Transcript Slide 1

ART FOR HIV PREVENTION:
PANACEA OR PANDORA’S BOX?
KENNETH H. MAYER, M.D.
HIV TRANSMISSION
• SIGNIFICANT, LOW PROBABILITY EVENT
(<1/100 AVERAGE)
MULTIPLE CO-FACTORS ARE INVOLVED
 PLASMA VIRAL LOAD   TRANSMISSION
CAN WIDER HAART ACCESS ↓ THE SPREAD OF NEW
INFECTIONS?
• SEXUALLY TRANSMITTED INFECTIONS (STI)  HIV
TRANSMISSION AND ACQUISITION:
CAN STI CONTROL ↓ HIV SPREAD?
• BLOOD AND GENITAL HIV MAY CHANGE IN PARALLEL,
BUT LOCAL FACTORS, E.G. STI, HAART
CONCENTRATIONS MAY ALTER HIV IN DIFFERENT
COMPARTMENTS
• BIOLOGICAL INTERVENTIONS MAY BE INFLUENCED BY
BEHAVIORAL ISSUES
APPROACHES TO PREVENT HIV TRANSMISSION
DECREASE SOURCE OF
INFECTION
•Barrier Protection
•Treat STI
•Antiretroviral Therapy
•Maternal-child
transmission
•partner’s HIV load
•Rx of acute infection
•Blood screening
•Circumcision
DECREASE HOST
SUSCEPTIBILITY
•Barrier protection
•Treat STI
•PEP
•PREP
•Microbicides
•Vaccines
•Infection Control
•Circumcision
ALTER RISK-TAKING BEHAVIOR
•Condom promotion
•Individual interventions
•Couples interventions
•Community-based interventions
•Structural interventions (e.g., economic)
30
Female-to-Male
Transmission
Male-to-Female
Transmission
All subjects
25
20
15
10
Viral load (HIV-1 RNA copies/ml) and HIV transmission
Source: Quinn N, et al, N Eng J Med 2000
>50 000
10 000-49 999
3500-9999
400-3499
<400
>50 000
10 000-49 999
3500-9999
400-3499
<400
>50 000
10 000-49 999
3500-9999
0
400-3499
5
<400
Transmission rate per 100 Person-Years
PLASMA HIV RNA PREDICTS
LIKELIHOOD OF TRANSMISSION
HOW HIV INFECTS MUCOSA
HSV control: Rationale for HSV-2 control
to reduce HIV transmission
Probability of HIV infection
in the HIV- partner
per 10 000 contacts
HIV plasma RNA in the
HIV+ partner (copies/ml)
HSV+
HSV-
<1700
10
0.4
1700-12,499
23
5
12,500-38,499
18
2
>38,500
36
7
Source: Wawer M et al, Lancet 1999
Syphilis Among Fenway Clients:
“The new normal”
60
2.5
50
2
Cases
Test +
1.5
30
%
No.
40
1
20
0.5
10
0
0
1997 1998 1999 2000 2001 2002 2003 2004 2005
Acute HIV and STD episodes
HIV RNA in Semen
(Log10 copies/ml)
(Cohen and Pilcher, JID, 2005
5
4
3
2
WHY ART FOR PREVENTION?
• HIV is spreading rapidly, more than 5 million
new infections in the next year!
• Behavioral interventions have not resulted in
long term changes in most settings
• Vaccines and Microbicides are years away
• ART is available now!
• HOWEVER, ART is relatively expensive,
needs to be used repetitively, may result in
toxicities, and can select for resistance, and
may result in behavioral disinhibition.
HOW HAART COULD ALTER HIV
TRANSMISSION: NEED TO MONITOR
PARTNERS
PVL

GENITAL TRACT
HIV

TRANSMISSION

SURVIVAL
PLHIV

DURATION OF
INFECTIOUSNESS

TRANSMISSION
• RELEVANT ISSUES: ACCESS, ADHERENCE,
PREVENTION, STI RX.
Effects of Disease Stage and Zidovudine Therapy on the
Detection of Human Immunodeficiency Virus Type 1 in Semen
Deborah J. Anderson, Thomas R. O’Brien, Joseph A. Politch, Adriana Martinez, George R. Seage III,
Nancy Padian, Robert Horsburgh, Kenneth H. Mayer
JAMA 267:2679-2774, 1992.
Cross-sectional (n=95) and longitudinal (n=35)
studies of HIV-1 in semen from HIV+ men.
Results: HIV-1 cultured from seminal plasma
and semen cells
Intermittent shedding
HIV with leukocytospermia
HIV in advanced disease stage
HIV with zidovudine ART
T Lymphocytes and Macrophages, but not Motile Spermatozoa,
are a Significant Source of HIV in Semen
Alison J. Quayle, Chong Xu, Kenneth H. Mayer, Deborah J. Anderson
Journal of Infectious Diseases 176:960-968, 1997.
T lymphocytes and macrophages are principal
sources of HIV-1 in semen.
Semen HIV in patients with suppressed
viral load
Patients (%) with
detectable HIV in semen
Potent ART
Controls (drug naive)
100
n=55
n=114
p<0.0001
80
p=0.025
60
40
20
0
HIV-RNA
HIV-DNA
Vernazza, Cohen et al., AIDS, 2000
Acute Infections and HIV Prevention
Rakai study: 40% of new transmissions were from
acutely infected pts (Wawer, JID, 2005)
Quebec study: almost ½ new infections were from
recently infected pts (Brenner, JID, 2007)
Using discordant HIV rapid tests results and RNA
pooling, almost 2% of STD clinic pts in Malawi
were identified with acute HIV infection (Pilcher,
NEJM, 2005)
Could the identification of “hot spots” of newly
infected pts present opportunities for early ART
and behavioral interventions to slow HIV spread?
Can Chronic HAART Decrease
HIV Transmission?
 HIV INCIDENCE IN BRAZIL AND TAIWAN
MULTIPLE REPORTS OF INCREASING
TRANSMISSION OF RESISTANT HIV I5-30%
OF NEWLY INFECTED PATIENTS
HPTN 052: RCT OF HAART TO ASSESS
EFFECT ON TRANSMISSION. 1750 HIV
discordant couples:India, Brazil, Thailand,
Malawi, Zimbabwe, U.S.
Early vs. later ART, CD4 >300
•Monthly monitoring, couples counseling
Preclinical PEP/PrEP Studies
• NNRTI or NRTI were protective
– 70% to 100% Effective/exposure
• Emtricitabine + Tenofovir
– The combination was effective
– Even after repeated rectal exposures (14)
• The prophylactic activity probably reflects
– Long intracellular half life
– Activity in Macrophages
– High concentration in genital tissues
Tsai ‘95; Van Rompay ‘99 ‘00 ‘01 ’04 ‘07; Subbarao ’05; Heneine ‘06
Male Genital Tract
Exposure
APV (20%)
LPV (5%)
NFV (5%)
EFV (3%)
SQV (3%)
RTV (3%)
d4T (2%)
IDV (100%)
ENF (ND)
NVP (70%)
0%
ABC (150%)
ZDV (200%)
100%
ddI (100%)
SQV (ND)
ABC (150%)
EFV (0.6%)
TDF (500%)
200%
300%
IDV (200%)
3TC (400%)
ZDV (200%)
TDF (400%)
400%
3TC (600%)
500%
FTC (600%)
d4T (4%)
RTV (20%)
Female Genital Tract
Exposure
DLV (20%)
ATV (30%)
LPV (30%)
ABC (40%)
APV (50%)
NVP (80%)
Fusion Inhibitors
Nucleoside
Reverse
Transcriptase
Inhibitors
Protease Inhibitors
Nonnucleoside
Reverse Transcriptase
Inhibitors
(Kashuba et al)
Example:
US
DHHS
Guidelines
for
NonOccupational
PEP
MMWR 2005
NPEP IN BRAZILIAN MSM
• PEP (AZT/3TC) 4 day starter pack
– 28 day course
• N=200 high risk men
– Followed over 24.2 months
• 68 used PEP 109 times
• HIV incidence 2.9/100py
–
–
–
–
10 in those who did not use PEP (N=132)
Thought partner was HIV-,
Did not appreciate risk of that contact
1 in a PEP user (N=68)
• Risk Behavior decreased
Schechter M et al (2004) JAIDS 35:519-525
Tenofovir DF + Emtricitabine or
Lamivudine for Non-Occupational PEP
– TDF/FTC (n=68)
– TDF/3TC (n=44)
– AZT/3TC (n=122)
– AZT/3TC+ 3rd drug
(n=119)
• Mainly MSM,
similar between
NPEP arms
Mayer KH, et al. JAIDS. 2007
Regimen Completion Rates
100
80
87.5%
72.7%
Patients (%)
Treatment arms
60
42.1%*
38.8%*
40
20
0
FTC/
TDF
TDF +
3TC
ZDV/
3TC
*P<0.0001 versus TDF-based regimens
ZDV/
3TC +
3rd Drug
Tenofovir DF + Emtricitabine or
Lamivudine for Non-Occupational PEP
• Tenofovir:
diarrhea or
abdominal
discomfort
• Zidovudine:
nausea and
vomiting: AE’s
more serious
Adverse Events (%)
FTC/
TDF
TDF +
3TC
ZDV/
3TC
ZDV/3TC +
3rd Drug
Diarrhea
47.5*
31.3
9.8
58.8
Fatigue
30
28.1
39.3
48.5*
Abdominal
discomfort
47.5†
20.3†
3.3
2.9
Nausea/
vomiting
22.5
18.8
55.7†
58.8†
Headache
22.5
18.8
24.6
11.8
Mayer KH, et al. JAIDS. 2007
*P<0.05 and †P<0.01.
Risk Behavior at Time of Incident
60
56.5
Percent
50
40
32.6
26.1
30
20
10
0
Unprotected Anal
Sex
Alcohol Use
Recreational Drug
Use
Note: TDF/3TC group reported more ua than the AZT/3TC group (30%),
and about the same as the AZT/3TC+1 group (52%).
RISK BEHAVIOR IS NOT UNIFORM

Calendar-based
retrospective history on
newly infected MSM

“Susceptible” period
from 3 months before last
negative to first HIV
positive test

Each row represents a
newly infected MSM

Each dot represents a
report of at least one
unprotected anal or oral
sex contact with HIV
positive or unknown
partner
S Buchbinder 2005
• Phase 2, Randomized, Double Blinded, Placebo Controlled Trial
• Conducted between June 2004 and March 2006
• Cameroon; Nigeria; Ghana
• Objective: Determine the safety and preliminary effectiveness of a
daily dose of 300 mg oral TDF vs Placebo for HIV prevention
among high risk women also receiving HIV testing, counseling,
and condoms
• Safety Evaluated in N=936 including 428 Person Years
HIV Seroconversions
• 8 on-product seroconversions
– 2 TDF : 6 placebo
• Difference is not statistically significant
– 95% confidence interval = 0.03-1.93
– p = 0.24
• On TDF seroconversions occurred after 1
and 2 months on product, neither TDF-R
– Baseline Specimens were not available
Peterson, Plos Clinical Trials, 2007
Sexual Behavior During PREP Trial
in West Africa
Screening
Follow-up
Number of partners
(30 days)
21
14
Number of new
partners (30 days)
Number of sex acts
(7 days)
11
6
12
15
52%
94%
Condom use
(last act)
Peterson, XVI AIDS Conference, Toronto, 2006
PREP and Drug Resistance?
• TDF/FTC resistance comes with a high fitness cost
• Monotherapy with TDF
– No resistance detected after 28d in people (Barditch-Crovo 2001)
– Resistant minor variants enriched in monkeys (Van Rampay 2007)
• Non-human primate studies
– TDF PEP partially effective vs drug resistant SIV (Van Rompay
2000)
– No TDF resistance after TDF or FTC/TDF failure (Subbarao 2006)
– FTC resistance intermittently detected (Garcia Lerma 2007)
• TDF and FTC resistance
– Makes AZT more active, but diminishes activity of other nRTIs
– Has no effect on other classes of drugs
CDC U.S. MSM PrEP Study
(Project T; Project PrEPare)
100
TDF
100
Placebo
100
No Pills
TDF
100
No Pills
Placebo
Enrollment
9 months
24 months
PrEP is not already in wide use
Outcome
Overall
(n=851)
SF Bay
Area
(n=403)
Circuit
Party
(n=176)
STD Clinic
(n=272)
Heard of PrEP
18%
20%
19%
15%
Knew PrEP user
2%
2%
4%
2%
0.12%
0%
0%
0.39%1
68%
(n=563)
69%
66%
n/a
Used PrEP
Would use PrEP
if safe/effective
1Had
not heard of PrEP and received 30 days of medication from clinician → may have been post-exposure prophylaxis (1
month of antiretroviral therapy started shortly after high-risk exposure)
Liu, IAS, 2006
An orally delivered CCR5 inhibitor
Provided partial protection of macaques
from SHIV-162P3 vaginal transmission
Condition
Infected p-value
Controls (no inhibitor, including historic controls) 16/18
CMPD 167 for 4 days prior to challenge
3/4
CMPD 167 for 10 days post challenge (inc. day 0)
4/9
CMPD 167 for 4 days prior + 10 days post challenge 6/11
0.47
0.023
0.051
(CMPD 167 +/- 4 days prior + 10 days post challenge 10/20
0.012)
Courtesy of John Moore
WHERE MICROBICIDES MAY WORK
Oral vs. Topical PrEP? (HPTN 050)
1000
PMPA ng/mL
100
10
LLOQ
1
0
4
8
12
Hours
16
20
24
NEW ART FOR PREVENTION STUDIES:
DRUGS, FREQUENCY, & ROUTE
• Karim: TDF Vaginal Gel dose just before and
just after intercourse
• MTN: Oral vs. topical chemoprophylaxis; design
challenges, double randomization
• New agents, combinations?
• Important to have sufficient studies to
understand dosing regimens/trade offs using
combinations (e.g. cost, AEs, efficacy,
adherence)
HIV incidence
among IDUs
has been
declining in
the U.S.
Multivariable analysis of seroconversion
risk: Drug use in Explore
N at
baseline
No. of
infections
Hazard ratio*
(95% CI)
Heavy alcohol**
419
41
1.9 (1.2, 2.8)
Amphetamines
527
67
1.9 (1.4, 2.6)
Alcohol/drugs
before sex
2952
205
1.6 (1.1, 2.3)
Drug
*REF = no/light/moderate use of alcohol; no speed use; no
use before sex
** 4+ drinks every day or 6+ drinks on a typical day
CONCLUSIONS
• Vaccines are years away, antiretrovirals are
available now
• However, because they will need to be used
recurrently and are not expected to be 100%
protective, further studies of pharmacology,
virology and behavioral sciences will be needed
to best understand their intended and
unintended consequences.
• They may become part of HAARP: highly active
antiretroviral prevention