Optimizing the frequency of kidney safety monitoring in HIV-uninfected persons using - PowerPoint Presentation

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Optimizing the frequency of kidney safety monitoring in HIV-uninfected persons using daily oral tenofovir disoproxil fumarate PrEP

Kenneth Mugwanya,

Renee Heffron

, Christina Wyatt, Nelly

Mugo

, Connie Celum, Elly

Katabira

, James Kiarie, Alan Ronald, and Jared M. Baeten

for

the Partners PrEP

Study

and

Partners Demonstration

Project Teams

Conflicts of InterestI have received research funding from the National Institutes of Health.I am the Principal Investigator of a study that received donated emtricitabine/tenofovir from Gilead.

Clinically relevant kidney toxicity is rare with TDF-based PrEP

In clinical trials, TDF-based PrEP has been associated with small non-progressive and clinically insignificant declines in creatinine clearance, a commonly used measure of overall kidney function.

Clinically relevant events are very rare and quickly resolve within weeks of PrEP discontinuation.

2.5% of people randomized to FTC/TDF in the Partners PrEP Study experienced a decline in

eGFR

>25% of their baseline

eGFR

value

(Mugwanya

et al

2015 JAMA

Intern

Med)

Optimal frequency of kidney

safety monitoring is a

key knowledge gap

As PrEP is bought to scale, defining the optimal frequency of kidney

safety monitoring

is

a key knowledge

gap

This is particularly important for regions with limited resources and/or less developed laboratory infrastructure

PrEP implementation guidance

recommend

periodic creatinine monitoring (when feasible

)

Clinical trials monitored creatinine clearance every 3 months

Demonstration projects have used a variety of monitoring schedules, from monthly to 6-monthly

US CDC recommends monitoring 6-monthly

Research objective

To investigate whether

6-monthly

kidney function monitoring could be as safe as 3-monthly monitoring

Data sources

Partners PrEP Study

Randomized clinical trial of PrEP efficacy and safety

Routine

3-monthly

creatinine monitoring; confirmatory testing of any abnormal results was conducted within ~1 week

Partners

Demonstration

Project

Open-label delivery study of integrated PrEP and ART

Routine

6-monthly

creatinine monitoring; confirmatory testing of any abnormal results was conducted within ~1 week

Both studies

HIV

uninfected

participants were members

of heterosexual HIV serodiscordant couples

Creatinine clearance >60 mL/min

was required

for study entry

PrEP

adherence was high

(>

80% by tenofovir blood measurements)

PrEP was not discontinued unless there was a confirmed creatinine

toxicity

MethodsAnalysis included people who initiated PrEP and had at least one post-enrollment serum creatinine measurement

Outcomes

Occurrence of

clinically relevant decline in creatinine

clearance, defined

as creatinine clearance <60

mL/minute

Occurrence

of

1.5-fold

creatinine increase from

baseline

Descriptive methods used to summarize creatinine eventsCox proportional hazards regression used to determine factors associated with the incidence of creatinine clearance falling below 60mL/minute

Participant baseline characteristics

Partners PrEP Study

(N=4404)

Mean

±

SD or %

Partners

D

emonstration

Project

(N=955)

Mean

±

SD or %

Age, years

35

±9

32 ±9Male63%67%Serum creatinine, mg/dL0.77 ±0.150.77 ±0.15Creatinine clearance, mL/min110 ±25116 ±25Creatinine clearance60-90 mL/min22%13%Weight ≤55kg22%9%Systolic blood pressure≥140 mmHg5%5%

Cumulative proportion

of

persons with

CrCl

<60

mL/min

*

Decline confirmed on repeating testing

3-monthly monitoring

(Partners PrEP Study)

N=4404

6-monthly

monitoring (Partners Demo) N=955

Months after study enrollment

3

6

12612Unconfirmed measurement1.4%63/44042.5%90/44042.7%120/44040.7%7/955 1.1%10/955Confirmed measurement*

0.4%

16/4404

0.5%

21/

4404

0.7%29/44040.2%2/9550.2% 2/955

Cumulative proportion

of

persons with 1.5-fold increase in creatinine

*

Increase confirmed on repeating testing

3-monthly monitoring

(Partners PrEP)

N=4404

6-monthly

monitoring (Partners Demo) N=955

Months after study enrollment

3

6

12

6

12

Unconfirmed measurement

1.3%57/44041.9%85/44042.8%123/44041.4%13/955 1.8%17/955Confirmed measurement0.4%18/4404

0.5%

23/4404

0.8%

33/

4404

0.3%3/9550.4%4/955

Baseline covariates associated with CrCl

<60 mL/min within 12 months of starting PrEP

% with confirmed

CrCl

<60 mL/min in 12 months

Adjusted HR

(95% CI)

p-value

Age

≥45 years

3.4%

(23/676)

2.5

(1.3-4.9)

p=0.0008

Age <45 years

0.6% (30/4685)CrCl 60-90 mL/min4.3% (35/812)74.4 (9.8-567.2)p<0.001CrCl >90 mL/min0.1% (4/4256)Weight ≤55 kg2.3% (25/1105)2.7 (1.4-5.2)p=0.004Weight >55kg0.7% (32/4549)

*Model includes variables listed plus systolic blood pressure and PrEP treatment (TDF/FTC or TDF) and stratification by site and gender. Other demographic

and medical factors were not significantly associated with

CrCl

<60mL/min

.

Results summary

The frequency of clinically

relevant decline in

creatinine clearance was rare in these 2 large cohorts with high adherence to TDF-based PrEP

Overall,

<1% of people in

the 2 cohorts experienced

a confirmed

decline in

CrCl

to <60

mL/min within 12 months of starting PrEPThe occurrence and pattern was not qualitatively different whether creatinine clearance monitoring was based on 3-monthly or 6-monthly monitoring

More than 75% of creatinine elevations

or declines in creatinine clearance

were un

confirmed on repeat testing

Implications

These data support US CDC recommendations for 6-monthly creatinine monitoring for people using PrEP

These data also suggest that less frequent testing may be possible for

a majority of persons using

PrEP, requiring fewer

resources

Reduced creatinine clearance was extremely rare among persons with baseline levels >90 mL/min, younge

r than age 45, and weighing >55kg. Monitoring might be able to target those with defined risk factors.

Partners PrEP Study Team

Sites:

Eldoret, Kenya (

Moi

U, Indiana U): Edwin Were (PI), Ken Fife (PI), Cosmas Apaka

Jinja

, Uganda (

Makarere

U, UW); Patrick Ndase (PI), Elly Katabira (PI), Fridah Gabona

Kabwohe

, Uganda (KCRC): Elioda Tumwesigye (PI), Rogers Twesigye

Kampala, Uganda (

Makarere

U): Elly Katabira (PI), Allan Ronald (PI), Edith Nakku-Joloba

Kisumu, Kenya (KEMRI, UCSF): Elizabeth Bukusi (PI), Craig Cohen (PI), Josephine Odoyo

Mbale, Uganda (TASO, CDC): Jonathan Wangisi (PI), Akasiima Mucunguzi

Nairobi, Kenya (KNH/U Nairobi, UW): James Kiarie (PI), Carey Farquhar (PI), Grace John-Stewart (PI), Harrison

TamoohThika, Kenya (KNH/U Nairobi, UW): Nelly Mugo (PI), Kenneth NgureTororo, Uganda (CDC, TASO): Jim Campbell (PI), Jordan Tappero (PI), Aloysious KakiaUniversity of Washington Coordinating Center: Connie Celum (PI and Co-Chair), Jared Baeten (Co-Chair and Medical Director), Deborah Donnell (Statistician), Justin Brantley, Robert Coombs, Carlos Flores, Lisa Frenkel, Harald Haugen, Ting Hong, Jim Hughes, Erin Kahle, Becky Karschney, Lara Kidoguchi, Meighan Krows, Jai Lingappa, Toni Maddox, Angela McKay, Julie McElrath, Allison Mobley, Susan Morrison, Kelly Moutsos, Apollo Odika, Hilda O’Hara, Dana Panteleeff, Marothodi Semenya, John Sparkman, Katherine Thomas Adherence Ancillary Study: David Bangsberg, Jessica Haberer, Norma Ware, Monique Wyatt, Steve Safren, Christina Psaros, Craig Hendrix, Namandjé Bumpus DF/Net (data center): Lisa Ondrejcek, Darryl Pahl, Jae ChongCLS (laboratory oversight): Wendy Stevens, Charlotte Ingram, Ute Jentsch, Mukthar Kader, Nombulelo Gqomane, Feroza Bulbulia, Jan van den HeuvelClinPhone/Perceptive Informatics (randomization)Gilead (study drug donation): Jim Rooney

Bill & Melinda Gates Foundation (study funder):

Stephen Becker

HIV

serodiscordant

couples who tested, screened, & participated

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

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 MarzinkeDF/Net Research (data management)FundersUS 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 participantsPartners Demonstration Project Team