1. ARV-based Microbicides and Resistance Jeanne Marrazzo, M.D., M.P.H. University of Washington John Mellors, M.D. University of Pittsburgh

2. Who we are?  Jeanne Marrazzo, MD, MPH Associate Professor of Infectious Diseases, University of Washington Medical Director, STD/HIV Prevention Training Center Research focus on vaginal health, vaginitis, STI diagnosis and prevention MTN-003 (VOICE) Study Co-chair  John Mellors, MD Chief of Infectious Diseases,University of Pittsburgh Oversees HIV-AIDS clinical research and primary care Research focus on ARV drug resistance MTN Virology Core Director

3. About the MTN  Funded by the U.S. National Institute of Allergy and Infectious Diseases until 2013  Co-funded by the National Institute of Mental Health and the National Institute of Child Health and Development  Based at the University of Pittsburgh and Magee-Womens Research Institute  18 clinical research sites in 7 countries

4. The MTN Mission  To reduce the sexual transmission of HIV through the evaluation of products applied topically to mucosal surfaces or administered orally

5. Presentation Overview  Key concepts: ARV and resistance  PrEP Resistance: A one-act play  ARV-based microbicides  Oral PrEP  Is resistance a risk? How can we reduce any potential risk?  Questions and open discussion

6. Key Concepts: HIV Life Cycle 1. Binding – HIV binds to T-cell via CD4 receptor. 2. Fusion – HIV fuses with cell, dumps contents. 3. Reverse Transcription – HIV genetic code (RNA) changed into DNA by reverse transcriptase enzyme. 4. Integration – HIV DNA is inserted into infected cell's DNA by integrase enzyme. 5. Transcription – HIV DNA is transcribed (made into) HIV RNA 6. Translation - HIV RNA is translated into proteins 7. Assembly and Release – Components of new virus particles assemble and leave the cell.

7. HIV Life Cycle From IAVI: Vaccine Blueprint 2006 1.Binding 2.Fusion 3.Reverse Transcription 4.Integration 5.Transcription 6.Translation 7.Assembly and Release

8. Key Concepts: ARVs  ARVs are drugs to treat HIV - designed to interfere with virus’s ability to replicate  They are best used in combination, i.e., anti-retroviral therapy (ART)  Different ARVs target different steps in the HIV life cycle  Generally, ARVs are safe and effective

9. Key Questions What is resistance? How does it happen? Are you concerned about it? Why are you concerned?

10. Key Concepts: Resistance Definition: ability of a microorganism to survive and multiply in the presence of drugs that would normally kill or weaken it.  For HIV, drug resistance means the virus is no longer sensitive to one or more ARV  HIV is “resistant” to a medicine if it keeps reproducing even while a person is taking that medicine

11. Key Concepts: Resistance How does it happen?  The enzyme HIV needs to replicate is error prone, resulting in mistakes (mutations)  Some mutations make the virus not sensitive to a drug  The drug-resistant virus can now replicate and take over other drug-sensitive virus

12. Resistant Virus: Like Hearty Weeds What if you spray a garden with weed killer that works only on some weeds?  The other weeds will thrive, grow bigger and take over.  The bigger weeds will get bigger and bigger if the weed killer continues to be used -- the weed “killer” is like fertilizer for resistant weeds.

13. How do we suppress resistance?  Take away the “fertilizer” drug  Introduce a new drug that suppresses that HIV variant along with the others

14. Resistance is not all doom  Resistance is common in HIV-infected people being treated with ART Where ART is widely used, 5-20% of new HIV infections can involve drug-resistant virus  Can be managed when detected early – suppressed by other ARV combinations  However, treatment options may be limited for some types of resistance.

15. Resistance: A Play in One Act The cast (in order of appearance): HIV “wild-type” virus: Audience volunteers ARV #1: Lisa HIV “mutant” (drug-resistant) virus: Sharon ARV #2: Sean

16. Resistance: A Play in One Act Scene 1 – Infection Scene 2 – Treatment with ARV #1 Virus suppression Scene 3 – Resistance Scene 4 – Treatment with ARV #2 Virus suppression Curtain Call (Audience Applause)

17. What just happened and why?  The mutant virus was not sensitive to ARV#1, allowing it to replicate and start taking over the other virus sensitive to ARV#1.  When ARV#1 was taken away, the mutant virus no longer had an advantage and the wild-type virus could replicate, increase in number and become stronger than the mutant virus.  ARV#2 worked to suppress all virus, including the ARV#1 drug-resistant virus.

18. Will resistance be a problem?  We don’t know No scientific or clinical information is available about the nature or incidence of resistance among those using ARV- based microbicides or oral ARVs for prevention

19. What do we know?  Resistant virus overtaken by sensitive virus within weeks of stopping ARVs Monkey studies: virus initially transmitted is usually not drug-resistant, but resistance is more likely with time if the PrEP ARV is continued

20. What do we know?  Mothers who took single dose nevirapine for pMTCT and developed nevirapine resistance: no decrease in response to ARV treatment if initiated after 6 months (Mashi Study)  Adding single-dose Truvada to the standard method of preventing mother-to-child HIV transmission is a “new, effective and feasible approach to reducing maternal nevirapine resistance.” The Lancet 2007; 370:1698-1705

21. What do we know?  Resistant virus overtaken by sensitive virus within weeks of stopping ARVs Monkey studies: virus initially transmitted is usually not drug-resistant, but resistance is more likely with time if the PrEP ARV is continued

22. Resistance with PrEP?  Impact on future care for people infected while on PrEP is unknown  FHI trial in 936 HIV-negative women in Ghana (primarily), Cameroon and Nigeria with daily tenofovir: Tenofovir safe – no serious side effects 8 seroconversions occurred: 2 in the active arm and 6 in placebo arm HIV infections too few to draw conclusions on efficacy

23. Moving Forward  Resistance will be a risk associated with being in a study like VOICE  We have some information from different animal and human studies suggesting how resistance may develop in a participant  At the same time, much more research is needed because we know very little  The risks are not considered high enough to think that PrEP studies should not be done

24. Microbicides What about ARV-based microbicides?

25. Evolution of the Microbicide Field  Focus on potent antiretrovirals rather than nonspecific inhibitors of HIV  Development of microbicides for use independent of the timing of sex: daily use sustained release delivery

26. Key Concepts: HIV Infection

27. Where different microbicides act Shattock & Moore Nature Rev Microbiol 1:25-34, 2003

28. Many Microbicide Candidates Pre-ClinicalSafetyEfficacy Entry InhibitorsCyanovirin BMS806 Plant lectins New Polyanions VivaGel CAP Polystyrene sulfate Pro2000 Carraguard Buffergel ARV - NRTITenofovir ARV - NNRTIDABO MIV-150 UC-781 TMC-120 Membrane activeSLS UnclassifiedBacteriaPraneem CombinationPC-815 Truvada NRTI/NNRTI NRTI/P NNRTI/P

29. Tenofovir Gel  Active ingredient is tenofovir, an ARV  Oral tenofovir has good safety profile  Gel has specific action against HIV  Low levels of drug in the blood  Low frequency of side effects  Farthest along in clinical testing of ARV- based microbicides

30. Tenofovir Gel: 8 Clinical Trials  HPTN 050 – Phase I safety  HPTN 059 – Phase II expanded safety/acceptability  Male tolerance  Tissue PK  CAPRISA 004 – Phase IIb  MTN-002 – Phase I PK (pregnant women)  MTN-001- Phase II (oral tenofovir and gel)  VOICE – Phase IIb

31. Tenofovir Gel - HPTN 059  Phase II study assessing local and systemic safety and acceptability of tenofovir gel used daily or before sex over 6 months  Study completed in 200 sexually active HIV- women at 3 sites in U.S. and India.  Results (at M2008): Daily use over 6 months not harmful Some women preferred daily use

32. Tenofovir Gel - MTN-001  Phase II adherence and PK study  Comparing 3 daily regimens (oral, vaginal, and dual use) in 144 sexually active, HIV- women at 6 sites in Uganda, South Africa and U.S.  Each regimen used for 6 weeks with 1 week off  Differences in drug absorption (systemic and local) to be evaluated at U.S. sites (48 women)  Anticipate enrolling April/May/June 2008

33. Tenofovir Gel - MTN-002  First microbicide study in pregnancy  Phase I study: How does pregnancy affect drug absorption? Is the drug transferred to the fetus?  Tenofovir gel to be applied as one-time dose in 16 HIV- women prior to scheduled caesarean delivery  IRB approval pending minor modifications

34. Tenofovir Gel - MTN-003 VOICE Vaginal and Oral Interventions to Control the Epidemic (VOICE)  Phase IIb safety & effectiveness trial, 5 study groups, 2 HIV prevention approaches: Once-a-day ARV tablet (PrEP) Once-a-day application of vaginal gel  4,200 women in Africa  Start date October 2008

35. VOICE Study TOTAL SAMPLE (4200) Oral Pill (2520) Truvada (840) Tenofovir (840) Oral Placebo (840) Vaginal Gel (1680) Tenofovir Gel (840) Placebo Gel (840) Two sequential randomizations. Women will use product daily for average of 21 months.

36. Why VOICE? Tenofovir Tenofovir Gel Truvada Which is safer? Which is effective? Which will women use?

37. ARVs used in PrEP (and VOICE) Tenofovir  NRTI approved for treatment of HIV-1  Dose - 300 mg tablet taken once a day  Used in combination with other oral agents  Safety profile comparable to placebo Also called Viread® or TDF

38. ARVs used in PrEP (and VOICE) Truvada  NRTI approved for treatment of HIV-1  Combination drug - tenofovir and emtricitibine (FTC)  One tablet contains 200mg of FTC and 300 mg tenofovir, taken once a day Also called Truvada®, FTC/TDF or tenofovir+FTC

39. Tenofovir Gel - CAPRISA 004  USAID funded  Phase IIb study of tenofovir gel  Will enroll 980 women: family planning, STI clinics, sex workers (3:2:1)  Screening started 18 May 2007  Regimen: Gel used within 12 hours before and 12 hours after sex; max. 2 applications within 24 hours  Drug absorption studies are ongoing  Effectiveness studies Prevention of HIV when gel used with sex Prevention HIV when gel used daily

40. Tenofovir gel summary  Studies completed in: HIV+ women – safety, 2 weeks use HIV- women – safety and acceptability, 6 months use  Drug absorption, other safety studies ongoing  Effectiveness studies ongoing or planned: Prevention of HIV when used with sex Prevention HIV when used daily

41. UC-781 Gel: 5 Phase I studies  Active ingredient is UC-781  NNRTI type-ARV  Gel has specific action against HIV  Phase 1 studies underway Information on safety and acceptability  Pharmacokinetic studies underway Information on amount of drug absorbed

42. UC-781 Gel: 5 Phase I studies  Safety and persistence in HIV- women (NIAID/CONRAD)  Safety and acceptability in HIV- women and male partners (CDC/CONRAD)  Safety and acceptability for rectal use in HIV- men and women (NIAID/CONRAD)  Male tolerance (CONRAD)  Safety and acceptability of 2 different doses in HIV- women and acceptability in male partners (CDC/CONRAD)

43. Dapivirine (TMC120)  Active ingredient is dapirivine  NNRTI-type ARV  Gel has specific action against HIV

44. Dapivirine (TMC120)  International Partnership for Microbicides developing as gel and vaginal ring  Phase 1 and Phase 1/2 drug absorption, safety and acceptability studies of both – completed or planned  Phase III study planned

45. ARV-based Microbicides  14 of 17 planned clinical trials are ARV-based microbicides (Alliance for Microbicide Development)  Other HIV-specific compounds are in the pipeline

46. ARV-based Microbicides and PrEP  We’re in this together  What happens in PrEP trials can be instructive  Resistance being studied in current trials

47. Current PrEP Studies Candidate name SponsorFormulation / Design PopulationSites TenofovirCDCOnce daily dose Tenofovir Phase III 2,000 injecting drug users Thailand Truvada Switched from tenofovir CDCOnce daily dose Truvada Phase III 1,200 men & women Botswana TenofovirCDCClinical safety and behavior in once daily dosing of Tenofovir Phase II 400 men who have sex with men United States TruvadaNIHOnce daily dose Truvada Phase III 3,000 men who have sex with men Peru / Ecuador/ Other sites

48. Planned PrEP Trials Candidate name SponsorPopulationSitesStart Tenofovir Truvada Gates3,900 HIV discordant couples Kenya and Uganda Early 2008 Tenofovir Truvada and Tenofovir Gel NIH (VOICE) 4,200 heterosexual women Southern AfricaMid 2008 TruvadaGates/ USAID 3,900 high risk women Southern Africa2008

49. Moving Forward Responsibly We must minimize as much as possible ARV exposure by a woman who has become infected.

50. The VOICE Study: Taking Precautions  To avoid enrolling anyone who is already HIV-infected, all prospective participants will be screened for HIV  Participants will have HIV tests every month. HIV infections will be diagnosed quickly Study drug or microbicide will be stopped immediately  Participants will only receive 30 doses of study drug at a time Participants can’t keep taking study drug for more than 30 days without coming in for an HIV test.

51. Participants who become HIV-infected:  Resistance testing Indicates if person’s HIV is resistant to any drugs Help healthcare providers decide which HIV drugs will work best or to avoid  Referred to local care and support services Medical care, including ART Psychosocial services Other programs, e.g., offered by CBOs  Invited into MTN-015 Frequent lab tests can help local provider better manage HIV care of participant The VOICE Study: Taking Precautions

52. Purpose of MTN-015  Assess potential long-term effects of exposure to study product among women who become infected with HIV while taking part in MTN trials Characterize the natural history of HIV infection and response to ART Assess differences in clinical progression and response to ART among women assigned to an active study product compared to women assigned to a control product (or to no product)

53. Take-home Messages  ARV-based microbicides are promising for HIV prevention – HIV-specific  Allow daily use, which may be more effective and some women may prefer  As pills, ARVs safe for treatment  Resistance fairly common in treatment of HIV and can be managed; lessons learned useful  We don’t know risks for prevention – need to be honest about what we know, don’t know  We are being cautious – trials include several risk- reduction measures

54. Thank You!

55. Key Concepts: HIV is Error Prone  HIV makes many millions of copies of itself in the body  The virus makes many mistakes when copying its genetic information  This means many, many types or variants of HIV existing in a person  Some of these variants are resistant to drugs (drug-resistant)

56. Your Questions  Will those who get infected have HIV resistant to the ARV in oral PrEP or ARV-based microbicide ? We don’t know anything for sure, but we will monitor monthly for infection and stop gel or oral PrEP as soon as infection is detected.  Will this affect their subsequent care and choice of ARV treatment? We don’t know if this will be the same for prevention as it is in the treatment setting

57. How will we talk about resistance?  We will state clearly in the consent: If you become infected and continue taking study drug you may develop resistant virus. We think participants who take study drug during an infection that hasn’t yet been diagnosed will not likely be on study drug long enough to hurt future treatment options, but we cannot guarantee this. The message will be repeated and explained throughout the study.