Antiretroviral resistance is not an important risk of the oral tenofovir prophylaxis trial in Botswana: a simple mathematical modeling approach Dawn K

Antiretroviral resistance is not an Antiretroviral resistance is not an important risk of the oral tenofovir important risk of the oral tenofovir

prophylaxis trial in Botswana: prophylaxis trial in Botswana: a simple mathematical modeling a simple mathematical modeling

approachapproach

Dawn K. Smith,Dawn K. Smith, Poloko Kebaabetswe, Kisanga Poloko Kebaabetswe, Kisanga Disasi, Douglas Fleming, Lynn Paxton, and Disasi, Douglas Fleming, Lynn Paxton, and Margarett DavisMargarett Davis

PrEP TrialsPrEP Trials

Concerns raised about the Concerns raised about the population effects of daily oral population effects of daily oral antiretroviral prophylaxis if found to antiretroviral prophylaxis if found to be substantially but not completely be substantially but not completely effectiveeffective– Availability and costAvailability and cost– Behavioral disinhibitionBehavioral disinhibition– Increased prevalence of resistant virus Increased prevalence of resistant virus

complicating treatmentcomplicating treatment

Phase II/IIIPhase II/III

600 men and 600 women600 men and 600 women Randomize 1:1 to TDF or placebo Randomize 1:1 to TDF or placebo

dailydaily Follow monthly for at least 12 Follow monthly for at least 12

monthsmonthsPhase II Phase III

Safet

y Interim F

inal

Confirm Safety Determine if TDF works

MASA ARV Treatment Sites

How large a problem is How large a problem is TDF resistance likely to TDF resistance likely to be?be? Participants could become infected Participants could become infected

with a virus with TDF resistance with a virus with TDF resistance mutation(s) by:mutation(s) by:– Exposure to virus from an HIV-Exposure to virus from an HIV-

infected person with a mutated virusinfected person with a mutated virus– Acquisition of wild-type virus and Acquisition of wild-type virus and

development of resistance mutations development of resistance mutations while on PrEP with undetected while on PrEP with undetected infectioninfection

Development of Development of resistanceresistance TDF dispensed monthlyTDF dispensed monthly HIV testing done monthlyHIV testing done monthly So max time on TDF monotherapy So max time on TDF monotherapy

while infection undetected is 1-2 while infection undetected is 1-2 monthsmonths

Resistance in trial Resistance in trial participants?participants?An estimate of the An estimate of the numbersnumbers

DEVELOP DEVELOP RESISTANCERESISTANCE

1200 on study1200 on study



1200 on study1200 on study 600 on TDF600 on TDF



1200 on study1200 on study 600 on TDF600 on TDF 15 (2.5%) infected 15 (2.5%) infected



1200 on study1200 on study 600 on TDF600 on TDF 15 (2.5%) infected 15 (2.5%) infected IfIf 1% develop 1% develop

resistanceresistance < 1< 1 person infected person infected

with resistant viruswith resistant virus

Resistance in trial Resistance in trial participants?participants?An estimate of the An estimate of the numbersnumbers INFECTED BY A INFECTED BY A

RESISTANT VIRUSRESISTANT VIRUS 330,000 HIV+330,000 HIV+


RESISTANT VIRUSRESISTANT VIRUS 330,000 HIV+330,000 HIV+ 45,000 on HAART45,000 on HAART


RESISTANT VIRUSRESISTANT VIRUS 330,000 HIV+330,000 HIV+ 45,000 on HAART45,000 on HAART 20,000 in Gabs/FT20,000 in Gabs/FT


RESISTANT VIRUSRESISTANT VIRUS 330,000 HIV+330,000 HIV+ 45,000 on HAART45,000 on HAART 20,000 in Gabs/FT20,000 in Gabs/FT 3060 (15.3%) detectable 3060 (15.3%) detectable

virusvirus



virusvirus 573 (3/16, 19%) with 573 (3/16, 19%) with

K65RK65R



virusvirus 573 (3/16, 19%) with K65R573 (3/16, 19%) with K65R Considering Considering

– Selection of partnersSelection of partners– Per act transmission ratePer act transmission rate– ~0~0 infected with resistant infected with resistant

virusvirus



1200 on study1200 on study 600 on TDF600 on TDF 1515 (2.5%) infected (2.5%) infected IfIf 1% develop 1% develop

resistanceresistance < 1< 1 person infected person infected

with resistant viruswith resistant virus

INFECTED BY A INFECTED BY A RESISTANT VIRUSRESISTANT VIRUS

330,000 HIV+330,000 HIV+ 45,000 on HAART45,000 on HAART 20,000 in Gabs/FT20,000 in Gabs/FT 3060 (15.3%) detectable 3060 (15.3%) detectable

virusvirus 573573 (3/16, 19%) with K65R (3/16, 19%) with K65R Considering Considering

– Selection of partnersSelection of partners– Per act transmission ratePer act transmission rate– ~0~0 infected with resistant infected with resistant

virusvirus

Measuring ResistanceMeasuring Resistance

All seroconverters continue in All seroconverters continue in follow-upfollow-up

Genotypic and phenotypic Genotypic and phenotypic resistance testing will be done for all resistance testing will be done for all seroconvertersseroconverters

Trial changeTrial change

Phase II still underway with TDF alonePhase II still underway with TDF alone Phase III will be done with TDF+FTC Phase III will be done with TDF+FTC

dailydaily– Macaque data suggesting better efficacyMacaque data suggesting better efficacy– PMTCT data suggesting 2 drugs more PMTCT data suggesting 2 drugs more

efficacious than 1efficacious than 1– Few added side effectsFew added side effects– Little additional costLittle additional cost– Still one pill per dayStill one pill per day

ConclusionsConclusions

Most drug-resistant virus will be generated Most drug-resistant virus will be generated in the ARV treatment populationin the ARV treatment population

The TDF PrEP trials will result in few (if The TDF PrEP trials will result in few (if any) additional infections with resistant any) additional infections with resistant virusvirus

Treatment alternatives are available in Treatment alternatives are available in Botswana for trial seroconverters if they Botswana for trial seroconverters if they acquire resistant virusacquire resistant virus

The switch to two drugs within the PrEP The switch to two drugs within the PrEP trial will further lower the risk of infections trial will further lower the risk of infections with resistant virus within trial participantswith resistant virus within trial participants

ContactContact

"The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy."

Dawn K. Smith

[email protected]

+267-390-1696 x210

Study 903: Phenotypic Susceptibility of NRTIs in Presence of K65R (n=8)

Fully Susceptible Intermediate Susceptibility Resistant

Patient AZT (2.5)

d4T (1.7)

ddI (1.7)

ABC (4.5/6.5)

3TC (2.5)

TDF (1.4/4.0)

1(+M184V) 0.3 0.9 3.7 6.2 >> 1.2

2(+M184V) 0.5 1.0 3.0 7.0 >> 1.3

3(+M184V) 0.3 0.8 1.9 4.6 >> 1.1

4 0.2 0.6 0.7 1.2 11 1.0

5 0.4 1.1 1.6 1.5 8.7 1.4

6(+M184V) 0.9 0.8 1.2 1.3 >> 0.9

7 0.5 1.2 1.9 4.2 13.3 2.2

8 0.5 0.9 1.6 2.4 13 1.0

Fold Change Phenosense Assay (ViroLogic cut-off)

Documents

Antiretroviral resistance is not an important risk of the oral tenofovir prophylaxis trial in Botswana: a simple mathematical modeling approach Dawn K