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HIV Resistance: Introduction
Myron S. Cohen, MD
J. Herbert Bate Professor of Medicine,
Microbiology and Immunology and Epidemiology
Director, UNC Center for Infectious Diseases
The University of North Carolina at Chapel Hill
Disclosures
• Nothing to disclose
Question:
What geographic region are you from?
North America
Europe
Asia/Pacific Rim
Africa
South America
Question:
What is your primary area of responsibility?
Administration
Research
Clinical
Industry
Other
Question:
How long have you been involved
in HIV care?
< 5 years
6-10 years
10-15 years
15-20 years
> 20 years
HIV Resistance Topics
• Transmission, resistance, and compartments (Cohen)
• Prevalence of transmitted resistance (Pillay)
• Selective pressure, resistance, and patient care (Eron)
• Testing for resistance (Sax)
– who, what, when, where, why and how???
• Moderator (Smith)
• Summary (Cohen)
Booth and Geretti. JAC 2007;59:1047-56.
Transmission of HIV:
Biological Requirements
Infectious
Susceptibility
Inoculum (concentration)
Hereditary resistance
Phenotypic factors
Innate resistance
Acquired (immune) resistance
Cohen and Galvin. Nat Microbiol Rev.
2004;2:33-42.
Blood Viral Load and
HIV-1 Transmission
% Partners Infected
30
20
10
0
<2.6
2.6-3.5
3.6-4.0
4.0-4.7
HIV-RNA Load (log10cp/mL)
Quinn et al. NEJM 2000;342:921-9.
>4.7
Viremia and Shedding
in Acute HIV
log10 HIV-1 RNA copies per mL
9
7
5
Blood
3
Semen
1
0
4
8
12
16
20
Weeks Since Acute HIV infection
Dumond et al. AIDS. 2007;21:1899-1908.
24
28
Resistance and the Spread
of HIV
• Resistance markers and sexual networks
– Brenner et al. JID 2007;195:951-9.
– Brenner et al. J Virol. 2002;76:1753-61.
• Resistance and representation: Ecological Analysis
– Corvasce et al. Antivir Ther. 2006;11:329-34.
– Turner et al. JAIDS 2004;37:1627-31.
– Yerly et al. Antivir Ther. 2004;93:75-84.
– de Mendoza et al. Clin Infect Dis. 2004;39:1231-8.
– Violin et al. JAIDS 2004;36:761-4.
– UK Collaborative study. BMJ 2001;322:1087-8.
Resistant Variants Missing
• 220 recent and 373 chronic infections
• Resistance in chronics = 72.4%
– one class 29.0%
– two classes 27.6%
– three classes 15.8%
• In recently infected patients = 10.5%
– one class 9.1%
– two classes 1.4%
– three classes 0%
• OR 0.39, p<.0001
Yerly et al. Antivir Ther. 2004;93:75-84.
HIV Diminished Representation
• Comparison of resistant variants in a “potential
transmitters” (n=380/552) vs.
• “Primary” HIV Infection (n=59/305)
…M184V was under-represented
-PHI/PT 0.14 vs. 0.93 for other mutations
-M184V lower plasma viremia (0.8 logs)
Turner et al. JAIDS 2004;37:1627-31.
HIV Resistance and Compartments
Male Genital Tract
Exposure (% of blood plasma)
0
50%
APV (20%)
ENF (ND)
100%
NVP (70%)
150%
ABC (150%)
200%
ZDV (200%)
500%
TDF (500%)
600%
3TC (600%)
IDV (100%)
d4T (2%)
EFV (3%)
SQV (3%)
RTV (3%)
LPV (5%)
NFV (5%)
NRTI
Cohen et al. adapted from Ann
Intern Med. 2007;146:591-601.
PI
NNRTI
FI
Female Genital Tract
Exposure (% of blood plasma)
0
200%
ddI (100%)
SQV(ND)
EFV (0.6%)
400%
600%
IDV (200%)
3TC (400%)
FTC (600%)
ZDV (200%)
TDF (400%)
ABC (150%)
d4T (4%)
RTV (20%)
DLV (20%)
ATV (30%)
LPV (30%)
ABC (40%)
APV (50%)
NVP (80%)
Cohen et al. adapted from Ann
Intern Med. 2007;146:591-601.
NRTI
PI
NNRTI
HIV Resistance and
the Genital Tract (examples…not inclusive)
• Eron JJ, Vernazza PL, Johnston DM, et al. Resistance of HIV-1 to
antiretroviral agents in blood and seminal plasma: implications for
transmission.
– AIDS 1998;12:F181-9.
• Si-Mohamed A, Kazatchkine M, Heard I, et al. Selection of drugresistant variants in the female genital tract of human
immunodeficiency virus type 1-infected women receiving
antiretroviral therapy.
– JID 2000;182:112-22.
• Solas C, Lafeuillade A, Halfon P, Chadapaud S, Hittinger G,
Lacarelle B. Discrepancies between protease inhibitor
concentrations and viral load in reservoirs and sanctuary sites in
human immunodeficiency virus-infected patients.
– Antimicrob Agents Chemother. 2003;47:238-43.
Resistant Variants in Semen
Sequential sampling in blood and semen
Persistent HIV resistant variants in semen >3 years
after HIV acquisition (2/5)
Onward transmission of resistant variants (n=2)
Smith et al. JID 2007:196:356
The End of the Beginning…of
this program
• Transmitted resistance is observed, albeit perhaps selective
• Viral resistance patterns likely affect the probability of
transmission through reduced viral fitness, replication and viral
concentration or “other factors” yet to be determined
• Minor variants not detected through bulk sequencing may prove
important
• The effects of resistance on transmission could ultimately affect
the selection of initial therapy, as well as the public health
implications of the choice of combinations of agents