Global epidemiology Over 7000 new infections a day in 2012 Western Europe 900,000 North america 1,400,000 Eastern Europe & Central Asia 1,400,000 InNorth 2012Africa & Middle: East New HIV infections 2.5 million 300,000 Deaths due to AIDS : 1.7 million East Asia 830,000 South-East Asia 4,000,000 Latin america 1,400,000 Sub-saharan Africa 23,500,000 Oceania 53,000 Adults and children living with HIV UNAIDS report on the global AIDS epidemic 2012 6 USA Estimates of New HIV Infections in the United States, 2011, for the Most-Affected Subpopulations 12,000 Fast Facts 11,200 1,148,200 persons living with HIV infection , including 207,600 persons undiagnosed (18.1%) 10,600 Number of New HIV Infections 10,000 8,000 ≈ 50,000 people newly infected/year +++ 20-24 years 6,700 6,000 5,300 4,000 2,700 2,000 0 1,300 1,200 1,100 White MSM Black MSM Hispanic/ Latino MSM Black Hetero sexual Women Black Hetero sexual Men White Hispanic/ Black Male Hetero Latino sexual Heterosexual IDUs Women Women 850 Classification by transmission: Male-to-male sexual contact : 28,782 Heterosexual contact : 12,875 Black Female IDUs Centers for Disease Control and Prevention EUROPE HIV infections, per 100,000 population, reported for 2011 : All cases ≈54,000 HIV diagnoses of which 28,000 in EU and EEA Rapport UNAIDS 2012 8 EUROPE HIV infections, per 100,000 population, reported for 2011 : Heterosexual cases Rapport UNAIDS 2012 9 EUROPE HIV infections, per 100,000 population, reported for 2011 : MSM cases Rapport UNAIDS 2012 10 EUROPE • Trends of reported HIV diagnoses, by transmission mode and year of diagnosis, adjusted for reporting delay, EU/EEA, 2004–2011 Heterosexual, excluding cases originating from sub-Saharan Africa Heterosexual cases originating from sub-Saharan Africa Men who have sex with men Injecting drug users Mother-to-child transmission Other/undetermined HIV/AIDS Surveillance in Europe 2011 by WhHO ECDC 11 FRANCE HIV Seropositivity Discovery 6100 people newly infected in 2011 8000 7500 7670 7451 7555 7098 7000 6464 6500 6318 6297 6262 6088 6000 5500 5000 2003 2004 2005 2006 2007 2008 Year of Diagnosis 2009 2010 2011 InVS données DO VIH au 31/12/2011 12 FRANCE Epidemiology of new infection by transmission mode Fast facts 2400 gay and bisexual men 40% of all new infections Year of diagnosis InVS données DO VIH au 31/12/2011 13 HIV prevention opportunities Sexual monogamy Behavioral Interventions Aim to lower of partner change, alter risk taking behavior Correct & consitent condom use Education Delayed sexual debut PrEP Sexual abstinence Treatment of STIs HIV Prevention toolbox Treatment of the infected population Biological Interventions Aim: to reduce the efficiency of transmission or to shorten the duration of infectiousness Male circumcision 15 What is PrEP ? • Pre-exposure prophylaxis (PrEP) is based on the use of antiretroviral therapy in HIV negative people at risk HIV to block transmission of the virus. • This treatment could be taken systemically (tablets) or topically (vaginal or rectal gels), continuously, daily, or intermittent, framing the risk of exposure. 16 New method ? 1994: Prevention of mother to child transmission 1997: PEP: PostExposure Prophylaxis TASP: Treatment as Prevention Test and treat 2012: Truvada® PrEP 17 Truvada® • Molecules: Emtricitabine 200mg (FTC) + tenofovir disoproxil fumarate 300mg (TDF) Fixed–dose combination tablet of two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) 18 Truvada® : Mechanism of action 19 Truvada® • Side effects – Serious : • Severe liver problems : hepatomegaly , steatosis Build-up of lactic acidosis • Kidney damage hypophosphataemia => Bone mineral density loss • Worsening of pre-existent hepatitis B infection – Common : • Headache • Dizziness • Vomiting, nausea, diarrhea • Raised blood levels of creatine kinase 20 HIV : where do we stand ? Truvada® : with other antiviral medicines, to treat HIV1 in adults NB: L’initiation d’abacavir ne peut être envisagée que chez des patients ne présentant pas l’allèle HLA-B57*01. http://www.sante.gouv.fr/IMG/pdf/05_Traitement_anti_retroviral.pdf 21 W TDF&FTC: potent inhibitors of HIV Increases the number of mutations required for resistance Penetrates well in sites of HIV exposure Why Truvada® ? Greater activity than TDF alone No drug interaction with ttm against malaria, tuberculosis, or oral contraceptives Long half-life 1 tablet a day Good safety and tolerability profile for treatment 22 Regulatory history Viread® (TDF) 2001 2001 Emtriva® (FTC) 2002 2003 Complera® (FTC/TDF/RPV) 2011 Truvada® (FTC/TDF) 2004 Atripla® (FTC/TDF/EFV) 2008 2004 TDF : tenofovir disoproxil fumarate FTC : emtricitabine EFV : efavirenz RPV : ripavirine 2006 2011 2012 2012 Truvada® PrEP (FTC/TDF) 24 FDA approval • July 2012 • Truvada® for pre-exposure prophylaxis indication : With safer sex practices at all times to reduce the risk of getting HIV1 : – in MSM who are at higher risk of getting infected with HIV1 through sex, – in heterosexual couples where one partner has HIV1 and the other has not. • Supplemental New Drug Application (sNDA) • Priority Review: 6 months instead of 10 25 Clinical trials of oral PrEP Trial Location Population Intervention Phase III/ IIb iPrEx Brazil, Ecuador, Peru, South Africa, Thailand, USA Adult MSM at high risk Daily oral FTC/TDF Partners PrEP Kenya, Uganda Serodiscordant couples Daily oral TDF or FTC/TDF CDC TDF2 Botswana Adult heterosexual men and women Daily oral FTC/TDF Fem-PrEP Kenya, South Africa, Tanzania Adult women at high risk Daily oral FTC/TDF VOICE Uganda, South Africa, Zimbabwe Adult women Daily oral FTC/TDF or TDF or tenofovir vaginal gel Phase II CDC 4323 USA Adult MSM Daily oral TDF (immediate vs oral treatment) FHI PrEP Ghana, Cameroon, Nigeria Adult women at high risk Daily oral TDF 28 Trial Designs Trial Population Randomized (N) Intervention iPrEx Adult MSM at high risk 2499 Daily oral FTC/TDF vs Placebo Partners PrEP Heterosexual serodiscordant couples 4747 Daily oral TDF or FTC/TDF vs Placebo • Randomized, prospective, placebo-controlled • Monthly HIV-testing • Powered to show at least 30% efficacy (standard threshold in HIV vaccine and microbicide trials) • Risk-reduction counseling, contraception counseling and referral for circumcision (for Partners PrEP), condoms, treatment of symptomatic STIs and HIV-1 testing provided at every visit 29 Trial Designs Primary outcome: Anti-HIV seroconversion and safety endpoints 30 Inclusion criteria • iPrEx : – Male (18 years and older) – HIV uninfected – High risk for HIV infection: any of the followings in the past 6 months: • no condom use during anal intercourse with male partner who is HIV+ or HIV status is unknown • anal intercourse with more than 3 male sex partners • prostitution • STI at screening or in the 6 months prior to study entry • inconsistent condom use with HIV+ partner • Partners PrEP : – Male and female – HIV-1 seropositive partner not yet eligible for ART treatment 31 iPrEx 64 infections 44% fewer • 44% efficacy overall (CI 95%: 15-63%) • P-value: 0,005 • 92% efficacy when the drug was detected in blood • Drug detection correlated with seronegative status 36 infections Placebo Truvada 33 IPrEx Cumulative HIV Incidence by Treatment Time 34 iPrEx • Adherence by intracellular TFV-DP levels: efficacy Non-Measurable Measurable 100% 87.5% 4.2% 4% 3.6% 3% 2% 1% 0.5% 0% Placebo Non-Measurable Measurable Relative risk reduction HIV conversion per PY (%) 5% 80% 60% 40% 20% 14.5% 0% Non-Measurable Measurable 35 Primary efficacy outcome mITT analysis Tenofovir Tenofovir/emtricita bine Placebo HIV acquisitions, n 17 13 52 HIV incidence/100 patient-years 0,65 0,50 1,99 Efficacy vs placebo (%) (95% CI) 67 75 (44-81) (55-87) P value <0,001 <0,001 mITT: modified intention to treat • If drug detected in the blood: TDF=86%; Truvada® : 90% • On july 2011, Data and Safety Monitoring Board recommanded discontinuation of placebo arm 36 Primary efficacy results 37 Efficacy (95% CI) P-value Interaction P-value TDF Women 71% (N=595) (37-87%) p=0,002 p=0,65 Men 63% (N=984) (20-83%) p=0,01 FTC/TDF Women 66% (N=566) (28-84%) p=0,005 p=0,24 Men 84% (N=1010) (54-94%) p<0,001 38 • Adherence by plasma TFV levels: efficacy 2.5 Hiv conversion per PY (%) 2 52/2607 2% 5/235 2,1% 1.5 Placebo 6/733 1 Never measurable 0,8% 0.5 Sometimes measurable 2/1648 Always measurable 0,1% 0 Placebo Never measurable Sometimes measurable Always measurable 39 IPrEx – Side effects: • Nausea and abdominal pain in <10%, mainly in the first 4 weeks • Loss of weight, mainly in the first 12 weeks • Average 1% Bone Mineral Density loss • Mild-moderate serum creatinine elevation (2,4% Truvada® vs 2,2% placebo) 41 IPrEx Safety : Severe and Serious Adverse Events (AE) 42 IPrEx Safety : Clinical Adverse Events Grade 2 and Above 43 – Side Effects: No significant differences with placebo Number (%) of participants TDF Death 8 SAE (<1%) 118 (7%) P-value vs placebo 0,80 1,00 FTC/TDF 8 (<1%) 115 (7%) P-value vs placebo 0,80 0,89 Placebo 9 (<1%) 118 (7%) 45 – Side Effects: Birth outcomes were similar TOTAL TDF FTC/TDF Placebo Number of pregnancies 288 112 80 96 Number of pregnancies With outcomes available 262 103 74 85 167 73 40 54 (64%) (71%) (54%) (64%) 95 30 34 31 (36%) (29%) (46%) (36%) 0,35 0,26 Data through 30 January 2012 Pregnancy outcome Live birth Pregnancy loss P-value, vs placebo 46 Safety Summary Overall Safety Renal safety Bone safety iPrEx Partners PrEP Similar to placebo with more gastro-intestinal events through week 4 Similar safey profile to placebo Mild-moderate serum ceratinine elevation: 2,4% FTC/TDF vs 2,2% placebo No increase in fracture, small decrease in BMD at the spine and hip, which returned toward baseline Infrequent serum creatinine abnormalities (<2%), similar across all arms No increase in fracture, Evaluation of BMD not performed 47 Resistance NRTI resistance/ infections Trial iPrEx Drug On treatment Baseline FTC/TDF 0/48 2/2 FTC/TDF 0/12 1/3 TDF 0/15 2/5 Partners PrEP 49 Risk Compensation 51 Other clinical trials: Population Design FEMPrEP African women Oral Truvada daily vs placebo TDF2 African heterosexual men and women Oral Truvada daily vs placebo African women Tenofovir gel 1% vs placebo CAPRISA 004 VOICE African women Oral: Truvada vs TDF vs placebo Vaginal gel: TDF vs placebo Efficacy Sexual behavior Compliance Resistance No (stopped futility) <26% (plasma level) On 68 infections, 1 resistant with placebo, 4 with Truvada 62% (strongly related to adherence) >80% in both groups (pill counts, results in blood not available) 1 person infected at enrollment developped resistance Number of partners declined in both arms no slight increase of condom use in both arms 39% Tenofovir gel and pills arms stopped due to inefficacy. Truvada arm continues. 60% (count of gel bottles) 53 Conditions of approval – collect viral isolates : • from individuals infected by HIV during PrEP – collect data on pregnancy outcomes : • for women who become pregnant during PrEP – conduct a trial for evaluation of drug adherence : • relationship to adverse events • risk of seroconversion • Development of resistance in seroconverters. – REMS 56 REMS Risk Evaluation & Mitigation Strategy = Risk Management Plan • Advised by FDA Antiviral Products Advisory Committee • Initial REMS approval : 07/16/2012 • Annual assessment • Central component : – Training and educational program 58 REMS Risks Description HIV-1 Acquisition Truvada PrEP may not always prevent HIV-1 acquisition, even when there is adherence to the dosing regimen and other prevention strategies are used. Poor adherence to Truvada and other prevention strategies further increases the risk of HIV-1 acquisition. Development of Resistance Resistant HIV-1 variants may emerge in subjects with unrecognized HIV-1 infection who continue to take Truvada to reduce the risk of acquiring HIV-1. Post-treatment exacerbations of HBV Acute exacerbations of HBV may occur upon discontinuation of Truvada in individuals treated with Truvada for HIV-1 pre-exposure prophylaxis who are infected with HBV. Identified risks Potential risk 59 REMS • Goals : – Inform and educate : • Prescribers, other healthcare professionals and individuals (taking or considering Truvada for PrEP) – About : • Importance of strict adherence • Importance of regular monitoring of HIV-1 status To reduce the risk of development of resistant HIV-1 variants • Truvada for PrEP which is only part of a comprehensive prevention strategy with other preventive measures 60 REMS • REMS Elements : – Timetable for submission of assessment – Medication guide – Elements to assure safe use : • Training & education program : – Safety inforamtion fact sheet – Important information for prescribers • Materials for healthcare providers – Dear Healthcare Providers Letter – Important Safety information : All these documents and information are : » For healthcare providers » For uninfected individuals appended and part of the REMS – Agreement form – Checklist for prescribers – Other supports for training and education : » Full prescribing information » Prescriber Educational Slide Deck » Training Guide for Healthcare Providers • Website • Additional actions to ensure safe use 61 Medication guide : • Dispensed with each Truvada® prescription • In paper hard copy • Give the most important informations for the patient : – Serious side effects & side effects – Negative status to begin and test every 3 months – Reminders (safer practises, does not always prevent HIV, does not cure HIV infection or AIDS) – indication – Contraindications (positive or unknown status, drugs) – Informations about : • Risks • Pregnancy (registry) • The drug (taking, storage, ingredients) 62 Elements to assure safe use : • Training & Education Program : – – – – Safety information fact sheet Important informations for prescribers Online Avaible as hard copy upon request – Targets : • • • • Primary Care physicians Infectious diseases specialists Obstetrician-gynecologists Addiction specialists 63 Safety Information Fact Sheet : • Dissemination bi-annually for 3 years • Sent to : – 12 associations of prescribers e.g. : HIV Medicine Association, Infectious Diseases Society of America – Medwatch 64 Safety Information Fact Sheet : • Indication • Boxed Warning o o • 3 key safety informations o o o • Negative status No sign/symptom of infection Drug resistant HIV-1 risk Comprehensive prevention strategy Recommended dosing regimen For more information 65 Important Informations for Prescribers : • Target healthcare providers through select professional scientific journals • Published quaterly for 3 years • In 5 professional society journals : – – – – – Journal of the American Medical Association Journal of the Academy of Family Physicians Obstetricians and Gynecologists Clinical Infectious Diseases New England Journal of Medicine 66 Important Informations for Prescribers : Indication Boxed Warning Negative status No sign/symptom of infection 3 key safety informations Drug resistant HIV-1 risk Comprehensive prevention strategy Recommended dosing regimen For more information 67 Elements to assure safe use : • Materials for Healthcare Providers : – Agreement form – Checklist for Prescribers 68 Agreement Form : • 3 parts : o Indication and factors to identify high risks o Prescriber Agreement and the list he has to do o Uninfected Individual Agreement and the list of understandings and explanations 69 Checklist for Prescribers : • Checklist : • Have to be done • At each visit • 17 points : o High risk evaluation o Negative status o Discussion about : o Risks, Screenings, adherence, prevention, STIs o HBV o Creatinine Clearance o Antiviral drugs o Access to information o Side effects o Medication Guide o Pregnancy 70 Elements to assure safe use : • Website : – www.TRUVADApreprems.com – Access to : • Specific information about Truvada® PrEP • Educational and training materials – Remain for 3 years 71 Elements to assure safe use : • Additional actions to ensure safe use : – Additional languages : • To the Boxed Warnings : – – – – “Negative HIV test must be confirmed” “HIV test every 3 months” “Drug resistant HIV-1 variant” “Lactic acidosis, hepatomegaly, HBV” • To the Warnings & Precautions : – “How Truvada® should be used” – “Strict adherence to the dosing regimen” – New contraindication for use as PrEP – start.truvada.com 72 Targeted populations : MSM in the US • MSM = 2% of the US population = 6.3 million 12,000 10,000 8,000 • But 61% of the new HIV infections in 2011 28,500 new cases in MSM every year in the US 6,000 4,000 2,000 0 • 30% of MSM are considered at « very-high risk » ≈ 2 million Centers for Disease Control and Prevention 74 Costs in the USA • Medicine cost $11,000/year • Initial consult: HIV-testing, physical exam, HBV testing, creatinine clairance… • Quarterly HIV-testing, medical $12,000/year consult $1,300/1st year, $1,020 after • Adherence promotion • Condoms Provided by Gilead for PrEP users Free coupons from Gilead 75 Number needed to treat • Mathematical model (Desai et al. Study) – Takes into account infections prevented in people NOT taking PrEP – Hypothesis: 50% efficacy and 50% adherence – For very-high risk MSM (5year treatment): 9 taking PrEP 1 infection averted Desai, AIDS 2008, 22:1829-1839 76 Number needed to treat • The iPrEx Trial = Without taking into account infections prevented in people NOT taking PrEP, during 2.5 years – 44% efficacy overall = closer to “real life conditions”: Number Needed to Treat : 36 persons to avoid 1 infection – 92% efficacy when the drug was detected in blood: Number Needed to Treat : 19 persons to avoid 1 infection 77 Costs per infection averted • From: – NNT = 9 $540,000 • To: Closer to « real-life » – NNT = 36 $1,080,000 – NNT = 19 $570,000 • Compared to: – Lifetime HIV-treatment : $379,668 78 QALY gained • Life expectancy – HIV+ : 32.1 years post diagnostic Loss of 11.5 years of life – HIV- : 43.6 years post testing • QALY values : – HIV : 0.87, lasting 28 years – AIDS : 0.62, lasting 4 years mean QALY value : 0.84 • QALY gained by HIV- : – HIV+ life expectancy : 26.7 QALY 16.9 QALY gained if HIV79 Cost-effectiveness • According to our data: – ICER = ($1,080,000 - $379,668) / 16.9 = 41,400 $/QALY Cost-effective According to US standards ($50,000 to $100,000) • BUT : Based on the iPrEx study Only high-risk MSM 80 Dynamic model : Cost-effectiveness of PrEP in men in the USA 250 ICER, $/QALY 200 216.48 172.091 188.421 150 All MSM Cost-effective H-R MSM 100 50 40.279 44.556 52.443 20% 50% % of MSM taking PrEP 100% 0 Ann Intern Med. 2012 Apr 17;156(8):541-50. Juusola JL, Brandeau ML, Owens DK, Bendavid E. The CostEffectiveness of Preexposure Prophylaxis for HIV Prevention in the United States 81 Reimbursment • Private insurance and Medicare positions : – Reimburse by main private insurances – Can be part of Medicare part D and Medicaid • Truvada® Medication Assistance Program : – For PrEP – For low income people – For people without Medicaid or any other public or private coverage for prescription drugs. 82 Truvada® US sales by trimester FDA approval 500 Sales in millions 400 $373,6 $373,3 Q4 2011 Q1 2012 $393 $414,5 $431,7 300 200 100 0 Q2 2012 Q3 2012 Q4 2012 83 Gilead Global pricing policy : 4 levels « Developed » countries : High prices USA : $11,000 France : $8,500 Japan: $17,000 Australia : $13,500 84 Gilead Global pricing policy : 4 levels Upper middle income: -70% compared to 1st level $3,000/yr Part of Gilead Access Program 85 Gilead Global pricing policy : 4 levels Lower-Middle Income $550/yr Part of Gilead Access Program 86 Gilead Global pricing policy : 4 levels Low Income : No-profit price $300/yr Part of Gilead Access Program 87 Gilead Access Program Growth of the Gilead Access Program • More than 130 countries • 3.1 million patients • Licensing partnerships with 14 Indian companies and one South African company Generic products • Branded Truvada® : $45 (LMI) to $26.25/mth (LI) Generic Truvada® : $7/mth 88 EUROPE CNS: Report in response to the referral of Mr Director General of Health February , 2012 EMA :Reflection paper on the non-clinical and clinical development for oral and topical HIV pre-exposure prophylaxis (PrEP) EMA Submission? March 2012 91 Raised issues • • • • • Resistance Reimbursement by French health authority Long term toxicity in healthy people Increase of high-risk sexual behaviour Change in prevention strategy 92 French experts Favourable impact of PrEP only if : • Population at high risk of infection (incidence rate > 1%) • Efficacy > 50% ( adherence) • No increase of high-risk sexual behaviour Decrease of 5 to 25 % of incidence in these populations In France, only possible for MSM 93 French Market access CNS* recommendation : • Include PrEP in a global approach linking prevention, treatment and HIV screening/testing. • Ensure permanent and adequate access to therapeutic education and information. • Monitor the impact of PrEP on risk taking and ensure an effective pharmacovigilance system. • Use a different brand name for PrEP and a packaging with condoms. Conseil National du Sida 94 European Trial • Need of European data for EU approval • Beginning: February 2012 • France and Canada, 1900 MSM (anal sex, without systematic use of condoms, at least 2 sexual partners in the last 6 months) • Oral Truvada® vs placebo, occasional intake (2 tablets a day before sexual intercourse, then once a day until 24h after the last intercourse) 95 Ipergay • Interests of an intermittent PrEP (on-demand): • Acceptability, compliance, closer to the MSM sexual activity • Long-term safety, reduce side effects • Less expensive 96 Clinical Trials : Recruitment • Proving efficacy : need to recruit people who recognize taking risk and not using condoms. Contrary to the aim of prevention • Informed consent : Providing full information about the risk and prevention methods to patients (iPrex, Ipergay) Cases of non-compliance of recruitment conditions in Thailand (coercive recruitment), Cameroun, France (TROD)… 99 Placebo arm • Is the placebo arm (Ipergay study) still ethical after the FDA approval ? ☞ maintain placebo arm ☞ change Ipergay design : replace placebo arm by continuous Truvada® ☞ stop Ipergay & evaluate PrEP on available data : RTU ? 100 Placebo arm ☞ maintain placebo arm Double-blind placebo-controlled randomized study : • Decreases the unsafe sex : use protection measures. • Effective assessment of PrEP efficacy (combined with condoms) ☞ change Ipergay design • Intermittent PrEP vs continuous PrEP not feasible (> 10,000 patients) AIDES and WARNING request the provision of a RTU as a « condition » 101 Placebo arm ☞ stop Ipergay & evaluate PrEP on available data : RTU ? AIDES arguments: • The benefit / risk ratio is favourable in a preventive indication. • The indication extension was recently granted by the FDA. • The risk of the development of an alternative Truvada market: Deprive patients of appropriate supervision. 102 Side Effects • Potential long-term side effects : • Truvada® for Healthy people and Prevention use: renal function, loss of bone mineral density… • For a mild effectiveness when poor adherence. 104 Behavior and Effectiveness • Unsafe Sex : • Substantial increase in unsafe sex offset the benefits of PrEP on a population level in real life. ≠ • The optimal conditions in the clinical study lead to decrease the unsafe sex. • Ensure an effective and clear communication /access to information. 105 Market access • Cost–effectiveness : • $12,000 per year • Is high-priced interventions cost-effective? • Exacerbation of healthcare inequalities : • Ensure Truvada® for PrEP when a lot of people still don’t have access to HIV treatment ? • If PrEP not reimbursed: taken only by people who can afford to pay. • If PrEP reimbursed: Justified for an intentional risk taking? • Displacement of funds : conventional prevention PrEP. 106 Drug resistance • Truvada® will be used for both treatment and PrEP • In case of seroconversion under PrEP: need to stop immediately. If not : possible drug resistance. • Could infect someone with a strain of HIV resistant-virus. potential public health benefits of PrEP VS potential public health risk of drug resistance 107 Conclusion 108 Discussion: What do you think? Any questions? Thanks • Dr Yves Poinsignon, CHBA • Pr André Tartar, Université Lille 2 111