The Science of HIV: One Clinician

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The Science of HIV One Clinicians Perspective

• Amy V. Kindrick, M.D., M.P.H.
• National HIV/AIDS Clinicians Consultation Center
• UCSF Department of Family and Community
  Medicine/SFGH

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Estimated Incidence of AIDS and Deaths of
Adults/Adolescents with AIDS, 1985-1999, United
States
25,000
1993 definition
AIDS
implementation
Deaths
20,000
15,000
Number of Cases/Deaths
10,000
5,000
0
1987
1985
1986
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Quarter-Year of Diagnosis/Death
Adjusted for reporting delays
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AIDS Cases by Exposure Category and
Year of Report, 1985-1997, United States
80
70
Men who have sex with men (MSM)
60
50
40
Percent of Cases
Injecting drug use (IDU)
30
Heterosexual contact
20
MSM IDU
10
0
1985
1987
1989
1991
1993
1995
1997
Year of Report
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Cases with other or unreported risk excluded
pending medical record review and
reclassification.
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Dianna and her Sons, 1995
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Adults and Children Living With HIV/AIDS, End 2000
Eastern Europe Central Asia 700 000
Western Europe 540 000
North America 920 000
East Asia Pacific 640 000
North Africa Middle East 400 000
South South-East Asia 5.8 million
Caribbean 390 000
Sub-Saharan Africa 25.3 million
Latin America 1.4 million
Australia New Zealand 15 000
Total 36.1 million
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Estimated Adult and Child Deaths From HIV/AIDS
During 2000
Eastern Europe Central Asia 14 000
Western Europe 7 000
North America 20 000
East Asia Pacific 25 000
North Africa Middle East 24 000
South South-East Asia 470 000
Caribbean 32 000
Sub-Saharan Africa 2.4 million
Latin America 50 000
Australia New Zealand lt 500
Total 3.0 million
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Estimated HIV Incidence in Adults and Children,
2000
Eastern Europe Central Asia 250 000
Western Europe 30 000
North America 45 000
East Asia Pacific 130 000
North Africa Middle East 80 000
South South-East Asia 780 000
Caribbean 60 000
Sub-Saharan Africa 3.8 million
Latin America 150 000
Australia New Zealand 500
Total 5.3 million
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Y2K Worldwide 15,000 New HIV Infections a Day

• More than 95 are in developing countries
• 1,700 are in children under 15 years of age
• 13,000 are in persons aged 15 to 49 years, of
  whom
• gt50 are 1524-year-olds
• 47 are women

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Human Immunodeficiency Virus
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HIV Structure
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HIV Genome
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Immune System Overview
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Protection and Eradication
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Innate and Adaptive Immunity
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Lymphocyte Classes
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CD4 CD8 Activation
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CD8 Expansion
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HIV T Cell Interaction
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Mucosal HIV Transmission
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HIV Distribution In Lymph Nodes
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The Infection Cycle
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Viral Markers During Primary HIV Infection
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Western Blot Evolution
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Western Blot Evolution in Treated and Untreated
Primary HIV Infection
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Primary HIV InfectionCD4 and CD8 Response
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Natural History of HIV Infection
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Immunosuppression and Opportunistic Complications
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HIV Life Cycle
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Possible Sites of Therapeutic Intervention
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Mechanisms of Antiretroviral Action
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Protease Inhibition
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Typical CD4 Response to HAART
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Lymphocyte Dynamics
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Viral Decay on HAART
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Current Medications Abbreviations

• NRTI
• Abacavir ABC
• Didanosine ddI
• Lamivudine 3TC
• Stavudine d4T
• Zidovudine ZDV
• Zalcitabine ddC
• Trizivir TRZ
• NNRTI
• Delavirdine DLV
• Efavirenz EFV
• Nevirapine NVP

• PI
• Amprenavir AMP, APV
• Indinavir IND, IDV
• Lopinavir LOP, LPV
• Nelfinavir NLF, NFV
• Ritonavir RIT, RTV
• Saquinavir SAQ, SQV
• soft gel SGC, FTV
• hard gel HGC, INV

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Whats a Clinician to Do?

• Expanding number of agents adds complexity
• Minimal clinical experience when drugs released
  adds toxicity risk
• Shortage of data adds uncertainty

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Antiretroviral Therapy Persistent Uncertainties

• When to start
• What to start with
• When to change
• What to change to
• When to stop (if ever)

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Challenges of HAART

• Complexity
• Toxicity
• Accessibility
• Incomplete efficacy
• Viral resistance

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Antiretroviral Adverse Effects

• NRTIs
• Zidovudine HA, GI, bone marrow suppression
• Didanosine GI intolerance, pancreatitis
• Stavudine peripheral neuropathy
• Zalcitabine - peripheral neuropathy
• Abacavir HA, GI, hypersensitivity reaction

• NNRTIs
• Nevirapine - rash, liver
• Delavirdine - rash
• Efavirenz teratogenic in primates, CNS, rash
• PIs
• Indinavir nephrolithiasis
• Ritonavir GI intolerance
• Nelfinavir diarrhea
• Amprenavir GI intolerance

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Emerging Toxicities of HAART

• Lipodystrophy
• Dyslipidemia
• Insulin Resistance
• Lactic Acidosis
• Osteopenia and avascular necrosis

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Fat Redistribution Syndromes
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Cervico-dorsal Fat Pad
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Central Fat Accumulation
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Facial Lipoatrophy
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Avascular Necrosis of the Hip
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Osteopenia and Avascular Necrosis of the Radial
Head
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Drug-drug Interactions

• With other antiretrovirals
• With other classes of medications
• Anti-infectives
• Psychotropics
• Anticonvulsants
• Statins
• Sildenafil
• With recreational drugs

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Why Does HAART Fail?
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Adherence

• Drugs dont work if people dont take them.
• C. Everett Koop

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What Is Resistance?

• Viral replication in the presence of drug pressure

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Basic Pharmacology Principles
Cmax
Drug Level
Cmin
IC90
Area of Potential HIV Replication
IC50
Dosing Interval
Time
Dose
Dose
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How Does Resistance Develop?

• High replication and transcription error rates
  generate mutant HIV variants
• Spontaneously generated variants often contain
  mutations that confer survival advantage in the
  presence of antiretroviral agents
• poor adherence or suboptimal regimens can lead to
  resistance and viral breakthrough

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Development of Drug Resistance
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Primary Resistance
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Antiretroviral Resistance Testing

• Goals
• Improve virologic control and immunologic benefit
• Minimize exposure to ineffective agents
• Options
• Genotype
• widely used but complex to interpret
• Phenotype
• intuitively simpler but complex to interpret
• Virtual phenotype

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Alternatives To HAART

• PREVENTION!!!
• More HAART
• Enhanced potency
• Better tolerability
• New targets
• Immune-based strategies
• Cytokines
• Vaccination
• Structured treatment interruption

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Immunosuppression and Opportunistic Complications
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Primary HIV Infection Rash
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Primary HIV Infection Oral Ulcers
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Pneumocystis Carinii Pneumonia
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Severe PCP
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Cytomegalovirus Retinitis
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Herpes Simplex Virus
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Herpes Simplex Virus, Treated
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Dermatomal Herpes Zoster
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Progressive Multifocal Leukoencephalopathy
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Oral Candidiasis
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CNS Toxoplasmosis
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CNS Toxoplasmosis, Treated
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Kaposi Sarcoma
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Kaposi Sarcoma, Severe
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Human Papillomavirus
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Molluscum Contagiosum
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Bacillary Angiomatosis
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Seborrheic Dermatitis
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Eosinophilic Folliculitis
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Drug Hypersensitivity
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Resources for Clinicians Caring for Patients With
HIV/AIDS

• Handbooks
• Sanford Guide to HIV/AIDS Therapy
• The Medical Management of HIV Infection
• Internet
• HIV InSite (http//hivinsite.ucsf.edu)
• Medscape (www.medscape.com)
• HIV/AIDS Treatment Information Service
  (www.hivatis.org)
• Johns Hopkins (www.hopkins-aids.edu)

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Consultation Services for Clinicians Caring for
Patients with HIV/AIDS

• Local expert clinicians
• Regional and local AIDS Education and Training
  Centers
• National HIV Telephone Consultation Service
  (Warmline)
• [phone]
• National Clinicians Post-Exposure Prophylaxis
  Hotline (PEPline)
• (888) HIV-4911

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National HIV/AIDS Clinicians Consultation Center

• A Joint Program of UCSF
• and San Francisco General Hospital
• Supported by HRSA and CDC
• http//www.ucsf.edu/hivcntr
• PEPLine [phone]
• Warmline [phone]

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