The Science of HIV:

One Clinician’s Perspective

Amy V. Kindrick, M.D., M.P.H.

National HIV/AIDS Clinicians’
Consultation Center
UCSF Department of Family and
Community Medicine/SFGH
 Estimated Incidence of AIDS and Deaths of
Adults/Adolescents with AIDS*, 1985-1999,
25,000
United States
AIDS 1993 definition
Number of Cases/Deaths

Deaths implementation
20,000

15,000

10,000

5,000

0
198519861987198819891990199119921993199419951996199719981999
Quarter-Year of Diagnosis/Death
*Adjusted for reporting delays
 AIDS Cases by Exposure Category and
Year of Report, 1985-1997, United States
80

70
Men who have sex with men (MSM)
Percent of Cases

60
50
40
Injecting drug use (IDU)
30

20 Heterosexual contact
10 MSM & IDU
0
1985 1987 1989 1991 1993 1995 1997
Year of Report
11

es with other or unreported risk excluded pending medical record review and reclassification.
Dianna and her Sons, 1995
Adults and Children Living With
HIV/AIDS, End 2000
Eastern
Western Europe
North Europe & Central
America Asia
920 540
North 700
East Asia &
000
Pacific
000
Caribbean Africa
000
South
640 000
& South-East
390 & Middle
Asia
East
000 400 Sub- 5.8
Latin Saharan
America 000Africa
million
Australia
& New
1.4 25.3 Zealand
million million 15 000

Total: 36.1 million

Estimated Adult and Child Deaths

From HIV/AIDS During 2000

Eastern
Western Europe &
North Europe Central Asia
America
20 000 7
North
000 14 000
East Asia &
Pacific
Caribbean Africa South
25 000
& South-East
32 000 & Middle
Asia
East
Latin 24Saharan
000
Sub- 470 000
America Australia
Africa & New
50 000 2.4 Zealand
million < 500

Total:
3.0 million
Estimated HIV Incidence in Adults
and Children, 2000
Eastern
Western Europe &
North Europe Central Asia
America
45 000 30
North
000 250 East Asia &
000
Pacific
South
Caribbean Africa 130 000
& South-East
60 000 & Middle
Asia
East
Latin 80Saharan
000
Sub- 780 000
America Australia
Africa & New
150 3.8 Zealand
000 million 500

Total: 5.3 million

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:
– >50% are 15–24-year-olds
– 47% are women
Human Immunodeficiency Virus
HIV Structure
HIV Genome
Immune System Overview
Protection and Eradication
Innate and Adaptive Immunity
Lymphocyte Classes
CD4 CD8 Activation
CD8 Expansion
HIV – T Cell Interaction
Mucosal HIV Transmission
HIV Distribution In Lymph Nodes
The Infection Cycle
Viral Markers During Primary HIV
Infection
Western Blot Evolution
Western Blot Evolution in
Treated and Untreated Primary
HIV Infection
Primary HIV Infection:
CD4 and CD8 Response
Natural History of HIV Infection
Immunosuppression and
Opportunistic Complications
HIV Life Cycle
Possible Sites of Therapeutic
Intervention
Mechanisms of Antiretroviral
Action
Protease Inhibition
Typical CD4 Response to HAART
Lymphocyte Dynamics
Viral Decay on HAART
Current Medications &
Abbreviations
NRTI PI
• Abacavir ABC • Amprenavir AMP,
• Didanosine ddI APV
• Lamivudine 3TC
• Indinavir IND, IDV
• Stavudine d4T
• Lopinavir LOP, LPV
• Zidovudine ZDV
• Zalcitabine ddC • Nelfinavir NLF, NFV
• Trizivir TRZ • Ritonavir RIT, RTV
NNRTI • Saquinavir SAQ, SQV
• Delavirdine DLV – soft gel SGC, FTV
• Efavirenz EFV
– hard gel HGC, INV
• Nevirapine NVP
What’s a Clinician to Do?
• Expanding number of agents adds
complexity
• Minimal clinical experience when
drugs released adds toxicity risk
• Shortage of data adds uncertainty
Antiretroviral Therapy:
Persistent Uncertainties
• When to start
• What to start with
• When to change
• What to change to
• When to stop (if ever)
Challenges of HAART
• Complexity
• Toxicity
• Accessibility
• Incomplete efficacy
• Viral resistance
 Antiretroviral Adverse Effects
NRTIs NNRTIs
• Zidovudine – HA, GI, • Nevirapine - rash,
bone marrow liver
suppression • Delavirdine - rash
• Didanosine – GI • Efavirenz –
intolerance, teratogenic in
primates, CNS, rash
pancreatitis
PIs
• Stavudine – • Indinavir –
peripheral nephrolithiasis
neuropathy • Ritonavir – GI
• Zalcitabine - intolerance
peripheral • Nelfinavir – diarrhea
neuropathy • Amprenavir – GI
• Abacavir – HA, GI, intolerance
Emerging Toxicities of HAART
• Lipodystrophy
• Dyslipidemia
• Insulin Resistance
• Lactic Acidosis
• Osteopenia and avascular necrosis
Fat Redistribution Syndromes
Cervico-dorsal Fat Pad
Central Fat Accumulation
Facial Lipoatrophy
Avascular Necrosis of the Hip
Osteopenia and Avascular
Necrosis of the Radial Head
Drug-drug Interactions
• With other antiretrovirals
• With other classes of medications
– Anti-infectives
– Psychotropics
– Anticonvulsants
– Statins
– Sildenafil
• With recreational drugs
Why Does HAART Fail?
Adherence

“Drugs don’t work if people don’t

take them.”
– C. Everett Koop
What Is Resistance?
• Viral replication in the presence of
drug pressure
 Basic Pharmacology Principles

Cmax

Drug Cmin
Level
IC90
Area of Potential HIV Replication
IC50
Dosing Interval
Time
Dose Dose
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’
Development of Drug Resistance
Primary Resistance
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”
Alternatives To HAART
• PREVENTION!!!
• More HAART
– Enhanced potency
– Better tolerability
– New targets
• Immune-based strategies
– Cytokines
– Vaccination
– Structured treatment interruption
Immunosuppression and
Opportunistic Complications
Primary HIV Infection Rash
Primary HIV Infection Oral Ulcers
Pneumocystis Carinii Pneumonia
Severe PCP
Cytomegalovirus Retinitis
Herpes Simplex Virus
Herpes Simplex Virus, Treated
Dermatomal Herpes Zoster
Progressive Multifocal
Leukoencephalopathy
Oral Candidiasis
CNS Toxoplasmosis
CNS Toxoplasmosis, Treated
Kaposi Sarcoma
Kaposi Sarcoma, Severe
Human Papillomavirus
Molluscum Contagiosum
Bacillary Angiomatosis
Seborrheic Dermatitis
Eosinophilic Folliculitis
Drug Hypersensitivity
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)
 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)
– (800) 933-3413
• National Clinicians’ Post-Exposure
Prophylaxis Hotline (PEPline)
– (888) HIV-4911
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 (888) 448-4911

Warmline (800) 933-3413