Transcript Document

Current and Future Trends in
HIV Therapy
Hail M. Al-Abdely
Consultant, Infectious Diseases
Clinical, Virological and Immunological Course
of HIV Infection
1000
CD4 Cell Count
800
600
RNA in Plasma
400
Symptoms
Virus in Plasma
200
Infection0
Death
Detectable
VIRUS IN PLASMA
Detectable
> 500 cells
CD4 COUNTS
< 200 cells
Time 0
12 Years
Seroconversion
Asymptomatic
AIDS
Development of AIDS is like an
impending train wreck
Viral Load = Speed of the train
CD4 count = Distance from cliff
HIV
infection
J. Coffin, XI International Conf. on AIDS, Vancouver, 1996
Viral Dynamics of HIV-1 Infection
Latently infected
CD4 lymphocytes
Productively infected
CD4 lymphocytes
1%
99%
T 1/2 ~1.6d
2.6 days
per
generation
Uninfected CD4
lymphocytes
T1/2 ~5.7 hrs
HIV
<1%
Uninfected activated
CD4 lymphocytes
Long-lived cell
populations
Perelson et.al. Science 271:1582 (1996)
CD4 lymphocytes
infected with
defective virus
Latency Theory
26
1
15
Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
Abacavir (Ziagen)
Abacavir + Lamivudine (Epzicom)
Abacavir+Lamivudine+Zidovudine
(Trizivir)
Didanosine (Videx, ddI)
Emtricitabine (Emtriva, FTC)
Emtricitabine + Tenofovir DF (Truvada)
Lamivudine (Epivir, 3TC)
Lamivudine+Zidovudine (Combivir)
Stavudine (Zerit, d4T)
Tenofovir DF (Viread)
Zalcitabine (Hivid, ddC)
Zidovudine (Retrovir, AZT, ZDV)
Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
Delavirdine (Rescriptor)
Efavirenz (Sustiva)
Nevirapine (Viramune)
Protease Inhibitors (PIs)
Amprenavir (Agenerase)
Atazanavir (Reyataz)
Fosamprenavir (Lexiva, 908)
Indinavir (Crixivan)
Lopinavir+Ritonavir (Kaletra)
Nelfinavir (Viracept)
Ritonavir (Norvir)
Saquinavir (Fortovase, Invirase)
Tipranavir
Fusion Inhibitors
Enfuvirtide (Fuzeon, T-20)
Total = 25 drug or
drug combinations
Current antiretroviral targets
Viral protease
RNA
Reverse
transcriptase
RNA
Proteins
RT
RNA
ZDV, ddI,
ddC, d4T,
3TC, ABC,
RNA
DNA
RT
DNA
DLV, NVP,
EFV
DNA
Provirus
SQV
RTV
IDV
NFV
APV
LPV
90
100
80
80
80
70
70
60
60
60
40
50
20
50
Monot herapy
Monotherapy
Monot herapy
90
Dual therapy
Monot herapy
Viral Suppression with Monotherapy
versus Multiple Drugs
Triple therapy
Hospitalization Days for AIDS
Patients
Hospitalization days (n)
2,000
1,500
1,000
500
0
Good News
Highly active antiretroviral therapy has
Changed our view toward HIV from
inevitably fatal (Cancer)
to a
manageable disease (Diabetes, HTN)
Bad News
1.
2.
3.
4.
5.
Incomplete response
Adherence & Complexity of treatment
Short and long term side effects
Resistance
Drug-drug interactions
Bad News
1. Incomplete response
•
•
2.
3.
4.
5.
Complete RNA suppression and sustained CD4
increase happens only in 60-80%.
Effectiveness is even lower in patients with high
replication rates and extensive antiretroviral
experience.
Adherence & Complexity of treatment
Short and long term side effects
Resistance
Drug-drug interactions
Viral Suppression with Monotherapy
versus Multiple Drugs
90
90
80
80
70
70
60
60
Monot herapy
Monotherapy
50
Monot herapy
50
Dual therapy
Monot herapy
Triple therapy
Bad News
1. Incomplete response
2. Adherence & Complexity of treatment
•
•
•
Too many tablets.
Difficult schedule.
Food factor
3. Short and long term side effects
4. Resistance
5. Drug-drug interactions
Predictors of Inadequate
Adherence
•
•
•
•
•
•
•
•
Regimen complexity and pill burden
Poor clinician-patient relationship
Active drug use or alcoholism
Unstable housing
Mental illness (especially depression)
Lack of patient education
Medication adverse effects
Fear of medication adverse effects
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Drug-drug interactions
5. Resistance
Metabolic Complications of PIs
• Hyperbilirubinemia
• Hyperlipidemia
– Coronary artery disease
• Insulin resistance
• Abnormal fat distribution.
• Lipodystrophy
From NEJM
Risk: Benefit Analysis of
Coronary Heart Disease and HAART
Average
calculated
increase in
CHD events =
0.14% per year
Risks
 Mortality
rates in HIVinfected
patients by
50%
Benefits
Adapted from Grunfeld. 6th CROI; 1999; Chicago. Palella. NEJM 1998;338:853.
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Drug-drug interactions
5. Resistance
Drugs That Should Not Be Used With Antiretrovirals
Drug Category
Indinavir
Ritonavir*
Saquinavir
Nelfinavir
Amprenavir
Nevirapine
Delavirdine
Efavirenz
Ca++ channel
blocker
(none)
bepridil
(none)
(none)
bepridil
(none)
(none)
(none)
Cardiac
(none)
amioderone
flecainide
propafenone
quinidine
(none)
(none)
(none)
(none)
(none)
(none)
Lipid Lowering
Agents
simvastatin
lovastatin
simvastatin
lovastatin
simvastatin
lovastatin
simvastatin
lovastatin
simvastatin
lovastatin
(none)
simvastatin
lovastatin
(none)
AntiMycobacterial
rifampin
none
rifampin
rifabutin
rifampin
rifampin
(none)
rifampin
rifabutin
(none)
Antihistamine
astemizole
terfenadine
astemizole
terfenadine
astemizole
terfenadine
astemizole
terfenadine
astemizole
terfenadine
(none)
astemizole
terfenadine
astemizole
terfenadine
cisapride
cisapride
cisapride
cisapride
cisapride
(none)
cisapride
H-2 blockers
Proton pump
inhibitors
cisapride
Neuroleptic
(none)
clozapine
pimozide
(none)
(none)
(none)
(none)
(none)
(none)
Psychotropic
midazolam
triazolam
midazolam
triazolam
midazolam
triazolam
midazolam
triazolam
midazolam
triazolam
(none)
midazolam
triazolam
midazolam
triazolam
Gastrointestinal
Drugs
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Drug-drug interactions
5. Resistance
Resistance
Genotypic Mutations Associated With Resistance to NRTI & NNRTIs
Agent
ZDV
41
67
69*
3TC
69*
ddI
65
ddC
65
d4T
70
Resistance mutations
151
69
50
ABC
151
184
69*
74
151
184
69*
74
151
184
69*
65
210
75
69*
74
Agent
151
115
215
219
333
333
178
151
184
Resistance mutations
DLV
103
EFV
100
103
NV
100
103
181
108
106
108
179
236
181
188
190
181
188
190
225
Resistance
Genotypic Mutations Associated With Resistance to PIs
Agent
APV
10
IDV
10
NFV
10
RTV
10
20
SQV
10
20
LPV
10
20
24
32
30
32
24
30
32
33
36
Resistance mutations
46 47 48 50 54
63
71
36
46
48
63
71
36
46
48
36
46
36
46
46
54
48
47
50
82
84
82
84
71
82
84
82
84
90
82
84
90
54
63
71
54
63
71
73
73
84
90
88
90
Overcoming Drug Resistance
Increase
exposure
to drug
RESISTANCE
Change to a
drug to which
virus shows
greater
susceptibility
Drug
Overcoming Drug Resistance
Change to a drug to which virus shows
greater susceptibility
Guided by Genotypic resistance testing
Goals of Antiretroviral
Therapy (ART)
• Eradication of HIV? Not possible with
currently available antiretroviral
medications.
GOALS OF THERAPY
Virologic goals
Immunologic goals:
Reduction in viral load to:
Achieve immune
reconstitution that is
quantitative (CD4 to
normal range) and
qualitative (pathogenspecific immune response)
1) halt disease progression
2) prevent/reduce resistant
variants
Therapeutic goals
Rational use of drugs
that achieves virologic
goals, but also:
1) maintains therapeutic
options
2) relatively free of side
effects
3) realistic in terms of
probability of adherence
Clinical goals
Prolongation of life
and improved
quality of life
Epidemiologic goals
Reduce HIV transmission
Importance of Initial Therapy
Naïve patient
Success Failure
Experienced
patient
Success Failure
Highlyexperienced
patient
Success Failure
HAART: Randomized Comparative Trials*:
HIV RNA <400 Copies/mL at Week 48 (ITT)
DuPont 006: IDV + AZT + 3TC
CNAAB 3005: IDV + AZT + 3TC
CNAAB 3005: ABC + AZT + 3TC
DuPont 006: EFV + IDV
Atlantic: NVP + d4T + ddI
Atlantic: 3TC + d4T + ddI
Agouron 542: NFV TID + d4T + 3TC
Atlantic: IDV + d4T + ddI
Agouron 542: NFV BID + d4T + 3TC
Study 863: NFV + d4T + 3TC
DuPont 006: EFV + AZT + 3TC
Study 863: LPV/r + d4T + 3TC
Gilead 903: TDF + 3TC + EFV
0
*All trials have 100 patients/arm
10
20
30
40
50
60
70
80
90
Patients (%)
Adapted from Bartlett J et al. 7th CROI, 2000
Correlation Between Nonadherence
and Virologic Failure
Patients with
virologic failure* (%)
100
80
60
40
20
0
>95
P<0.001, r=–0.554
*Virologic failure defined as HIV RNA
>400 copies/mL at last study visit
90–95
80–90
70–80
Adherence (%)
<70
Paterson DL et al. Ann Intern Med, 2000
Duration of initial HAART
Patients without change
in therapy (%)
100
80
60
40
20
0
0
120
240
360
480
600
720
Days
197 patients, Cologne 1997–1999
Fätkenheuer G et al. 8th ECCATH, 2001
Reasons for Modification of
Initial HAART
35
Patients (%)
30
25
20
15
10
5
0
Adverse
events
197 patients, Cologne 1997–1999
113/197 (57%) modified therapy
Virologic
failure
Lost to
follow-up
Other
Fätkenheuer G et al. 8th ECCATH, 2001
Considerations in Initiating
ART: Asymptomatic HIV
• 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
• 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):
• 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
Initial Treatment for Previously
Untreated Patients: Choosing
Regimens
• Three categories:
– 1 NNRTI + 2 NRTIs
– 1 PI + 2 NRTIs
– 3 NRTIs
• Few clinical endpoints to guide choices
• Advantages and disadvantages to each type of
regimen
• Individualize regimen choice
GUIDELINES
1987 AZT
1992 AZT/ddI
1995 2 NRTIs
1997 2 NRTIs + PI
1999 2 NRTI + PI/NNRTI
2002 2 NRTI + NNRTI or
PI or 3d NRTI
2004 2 NRTIs + PI/r or NNRTI
Initial Treatment:
Preferred Regimens
NNRTI-Based
# pills/day
Efavirenz*
+ (lamivudine or emtricitabine)
+ (zidovudine or tenofovir)
2-5
PI-Based
Lopinavir/ritonavir (Kaletra)
+ (lamivudine or emtricitabine)
+ zidovudine
*Avoid in pregnant women and women with pregnancy potential.
8-10
Future Trends
New agents in the pipeline
New agents should:
1.
2.
3.
4.
Exhibit high potency.
Adequate drug levels.
Activity against resistant isolates.
Penetration into all cellular and bodily compartments
(eg, central nervous system, genital tract).
5. Favorable drug interaction profile.
6. Minimal side effects.
7. Convenient to take, with no food restrictions and
minimal dosing requirements; preferably once daily.
Entry inhibitors under development
Class
Attachment
Inhibitors
Co-receptor
Inhibitors
Fusion
Inhibitors
Target
gp120, CD4
CXCR-4
Example Compounds
specific Mab, PRO 542
soluble CD4 and CD4-Ig
AMD-3100
CCR-5
SCH-C, specific Mab,
gp41
T-1249, D-peptides
Barriers to the Development of an
Effective AIDS Vaccine
• Sequence variation
• Protective immunity in natural infection not clearly
established
• Lack of adequate animal model to study vaccine protection
with HIV
• Latency and integration of HIV into host genome
• Transmission by cell-associated virus
• Limited knowledge about mucosal transmission and
immune responses
• Financial disincentives
• Ethical issues
Conclusion
• HIV/AIDS is no longer a “death sentence” for infected
individuals
• Cure is beyond reach at this stage, but patients can survive
years to decades longer.
• Better understanding of the HIV has allowed better
treatment modalities.
• More drugs and drug problems are on the horizon.
• Control of HIV replication by the host immune system may
be the best outlook for future research.
• Intense vaccine research is ongoing and ultimately will be
the major preventive measure against HIV infection