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HIV: Optimizing Antiretroviral Therapy

HIV: Optimizing Antiretroviral Therapy. Dr Christopher KC Lee Infectious Diseases Unit Department of Medicine Sungai Buloh Hospital Malaysa. Therapeutic Goal of HAART. CD4+ T-cells. Relative Levels. Plasma HIV Viremia. ? Long term durability. Viral Load: Limit of detection. Months.

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HIV: Optimizing Antiretroviral Therapy

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  1. HIV: Optimizing Antiretroviral Therapy Dr Christopher KC Lee Infectious Diseases Unit Department of Medicine Sungai Buloh Hospital Malaysa

  2. Therapeutic Goal of HAART CD4+ T-cells Relative Levels Plasma HIV Viremia ? Long term durability Viral Load: Limit of detection Months Years After HIV Infection Acute HIV infection Symptom

  3. Declining morbidity & mortality among patients with advanced HIV infection 100 75 50 ARV therapy including protease inhibitors Deaths per 100 person yrs 25 0 ‘94 ’95 ‘96 ‘97 Pallella FJ et al, HIV Outpatient Study Investigations, N Engl J Med 1998; 338:853-860

  4. 20 countries with the highest ARV need Sudan China TARGET MET Botswana People receiving ARV therapy Russian Federation Cameroon As of June 2004 Côte d'Ivoire June to December 2004 Uganda TARGET MET Thailand January to June 2005 Malawi Zambia People still needing treatmentto reach "3 by 5" target Republic of Congo Mozambique Kenya Ethiopia Tanzania TARGET MET Brazil Zimbabwe Nigeria India South Africa 0 50K 100K 150K 200K 250K 300K 350K 400K 450K 500K The Global Goal:Progress Toward "3 by 5" Targets WHO 2005

  5. ART Care (n = 7979) 7000 6000 5000 4000 Rwanda 3000 Kenya 2000 Tanzania 1000 Mozambique South Africa 0 Antiretroviral Access in Resource-Limited Countries • Enrollment in Columbia University-PEPFAR supported programs increasing Total in care (n = 23,177) 7000 Mozambique 6000 Rwanda 5000 Kenya People enrolled 4000 3000 South Africa 2000 Tanzania 1000 0 Sep- Oct- Nov- Dec- Jan- Feb- Mar- Sep- Oct- Nov- Dec- Jan- Feb- Mar- 04 04 04 04 05 05 05 04 04 04 04 05 05 05 Nash D, et al. IAS 2005. Abstract MoOa0206.

  6. NRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Zalcitabine DDC Tenofovir TDF NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP Protease Inhibitor Amprenavir APV Atazanavir ATV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV soft gel SGC hard gel HGC tablet INV Tipranavir TPV Darunavir DRV Fusion Inhibitor Enfuvirtide T-20 Current Antiretroviral Medications ARVS available in Malaysia 5/2006

  7. M’sian ARV Guidelines 2004 Triple ARV Treatment 2 NRTI + NNRTI /Boosted PIs Non-Thymidine Analog NNRTI (EFV, *NVP) or Boosted PIs Thymidine Analog + + AZT d4T 3TC ddI Objective: Maximal HIV viral suppressionfor the longest duration

  8. Clinical Category CD4 Count Viral Load Recommendat-ions Symptomatic AIDS defining illness Severe Symptoms * Any value Any value Treat Asymptomatic < 200/mm3 Any value Treat Asymptomatic >200 but < 350/mm3 Any value Treatment recommended Asymptomatic > 350/mm3 > 50,000 copies/ml Treatment may be considered Recommendations on when to commence HAART(MOH, Malaysia 2004)

  9. Approval & Accessibility of Antiretrovirals: ATV FPV ENF FTC Last ARV registered in Malaysia DRV TPV 25 20 LPV/RTV TDF APV EFV ABC Antiretrovirals 15 NFV DLV RTV IDV NVP 10 SQV 3TC d4T 5 ddC ddI ZDV 0 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Year

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

  11. 0 How Drug Resistance Arises How drug resistance arises. Richman, DD. Scientific American , July 1998

  12. 0 How does resistance develop? Continuation of a failing ART regimen after early resistance has developed, selects for expansion of resistance

  13. 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

  14. 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

  15. 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

  16. 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

  17. 3-Drug Combination: 2006 At Bedtime TDF/FTC + EFV

  18. 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

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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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)

  26. 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>

  27. 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

  28. 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

  29. 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.

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

  31. 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

  32. 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

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

  34. 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

  35. 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.

  36. Adverse Effects of NNRTIs • Rash, including Stevens-Johnson syndrome with nevirapine • Elevated liver enzymes (nevirapine > efavirenz) • 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)

  37. 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

  38. 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

  39. 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

  40. 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

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

  42. Abdominal MRI Scans Control subject Increased Visceral Fat

  43. “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 Fram J Acquir Immune Defic Syndr 2005;40:121-131

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

  45. 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

  46. 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

  47. 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

  48. 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

  49. Thank You “Persistence is what makes … The Impossible Possible The Possible Likely And the Likely Definite” Robert Half

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