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Innovative Approaches to Prevention of HIV infection
Josip Begovac, Sarajevo 2012
HIV prevention
Type
Behavioral
Biomedical
Structural
Level
Individual
Relationship (couples)
Community
Societal
Prevention of HIV- behavioral interventions
Abstinence only programs
– No effect in 12 studies a negative effect in one
Fewer sexual partners, faithfulness
Condoms (inconsistent use)
Needle exchange (coverage)
Testing and counceling
Prevention of HIV- biomedical interventions
– Circumcision (benefit for the men who are c)
– Treatment of STIs = mixed results (mostly negative)
– Microbicides (tenofovir gel)
– Pre-exposure/post-exposure prophylaxis with antiretrovirals
– Treatment of HIV (less transmission) (test and treat strategy)
– Vaccine (no benefit)
– Blood safety (testing)
Role of antiretrovirals in prevention of HIV transmission
Antiretrovirals for HIV negative individuals
– Before exposure (pre-exposure prophylaxis)
– Oral medication
– micobicide
– After exposure (post-exposure prophylaxis)
Antiretrovirals for HIV infected individuals
– Prevention of MTCT
– Prevention of sexual transmission
Antiretrovirals for HIV negative individuals
Pre- vs Postexposure Prophylaxis
Postexposure prophylaxis
HIV infection
0 hr 36 hrs 72 hrs 1 mos 3 mos 5 mos
HIV
Pre- vs Postexposure Prophylaxis
Pre-exposure prophylaxis
HIV infection
0 hr 36 hrs 72 hrs 1 mos 3 mos 5 mos
HIV
Pre- vs Postexposure Prophylaxis
HIV HIV
Pre-exposure prophylaxis
0 hr 36 hrs 72 hrs 1 mos 3 mos 5 mos
HIV
TDF and TDF/FTC for PrEP
Most data in animal and human trials gained with
– Tenofovir (TFV or TDF)
– Fixed-dose tenofovir/emtricitabine (TDF/FTC)
Trials with oral medications or vaginal gel
iPREX- study in MSM
Partners PrEP: TDF vs TDF/FTC vs Placebo in HIV-Serodiscordant Couples
Baeten J, et al. IAS 2011. Abstract MOAX0106.
HIV-negative partners in HIV-serodiscordant
heterosexual couples(N = 4747)
Oral Tenofovir QD(n = 1584)
Oral Tenofovir/Emtricitabine QD(n = 1579)
Oral Placebo*(n = 1584)
*Placebo arm terminated early on July 10, 2011, by DSMB.
Follow-up:36 mos
Partners PrEP: Both PrEP Strategies Significantly Reduce HIV Acquisition
Both PrEP strategies associated with significant reduction in HIV acquisition vs placebo in both men and women
– TDF efficacy: 71% in women, 63% in men
– TDF/FTC efficacy: 66% in women, 84% in men
Baeten J, et al. CROI 2012. Abstract 29.
Primary Efficacy Outcome, mITT Analysis
TDF(n = 1584)
TDF/FTC(n = 1579)
Placebo (n = 1584)
HIV acquisitions, n 17 13 52
HIV incidence/100 PY 0.65 0.50 1.99
Efficacy vs placebo, % (95% CI)
67(44-81)
75(55-87)
--
P value < .0001 < .0001 --
TDF2: PrEP With TDF/FTC in HIV-Negative Heterosexuals in Botswana
Thigpen MC, et al. IAS 2011. Abstract WELBC01.
Oral Tenofovir/Emtricitabine(n = 601)
Oral Placebo(n = 599)
HIV-uninfected adults,heterosexually active,
aged 18-39 yrs(N = 1219*)
≥ 12-mofollow-up
*19 patients excluded for failure to start study medication or for HIV infection.
TDF2: PrEP With TDF/FTC Significantly Reduces HIV Acquisition
Thigpen MC, et al. IAS 2011. Abstract WELBC01.
9 vs 24 patients seroconverted in TDF/FTC vs placebo arms, respectively
Overall protective efficacy of TDF/FTC: 62.6% (95% CI: 21.5-83.4; P = .0133)
Reduction in HIV acquisition with TDF/FTC observed in both men and women but study underpowered to demonstrate sex-based differences in outcomes
Fai
lure
Pro
bab
ility
0.02
0.04
0
0.06
0.08
0 1 2 3Yrs
TDF/FTC
Placebo
0.10Time to Seroconversion (ITT Analysis)
CAPRISA: Reduced HIV Incidence With Tenofovir vs Placebo Gel
Tenofovir gel associated with decrease in HIV incidence[1]
– 50% decrease at 12 mos
– 39% decrease at 30 mos
1. Abdool Karim Q, et al. Science DOI: 10.1126/science.1193748. 2. Kashuba A, et al. AIDS 2010. Abstract TUSS0203. 3. Abdool Karim S, et al. AIDS 2010. Abstract TUSS0204.
0
2
4
6
8
10
12
Inci
den
ce
Rat
e
(In
fect
ion
s/10
0 P
Y)
Mo 12 Mo 30
5.2
10.5
5.6
9.1
P = .007 P = .017
Placebo
Tenofovir Efficacy vs Levels of Adherence
Adherence Level, %
n No. of Infections
Efficacy, %
> 80 336 36 54
50-80 181 20 38
< 50 367 41 28
cervicovaginal fluid tenofovir concentrations associated with ↓ HIV seroconversion[2]
No HIV resistance to tenofovir in patients infected while using gel
Use of tenofovir gel also associated with 51% decrease in HSV-2 infection[3]
Tenofovir
Treatment for HIV infected patients
PACTG 076: Results
ZDV therapy reduced risk of perinatal transmission by 67%
Excellent short-term safety
Sources: Connor. N Engl J Med 1994;331:1173. Sperling. N Engl J Med 1996;335:1621.
•22.622.6
0
10
20
30
Placebo ZDV
7.6
Tra
ns
mis
sio
n, %
HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples
Single transmission in patient in immediate HAART arm believed to have occurred close to time therapy began and prior to suppression of genital tract HIV
Total HIV-1 Transmission Events: 39(4 in immediate arm and
35 in delayed arm; P < .001)
Linked Transmissions: 28
Unlinked or TBD Transmissions: 11
P < .001
Immediate Arm: 1
Delayed Arm: 27
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
HPTN 052: Analysis of Primary Clinical Events During Follow-up
41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy
– Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly extrapulmonary TB (17 vs 3 cases) (P = .002)
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
Eve
nt
Pro
bab
ility
0
0.10
0.15
0.20
0.25
Yrs Since Randomization
0 1 2 3 4 5
0.05
HR: 0.59(95% CI: 0.40-0.88)
Delayed
Immediate
877886
701700
317333
3236
2529
Pts at Risk, n8685
Efficacy of HIV Prevention Strategies From Randomized Clinical Trials
Abdool Karim SS, et al. Lancet. 2011.
1000 20 40 60 80
Efficacy (%)
Study Effect Size, % (95% CI)
ART for prevention; HPTN 052, Africa, Asia, Americas
PrEP for discordant couples;Partners PrEP, Uganda, Kenya
PrEP for heterosexual men and women; TDF2, Botswana
Medical male circumcision; Orange Farm, Rakai, Kisumu
PrEP for MSMs; iPrEX, Americas, Thailand, South Africa
Sexually transmitted diseases treatment; Mwanza, Tanzania
Microbicide;CAPRISA 004, South Africa
HIV vaccine;RV144, Thailand
96 (73-99)
73 (49-85)
63 (21-84)
54 (38-66)
44 (15-63)
42 (21-58)
39 (6-60)
31 (1-51)
An Advisory Committee to the United States Food and Drug Administration (FDA) recommended the approval of Truvada, an antiretroviral drug, for the prevention of HIV among sexually active men and women (April 11 2011).
The FDA is expected to make a final decision on the approval of Truvada for the prevention of HIV by June 15, 2012
United States, 1968-1976
Reductions in Death From Heart Disease
Age-adjusted mortality from CHD fell by 50% in US from 1980-2000
– ~ 1/2 from risk factor reduction
– ~ 1/2 from treatment
Ford ES, et al. N Engl J Med. 2007;356:2388-2398.
Treatments Risk factors Unexplained
0 50 100
Decrease in Deaths (%)
New Zealand, 1974-1981
The Netherlands, 1978-195
United States, 1980-1990
IMPACT Scotland, 1975-1994
IMPACT New Zealand, 1982-1993
IMPACT England and Wales, 1981-2000
IMPACT United States, 1980-2000 (our study)
Finland, 1972-1992
IMPACT Finland, 1982-1997
40 54 6
40 60
46 44 10
43 50 7
35 55 10
35 60 5
38 52 10
47 44 9
24 76
23 53 24
Structural intervention
What is combination prevention?
rights-based, evidence-informed, and community-owned programmes that use a
mix of biomedical, behavioural, and structural interventions, prioritized to meet the
current HIV prevention needs of particular individuals and communities, so as to have
the greatest sustained impact on reducing new infections.
UNAIDS 2010