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Clinical Issues in HIV
Eynat Kedem MD
Clinical Immunology, Allergy & Aids
Rambam Medical Center
Objectives
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HIV epidemiology
Natural history
Current antiretroviral therapies
Treatment guidelines
Adherence
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Adults and children estimated to be living with HIV, 2005
Western & Eastern Europe
Central Europe & Central Asia
720 000
North America
1.3 million
[770 000 – 2.1 million]
Caribbean
330 000
[550 000 – 950 000]
1.5 million
[1.0 – 2.3 million] East Asia
North Africa & Middle
East
[240 000 – 420 000]
440 000
[250 000 – 720 000]
Sub-Saharan Africa
Latin America
1.6 million
[1.2 – 2.4 million]
24.5 million
[21.6 – 27.4 million]
680 000
[420 000 – 1.1 million]
South & South-East
Asia
7.6 million
[5.1 – 11.7
million]
Oceania
78 000
[48 000 – 170 000]
Total: 38.6 (33.4 – 46.0) million
Estimated number of adults and children
newly infected with HIV, 2005
Western & Eastern Europe
Central Europe & Central Asia
22 000
North America
43 000
[34 000 – 65 000]
Caribbean
37 000
[18 000 – 33 000]
220 000
[150 000– 650 000] East Asia
North Africa & Middle
East
[26 000 – 54 000]
64 000
[38 000 – 210 000]
Sub-Saharan Africa
Latin America
140 000
[100 000 – 420 000]
2.7 million
[2.3 – 3.1 million]
97 000
[55 000 – 290 000]
South & South-East
Asia
830 000
[530 000 Oceania
– 2.3 million]
7200
[3500 – 55 000]
Total: 4.1 (3.4 – 6.2) million
Estimated adult and child deaths from AIDS, 2005
Western & Eastern Europe
Central Europe & Central Asia
12 000
North America
18 000
[11 000 – 26 000]
Caribbean
27 000
[<15 000]
53 000
[36 000 – 75 000] East Asia
North Africa & Middle
East
[19 000 – 36 000]
37 000
[20 000 – 62 000]
Sub-Saharan Africa
Latin America
59 000
[47 000 – 76 000]
2.0 million
[1.7 – 2.3 million]
33 000
[20 000 – 49 000]
South & South-East
Asia
560 000
[370 000 Oceania
– 810 000]
3400
[1900 – 5500]
Total: 2.8 (2.4 – 3.3) million
Objectives
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HIV epidemiology
Natural history
Current antiretroviral therapies
Treatment guidelines
Adherence
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
HIV in Body Fluids
Blood
18,000
Semen
11,000
Vaginal
Fluid
7,000
Amniotic
Fluid
4,000
Saliva
1
Average Number of HIV Particles in 1 cc of these body fluids
HIV Testing
ELISA
Test
Positive
Negative
No HIV Exposure
Low Risk
Negative
Repeat ELISA
Every 3 months
for 1 year
Repeat every
6 months for continued
High risk behavior
End Testing
Repeat
Positive
HIV Exposure
High Risk
Negative
Positive
Indeterminate
Repeat at
3 weeks
Run IFA
Confirmation
Negative
Repeat at
2-4 months
Positive
HIV
+
Temporal Course of HIV Infection
Acute Infection
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40-90%
Fever
Headaches
Weakness
Appetite decrease
Lymphadenopathy
Skin Rash
AIDS
•
•
•
•
CD4<200 = morbidity
8-12 years after
infection (untreated)
Morbidity=
opportunistic infections
and malignancies
Symptoms and signs:
prolonged fever,
lymphadenopathy,
weight loss, diarrhea…
Common Illnesses in
AIDS Patients
•
•
•
•
•
•
•
PCP- pneumocystis
carinii pneumonia
Dissaminated fungal
infections
CMV retinitis
Toxoplasmosis of brain
Malignancies
Wasting syndrome
TB & other spirochetal
diseases
Objectives
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HIV epidemiology
Natural history
Current antiretroviral therapies
Treatment guidelines
Adherence
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Targets of HIV Therapy
Integrase Inhibitors
Entry
Inhibitors:
Fusion, CD4, CCR5
CXCR4
Nucleus
RNA
Protease
HIV
Reverse
transcriptase
DNA
CD4+ T-Cell
Reverse transcriptase inhibitors:
NRTI (nucleosides, nucleotides)
NNRTI
Protease inhibitors
Approved Antiretrovirals
Between ’87 and ’95, 4 antiretrovials were launched.
Since ’95, 19 new products have been introduced.
Combivir
Hivid
Retrovir
Videx
Epivir
Zerit
Rescriptor
Viread
Ziagen
Viramune
Sustiva Trizivir
Emtriva
’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ‘00 ’01 ‘02 ‘03 ‘04
RTI
NNRTI
PI
Invirase
Viracept Kaletra
Fortovase Agenerase
Reyataz
Fuzeon
Norvir
Lexiva
Crixivan
FDA-APPROVED HIV DRUGS
Current drugs and classes
FEI
ENF
NRTI
AZT
ddI
ddC
d4T
3TC
ABV
FTC
NtRTI
TFV
NNRTI
NVP
DLV
EFV
Taken with permission from DA Cooper. Role of PIs in antiretroviral therapy,
Bangkok Symposium on HIV Medicine, Bangkok, Thailand, January 16-18,
2006.
PI
SQV
RTV
IDV
NFV
APV
LPV/r
ATV
fAPV
TPV
DRV 21
Objectives
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HIV epidemiology
Current antiretroviral therapies
Treatment guidelines
Adherence
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Patients Prefer QD Regimens
to BID Regimens
Which Do You Prefer?
80
70
68%
Patients (%)
60
50
40
30
24%
20
10
5%
0
4 pills QD
1 morning,
1 evening
1 morning,
4 evening
Bass D, et al. Presented at XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain Abstract MoPe3290.
More Frequent Dosing is Associated
with Poorer Adherence
% of Patients ever forgetting
to take HIV medication
80
70
71%
>36%
Reduction
63%
66%
60
50
40%
40
30
20
10
0
QD
BID
TID
TID+
Moyle G et al. 6th International Congress on Drug Therapy in HIV Infection; Glasgow, Scotland; November 17-21, 2002. Poster 99.
Adherence
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A major determinant of degree and
duration of viral suppression
Poor adherence associated with
virologic failure
Optimal suppression requires 9095% adherence
Suboptimal adherence is common
Predictors of Inadequate
Adherence
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Age, race, sex, educational level,
socioeconomic status, and a past
history of alcoholism or drug use do
NOT reliably predict suboptimal
adherence.
Higher SES and education levels and
lack of history of drug use do NOT
reliably predict optimal adherence.
Predictors of Good
Adherence
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Emotional and practical supports
Convenience of regimen
Understanding of the importance of
adherence
Belief in efficacy of medications
Feeling comfortable taking medications
in front of others
Keeping clinic appointments
Severity of symptoms or illness
Improving Adherence
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Establish readiness to start therapy
Provide education on medication dosing
Review potential side effects
Anticipate and treat side effects
Utilize educational aids including pictures,
pillboxes, and calendars
Improving Adherence
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Simplify regimens, dosing, and food
requirements
Engage family, friends
Utilize team approach with nurses,
pharmacists, and peer counselors
Provide accessible, trusting health
care team
Objectives
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HIV epidemiology
Current antiretroviral therapies
Adherence
Treatment guidelines
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Goals of Antiretroviral
Therapy (ART)
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Eradication of HIV? Not possible with
currently available antiretroviral
medications.
IT’S THE VIRUS!
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THE FIRST CHANCE is the BEST
CHANCE: GO for GOLD
THE GOLD: UNDETECTABILITY
Goals of Antiretroviral
Therapy
& Tools to Achieve Goals
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Improvement of quality
of life
Reduction of HIV-related
morbidity and mortality
Restoration and/or
preservation of
immunologic function
Maximal and durable
suppression of viral load
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Selection of ARV regimen
Preservation of future
treatment options
Rational sequencing of
therapy
Maximizing adherence
Use of resistance testing
in selected clinical
settings
Considerations in
Initiating ART:
Asymptomatic HIV
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Willingness of patient to begin and the
likelihood of adherence
Degree of immunodeficiency (CD4+ T
cell count)
Plasma HIV RNA
Risk of disease progression
Potential benefits and risks of therapy
Considerations in
Initiating ART:
Chronically HIV-Infected
Patient, Asymptomatic
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Strong evidence of decreased mortality and
morbidity with ART if CD4 <200 cells/µL or
symptomatic
Theoretical benefit of treatment at higher CD4
Few data establish clinical benefit for treatment
if CD4 >200 cells/µL; optimal point to initiate
ART is unknown
Individualize treatment decisions
Indications for ART in the
Chronically HIV-Infected
Patient
Treat all (regardless of viral load):
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Symptomatic (AIDS, severe symptoms)
Asymptomatic, CD4 count <200 cells/µL
Indications for ART in the
Chronically HIV-Infected
Patient
Offer treatment, after discussion of
pros and cons:

Asymptomatic, CD4 count 200-350
cells/µL
Indications for ART in the
Chronically HIV-Infected
Patient
Defer Treatment:
Asymptomatic, CD4 count >350 cells/µL
– If HIV RNA >100,000 copies/mL, may
consider treatment
Benefits and Risks of
Deferred Therapy
BENEFITS
RISKS
 Avoid negative effects on
 Possibility of irreversible
quality of life
immune system
 Avoid drug-related
depletion
toxicity
 Increased possibility of
 Preserve future drug
progression to AIDS
options
 Possible increased risk of
 Delay development of
HIV transmission
drug resistance
 Decrease total time on
medications
The HIV Provider’s Challenge
POSSIBLE COMBINATION OF 1ST
LINE ARV REGIMENS
 2NRTI + PI
 2NRTI + NNRTI
 2NRTI + Boosted PI
 3NRTI
 3NRTI + NNRTI
 2NRTI + 2NNRTI
 PI + NNRTI
 Triple Drug Classes
 Dual PIs
42
Antiretroviral
Medications: Should not
be offered
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Regimens not recommended:
– Monotherapy (except possibly in prevention of
perinatal HIV transmission)
– Dual NRTI therapy
– 3-NRTI regimen with abacavir + tenofovir +
lamivudine
– 3-NRTI regimen with didanosine + tenofovir
+ lamivudine
Antiretroviral Medications:
Should not be offered at
any time
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Antiretroviral components not recommended:
– Didanosine + stavudine
– Stavudine + zidovudine
– Emtricitabine + lamivudine
– Zalcitabine + stavudine; zalcitabine +
didanosine; zalcitabine + lamivudine

Antiretroviral Medications:
Should not be offered at
any time
Antiretroviral components not recommended:
– Efavirenz in pregnancy and in women with high
potential for pregnancy*
– Nevirapine initiation in women with CD4 >250
cells/mm3 or men with CD4 >400 cells/mm3
* Women with high pregnancy potential are those who are
trying to conceive or who are not using effective and consistent
contraception.
Objectives
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HIV epidemiology
Current antiretroviral therapies
Adherence
Treatment guidelines
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Unique Features - NRTI
Class
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The “backbone” of HAART
Increasingly simplified regimens
Drugs with high and others with low
barriers to resistance
Peripheral neuropathy with “D” drugs
Mitochondrial toxicity
Specific Issues: NRTIs
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Anemia
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– Stavudine (D4T)
– Zidovudine (ZDV)
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Neuropathy
– D4T, DDI, DDC
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Pancreatitis
– DDI, DDC
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Hypersensitivity
– Abacavir
Hypertriglyceridemia
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Lactic acidosis
– Greater risk with ZDV,
D4T, DDI
– More common with
greater adipose
Adverse Effects: NNRTIs
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All NNRTIs:
– Rash
– Drug-drug interactions
Nevirapine – hepatotoxicity (may be severe
and life-threatening), rash including
Stevens-Johnson syndrome
Efavirenz - neuropsychiatric, teratogenic in
primates (FDA Pregnancy Class D)
Adverse Effects: PIs
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All PIs:
– Hyperlipidemia
– Insulin resistance and diabetes
– Lipodystrophy
– Elevated liver function tests
– Possible increased bleeding risk in
hemophiliacs
– Drug-drug interactions
Specific Issues: PIs
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Kidney stones
– Indinavir; avoid with renal insufficiency
Diarrhea
– Nelfinavir, ritonavir, lopinavir/ritonavir
Dyspepsia
– SGC saquinavir, ritonavir, lopinavir/ritonavir,
amprenavir
Rash
– Amprenavir & fosamprenavir: sulfa-containing
Jaundice/indirect hyperbilirubinemia
– Atazanavir, indinavir
Hyperlipidemia
– All but atazanavir
Adverse Effects: Fusion
Inhibitors
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Enfuvirtide – injection-site reactions,
hypersensitivity reaction, increased risk of
bacterial pneumonia
Drug Interactions with
ARVs: Dose Modification or
Cautious Use
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Lipid-lowering agents
Antimycobacterials, especially rifampin*
Psychotropics - midazolam, triazolam
Ergot alkaloids
Antihistamines - astemizole
Anticonvulsants
*Of available NNRTIs and PIs, rifampin may be used only with fulldose ritonavir or with efavirenz
Drug Interactions with
ARVs: Dose Modification
or Cautious Use
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Oral contraceptives (may require second
method)
Methadone
Erectile dysfunction agents
Herbs - St. John’s wort
CD4 Cell Counts Increase through 5 Years
Regardless of Baseline CD4 Cell Count Strata
600
510 cells/mm3
Cells/mm3
500
400
300
All Patients
Baseline <50 (n=17)
Baseline 50-200 (n=19)
Baseline 200-350 (n=19)
Baseline 350-500 (n=19)
Baseline >500 (n=26)
200
100
0
0
24
48
72
96
120
144
168
192
216
240
264
Week
Sample Size: 100
86
Eron J, et al , 43rd ICAAC, Chicago, September 2003, H-844
72
68
Study 720
Once-Daily Options
Nucleosides/-tides
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Lamivudine
Didanosine
Emtricitabine
Tenofovir DF
Abacavir
– Some data
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Stavudine XR
– Production problems
Non-nucleosides
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Efavirenz
Nevirapine
– Greater liver toxicity
in 2NN
Once-Daily Options
Unboosted
Protease Inhibitors
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Atazanavir
– naive
Boosted
Protease Inhibitors
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Atazanavir/ritonavir 300/100
– experienced
Lopinavir/ritonavir 6/d
– naive
Fosamprenavir/ritonavir
1400/200
– naive
Saquinavir/ritonavir 1600/100
– naive
Objectives
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HIV epidemiology
Current antiretroviral therapies
Adherence
Treatment guidelines
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Causes of Drug
Resistance
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Poor adherence
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Insufficient Drug
potency
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PK factors
Emergence of virus
populations with
reduced susceptibility
Transmitted Drug Resistance
in Primary HIV Infection
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11 patients with transmitted drug
resistance at time of primary
infection, who deferred ARV therapy
Transmitted NNRTI resistance in 9/11
subjects persisted in all but 1 of the
9, out to nearly 3 years
PI mutations persisted, as well
Little S et al. 11th CROI San Francisco, CA 2004 Abst 36 LB
Drug Resistance Testing
(RT)
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Drug resistance tests have long been used to
guide the treatment of many infectious
diseases, especially bacterial infections
Drug resistance tests predict which drugs
may not work (and why they won’t work)
and which drugs might be useful
2 types of HIV drug resistance assays
– Genotype +/- virtual phenotype
– Phenotype
GeneSeqTM HIV Patient Report
PhenoSense™ HIV Report
Black bars represent
drugs unlikely to be
active against isolate
ABC, 3TC
NFV
Blue bars represent
drugs likely to be
active against isolate
DDI, D4T, DDC, ZDV
DLV, EFV, NVP
AMP, IDV, RTV, SQV
Resistance Testing Guidelines

International AIDS
Society–USA Panel
(May 2000)
– Treatment failure
(slow response, early
or late rebound)
– Pregnancy
– Consider for newly
infected and
untreated patients

US Department of
Health and Human
Services
(November, 2003)
– Treatment failure on
HAART
– Incomplete viral
response
– Consider for acutely
infected patients
Hirsch MS, et al. JAMA 2000;283:2417–2426.
US Department of Health and Human Services. Rockville, MD: February 4, 2002.
Objectives
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HIV epidemiology
Current antiretroviral therapies
Adherence
Treatment guidelines
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
CURRENT APPLICATION OF
TDM IN CLINICAL PRACTICE
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Individualizing therapy
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Preventing drug toxicity
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Follow up compliance
Objectives
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HIV epidemiology
Current antiretroviral therapies
Adherence
Treatment guidelines
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Immune Reconstitution
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Reconstitution of the immune system after
HAART initiation in severely
immunocompromised patients
Three phases:
1. CD4+ memory cells increase
2. T-cell activation decrease, reaction to
recall antigens increase
3. CD4+ naïve cells increase & CD8+
decline
Immune Reconstitution
Syndrome
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Augmentation of inflammation
Within days to months of HAART
initiation
10-25% of severely
immunocompromised patients
CD4+ X2-4 fold increment
Immune Reconstitution
Syndrome
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Clinical / laboratory worsening despite
HIV surrogate markers improvement
Targets: infectious, autoimmune,
tumor
Diagnosis difficult
Therapy varies
Objectives
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HIV epidemiology
Current antiretroviral therapies
Adherence
Treatment guidelines
Long-term complications of HAART
Resistance testing
Therapeutic Drug Monitoring
Immune Reconstitution Syndrome
Novel Therapeutic Approaches
Therapeutic Approaches
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Therapeutic concepts
Immunomodulation
Basic Therapeutic
Concepts
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When to start?
When to stop?
Which markers to use?
Co-infections- At diagnosis
During treatment
Immunomodulation
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Immunization
IL-2
Thank you for listening