Africa in 1979

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Africa in 1979
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The United States in 1979
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Volume 305 December 10, 1981
Number 24
Opportunistic infections and Kaposis sarcoma
inhomosexual men
Pneumocystis carinii pneumonia and mucosal
candidiasisin previously healthy homosexual men
evidence of a newacquired cellular
immunodeficiency
D. Durack
MS Gottlieb, R Schroff, HM Schanker, JD Weisman,
PT Fan, RA Wolf, and A Saxon
An outbreak of community-acquired Pneumocystis
cariniipneumonia initial manifestation of
cellular immunedysfunction
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 simplexlesions
FP Siegal, C Lopez, GS Hammer, AE Brown, SJ
Kornfeld, J Gold, J Hassett, SZ Hirschman, C
Cunningham-Rundles, BR Adelsberg, and et al.
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TIME Magazine AIDS
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Response to AIDS Epidemic

• Stigmatization
• Consternation
• Resolve
• Scientific
• Personal
• Political

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The First Therapeutic Phase

• Recognize and treat the acute opportunistic
  infections early

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The Second Therapeutic Phase

• Prevent Opportunistic Infections

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The Third Phase
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AZT vs Placebo for Patient with AIDS
Fischl, MA. NEJM, Jul 1987
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1987 AZT is developed and approved
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Antiretroviral Agents Approved in the U.S.
Nucleoside RTIs Zidovudine (ZDV)
Didanosine (ddI) Zalcitabine (ddC) Stavudine
(d4T) Lamivudine (3TC) Abacavir
(ABC) Emtricitabine (FTC)
Non-Nucleoside RTIs Nevirapine (NVP)
Delavirdine (DLV) Efavirenz (EFZ)
Protease Inhibitors Saquinavir (SQV)
Ritonavir (RTV) Indinavir (IDV) Nelfinavir
(NFV) Amprenavir (APV) Lopinavir/r (LPV/r)
Atazanavir (ATZ)
Entry Inhibitor Enfuvirtide
Nucleotide RTI Tenofovir DF
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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
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The Third Therapeutic Phase

• Treat the retroviral causative agent quickly and
  aggressively
• Its the virus, stupid!
• Hit hard, hit early!

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Estimated Incidence of AIDS and Deaths of Adults/
Adolescents with AIDS, 1985-1999, United States
Adjusted for reporting delays
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Fat Redistribution Syndrome
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Complications of Antiretroviral Therapy and
Chronic HIV Infection
Decreased bone density Mitochondrial toxicity
hypothesis Insulin resistance Dyslipidemia Morphol
ogic changes/lipodystrophy
Increased cardiovascular risk??
Lactic acidosis
Hypertriglyceridemiaand low HDL-C
Buffalo hump
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NRTIMonotherapy
Dual-NRTI Therapy
HAART
Adapted from http//www.medscape.com/viewarticle/4
41490_2
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The Fourth Therapeutic Phase

• Strategic planning maximize benefit and minimize
  harm

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Metabolic Abnormalities in Patients with HIV
Infection
Drug Associated
Insulin Resistance
Age and Other Associated
Protease Inhibitors
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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?)
MethadoneErgotamine Efav/Nevir, Roton/LopinProteases ? 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. Johns WortGarlic?Milk thistle, Ginger ? PI AUC
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Prescribing Antiretrovirals

• What can be accomplished in 2004?
• What is the standard of care?

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Expected Virologic Response of Highly Active
Antiretroviral Therapy
105 104 103 102 101 0
0.5 log ?
1 log ?
lt 50 ?
Assay Detection Limit
4
8
12
16
20
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Time after initiation of therapy (wk)
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Failure of ARV Therapy

• Virologic
• Adherence
• Absorption
• Metabolism
• Drug Interaction
• Resistance
• Immunologic
• Drug specific
• Unknown

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Genotype - Phenotype Database
Genotypic Data
Phenotypic Data
Sequence (Database interrogation)
gt 55,000
gt 50,000
gt20,000 matched samples
VirtualPhenotype output (average phenotype)
Proportion sensitive resistant
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Chronology of AIDS

• 1979 First case recognized
• 1981 Report in MMWR, NEJM
• 1984 HIV virus discovered
• 1985 HIV serology developed
• 1987 AZT approved
• 1989 PCP Prophylaxis became standard
• 1997 Proteases and Non-nucleosides approved
• 2002 Global antiretroviral therapies become
  more realistic with generic drugs

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Role of Research
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The History of Antipneumocystis Prophylaxis
50,000
Number of Cases
1,000
50
1980
1970
1990
2000
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Likelihood of Developing AIDS Within 3 Years
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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
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Antiretroviral Drug Approval1987 - 2003
Fos-AmpFTCT-20ATAZ
LPV/r
TDF
APV
AMP
EFV ABC
NFV DLV
RTV IDV NVP
3TC SQV
d4T
ddC
ddI
AZT
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Indications for Initiating Antiretroviral Therapy
for the Chronically HIV-1 Infected Patient
11/10/2003
AIDSINFO.NIH.GOV
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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

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Protease InhibitorsAdverse Effects
Fortovase
Ritonavir
Indinavir
Nelfinavir
Amprenavir
Lopinavir
Nausea Vomiting Abd. Pain Headache Increased
LFTsHypertriglyc Fat Redistr
Nausea Vomiting Anorexia Diarrhea Abd.
Pain Headache Insomnia ParesthesiasHypertriglyc
Fat Redistr
Nephrolithiasis Hematuria/pyuria Nausea Vomiting D
iarrhea Increased bilirubin, LFTsHair, nail
disorders Hypertriglycer Fat Redistr
Diarrhea Hypertrigly Fat Redistr
Prop glycol Nausea Vomiting Rash Hypoglyc Hype
rtrigly Fat Redistr
Nausea Vomiting Diarrhea LFTs 42 Etoh in
oral solHypertrigl Fat Redistr
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Other Abnormalities Associated with ART

• Bone
• Dimineralization
• Osteonecrosis
• Cardiovascular
• Premature atherosclerosis
• Other

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Metabolic Abnormalities in Patients with HIV
Infection
Insulin Resistance
Insulin Resistance
Protease Inhibitors
Protease Inhibitors
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Protease Inhibitor Drug Interactions

• Ritonavir gt other Pis
• Concurrent medical issues
• e.g.Tuberculosis!

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Likelihood of Developing AIDS Within 3 Years
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Antiretroviral Regimens Recommended for Treatment
of HIV-1 Infection in Antiretroviral Naïve
Patients
11/10/2003
AIDSINFO.NIH.GOV
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Antiretroviral Treatment Failure Causes to
Consider

• Adherence
• Therapeutic drug monitoring
• Cmin
• Resistance testing
• Genotype
• Phenotype
• Inhibitory quotient (IQ)
• Plasma Cmin/IC50 or IC90

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Antiretroviral Regimens or Components that Should
Not be Used at Any Time
Table 13 from www.AIDSinfo.NIH.GOV July 14, 2003
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AZT vs Placebo for Patient withAIDS Related
Complex
Fischl, MA. NEJM, Jul 1987
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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-ClCO2 gt16

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Nucleoside Related Hepatic Steatosis/Lactic
Acidosis
CT SOME patients have enlarged, fatty
liver Screening Do NOT stop RTI in every patient
with ? lactate or ? LFT Lactic
measurements are complicated Therapy Stop RT if
patient is symptomatic, acidosic, or
lactate gt 5 Rx Unknown (Riboflavin,
carnitine, thiamine) Rechallenge Are any
nucleosides safe? Switch to NRTI sparing regimen?
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Protease Associated Coagulopathy

• Hemophilia A B
• ? PTT
• ? Spontaneous bleeds
• Mechanism unknown
• May recur if rechallenged

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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

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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

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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

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Prevalence of Drug Selection in Antiretroviral
TherapyNaive Persons
Weinstock H, et al. Antivir Ther. 20005(suppl
3)135 Boden D, et al. JAMA. 19992821135-1141
Brenner B, et al. Int J Antimicrob Agents.
200016429-434 Hecht FM, et al. N Engl J Med.
1998339307-311 Kijak GH, et al. Antivir Ther.
2001671-77 Little SJ, et al. JAMA.
19992821142-1149 Pillay D, et al. Antivir
Ther. 20005(suppl 3)128 Yerly S, et al.
Lancet. 1999354729-733.
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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)

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Recommendations for When to Perform Resistance
Testing
Clinical Setting DHHS
PrimaryInitiating Rx Consider
ChronicInitiating Rx No
First Failure Rec
Multiple Failure Rec
After discontinuing drugs(test while on regimen) NO
Suboptimal supression Rec
Pregnant Same as Non-Preganant
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Stigmatization

• AIDS involved deviant behavior
• Anyone with AIDS was suspected of deviancy
• Fear Transmission routes not well known
• Community acquisition
• Health care acquisition

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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

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VirtualPhenotypeTM lower section of report
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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
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Mitochondrial Toxicities Related to NRTIs

• Neuropathy
• Myopathy
• Myocarditis
• Pancreatitis
• Hepatic steatosis
• Lipodystrophy
• Lactic acidosis

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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 etcusually
  self limiting
• Hepatitis, rash uncommon
• False positive cannabis test
• Do not use in pregnancy (non-human primate
  teratogenicity)
• Delavirdine
• Almost never used

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Fat Redistribution Syndrome