Title: Dr' Elizabeth'K'E'
1Highly Active Antiretroviral Therapy (HAART)
- Dr. Elizabeth.K.E.
- Dept. of Pediatrics
- MEDICAL COLLEGE
- Trivandrum
2Natural History of HIV Infection Without the Use
of Antiretroviral Therapy
Primary Infection
Death
Acute HIV syndrome Wide dissemination of
virus Seeding of lymphoid organs
1200 1100 1000 900 800 700 600 500 400 30
0 200 100 0
OpportunisticDiseases
Clinical latency
HIV/RNA Copies per ml Plasma
Constitutional Symptoms
CD4 T Lymphocyte Count (cells/mmm3)
0 3 6 9 12
1 2 3 4 5
6 7 8 9 10
11
Years
Weeks
Source Fauci et al 1996.
3Plasma Viral Load - Prognosis
4CD4 Cell Counts and Opportunistic Infections
5Relating Disease Progression to Plasma HIV-1 RNA
Level and CD4 Cell Count
Viral Load
1,000
100
10,000
200
100,000
300
400
1000
900
800
700
600
500
CD4 COUNT
Adapted with permission from Coffin. AIDS.
199610(suppl 3)S75-S84.
6Incidence of Selected OI in Patients with HIV
Infection, 1992 - 1997, Based on a Cohort Study
Kovacs, J. A. et. al. N Engl J Med
20003421416-1429
7Goals of Antiretroviral Therapy
- Maximal durable suppression of viral
replication - Preservation and/or restoration of immunologic
functions - Improvement of QOL
- Reduction of HIV-related morbidity mortality
8Goals of Therapy
- Eradication of HIV? Not yet
- in spite of plasma RNA below detection there is
evidence of genetic evolution in reservoirs.
9Current Ultimate Goal of HAART
CD4 T-cells
Relative Levels
Plasma HIV Viremia
Limit of detection
Months
Years After HIV Infection
Acute HIV infection Symptom
10Increasing Choices for HIV Therapy
11Evolution of Antiretrovirals
- Year Generic Name Key Clinical Trial
- 1987 AZT
- 1991 ddI
- 1992 ddC
- 1994 d4T
- 1995 3TC, SQV (hgc) ACTG 175, Delta
- 1996 RTV, IDV, NVP ACTG 320
- 1997 NFV, DLV, AZT/3TC, SQVsgc
- 1998 EFV
- 1999 ABC, APV
- 2000 Lopanavir/r, TrizivirTM
12Antiretroviral TherapyA Historical Perspective
1994 Dual Therapy
1997 HAART
1987 AZT Monotherapy
0
0
-0.5
-0.5
-1
-1
-1.5
-1.5
HIV RNA change (log10 c/mL)
-2
-2
-2.5
-2.5
-3
-3
24-week response
24-week response
24-week response
Fischl, NEJM, 1987 Katzenstein, NEJM, 1996
Eron, NEJM, 1995Hammer, NEJM, 1996
Gulick, NEJM, 1997 Cameron, Lancet, 1998
13Progression to AIDS/Death
No therapy
Mono-therapy
Dual-therapy
of patients progressing
Triple therapy
Months
JAMA 1998 CMAJ 1999
14Highly Active Antiretroviral Therapy (HAART)
- Combination of different classes of
antiretrovirals - to achieve maximal (below level of detection) and
most durable suppression of viral replication - prevent emergence of drug resistant mutants
- to improve survival quality of life
15HAART Problems
- Cost
- Pill burden
- Complex dosing schedules
- Drug interactions
- Cure not possible
- Drug toxicity
- Need for strict adherence
- Viral resistance
16Currently Available Antiretroviral Drugs
Fusion Inhibitor Enfuvirtide (T-20)
17Viral zinc-finger nucleocapsid proteins
Fusion inhibition
Viral protease
RNA
RNA
Proteins
Reversetranscriptase
RT
RNA
RNA
DNA
DNA
RT
Viral regulatory proteins
DNA
DNA
DNA
DNA
Provirus
Viral integrase
18Highly Active Antiretroviral Therapy (HAART)
- COLUMN A
- AZT 3TC
- AZT ddI
- d4T 3TC
- d4T ddI
- COLUMN B
- NVP
- EFV
- IDV
- NFV
- SQV-SGC
- RTV SQV
- RTV IDV
- RTV LPV
19Initial Treatment Regimens for Previously-Untreate
d Patients
- Three categories
- One NNRTI two NRTIs
- One PI/boosted-PI two NRTIs
- Three NRTIs
- Few clinical endpoints to guide choices
- Advantages and disadvantages to each type of
regimen - Individualize regimen choice
- Regimen should be potent, tolerable, preserve
future options
20Not Recommended
- Stavudine Zidovudine
- Zalcitabine Lamivudine
- Zalcitabine Stavudine
- Zalcitabine Didanosine
21Hit HIV-1 Hard, but only when necessary
- Harrington M, Carpenter CJ
- Lancet 2000355(7)2147-52
22Recommendations for Initiating ART in Adults with
HIV Infection (BHIVA DHHS)
23Recommendations for Initiating ART in Adults with
HIV Infection (WHO)
- If CD4 testing available
- WHO Clinical Stage IV disease
- WHO Clinical Stage I , II and III disease with
CD4 lt200 cells/mm3 - If CD4 testing NOT available
- WHO Clinical Stage III and IV disease
- WHO Clinical Stage II disease with ALC lt1200/mm3
24Considerations Before Initiating HAART
- Patient readiness
- Medical eligibility
- OI treated/stabilized
- Concomitant medical conditions medications
- Sustainable drug supply
25Nucleoside Reverse Transcriptase Inhibitors
(NRTI's)
- NRTI's or "nukes" block reverse transcriptase,
preventing the transformation from RNA to DNA. - Without the DNA, HIV is unable to make functional
copies of itself and its proliferation in the
body is halted
26Nucleoside Reverse Transcriptase Inhibitors
(NRTI's)
- AZT
- Lamivudine (3TC)
- Stavudine (D4T)
- ddC (Zalcitabane)
- ddI (Didanosine)
- Abacavir
27AZT (Zidovudine)
- Form 100mg capsule and 300mg tablet
- Usual Dosage 300mg twice per day
- Instructions taking with food may help reduce
nausea
28AZT (Zidovudine)
- ADR
- Anemia, neutropenia
- Nausea / vomiting
-
- Drug interactions or incompatibility
- D4T will decrease the effectiveness of AZT
- Concomitant use with nephrotoxic /
myelosupressive / cytotoxic drugs eg. Flucytosine
may increase toxicity risk - Phenytoin altered levels.Phenytoin also
decreases AZT clearance
29Lamivudine (3TC)
- Form 150mg tablets
- Usual Dosage 150mg twice per day
-
- ADR Well tolerated Nausea /
vomiting - DI Nil
30Stavudine (D4T)
- Form 30mg and 40mg capsules
- Usual Dosage 40mg twice per day for gt 60 Kg. And
30 mg BD for lt60 Kg. - ADRPerepheral neuropathy
- Abdominal pain, Nausea / vomiting
- Drug interactions or incompatibility
- Should not be co administered with AZT
- Use with caution in combination with other
drugs that cause peripheral neuropathy
31DdI/Didanosine
- Form 100 mg tablet
- Usual Dosage 200 mg two times per day for gt60 Kg
and 125mg for lt60 Kg. - Instructions take 30min before or 2 hours after
food,
32DdI/Didanosine
- ADR
- Peripheral neuropathy
- Pancreatitis
- Lactic Acidosis
- Drug Interactions
- Possible interactions with ketoconazole and
quinolones
33ddC/Zalcitabane
- Form 0.75mg tablet
- Usual Dosage 0.75mg three times per day
- ADR
- Peripheral neuropathy
- Nausea / vomiting
- Ulcers in mouth
- Drug interactions or incompatibility
- Don't use with ddI
- Don't take with magnesium or aluminum containing
antacids
34Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTI's)
- Nevirapine
- Efavirenz
- Delavirdine
35Nevirapine
- Form 200mg tablet
- Usual Dosage Lead-in dosing helps decrease the
incidence of side effects. 200mg once per day for
the first 14 days then 200mg twice per day. - ADR Rash, hepatitis in 6 wks, liver enzyme
elevation - DI may decrease the effectiveness of oral
contraceptives
36Efavirenz
- Form 200mg capsule and 600mg tablet
- Usual Dosage 600mg once a day
- Instructions Take on empty stomach or with a
light snack. Recommended to be taken at bedtime.. - ADR Dizziness, insomnia, Vivid dreams, Mood
changes CNS side effects.Transient rash, liver
enzyme inducer
37Protease Inhibitors
- block the functioning of the enzyme protease
- without functioning protease, HIV is unable to
mature and therefore can not make more copies of
itself.
38Protease Inhibitors
- Indinavir
- Saquinavir
- Nelfinavir
- Ritonavir
- Amprenavir
39Indinavir
- Form 400mg capsule
- Usual Dosage 800mg three times per day
- Instructions Take on empty stomach 1 hour before
or 2 hours after eating (may be taken with a
light, low fat snack). Must drink at least 1 1/2
liters of water per day. - ADR Nausea / vomiting
- Diarrhea, Abdominal pain
- Kidney stones
- indinavir is sensitive to moisture. It should be
stored in its original bottle which contains a
desiccant (a material that keeps the drug dry). - Rifampicin decreases the levels
40Saquinavir
- Form 200mg soft gel capsule / 200mg capsule
- Usual Dosage 1200mg three times per day
- Instructions Must be taken on full stomach for
proper absorption. Keep at room temperature. In
hot climates should be refrigerated.
41Saquinavir
- ADR
- Nausea / vomiting
- Diarrhea
- Numbness, tingling, or burning in feet or hands
- Drug interactions or incompatibility
- Rifampin and Rifabutin should not be used with
saquinavir because it decreases blood levels.
42Nelfinavir
- Form 250mg tablet
- Usual Dosage 750mg three times per day or 1250mg
twice per day - Instructions Take with a meal or a light snack.
- ADR Diarrhoea, nausea, rash
43Ritonavir
- Form 100mg capsule or 400mg
- Usual Dosage 600mg twice per day. Escalate dose
over 14 days from 300 BD - Instructions Preferably a high fat meal.
Capsules need to be refrigerated. - ADR Nausea / vomiting,.Abdominal pain
- Numbness, tingling,burning in feet or hands
44Selected In Vivo Manifestations of NRTI
Toxicities
Features/Pathology Disrupted mitochrondrial
synthesis, anemia, neutropenia Weakness,
fatigue, red ragged fibers, swollen
mitochondria Mitochrondrial alterations
axonal degeneration Nonspecific GI complaints,
fatigue, distention, anion
gap, elevated lactate level
Drug(s) AZT ddC AZT d4T ddI ddC All NRTIs
Organ/Tissue Bone marrow Muscle Peripheral
nerves Liver
Toxicity Cytopenias Myopathy Cardiomyopathy Neu
ropathy Hepatic steatosis/ lactic acidosis
Brinkman. AIDS 1998121735.
45Drug Toxicity
- Hypersensitivity (ABC)
- Drug rash (NNRTI)
- Mitochondrial dysfunction (NRTI)
- Lipodystrophy (PI)
- Hyperglycemia (PI)
- Hyperlipidemia (PI)
- Osteonecrosis, osteoporosis
46Dimensions of Response and Failure
47Expected Virologic Immunologic Response in
Treatment Naïve Patients
- Virologic response
- Decrease 0.7-1.0 log10 copies/mL at 1 week
(Lancet 20013581760 J AIDS 200230167) - Decrease 1.5-2.0 log10 copies/mL at 4 weeks (AIDS
1999131873 JAIDS 20002536) - Decrease to lt500 copies/mL at 8 to 16 weeks and
lt50 copies/mL at 16 to 24 weeks (Ann Intern Med
2001135954 JAIDS 200024433) - Immunologic response
- 50 cells/mm3 at 4 to 8 weeks (with some
exceptions as discordant response in 20) - Expect additional increase of 50-100 cells/mm3
per year
48Indications of Regimen Failure in the Treatment
Naïve Patient
- Virologic
- lt0.5 to 0.75 log decline in plasma viral load by
4 weeks - Failure to achieve undetectable viral load by 4-6
months - Repeated detection of significant viremia after
initial suppression to undetectable levels
(assuming high levels of adherence) - Immunologic
- Persistent decline in CD4 counts
- Clinical
- Failure to gain weight and improve sense of
well-being, or new or recurrent opportunistic
infection (not due to immune reconstitution
syndrome)
49Laboratory Monitoring for Toxicity and
Effectiveness of ARV Therapy
Adapted from WHO 2002.
50Criteria for Changing Therapy
- Less than a 0.5-0.75 log reduction in plasma HIV
RNA by 4 weeks following initiation of therapy,
or less than a 1 log reduction by 8 weeks - Failure of a 1st or 2nd line regimen to suppress
plasma HIV RNA to undetectable levels within 4-6
months of initiating therapy - Repeated detection of virus in plasma after
initial suppression to undetectable levels,
suggesting the development of resistance
51Long-term Efficacy of HAART No Magic Bullet, No
miracle
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence
52Adherence
- 95 doses to be taken for complete viral
suppression - No evidence that degree of adherence required
varies with different classes/drugs - Poor adherence ? resistance ? virologic failure
53Predictors of Poor Adherence
- Poor patient-doctor relationship
- Active alcohol/drug use
- Active mental illness
- Lack of patient education
- Adverse drug reactions
54Causes of Treatment Failure
- Sequential monotherapy
- Sub-therapeutic plasma drug levels
- Nonadherence
- Inter-patient variability (pharmacokinetics)
- Bioavailability
- Drug-drug interactions
- Resistance/cross-resistance
- Advanced HIV disease (low CD4, high VL)
55How Does Resistance Emerge?
56Drug-Resistant HIVin Treatment-Naïve Patients
gt10-fold increase via PhenoSense HIV, ViroLogic.
Little SJ, et al. N Engl J Med. 2002347385-394.
57(No Transcript)
58Impact of Various ART Strategies in South Africa
Based on Wood E et al. Lancet 20003552095-2100
25 Antiretroviral Therapy Use
Life Expectancy at Birth
No Therapy
Year
59CONCLUSIONS
- Benefits of ART continue to strongly outweigh the
disadvantages - Challenges remain
- Eradication of latent reservoirs
- Managing drug toxicities resistance
- Improving adherence
- Improving access to ART
60Thank You