PrEP and interpreting the iPrEx trial results James Wilton Biomedical Science of HIV Prevention Project Coordinator Decemb...
Pre-exposure prophylaxis (PrEP)
What is pre-exposure prophylaxis? <ul><li>Breaking it down </li></ul><ul><li>Pre-exposure = before an exposure </li></ul><...
How would PrEP work? <ul><li>Steps leading to HIV infection </li></ul><ul><ul><ul><li>An infected body fluid comes into co...
Potential PrEP strategies Route of drug delivery <ul><li>Oral (pill) </li></ul><ul><li>Topical microbicide(gel) </li></ul>...
What’s being researched? <ul><li>Large-scale studies </li></ul><ul><li>Oral PrEP </li></ul><ul><ul><li>Daily pill containi...
Concerns <ul><li>Partial protection </li></ul><ul><li>Medical Concerns </li></ul><ul><ul><li>Safety </li></ul></ul><ul><ul...
CAPRISA 004 Study “ Proof-of-concept” for PrEP
CAPRISA Strategy Route of drug delivery <ul><li>Oral (pill) </li></ul><ul><li>Topical (microbicide) </li></ul><ul><ul><li>...
Effectiveness of tenofovir gel <ul><li>Key Points </li></ul><ul><li>Overall, the HIV incidence was 39% lower among women r...
Safety, resistance, and risk behavior <ul><li>No increase in side-effects </li></ul><ul><ul><li>Mild, self-limiting diarrh...
Oral pre-exposure prophylaxis What do we know?
<ul><li>Key Points </li></ul><ul><li>Daily oral tenofovir was generally safe and well tolerated when used by women and men...
The Pre-Exposure Prophylaxis Initiative (iPrEx) Study
iPrEx Study Basics <ul><li>A Phase III randomized, double-blind, placebo-controlled, </li></ul><ul><li>safety/efficacy stu...
iPrEX Strategy Route of drug delivery <ul><li>Oral (pill) </li></ul><ul><li>Topical (microbicide) </li></ul><ul><li>Inject...
Inclusion/exclusion criteria <ul><li>Inclusion criteria </li></ul><ul><ul><li>HIV-uninfected men who are 18 years or older...
Study participant characteristics <ul><li>Average age was 27 (50% were between 18-24) </li></ul><ul><li>1% transgender wom...
Study Measures  <ul><li>Study visits scheduled every 4 weeks </li></ul><ul><li>Safety </li></ul><ul><ul><li>Side-effects <...
Interpreting the results
Overall effectiveness of daily Truvada  <ul><li>Key Points </li></ul><ul><li>The HIV incidence in the Truvada group was 44...
More effective when taken consistently <ul><li>Key Points </li></ul><ul><li>Adherence was measured through self-report and...
Subanalysis of Truvada group  <ul><li>Key Points </li></ul><ul><li>Many participants did not have drug in their blood desp...
Safety of daily Truvada <ul><li>Key Points </li></ul><ul><li>Daily Truvada was generally safe and well tolerated </li></ul...
Risk behavior  <ul><li>No evidence of increased risk behavior </li></ul><ul><ul><li>Total number of sexual partners (in th...
Effect of daily Truvada after infection <ul><li>Drug resistance was detected </li></ul><ul><ul><li>Drug resistance was det...
What did the trial tell us? <ul><li>Daily Truvada, in combination with a comprehensive prevention package, reduced HIV inc...
What didn’t the trial tell us? <ul><li>Safety/effectiveness of other antiretrovirals </li></ul><ul><li>The safety and effe...
Questions?
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  1. 1. PrEP and interpreting the iPrEx trial results James Wilton Biomedical Science of HIV Prevention Project Coordinator December 6 th , 2010
  2. 2. Pre-exposure prophylaxis (PrEP)
  3. 3. What is pre-exposure prophylaxis? <ul><li>Breaking it down </li></ul><ul><li>Pre-exposure = before an exposure </li></ul><ul><ul><li>Medication used before an exposure occurs </li></ul></ul><ul><li>Prophylaxis = prevention </li></ul><ul><ul><li>Medication used for prevention instead of treatment </li></ul></ul><ul><li>Putting it together </li></ul><ul><li>Medication used BEFORE an exposure in order to prevent a disease or condition </li></ul><ul><li>Currently being used </li></ul><ul><li>Pregnancy (progesterone-based birth control) </li></ul><ul><li>Malaria (malarone, doxycycline) </li></ul><ul><li>Tuberculosis (isoniazid) </li></ul><ul><li>HIV prevention </li></ul><ul><li> Antiretrovirals? </li></ul>
  4. 4. How would PrEP work? <ul><li>Steps leading to HIV infection </li></ul><ul><ul><ul><li>An infected body fluid comes into contact with a mucous membrane such as the rectum, vagina, or penis </li></ul></ul></ul><ul><ul><ul><li>HIV crosses the epithelial barrier and enters underlying tissue </li></ul></ul></ul><ul><ul><ul><li>Replicates in the mucous membrane tissue (1-3 days) </li></ul></ul></ul><ul><ul><ul><li>Enters the lymphatic and circulatory system and spreads throughout the body </li></ul></ul></ul><ul><li>“ Window of opportunity” </li></ul><ul><ul><li>The time when the amount of virus is small and is replicating at the mucous membrane </li></ul></ul><ul><ul><li>Antiretrovirals could prevent HIV infection by helping the body clear the virus before it spreads </li></ul></ul><ul><ul><li>Potential for therapeutic benefit </li></ul></ul>
  5. 5. Potential PrEP strategies Route of drug delivery <ul><li>Oral (pill) </li></ul><ul><li>Topical microbicide(gel) </li></ul><ul><ul><li>Rectal </li></ul></ul><ul><ul><li>Vaginal </li></ul></ul><ul><li>Injection </li></ul><ul><li>Intravaginal ring </li></ul>Dosing schedule <ul><li>Daily </li></ul><ul><li>Intermittently </li></ul><ul><li>Coitally (before/sex) </li></ul>Number of antiretroviral drugs <ul><li>Single </li></ul><ul><li>Combination </li></ul>Choice of antiretroviral drug <ul><li>Over 25 available </li></ul>
  6. 6. What’s being researched? <ul><li>Large-scale studies </li></ul><ul><li>Oral PrEP </li></ul><ul><ul><li>Daily pill containing tenofovir (Viread) or tenofovir combined with emtricitabine (Truvada) </li></ul></ul><ul><li>Topical PrEP </li></ul><ul><ul><li>1% tenofovir vaginal gel applied daily or coitally (before/after sex) </li></ul></ul><ul><li>Smaller Studies </li></ul><ul><li>Gels used rectally </li></ul><ul><li>Pills used intermittently or coitally </li></ul><ul><li>Slow-release intravaginal rings </li></ul><ul><li>Long-lasting injections </li></ul><ul><li>Antiretrovirals other than tenofovir and emtricitabine </li></ul>
  7. 7. Concerns <ul><li>Partial protection </li></ul><ul><li>Medical Concerns </li></ul><ul><ul><li>Safety </li></ul></ul><ul><ul><li>Drug resistance </li></ul></ul><ul><li>Behavioral Concerns </li></ul><ul><ul><li>Adherence </li></ul></ul><ul><ul><li>Increased risk behavior (risk compensation/disinhibition) </li></ul></ul>
  8. 8. CAPRISA 004 Study “ Proof-of-concept” for PrEP
  9. 9. CAPRISA Strategy Route of drug delivery <ul><li>Oral (pill) </li></ul><ul><li>Topical (microbicide) </li></ul><ul><ul><li>Vaginal Gel </li></ul></ul><ul><li>Injection </li></ul>Dosing schedule <ul><li>Daily </li></ul><ul><li>Intermittently </li></ul><ul><li>Coitally </li></ul><ul><ul><li>Before and after sex </li></ul></ul>Number of antiretroviral drugs <ul><li>Single </li></ul><ul><li>Combination </li></ul>Choice of antiretroviral drug <ul><li>Tenofovir </li></ul><ul><li>Tenofovir + emtricitabine </li></ul>
  10. 10. Effectiveness of tenofovir gel <ul><li>Key Points </li></ul><ul><li>Overall, the HIV incidence was 39% lower among women receiving the tenofovir gel compared to those using a placebo gel </li></ul><ul><li>Women who used the gel more consistently, both before and after sex, had a greater level of protection against HIV infection </li></ul><ul><li>The tenofovir gel also reduced the incidence of herpes by 51% </li></ul>Effectiveness Overall 39% >80% of sex acts 54% 50-80% of sex acts 38% Less than 50% of sex acts 28%
  11. 11. Safety, resistance, and risk behavior <ul><li>No increase in side-effects </li></ul><ul><ul><li>Mild, self-limiting diarrhea slightly higher in women using the Tenofovir gel </li></ul></ul><ul><li>No renal toxicity </li></ul><ul><li>No safety concerns in pregnancy </li></ul><ul><li>No liver effects in people with Hepatitis B </li></ul><ul><li>No increase in risk behavior </li></ul><ul><li>No drug resistance </li></ul><ul><li>No therapeutic benefit </li></ul>
  12. 12. Oral pre-exposure prophylaxis What do we know?
  13. 13. <ul><li>Key Points </li></ul><ul><li>Daily oral tenofovir was generally safe and well tolerated when used by women and men who have sex with men </li></ul><ul><li>No conclusions could be made on the effectiveness of daily tenofovir </li></ul>Study #1 Study #2 Population Heterosexual women (n=~900) Men who have sex with men (n=400) Location(s) Ghana, Nigeria, Cameroon United States Intervention Daily oral tenofovir Daily oral tenofovir Adherence 69% (pill counts) N/A Safety <ul><li>No safety problems </li></ul><ul><li>No drug resistance </li></ul><ul><li>No risk compensation </li></ul><ul><li>Slightly higher frequency of back pain </li></ul><ul><li>No drug resistance </li></ul><ul><li>No risk compensation </li></ul># HIV infections 6 (placebo) vs. 2 (daily tenofovir) 3 (placebo) vs. 3 (delayed arm) vs. 0 (daily tenofovir)
  14. 14. The Pre-Exposure Prophylaxis Initiative (iPrEx) Study
  15. 15. iPrEx Study Basics <ul><li>A Phase III randomized, double-blind, placebo-controlled, </li></ul><ul><li>safety/efficacy study </li></ul>Locations Brazil, Ecuador, Peru, South Africa, Thailand, United States Population Men who have sex with men (n=2499) Study length July 2007 to October 2010 Study groups <ul><li>1. Daily oral Truvada pill </li></ul><ul><ul><li>tenofovir (TDF) and emtricitabine (FTC) </li></ul></ul><ul><li>2. Daily placebo pill </li></ul>Comprehensive package of prevention services <ul><li>HIV testing and risk-reduction counseling </li></ul><ul><li>Diagnosis and treatment of STIs </li></ul><ul><li>Condoms </li></ul><ul><li>Post-exposure prophylaxis </li></ul>
  16. 16. iPrEX Strategy Route of drug delivery <ul><li>Oral (pill) </li></ul><ul><li>Topical (microbicide) </li></ul><ul><li>Injection </li></ul>Dosing schedule <ul><li>Daily </li></ul><ul><li>Intermittently </li></ul><ul><li>Coitally </li></ul>Number of antiretroviral drugs <ul><li>Single </li></ul><ul><li>Combination </li></ul>Choice of antiretroviral drug <ul><li>Tenofovir </li></ul><ul><li>Tenofovir + emtricitabine </li></ul>
  17. 17. Inclusion/exclusion criteria <ul><li>Inclusion criteria </li></ul><ul><ul><li>HIV-uninfected men who are 18 years or older </li></ul></ul><ul><ul><li>High risk for HIV infection (one or more of the following) </li></ul></ul><ul><ul><ul><li>No condom use during anal intercourse with a male HIV-positive partner or a male partner of unknown HIV status during the last 6 months </li></ul></ul></ul><ul><ul><ul><li>Anal intercourse with more than 3 male sex partners during the last 6 months </li></ul></ul></ul><ul><ul><ul><li>Exchange of money, gifts, shelter, or drugs for anal sex with a male partner during the last 6 months </li></ul></ul></ul><ul><ul><ul><li>Sex with a male partner and STI diagnosis during the last 6 months or at screening </li></ul></ul></ul><ul><ul><ul><li>Sexual partner of an HIV-infected man with whom condoms are not consistently used in the last 6 months </li></ul></ul></ul><ul><li>Exclusion criteria </li></ul><ul><ul><li>Previously diagnosed active or serious infections (ie. Tuberculosis, bone conditions) </li></ul></ul><ul><ul><li>Active medical problems (ie. heart disease, lung disease, diabetes, cancer) </li></ul></ul><ul><ul><li>Acute HBV infection or liver cirrhosis </li></ul></ul><ul><ul><li>Glucose or protein in urine (kidney disorder) </li></ul></ul><ul><ul><li>History of bone fractures </li></ul></ul>
  18. 18. Study participant characteristics <ul><li>Average age was 27 (50% were between 18-24) </li></ul><ul><li>1% transgender women </li></ul><ul><li>Over 70% Hispanic </li></ul><ul><li>An average of 18 sexual partners in past 12 weeks </li></ul><ul><li>40% had transactional sex in past 6 months </li></ul><ul><li>60% had unprotected receptive anal intercourse in past 12 weeks </li></ul><ul><li>35% infected with HSV-2 (herpes) </li></ul>
  19. 19. Study Measures <ul><li>Study visits scheduled every 4 weeks </li></ul><ul><li>Safety </li></ul><ul><ul><li>Side-effects </li></ul></ul><ul><ul><li>Clinical and laboratory adverse events </li></ul></ul><ul><li>Risk behavior and STIs </li></ul><ul><li>Adherence </li></ul><ul><li>HIV status </li></ul><ul><li>Participants who became HIV-infected </li></ul><ul><li>CD4 count </li></ul><ul><li>Viral load </li></ul><ul><li>Drug resistance </li></ul>
  20. 20. Interpreting the results
  21. 21. Overall effectiveness of daily Truvada <ul><li>Key Points </li></ul><ul><li>The HIV incidence in the Truvada group was 44% lower relative to the placebo group </li></ul><ul><li>The result was statistically significant </li></ul><ul><li>The overall self-reported adherence was 95% </li></ul><ul><li>Daily Truvada did not reduce the risk of other STIs </li></ul>Truvada Placebo # Study participants 1251 1248 # HIV infections 36 64
  22. 22. More effective when taken consistently <ul><li>Key Points </li></ul><ul><li>Adherence was measured through self-report and pill counts </li></ul><ul><li>Participants with higher adherence were less likely to become infected </li></ul><ul><li>Participants had over 90% adherence at 49% of study visits and over 50% adherence at 81% of study visits </li></ul>Effectiveness > 90% adherence 73% > 50% adherence 50% < 50% adherence 32%
  23. 23. Subanalysis of Truvada group <ul><li>Key Points </li></ul><ul><li>Many participants did not have drug in their blood despite high self-reported adherence </li></ul><ul><li>Most participants who became HIV-infected during the trial </li></ul><ul><li>did not have drug in their blood </li></ul><ul><li>People with drug in their blood had a 92% lower risk of infection compared to those without drug in their blood </li></ul>Participants who remained HIV-negative Participants who became HIV-positive % with drug in their blood 51% 9%
  24. 24. Safety of daily Truvada <ul><li>Key Points </li></ul><ul><li>Daily Truvada was generally safe and well tolerated </li></ul><ul><li>Elevated serum creatinine levels returned to normal after discontinuing drug </li></ul><ul><li>Nausea was only higher during the first four weeks </li></ul><ul><li>Unintentional weight loss may have been due to nausea </li></ul>Truvada Placebo Elevated serum creatinine levels 2% 1% Moderate nausea (first 4 weeks) 9% 5% Unintentional weight loss (5% or more) 2.2% 1.1%
  25. 25. Risk behavior <ul><li>No evidence of increased risk behavior </li></ul><ul><ul><li>Total number of sexual partners (in the past 12 weeks) decreased from 12 to 5 partners </li></ul></ul><ul><ul><li>Use of condoms increased from about 50% to 80% </li></ul></ul><ul><ul><li>Prevalence of STIs decreased </li></ul></ul><ul><li>Comprehensive prevention services offered </li></ul><ul><ul><li>39,754 visits for HIV counseling and testing </li></ul></ul><ul><ul><li>1,019 cases of syphilis were diagnosed and treated </li></ul></ul><ul><ul><li>585,000 condoms were distributed </li></ul></ul>
  26. 26. Effect of daily Truvada after infection <ul><li>Drug resistance was detected </li></ul><ul><ul><li>Drug resistance was detected in 2 study participants who started Truvada when they were already HIV-positive </li></ul></ul><ul><ul><li>No drug resistance was detected in study participants in the Truvada group who became infected during the trial </li></ul></ul><ul><li>No therapeutic benefit was provided </li></ul><ul><ul><li>Viral load and CD4 count was similar between those who became infected in the Truvada vs. Placebo group </li></ul></ul>
  27. 27. What did the trial tell us? <ul><li>Daily Truvada, in combination with a comprehensive prevention package, reduced HIV incidence among high-risk men who have sex with men. </li></ul><ul><li>Daily Truvada was more effective when taken consistently </li></ul><ul><li>The risk of side-effects, toxicity, and drug resistance were low (but this may have been due to poor adherence) </li></ul>
  28. 28. What didn’t the trial tell us? <ul><li>Safety/effectiveness of other antiretrovirals </li></ul><ul><li>The safety and effectiveness of oral Truvada… </li></ul><ul><ul><li>Over a longer period of time </li></ul></ul><ul><ul><li>If used only occasionally (intermittently) or coitally </li></ul></ul><ul><ul><li>In excluded populations (ie. Adolescents and people with underlying health conditions) </li></ul></ul><ul><ul><li>In preventing against other routes of HIV transmission (ie. intravenous, vaginal/penile) </li></ul></ul><ul><ul><li>In reducing HIV incidence outside of a clinical trial </li></ul></ul><ul><li>Risk behavior and adherence under “real life” conditions </li></ul><ul><li>The “true” risk of drug resistance and side-effects </li></ul>
  29. 29. Questions?

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