Integrated delivery of PrEP and ART results in sustained near elimination of HIV transmission - PowerPoint Presentation

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Integrated delivery of PrEP and ART results in sustained near elimination of HIV transmission in African HIV serodiscordant couples: Final results from the Partners Demonstration Project

Jared M. Baeten, Renee

Heffron

, Lara

Kidoguchi

, Nelly Mugo,

Elly

Katabira

, Elizabeth Bukusi, Stephen Asiimwe, Jennifer Morton, Kenneth

Ngure

,

Nulu

Bulya

, Josephine

Odoyo

, Edna

Tindimwemba

, Jessica E.

Haberer

, Mark

Marzinke

, Deborah Donnell, Connie

Celum

, for on behalf of the Partners Demonstration Project Team

AIDS 2016, Durban

Conflicts of InterestI have received research funding for PrEP

, ART for HIV prevention, and microbicides from the Bill & Melinda Gates Foundation, the US NIH, and USAID.

For some research studies, including that described in the present abstract,

PrEP

medication has been donated by Gilead Sciences.

I have no other conflicts of interest.

BackgroundART and PrEP substantially reduce HIV risk, by more than 90% when used with high adherence

(Cohen et al. NEJM 2011, Baeten et al. NEJM 2012)

For HIV serodiscordant couples, both ART and PrEP are recommended prevention tools

(WHO 2014/2015)

Developing effective strategies to deliver ART and

PrEP

to couples is a priority. Approaches that integrate ART and PrEP may have maximal benefits, since neither alone eliminates HIV risk:

ART:

Delays or declines are common

(

Mujugira

et al. JAIDS 2014)

and HIV risk persists for months after ART start

(Mujugira et al. JAIDS

2016;

Daar

&

Corado

JAMA 2016)

PrEP:

When offered,

many, but not all,

at-risk persons use PrEP

(Donnell et al. JAIDS

2014;

many others)

Demonstration projects for new innovations in prevention

The pathway from a clinical trial results to programmatic roll-out is not fully defined for a new prevention intervention.

Demonstration projects have been

called for

as part of the pathway to scale-up of

PrEP

including in Kenya and Uganda, which had hosted one of the pivotal clinical trials of PrEP for HIV prevention, among HIV serodiscordant couples (the Partners PrEP Study)

Graphic: AVAC

Partners Demonstration ProjectThe Partners Demonstration Project was an open-label, prospective interventional study of integrated ART and

PrEP

delivery for HIV prevention among heterosexual HIV serodiscordant couples

The project was conducted at 4 clinical sites:

Kisumu & Thika in Kenya and

Kabwohe

& Kampala in Uganda

The overall goal was to evaluate, using implementation science methods, a scalable delivery system for PrEP and ART for HIV prevention in couplesWith counseling, adherence promotion, and follow-up designed to reflect approaches suitable for public health clinic settingsInitiated November 2012 & concluded follow-up June 2016

DesignPopulation: Heterosexual HIV serodiscordant couples, not using ART or PrEP and with characteristics defining higher risk for HIV transmission

None participated in the Partners

PrEP

Study clinical trial of

PrEP

Intervention:

ART offered per Kenya/Uganda guidelines, which recommend ART for all infected partners in

serodiscordant couples, regardless of CD4 countPrEP (daily oral FTC/TDF) offered to the uninfected partner until the infected partner has been on ART for 6 months, permitting time to achieve viral suppression (=PrEP as a bridge to ART)Follow-up:

Month 1 and then quarterly thereafter, for 24 months, including HIV testing, risk reduction, brief adherence support, and primary HIV care

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped:

ART

PrEP

HIV+ partner

HIV- partner

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped:

PrEP

prior to viral suppression in HIV+ partner

ART

PrEP

HIV+ partner

HIV- partner

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped:

Protection through sustained ART use



PrEP

prior to viral suppression in HIV+ partner

ART

PrEP

HIV+ partner

HIV- partner

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped:

For couples in which the infected partner delayed or declined ART, PrEP was continued until 6 months after ART initiation:

This strategy is supported by mathematical modeling as potentially highly effective and cost-effective

(Hallett et al.

PLoS

Med 2011; Ying et al. JIAS 2015)

Protection through sustained ART use



PrEP

prior to viral suppression in HIV+ partner

ART

PrEP

HIV+ partner

HIV- partner

Protection through sustained ART use



PrEP

prior to ART initiation and then prior to viral suppression in HIV+ partner

ART

PrEP

ART

delayed

HIV+ partner

HIV- partner

Recruitment of higher-risk couplesHIV risk is heterogeneous, even in at-risk populations

We previously developed an objective risk scoring tool to identify serodiscordant couples with higher risk

(

Kahle

et al. JAIDS 2013)

Components of the

score:

younger age, fewer children, lack of circumcision (HIV- men), cohabiting, unprotected sex in the prior month, and high plasma HIV RNA levels in HIV+ partnerFor the Partners Demonstration Project, we enrolled only couples with high risk scoresTo demonstrate whether the highest-risk couples could take up PrEP and ART and achieve high HIV

protection

Quantifying HIV protectionHIV incidence was calculated for follow-up time through June 2016 (* data are updated beyond the published abstract)

The comparison was a

counterfactual simulation model

, bootstrapping data from the placebo arm of the Partners

PrEP

Study clinical trial

(= no PrEP and ART @ CD4 <350 cells/µL)

, sampling for a subset with a matching distribution of risk scores and duration of follow-upA placebo group or delayed provision of ART & PrEP was deemed not to be ethical for this study, and using a counterfactual model was consistent with the implementation science approach

Results: Participant Characteristics1013 couples were enrolled. Characteristics were consistent with elevated HIV risk:

Characteristic

%

or

median (IQR)

Gender,

HIV- partner

33% female / 67% male

Age

Median 30 years

(IQR 26-36)

,

20% <25 years

No children with study partner

56%

Unprotected sex in the prior month

65%

CD4 count,

HIV+ partner

Median 436

(IQR 272-638)

,

41% >500 cells/µL

Plasma HIV RNA,

HIV+ partner

Median 37,095

(IQR 7058-104,462)

,

41% >50,000 copies/mL

Results: Follow-up High retention and high risk

~1700

person-years of follow-up, retention

86%

at 24 months

Pregnancy incidence =

18.5%/

year High use of PrEP and ART: PrEP: 97% initiated. Tenofovir detected in 82% of plasma samples.

ART: 91% initiated by 24 months, viral suppression >90% after initiation

Appealing, acceptable, safe approach to prevention.

(Mugwanya et al., abstract FRAE0106LB; Wyatt et al., abstract FRAE0103)

For

20%

of follow-up, couples used PrEP alone (prior to initiating ART),

33%

had

PrEP

& ART overlapping,

39%

ART alone, and

7% neither

PrEP

nor ART.

ART increased &

PrEP

decreased over longer follow-up, reflecting the use of PrEP as a bridge to ART in the partnership.

Median duration of PrEP use = 12 months (IQR 6-18) (Heffron

et al., abstract WEPEC250)

HIV incidence

EXPECTED

Given the risk score distribution of the enrolled population, the counterfactual simulations predicted

83

HIV infections would be

expected

to date in this population, at an overall incidence of 4.9 per 100 person-years

N=83

infections

incidence = 4.9

(95% CI 3.9-6.0)

HIV incidence

EXPECTED

However, only four incident HIV infections were

observed

, for an HIV incidence of 0.2 per 100 person-years

N=83

infections

incidence = 4.9

(95% CI 3.9-6.0)

OBSERVED

N=4 infections

incidence = 0.2

(95% CI 0.1-0.6)

HIV incidence

EXPECTED

The observed incidence is a

95

% reduction

compared to expected, a result that was highly statistically significant

N=83

infections

incidence = 4.9

(95% CI 3.9-6.0)

OBSERVED

N=4 infections

incidence = 0.2

(95% CI 0.1-0.6)

95% reduction

(95% CI 87-98%)

P<0.0001

HIV incidence

EXPECTED

In subgroup analyses, similarly high HIV protection was

seen for:

Men

(

97%

p<0.0001

)Women (93%

p<0.0001

)

Those

in which the HIV- partner was <25

years of age

(95%

p<0.0001

)

Couples in which the HIV+ partner had a

plasma viral

load ≥50,000 copies/mL

(95

%

p<0.0001

)

N=83

infections

incidence = 4.9

(95% CI 3.9-6.0)

OBSERVED

N=4 infections

incidence = 0.2

(95% CI 0.1-0.6)

95% reduction

(95% CI 87-98%)

P<0.0001

Incident HIV casesThe four HIV seroconverters did not use

PrEP

(or ART):

Case 1.

26F, seroconversion @ Month 15, no

tenofovir

detected in plasma, had separated from HIV+ partner and had partner of unknown HIV status.

Case 2. 42M, seroconverted @ Month 18, declined PrEP, had multiple partners.Case 3. 19F, seroconverted @ Month 12, inconsistent PrEP use, no tenofovir detected in plasma, commercial sex work.Case 4.

30F, seroconverted @ Month 3, no tenofovir detected in plasma, HIV+ partner not on ART.None had resistance to TDF or FTC.

SummaryIn this open-label demonstration project of integrated delivery of ART and PrEP for prevention in HIV serodiscordant couples, we observed virtual elimination of incident HIV.

These findings are the first demonstration of the effectiveness of

PrEP

in

Africa outside of clinical trials.

Our results demonstrate that

time-limited PrEP as a bridge to ART is not only feasible but highly effective in preventing HIV transmission in serodiscordant couples in Kenya and Uganda.Thus, these findings offer a model for integrated delivery of ART and PrEP

for couples as a highly potent combination prevention intervention.

Investigators

University of Washington Coordinating Center: Jared Baeten (protocol chair),

Connie Celum (protocol co-chair), Renee Heffron (project director), Deborah Donnell (protocol statistician),

Ruanne

Barnabas, ICRC Operations, Data and Administration teams

Kabwohe, Uganda (KCRC): Stephen Asiimwe, Edna Tindimwebwa, Elioda Tumwesigye

Kampala, Uganda (

Makerere

University): Elly Katabira, Nulu Bulya

Kisumu, Kenya (KEMRI): Elizabeth

Bukusi

, Josephine Odoyo

Thika, Kenya (KEMRI): Nelly Mugo, Kenneth Ngure

MGH/Harvard:

Jessica Haberer, Norma Ware

Johns Hopkins: Craig Hendrix, Mark

Marzinke

DF/Net

Research (data management)

Funders

US National Institutes of Health (grants R01 MH095507, R01 MH100940, R01 MH 101027, R21 AI104449, K99 HD076679, R00 HD076679)

Bill & Melinda Gates Foundation (grants OPP47674, OPP1056051)

US Agency for International Development (contract AID-OAA-A-12-00023)

Research participants

Partners Demonstration

Project Team