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Initiation of Antiretroviral Therapy (ART)

Initiation of Antiretroviral Therapy (ART). Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington. When Should Patients with HIV be Treated with ART?. Benefits reduced morbidity & mortality immune system recovery Drawbacks toxicities

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Initiation of Antiretroviral Therapy (ART)

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  1. Initiation of Antiretroviral Therapy (ART) Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington

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

  3. Initiation of Antiretroviral Therapy: Key Considerations • Symptoms & Opportunistic Infections • CD4 count • Viral Load • Anticipated Adherence - patient ‘readiness’

  4. Initiation of ART: Case • A 29-year old woman comes to the clinic for routine HIV care; she has been HIV-infected for about 4 years, and has never received antiretroviral treatment. Her most recent CD4 count is 330 cells/mm³ and her viral load is 88,000 copies/mL. • Would you suggest she start antiretroviral therapy?

  5. What does a CD4 count of 330 cells/mm³mean?

  6. HIV Infection is characterized by a steady decline in the number of CD4 cells CD4 Cell Count (cells/mm³) Acute Infection Asymptomatic HIV Infection AIDS 1,000 CD4 cell count 500 200 high risk of opportunistic infections 4-8 Weeks Up to 12 Years 2-3 Years Time

  7. mm³ (cells/mm³) Mellors et al. Ann Intern Med 1997;126:946.

  8. 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 followup Egger et al. Lancet 2002; 360:119-30.

  9. Analysis of 13 cohort studies: effect of baseline CD4 count on response to initial ART Years from starting HAART Egger et al. Lancet 2002; 360:119-30.

  10. Findings: effects of clinical stage on clinical progression Years after starting HAART Egger et al. Lancet 2002; 360:119-30.

  11. Findings: effect of baseline HIV Viral Load on response to ART Years from starting HAART Egger et al. Lancet 2002; 360:119-30.

  12. Cohort studies: conclusions • 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 1. Chen RY et al. 8th CROI, Chicago 2001 2. Hogg RS et al. JAMA. 2001;286:2568-2577 3. Sterling et al, 9th CROI, Seattle 2002 4. Palella et al, 9th CROI, Seattle 2002

  13. 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 1. Philips AN et al. JAMA 2001;286:2560-2567. 2. Hogg RS et al. JAMA 2001;286:2568-2577.

  14. Implications for Clinical Practice • Ideally, initiate ART before CD4 count drops below 200 cells/mm³ 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

  15. Implications for Clinical Practice: Significance of 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? 1. XIV International AIDS Conference, July 2002. Abstract TuOrB1189 2. Arribas JR et al. AIDS 2002;16(11):1554-6. 3. Walmsley S et al. NEJM 2002 346(26):2039-46.

  16. CD4 Count, Viral Load, and Clinical Course Primary Infection Sero-conversion Intermediate Stage AIDS CD4 Cell Count Plasma RNA Copies 1,000 CD4 Cells 500 4-8 Weeks Up to 12 Years 2-3 Years

  17. When Should ART be Initiated? DHHS Guidelines DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, October 6, 2005.

  18. When Should ART be Initiated? IAS-USA Guidelines Yeni et al. JAMA. 2004;292:251-265.

  19. Recent Advances in Antiretroviral Therapy incremental gains in convenience, tolerability, and insights into toxicity have added up to significant improvements in management of HIV disease

  20. Lower pill burden Fixed dose combinations TDF/FTC (Truvada) ABC/3TC (Epzicom) AZT/3TC (Combivir) AZT3TC/ABC (Trizivir) Fewer pills for same effect efavirenz nelfinavir fosamprenavir lopinavir/ritonavir saquinavir Once-daily dosing tenofovir 3TC, FTC abacavir ddI efavirenz atazanavir fosamprenavir (w/ ritonavir) saquinavir (w/ ritonavir) lopinavir/ritonavir Advances in Antiretroviral Therapy: Easier Regimens • Fewer food restrictionswith newer agents and with ritonavir boosting of protease inhibitors

  21. Advances in Antiretroviral Therapy: Improvements in Toxicity • New drugs with less toxicity • Tenofovir: no dyslipidemia compared with d4T • Atazanavir: no dyslipidemia compared with other PIs • Improved Understanding of Toxicities • Nevirapine toxicity: identification of high-risk groups • women CD4 >250 cells/mm³ • men CD4 >400 cells/mm³ • Mitochondrial toxicity as basis for many long-term toxicities • Clarification of which NRTIs are most likely to cause mitochondrial toxicity (d4T, ddI, ddC) • Partial clarification of lipodystrophy

  22. Timing of Initiation of ART Is the Pendulum Swinging Back to Earlier Treatment?

  23. Before you start… Resistance Testing Adherence Issues

  24. 0 Resistance in treatment-naïve individuals is becoming more common Recently Infected, ART Naïve, United States Little SJ, Holte S, Routy JP, et al. N Engl J Med. 2002;347:385-94

  25. Persistence of Resistant Strains Following Primary HIV Infection • 11 subjects with primary HIV infection who deferred ART and who had at least one major drug resistance mutation identified at presentation, followed with serial resistance assays. • 7 subjects with NNRTI resistance • 2 with NRTI and PI resistance • 1 with NNRTI and PI resistance • 1 with resistance to all three classes of drugs • NNRTI resistance was lost slowly: the average time to reversion of 103N variants to mixed 103N/K populations was 196 days following the estimated date of infection (153 to 238 days, 95%CI). • PI resistance was not lost at all: In the 4 patients with protease resistance mutations, no reversion was detected at 64, 191, 327, and 342 days after infection. • Complete reversion of genotypic resistance was observed in only one patient, at 1019 days after infection. Little SJ. 11th CROI, February 2004, Abstract 36LB

  26. Antiretroviral Resistance Testing: Guidelines for Implementation Adapted from DHHS, Antiretroviral Guidelines, October 6, 2005

  27. Initiation of Antiretroviral Therapy: Key Considerations • Symptoms & Opportunistic Infections • CD4 count • Viral Load • Anticipated Adherence - patient ‘readiness’

  28. Adherence: Case 1 • A 23 year old single woman with HIV infection diagnosed two years ago. • No history of antiretroviral therapy. • Current CD4 count is 230 cells/mm³. • Her physical exam is remarkable only for oral candidiasis (thrush). • Review of her past medical history includes depression, which she admits has been worse lately. • Current medications include nortriptyline and oral contraceptives.

  29. Adherence • Which of the following factors in her situation suggests that adherence may be problematic for her? • her depression • she is already symptomatic with HIV infection • her age (less than 30 years old) • all of the above factors are associated with reduced adherence to antiretrovirals.

  30. Adherence • Which of the following factors in her situation suggests that adherence may be problematic for her? • her depression • she is already symptomatic with HIV infection • her age (less than 30 years old) • all of the above factors are associated with reduced adherence to antiretrovirals.

  31. Adherence “Drugs don’t work if people don’t take them.” - C. Everett Koop

  32. Virologic Control falls sharply with diminished adherence Patients with HIV RNA<400 copies/mL, % PI adherence, % (electronic bottle caps) Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.

  33. Self-Adminstered vs Directly Observed Therapy During Incarceration N = 50 in each group p < 0.01 Fischl et al 8th CROI, 2001 abstract 528

  34. 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 1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281. 2. Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407. 3. Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588. 4. Wenger N, et al. 6th CROI, 1999, Abstract 98. 5. Stone VE, et al. JAIDS 2001; 28:124-131

  35. 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 1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125. 2. Morse EV et al, Soc Sci Med 1991;32:1161-1167. 3. Singh N, et al, AIDS Care 1996;8:261-269. 4. Stone VE, et al. JAIDS 2001; 28:124-131

  36. Factors Associated with Higher Levels of Adherence • Belief in efficacy of antiretroviral therapy • Belief that non-adherence will lead to viral resistance Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.

  37. How good are clinicians at predicting their patients’ adherence? • 95% • 85% • 75% • Not much better than flipping a coin

  38. Clinicians’ Estimates of Adherence Not Much Better Than Random Bangsberg 2001 JAIDS ART Paterson 2000 Annals Int Med ART Haubrich 1999 AIDS ART Steiner 1995 Arch Int Med AZT Bosely 1995 Eur Resp J Inhaled terbutaline Charney 1967 Pediatrics Penicillin Caron 1978 Clin Pharmacol Antacids Gilbert 1980 Can Med Assoc J Digoxin Blowey 1997 Ped Nephrology Cyclosporin Mushlin 1977 Arch Int Med Hypertensive

  39. Improving Adherence: Before Initiation of Therapy • Assess patient's understanding and acceptance of the regimen: negotiated plan • Investigate and manage medical barriers to adherence • Try to use simple regimens • Twice-daily or better • Without food requirements if possible Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

  40. Improving Adherence: After Initiation of Therapy • Close follow-up • Ask patient to verbalize treatment regimen • Education about adherence • Consider cues, alarms to remind patients of dosing • Referral to community support groups • Involve other members of the health care team

  41. Back to Case 1 • You confirm her viral load and CD4 count; she keeps her follow-up appointments and appears to understand the importance of adherence. You start her on an antidepressant medication and refer her for counseling. 3 months later her depression is significantly improved and she feels ready to initiate ART. • What regimen would you recommend?

  42. Selecting the Initial ART Regimen

  43. 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. 0 HIV Life Cycle and Classes of ARVs Nucleoside Analogues (NRTIs) HIV Reverse Transcriptase RNA DNA Nucleus Fusion Inhibitors Host Cell Non-Nucleosides (NNRTIs) Protease Inhibitors (PIs)

  45. FDA-Approved ARVS: NRTIs

  46. FDA-Approved ARVS: NNRTIs and PIs

  47. FDA-Approved ARVS: PIs (cont.) and Fusion Inhibitor

  48. Ritonavir intensification of other Protease Inhibitors (PIs) • PIs, like many medications, are metabolized in the liver by the cytochrome P450 enzyme complex • Ritonavir inhibits this complex, thereby boosting serum levels of co-administered PIs • Low doses of ritonavir can be used to increase the potency and simplify the dosing of PI-based regimens

  49. An Example of Ritonavir Boosting:Indinavir/Ritonavir BID PK Study 10,000 IDV/RTV q12h: 800/200 High-fat Meal 800/100 High-fat Meal 400/400 High-fat Meal IDV q8h: 800 mg Fasted IndinavirPlasmaConcentration(nM) 1,000 100 0 2 4 6 8 10 12 Time after dose (hours) 6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.

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