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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

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

Jeffrey B. Greene, MD

Chairperson- MCCC

AIDS Institute

h a a r t
H.A.A.R.T.

Highly

Active

Anti-

Retroviral

Therapy

1994 5 the haart stage was set
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
short term clinical effects of haart
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
change in the treatment paradigm
Change in the treatment paradigm

The success of therapy was assessed by laboratory outcomes, instead of clinical outcomes

it s the virus stupid
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”
keeping the goals of therapy in focus
Keeping the Goals of Therapy in Focus

Successful Treatment/ At the Expense of the Patient?

limitations of aggressive haart
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
optimal haart requires optimal adherence
Optimal HAART Requires Optimal Adherence
  • Understand patient-specific issues
  • Deal with patient concerns
  • Weigh efficacy against toxicity
  • Build a trusting provider/ patient relationship
defining optimal adherence
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
helping patients juggle the therapies
Helping Patients Juggle The Therapies
  • Trusting provider relationships
  • Ongoing patient education
  • Utilize entire support team
  • Simply regimens
  • Dosing reminders (pill boxes, alarms, beepers)
helping providers juggle the therapies
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
lopinivir kaletra neviripine viramune
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 ™)
long term toxicity of haart
Long term toxicity of HAART
  • Hypercholesterolemia, Hypertriglyceridemia
  • Diabetes mellitis
  • Atherosclerotic cardiovascular and cerebrovascular disease
  • Lipodystrophy, fat- redistribution
  • Lipoatrophy
  • Lactic acidosis
  • Osteoporosis
initiating haart
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
reasons for changing successful haart
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
definition of failing haart
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
factors favoring mutational drug resistance
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
slide22

DNA

R-T Enzyme

R-T Enzyme

RNA

RNA

tests of hiv drug resistance
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
roles of hiv resistance testing
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
reasons for interruption of haart
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
strategic structured treatment interruption sti rationale
Strategic/Structured Treatment Interruption(STI)- Rationale
  • ? Enhanced HIV-specific cellular and humoral immune response?
  • ? Reduction of long term toxicity?
possible effects of haart induced long term survival
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)
new directions in haart
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)
selected hiv agents in development
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
selected hiv agents in development con t
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