Dr' Elizabeth'K'E' - PowerPoint PPT Presentation

1 / 60
About This Presentation
Title:

Dr' Elizabeth'K'E'

Description:

Recommendations for Initiating ART in Adults with HIV Infection (BHIVA & DHHS) ... Without the DNA, HIV is unable to make functional copies of itself and its ... – PowerPoint PPT presentation

Number of Views:19
Avg rating:3.0/5.0
Slides: 61
Provided by: ocabr
Category:
Tags: elizabeth

less

Transcript and Presenter's Notes

Title: Dr' Elizabeth'K'E'


1
Highly Active Antiretroviral Therapy (HAART)
  • Dr. Elizabeth.K.E.
  • Dept. of Pediatrics
  • MEDICAL COLLEGE
  • Trivandrum

2
Natural 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.
3
Plasma Viral Load - Prognosis
4
CD4 Cell Counts and Opportunistic Infections
5
Relating 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.
6
Incidence 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
7
Goals 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

8
Goals of Therapy
  • Eradication of HIV? Not yet
  • in spite of plasma RNA below detection there is
    evidence of genetic evolution in reservoirs.

9
Current Ultimate Goal of HAART
CD4 T-cells
Relative Levels
Plasma HIV Viremia
Limit of detection
Months
Years After HIV Infection
Acute HIV infection Symptom
10
Increasing Choices for HIV Therapy
11
Evolution 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

12
Antiretroviral 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
13
Progression to AIDS/Death
No therapy
Mono-therapy
Dual-therapy
of patients progressing
Triple therapy
Months
JAMA 1998 CMAJ 1999
14
Highly 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

15
HAART Problems
  • Cost
  • Pill burden
  • Complex dosing schedules
  • Drug interactions
  • Cure not possible
  • Drug toxicity
  • Need for strict adherence
  • Viral resistance

16
Currently Available Antiretroviral Drugs
Fusion Inhibitor Enfuvirtide (T-20)
17
Viral 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
18
Highly 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

19
Initial 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

20
Not Recommended
  • Stavudine Zidovudine
  • Zalcitabine Lamivudine
  • Zalcitabine Stavudine
  • Zalcitabine Didanosine

21
Hit HIV-1 Hard, but only when necessary
  • Harrington M, Carpenter CJ
  • Lancet 2000355(7)2147-52

22
Recommendations for Initiating ART in Adults with
HIV Infection (BHIVA DHHS)
23
Recommendations 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

24
Considerations Before Initiating HAART
  • Patient readiness
  • Medical eligibility
  • OI treated/stabilized
  • Concomitant medical conditions medications
  • Sustainable drug supply

25
Nucleoside 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

26
Nucleoside Reverse Transcriptase Inhibitors
(NRTI's)
  • AZT
  • Lamivudine (3TC)
  • Stavudine (D4T)
  • ddC (Zalcitabane)
  • ddI (Didanosine)
  • Abacavir

27
AZT (Zidovudine)
  • Form 100mg capsule and 300mg tablet
  • Usual Dosage 300mg twice per day
  • Instructions taking with food may help reduce
    nausea

28
AZT (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

29
Lamivudine (3TC)
  • Form 150mg tablets
  • Usual Dosage 150mg twice per day
  • ADR Well tolerated Nausea /
    vomiting
  • DI Nil

30
Stavudine (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

31
DdI/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,

32
DdI/Didanosine
  • ADR
  • Peripheral neuropathy
  • Pancreatitis
  • Lactic Acidosis
  • Drug Interactions
  • Possible interactions with ketoconazole and
    quinolones

33
ddC/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

34
Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTI's)
  • Nevirapine
  • Efavirenz
  • Delavirdine

35
Nevirapine
  • 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

36
Efavirenz
  • 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

37
Protease 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.

38
Protease Inhibitors
  • Indinavir
  • Saquinavir
  • Nelfinavir
  • Ritonavir
  • Amprenavir

39
Indinavir
  • 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

40
Saquinavir
  • 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.

41
Saquinavir
  • 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. 

42
Nelfinavir
  • 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

43
Ritonavir
  • 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

44
Selected 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.
45
Drug Toxicity
  • Hypersensitivity (ABC)
  • Drug rash (NNRTI)
  • Mitochondrial dysfunction (NRTI)
  • Lipodystrophy (PI)
  • Hyperglycemia (PI)
  • Hyperlipidemia (PI)
  • Osteonecrosis, osteoporosis

46
Dimensions of Response and Failure
47
Expected 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

48
Indications 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)

49
Laboratory Monitoring for Toxicity and
Effectiveness of ARV Therapy
Adapted from WHO 2002.
50
Criteria 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

51
Long-term Efficacy of HAART No Magic Bullet, No
miracle
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence

52
Adherence
  • 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

53
Predictors of Poor Adherence
  • Poor patient-doctor relationship
  • Active alcohol/drug use
  • Active mental illness
  • Lack of patient education
  • Adverse drug reactions

54
Causes 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)

55
How Does Resistance Emerge?
56
Drug-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)
58
Impact 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
59
CONCLUSIONS
  • 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

60
Thank You
Write a Comment
User Comments (0)
About PowerShow.com