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PpZT"g=ǶiHκAu8ЭAxIhy,N9i{(PBm6mOjj .z^ B\ϹJGuhq)|,#T} u/Iod[BB.4()H ڂ"WCmA Ŷǧj[xh.T,|ŭl![|j gPB|5z-moP?m:p?]{'I$YP/o4PG4PӡŚ>8oKS vdGlԵ tDGEzZ#cgv"BAmm*AEG5}+#rR%ꔅ9V»Scq: ųf;qrN7$ܗTq">Jԇj$y;/p0pxH,C&\:j*]wom] )$l|><,4ojj5$ wQ򢽿ݮ:SA%Q!oie[UOs!.[l4qqs*:NLo>RdT; #͔-xmRƀټW-96Q^y#Uؤ}hx%2f>48_j[vBӸpmj;XvނYADkڎ  7omG2ڑ(m< (qh=1xfȷͨWl.4TDƳ>C:;jxBHCݽE>o: ?#? gC}Hj)pBZi ~r~i#ģM1.)hǭל%b^֊v+'YnHk܆DC*Kʓe%ܝ4ye3Fז'ˀ/A7UЫ33L|؏#As"M6"4#.&;{v$E[bq '~$,MA֛CJQy"ޝt2󈜫=a dzP\ql̊ra K6/Z H)ܦ.K=t%EE+Me򽭤|h {i>4BumTӯݰ4iQqցoe.6m(mBR"  Lm-i$x ^ Pћ\ZqڟM Z/xRV?(NaUrRڝ/.hBSAO3}gifJe ܦ/eJMj+@JqIܹMK!փ)nz}(=q̰ᩌ#'-`ɗ5"Gr_qvv5z*[f6vsv.qB ̘e(}Gl>uİ,fr+ن u0BJJoԦ $O+ᒳs+xy$'!GS%.U03rqX9u1nlC:O-sA),`䴐nmĂ 1NEҁ @:t[ƃu#ƂTX:Ztazk7WP(ZIR֔ؓmHKlHGoP6B;q|D\|b1뭲j/ %=j.J!`NʇL%MZۍdIqJbTx}i 4rwvv}mqtT2#CCJǂQz ҅GQ𠴌cHTtgCk[@f=(!$뭣ǠQ+cWU?zDP6h>Aag^/g,2?ֿ4줬YSdYiFSIS_n=Iw]% m#Ƃ\l"p7m'Lm*9<;p)_ nP'#/o ~ ėžN%V{x~h:rGK*>kyZ6A( ( V  B.http://tell-someone.comb/ 0DArialngs ) ) PIn@>!  $b$l=3U3b$GH.>gS3R$L}=W&Qm(>R$+ʇ#")Q09\R$UVm_2)qR$kZ6zVr_ZR$J;ytGF/ꂞrb$p~IxR$cUORz*tZxk&a 0AA@ S ʚ;$ʚ;g4rdrdn` xppp@ <4dddd@@gʚ; <4BdBd@@ʚ;<4!d!d@@ʚ;(h___PPT2001D<4X___PPTMac11@f   hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography ?  %2 HPV Vaccines#Hilary Suzawa Med/Peds October 2006 HPV: Human Papillomavirus Genital HPV is the most common STD in the US ~20 million Americans infected with HPV ~6 million new cases annually 75% of all sexually active men and women will develop HPV infection during their lifetime Peak prevalence adolescence-29 yearsHPVWomen become infected with HPV soon after they become sexually active ~40% infected within 2 years some say ~40% within 16 months ~60% infected after 5 years CDC estimates ~7% of girls have had sex by age 13 years 28% by the 9th gradeFZZZZZZ?ZF 6  HPV and WartszHPV 6 and 11 are responsible for ~90% of genital warts There are ~1 million new cases of genital warts annually in the US{Z{  HPV and CancerHPV well established as etiologic agent of cervical cancer Odds ratio of 158 for association between HPV infection and cervical cancer HPV 16 and 18 are responsible for 70% of cervical cancer cases in US worldwide ranges ~65-75% Other types 31, 33, 45, 52, 58: HPV and CancerWorldwide incidence of cervical cancer is 470,000 new cases annually 10,000 in US Cervical cancer kills ~230,000 women each year worldwide 3700 women in the US Anal and penile cancers are more rare HPV types are associated with 80-90% of these cancerslFZ Z:ZZ\ZF : \'$Cervical CA ScreeningRoutine screening and early intervention has reduced cervical CA rates by approximately 75% in compliant individuals by monitoring and removing pre-malignant dysplastic lesions.&JW  Cervical Dysplasia  Cervical Cancer2 New VaccinesRecombinant Vaccines against HPV Cervarix Targets HPV 16 and 18 Not yet released Gardasil Targets HPV 16, 18 and HPV 6, 11 FDA approved June 2006 For women age 9-26 yearsN*' Q*' Q ,!(R Basic Science6Outer capsid of HPV is an icosahedron made up of hundreds of copies of viral protein L1 Purified recombinant L1 self-assembles into virus-like particles (VLPs) Since they lack DNA (empty shells) VLPs are NOT infectious Recombinant L1 protein cross-reacts with antibodies to native HPV in a type-specific manner77P u%p Basic SciencewBoth Cervarix and Gardasil are VLP-based Different sources for L1 For Cervarix L1 protein is made from a baculovirus/insect cell expression system For Gardasil L1 protein is made from the yeast Saccharomyces cerevisiae Different adjuvant Cervarix uses ASO4 (aluminum hydroxide and 3-deacylated monophosphoryl lipid A) Gardasil uses amorphous aluminum hydroxyphosphate sulfatenBB  , ##  0  AdministrationCervarix Dose 0.5      !"#$%&'()*+,-./01234569:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnoqrs cc IM at day 1, month 1, month 6 Gardasil Shake well White cloudy liquid 3 shots Dose 0.5 cc IM at day 1, month 2, month 6 Inject into deltoid or antero-lateral thigh Each dose costs $120 (total $360) Antibody titers typically peak after third injection Antibody titers have remained elevated for as long as 36 months Z*Z ZZuZ *   u6+l"Who should be vaccinated?AWomen Age 9-26 years Ideally administered before onset of sexual activity but still vaccinate if pt has already had intercourse Not for pregnant women Caution in nursing women US Advisory Committee on Immunization Practices (ACIP) recommends vaccination in all females 11-26 years Start at age 9 years at discretion of MD.Z)Z) Side EffectsMost common is local injection site reaction Pain Erythema Swelling Pruritus Headache Urticaria Fever 1-15 days post-vaccinationN- -  ,D "%" Side Effects@Gardasil lists HA (0.03% vs. 0.02% placebo) Gastroenteritis (0.03% vs. 0.01% placebo) Appendicitis (0.02% vs. 0.01% placebo) Pelvic inflammatory disease (0.02% vs. 0.01% placebo) One case of bronchospasm and 2 cases of asthma were reported as serious adverse events that occurred during day 1-15 of any vaccination visit@$ vEfficacy)Both vaccines have been effective in preventing persistent infection with targeted HPV types preventing cervical intraepithelial lesions Gardasil has also been effective in preventing vulvar and vaginal neoplasia preventing genital warts Unknown efficacy regarding prevention of cervical cancerv&ZeZ$ZBZ9Z&e$B  9>' TPhase II Trial: HPV-16Multicenter, randomized, placebo-controlled, double blind 2392 women Age 16-23 years No more than 5 male sex partners Never had an abnormal PAP smear&FQFQ Phase II Trial: HPV-16Given HPV-16 vaccine or placebo at months 0, 2, 6 Primary endpoint was persistent infection with HPV-16 occurring after month 7 Exclusion criteria HPV-16 infection by PCR at enrollment or prior to month 7 Protocol violation incorrect vaccine or incorrect timing of visits*Z}Z}Phase II Trial: HPV-164768 vaccine group and 765 placebo group Median follow-up 17.4 months 41 primary endpoint events were detected after month 7 ALL of these events occurred in the placebo group All doses of vaccine tested resulted in antibody titers 38-76 times higher than those observed in women after natural HPV-16 infection55Phase II Trial: HPV 16 and 18"Double-blind, randomized, placebo-controlled 1113 women Ages 15-25 years Test seronegative for HPV 16 and 18 and DNA negative for oncogenic HPV types within 90 days Exclusion criteria History of abnormal PAP or tx of cervical lesions More than 6 sexual partners Current tx for genital wartsV8mk8mk  PN ( H9Phase II Trial: HPV 16 and 18Given vaccine or placebo at 0, 1, 6 months Primary endpoint was prevention of HPV 16 and 18 infection between months 6-27 Both intent-to treat and according-to-protocol analysesPhase II Trial: HPV 16 and 18Phase II: HPV 16, 18, 6, 11Randomized, double-blind 277 women Age 16-23 years Never had an abnormal PAP No more than 4 male sex partners Vaccine or placebo at months 0, 2, 6 Primary endpoint was combined end point of persistent infection with HPV 6, 11, 16 or 18 OR cervical lesions OR genital warts at 7 months@$K$KPhase II: HPV 16, 18, 6, 11Exclusion criteria Women seropositive to HPV-6, 11, 16, or 18 at enrollment Women with detection of HPV DNA from these types before the end of the vaccination period Modified intent-to-treat analysis ATP analysis (also excluded protocol violations)@ZZSZS Phase II: HPV 16, 18, 6, 1173% of participants included in ATP analysis 36 primary endpoints: 32 in placebo group 4 in vaccine group Efficacy estimate 90%:F(F(#!Phase III: FUTUREFemales United to Unilaterally Reduce Endo/Ectocervical Disease Two studies FUTURE I (Protocol 013): 5,442 patients FUTURE II (Protocol 015): 12,157 patients+ h&#Gardasil Studies yFour studies: Protocol 005 Protocol 007 FUTURE I FUTURE II 20,541 women Age 16-26 years Median follow-up from 2-4 years:-=-= Undetermined IssuesBOptimal age for vaccination No clinical data available in patient <15 years old Ideal combination of HPV subtypes Duration of protection ? Booster needed Efficacy for prevention of cervical cancer Most efficient combination of vaccination and cervical cancer screening Application to the developing world ? Vaccinate malesvZ4Z9ZZZ49  $  Main PointsPHPV 6, 11 cause ~90% of genital warts HPV 16, 18 cause ~70% of cervical CA HPV vaccines have proven efficacy at Decreasing infection with HPV Decreasing cervical intraepithelial lesions Efficacy of preventing cervical CA unknown Routine screening reduces cervical CA rates 75% HPV vaccine does NOT replace cervical CA screening program@qJqJ!Patient Information2Website http://tell-someone.com sponsored by Merckp  Bibliography5Schmiedeskamp M and Kockler D. Human Papillomavirus Vaccines. Annals of Pharmacotherapy 2006 July/August Volume 40. The Medical Letter, A Human Papillomavirus Vaccine. Volume 48, Issue 1241/2. August 14/28, 2006. 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