A Quarterly Update Px Wire: on HIV Prevention Research Volume 4 | No. 1 January–March 2011 AVAC’s Take Proof-of-Concept Trial Results (2009-2010) Effect size (CI) In just over a year, three large-scale trials provided evidence AIDS Vaccine 31% (1; 51) of efficacy for long-sought biomedical prevention strategies: (RV144, prime-boost) a vaccine (a prime-boost evaluated in the RV144 trial), a Microbicide 39% (6; 60) microbicide (1% tenofovir gel evaluated in the CAPRISA 004 (CAPRISA 004, trial) and an oral pre-exposure prophylaxis (PrEP) strategy tenofovir gel) (daily TDF/FTC evaluated in the iPrEx trial). At first glance, PrEP 44% (15; 63) the outcomes appear similar—each had a point estimate of (iPrEx, TDF/FTC) efficacy between 30 and 44 percent. But scratch the surface 0% 10 20 30 40 50 60 70 80 90 100% and it becomes clear that the interpretations and ramifications Efficacy for each of these trials are quite distinct. In this exciting time, advocates’ voices are needed to guide next steps. This is why we’ve chosen to start 2011 with a review of what’s happened and what lies ahead for each strategy. vaccine candidate to learn more about immune responses over the long term. AIDS Vaccines • The RV144 trial partners are developing a follow-up trial It’s been 15 months since the team behind the in Thailand that would enroll MSM and could serve as 16,400-person Thai prime-boost trial (also known as a confirmatory trial for the initial RV144 finding in a RV144) announced that a strategy, comprised of ALVAC-HIV higher-incidence cohort. Key questions include: What (vCP1521) and AIDSVAX B/E, reduced risk of infection by vaccine regimens will be used, and how will the iPrEx 31 percent overall. The trial was a huge undertaking and findings impact trial design? the results were a big surprise, in large part because of the • HVTN 505 trial leaders and staff continue to reach evidence that the vaccine regimen protected against out to various community advocates for discussions infection but did not have any impact on viral load in about what the iPrEx data could or should mean for HIV-negative people who received it and later became the HVTN 505 protocol. HIV-infected. There is no clear explanation for the • A newly energized search for broadly effective immunologic basis of the protection. A range of questions neutralizing antibodies continues in addition to the also remains about the durability of protection, whether the Thai vaccine follow-up research. result can be repeated, or whether the finding would be the ARV-based prevention (microbicides and PrEP) same for a high-risk population. Future efficacy trials using a similar prime-boost regimen are planned to begin in 2014 in In July 2010, the CAPRISA 004 trial team announced Thailand and southern Africa, and it is likely that new lots of the finding that the microbicide 1% tenofovir gel reduced vaccine will need to be manufactured for these efficacy trials. women’s risk of HIV infection by an estimated 39 percent At present, the only ongoing large-scale vaccine trial is overall when applied within 12 hours before and after sex. HVTN 505, a trial of a DNA prime/Ad5 boost vaccine This was a relatively small, proof-of-concept trial, and there strategy that is being studied in the US. Its researchers are has been general consensus that more trial data are needed considering the implications of the positive iPrEx data on before asking regulators to evaluate 1% tenofovir gel for the HVTN 505 protocol. Like iPrEx, HVTN 505 is targeting licensure. There are open questions about what additional gay men and other men who have sex with men (MSM). data are needed for regulators in South Africa, the US and Therefore iPrEx has raised questions like: Should the protocol elsewhere, and what trials in addition to CAPRISA 004 and for 505 be amended to evaluate PrEP as well as the vaccine the ongoing VOICE study might be necessary for regulatory strategy? What data on informal PrEP use could the trial approval and/or for optimizing future delivery. collect­­—and how? In November 2010, the iPrEx trial team announced that the PrEP strategy daily oral TDF/FTC (brand name What lies ahead for AIDS vaccines? Truvada) reduced risk of HIV infection by an estimated 44 • RV144 data are still being analyzed. A working group percent overall in sexually active MSM and transgender of leading researchers is vetting and conducting a women from four continents. This widely anticipated result range of immune analyses designed to identify a correlate involved a pill that is already licensed for use as an HIV of protection. treatment. This means that PrEP using TDF/FTC is far • RV144 participants are still being followed and plans are more readily available than vaccines or microbicides, which underway to obtain informed consent from participants to are not available outside of clinical trial settings. receive an additional boost with a yet-to-be-determined Continues on back A Quarterly Update Px Wire: on HIV Prevention Research Volume 4 | No. 1 January–March 2011 ONGOING TRIALS OF NEW PREVENTION OPTIONS WORLDWIDE Belgium Botswana Sweden Russia Brazil United Kingdom Belgium Germany China France Switzerland Dominican Republic United States China Ecuador Dominican Republic France India Germany Thailand India Kenya Malawi Uganda Ecuador Kenya Rwanda Peru Tanzania Peru Brazil Russia Malawi Rwanda Zimbabwe Botswana South Africa Sweden South Africa Switzerland Tanzania Thailand Uganda United Kingdom United States Zimbabwe VACCINES MICROBICIDES PRE-EXPOSURE PROPHYLAXIS (PrEP) PrEP & MICROBICIDE PARTNER TREATMENT January 2011 BIOMEDICAL HIV PREVENTION RESEARCH: A COMPREHENSIVE TIMELINE OF EFFICACY TRIAL RESULTS* 2007 2008 2009 2010 2011 2012+ CONRAD CELLULOSE SULFATE HSV-2 SUPPRESSION (HPTN 039) HPTN 035 CAPRISA 004 CDC 4940 (TDF2) CDC 4370 Phase III trial to evaluate the effect Phase III trial to evaluate suppressive Phase II/IIb trial to evaluate the Phase IIb trial to evaluate the safety Phase II trial to evaluate the safety Phase II/III trial to evaluate the of cellulose sulfate gel on vaginal HIV acyclovir treatment for the reduction safety and effectiveness of the and effectiveness of 1% tenofovir gel of daily oral TDF/FTC in safety and efficacy of daily oral TDF transmission in women (Benin, India, of HIV infection in HSV-2 seropositive vaginal microbicides, BufferGel and to prevent HIV infection in women heterosexual men and women to prevent HIV infection in injecting South Africa, Uganda, Zimbabwe) women and men who have sex with 0.5% PRO 2000/5 gel, to prevent HIV (South Africa) (Botswana) drug users (Thailand) Trialstoppedearly.Noevidenceof men (Peru, South Africa, US, Zambia, infection in women (Malawi, South Therewere39percentfewerinfections benefit.Thereweremoreinfections Zimbabwe) Africa, US, Zambia, Zimbabwe) amongwomenwhoreceived1% PARTNERS PrEP amongwomenusingthegelthan Noevidenceofbenefit. Therewerefewerinfectionsinwomen tenofovirgelcomparedtowomenwho Phase III trial to evaluate the thoseusingplacebo,butthiswasnot usingPRO2000thanwomenusing receivedtheplacebogel. safety and efficacy of two statisticallysignificant. MALE CIRCUMCISION IN HIV- theplacebogel,butthisdifference different strategies to prevent HIV POSITIVE MEN wasnotstatisticallysignificant.No CDC 4323 transmission in HIV-serodiscordant FHI CELLULOSE SULFATE Large-scale trial to evaluate the evidenceofbenefitinwomenusing Phase II trial to evaluate the clinical couples: daily oral TDF and daily oral Phase III trial to evaluate the safety safety of male circumcision and BufferGel. and behavioral safety of daily oral TDF/FTC (Kenya, Uganda) and effectiveness of cellulose sulfate its potential protective effect for TDF among men who have sex with gel to prevent HIV infection in women HIV-negative female partners of HIV- PARTNERS IN PREVENTION men (US) FEM-PrEP (Nigeria) positive circumcised males (Uganda) Phase III study to evaluate the effect Thetrialreportednoseriousadverse Phase III trial to evaluate the safety Trialstoppedfollowingannouncement Trialstoppedenrollment,December of suppressive acyclovir treatment eventsandpreliminarydatashowed and effectiveness of daily oral ofdatafromCONRADtrial.No 2006.Nostatisticallysignificantcon- for HSV-2 on HIV transmission in PrEPusedidnothaveasignificant TDF/FTC for HIV prevention in women evidenceofsafetyconcernsor clusionscouldbedrawnfromsample HIV-serodiscordant couples effectonHIVriskbehavior.Additional (Kenya, South Africa, Tanzania, ofeffectiveness. size.However,menwhoresumedsex (Botswana, Kenya, Rwanda, South dataexpectedin2011. Zimbabwe) priortowoundhealingweremore Africa, Tanzania, Uganda, Zambia) MIRA likelytotransmitHIVtotheirfemale NoevidenceofreducedratesofHIV iPrEx HVTN 505 Phase III trial to evaluate partners. transmission,buttherewerereduced Phase III trial to evaluate the safety Phase II test-of-concept trial to effectiveness of the female ratesofgenitalulcersandHIV and efficacy of daily oral TDF/FTC evaluate the safety and effect on diaphragm to prevent HIV infection CARRAGUARD viralload. to prevent HIV infection among men post-HIV infection viral load of the (South Africa, Zimbabwe) Phase III trial to evaluate the safety who have sex with men (Brazil, VRC’s DNA prime / Ad5-boost vaccine Noevidenceofbenefit. and efficacy of the vaginal micro- ALVAC-AIDSVAX (RV 144) Ecuador, Peru, South Africa, Thailand, US) strategy in HIV-negative, Ad5- bicide Carraguard to prevent HIV Phase III trial to evaluate the safety ShowedthatdailyTDF/FTCreduced seronegative and circumcised men STEP (HVTN 502/Merck