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Limitations of Antiretroviral Therapy

Limitations of Antiretroviral Therapy. Marshall J Glesby MD PhD Associate Professor of Medicine and Public Health Weill Medical College of Cornell University March 2006. Limitations of Current Antiretrovirals. Adherence Resistance Cost Drug-drug interactions Side effects. Adherence.

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Limitations of Antiretroviral Therapy

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  1. Limitations of Antiretroviral Therapy Marshall J Glesby MD PhD Associate Professor of Medicine and Public Health Weill Medical College of Cornell University March 2006

  2. Limitations of Current Antiretrovirals • Adherence • Resistance • Cost • Drug-drug interactions • Side effects

  3. Adherence • A major determinant of degree and duration of viral suppression • Poor adherence associated with virologic failure • Optimal suppression requires excellent adherence • Suboptimal adherence is common

  4. What Degree of Adherence is Needed? Data From Unboosted PIs Adherence to a PI-containing regimen correlates with HIV RNA response at 3 months 100 80 60 % VL < 400 copies/mL 40 20 0 < 70 70–-0 80-90 90–-5 > 95 PI Adherence, % (MEMS caps) Paterson DL et al. Ann Intern Med. 2000;133:21-30

  5. 109 indigent patients in San Francisco 56 unboosted PI, 53 NNRTI regimen NNRTI Regimens May Be More Forgiving of Suboptimal Adherence 100 100 PI NNRTI 80 80 60 60 % VL < 400 copies/mL 40 40 20 20 0 0 0-53 54-73 74-93 94-100 0-53 54-73 74-93 94-100 % Adherence (Electronic Measurement) % Adherence (Pill Count) Bangsberg DR et al. 12th CROI, 2005; abstract 616

  6. Predictors of Inadequate Adherence • Regimen complexity and pill burden • Poor clinician-patient relationship • Active drug use or alcoholism • Unstable housing • Mental illness (especially untreated depression) • Lack of patient education • Medication adverse effects (or fear of them) Not age, race, sex, educational level, socioeconomic status, past history of alcoholism or drug use

  7. 3-Drug Combination ART: 1996 8AM 4PM 12 MID AZT + 3TC + IDV fasting (1 hour before/2 hours after meals)1.5 liters of hydration/day

  8. 3-Drug Combination: 2006 At Bedtime TDF/FTC + EFV

  9. Improving Adherence • Establish readiness to start therapy • Provide education on medication dosing • Review potential side effects • Anticipate and treat side effects • Utilize educational aids including pictures, pillboxes, and calendars • Individualized adherence programs

  10. Limitations of Current Antiretrovirals • Adherence • Resistance • Cost • Drug-drug interactions • Side effects

  11. Mutations Occur Spontaneously in the HIV Genome • HIV makes copies of itself very rapidly ~ 1-10 billion new virus particles/day • During its replication, HIV is prone to make errors when copying itself • This results in mutations or errors in the genetic material of the virus which make the structure of the offspring virus slightly different to that of the parent virus • Some of these mutations will result in an increased ability of the virus to grow in the presence of antiretroviral drugs

  12. Partial Viral Suppression Leads to Selection of Resistant Virus • When HIV replication is not blocked completely…. • Sub-optimal therapy regimens (e.g. partially suppressive regimens) • Adherence problems • Pharmacokinetic problems: poor drug absorption, inadequate dosing, drug-drug interactions, interperson differences in PK • ….drug-resistant virus, already present in the population, is selected for and ultimately dominates

  13. Drug Levels and Resistance 1 Increased risk of side effects Drug concentration MEC (Minimum Effective Concentratin) Increased risk of resistance 0 dose dose dose dose

  14. Drug Levels and Resistance 2 Increased risk of side effects Drug concentration MEC (Minimum Effective Concentratin) Increased risk of resistance 0 missed dose late dose dose dose dose

  15. 3.0% 0.7% 0.7% CDC Surveillance of Resistance Mutations In Naive Patients • 633 newly diagnosed patients genotyped at 89 sites in 6 states in 2003-2004 • 14.5% prevalence of resistance mutations • NRTI, 7.8% • NNRTI, 3.0% • PI, 0.7% • Multiclass, 0.7% 7.8% 8 6 Prevalence (%) 4 2 0 NRTI NNRTI PI Multi Bennett D et al. 12th CROI 2005; abstract 674

  16. HAART Observational Medical Evaluation & Research Study • Pts who initiated HAART from 8/96-9/99 in B.C. • ~25% developed drug resistance mutations during 30 m of f/u • However, with 7-year f/u of lopinavir/r + d4T/3TC in naïve pts: no d4T or LPV resistance; 3% 3TC resistance Harrigan et al. J Infect Dis 2005;191:339-47 Murphy et al. EACS 2005

  17. Resistance Testing • Genotypic resistance test • Perform test that gives mutations in viral genes • Phenotypic resistance test • Perform test that describes growth of virus in the presence of anti-HIV drugs • Limitations: • Cannot detect minority species (< 10% of viral population)

  18. Multi-PI 10 46 54 82 84 90 IDV V M M M I I A G V V V I I L L L L K L 10 20 24 32 36 46 54 71 73 77 82 84 90 G IRV FIRV MR I I I IL IL VML V VT SA I AFT AFTS V V M M TPV- RTV RTV 48 L L K K V L L M M M I I A V V V I I L L V 10 10 20 20 32 33 33 36 46 46 54 54 71 77 82 82 84 84 90 90 IV FIRV MR MLT I IFV F I IL I VL V VT I AFTS AFLT V V M M SQV L G I A G V V I L 10 48 54 71 73 77 82 84 90 IRV V VL VT S I A V M NFV L D M M A V V I N L 10 30 36 46 71 77 82 84 88 90 FI N I IL VT I AFTS V DS M APV L K L V L M I I F I L A G V I L L V M I I I I G I I L V LPV-RTV 10 20 24 32 33 46 47 50 53 54 63 71 73 82 84 90 50 50 54 73 84 84 90 10 10 32 46 47 20 24 33 36 48 32 FIRV I IL V V L LVM S V V M FIRV MR I I F IL VA V L VLMTS P VT S AFTS V M A N G V L K L L M V M I L I 71 73 88 46 54 90 10 20 24 33 36 ATV 32 82 V CSTA S A I L M IFV RMI I IFV ILV I Mutations Selected by PIs <www.iasusa.org>

  19. Genopheno: An Example RT: Q102K, D123E, I142V, C162S, V179I, T200A, I202V, R211Q, R277K, T286P, E297A PR: K14R, I15V, M36A, R41K, K55R, I62V, I66L, G68E, H69Y, K70KIK, I93L

  20. Recommendations for Resistance Tests Clinical Setting Recommended • Virologic failure • Suboptimal virologic suppression • Acute HIV infection Consider • Chronic HIV infection prior to starting ART Not generally recommended • >4 weeks after ART drugs are stopped • Viral load levels <1000 cpm DHHS Guidelines, 4/7/05

  21. Antiretroviral Resistance: Conclusions • HIV growth leads to diversity. • Not suppressing viral load levels in the presence of antiretroviral drugs leads to resistant virus. • HIV drugs have unique resistance patterns, but cross-resistance may occur. • Resistance testing offers benefits in choosing the next drug combination.

  22. Limitations of Current Antiretrovirals • Adherence • Resistance • Cost • Drug-drug interactions • Side effects

  23. Metabolism of PIs/NNRTIs • Metabolized by cytochrome P450, especially CYP 3A4 • Levels of PIs and NNRTIs may be affected by concurrently administered drugs • PIs, especially ritonavir, inhibit CYP 3A4 potentially leading to increased levels of concurrently administered drugs • Efavirenz and nevirapine can induce and inhibit CYP 3A4 • Fewer drug-drug interactions with NRTIs

  24. Drug Interactions with ARVs: Dose Modification or Cautious Use • Oral contraceptives (may require second method) • Methadone • Erectile dysfunction agents • Herbs - St. John’s wort • Lipid-lowering agents • Anti-mycobacterials, especially rifampin • Psychotropics – midazolam, triazolam • Ergot Alkaloids • Antihistamines – astemizole • Anticonvulsants

  25. Limitations of Current Antiretrovirals • Adherence • Resistance • Cost • Drug-drug interactions • Side effects

  26. Treatment-Limiting Side Effects Reasons for treatment switch / discontinuation of 1st HAART regimen • Cohort data from pts on older PI-based HAART regimens (e.g. IDV, NFV) indicated that 20-25% or more stopped or changed their 1st regimen due to side effects • Appears to be less frequent with current regimens • Rate of life-threatening adverse events exceeded AIDS events among ~3,000 pts in 5 multicenter trials Virologicalfailure 14.1% Toxicity58.3% n = 312 Non-adherence19.6% Other 8.0% Monforte A et al. AIDS 2000;14:499-507d'Arminio MA et al. AIDS 2000; 14:499-507O'Brien ME et al. JAIDS 2003; 34:407-14Reisler RB et al. JAIDS 2003; 34:379-86

  27. Adverse Effects of NRTIs* • Zidovudine (AZT)- headache, GI intolerance, bone marrow suppression • Abacavir - hypersensitivity reaction • Didanosine (ddI) - GI intolerance, pancreatitis, peripheral neuropathy • Stavudine (d4T) - peripheral neuropathy, pancreatitis, lipoatrophy • Zalcitabine (ddC) - peripheral neuropathy, oral ulcers • Lamivudine (3TC) – rare side effects • Emtricitabine (FTC) – side effects uncommon; hyperpigmentation of palms/soles < 2% (non-Whites) • Tenofovir - headache, GI intolerance, renal insufficiency *Lactic acidosis is a class effect, most strongly associated with d4T/ddI; 3TC, FTC, and tenofovir are active against HBV. Development of HBV resistance may lead to flare of hepatitis.

  28. Adverse Effects of NNRTIs • Rash, including Stevens-Johnson syndrome with nevirapine • Elevated liver enzymes (nevirapine > efavirenz, delavirdine) • Incidence of hepatotoxicity highest in women with pre-nevirapine CD4 counts >250 cells/mm3 and men with >400 cells/mm3 • Efavirenz - neuropsychiatric, teratogenic in primates (FDA Pregnancy Class D)

  29. Acute Adverse Effects of PIs • GI intolerance, diarrhea • Hyperbilirubinemia –atazanavir, indinavir • Hepatotoxicity • Increased bleeding in hemophiliacs • Adverse metabolic effects • Dyslipidemia • Insulin resistance • ? Lipodystrophy/fat redistribution • Atazanavir has favorable metabolic profile

  30. Adverse Effects of Entry Inhibitors • Enfuvirtide (T-20) • Injection-site reactions • Hypersensitivity reaction • Increased incidence of bacterial pneumonia

  31. Bone Disorders Mitochondrial toxicity Metabolic Complications of HIV/Antiretroviral Therapy • One syndrome or several? • One etiology or multifactorial? Disordered glucose metabolism Lipid abnormalities Body fat redistribution

  32. Multifactorial Etiology of Dyslipidemia Traditional risk factors HIV-related factors Familial hypercholesterolemia; obesity ↑ TGs, ↓ HDL, ↓ total chol, ↓ LDL in untreated advanced HIV Antiretroviral-related factors Most PIs & d4T: ↑ TGs, ↑ total chol, ↑ LDL; NNRTIs: ↑ total chol, ↑ HDL; EFV: ↑ LDL

  33. Cardiovascular and cerebrovascular events (CVE) in the D:A:D Study Incidence of CVE according to duration of ART exposure • Follow-up of ongoing, prospective, multinational cohort study1 • 36,151 pt-years follow up • Endpoints include documented: • Myocardial infarction (n=127) • CAD on angiography (n=42) • Stroke (n=30 ) • Estimation of theincidence of MI based upon the Framingham algorithm2 • Observed rate exceeded predicted rate by approximately 25% 12 10 8 6 4 2 0 Incidence/1000 PY (95% Cl) Test for trend p<0.00001 ART exposure (yrs) None <1 1-2 2-3 3-4 >4 Total Events 7 15 22 30 49 76 199 PYFU 5711 4139 4795 5841 7210 8456 36151 http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof Law MG et al. 11th CROI 2004; abstract 737

  34. Disordered Glucose Metabolism • Prevalence of diabetes mellitus increased among HIV+ pts on protease inhibitors • Prevalence ~2-14% • Insulin resistance (higher concentrations of insulin required for usual effects) more common • MACS: Risk of new onset DM ~ 4 x higher in HIV+ men vs. HIV- men (adjusted for age, BMI) Dube M Clin Infect Dis 2000; 31:1467-75 Brown TT et al. Arch Intern Med 2005;165:1179-84

  35. Carr A Cooper DA. N Engl J Med 1998;339:1296

  36. Abdominal MRI Scans Control subject Increased Visceral Fat

  37. “Lipodystrophy Syndrome” • No generally accepted case definition of syndrome(s) • Initial reports suggested clustering of: • Central fat accumulation/adiposity • Lipoatrophy/fat wasting • Dyslipidemia • Insulin resistance/type 2 diabetes mellitus • Recent cross-sectional epidemiological data question linkage of lipoatrophy and fat accumulation Fram J Acquir Immune Defic Syndr 2005;40:121-131

  38. HIV infection Potential Etiologies Antiretroviral therapy Host factors Hormonal influence Etiology? Mitochondrial dysfunction Immune dysregulation Non-HIV causes

  39. Prometheus Study: d4T & Clinician Reported Lipodystrophy 1.00 SQV/RTV P = 0.003 0.75 SQV/RTV/d4T 0.50 Lipodystrophy-free survival 0.25 0.00 48 0 12 24 36 60 72 84 96 Time (weeks) n = 87 85 82 n = 88 88 75 No. of patients not reported at 96 weeks van der Valk M, et al. AIDS 2001; 15:847–855

  40. Role of Different NRTIs on Morphologic Changes: Change in Limb Fat (A5005) N=156; analysis by intent to treat 3TC/ZDV ddI+d4T 20 † † 10 † † IQR 0 Median % change from baseline * † -10 † * * -20 -30 Entry 16 32 48 64 80 Study Week *P<0.05 between groups; †P<0.05 within groups. Dube M, et al. 4th Lipo Wkshp 2002; abstract 27

  41. Dube MP et al. AIDS 2005;19:1807-18

  42. MITOX: Limb Fat over 18 months HIV-infected patients with moderate to severe lipoatrophy 1.29 kg (36%) Mean change (kg) 0.55 kg (15%) 0.16 kg (4%) Week n= ABC 47 42 35 33 ABC week 24 23 19 15 13d4T or ZDV 29 25 22 19 Martin A et al. AIDS 2004; 18:1029

  43. TDF + 3TC + EFV d4T + 3TC + EFV *p < 0.001 Will Non-Thymidine Analog Based RegimensPrevent Lipoatrophy? Gilead 903 Study 10 9 8.6* 7.9* 8 7 6 Kilograms 5.0 5 4.5 4 3 2 1 0 48 96 144 Weeks TDF + 3TC + EFV 128 115 d4T + 3TC + EFV 134 117 Gallant JE et al. JAMA 2004;292:191-201

  44. Cardiovascular Risk Factors in Lipodystrophy • Compared with age and BMI matched controls from the Framingham Offspring Study, HIV+ pts with self-reported lipodystrophy had: • higher prevalence of impaired glucose tolerance/diabetes • higher diastolic blood pressure • elevated triglycerides, total cholesterol (not LDL-C) • lower HDL-C • increased PAI-1 and tPA (markers of impaired fibrinolysis-- ability to break down blood clots ) • Some pts with lipodystrophy appear to have a metabolic syndrome that theoretically could predispose to accelerated atherosclerosis and diabetes Hadigan et al, Clin Infect Dis2001;32:130 Hadigan et al, JCEM 2001;86:939-43

  45. Osteopenia/Osteoporosis • Decreased bone mineral density (BMD) initially reported in HIV+ on PIs (plus NRTIs) • Subsequent reports of higher prevalence of decreased BMD in ARV naïve pts and increases in BMD while on PI-containing HAART • Multifactorial etiology: HIV, cytokines, endocrine factors, liver disease, smoking, ? antiretrovirals Tebas P et al, AIDS 2000;14:F63-7 Mondy K et al, Clin Infect Dis 2003 ;36:482-90

  46. Osteonecrosis • Avascular necrosis = aseptic necrosis = osteonecrosis • death of cellular constituents of bone & marrow due to ischemia (decreased blood supply) • Associated with corticosteroid use, possibly duration of antiretroviral therapy & immune recovery • Most commonly presents as hip pain • MRI is test of choice if symptoms suggest dx • Conservative management for early stages of disease • Surgery • total hip replacement vs. core decompression Allison et al, AIDS 2003;17:1-9

  47. Conclusions • Adherence, resistance, drug-drug interactions, and side effects (short- and long-term) are important limitations of antiretroviral therapy • Regimen choices usually based on potential advantages/options • Decreased dosing frequency and pill burden • Tolerability • Pharmacokinetic profiles • Resistance considerations • Improved metabolic profiles

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