haart: where we’ve come, and where we’re going

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

Jeffrey B. Greene, MD

Chairperson- MCCC

AIDS Institute

H.A.A.R.T.

Highly

Active

Anti-

Retroviral

Therapy

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

The Birth of HIV/AIDS Therapeutics

0

2

4

6

8

10

12

14

16

Number of Available Agents

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

• 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 HARD ! TREAT EARLY!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

• 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 patient-specific 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 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

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

• 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

• 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

RNA

RNAD

NA

R-T EnzymeR-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 HAART-experienced

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 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

• “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, 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

• 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