Transcript 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.
Highly
Active
AntiRetroviral
Therapy
1994-5: The HAART stage
was set
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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
The Birth of HIV/AIDS Therapeutics
Number of Available Agents
16
14
12
10
8
6
4
2
0
1987 1989 1991 1993 1995 1997 1999
Lopinivir
Amprenavir
Abacavir
Efavirenz
Delavridine
Neviripine
Nelfinivir
Indinivir
Ritonivir
Saquinivir
DDC
D4T
3TC
DDI
AZT
Short-term Clinical Effects of
HAART
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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
The success of therapy was assessed
by laboratory outcomes, instead of
clinical outcomes
TREAT HARD !
TREAT EARLY!
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
Successful
Treatment/ At the
Expense of the
Patient?
Limitations of Aggressive
HAART
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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
• Understand patientspecific issues
• Deal with patient
concerns
• Weigh efficacy against
toxicity
• Build a trusting
provider/ patient
relationship
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
• Trusting provider
relationships
• Ongoing patient
education
• Utilize entire support
team
• Simply regimens
• Dosing reminders (pill
boxes, alarms, beepers)
Helping Providers Juggle the
Therapies
• Know what therapeutic response to expect
• Anticipate toxicity and
monitor for it
• Set reasonable treatment 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
Resist the urge to try
the
“Drug-de-Jour”
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
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
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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
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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
R-T Enzyme
R-T Enzyme
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 HAARTexperienced patients needing salvage, may be
able to semi-quantitate resistance
– Drawbacks: Long turn-around, expensive
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
• 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
• ? Enhanced HIV-specific cellular and
humoral immune response?
• ? Reduction of long term toxicity?
Possible Effects of HAARTinduced 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
• “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
• Nucleosides- DAPD, Tenofovir,
Emtricitabine(FTC), DOTC, GW-42086, DD4FC
• 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
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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
For more HIV-related resources,
please visit www.hivguidelines.org