1. Antiretroviral resistance is not an important risk of the oral tenofovir prophylaxis trial in Botswana: a simple mathematical modeling approach Dawn K. Smith, Poloko Kebaabetswe, Kisanga Disasi, Douglas Fleming, Lynn Paxton, and Margarett Davis

2. PrEP Trials Concerns raised about the population effects of daily oral antiretroviral prophylaxis if found to be substantially but not completely effective Concerns raised about the population effects of daily oral antiretroviral prophylaxis if found to be substantially but not completely effective –Availability and cost –Behavioral disinhibition –Increased prevalence of resistant virus complicating treatment

3. Phase II/III 600 men and 600 women 600 men and 600 women Randomize 1:1 to TDF or placebo daily Randomize 1:1 to TDF or placebo daily Follow monthly for at least 12 months Follow monthly for at least 12 months Phase IIPhase III Safety Interim Final Confirm SafetyDetermine if TDF works

4. MASA ARV Treatment Sites

5. How large a problem is TDF resistance likely to be? Participants could become infected with a virus with TDF resistance mutation(s) by: Participants could become infected with a virus with TDF resistance mutation(s) by: –Exposure to virus from an HIV-infected person with a mutated virus –Acquisition of wild-type virus and development of resistance mutations while on PrEP with undetected infection

6. Development of resistance TDF dispensed monthly TDF dispensed monthly HIV testing done monthly HIV testing done monthly So max time on TDF monotherapy while infection undetected is 1-2 months So max time on TDF monotherapy while infection undetected is 1-2 months

7. Resistance in trial participants? An estimate of the numbers DEVELOP RESISTANCE DEVELOP RESISTANCE 1200 on study 1200 on study

8. Resistance in trial participants? An estimate of the numbers DEVELOP RESISTANCE DEVELOP RESISTANCE 1200 on study 1200 on study 600 on TDF 600 on TDF

9. Resistance in trial participants? An estimate of the numbers DEVELOP RESISTANCE DEVELOP RESISTANCE 1200 on study 1200 on study 600 on TDF 600 on TDF 15 (2.5%) infected 15 (2.5%) infected

10. Resistance in trial participants? An estimate of the numbers DEVELOP RESISTANCE DEVELOP RESISTANCE 1200 on study 1200 on study 600 on TDF 600 on TDF 15 (2.5%) infected 15 (2.5%) infected If 1% develop resistance If 1% develop resistance < 1 person infected with resistant virus < 1 person infected with resistant virus

11. Resistance in trial participants? An estimate of the numbers INFECTED BY A RESISTANT VIRUS INFECTED BY A RESISTANT VIRUS 330,000 HIV+ 330,000 HIV+

12. Resistance in trial participants? An estimate of the numbers INFECTED BY A RESISTANT VIRUS INFECTED BY A RESISTANT VIRUS 330,000 HIV+ 330,000 HIV+ 45,000 on HAART 45,000 on HAART

13. Resistance in trial participants? An estimate of the numbers INFECTED BY A RESISTANT VIRUS INFECTED BY A RESISTANT VIRUS 330,000 HIV+ 330,000 HIV+ 45,000 on HAART 45,000 on HAART 20,000 in Gabs/FT 20,000 in Gabs/FT

14. Resistance in trial participants? An estimate of the numbers INFECTED BY A RESISTANT VIRUS INFECTED BY A RESISTANT VIRUS 330,000 HIV+ 330,000 HIV+ 45,000 on HAART 45,000 on HAART 20,000 in Gabs/FT 20,000 in Gabs/FT 3060 (15.3%) detectable virus 3060 (15.3%) detectable virus

15. Resistance in trial participants? An estimate of the numbers INFECTED BY A RESISTANT VIRUS INFECTED BY A RESISTANT VIRUS 330,000 HIV+ 330,000 HIV+ 45,000 on HAART 45,000 on HAART 20,000 in Gabs/FT 20,000 in Gabs/FT 3060 (15.3%) detectable virus 3060 (15.3%) detectable virus 573 (3/16, 19%) with K65R 573 (3/16, 19%) with K65R

16. Resistance in trial participants? An estimate of the numbers INFECTED BY A RESISTANT VIRUS INFECTED BY A RESISTANT VIRUS 330,000 HIV+ 330,000 HIV+ 45,000 on HAART 45,000 on HAART 20,000 in Gabs/FT 20,000 in Gabs/FT 3060 (15.3%) detectable virus 3060 (15.3%) detectable virus 573 (3/16, 19%) with K65R 573 (3/16, 19%) with K65R Considering Considering –Selection of partners –Per act transmission rate –~0 infected with resistant virus

17. Resistance in trial participants? An estimate of the numbers DEVELOP RESISTANCE DEVELOP RESISTANCE 1200 on study 1200 on study 600 on TDF 600 on TDF 15 (2.5%) infected 15 (2.5%) infected If 1% develop resistance If 1% develop resistance < 1 person infected with resistant virus < 1 person infected with resistant virus INFECTED BY A RESISTANT VIRUS INFECTED BY A RESISTANT VIRUS 330,000 HIV+ 330,000 HIV+ 45,000 on HAART 45,000 on HAART 20,000 in Gabs/FT 20,000 in Gabs/FT 3060 (15.3%) detectable virus 3060 (15.3%) detectable virus 573 (3/16, 19%) with K65R 573 (3/16, 19%) with K65R Considering Considering –Selection of partners –Per act transmission rate –~0 infected with resistant virus

18. Measuring Resistance All seroconverters continue in follow-up All seroconverters continue in follow-up Genotypic and phenotypic resistance testing will be done for all seroconverters Genotypic and phenotypic resistance testing will be done for all seroconverters

19. Trial change Phase II still underway with TDF alone Phase II still underway with TDF alone Phase III will be done with TDF+FTC daily Phase III will be done with TDF+FTC daily –Macaque data suggesting better efficacy –PMTCT data suggesting 2 drugs more efficacious than 1 –Few added side effects –Little additional cost –Still one pill per day

20. Conclusions Most drug-resistant virus will be generated in the ARV treatment population Most drug-resistant virus will be generated in the ARV treatment population The TDF PrEP trials will result in few (if any) additional infections with resistant virus The TDF PrEP trials will result in few (if any) additional infections with resistant virus Treatment alternatives are available in Botswana for trial seroconverters if they acquire resistant virus Treatment alternatives are available in Botswana for trial seroconverters if they acquire resistant virus The switch to two drugs within the PrEP trial will further lower the risk of infections with resistant virus within trial participants The switch to two drugs within the PrEP trial will further lower the risk of infections with resistant virus within trial participants

21. Contact "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 dks1@cdc.gov +267-390-1696 x210

22. Study 903: Phenotypic Susceptibility of NRTIs in Presence of K65R (n=8) Fully Susceptible Intermediate Susceptibility Resistant Fold Change Phenosense Assay (ViroLogic cut-off)