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Africa in 1979
The United States in 1979
Volume 305
December 10, 1981
Pneumocystis carinii pneumonia and mucosal candidiasis
in previously healthy homosexual men: evidence of a new
acquired cellular immunodeficiency
MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan,
RA Wolf, and A Saxon
An outbreak of community-acquired Pneumocystis carinii
pneumonia: initial manifestation of cellular immune
dysfunction
H Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman,
G Wormser, L Brettman, M Lange, HW Murray, and S Cunningham-Rundles
Severe acquired immunodeficiency in male homosexuals,
manifested by chronic perianal ulcerative herpes simplex
lesions
FP Siegal, C Lopez, GS Hammer, AE Brown, SJ Kornfeld, J Gold, J
Hassett, SZ Hirschman, C Cunningham-Rundles, BR Adelsberg, and et al.
Number 24
Opportunistic infections and Kaposi’s sarcoma in
homosexual men
D. Durack
TIME Magazine: AIDS
Response to AIDS Epidemic
• Stigmatization
• Consternation
• Resolve
– Scientific
– Personal
– Political
The First Therapeutic Phase
• Recognize and treat the acute
opportunistic infections early
The Second Therapeutic
Phase
• Prevent Opportunistic Infections
The Third Phase
AZT vs Placebo for Patient with
AIDS
Fischl, MA. NEJM, Jul 1987
1987: AZT is developed and
approved
Antiretroviral Agents Approved in the U.S.
Nucleoside RTI’s
Zidovudine
Didanosine
Zalcitabine
Stavudine
Lamivudine
Abacavir
Emtricitabine
(ZDV)
(ddI)
(ddC)
(d4T)
(3TC)
(ABC)
(FTC)
Nucleotide RTI
Tenofovir DF
Non-Nucleoside RTI’s
Nevirapine
Delavirdine
Efavirenz
(NVP)
(DLV)
(EFZ)
Protease Inhibitors
Saquinavir
Ritonavir
Indinavir
Nelfinavir
Amprenavir
Lopinavir/r
Atazanavir
(SQV)
(RTV)
(IDV)
(NFV)
(APV)
(LPV/r)
(ATZ)
Entry Inhibitor
Enfuvirtide
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
The Third Therapeutic Phase
• Treat the retroviral causative agent
quickly and aggressively
• “It’s the virus, stupid!”
• “Hit hard, hit early!”
Estimated Incidence of AIDS and Deaths of Adults/
Adolescents with AIDS*, 1985-1999, United States
No. Cases/deaths
25,000
1993 definition
implementation
AIDS
Deaths
20,000
15,000
10,000
5,000
0
85
86
87
88
89
90
91
92
93
94
95
96
Quarter-Year of Diagnosis/Death
*Adjusted for reporting delays
97
98
99
Fat Redistribution Syndrome
Complications of Antiretroviral Therapy
and Chronic HIV Infection
Decreased bone density
Mitochondrial toxicity hypothesis
Insulin resistance
Increased
cardiovascular risk??
Dyslipidemia
Morphologic changes/
“lipodystrophy”
Lactic acidosis
Hypertriglyceridemia
and low HDL-C
82
83
84
85
Buffalo hump
85
NRTI
Monotherapy
86
87
88
89
90
91
92
93
Dual-NRTI Therapy
94
95
96
97
98
00
02
HAART
Adapted from http://www.medscape.com/viewarticle/441490_2
The Fourth Therapeutic Phase
• Strategic planning: maximize benefit
and minimize harm
Metabolic Abnormalities in
Patients with HIV Infection
HIV
Associated
Dyslipidemias
Drug
Associated
Insulin
Resistance
Age
and Other
Associated
Protease
Inhibitors
Significant Drug Interactions
Primary Drug
Interacting Drug
Comment
Fluoroquinolone
DDI (non-enteric)
 Cipro AUC (separate by 2 hrs) (use DDI enteric)
Protease
Rifampin
 Protease AUC 70-90% (use boosted PI?)
Methadone
Ergotamine
Efav/Nevir, Roton/Lopin
Proteases
 Methadone
 Ergot levels
Rifabutin
Protease
Macrolide, FQ
Rifabutin AUC  2-3x 50%
 Rifabutin AUC Uveitis
Sildenafil
Protease
 Sildenfil AUC 2-11x (Hypertension)
Atorvastatin et al.
Protease
 Statin AUC 4-30x (Rhabdomyolysis)
Oral
contraceptives
Rifampin, Nevir,
Protease
 OC AUC - Find alternative
Benzodiazepine
Protease
 Benzo AUC
PI (Indin)
St. John’s Wort
Garlic
?Milk thistle, Ginger
 PI AUC
Prescribing Antiretrovirals
• What can be accomplished in 2004?
• What is the standard of care?
Expected Virologic Response of
Highly Active Antiretroviral Therapy
105
104
103
0.5 log 1 log 

< 50 
102
101
0
Assay
Detection
Limit
4
8
12
16
20
24
Time after initiation of therapy (wk)
Failure of ARV Therapy
• Virologic
–
–
–
–
–
Adherence
Absorption
Metabolism
Drug Interaction
Resistance
• Immunologic
– Drug specific
– Unknown
Genotype - Phenotype Database
Genotypic
Data
Phenotypic
Data
> 55,000
> 50,000
Sequence
(Database
interrogation)
>20,000 matched samples
VirtualPhenotype output
(average phenotype)
Proportion sensitive
& resistant
Chronology of AIDS
•
•
•
•
•
•
•
•
1979
1981
1984
1985
1987
1989
1997
2002
First case recognized
Report in MMWR, NEJM
HIV virus discovered
HIV serology developed
AZT approved
PCP Prophylaxis became standard
Proteases and Non-nucleosides approved
Global antiretroviral therapies become
more realistic with generic drugs
Role of Research
The History of Antipneumocystis
Prophylaxis
Number of Cases
50,000
CANCER
TREATMENT
PCP
1,000
INFANTILE
PCP
50
1970
1980
1990
2000
Likelihood of Developing
AIDS Within 3 Years
90.0%
85.5%
80.0%
70.0%
64.4%
60.0%
50.0%
40.1%
42.9%
40.0%
40.1%
32.6%
30.0%
20.0%
10.0%
0.0%
> 750
501-750
351-500
201-350
Š 200
32.6%
16.1%
16.1%
9.5%
8.1%
8.1%
2.0%
8.1%
3.7%
2.0%
3.2%
2.0%
Prevention of Opportunistic
Infections: Impact on Survival
Pathogen
Impact on
Prolong Survival Reference
Pneumocystis
+
Osmond, JAMA 1994
Chaisson, Arch 1992
Tuberculosis
+
Pape, Lancet 1993
MAC
+
Benson, JID 2000
CMV
-
Spector, NEJM 1996
Antiretroviral Drug Approval:
1987 - 2003
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Fos-Amp
FTC
T-20
ATAZ
EFV AMP
ABC
LPV/r TDF
APV
NFV
RTV DLV
IDV
NVP
3TC
SQV
d4T
ddC
ddI
AZT
1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2003
Indications for Initiating Antiretroviral Therapy for
the Chronically HIV-1 Infected Patient
AIDSINFO.NIH.GOV 11/10/2003
Do No Harm
• What trouble can your patient get into
while receiving antiretroviral therapy
• What complications should YOU
recognize when you see a patient in
consultation
Protease Inhibitors
Adverse Effects
Fortovase
Nausea
Vomiting
Abd. Pain
Headache
Increased LFTs
Ritonavir
Indinavir
Nelfinavir
Amprenavir
Lopinavir
Nausea
Vomiting
Anorexia
Diarrhea
Abd. Pain
Headache
Insomnia
Paresthesias
Nephrolithiasis
Diarrhea
Hematuria/pyuria
Nausea
Vomiting
Diarrhea
Increased bilirubin,
LFTs
Hair, nail disorders
Prop glycol
Nausea
Vomiting
Rash
Hypoglyc
Nausea
Vomiting
Diarrhea
LFTs
Hypertriglyc
Hypertriglyc
Hypertriglycer
Hypertrigly
Hypertrigly
42% Etoh
in oral sol
Hypertrigl
Fat Redistr
Fat Redistr
Fat Redistr
Fat Redistr
Fat Redistr
Fat Redistr
Other Abnormalities Associated with ART
• Bone
– Dimineralization
– Osteonecrosis
• Cardiovascular
– Premature atherosclerosis
• Other
Metabolic Abnormalities in
Patients with HIV Infection
Dyslipidemias
Dyslipidemias
Insulin
Insulin Resistance
Resistance
Protease
ProteaseInhibitors
Inhibitors
Protease Inhibitor Drug
Interactions
Ritonavir > other Pis
Concurrent medical issues
e.g.Tuberculosis!
Likelihood of Developing
AIDS Within 3 Years
90.0%
85.5%
80.0%
70.0%
64.4%
60.0%
50.0%
40.1%
42.9%
40.0%
40.1%
32.6%
30.0%
20.0%
10.0%
0.0%
> 750
501-750
351-500
201-350
Š 200
32.6%
16.1%
16.1%
9.5%
8.1%
8.1%
2.0%
8.1%
3.7%
2.0%
3.2%
2.0%
Antiretroviral Regimens Recommended for Treatment of
HIV-1 Infection in Antiretroviral Naïve Patients
AIDSINFO.NIH.GOV 11/10/2003
Antiretroviral Treatment Failure
Causes to Consider
• Adherence
• Therapeutic drug monitoring
– Cmin
• Resistance testing
– Genotype
– Phenotype
• Inhibitory quotient (IQ)
– Plasma Cmin/IC50 or IC90
Antiretroviral Regimens or Components that
Should Not be Used at Any Time
Table 13 from www.AIDSinfo.NIH.GOV; July 14, 2003
AZT vs Placebo for Patient with
AIDS Related Complex
Fischl, MA. NEJM, Jul 1987
Nucleoside Related Hepatic
Steatosis/Lactic Acidosis
• Mechanism:
– Inhibitor of DNA polymerase gamma
(mitochondrial
DNA synthesis)
• Incidence:
– “Low”, but high fatality rate
• Risk Factors:
– Female, obesity, prolonged use, pregnancy
• Presentation:
– GI (nausea, anorexia, pain, diarrhea)
– Weakness, dyspnea, hepatomegaly
–  lactate,  LFT (OT/PT),  anion gap (Na-[Cl+CO2] >16
Nucleoside Related Hepatic
Steatosis/Lactic Acidosis
CT
Screening
Therapy
Rechallenge
SOME patients have enlarged,
fatty liver
Do NOT stop RTI in every patient with
 lactate or  LFT
Lactic measurements are complicated
Stop RT if patient is symptomatic,
acidosic, or lactate > 5
Rx: Unknown
(Riboflavin, carnitine, thiamine)
Are any nucleosides safe?
Switch to NRTI sparing regimen?
Protease Associated
Coagulopathy
• Hemophilia A + B
–  PTT
–  Spontaneous bleeds
• Mechanism unknown
– May recur if rechallenged
Indinavir Crystals
•
•
•
•
•
•
Crystals: hematuria, pyuria
Crystals do not predict stone formation
Flank pain can occur without stones
Stones are radiolucent
(image with ultrasound or dye)
Therapy
– Treatment interruption for 1-3 days and hydration
Unusual
– Creatine , obstruction, “nephropathy”
HIV Associated Metabolic
Disorders
• Insulin resistance/glucose intolerance/diabetes
– Protease inhibitors (especially indinavir)
– Occur after 2-390 days
• Dyslipidemias
–
–
–
–
 cholesterol, TG ( TG: PI associated)
Fat wasting/atrophy (D4T associated)
Fat redistribution (PI)
Risk of pancreatitis
• Premature atherosclerosis
• Bone
– Demineralization
– Osteonecrosis
Treatment of HIV Associated
Metabolic Disorders
• Diabetes/Glucose Intolerance
– Follow usual guidelines including insulin sensitizing agents
– Only occasionally reverses after cessation of PI
• Hypertriglyceridemia/Hyprcholesterolemia
– Follow National Cholesterol Education Program
– Prefer prevastatin over p450 metabolized statins
– Switch HAART to NNRTI or Atazanavir or Abacavir based
regimen
• Fat redistribution
– Switch from D4T (atrophy)
– Switch from PI (redistribution)
– ? Metformin, growth hormone, STI, surgery
Prevalence of Drug Selection in
Antiretroviral Therapy–Naive Persons
Montreal
15%
United
Kingdom
10%
Boston
10%
San
Francisco
16%
Geneva
10%
New York
16%
US
cities
7%
Buenos Aires
15%
Weinstock H, et al. Antivir Ther. 2000;5(suppl 3):135; Boden D, et al. JAMA. 1999;282:1135-1141; Brenner B, et al. Int J Antimicrob Agents.
2000;16:429-434; Hecht FM, et al. N Engl J Med. 1998;339:307-311; Kijak GH, et al. Antivir Ther. 2001;6:71-77; Little SJ, et al. JAMA.
1999;282:1142-1149; Pillay D, et al. Antivir Ther. 2000;5(suppl 3):128; Yerly S, et al. Lancet. 1999;354:729-733.
Criteria for Considering Changing
Initial Antiretroviral Therapy
• Failure to attain reduction in viral load
– Week 4: 0.5-0.75 log  (CIII)
– Week 8: 1 log  (CIII)
– Week 16-24: Below assay detection (BIII)
• Detection of virus repeatedly after initial suppression below assay
•
•
•
•
detection
Reproducible, significant, (3x) increase in nadir viral load not
attributable to infection, vaccination test methodology, adherence
(BIII)
Double nucleoside therapy, even if undetectable (BIII)
Persistently declining CD4 count (CIII)
Clinical deterioration (DIII)
Recommendations for When to
Perform Resistance Testing
Clinical Setting
DHHS
Primary:
Initiating Rx
Consider
Chronic:
Initiating Rx
No
First Failure
Rec
Multiple Failure
Rec
After discontinuing drugs
(test while on regimen)
NO
Suboptimal supression
Rec
Pregnant
Same as Non-Preganant
Stigmatization
• AIDS involved deviant behavior
• Anyone with AIDS was suspected of
deviancy
• Fear: Transmission routes not well
known
– Community acquisition
– Health care acquisition
Scientific Challenge
• What causes the syndrome
• How can the syndrome be identified
• How is the disease transmitted
• How fast will the epidemic grow
• How to treat the syndrome
• How to prevent the syndrome
VirtualPhenotypeTM: lower section of report
Nucleoside Antiretrovirals
AZT
ddI
ddC
d4T
3TC/FTC
Abacavir
Efficacy
(log)
0.5-1.0
0.5-1.0
0.5-1.0
0.5-1.0
0.5-1.0
1.0-2.0
Dosing
Q12h
Q24h
Q8h
Q12h
Q12-24h
Q12h
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+/-
+/-
Toxicity
Macroanemia
Neutropenia
Myopathy
Neuropathy
Pancreatitis
Lactic acidosis
Lipodystrophy
+
+
Mitochondrial Toxicities
Related to NRTIs
• Neuropathy
• Myopathy
• Myocarditis
• Pancreatitis
• Hepatic steatosis
• Lipodystrophy
• Lactic acidosis
Non-Nucleoside RT Inhibitors
•
•
•
Nevirapine
– Autoinduction of metabolism
– Rash , fever, eosinophilia
– Hepatitis esp females, first 12 wks, health care
workers
Efavirenz
– CNS: vivid dreams, poor concentration etc
usually self limiting
– Hepatitis, rash uncommon
– False positive cannabis test
– Do not use in pregnancy (non-human primate
teratogenicity)
Delavirdine
– Almost never used
Fat Redistribution Syndrome