" Treatment of Co-Infections and Innovative Methods in Prevention of HIV": Prof.dr. Josip Begovac: Opening theme at the 6th Regional Conference in Sarajevo, May 17 2012.
2. HIV prevention
Type Level
Behavioral Individual
Biomedical Relationship
(couples)
Structural
Community
Societal
3. 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
4. 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)
5. 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
7. Pre- vs Postexposure Prophylaxis
HIV HIV
infection
Postexposure
prophylaxis
0 hr 36 hrs 72 hrs 1 mos 3 mos 5 mos
8. Pre- vs Postexposure Prophylaxis
HIV HIV
infection
Pre-exposure
prophylaxis
0 hr 36 hrs 72 hrs 1 mos 3 mos 5 mos
9. Pre- vs Postexposure Prophylaxis
HIV HIV HIV
Pre-exposure
prophylaxis
0 hr 36 hrs 72 hrs 1 mos 3 mos 5 mos
10. 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
12. Partners PrEP: TDF vs TDF/FTC vs
Placebo in HIV-Serodiscordant
Couples Follow-up:
36 mos
Oral Tenofovir QD
(n = 1584)
HIV-negative partners in
HIV-serodiscordant
Oral Tenofovir/Emtricitabine QD
heterosexual couples
(n = 1579)
(N = 4747)
Oral Placebo*
(n = 1584)
*Placebo arm terminated early on July 10, 2011, by DSMB.
Baeten J, et al. IAS 2011. Abstract MOAX0106.
13. Partners PrEP: Both PrEP Strategies
Significantly Reduce HIV Acquisition
Primary Efficacy TDF TDF/FTC Placebo
Outcome, mITT Analysis (n = 1584) (n = 1579) (n = 1584)
HIV acquisitions, n 17 13 52
HIV incidence/100 PY 0.65 0.50 1.99
Efficacy vs placebo, % 67 75
--
(95% CI) (44-81) (55-87)
P value < .0001 < .0001 --
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.
14. TDF2: PrEP With TDF/FTC in HIV-
Negative Heterosexuals in Botswana
≥ 12-mo
follow-up
Oral Tenofovir/Emtricitabine
HIV-uninfected adults, (n = 601)
heterosexually active,
aged 18-39 yrs
(N = 1219*) Oral Placebo
(n = 599)
*19 patients excluded for failure to start study medication or for HIV infection.
Thigpen MC, et al. IAS 2011. Abstract WELBC01.
15. TDF2: PrEP With TDF/FTC Significantly
Reduces HIV Acquisition
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
Time to Seroconversion (ITT Analysis)
0.10
Failure Probability
0.08 Placebo
0.06
0.04 TDF/FTC
0.02
0
0 1 2 3
Yrs
Thigpen MC, et al. IAS 2011. Abstract WELBC01.
16. CAPRISA: Reduced HIV Incidence With
Tenofovir vs Placebo Gel
Tenofovir gel associated with Tenofovir Efficacy vs Levels of Adherence
decrease in HIV incidence[1]
Adherence n No. of Efficacy,
– 50% decrease at 12 mos Level, % Infections %
– 39% decrease at 30 mos > 80 336 36 54
50-80 181 20 38
Tenofovir Placebo < 50 367 41 28
P = .007 P = .017 ↑ cervicovaginal fluid tenofovir
12
10.5 concentrations associated with ↓ HIV
(Infections/100 PY)
10 9.1 seroconversion[2]
Incidence Rate
8
6 5.2 5.6 No HIV resistance to tenofovir in
4 patients infected while using gel
2
Use of tenofovir gel also associated
0
Mo 12 Mo 30 with 51% decrease in HSV-2
infection[3]
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.
18. PACTG 076: Results
ZDV therapy reduced risk of perinatal transmission by
67%
Excellent short-term safety
30
Transmission, %
•22.6
20
10
7.6
0
Placebo ZDV
Sources: Connor. N Engl J Med 1994;331:1173. Sperling. N Engl J Med 1996;335:1621.
19. HPTN 052: HIV Transmission Reduced
by 96% in Serodiscordant Couples
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .001)
Linked Unlinked or TBD
Transmissions: 28 Transmissions: 11
Single transmission in patient in
Delayed Immediate immediate HAART arm believed
Arm: 27 Arm: 1 to have occurred close to time
therapy began and prior to
suppression of genital tract HIV
P < .001
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
20. 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)
0.25 Delayed
Event Probability
0.20 HR: 0.59
(95% CI: 0.40-0.88)
0.15
Immediate
0.10
0.05
0
877 701 317 86 32 25 Pts at Risk, n
886 700 333 85 36 29
0 1 2 3 4 5
Yrs Since Randomization
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
21. Efficacy of HIV Prevention Strategies
From Randomized Clinical Trials
Study Effect Size, % (95% CI)
ART for prevention; HPTN 052, Africa, 96 (73-99)
Asia, Americas
PrEP for discordant couples; 73 (49-85)
Partners PrEP, Uganda, Kenya
PrEP for heterosexual men and 63 (21-84)
women; TDF2, Botswana
Medical male circumcision; 54 (38-66)
Orange Farm, Rakai, Kisumu
PrEP for MSMs; iPrEX, Americas, 44 (15-63)
Thailand, South Africa
Sexually transmitted diseases 42 (21-58)
treatment; Mwanza, Tanzania
Microbicide; 39 (6-60)
CAPRISA 004, South Africa
HIV vaccine; 31 (1-51)
RV144, Thailand
0 20 40 60 80 100
Efficacy (%)
Abdool Karim SS, et al. Lancet. 2011.
22. 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
23. Reductions in Death From Heart Disease
Age-adjusted mortality Treatments Risk factors Unexplained
from CHD fell by 50% in United States, 1968-1976 40 54 6
US from 1980-2000 New Zealand, 1974-1981 40 60
The Netherlands, 1978-195 46 44 10
– ~ 1/2 from risk factor United States, 1980-1990 43 50 7
reduction IMPACT Scotland, 1975-1994 35 55 10
IMPACT New Zealand, 1982-1993 35 60 5
– ~ 1/2 from treatment IMPACT England and Wales, 1981-2000 38 52 10
IMPACT United States, 1980-2000 (our 47 44 9
study)
Finland, 1972-1992 24 76
IMPACT Finland, 1982-1997 23 53 24
0 50 100
Decrease in Deaths (%)
Ford ES, et al. N Engl J Med. 2007;356:2388-2398.
27. 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
CI, confidence interval; FTC, emtricitabine; ITT, intent to treat; PrEP, pre-exposure prophylaxis; TDF, tenofovir.
There was a significant effect of immediate therapy on preventing linked transmissions (those that were documented from one partner to the other). There was only 1 transmission documented in an infected partner who received earlier treatment and that transmission occurred very early after the start of therapy, almost certainly before viral load was suppressed in that patient.
There was also evidence of a clinical advantage in that there were fewer clinical events in the infected partner who received the earlier treatment. If we want to relate these data to our case patient, we must remember that the patients in this study had CD4+ cell counts 550 cells/mm3. However, in this group of patients, there was evidence of clinical benefit.