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Resistance and Adherence: The Odd Couple of HIV

Resistance and Adherence: The Odd Couple of HIV. Ernesto J. Lamadrid, MD, AAHIVS Florida/Caribbean AETC Gainesville, FL 8/11/07. Disclosure of Financial Relationships. This speaker has no significant financial relationships with commercial entities to disclose.

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Resistance and Adherence: The Odd Couple of HIV

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  1. Resistance and Adherence: The Odd Couple of HIV Ernesto J. Lamadrid, MD, AAHIVS Florida/Caribbean AETC Gainesville, FL 8/11/07

  2. Disclosure of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose. This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

  3. Antiretroviral Resistance • Decreased ability of antiretroviral agent to suppression replication of patient’s virus • Can be transmitted from a patient with a drug-resistant strain or can develop under selective drug pressure • Not an all or none phenomenon, can be relative to drug concentration

  4. What is Treatment Failure? Treatment failure can be classified as: • Virologic:a confirmed HIV RNA level >400 copies/mL after 24 weeks, >50 copies/mL after 48 weeks, or a repeated HIV RNA level >400 copies/mL after prior suppression of viremia to <400 copies/mL. • Immunologic:persistently decline on CD4 count. • Clinical:viral supression with intolerable side effects of ARV’s compromising quality of life.

  5. Types of Resistance Tests • Genotype • Phenotype • “Virtual” phenotype Hirsch MS, et al. Clin Infect Dis. 2003;37:113-128.

  6. Limitations of Resistance Testing • Lack of uniform quality controls across different laboratories • High cost compared with other tests routinely done in HIV care • Cannot be reliably performed with HIV RNA < 500-1000 copies/mL • May not be able to detect minority populations of resistant virus if they account for < 20% of the sample—especially common after drug discontinuation • Resistant strains that are in viral reservoirs also not detected DHHS Guidelines, May 2006. Devereux HL, et al. AIDS 1999;13:F123-F127.

  7. Interpreting Resistance Tests: A Step-by-Step Approach • Collect all prior resistance tests for review • Make sure current treatment, level of adherence, HIV RNA, and CD4+ cell count are known • Take each drug class individually • Start with NNRTIs • Next is NRTIs: M184V alone vs broader resistance • Finish with PIs: Is resistance present at all? If so, is cross-resistance minimal, moderate, or high? • Choose new regimen incorporating resistance data, treatment history, and results from clinical studies

  8. Resistance Testing Guidelines: Treatment-Naive Patients

  9. Resistance Testing Recommended DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 10th, 2006. www.aidsinfo.nih.gov

  10. Resistance Testing Not Recommended DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 10th, 2006. www.aidsinfo.nih.gov

  11. M Zidovudine 41 L Didanosine L T K D K 210 215 219 67 70 W YF QE N R K M L Y Stavudine 184 65 74 115 R V F V M 41 M M D K L T K Abacavir L 184 184 67 70 210 215 219 VI VI Emtricitabine Tenofovir N R W YF QE K L K K K K 65 70 74 65 65 65 E R V R R R Lamivudine Mutations Selected by nRTIs

  12. K V V V V Y Y G L Nevirapine 100 103 106 106 106 108 181 188 190 I N M M AM I CI CLH A Y K Y P Delavirdine 188 103 181 236 N C L L L K V Y Y G P Efavirenz 100 103 108 181 188 190 225 H I N I CI L SA Mutations Selected by NNRTIs

  13. A N L V V F I M I D 20 24 33 36 48 53 71 46 54 60 90 64 88 Atazanavir +/-ritonavir 32 82 LVMTA E M LMV LY VITL S ATFI IL I G 48 M I V 62 36 V ILV L I G L V V L I I V M M I A G V V I L L K L I Darunavir/ritonavir Indinavir/ritonavir 73 89 76 11 32 33 54 84 47 10 20 24 32 36 46 50 54 71 73 77 82 84 90 V S V I I F ML V V V IRV MR I I I IL V VT SA I AFT V M L K L V L M I I F I L A G V I L Lopinavir/ritonavir 10 20 24 32 33 46 47 50 53 54 63 71 73 82 84 90 MR I I F IL VA V L VLA MTS P VT S AFTS V M I 50 10 V L V M I I I G I L L 82 50 54 73 84 90 10 32 46 47 Fosamprenavirritonavir G L K G I L I I E L FIRV I IL V V LVM S V M AFTS 73 10 20 84 24 16 85 93 33 34 CSTA IFVC RMITV E V I LM V IFV Q Mutations Selected by PIs 82 FIRV

  14. M K I 62 36 43 V L G I A G I L I T L Saquinavir/ritonavir 10 48 54 71 73 84 90 24 IRV V VL VT S V M L K L M I V I L I Q T H N I Tipranavir/ritonavir 58 10 20 33 46 54 82 84 90 47 69 74 83 L D M M A V V I N L V MR F L AMV LT V M E P K D V 10 30 36 46 71 77 82 84 88 90 V V FI N I IL VT I AFTS V DS M Nelfinavir 77 82 I AFTS E I 35 13 V G Mutations Selected by PIs (cont)

  15. Case 1 • 40-yr-old man, new HIV diagnosis,antiretroviral therapy naive • Last negative test in 1999; sexually active with other men • Works in construction • CD4+ 110 cells/mm3; HIV RNA 550,000 copies/mL • Hepatitis C Ab (+) w/ normal transaminases What is your next step?

  16. New dx, ART naive

  17. Resistance Issues in Naive Patients • When should clinicians test for resistance in HIV-1-infected treatment-naive patients? • How often does transmission of resistant variants occur? • What is the best method for testing for resistant variants and how to interpret results? • What benefit is derived from the knowledge gained by resistance testing in treatment-naivepatients? clinicalcareoptions.com/hiv

  18. Resistance Issues inNaive Patients • When should clinicians test for resistance in HIV-1-infected treatment-naive patients? • How often does transmission of resistant variants occur? • What is the best method for testing for resistant variants and how to interpret results? • What benefit is derived from the knowledge gained by resistance testing in treatment-naive patients? clinicalcareoptions.com/hiv

  19. Resistance Testing in Rx-Naive Patients Should Be Done at Diagnosis 2002 New Dx 2005 Still Rx Naive

  20. Re-emergence vs Reversion ofWild-TypeVirus Selected drug resistance Re-emergence of wild-type when therapy discontinued Initial wild-type Resistant variants selected during therapy Wild-type HIV Resistant HIV Transmitted drug resistance Initial resistant Reversion toward wild-type during untreated chronic infection

  21. Considerations Regarding Testing for Transmitted Resistance • Practice setting • Lower threshold in urban areas or areas that commonly treat HIV • Patient characteristics • Infection source and antiretroviral history of source • Duration of infection • MSM may be more likely to acquire resistant variants than women or IDUs • Travel history • If CD4+ count < 100 cells/mm3 and infection duration > 10 years, resistance test unlikely to guide therapy

  22. Demographic Differences • Different prevalence in different populations • Incidence of resistant virus in SHCS by subgroup: • Women (10.4%) • Men (2.6%) • Heterosexual contact (6.1%) • Homosexual contact (11.3%) • IDU (13%) Yerly S, et al. AIDS. 2001;15:2287-2292.

  23. Resistance Issues in Naive Patients • When should clinicians test for resistance in HIV-1-infected treatment-naive patients? • How often does transmission of resistant variants occur? • What is the best method for testing for resistant variants and how to interpret results? • What benefit is derived from the knowledge gained by resistance testing in treatment-naive patients? clinicalcareoptions.com/hiv

  24. Increasing Prevalence of Resistant Virus In Newly Infected Patients: Genotypic Analysis 25 22.7 1995-1998 20 1999-2000 15.9 15 Presence of major resistance mutations (%) 10.2 9.1 10 8.5 8.0 7.3 3.8 5 1.7 0.9 0 Any ARV NRTIs NNRTIs PIs MDR Little SJ, et al. N Engl J Med. 2002;347:385-394.

  25. Resistance Issues in Naive Patients • When should clinicians test for resistance in HIV-1-infected treatment-naive patients? • How often does transmission of resistant variants occur? • What is the best method for testing for resistant variants and how to interpret results? • What benefit is derived from the knowledge gained by resistance testing in treatment-naive patients? clinicalcareoptions.com/hiv

  26. What Resistance Test to Use in Naïve Patients? • The available resistance tests are: genotype and phenotype. • The genotype identifies the mutations present in the viral genome • The phenotype grows the virus in presence of the different drugs • Genotype is the test used to measure resistance in naïve patients

  27. Resistance Issues in Naive Patients • When should clinicians test for resistance in HIV-1-infected treatment-naive patients? • How often does transmission of resistant variants occur? • What is the best method for testing for resistant variants and how to interpret results? • What benefit is derived from the knowledge gained by resistance testing in treatment-naive patients? clinicalcareoptions.com/hiv

  28. Without baseline mutation With baseline mutation Impact of Baseline Resistance on Treatment Outcome: FTC-301A Study Naive pts, baseline VL > 5000 copies/mL Incidence of Virologic Failure (%) Any NNRTI NRTI K103N Any NNRTI NRTI K103N Mutation type: FTC + ddI + EFV n = 270 d4T + ddI + EFV n = 276 Borroto-Esoda K, et al. CROI 2004. Abstract 672.

  29. Summary Points • Up to one quarter of acutely or recently infected patients have detectable drug resistance mutations • Among chronically infected patients, detectable drug resistance mutations are generally present in 5% to 10% • May reflect acquisition of HIV when transmission of resistant strains was less common, and/or back-mutation of transmitted resistant virus to WT • These rates support the use of resistance testing in treatment-naive individuals, particularly in recently infected patients • Prevalence of transmitted resistance varies by population, and may have declined in recent years

  30. NNRTIs: Important Mutations • Most common: K103N, Y181C • These also lead to NNRTI resistance: L100I, V106A, V108I, Y188L, G190A/S, P225H • Other substitutions in loci close to the above may induce NNRTI resistance

  31. Clinical Consequences of Resistance to First-Generation NNRTIs • Important points about NNRTI resistance • Extensive cross-resistance between drugs • No impairment of replication capacity or ongoing antiviral effect once resistance develops • Why resistance reports may be misleading • NVP failures often select for Y181C; EFV still active phenotypically • G190A may lead to DLV hypersusceptibility; rarely present in isolation

  32. Case 2 • 29-yr-old female, with ITP • Pretreatment lab values: CD4+ 210; HIV RNA 88,000; PLT 27K • Antiviral history • 2000: treated with ZDV/3TC + NVP, adherent during pregnancy with HIV RNA < 400; PLT > 100K • Started taking ART intermittently after her baby was born HIV negative • Returned for follow-up when she noted new rash • PE: scattered petechiae, otherwise normal; platelet count 14K; CD4+ 350; HIV RNA 45,000 What’s the next step?

  33. Current Rx: ZDV/3TC, NVP HIV RNA 45,000, CD4+ 350

  34. The Special Case of M184V • M184V emerges rapidly in nonsuppressive regimens containing 3TC or FTC • Associated with high-level phenotypic resistance to 3TC/FTC in vitro but also reduction in replication capacity, HIV RNA < baseline • Increases susceptibility to ZDV, d4T, TDF; decreases (slightly) ABC, ddI, but all NRTIs have some activity

  35. M184V Increases Susceptibility to d4T, ZDV, and TDF

  36. Which NRTI Combinations Should Be Used After M184V? • No prospective data on the optimal NRTI choice • Based on results of 3TC discontinuation studies and resistance testing, the following are likely to be most active • ZDV/3TC – TDF/FTC • TDF/ZDV – TDF/FTC/ZDV • If above cannot be used, these combinations would also retain activity • ddI/3TC – ABC/3TC • ZDV/3TC/ABC • TDF/ddI should be avoided even though both retain activity vs M184V-containing viruses

  37. Strategic Treatment Interruption (STI) “discussions on the risks and benefits of planned long-term antiretroviral treatment interruption in chronically infected patients with viral suppression. Recent data from two prospective trials showed a higher incidence of HIV disease progression and death in patients who discontinued therapy when CD4 cell counts rose above 350 cells/mm3 and who restarted when CD4 cell counts fell below 250 cells/mm3. The Panel emphasizes the need for more controlled clinical trials, using other strategies, to address the risks and benefits of treatment interruption. The Panel cautions patients and clinicians that treatment interruption should only be done in the setting of a clinical trial and under close observation.” DHHS Guidelines October 2006

  38. ADHERENCE

  39. Adherence to HAART Is Essential • “Adherence to the [HAART] regimen is essential for successful treatment and has been reported to increase sustained virologic control, which is critical in reducing HIV-related morbidity and mortality.”1 • “Conversely, suboptimal adherence has been reported to decrease virologic control and has been associated with increased morbidity and mortality. Suboptimal adherence also leads to drug resistance, limiting effectiveness of therapy.”1 • DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. • Mar 23, 2004:9. 1

  40. Assessing and Monitoring Adherence “The first principle to success is to negotiate an understandable treatment plan to which the patient can commit. Trusting relationships among the patient,clinician, and health care team managers, social workers, pharmacists, and others) are essential for optimal adherence.” DHHS Guidelines October 2006

  41. HIV Medication is Highly Effective When Taken as Directed • 100% of people in the Department of Corrections (n=42) who took all pills on time every day had an undetectable viral load by 32 weeks and out to 88 weeks 100 80 Patients Reaching Undetectable HIV RNA LOQ 400 (%) 60 40 DOT <400 SAT <400 20 0 0 4 8 16 32 48 64 72 80 88 Week Directly Observed Therapy (DOT)vs Self-administered Therapy (SAT) Fischl. 8th CROI; 2001; Chicago. Abstract 528

  42. Why Isn’t HIV Medication Always Taken As Directed? % Possible Keys to Success simplify dosing schedule decrease pill burden other Reasons given for missing antiretroviral doses (structured questionnaire) Adapted from: Gifford AL et al. JAIDS 2000; 23: 386-395

  43. Helps Adherence No Effect Hurts Adherence Patients’ Beliefs About Taking Pills Fewer Times A Day QD BID QD/BID TID/BID Dosing frequency Jordan J, et al. 5th ICDT HIV, 2000: Abst. 121.

  44. Relationship Between Adherence and HIV Suppression †Prospective, observational study of 81 HIV patients. ‡MEMS, Medication Events Monitoring System. *Series of 886 treatment-naive HIV patients; CD4 cell count <500 x 106 cells/L or plasma viral load >5000 copies/mL. 1. Low-Beer S et al. JAIDS. 2000;23:360-361. Letter. 2. Paterson DL et al. Ann Intern Med. 2000;133:21-30. 2

  45. Relationship Between Adherence and CD4 Cell Count Homer Study*1 *Observational and research study of 1522 ART-naive patients initiated on HAART; adherence was measured as prescriptions refilled. 1. Wood et al. JAIDS. 2004;35:261-268. 3

  46. Virological Response by Daily Pill Burden * Symbol size is directly proportional to weight of the data point in analysis. 1. Bartlett JA et al. AIDS. 2001;15:1369-1377. 4

  47. For every 10% decrease in adherence Adherence Impacts HIV-Related Mortality and AIDS Progression*1 *Prospective, observational study of 950 ART-naive patients treated with triple- combination therapy; adherence was estimated by prescriptions dispensed. 1. Hogg et al. 7th CROI 2000. Abstract 73. 16% increase in HIV-related mortality 1.17 times higher likelihood of progression to AIDS and/or death 5

  48. Regimen-Related Drivers of Adherence DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:12. 1. 6

  49. HAART Patients Commonly Miss Doses Due to Side Effects*1 *Community Prescription Service (CPS) phone survey of 400 people with HIV, most of whom were on triple combination therapy. 1. Munk. CPS Info Pack (suppl). POZ. 1998. 7

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