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Principles of Antiretroviral Therapy . Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington. CBB/2002. Current Treatment Strategies. DHHS Guidelines regarding when to initiate antiretroviral therapy Adherence Strategic antiretroviral combinations

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Principles of Antiretroviral Therapy


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    1. Principles of Antiretroviral Therapy Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington CBB/2002

    2. Current Treatment Strategies • DHHS Guidelines regarding when to initiate antiretroviral therapy • Adherence • Strategic antiretroviral combinations • Popular regimens • Follow-up monitoring CBB/2002

    3. HIV: Case History • 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 and her viral load is 88,000. • You explain the meaning of her CD4 count and viral load • She asks you if you would recommend antiretroviral therapy CBB/2002

    4. Advantages decrease viral load, increase CD4 count prevent further damage to immune system immune reconstitution reduced morbidity & mortality (if effective) prevent viral heterogeneity decrease infectivity Disadvantages toxicities, both short- & long-term pill burden, lifestyle changes potential for developing resistance may limit future options potential for transmission of resistant virus cost Initiation of Antiretroviral Therapy CBB/2002

    5. Initiation of Antiretroviral Therapy: Key Considerations • Symptoms & Opportunistic Infections • CD4 count • Viral Load • Anticipated Adherence - patient ‘readiness’ CBB/2002

    6. Indications for Initiation of Antiretroviral Therapy for HIV DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6. CBB/2002

    7. Indications for Initiation of Antiretroviral Therapy for HIV DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6. CBB/2002

    8. Baseline CD4 Count and Survival after initation of HAART: prospective cohort of 715 patients 1.0 0.5 CD4 Count when Initiate HAART proportion surviving < 50 51 - 200 201 - 350 > 350 0.0 1 3 4 5 0 2 Survival in Years Chen RY et al, 8th CROI, Chicago 2001

    9. Cumulative Mortality by Baseline CD4 Count Baseline CD4 Count and Survival after Initiation of HAART CD4> 200 ==================== CD4 50-199 Probability of Survival (%) N = 1219 therapy- naïve individuals initiating HAART in British Columbia 1996 - 1999 CD4 < 50 Time From Start of HAART (months) JAMA. 2001;286:2568-2577 CBB/2002

    10. Indications for Initiation of Antiretroviral Therapy for HIV DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6. CBB/2002

    11. Survival after Initiation of HAART by Baseline CD4 Count and Viral Load =================== Probability of Survival (%) N = 1219 therapy- naïve individuals initiating HAART in British Columbia 1996 - 1999 JAMA. 2001;286:2568-2577 Time from initation of HAART (mos)

    12. Impact of CD4 and Viral Load on Initiation of HAART: Summary • The optimal time to initiate therapy is: • unclear • before CD4 drops below 200 • probably when CD4 between 200 and 350 • determined more by CD4 count than viral load • Viral Load • predicts the slope of CD4 decline • may help determine whether to start closer to CD4 count of 200 or 350 CBB/2002

    13. HIV: Case History • 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 and her viral load is 88,000. • Would you suggest she start antiretroviral therapy? CBB/2002

    14. Initiation of Antiretroviral Therapy: Key Considerations • Symptoms & Opportunistic Infections • CD4 count • Viral Load • Anticipated Adherence - patient ‘readiness’ CBB/2002

    15. Adherence “Drugs don’t work if people don’t take them.” - C. Everett Koop CBB/2002

    16. 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. CBB/2002

    17. Adherence O 90–100% O50–89% O 0–49% Adherence and AIDS-Free Survival 10% Adherence difference = 21% reduction in risk of AIDS 1.00 0.75 Proportion AIDS-Free 0.50 0.25 P = .0012 0.00 0 5 10 15 20 25 30 Months from entry Bangsberg D, et al. AIDS. 2001:15:1181

    18. Reasons for Non-Adherence: Clinician vs Patient Views Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281 CBB/2002

    19. Predictors of Poor Adherence • active alcohol1 or substance2 abuse • work outside the home for pay1 • depressed mood1 • lack of perceived efficacy of HAART3 • lack of advanced disease4 • concern over side effects4 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 Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98. CBB/2002

    20. Predictors of Poor Adherence, continued • inability to fit medications into daily schedule • tid dosing, food requirements1 1. Stone VE, et al. JAIDS 2001; 28:124-131 CBB/2002

    21. 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 CBB/2002

    22. 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.

    23. Interventions Shown to Improve Adherence to Antiretrovirals • medication alarms1 • education & counseling sessions2,3 • Directly Observed Therapy (DOT)4,5 1. Samet JH, et al. Am J Med. 1992;92:495-502. 2. Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4. 3. Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract 595. 4. Sorensen JL, et al. AIDS Care. 1998;10:297-312. 5. Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269.

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

    25. Putting it all Together Practical Strategies to Improve Adherence

    26. Improving Adherence: before Initiation of Therapy • Assess patient's understanding and acceptance of the regimens • Determine other medical barriers to adherence • Manage or refer for management of adherence-limiting co-morbid conditions Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

    27. Improving Adherence: before Initiation of Therapy • Try to use simple regimens • bid or better • avoid food requirements if possible • Clear & simple instructions • Negotiated treatment plan

    28. Improving Adherence: After Initiation of Therapy • Close follow-up • Ask patient to verbalize treatment regimen • Education about adherence • re-emphasize importance of adherence at each visit, even in patients with good virologic control • review incidence & management of adverse effects often

    29. Improving Adherence: After Initiation of Therapy • consider cues to remind patients of dosing • other reminders: alarms, watches, pagers • consider recruiting family/friends as support • referral to community support groups • involve other members of the health care team Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

    30. Back to the case • You confirm her viral load and CD4 count; she keeps her follow-up appointments and appears to understand the importance of adherence. She has no significant co-morbid conditions or medications. • What regimen would you recommend?

    31. Highly Active Antiretroviral Therapy (HAART) • 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

    32. Classes of Antiretroviral Agents Nucleoside Analogues HIV RT RNA DNA Nucleus Host Cell Non-Nucleosides Protease Inhibitors Adapted from: Walker B. IDSA 1998

    33. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) • Nucleoside analogues that block translation of HIV RNA into DNA by inhibiting HIV Reverse Transcriptase enzyme • AZT (zidovudine; Retrovir) • 3TC (lamivudine; Epivir) • d4T (stavudine; Zerit) • ddI (didanosine; Videx) • Abacavir (Ziagen) • ddC (zalcitabine; Hivid)

    34. Tenofovir: a new NRTI • Nucleotide Reverse Transcriptase Inhibitor • one 300mg tablet daily with food • well-tolerated and effective in clinical trials to date • effective against many strains of HIV with NRTI resistance • also active against hepatitis B • generally being reserved for salvage therapy

    35. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Also inhibit HIV Reverse Transcriptase, but at a different site than NRTIs • Efavirenz (Sustiva) • Nevirapine (Viramune) • Delavirdine (Rescriptor)

    36. Protease Inhibitors (PIs) • Block release of the assembled HIV virus particles from infected cells • Ritonavir (Norvir) • Saquinavir (Fortavase; Invirase) • Nelfinavir (Viracept) • Indinavir (Crixivan) • Amprenavir (Agenerase) • Lopinavir (co-formulated w/ ritonavir as Kaletra)

    37. Ritonavir intensification of other Protease Inhibitors (PIs) • Protease Inhibitors, 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 protease inhibitors

    38. Basic Pharmacology Principles Cmax Drug Level Cmax Cmin IC90 Area of Potential HIV Replication IC50 Cmin Dosing Interval Time Dose Dose

    39. 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 Postdose (hours) 6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.

    40. Ritonavir intensification of other Protease Inhibitors (PIs) • This can be used to ease pill burden, dosing intervals, and potentially overcome HIV resistance among protease inhibitors • This can also lead to potentially dangerous or fatal interactions with other medications and recreational drugs

    41. So What to Start With? • PI - based regimens (2 NRTIs + 1-2 PIs) • NNRTI - based regimens (2 NRTIs + 1 NNRTI) • NRTI - based regimens (3 NRTIs)

    42. The most clinical outcome data available for PI-based regimens Allow deferral of NNRTIs High genetic barrier to resistance (multiple mutations required) high pharmacologic barrier to resistance for pharmaco-kinetically boosted PIs Short-term side effects (esp. gastrointestinal) Long-term metabolic/morphologic side effects Inconvenience & adherence (schedule, pill burden, food requirements) Drug-drug interactions Protease Inhibitor -based regimens Disadvantages Advantages

    43. Simpler regimens Fewer long-term toxicities Potent at high viral loads/low CD4+ cell counts (efavirenz) Allow deferral of PIs Fewer drug-drug interactions NNRTIs vary in potency; some may be less effective at high viral loads/low CD4+ counts (nevirapine, delavirdine) Low genetic barrier to resistance Extensive NNRTI cross-resistance toxicities: CNS, hyperlipidemia (efavirenz); rash (all); hepatotoxicity (NVP > EFV) NNRTI - based regimens Disadvantages Advantages

    44. Allows deferral of PIs and NNRTIs Simple, low pill burden Well tolerated minimal long-term toxicity virtually no drug interactions Limited data, no clinical endpoint data Relative potency and durability not established Efficacy at high viral loads questionable Abacavir hypersensitivity NRTI - based regimens(AZT + 3TC + Abacavir) Advantages Disadvantages

    45. Recommended Antiretroviral Combinations for Initial Therapy Choose one from Column A and one from Column B DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, August 13, 2001, Table 12.

    46. Inverse Association Nelfinavir Indinavir Nevirapine Delavirdine triple NRTI No Association Efavirenz Lopinavir/ritonavir (Kaletra) Unknown Association dual PI combination Effect of Baseline Viral Load on Efficacy

    47. VL > 100,000 Proven LPV/RTV + 2 NRTIs Efavirenz + 2 NRTIs Unproven Boosted PI + 2 NRTIs 3 NRTIs + PI 3 NRTIs + Nevirapine NRTI/NNRTI/PI VL < 100,000 LPV/RTV + 2 NRTIs Efavirenz + 2 NRTIs Nevirapine + 2 NRTIs 1-2 PIs + 2 NRTIs AZT/3TC/Abacavir Choice of initial regimen by baseline Viral Load

    48. Popular Initial HAART Regimens: Efavirenz + 2 NRTIs • d4T/3TC/Efavirenz • highly potent • generally well tolerated • CNS side effects from efavirenz • AZT/3TC/Efavirenz (or Combivir/Efavirenz) • low pill burden • more side effects from AZT