iprex Fact Sheet: Key Results

Transcription

1 EMBARGOED UNTIL RELEASE Tuesday, 23 Nvember 2010, 8 a.m. EST CONTACT Mark Aurigemma; ; mark@aucmm.net Pedr Gicchea; pgicchea@gladstne.ucsf.edu iprex Fact Sheet: Key Results iprex is the first efficacy study t reprt results n ral pre-expsure prphylaxis (PrEP); the first HIV preventin study fcused n men and transgender wmen wh have sex with men (MSM) t take place in Africa r Asia; and the first study t demnstrate efficacy fr a bimedical HIV preventin interventin in MSM. The iprex study enrlled participants at 11 sites in 6 cuntries (Brazil, Ecuadr, Peru, Suth Africa, Thailand and the United States) n 4 cntinents. Participants in the study were randmly assigned t receive ral c-frmulated emtricitabine 200 mg/tenfvir 300 mg (FTC/TDF), als knwn as Truvada, r placeb. All study participants als received a cmprehensive package f HIV preventin services including HIV testing, risk reductin cunseling, cndms and screening fr and management f sexually transmitted infectins. The sexual partners f participants were als ffered treatment fr sexually transmitted infectins. In additin, all study participants wh were fund t be susceptible were ffered vaccinatin against HBV infectin. iprex enrlled 2,499 participants; 1,251 were assigned t FTC/TDF and 1,248 were assigned t take a placeb tablet. Participants were fllwed fr a median f 14 mnths. The iprex study invlved: 43,248 participant visits 39,754 visits fr HIV testing and cunseling 650,000 pages f data faxed t the data management center 1,184,400 tablets f study drug dispensed 4,533 HBV vaccinatin dses given 1,019 syphilis cases diagnsed and treated ~500,000 cndms distributed t participants Efficacy iprex fund that a daily dse f ral c-frmulated emtricitabine 200 mg/tenfvir 300 mg (FTC/TDF), als knwn as Truvada, reduced HIV infectin risk amng men and transgender wmen wh have sex with men (MSM) by an average f 43.8% verall. This is a statistically significant level f efficacy and an imprtant step frward fr HIV preventin research. iprex fund 36 HIV infectins amng participants wh received FTC/TDF and 64 infectins amng participants receiving placeb a reductin f 43.8% (p=0.005) in the study arm that received FTC/TDF and cmprehensive preventin services versus thse that received placeb plus cmprehensive preventin services. iprex Fact Sheet: Key Results 1

2 PrEP prevented 28 infectins in the active drug arm. Dividing the 64 infectins recrded in the placeb arm by the 28 fewer infectins recrded in the active drug arm prduces a net reductin in infectins f 43.8% amng study participants wh received FTC/TDF. The 95% cnfidence interval fr this effect is 15.4 t 62.6% (P=0.005) P-value measures hw likely it is that these differences culd have arisen by chance. The P-value f the mdified intent-t-treat analysis in iprex is 0.005, indicating that there is nly a 5 in 1,000 chance that the difference between infectins in the study arm culd have arisen by chance. Cnfidence interval is the range f effectiveness that the interventin culd have, given the amunt f evidence in hand. The mdified intent-t-treat analysis f iprex indicates that it can be determined with 95% cnfidence that the efficacy f PrEP with FTC/TDF, which is estimated at 43.8%, culd be as high as 62.6% r as lw as 15.4% amng all thse wh received active drug in the study, regardless f whether they used the pill r nt. This result includes available data n all participants wh were HIV-negative at the time f enrllment -- even if the participant was nt taking the study pill fr any reasn. A variety f measures and analyses fund that PrEP was mre prtective in peple at higher risk fr HIV and amng thse wh tk the pill mre cnsistently. PrEP efficacy was higher amng participants at particularly high risk fr HIV, as measured by their reprts f unprtected receptive anal intercurse (URAI) at the time f enrllment in the study (efficacy 58%, 95% CI 32-74%). Amng study participants wh used PrEP n 50% r mre f days, as measured by pill cunts, dispensatin and self-reprt, risk f HIV infectin fell by 50.2% (95% CI %; P=0.006). Thse wh reprted using PrEP n 90% r mre f the days had 72.8% efficacy (95% CI %; P=0.001). It shuld be nted that these pill-taking measures rely n self-reprts and are nt bjective. Self-reprted pill use was significantly higher than pill use measured by bld testing. The ptimal timing and frequency f PrEP dsing is nt knwn and requires further study. The next generatin f PrEP research shuld fcus n ways t imprve the use f PrEP as well as the reliability f pill use reprting. An additinal analysis f PrEP drug levels amng a sub-set f study participants wh received FTC/TDF in the study indicates a strng cnnectin between use f the PrEP drug and the level f prtectin against infectin achieved. Only 3 f the 34 peple (9%) wh became HIV-psitive in the grup receiving FTC/TDF had any detectable level f the PrEP drug in their systems. By iprex Fact Sheet: Key Results 2

3 cmparisn, 22 f 43 participants (51%) wh remained sernegative in the grup that received FTC/TDF PrEP, and whse bld was tested t determine whether they were taking the drug, had detectable levels f drug in their systems. There are several caveats that shuld be cnsidered in lking at this data n the bilgical activity f PrEP: Measurement f drug levels were taken at the first clinic visit after a persn became HIV-psitive, and d nt indicate what their bld drug levels were at the exact mment f infectin. It is pssible that there are links between the behaviral characteristics that wuld make a persn mre r less able t take PrEP regularly and the characteristics that culd decrease r increase their risk f HIV infectin (e.g., a persn wh is better able t take PrEP mre regularly may als be mre cautius abut their HIV risk behavir) An additinal analysis that adjusted fr the high risk sexual behavir f unprtected receptive anal intercurse, hwever, cntinued t find a very high level f prtectin amng thse with detectable levels f drug in their systems. Safety Data n the bilgical activity f the PrEP drug must be cnfirmed thrugh additinal studies. Oral PrEP des nt prevent STIs such as gnrrhea, chlamydia, syphilis, herpes, warts, r chancrid. PrEP des nt prevent hepatitis C infectin, which may be sexually transmitted in MSM. All MSM, whether they use PrEP r nt, shuld have regular medical attentin including peridic screening fr STIs. Vaccinatin fr HBV infectin is imprtant. Vaccinatin f MSM fr human papillma virus (HPV) may be effective fr preventin f warts and anal cancer. Cndms are effective fr decreasing the transmissin f many f these infectins. MSM shuld cmmunicate with partners abut HIV test results and ther aspects f sexual health. iprex fund that PrEP with FTC/TDF is safe and well tlerated. This finding is cnsistent with ther safety studies (f TDF fr PrEP by Family Health Internatinal amng wmen in West Africa; f TDF fr PrEP by the U.S. CDC amng MSM in the United States), and with extensive experience with FTC/TDF as an apprved therapy fr HIV. On the placeb arm 164 participants develped a mderate r severe adverse event cmpared t 151 participants n FTC/TDF. There was n statistically significant difference between the tw study grups in a wide variety f labratry tests including tests related t liver functin, pancreatitis, electrlytes, glucse, phsphate, cmplete bld cunt and abslute neutrphil cunt. iprex Fact Sheet: Key Results 3

4 Side effects related t use f the PrEP pill were mild: Nine percent (9%) f individuals wh received the PrEP pill reprted nausea in the first mnth, cmpared t 5% f thse wh received placeb. After the first mnth there was n excess nausea amng thse wh received the active pill. Similar rates f nausea are als reprted by HIV infected peple starting antiretrviral treatment. As with treatment, prviding reassurance that the nausea reslves after the first few weeks may help encurage lnger term use f PrEP. The drugs used in this study are knwn t cause small increases in serum creatinine, a naturally ccurring mlecule filtered by the kidneys. In this study, 5 f 1251 participants (0.3%) wh received the PrEP pill experienced mild increases in serum creatinine that persisted until the next test. All creatinine elevatins reslved with discntinuatin f the pill. Fur f the 5 participants restarted PrEP withut recurrence f the creatinine increase. Investigatrs mnitred renal functin thrughut the study and fund n serius kidney prblems. Unintentinal weight lss f mre than 5% was reprted in 2.2% f peple using PrEP cmpared with 1.1% f placeb users (P=0.04). Sixty-six (66) headache events were reprted by 56 (4.5%) f participants in the FTC/TDF grup, as cmpared t 55 headache events amng 41 (3.3%) f the placeb grup (p=0.10). Mre infrmatin is needed t evaluate any pssible subclinical effects f FTC/TDF PrEP, including thse that may affect bne, lw-level drug resistance r kidney functin. HBV hepatic flares after stpping PrEP were nt bserved in the study f TDF PrEP in West Africa. Mre infrmatin will cme frm iprex as HBV infected participants stp taking PrEP. These issues are als being investigated in sub-studies f iprex and in ther PrEP trials. The reprted numbers f partners decreased and cndm use increased amng participants in bth arms f the iprex study, as was bserved during previus studies f PrEP. Whether HIV risk behavir will increase r decrease in PrEP users in the future is unknwn. Overall, lw drug levels and pill taking amng the study participants likely diminished bth the efficacy f PrEP and he study s pwer t assess safety. Mre infrmatin will cme frm ther studies in the field. Fr mre infrmatin, please see iprex Fact Sheet: Safety iprex Fact Sheet: Key Results 4

5 Resistance N resistance mutatins fr TDF were fund amng iprex participants. Three cases f resistance t FTC were fund. Of these, ne was in a participant in the placeb arm, and tw were participants in the FTC/TDF arm. All three participants with FTC resistance mutatins were fund t be HIVinfected at the time f study enrllment. FTC resistance limits the activity f HIV treatment using FTC (emtricitabine, Emtriva) and 3TC (lamivudine, Epivir). Hwever, the FTC resistant infectins that appeared in the PrEP arm f this study were fully susceptible t nnnucleside reverse transcriptase inhibitrs such as Nevirapine and Efavirenz; all prtease inhibitrs such as Lpinavir, Atazanavir and Daurunavir; integrase inhibitrs; and entry inhibitrs. The tw FTC resistant viruses that appeared in the PrEP arm exhibited increased susceptibility t zidvudine (AZT). Fr mre infrmatin, please see iprex Fact Sheet: Drug Resistance. Pill-taking (Adherence) PrEP with FTC/TDF was mst effective when the participants tk PrEP cnsistently. iprex participants received intensive adherence cunseling, including mnthly cunseling and aids such as pill bxes. Pill taking in the study was measured in multiple ways, including thrugh cmputer assisted self interviews (CASI), intervieweradministered interviews, pill cunts, bttle returns and measurements f drug cncentratins in bld. Althugh self-reprted pill use was high in bth study arms, actual pill use and drug expsure may have been substantially lwer, and this appears t have impacted the verall efficacy f PrEP in the study. The drugs used in the iprex study wuld generally be detectable in bld cells if the PrEP pill had been taken within 7 t 14 days f testing. Only 51% (22/43) f the participants in the active drug arm wh remained sernegative, and whse bld was tested t determine whether they were taking the drug, had detectable levels f the PrEP drugs in their systems. Only 9% (3/34) f participants in the active drug arm wh became HIV-psitive during the study had detectable levels f the PrEP drugs in their systems at the time the infectin was fund. All had drug levels far lwer than thse f the participants in the PrEP arm wh remained sernegative. The lw drug levels indicate the prmise and challenges f PrEP. While PrEP appears t prvide prtectin when used, many participants in the study did nt take the drug iprex Fact Sheet: Key Results 5

6 cnsistently pinting ut the need fr greatly enhanced supprt and infrmatin t enable cnsistent use f the pill. Studies in a number f disease areas and ppulatins shw that tracking and accurately reprting n adherence is very difficult fr individuals t d. Overreprting adherence can be due t multiple factrs, including a participant simply frgetting whether r nt they tk their pill n a certain day and the desire t fulfill the gals f full participatin in the study. A cmplete analysis f participant characteristics that were assciated with having a drug level in this study is underway. Fr mre infrmatin, please see iprex Fact Sheet: Adherence. Next steps Whether iprex data alne are sufficient t warrant apprval f PrEP is a decisin t be made by regulatry authrities after careful review f the data and discussin with experts and peple impacted by the epidemic. The iprex investigatrs urge WHO, UNAIDS and ther glbal and natinal HIV plicymaking bdies, especially thse in the cuntries in which the iprex study was cnducted, t meet prmptly t review these findings and develp clear recmmendatins fr next steps in the study f PrEP. In additin t data n efficacy, iprex prvides imprtant infrmatin in a number f areas that can help authrities develp the best and mst effective access strategies fr PrEP, nw r in the future. Specifically, iprex shwed that: Drug resistance did nt ccur amng the 100 persns wh became infected after starting PrEP; drug resistance was seen, hwever, in three persns (tw in the active drug arm, ne n the placeb arm) wh started PrEP wh were in the RNA psitive/antibdy negative windw perid at enrllment. Signs and symptms f acute HIV infectin shuld be checked befre starting PrEP, t help avid resistance. RNA testing culd be used as well. Side effects frm PrEP were mild and manageable. Mst elevatins in creatinine were mild and reslved withut interruptin f PrEP. iprex results cannt be extraplated beynd MSM. Other PrEP studies are underway in different cmmunities at risk and shuld cntinue. Risk reductin cunseling, cndms, and peridic testing fr HIV and ther STIs shuld be prvided as part f any PrEP trial and prgram. An pen label phase f iprex, in which all HIV-negative iprex participants wh wish t participate will receive the PrEP treatment fr almst 18 mnths, is scheduled t begin next year and shuld prvide additinal infrmatin n efficacy, safety, behavir and pill iprex Fact Sheet: Key Results 6

7 taking. The ethical cnduct f efficacy trials requires that peple be infrmed that the pill they are taking culd be a placeb, and that the active drug has n prven benefit. Nw that PrEP is knwn t ffer sme prtectin t MSM, pen-label PrEP studies can prvide clearer infrmatin t prspective users, which might increase their use f the pill. Additinal data frm the iprex study will be cllected, analyzed and released in the cming year. This will include analyses f: Bne mineral density f participants in bth study arms Drug resistance using mre sensitive investigatinal assays Urine analysis fr evidence f lw level kidney effects Drug levels in hair t assess patterns f drug expsure ver time Sexually transmitted infectins, including herpes, in the trial Additinal safety and efficacy data A better understanding f pill taking during iprex Fr mre infrmatin, please see iprex Fact Sheet: Rllver Study and Next Steps Everyne invlved in iprex is deeply grateful t 2,499 study participants, their families and cmmunities, wh inspired us and trusted us and wh made this study pssible; ur study spnsr, the U.S. Natinal Institutes f Health (NIH); the Bill & Melinda Gates Fundatin, which prvided critical funding t expand the iprex study; and Gilead Sciences, which dnated drug and placeb fr the study. # # # iprex Fact Sheet: Key Results 7