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  • Date of first publication: 2/1/99 Keywords: Adherence, antiretroviral therapy, viral load Subject: Degree of adherence needed for optimal viral suppression Title: “What degree of adherence is needed?” Discussion and teaching points: How much adherence is needed for optimal viral load suppression is addressed in the graph from Paterson which shows that the best performance was achieved in patients who by self-report and MEMS-caps were found to have >95% adherence, I.e. Better than 95% of doses were taken during the 3 months of study. Sig- nificant differences were observed between >95%, 90-95%, 80-90%, 70-80%, and <70% adherence, as shown. Note that <70% adherence was associated with only 10% of patients achieving a viral load below detection. Author(s): Paterson et al. Sources: University of Pittsburgh Sponsors: NA
  • *For example, learn patient's sleeping, eating, and work patterns; amount of time away from home; and frequency of weekend or overnight trips. † For example, say: "Many people find taking HIV medications very difficult. What sort of difficulties have you had taking your medications?" ‡ For example, say: "Tell me what times you take your medications," or "How does this fit into your lifestyle?" § Consider alcohol or drug abuse, depression, and poor coping skills. Adapted in part from Centers for Disease Control and Prevention. MMWR. 1999. [37] Source: http://hiv.medscape.com/SCP/TAR/2000/v10.n03/a1003.05.mill/a1003.05.mill-01.html
  • At this point I would like to digress briefly to address a question that often arises when making treatment decisions. It is not uncommon to be confronted with an HIV+ patient who clearly merits treatment based on his/her clinical condition and/or CD4 count & viral load, but at the same time we don’t have a lot of confidence in their ability to adhere to medications despite all of our best efforts. How concerned should we be that initiation of therapy will lead to resistant strains of HIV that could be spread to other individuals in the community?
  • I think this is a legitimate concern because the multi-drug resistant tuberculosis epidemic provides a frightening precedent. In the early 1990s, on the east coast and especially in New York City, TB was on the rise and there was a new epidemic of Multidrug resistant TB. The new forms of MDR TB were incurable in many and fatal in some. Poor adherence to TB meds was the root cause of MDR TB. Drug resistant tuberculosis became the number one public health threat in New York City. This NYT article in Nov 1991 says “TB threat: not taking medicine – partly cured patients are the deadliest carriers.” Two factors things contributed to poor adherence to TB therapy. First there was the population, consisting of drug users, the mentally ill and the homeless. Second, there was also a under-funded and chaotic healthcare system that made it difficult, if not impossible to adhere. Eventually, the health care system was revamped, DOT was instituted and MDR rates fell. Might a similar public health threat of antiretroviral-resistant HIV occur as a result of recklessly prescribing HAART to patients with poor adherence? Do we need to implement extraordinary measures such as DOT for patients in whom we fear poor adherence?
  • 1 And in fact, we are already seeing increasing rates of resistant strains of HIV in patients newly infected with HIV. While the overall rates of resistance are still relatively low, there has been a marked increase in the transmission of drug-resistant strains of HIV over the past few years, across all drug classes. But the key question that remains is: which patients are generating these resistant strains?
  • This is a plot of adherence, as measured by pill count, versus viral load. As expected, we see a rough inverse relationship: the higher the individual’s adherence is, the lower their viral load. Now according to our understanding of adherence and viral dynamics, which patients might we expect to be generating the resistant strains? -The ones with poor adherence, over here at the left side of the graph.
  • However, what was found in a recent study, was just the opposite: it was the patients with high levels of adherence that were predominantly generating the drug resistant strains of HIV. What could explain this? The likely explanation is that a high level of exposure to antiretroviral drugs is required to generate the pressure on HIV to develop and maintain resistance mutations. This high level of exposure is necessary because the same mutations that confer resistance generally also make HIV “less fit” - it doesn’t replicate as well. For this reason, HIV would rather not develop these mutations if it doesn’t have to - and in patients who take their medications infrequently, it doesn’t have to. Only patients who have high - though not perfect - adherence to their medications generate enough pressure on HIV to develop and maintain resistance mutations.
  • This slide documents that drug pressure is necessary to maintain most resistance-conferring mutations. In this study, several patients with high level drug resistance were randomized to stop antiretroviral therapy. These are four patients who stopped antiretroviral therapy and the lines represent the level of resistance to each drug. Resistant virus disappeared shortly after stopping therapy and was over grown by wildtype virus. The reason for this was resistant virus was much less fit, or had poor replicative capacity compared to wildtype virus. This suggests that poorly fit resistant virus needs a sufficient level of drug pressure, likely associated with a high level of adherence in order to outcompete wildtype virus. Patients with low levels of adherence simply may not generate enough selective drug pressure to generate resistant virus.
  • So this slide presents a model of what may be happening. There is this portion of the population with near perfect adherence who are able to suppress virus below the level of detection. Presumably these individuals have fully suppressed virus and are low risk for developing resistance. On the other end there are individuals will low levels of adherence who are also at low risk for resistance because their level of adherence simply does not create enough drug pressure to develop resistant virus with poor fitness. In the middle are patients with generally high but not quite perfect levels of adherence - these are the patients who maintain enough drug pressure to generate and sustain drug-resistant mutations in HIV.
  • Transcript

    • 1. Adherence to HIV Medications: An Evidence-Based Review Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington
    • 2. Adherence
      • ” [physicians] should keep aware of the fact that patients often lie when they state that they have taken certain medicines."
      • - Hippocrates
      • “ Drugs don’t work if people don’t take them.”
            • - C. Everett Koop
    • 3. Adherence and Antiretroviral Therapy
      • Measuring Adherence
      • Why Adherence Matters
        • antiretroviral efficacy
        • development of resistance
      • Factors associated with adherence
      • Interventions to improve adherence
    • 4. How do we Measure Adherence?
      • Provider Estimates
      • Patient self-report
      • Diaries
      • Pill Count
      • Laboratory Markers
      • Electronic Devices
    • 5. Current DHHS guidelines on Initiation of Antiretroviral Therapy
        • “ The likelihood of patient adherence should be discussed and determined by the individual patient and clinician before therapy is initiated.”
        • “ Before the first prescription is written, patient ‘readiness’ to take medication should be clearly established”
      August 2001 Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents
    • 6. Clinicians’ Estimates of Adherence Not Much Better Than Random
      • Bangsberg 2001 JAIDS HAART
      • Paterson 2000 Annals Int Med HAART
      • Haubrich 1999 AIDS HAART
      • Steiner 1995 Arch Int Med AZT
      • Bosely 1995 Eur Resp J Inhaled terbutaline
      • Charney 1967 Pediatrics Penicillin
      • Caron 1978 Clin Pharmacol Anatacids
      • Gilbert 1980 Can Med Assoc J Digoxin
      • Blowey 1997 Ped Nephrology Cyclosporin
      • Mushlin 1977 Arch Int Med Hypertensive
    • 7. Provider Estimate vs.Three 3-Day Patient Report Compared to Pill Count Provider Estimate R sq = 0.26 Patient Report R sq = 0.72 Bangsberg et al JAIDS 2001:26:435 n=45 Three 3-day Self Report and Pill Count Adherence Pill Count 100 80 60 40 20 0 Patient Report 100 80 60 40 20 0 Provider Estimate and Pill Count Adherence Pill Count 100 80 60 40 20 0 Provider Estimate 100 80 60 40 20 0
    • 8. Measuring Adherence: Patient Self-Report
      • patients tend to report what they think the provider wants to hear 1
      • patients are unlikely to misrepresent high levels of adherence 3 - hence, patient-reported poor adherence is specific but not sensitive
      • patient-reported adherence tends to exceed adherence by more objective measurements, such as pill count or electronic monitoring 2
      1. DiMatteo MR, DiNicola DD, eds. Achieving Patient Compliance. New York: Pergamon Press; 1982:1-28. 2. Golin C et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95. 3. Bond W, Hussar DA, Am J Public Health 1991;81:1978-1988.
    • 9. How Do Adherence Measurement Techniques Compare to One Another? ADEPT Study; N=81 patients Adapted from Golin C et al. 1999; Miller L et al. 1999. Adherence, %
    • 10. Measuring Adherence: Patient Self-Report
      • Nevertheless, studies have documented an association between patient-reported adherence and viral outcome 1-3
      • patient-reported adherence may be a useful tool to evaluate adherence at a group level but not so much on an individual level
      1. Bangsberg DR, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 93. 2. Duong M, et al. 39th ICAAC; 1999; San Francisco. Abstract 2069 3. Demasi R, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 94.
    • 11. Measuring Adherence: Diaries
      • In theory, better than relying on memory
      • in practice, not very useful
        • many patients do not fill them in 1
        • those that do may do so immediately before office visit
      1. Golin C, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95.
    • 12. Measuring Adherence: Pill Counts
      • Advantages:
        • more objective than patient report
        • correlates better with electronic bottle caps than does self-reported adherence 1
      • Drawbacks:
        • many patients forget to bring their bottles
        • patients can still exaggerate adherence
        • time consuming
        • patients may find it too paternalistic
        • does not reveal patterns of missed doses
      1. Golin C, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95
    • 13. Measuring Adherence: Laboratory Markers
      • many antiretroviral agents associated with changes in laboratory parameters
        • AZT, d4T produce macrocytosis
        • indinavir associated with hyperbilirubinemia
        • didanosine changes urinary uric acid levels
      • drug levels could also potentially be used to monitor adherence
    • 14. Laboratory Markers to Assess Adherence: Drawbacks
      • lab markers not highly sensitive nor specific
      • do not give any information regarding the pattern of non-adherence
      • patients who take their medications immediately before having blood levels drawn could exaggerate their adherence
      • measurement of drug levels has not been standardized
      • other factors besides adherence can affect drug levels
    • 15. Measuring Adherence: Electronic Bottle Caps
      • caps harbor chips that register each time a bottle is opened or closed
      MEMScaps, Aardex Corp.
    • 16. QuickRead software, for use with MEMScaps system http://www.aardex.ch/QRCalendar.htm
    • 17. http://www.aardex.ch/QRChronology.htm QuickRead software, for use with MEMScaps system
    • 18. Measuring Adherence: Electronic Bottle Caps
      • Advantages
        • more difficult for patients to exaggerate their adherence
        • reveals patterns of non-adherence
        • studies using these devices have documented relationship between adherence & dosing
      • Disadvantages
        • too expensive for routine use outside of research studies
        • cannot be used for patients who use pillboxes
    • 19. The Future of Adherence Assessment? Computer-Assisted Self-Interviewing (CASI)
      • Advantages of CASI
        • Privacy may improve disclosure
        • Visual ARV recognition
        • Standardizes adherence assessment
        • Not personnel intensive
        • Could be administered in waiting room or at home via the web
      Bangsberg D et al. AIDS Care, 2002 (in press)
      • Purposes of CASI
        • Determine patient’s understanding of medication regimen
        • Determine patient’s adherence over 3-day period
      http://www.edermpda.com/hivadhere/
    • 20. Printed with permission from West Portal Software Corp.
    • 21. Printed with permission from West Portal Software Corp.
    • 22. Printed with permission from West Portal Software Corp.
    • 23. Printed with permission from West Portal Software Corp.
    • 24. Printed with permission from West Portal Software Corp.
    • 25. Printed with permission from West Portal Software Corp.
    • 26. Printed with permission from West Portal Software Corp.
    • 27. Printed with permission from West Portal Software Corp.
    • 28. Printed with permission from West Portal Software Corp.
    • 29. Pilot CASI Adherence Measurement
      • 111 patients, 11 providers in study
      • over 50% of patients made at least one error in describing their regimen
      • providers missed 76% of non-adherent patients
      • patients’ reports of adherence significantly associated with viral load counts
      • 65% of patients reported that CASI made them think more about how they take their medications
      Bangsberg, Bronstone & Hoffman AIDS Care 2002 (in press)
    • 30. Why is Adherence so Important for Antiretroviral Therapy? I. Efficacy II. Resistance
    • 31. Virologic Control falls sharply with diminished adherence Adherence, by prescription refill % Achieving <500 copies/mL N = 504 pts on HAART Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056 .
    • 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. 10% Adherence difference = 21% reduction in risk of AIDS Adherence and AIDS-Free Survival Bangsberg D, et al. AIDS. 2001:15:1181 Proportion AIDS-Free Months from entry P = .0012 0 5 10 15 20 25 30 0.00 0.25 0.50 0.75 1.00 Adherence O 90 – 100% O 50 – 89% O 0 – 49%
    • 34. Adherence & Drug Resistance
      • HIV Reverse Transcriptase (RT) is error-prone
      • on average, HIV RT generates one mutation in each copy of HIV produced
      • billions of HIV virions produced daily in untreated patients
      • some HIV mutations associated with drug resistance
    • 35. Sub-Optimal Adherence Predisposes to Resistance
      • Sub-optimal adherence ==> sub-therapeutic drug levels ==> incomplete viral suppression ==> generation of resistant HIV strains by selection for mutant viruses
      • association between poor adherence and antiretroviral resistance well-documented 1,2
      1. Vanhove G, et al. JAMA. 1996;276:1955-1956. 2. Montaner JS, et al. JAMA. 1998;279:930-937.
    • 36. What Contributes to Sub-Optimal Adherence?
    • 37. Reasons for Non-Adherence: Clinician vs Patient Views Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281
    • 38. Predictors of Poor Adherence
      • active alcohol 1 or substance 2 abuse
      • work outside the home for pay 1
      • depressed mood 1
      • lack of perceived efficacy of HAART 3
      • lack of advanced disease 4
      • concern over side effects 4
      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.
    • 39. Predictors of Poor Adherence, continued
      • non-caucasian race documented in some studies 1-3 but not others 5
        • association of race with adherence not found in other disease states
        • lower literacy rate a confounder? 4
      1. Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago, IL. Abstract 92. 2. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago, IL. Abstract 98. 3. Mar-Tang M, et al. J Gen Intern Med. 1999;14(suppl 2):53. 4. Kalichman SC, et al. J Gen Intern Med. 1999;14:267-273. 5. Stone VE, et al. JAIDS 2001; 28:124-131
    • 40. Predictors of Poor Adherence, continued
      • inability to fit medications into daily schedule
      • tid dosing, food requirements 1
      1. Stone VE, et al. JAIDS 2001; 28:124-131
    • 41. Other Considerations
      • a large proportion of patients incorrectly recall their medication schedules 1,2
      • Virologic control does not necessarily imply high levels of adherence 3
        • patients with virologic control despite poor adherence may not maintain durable viral suppression without improved adherence
      1. Chesney MA, International AIDS Society USA Meeting, 1998; Los Angeles. 2. Kravitz RL, et al. Arch Intern Med. 1993;153:1869-1878. 3. Kaplan A, et al. 6th Conference on Retro-viruses and Opportunistic Infections; 1999; Chicago. Abstract 96.
    • 42. Factors Associated with Higher Levels of Adherence
      • twice-daily or once-daily regimens 1,4
      • belief in own ability to adhere to regimen 1
      • not living alone 2
      • dependent on a significant other for support 2
      • history of Opportunistic Infection or Advanced HIV disease 3
      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
    • 43. 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.
    • 44. Interventions Shown to Improve Adherence to Antiretrovirals
      • medication alarms 1
      • education & counseling sessions 2,3
      • 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.
    • 45. Self-Adminstered vs Directly Observed Therapy During Incarceration Fischl et al 8 th CROI, 2001 abstract 528 p < 0.01 N = 50 in each group
    • 46. Interventions to Improve Adherence: Lessons from Other Disease States
      • addressing multiple factors most effective
      • education
      • behavioral support from other members of the health care team
      Miller et al., The AIDS Reader 10(3):177-185, 2000.
    • 47. Putting it all Together Practical Strategies to Improve Adherence
    • 48. Improving Adherence: before Initiation of Therapy
        • Assess how medications fit into patient's lifestyle
        • Consider adherence trial with jelly beans to mesh pill taking with daily schedule
        • Make contingency plans for pill taking during weekends, holidays, or other changes in routine
        • Assess adherence and barriers to adherence in a nonjudgmental manner
      Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.
    • 49. 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.
    • 50. 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
    • 51. 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
    • 52. 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
      • formal recognition of adherence as a job responsibility
      Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.
    • 53. Should Public Health Concerns about HIV Resistance Influence Prescribing Practices?
    • 54.  
    • 55. Are Non-Adherent Patients Responsible for Rising Levels of Antiretroviral Resistance? DHS/HIV/Resistance /PP From: Little SJ. JAMA 1999;282:1142-9. Little SJ. 8th Conf Retrovirus. Abstract 756 N = 108 Patients Newly HIV-Infected Phenotypic Data: 10-fold Resistance
    • 56. Adherence and Viral Load Suppression 10% adherence difference : 0.33 log VL difference Pill count percent adherence Bangsberg D, et al. AIDS. 2000:14:357 Log 10 HIV RNA copy numbers 7 0 1 2 3 4 5 6 0 10 20 30 40 50 60 70 80 90 100
    • 57. High Levels of Adherence are Required to Generate Antiretroviral Resistance Pill count percent adherence Resistant* Sensitive *Primary Drug Resistant Mutation IAS-USA Bangsberg D, et al. AIDS. 2000:14:357 Log 10 HIV RNA copy numbers 7 0 1 2 3 4 5 6 0 10 20 30 40 50 60 70 80 90 100
    • 58. Discontinuation of HAART Leads to Rapid Decline in Resistant Strains of HIV SG Deeks et al NEJM 344:472-480
    • 59. Adherence, Antiviral Activity & Risk of Resistance Mutations Increasing probability of selecting mutation Increasing Adherence Low Risk of Resistance: Inadequate Drug Pressure to Sustain Poorly Fit Virus Low Risk of Resistance: Complete Viral Suppression High Risk of Resistance: Drug Pressure Sustains Replication of Poorly Fit Virus
    • 60. Hypothesis
      • Prescribing HIV antiretroviral therapy to patients with marginal adherence will not accelerate the rise in population levels of drug resistance
        • Nonadherence is associated with insufficient drug pressure to select or sustain resistant virus
        • It is the patients with higher levels of adherence that may be generating resistant strains
    • 61. Counseling Your Patients about Adherence An Illustrative Cartoon
    • 62. How Resistance Develops to HIV
      • This is the virus known as HIV. The only thing that matters to him in his short, nasty life is to destroy T-Cells. To do this, he must somehow get over this wall.
      • The wall is created by taking anti-HIV medications. When the medicines are taken correctly, the virus is unable to climb over the wall to get to your T-cells
    • 63. Sometimes the Wall Comes Down
      • When you forget to take your evening dose, or only take 2 of your anti-HIV medicines, the strong wall comes down
      • The virus breaks free and is able to get over the wall.
      • When he gets to the other side, he discovers a way to get over the wall in the future. This is called resistance . He finds a spring that will give him a little more bounce.
    • 64. The Wall Goes Back Up
      • When you start taking the medicine regularly again, the wall goes back up.
      • Sometimes,it’s too late and the virus uses the spring to jump over the wall. At this point, it is a resistant virus The drugs may not be able to keep the wall high enough to stop the springing virus.
    • 65. Lessons to Be Learned
      • It is better to not take anti-HIV drugs at all than to take them only some of the time.
      • If you think you may be missing doses often, please tell your health care provider or pharmacist! We promise not to tell your mother.

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