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February 12, 2009

February 12, 2009 International Perspectives of Adherence and Resistance to HIV Antiretroviral Therapy David Bangsberg, MD, MPH.

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February 12, 2009

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  1. February 12, 2009 International Perspectives of Adherence and Resistance to HIV Antiretroviral Therapy David Bangsberg, MD, MPH

  2. Will “widespread, unregulated access to antiretroviral drugs in sub-Saharan Africa, lead to the rapid emergence of drug resistant viral strains, spelling doom for the individual, curtailing future treatment options, and [leading] to transmission of resistant virus?” “Preventing antiretroviral anarchy in sub-Saharan Africa” Harries et al Lancet 2001; 358:410-4.

  3. Bell-shaped Adherence and Resistance Curve Inadequate Drug Pressure To Select Resistant Virus Complete Viral Suppression Drug Pressure Selects Resistant Virus Increasing probability of selecting mutation Increasing Adherence

  4. Adherence and Prospective Accumulation of Drug Resistance Mutations in The REACH Cohort Outcome: # IAS-USA primary or secondary drug resistant mutations at Genotype #2 not present at Genotype #1 >7 mo HAART w/o change in regimen 6 mo HAART >1mo HAART >3 mo pill count Genotype #1 VL>50 copies Genotype #2 VL >50 copies Bangsberg et al AIDS 2003:17:1325

  5. New Drug Resistance Mutations Over 6 Months in by Adherence Quintile in Viremic PatientsREACH Cohort n=57 p=0.0002 #New DRM Bangsberg et al AIDS 2003:17:1325

  6. Proportion VL>50 copies/ml by Adherence QuintileREACH Cohort n=148 p=<0.0001 Proportion VL>50 Bangsberg et al AIDS 2003:17:1325

  7. Resistance Risk by Adherence and Regimen Class Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.

  8. Ritonavir Boosted PIs Lead to Better Viral Suppression at Moderate Adherence LevelsViral Suppression <50 copies/ml for RTV Boosted and Unboosted PI P=0.04 N=67 N=46 N=83 n=71 Bangsberg et al Int Conference on Adherence to HIV Treatment 2007

  9. Resistance Risk by Adherence and Regimen Class Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.

  10. Why NNRTI Might Have A Different Adherence-Resistance Relationship • NNRTI potent and exert high selective pressure • NNRTI act distant to the active site – little impact on fitness • NNRTI resistance seen with single dose therapy

  11. NNRTI Lead to Better Viral Suppression (<400 copies/ml) than Unboosted PIs at Moderate Electronic Medication Monitor Adherencen=65 p=0.01 Bangsberg CID 2006:43:939-41

  12. Prevalence of NNRTI Resistance by AdherenceBangsberg AIDS 2006 20:223-232 N=54

  13. Resistance Risk by Adherence and Regimen Class Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.

  14. Subjects selecting for viral mutations (NN = any mutation; PI =  1 major or  3 minor) Percent of patients selecting for mutations at by adherence level % Adherence Maggiolo et al HIV Clin Trials. 2007 Sep-Oct;8(5):282-92.

  15. Resistance Risk by Adherence and Regimen Class Bangsberg et al J. Antimicrob Chem; 2002 53(5):696-9.

  16. Replicative Capacity HIV PR and RT Sequences Purify Viral RNA AAAA RT-PCR AAAA AAAA Patient Plasma PR-RT Transfection Luciferase Luciferase + + Pool of Patient-Derived Recombinant Viruses Containing Luciferase A-MLV env

  17. Luciferase Activity (Replication) of Sensitive “Wild-Type” Virus Decreases at Higher Drug Levels 10,000,000 WT Control (NL4-3) 1,000,000 100,000 Luciferase 10,000 1,000 100 0 1 10 100 1,000 Drug concentration, nM

  18. Replication of Sensitive vs. Resistant Virus 10,000,000 WT Control (NL4-3) Resistant (pt-derived) 1,000,000 100,000 Luciferase 10,000 1,000 100 0 1 10 100 1,000 Drug concentration, nM

  19. 10,000,000 WT Control (NL4-3) 100 Resistant (pt-derived pol) Resistant virus favored Resistance:WT >1 1,000,000 10 High RC 100,000 Luciferase Resistant:WT ratio 1 Wildtype virus favored Resistance:WT <1 10,000 0.1 Low RC 1,000 0.01 0 1 10 100 1,000 (nM) Drug concentration 100 1 10 100 1,000 0 Sensitive HIV is More Fit than Resistant HIV at Lower Drug Concentrations and Becomes Less Fit at Higher Drug Concentration Comparing Resistant Subject Isolates With Sensitive Reference Strain Resistant : Wildtype Replication Ratio Bangsberg et al AIDS 2006 20:223-232

  20. Methods Derive average resistant/WT fitness curve Convert adherence adjusted predicted in vivo concentrations to comparable in vitro concentrations Bangsberg et al. AIDS 2006; 20:223-231

  21. Level of adherence above which the resistant virus is more fit than the wild-type virus is ~ 2% for efavirenz and nevirapine and ~ 85% for nelfinavir Bangsberg et al. AIDS 2006; 20:223-231

  22. Antiretroviral therapy in AfricaWarren Stevens, Steve Kaye, Tumani Corrah BMJ  2004;328:280-282 [In sub-Saharan Africa]….the potential short term gains from reducingindividual morbidity and mortality may be far outweighed bythe potential for the long term spread of drug resistance…. In Africa, a higher proportionof patients are likely to fall into the category of potentialpoor adherers unless resource intensive adherence programmesare available.

  23. Adherence to HIV Therapy in the Industrialized North

  24. Mbarara, Uganda

  25. Adherence in Patients Purchasing Generic D4T/3TC/NVP in UgandaN=36 Oyugi et alJAIDS 2004 36:1100-1102

  26. Meta-Analysis of Barriers to Adherence in Africa and North AmericaMills and Bangsberg JAMA 2006:296:679-690 • Systematic review of adherence • 28,689 patients in 228 studies • North America • Brazil, Uganda, Cote d’Ivoire, South Africa, Malawi, Bostwana, Costa Rica, Romania Resource-Rich Country Summary 54.7% (95CI: 48.0-61.3%) Resource-Poor Country Summary 77.1% (95CI:67.3%-85.6%)

  27. UARTO Adherence Over 12 Months on Free ARV Therapy n=274Bangsberg et al CROI 2008

  28. A Social Model of Adherence for sub-Saharan Africa Ware and Bangsberg PLoS Medicine (in press) Improving Health

  29. A Social Model of Adherence for sub-Saharan Africa Ware and Bangsberg PLoS Medicine (in press) Improving Health Resource Scarcity Resource Scarcity

  30. A Social Model of Adherence for sub-Saharan Africa Ware and Bangsberg PLoS Medicine (in press) Improving Health Resource Scarcity Resource Scarcity

  31. A Social Model of Adherence for sub-Saharan Africa Ware and Bangsberg PLoS Medicine (in press) Improving Health Resource Scarcity Resource Scarcity

  32. A Social Model of Adherence for sub-Saharan Africa Ware and Bangsberg PLoS Medicine (in press) Improving Health Resource Scarcity Resource Scarcity

  33. A Social Model of Adherence for sub-Saharan Africa Ware and Bangsberg PLoS Medicine (in press) Improving Health Social Structural: Patterns of Inequality, e.g., stigma, gender inequality Individual: HIV knowledge Med side effects Cognitive function Mental health Alcohol Use Resource Scarcity Resource Scarcity Infrastructural: Few treatment sites Distance to care Cost/Availability of Transportation Cultural: Religious Beliefs Respect for Authority Importance of having children

  34. Triomune D4T/3TC/Nevirapine17 USD per month

  35. MONOTHERAPY Stopping drugs with different half lives Last Dose Day 1 Day 2 Drug concentration IC90 Zone of potential replication IC50 12 0 24 36 48 Time (hours) S. Taylor et al. 11th CROI Abs 131

  36. NNRTI Resistance and Treatment DiscontinuationParienti et al CID 2004:38:1311-6 No. patients at Risk ≤1 drug holiday 52 47 38 30 19 4 >= 2 drug holidays 19 17 13 10 6 1

  37. Frequency and Duration of Treatment Interruptions >48hrs over 24 weeks on Self-pay ARTOyugi and Bangsberg AIDS 2007

  38. Frequency and Duration of Treatment Interruptions >48hrs over 24 weeks on Self-pay ARTOyugi and Bangsberg AIDS 2007 Correlates: Financial difficulty securing ARVs and pharmacy stockouts

  39. Frequency and Duration of Treatment Interruptions >48hrs over 24 weeks on Self-pay ARTOyugi and Bangsberg AIDS 2007 Correlates: Financial difficulty securing ARVs and pharmacy stockouts 90% of all missed doses occur during an interruption

  40. MEMS-Defined 48 Hour Treatment Interruptions Predict Resistance to Self-pay ART in UgandaOyugi and Bangsberg AIDS 2007 P=0.04

  41. Longer interval of treatment discontinuation in days + Controls O Cases Estimated 95% confidence interval Duration of MEMS Defined Treatment Interruption and Probability of NNRTI ResistanceParienti and Bangsberg PLoS One 2008 n=72 Estimated probability of viral control

  42. Kesselrling et al Maximum Capacity of Restoration of CD4 Counts is Lower in Patients from Sub-Saharan Africa CROI 2008 poster 817

  43. Blunted CD4 Response in sub-Saharan Africa • Treatment interruptions • Sub-clinical viral replication in gut lymphoid tissue • Bacterial translocation • Immunologic stimulation • Overt virologic failure and ART resistance • Treatment interruption prevention

  44. Africans “don’t know what Western time is,”and “do not know what you are talking about,” when asked to take drugs at specific times. Andrew Natsios USAID Administrator

  45. How to Take ARVs on Time in Rural Uganda Without a Watch: John’s Adherence StoryMaier, Mwebesa, Emenyonu, Pepper, BangsbergPLOS 2006 • No education • Works as a farmer. • Lives with his brother, sister-in-law, and three nieces in a three room mud-walled house without electricity. • Owns a lantern, bed, sofa, bike, and a radio, but no watch. • HIV in April 2005 and started generic D4T/3TC/NVP (Triomune) after disseminated herpes zoster and Kaposi’s sarcoma • CD4 count of 151

  46. Electronic medication monitor record of time of bottle openings for am and pm doses.

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