Download PMB Dept of Internal medicine : Presentation: ARV Therapy

ARV therapy
Past, present and future
What is old, what is new, what is next?
•
1980’s
– No anti-HIV treatments were promising
•
1990’s
–
–
–
–
•
Anti-HIV Rx ~ worked, but made drug resistance
Acute and chronic drug toxicities were expected and delivered
Drug resistance led to illness and death
optimal management of drug toxicity versus HIV disease?
2000’s
– Successful anti-HIV Rx is expected, less toxic, taken for granted
– MDR HIV is evolving with super-infections
– NYC: transmissible and virulent MDR HIV
What did we learn in the past?
•
High doses of inadequate drug combinations do not work
– ZDV 300 mg Q4H is intolerable, and ineffective
– ZDV 300 mg BID is tolerable and transiently effective
•
Early treatment (high CD4) is generally better tolerated
– anemia, neuropathy on ZDV + ddI with baseline CD4 > 200
•
Early treatment is generally less prone to failure
– ZDV + 3TC + IDV with baseline high CD4 and low VL have lower virologic failure
•
Drug interactions are complex, and clinically important
– More than two simultaneous non-linear bidirectional drug-drug interactions are
more than hard to predict, and may be managed empirically or avoided
– PI’s are all CYP450 3A4 substrate, blocker and inducers to different degrees
• Ritonavir is the best blocker
• Tipranvir is the best inducer (more than rifampin)
• Saquinavir is the best substrate (like itraconzole)
The Present:
2005 DHHS HIV treatment guidelines
Preferred
lopinavir + ritonavir +
efavirenz +
ZDV + (3TC / FTC)
(ZDV / TDF) + (3TC / FTC)
Alternative
PI-Based
Atazanavir, fosamprenavir, or fosamprenavir,
indinavir, nelfinavir, saquinavir + ritonavir
NNRTI-Based
Efavirenz + (3TC / FTC) + (ABC / ddI / d4T)
Nevirapine + (3TC / FTC) + (ZDV / d4T / ddI/
ddI/ ABC / TDF)
All used in conjunction with
(3TC / FTC) + (ZDV / d4T / ABC/ TDF / ddI)
lopinavir/ritonavir + (3TC / FTC) +
(d4T / ABC / TDF / ddI)
Triple NRTI
abacavir + 3TC + ZDV
(definitely the third choice)
Efavirenz is not recommended for use in 1st trimester or in women with high pregnancy potential
Ritonavir is used in low dose: 100 to 400 mg/day as a pharmacologic booster; 100 mg/day is recommended for tenofovir + atazanavir.
Nevirapine has increased risk of rash and hepatitis in adult
dult females and males with CD4 cell counts >250 and >400 cells/mm
cells/mm3, respectively.
Saquinavir is supplied as softsoft- or hardhard-gel capsules or tablets.
Available at: http://aidsinfo.nih.gov/Default.aspx. Revision October 6, 2005.
When-to’s in ARV treatment
• When to start treatment
– When the patient is ready
– When the treatment will work best
– Before the patient gets sick
• When to change treatment
– When the treatment has stopped working
– When the treatment has caused harm
– When there is a better treatment to try
• When to stop treatment
–
–
–
–
When the treatment has stopped working
When the treatment has caused harm
When there is no alternative left to try
When the patients says stop
What are the requirements for
successful ARV therapy?
• HIV diagnosis, acceptance and knowledge
– Social as well as individual levels
• Access to general and specific health care
– Socialised versus commoditised medicine
– Distributive justice versus the social lottery
• Drug reimbursement, access and supply
– Only a societal issue
More requirements for
successful ARV therapy
•
susceptible HIV infection, adequate ARV prescription
– individual safety and tolerance of drug combination treatment
– Individual required potency of regimens (3 drugs at maximal tolerated doses?)
– Uniform or individual dosing and prescribing?
•
medical follow-up and monitoring
–
–
–
–
–
•
Maintain the established relationship
Recruit the patient into their own health maintenance
Anticipate acute and chronic toxicities, IRIS, drug interactions
Monitor clinical, immunologic and virologic outcomes
Rotate the poisons for chronic toxicities?
care for concurrent health problems
– sexual and reproductive health, especially other STD’s
– tuberculosis, pneumocystosis, candida, cryptococcosis, toxoplasmosis
– Malnutrition and micronutient supplementation?
The most important requirement for
successful ARV therapy
• Adherence & compliance
– health locus of control, personal daily organisation
– depression and survivor guilt
– Empiric 95% rule for virologic success
• What to do about it?
–
–
–
–
Better to start right, than to start now
When the patient is ready is right
Empiric pragmatic self-evaluation (30 pills/ 10 days)
Psychoeducational interventions
HOMER Cohort: Is >95% Adherence
Needed to Maintain Viral Suppression?
•
Previously treatment-naïve
patients on suppressive
HAART (n=1634; 1996-2003)
-
•
Association Between
<95% Adherence and
Viral Breakthrough
HIV RNA <500 copies/mL on
2 consecutive occasions
Regimen
Primary outcome
-
Time to viral breakthrough
• HIV RNA >1000 copies/mL
on 2 consecutive occasions
•
<95% adherence was most
strongly associated with
breakthrough with unboosted
PI- and NNRTI-regimens
-
No association for boosted
PI regimens
Adjusted
Hazard Ratio
(95% CI)
Unboosted PI
(n=752)
1.77
(1.41-2.24)
NNRTI (n=631)
1.47
(1.01-2.14)
Boosted PI (n=251)
1.05
(0.46-2.42)
Adjusted for sex, age, IDU, CD4 cell count,
AIDS diagnosis, physician experience.
Gross R, et al. 13th CROI. Denver, 2006. Abstract 533.
HOPS Cohort: Improved Outcomes
With Early Initiation of HAART
- 8-year follow-up
•
Mortality (per 1000 person-years)
Prospective cohort (n=4421)
Higher pre-HAART CD4 cell count
and >95% adherence
- Lower incidence of:
•
•
80
Incidence
•
40
These data suggest there are
immunologic benefits and less
toxicity when HAART is initiated
earlier and adherence is >95%
*
20
<50
5050-199
200200-349
350350-499
>500
Pre-HAART CD4 Category (cells/mm3)
OIs (per 1000 person-years)
80
Incidence
RNA <50 copies/mL (P<0.01)
*P<0.05.
*
Renal insufficiency, distal
symmetrical polyneuropathy, and
lipoatrophy
- Higher percentage achieving HIV
•
60
0
Mortality and OIs
Adherence
<95%
>95%
Adherence
<95%
>95%
60
40
20
0
*
*
*
<50
5050-199
200200-349
*
350350-499
>500
Pre-HAART CD4 Category (cells/mm3)
Lichtenstein KA, et al. 13th CROI. Denver, 2006. Abstract 769.
Still more requirements for
successful ARV therapy
• Individual dosing, ADME (PK)
– Adequacy of systemic drug exposure
– Inter-person & disease-related variation
• PK and pharmacodynamic (PD) interaction
– oxidative enzymes (CYP450 3A4)
– Epithelial, endothelial and cellular MDT (P-gp)
– Drug-drug interactions of concurrent treatments
• anti-HIV, -TB, -fungal and -coagulant therapies
• phytochemical, and micronutrient interactions
What is anti-HIV drug potency?
• Inhibition of HIV replication (per unit time) per unit drug
mass (concentration) in vitro
• Clinically, ‘completeness’, speed and duration of plasma
viremia suppression, meaning anti-HIV activity in vivo:
BUG
susceptibility
activity
potency
DRUG
Clinical potency of therapy means the net rate and degree of
treatment-related suppression of HIV plasma viremia,
which is a relationship between drug and bug
Relationships in Drug Therapy of Infectious Disease
BUG
activity
susceptibility
pathogenicity
EFFICACY
virulence
potency
DRUG
pharmacodynamics
toxicity
immunity
pharmacokinetics
HOST
© DWC 1999
How do we measure and compare
drug potency (a fragment of treatment efficacy)?
High initial VL (ie exclude < 104 copies/mL)
maximizes drop from baseline
log10 0
drop
from
baseline
virus 1
load
2
Low quantitation limit (ie 5 x 101 copies/mL)
maximizes drop from baseline
3
0
1
2
3 weeks or months
Integrase Inhibitor (GS-9137):
10-Day Monotherapy Study
•
Phase IIb, placebo-controlled,
monotherapy study
Change in
HIV RNA
at Day 10
- 40 treatment-naïve and
treatment-experienced patients
- Baseline
•
• HIV RNA: 4.75 log10 copies/mL
• CD4: 442 cells/mm3
At day 10
- >1 log10 reduction in HIV RNA
•
•
GS-9137: 83%
Placebo: 0%
- No serious adverse events and
no study drug discontinuations
- Most common adverse events
•
Fatigue, diarrhea, headache,
nausea
(log10 copies/mL)
Placebo
-0.13
GS-9137
800 mg qd
-0.89*
200 mg bid
-1.44*
400 mg bid
-1.98*
800 mg bid
-1.78*
50 mg + RTV qd
-2.03*†
*P<0.01 versus placebo.
P<0.05 versus 800 mg qd.
†
P<0.05
DeJesus E, et al. 13th CROI. Denver, 2006. Abstract 160LB.
Maturation Inhibitor (PA-457):
Phase II Dosing Study
Phase II, placebo-controlled,
monotherapy study
-
Baseline
copies/mL
• CD4: 441 cells/mm3
Oral doses of PA-457
-
•
25, 50, 100, 200 mg qd
At day 11
-
0.2
32 treatment-naïve patients
• HIV RNA: 4.73 log10
•
Change in HIV RNA at Day 11
AUC and trough levels were
significantly associated with
antiviral response (P<0.01)
0.046
0
Log10 Copies/mL
•
-0.2
-0.174
-0.4
-0.483
-0.6
-0.8
-1
-1.05
-1.2
25
50
100
PA-457 mg qd
200
Smith P, et al. 13th CROI. Denver, 2006. Abstract 52.
How do we measure and compare
drug activity (a bigger fragment of efficacy) ?
BLQ
100%
Serial point prevalence of viremia suppression
DRUG EFFECT
- causation
50%
COHORT EFFECT
- bias
0%
6 MONTHS
Cohort: N= 100%
85%
70%
Integrase Inhibitor (MK-0518):
Study 005
- Baseline
•
• HIV RNA: 4.7 log10 copies/mL
• CD4: 243 cells/mm3
• 3-class resistance
Regimens
- Placebo
- MK-0518: 200, 400, or 600 mg bid
oral administration
- All patients received an
optimized background regimen
•
Most common adverse events
among all groups
- Diarrhea, nausea, fatigue,
injection site reaction,
headache, and pruritus
Viral Load (<50 copies/mL)
100
Patients (%)
Treatment-experienced patients
(n=167)
200 mg
400 mg
600 mg
80
60
40
20
0
Change From Baseline
•
Placebo
0
2
4
8
Weeks
12
16
CD4 Cell Count (cells/mm3)
200
200 mg
400 mg
600 mg
150
100
50
0
Placebo
0
2
4
8
Weeks
12
16
Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.
What is the preferred measure of
anti-HIV treatment activity?
•
Degree and time to virologic suppression
– Multifactorial, determined by baseline viremia
– Close to ‘clinical potency’
•
Proportion ‘suppressed’ over a time period
– susceptible to inaccurate rates (ITT) or biased comparison (OT)
– Intuitively pleasing
•
Time to virologic failure, or subsequent re-treatment failure
– Multifactorial, low outcome rate
– pragmatic
•
Time to drug discontinuation
– Multifactorial, related to either drug intolerance and drug resistance
– pragmatic
Comparison of anti-HIV outcomes by
serial point prevalence differences
• OT (on treatment), or AT (as treated) analysis results are
biased by non-random, or selective loss to follow-up
• ITT (intention to treat) protects from bias at the cost of
accuracy:
– LOCF (last observation carried forward)
– M=F (missing = failure)
• Both analyses have many imputed results
• ITT analyses have meaning where one has
intention-to-follow the patients
Statistics are useful in clinical trials
Ritonavir boosted v unboosted atazanavir
• Treatment-naïve patients (n=200)
100
•
•
Patients (%)
Open-label, non inferiority trial
Baseline
CD4: 235 cells/mm3
HIV RNA: 5.0 log10 copies/mL
• Regimens
-
Atazanavir 400 mg qd
Atazanavir + ritonavir (300/100 mg qd)
All patients received 3TC + d4T qd
• At 48 weeks (ATV vs ATV+RTV)
-
Virologic failures: 10 vs 3 patients
PI resistance: 3 vs 0 patients
Jaundice: 7% vs 22%
• Increased lipids in ATV + RTV arm
-
T-C +15%, LDL-C +23%, TG +26%
ITT
80
75%
60
70%
40
Atazanavir qd (n=105)
Atazanavir + RTV qd (n=95)
20
0
Change From Baseline
-
Viral Load (<50 copies/mL)
0
8
16
24
32
Weeks
40
48
CD4 Cell Count (cells/mm3)
250
224
200
189
150
100
Atazanavir qd
Atazanavir + RTV qd
50
0
0
8
16
24
32
40
48
Weeks
Malan N, et al. 13th CROI. Denver, 2006. Abstract 107LB.
What limits anti-HIV treatment today?
• Adherence to treatment
-
pill burden and dosing schedule
• Individual host and disease-related variation
-
Acute and chronic drug toxicity
Drug absorption and anti-HIV activity
Primary HIV-1 Infection is Associated with Preferential
Depletion of CD4+T Lymphocytes from Effector Sites
in the Gastrointestinal Tract
Copyright: Rockefeller University Press
Saurabh Mehandru, et al. J. Exp. Med. 2004. 200(6):761-770.
Model for the Depletion of Gut CD4Expressing T Lymphocytes by SIV/HIV
Why is MDR TB
associated with HIV everywhere?
• Monotherapy of active TB infection?
• Intermittent or partial non-adherence?
• Under-dosing of anti-TB treatment?
Participants
48 persons without TB
Group I:
Š 12 healthy volunteers
Group II:
Š 12 HIV positive, asymptomatic, CD4+ T-cell counts > 300 cells/mm3
Group III:
Š 12 HIV positive, symptomatic, CD4+ T-cell counts < 200 cells/mm3
Group IV:
Š 12 HIV positive, symptomatic, CD4+ T-cell counts < 200 cells/mm3
Š persistent diarrhea
Isoniazid
Mean AUC 0-24h and Cmax
P = .192 I - IV
P = .713 I - III
15
AUC
10
µg•h/mL
5
0
I
P = .046 I - IV
P = .802 I - III
µg/mL
II
III
7
6
5
4
3
2
1
0
IV
Cmax
I
II
III
Group
IV
Rifampin
Mean AUC 0-24h and Cmax
P = .065 I - IV
P = .085 I - III
µg•h/mL
50
AUC
40
30
20
10
0
I
P = .006 I - IV
P = .006 I - III
µg/mL
II
III
10
IV
Cmax
8
6
4
2
0
I
II
III
Group
IV
Pyrazinamide
Mean AUC 0-24h and Cmax
400
AUC
300
µg•h/mL 200
P = .0001 I - IV
P = .0147 I - III
P = .056 I - IV
P = .193 I - III
µg/mL
100
0
I
II
III
30
25
20
15
10
5
0
IV
Cmax
I
II
III
Group
IV
Number of Participants with
Suboptimal Drug Concentrations
G ro u p
N = 1 2 /g ro u p
B e lo w n o rm a l C m a
o f a t le a s t o n e d ru g
P
=
.0 1
x
R IF : <
P Z A : <
II
III
IV
0
4
6
7
0
0
0
4
0
0
3
3
0
3
3
1
0
0
0
2
0
4
6
6
0
0
3
4
F is h e r’s e x a c t te s t
1 d ru g
2 d ru g s
3 d ru g s
IN H : <
I
2 .1 µ g /m L
5 .1 µ g /m L
1 9 .5 µ g /m L
Conclusions…
• Isoniazid was generally well absorbed but diarrhea
reduced the rate of absorption
• Most frequent and largest decreases in AUC and Cmax (>
30%) were observed for rifampin
– 16 of 36 HIV infected patients had suboptimal peak drug
exposure
• Trend of decreased pyrazinamide exposure in later-stage
HIV disease
• Below normal Cmax levels of two or more drugs occurred
in only symptomatic patients
…Conclusions
• Malabsorption is likely the cause of low drug levels
• Patients with no visible signs of GI dysfunction have low
drug levels
– therapeutic drug monitoring?
– D-xylose screen?
• Long-term clinical consequences of reduced drug
exposure have been studied, and link HIV with MDR-TB
through anti-TB drug malabsorption in independent trials
in India, South Africa, and in ecologic studies.
An RCT of carotene in AIDS
• low carotene is a risk factor for death in AIDS
– Vitamin A deficiency?
– Oxidative stress?
– Malnutrition due to malabsorbtion?
• 22 centres of the Canadian HIV Trials Network
• Community based controlled clinical trial of
multi-vitamin, trace element and antioxidant with
or without high dose natural carotenoids
micronutrient
Amount per
Caplet
Carotenea
Natural, mixed carotenoids comprised
95% beta-carotene, 3% alpha
carotene, 0·6% zeaxanthin, 0·7%
cryptoxanthin, 0·5% lutein)
30,000 IU
(18 mg)
Vitamin A
1,500 IU
Vitamin D
56 IU
Vitamin C
63 mg
Vitamin E
56 IU
Vitamin B1
9·38 mg
Vitamin B2 (riboflavin)
4·68 mg
Vitamin B2 (riboflavin-5' phosphate Na )
2·25 mg
Vitamin B3 (niacin)
3·75 mg
Vitamin B3 (niacinamide)
9·38 mg
Vitamin B5 (d-calcium pantothenate)
18·75 mg
Vitamin B6 (pyridoxine hydrochloride)
9·38 mg
Vitamin B6 (pyridoxine-5'-phosphate)
3 mg
Folic acid (folacin)
0·08 mg
Biotin
0·06 mg
mineral / element
Amount per
Caplet
Magnesium
37·5 mg
Zinc
7·5 mg
Iron
1·5 mg
Copper
0·38 mg
Manganese
1·5 mg
Potassium
9·38 mg
Chromium
0·018 mg
Selenium
0·018 mg
Molybdenum
0·00938 mg
Vanadium
0·00938 mg
Choline bitartrate
9·38 mg
Iodine
0·00938 mg
anti-oxidant
Amount per
Caplet
N-acetyl-Lcysteine
150 mg
Glutathione (reduced)
37·5 mg
Carotene RCT flow chart
Carotene treatment increased
serum levels over 18 months
Treatment increased CD4 count
…and not plasma HIV load (not shown)
Treatment increased survival
13 (7·8%) deaths in treatment vs
23 (13·9%) deaths in controls
HR 1·76 (0·89, 3·47), p = 0·11
Effect of treatment stratified by baseline characteristics
Death by:
Treatment
Control
n=165
n=166
15·6 %
0·0 %
HR
P
19·4 %
9·5 %
1·25
NC
0·56
0·004
4·5 %
11·5 %
12·3 %
17·9 %
2·70
1·67
0·14
0·23
5·4 %
4·7 %
16·0 %
7·5 %
3·42
1·36
0·03
0·68
CD4 count
<50 cells/μL
≥50 cells/μL
HIV load
< median
≥ median
Serum carotene
< median
≥ median
Multivariate intention-to-treat analysis of time to death
for baseline predictors and treatment
Variable
Adjusted HR
95% CI
P
CD4 T lymphocyte count
0.63
0.46, 0.87
0.005
0.59
0.35, 0.99
0.04
3.15
1.10, 8.98
0.03
per 25 cell/mcL increase
Serum carotene
per 1 μmol/L increase
Controls v carotenoids
Conclusions
• High dose natural mixed carotenoids in AIDS
–
–
–
–
–
increases serum carotene levels
appeared to increase CD4
did not change plasma viremia
had no effect on the incidence of AIDS
may improve survival in advanced AIDS
• Subsequent study shows
– OTC carotene is unstable and unreliable
– No PK interaction of carotene and CYP450 drugs
What will we learn in the future?
•
Anti-HIV activity studies are not the same as clinical efficacy (again).
•
All-cause mortality, or health-related quality of life are better outcome
measures in trials of clinical effectiveness, than the familiar epidemiologic
case definition of an AIDS-defining or related illness
•
Therapeutic individualization: Host predictors of drug activity & toxicities
–
–
–
–
CD4 350, VL 5000 versus CD4 10, VL > 500,000
Phenotypic tests for PK and PD genotypes
BMI & disease stage adjusted dosing versus fixed-dose co-formulations
Detection of HIV-related anti-HIV drug malabsorption
•
Which micronutrient deficiencies are present, clinically important, and
whether supplementation or replacement works or not in AIDS Rx
•
What manner of immune modulation enhances ARV efficacy, and immune
control of HIV infection