1. Should We Embrace Proactive Therapy Switches in Patients Who Are Tolerating Their Current Regimen, Based on Concerns About Potential Long-term Toxicity? The Pro Arguments PROGRAM DIRECTOR Anton L. Pozniak, MD, FRCP Consultant Physician Department of HIV and Genitourinary Medicine Chelsea and Westminster Hospital London, United Kingdom FACULTY Jens D. Lundgren, MD Director, Copenhagen HIV Programme Hvidore University Hospital Hvidore, Denmark

2. clinicaloptions.com/hiv Refining Antiretroviral Regimens Strengths and Limitations of Antiretroviral Therapy  Strengths –It works –Effect is durable –Expanding number of drugs without cross-resistance and with different adverse effect –Reduced risk of resistance due to appreciation of tight adherence, lowering pill burden, and “forgiving PK profile”  Limitations –Must be continued for life –Only works if taken –Resistance may emerge to all drugs –Combination of ≥ 2 drugs required for durable complete suppression –All drugs may cause adverse effects –Longer-term individual prognosis is determined by number of tolerable and still active drugs

3. clinicaloptions.com/hiv Refining Antiretroviral Regimens CV diseasePIsAge, gender, smoking, etc Diabetes mellitus PIs + thymidine analogues (?)Obesity, age Hypertension?Obesity, age LipoatrophyThymidine analoguesAge Renal diseaseTenofovir, cidofovir, adefovir, foscarnet, pentamidine Nephrotoxic agents; baseline renal disease Liver diseaseNRTIs (?)Chronic viral hepatitis, alcohol Bone disease? (tenofovir ?)Androgens, steroid, physical inactivity Long-term Toxicity = Late-Onset Toxicity

4. clinicaloptions.com/hiv Refining Antiretroviral Regimens Drugs Involved CV diseasePIsAge, gender, smoking, etc Diabetes mellitus PIs + thymidine analogues (?)Obesity, age Hypertension?Obesity, age LipoatrophyThymidine analoguesAge Renal diseaseTenofovir, cidofovir, adefovir, foscarnet, pentamidine Nephrotoxic agents; baseline renal disease Liver diseaseNRTIs (?)Chronic viral hepatitis, alcohol Bone disease? (Tenofovir?)Androgens, steroid, physical inactivity Long-term Toxicity = Late-Onset Toxicity

5. clinicaloptions.com/hiv Refining Antiretroviral Regimens Drugs InvolvedContributing Factors CV diseasePIsAge, sex, smoking, etc Diabetes mellitus PIs + thymidine analogues (?)Obesity, age Hypertension?Obesity, age LipoatrophyThymidine analoguesAge Renal diseaseTenofovir, cidofovir, adefovir, foscarnet, pentamidine Nephrotoxic agents; baseline renal disease Liver diseaseNRTIs (?)Chronic viral hepatitis, alcohol Bone disease? (Tenofovir?)Androgens, steroid, physical inactivity Long-term Toxicity = Late-Onset Toxicity (cont’d)

6. clinicaloptions.com/hiv Refining Antiretroviral Regimens Absolute vs Relative Risk: Implications for Management  Absolute risk = incidence of disease  Relative risk = difference in incidence between 2 groups of patients (eg, treated with 2 different medications)  Certain drugs may elevate the relative risk of certain unintended outcomes (ie, toxicities)... ... However, the clinical implications of an increased relative risk are determined by the absolute risk of the outcome in the individual patient –Must evaluate risk vs benefit

7. clinicaloptions.com/hiv Refining Antiretroviral Regimens Other Elements to Consider When Contemplating a Preventive Switch  Mechanism of action of toxicity –Time course of toxicity caused by “switch from” drug –Susceptible subgroup –Overlapping toxicity profile of several drugs (if one poses a problem, others may as well, eg, PIs and elevation of total cholesterol)  All drugs have a toxicity profile! –This may be also true of the drug to which the patient is switched  Each switch disturbs the routine of taking drugs –Requires careful instruction of patient

8. clinicaloptions.com/hiv Refining Antiretroviral Regimens Summary  Proactive switches to reduce risk of late-onset toxicities are entirely appropriate provided that –The individual patient’s absolute risk of the toxicity–if remaining on same drug–is clinically important –If the drug that is switched to –Substantially reduces this absolute risk –Does not have other toxicities of equal magnitude –The patient is well informed about the decision process and understands that there is the potential for other adverse effects from the new drug, immediately or later on

9. Should We Embrace Proactive Therapy Switches in Patients Who Are Tolerating Their Current Regimen, Based on Concerns About Potential Long-term Toxicity? The Con Arguments PROGRAM DIRECTOR Anton L. Pozniak, MD, FRCP Consultant Physician Department of HIV and Genitourinary Medicine Chelsea and Westminster Hospital London, United Kingdom FACULTY Benjamin Young, MD, PhD Assistant Clinical Professor of Medicine University of Colorado Health Sciences Center Denver, Colorado

10. clinicaloptions.com/hiv Refining Antiretroviral Regimens Why Switch Treatment?  Simplify treatment  Enhance adherence  Maintain or improve immunologic function  Improve short-term tolerability  Avoid long-term toxicity  Improve quality of life

11. clinicaloptions.com/hiv Refining Antiretroviral Regimens Why Switch Treatment? (cont’d)  Let’s be clear: switches that –Improve adherence –Eliminate existing toxicity –Improve quality of life –Improve virologic control... should be considered and implemented

12. clinicaloptions.com/hiv Refining Antiretroviral Regimens Why Switch Treatment? (cont’d)  What about the patient with excellent tolerability and adherence? –Informed decisions require understanding potential risks and potential benefits

13. clinicaloptions.com/hiv Refining Antiretroviral Regimens Simplify Treatment? Dosing Frequency  Is this merely a convenience factor?  Current regimens are either twice or once daily –Little evidence suggests that clinical outcomes actually improve from twice to once daily –Other treatments may have twice-daily dosing

14. clinicaloptions.com/hiv Refining Antiretroviral Regimens Simplify Treatment? Pill Burden  Is this merely a convenience factor?  Current regimens are low pill burden –NRTI FDC + EFV: 1-3 pills –NRTI FDC + ATV: 2-4 pills –NRTI FDC + boosted PI: 4-6 pills  Will patients who cannot take 2, 3, or even 5 pills per day really adhere better on 1 pill per day?

15. clinicaloptions.com/hiv Refining Antiretroviral Regimens Simplify Treatment? Improve Counseling  Will patients who cannot take 2 or 3 antiretroviral pills per day really adhere better on 1 pill a day? –Patients and healthcare providers often forget (or ignore) the price of nonadherence to antiretrovirals –Many patients take many more additional pills (concomitant medications, vitamins, supplements)

16. clinicaloptions.com/hiv Refining Antiretroviral Regimens Improve Short-term Tolerability?  Even the “best” regimens result in some level of discontinuation –TDF + FTC + EFV [1] –12/257 (5%) because of toxicity –ABC/3TC + LPV/RTV [2] –24/444 (5%) because of adverse event 1. Gallant JE, et al. IAC 2006. Abstract TUPE0064. 2. Eron JJ Jr, et al. Lancet. 2006;368:476-482.

17. clinicaloptions.com/hiv Refining Antiretroviral Regimens Maintain Virologic Suppression?  Even the “best” regimens result in virologic failure –TDF + FTC + EFV [1] –4/255 (1.6%) because of virologic failure –ABC/3TC + LPV/RTV [2] –30/44 (6.7%) because of virologic failure 1. Gallant JE, et al. N Engl J Med. 2006;354:251-260. 2. Eron JJ Jr, et al. Lancet. 2006;368:476-482.

18. clinicaloptions.com/hiv Refining Antiretroviral Regimens Maintain Virologic Suppression? (cont’d)  Even suppressed patients experience virologic failure when switched –PI to EFV [1] –12/156 (8%) –ZDV/3TC to TDF/FTC [2] –6% of patients with VL > 400 at 24 weeks 1. Martinez E, et al. CROI 2006. Abstract 521. 2. DeJesus E, et al. CAHR 2006. Abstract 214.

19. clinicaloptions.com/hiv Refining Antiretroviral Regimens Faulty Crystal Balls?  Sometimes “good” drugs are not so good –Rofecoxib (approved May 1999) –Latent risk of cardiovascular disease –Withdrawn September 2004 –Stavudine (approved September 1994) –Latent risk of lipoatrophy –Association identified ~ 2001 –Tipranavir (approved June 2005) –Latent risk of intracranial hemorrhage –Association identified June 2006

20. clinicaloptions.com/hiv Refining Antiretroviral Regimens Faulty Crystal Balls? (cont’d)  History of HIV medicine is filled with irrational exuberance –Nucleoside monotherapy –Nucleoside dual therapy –Sequential addition of PIs –“Hit hard, hit early” –Treatment during primary HIV infection –Strategic treatment interruption –ERADICATION

21. clinicaloptions.com/hiv Refining Antiretroviral Regimens If It Ain’t Broke, Don’t Fix It!  Persons living with HIV are living –Longer –Better –With fewer adverse effects –With fewer pills  The relative benefit of continuing antiretroviral therapy has increased  The relative risk of switching has not decreased