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HAART: Where we’ve come, and where we’re going

HAART: Where we’ve come, and where we’re going. Jeffrey B. Greene, MD Chairperson- MCCC AIDS Institute. H.A.A.R.T. H ighly A ctive A nti- R etroviral T herapy. 1994-5: The HAART stage was set. Concorde Study ACTG studies of dual nucleosides

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HAART: Where we’ve come, and where we’re going

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  1. HAART: Where we’ve come, and where we’re going Jeffrey B. Greene, MD Chairperson- MCCC AIDS Institute

  2. H.A.A.R.T. Highly Active Anti- Retroviral Therapy

  3. 1994-5: The HAART stage was set • Concorde Study • ACTG studies of dual nucleosides • Availability of reliable tests of viral load • Link between viral resistance and success of therapy • Saquinavir- 1st of a new class of antiviral

  4. The Birth of HIV/AIDS Therapeutics

  5. Short-term Clinical Effects of HAART • Resolution of HIV-induced symptoms • Marked reduction of HIV load in plasma • Increase in CD-4 cell counts • Control of active O.I.’s (e.g.: MAC, CMV) • Reduction in the incidence of new O.I.’s • Reduction of hospital days, and need for home IV therapies/ nutrition • 50% reduction in mortality rate in NY

  6. Change in the treatment paradigm The success of therapy was assessed by laboratory outcomes, instead of clinical outcomes

  7. TREAT HARD ! TREAT EARLY!

  8. It’s the Virus, STUPID! • Frequent alterations of regimen to address “bumps” in viral load • Increasing doses of antiviral agents • Adding pharmacologic enhancers to increase blood levels of antivirals (e.g.- Indinivir + Ritonivir) • “Mega-HAART”

  9. Keeping the Goals of Therapy in Focus Successful Treatment/ At the Expense of the Patient?

  10. Limitations of Aggressive HAART • Pill burden • Food and storage restrictions • Drug- drug interactions • Severe side-effects • Reduction in Quality of Life measures • Emergence of multiple drug resistance mutations

  11. Optimal HAART Requires Optimal Adherence • Understand patient-specific issues • Deal with patient concerns • Weigh efficacy against toxicity • Build a trusting provider/ patient relationship

  12. Defining “Optimal” Adherence • 95% accuracy in dosing • e.g.- missing no more than 3/ 60 doses/ month in a b.i.d. regimen • Respecting dietary restrictions • Proper storage of medication • Avoiding co-therapies that might alter the HAART blood levels

  13. Helping Patients Juggle The Therapies • Trusting provider relationships • Ongoing patient education • Utilize entire support team • Simply regimens • Dosing reminders (pill boxes, alarms, beepers)

  14. Helping Providers Juggle the Therapies • Know what therapeut-ic response to expect • Anticipate toxicity and monitor for it • Set reasonable treat-ment goals for patient • Understand and consider drug-drug interactions

  15. ABBOTT Labs Effect of Lopinivir on Viramune- None Effect of Viramune on Lopinivir- Negligible Recommendation: No change in recommended doses Boheringer-Ingleheim Effect of Lopinivir on Viramune- None Effect of Viramune on Lopinivir- 25% reduction in levels Recommendation: Increase dose of Lopinivir Lopinivir(Kaletra™) + Neviripine (Viramune ™)

  16. Resist the urge to try the “Drug-de-Jour”

  17. Long term toxicity of HAART • Hypercholesterolemia, Hypertriglyceridemia • Diabetes mellitis • Atherosclerotic cardiovascular and cerebrovascular disease • Lipodystrophy, fat- redistribution • Lipoatrophy • Lactic acidosis • Osteoporosis

  18. Then (1998) HIV symptoms CD-4 counts < 500 HIV-1/PCR > 10K Now (2001) HIV symptoms CD-4 counts < 350 HIV-1/PCR > 20-30K Initiating HAART

  19. Reasons for changing successful HAART • Drug Toxicity (e.g.- neuropathy, pancreatitis, renal stones, diarrhea/ nausea, insomnia/ neuroirritability, lipoatrophy, fat redistribution, diabetes, lipid abnormalities) • Quality of Life issues (e.g.- conflict of schedules, privacy, refrigeration) • Fear of long-term adverse drug reactions

  20. Definition of Failing HAART • Incompatible with proper adherence • Less than a 1.5- 2.5 log drop in viral load • Rising viral load after an initial drop • Falling CD-4 counts • ? CD-4 counts that do not increase from baseline? • Continued HIV-associated symptoms

  21. Factors Favoring Mutational Drug Resistance • Rapid rate of spontaneous mutation • Low therapeutic margins of many drugs • Erratic pharmacokinetics • Cross- resistance within classes • Providers with low index of suspicion • Prior exposure to sub-optimal therapy • Long duration of HAART • Poor adherence

  22. DNA R-T Enzyme R-T Enzyme RNA RNA

  23. Tests of HIV drug resistance • Genotypic Assays • Benefits: cheaper, quicker, may detect the emergence of resistance earlier. • Draw backs: Predictive, not demonstrative • Phenotypic Assays • Benefits: Useful in highly HAART-experienced patients needing salvage, may be able to semi-quantitate resistance • Drawbacks: Long turn-around, expensive

  24. Roles of HIV-Resistance Testing • Assessment of susceptibility prior to changing HAART; • Starting therapy in a previously treated patient • Changing successful therapy (PCR > 1-2,000) • Changing a failing regimen • ? Use in choosing an initial HAART regimen in treatment naïve patients • ? Use in choosing PEP

  25. Reasons for Interruption of HAART • Patient Fatigue, lack of confidence in rx., fear of toxicity, travel • Surgical or medical conditions requiring npo • A failing regimen, while resistance studies are pending • Poor adherence and need for further patient education

  26. Strategic/Structured Treatment Interruption(STI)- Rationale • ? Enhanced HIV-specific cellular and humoral immune response? • ? Reduction of long term toxicity?

  27. Possible Effects of HAART-induced long-term survival • Neurological (e.g.- neuropathy, dementia, neuromuscular) • Neoplastic • Skeletal/ Joint • Cardiovascular (e.g.- ASHD, ASPVD, cardiomyopathy) • Endocrinologic (e.g.- thyroid, hypothalamic, adrenal)

  28. New Directions in HAART • “User Friendly” drugs- (e.g.- QD/ BID, reduced toxicity, fewer drug-drug interactions) • Optimize pharmacodynamics of existing drugs • Develop NRTI, NNRTI, PI’s with improved resistance pattern • New Classes of drugs (e.g.- Fusion inhibitors, Chemokine antagonists, integrase inhibitors, TAT protein and CD-4 antagonists, vaccines, immunostimulants)

  29. Selected HIV agents in development • Nucleosides- DAPD, Tenofovir, Emtricitabine(FTC), DOTC, GW-42086, D-D4FC • Non-nucleosides- DPC 961, DPC 083, Capravirine, Calanolide A, TMC 120 • PI’s- Tipranavir, BMS 232632, AG 1776, DMP 450, CGP61755, DPC 681, DPC 684, TMC 126

  30. Selected HIV agents in development-con’t • Fusion Inhibitors- T-20, T- 1249 • Interleukin-2 • Vaccine development- vCP1452, gp-160 • Integrase Inhibitors- DCQA/DCTA, Zintevir • Hydroxyurea-like Compds- BCX-34, mycophenolate mofetil

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