients (range: 2% to 9%) All 9 studies used ZIAGEN BID In CNA30024 suspected hypersensitivity was reported in 3% of patients in the comparative arm who were not receiving ABC compared with 9% in the ABC arm Across GSK�s series of 37 clinical trials with abacavir, the frequency of hypersensitivity reactions remains 5.4%

69. ABC hypersensitivity may be more severe with qd versus bid dosing CNA30021: n = 770 treatment na�ve patients randomized to ABC 300mg bid versus ABC 600mg qd Combined with 3TC plus efavirenz (each once daily) Equivalent treatment efficacy ? More severe hypersensitivity with qd dosing

70. Immune Reconstitution Syndrome Reflects newly invigorated immune system mounting an inflammatory response against an infection that was previously clinically silent in the face of severe immunodeficiency Common among patients with robust rise in CD4 count (e.g., over 100 cells/mm�) in the first several weeks following initiation of ART Typically managed by continuing ART and administering anti-inflammatory medications to control symptoms, such as NSAIDS and/or steroids Occasionally discontinuation of antiretrovirals is necessary

71. Clinical Presentation & Course of Common Immune Reconstitution Syndromes

72. Virologic Control falls sharply with diminished adherence

73. Predictors of Poor Adherence active alcohol1 or substance2 abuse work outside the home for pay1 depressed mood1 lack of perceived efficacy of ART3 lack of advanced disease4 concern over side effects4 regimen complexity5

74. Improving Adherence Simplify regimens, dosing, and food requirements Engage family, friends Utilize team approach with nurses, pharmacists, and peer counselors Provide accessible, trusting health care team

75. Factors Associated with Higher Levels of Adherence twice-daily or once-daily regimens1,4 belief in own ability to adhere to regimen1 not living alone2 dependent on a significant other for support2 history of opportunistic infection or advanced HIV disease3

76. Factors Associated with Higher Levels of Adherence Belief in efficacy of antiretroviral therapy Belief that non-adherence will lead to viral resistance

77. ARV Options for Patient LM20 Scripts written Met with peer educator Stressed compliance and to call for any side effect Encouraged alcohol abstinence and control of crack habit to 1-2 hits/week Keep appointments.

78. Antiretroviral Therapy: Optimal Response

79. Follow-up Laboratory Testing CBC, CMP, and compliance evaluation within 14d of regimen start Viral load, CD4 counts, CBC, CMP, compliance check at one month +/- lipid. Pending one month results can monitor q 2-3 months: CBC, CD4, VL. CMP and Lipid at least q 6 months Anticipate undetectable VL by 6 months. Trend should be downward. Good CD4 response averages about 100 cells in one year.

80. Defining ARV Regimen Failure Virologic � persistent detection of viremia > 400 copies/mL after suppression to < 400 copies/mL Immunologic � failure to see a rise in CD4 cell count or a decline in CD4 occurs.

81. Initial Antiretroviral Therapy: Summary ART has made HIV a treatable and manageable chronic disease for many patients ART consists of at least 3 drugs, generally from 2 or more classes When to initiate therapy remains controversial, but probably best to start before CD4 falls below 200 cells/mm� and before symptoms Consider adherence and baseline viral load when designing initial regimen

82. Initial Antiretroviral Therapy: Summary Consider co-morbid conditions in choosing ARV therapy Hepatitis B or C Bone marrow/hepatic/renal abnormalities Diabetes/heart disease/age Substance abuse Goal is undetectable viral load (<50 copies/mL) and rise in CD4 count Monitor closely after initiation of therapy