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