Pharmacoprevention. HIV-drugs for prevention. Instituut Tropische Geneeskunde, Antwerpen

Transcription

1 Pharmacoprevention HIV-drugs for prevention Instituut Tropische Geneeskunde, Antwerpen

2 Introduction Afkortingskunde: What s in a name/ abbreviation? PEP PrEP TASP PMTCT

3 Introduction PEP: Post-Exposure prophylaxis Well known & implemented concept Risk situations Professional exposure Sexual exposure

4 Introduction PrEP: Pre-exposure profylaxis Oral HIV-drugs for HIV-negative people It works if you take your pills

5 Introduction PrEP More questions then answers Practically Medics & paramedics level Patient level Ethically Low income countries: no antivirals for all HIV-positives High income countries: antivirals for HIV-negatives Economically Cost-effectiviness Who will pay?

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7 Introduction TASP Treatment as prevention Hiv-positive persons Treat to prevent hiv-transmission What is efficacy of TASP In trial setting? In real life situation?

8 Introduction Efficacy of TASP trial setting? 96% and more Biologically

9 Introduction Efficacy of TASP trial setting? 96% and less Behaviourly In real life situation

10 Introduction PMTCT Prevention Mother-to-child Transmission = TASP + PrEP + PEP

11 HIV-drugs passing placenta Source: DHHS Guidelines July 2012 NRTI Compound Transfer Evidence Sources Abacavir Yes Low Rats Didanosine Limited High Human Emtricitabine Excellent High Human Lamivudine Yes High Human Stavudine Yes Medium Rats/primates (monkey) Tenofovir DF High High Human Zidovudine Yes N/A Human NNRTI Compound Transfer Evidence Sources Efavirenz Yes Medium Rats/rabbits/primates (human) Etavirine Unknown Nevirapine Yes High Human Rilpiverine Unknown Protease Inhibitors Compound Transfer Evidence Sources Atazanavir Limited High Human Darunavir Limited Medium Human Fosamprenavir Limited Low Human Indinavir Minimal High Human Lopinavir/r Limited High Human Ritonavir Minimal High Human Nelfinavir Minimal High Human Saquinavir Minimal High Human Tipranavir Unknown DHSS perinatal guidelines Entry Inhibitors Compound Transfer Evidence Sources Enfuvirtide Unknown Maraviroc Unknown Integrase Inhibitors Compound Transfer Evidence Sources Raltegravir High Medium Human/rabbits/rats

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13 exposure UN Clinical Pharmacology & Therapeutics September 2010

14 Concept drugs for prevention Anti-malaria-pills When used first time? Anticonception pill Early 1960 s Anti-gonorhoe-shot, Vietnam War Early 1960

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16 Vaginal transmission of SIV: fast phase of lenti-virusses PEP opportunity < 72 hours Nature Vol March

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18 Can a pill a day prevent HIV? Source of slide Albert Liu San Francisco Dept of Public Health

19 Pre-exposure profylaxis: iprex-trial 2499 MSM Hiv-negative at start Placebo group N = 1248 Truvada group N = 1251 Characteristics % South America 80 US 9 Thailand 5 South Africa 4 In commercial sexwork 40 Hepatitis B not vaccinated 65

20 Pre-exposure profylaxis: iprex-trial Hiv-infections N Placebo 83 Truvada 48 Protection by Truvada use % Overall 44 >= 50% pill use 50 >=90% pill use 72

21 Pre-Exposure prophylaxis FTC-TDF vs Placebo Grant et al NEJM p 2587

22 iprex-trial Grant et al NEJM p 2587

23 PrEP: only 36 weeks gain? Grant et al NEJM p 2587

24 Pre-exposure profylaxis partially works HIV-seroconverters No resistance observed Drugs levels

25 Protection

26 Protection If optimal adherence %

27 FEM-PrEP young women Lut Van Damme N Engl J of Med August

28 Young women < 25 year 5,7 5,9

29 Do you think you are at risk for HIV-infection? 70%: No But question not optimally phrased. Do you think you are at risk for getting HIV in 4 weeks from now?

30 PrEP already in use? Survey USA Hiv-healthcare workers Responding 189/2000 IDSA % had questions about PrEP last 6 months 19% made a perscription Weblink to: Poster at Infectious Diseases Society of America Congres

31 PrEP already in use in Belgium? AIDS reference centers via BREACH 8 MD s from 8 different centres responded Formal PrEP request ever? Yes : 3/8 Perscription made ever? Yes : 0/8 Case report Discordant couple: MSM Hiv-negative person wants PrEP during holiday» Intention to buy it in South Africa» Truvada 50 (in Belgium: 569,03 ) Suggestion Frequent PEP-users Why not PrEP in stead of PEP?

32 PrEP: Research continues other drugs Approved HIV-drugs Entree inhibitors Maraviroc Integrase inhibitors Raltegravir Investigational drugs Long-acting rilpivirine: IM GSK Ibalizumab

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34 PrEP: More questions then answers Acceptability Medics & paramedics level Patient level Agree to be tested? Stigma related to PrEP? Adherence: Will people take their drugs? Impact Does is reduce transmission? Can we handle resistance?

35 PrEP: More questions then answers Ethically Low income countries: no antivirals for all HIVpositives High income countries: antivirals for HIV-negatives Economically. Cost-effectiviness Who will pay? Health Insurance? Generic drugs in low income countries?

36 Pre-exposure profylaxis: meer vragen dan antwoorden Guidelines Wie schrijft voor? In welke setting? Aan wie toedienen? Hoogrisico-situaties Seksueel risico Gezondheidswerkers? Follow up Chirurgen? Gynaecologen? Neveneffecten medicatie? Indien hiv-positief Hiv-resistentie-testen

37 Recente teamvergadering ITG-ARC MSM-koppel discordant koppel Start nieuwe relatie Kennen concept TASP & relatie viral load & transmissiekans Hiv-positieve index VL > k/ml CD4 > 500 per µl Dokter, ik wil alles doen om mijn nieuwe partner niet te besmetten.

38 Therapy as prevention Dosis-effect-relatie Virale lading &hiv-overdracht discordante hetero koppels % Transmissiekans per 100 persoonsjaren Rakai-project Quinn NEJM 2000;342: A B C D E Virale lading hiv-positieve index A: <400 B: C: D: E >

39 TASP Treatment as prevention HPTN 052-trial Discordant couples Sub-Saharan Africa Brazil Thailand Boston Index HIV-positive CD Therapy-groups Early start Late start

40 Highlights of AIDS 2012 clinicaloptions.com/hiv HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: cells/mm 3 (N = 1763 couples) Immediate ART Initiate ART at CD4+ cell count cells/mm 3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count 250 cells/mm 3 * (n = 877 couples) Primary efficacy endpoint: virologically linked HIV transmission Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death Couples received intensive counseling on risk reduction and use of condoms Cohen MS, et al. N Engl J Med. 2011;365: *Based on 2 consecutive values 250 cells/mm 3.

41 Highlights of AIDS 2012 clinicaloptions.com/hiv HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 Delayed Arm: 27 P <.001 Immediate Arm: 1 Cohen MS, et al. N Engl J Med. 2011;365: Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression

42 Preventive effect c-art in HTPN 052 HIV-infections (95% CI) All 89% (68-96) Linked infections 96% (83-99) Indeces with suppressed viral load >96%

43 Preventive effect HTPN 052 HIV-infections (95% CI) All 89% (68-96) Linked infections 96% (83-99) Indeces with suppressed viral load >96% HPTN = Proof of concept TASP

44 Highlights of AIDS 2012 clinicaloptions.com/hiv HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 Delayed Arm: 27 P <.001 Immediate Arm: 1 Cohen MS, et al. N Engl J Med. 2011;365: Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression

45 Certainty linked/ unlinked transmission? Fixed couples Hiv + Hiv neg Outside relation

46 China TASP heterosexual HIV-discordant couples Retrospective observational cohort couples!!!! person-years follow up!!!! FU 2 times per year HIV-positive index HIV-negative partner Zhongwei et al Lancet Dec Free full text

47 China TASP heterosexual discordant couples Combination-AntiRetroviral Therapy start if CD4 < 200 ( ) < 350 ( ) Only first line c-art No resistance testing available Zhongwei et al Lancet Dec Free full text

48 China TASP heterosexual discordant couples Case-couples & control couples Different at start Case-indeces at start Lower CD4-cells Older Route of transmission: different Zhongwei et al Lancet Dec Free full text

49 China TASP heterosexual discordant couples Zhongwei et al Lancet Dec Free full text

50 China TASP heterosexual discordant couples Authors conclude Protection of c-art in observational cohort 26% Only first year of follow-up After first year Not significant Zhongwei et al Lancet Dec Free full text

51 China TASP heterosexual discordant couples Strenght of study Proxi for real life situation Possible bias No control for unlinked transmissions See HPTN 052-trial Zhongwei et al Lancet Dec Free full text

52 Review: Heterosexual HIV-1 Infectiousness and c-art-use Meta-analysis 50 studies 9 studies Comparison c-art- use & non-use possible Baggaley et al Epidemiology 2013 january vol 24 no 1 Abstract

53 Review: Heterosexual HIV-1 Infectiousness and c-art-use Baggaley et al Epidemiology 2013 january vol 24 no 1 Abstract

54 Review: Heterosexual HIV-1 Infectiousness and c-art-use Authors conclude c-art substantially reduces infectioussness index Protection 91% (95%Confid Interval: 79-96%) Is not: zero risk!!! Other risk-reduction strategies necessary Baggaley et al Epidemiology 2013 january vol 24 no 1 Abstract

55 Conclusions Pharmaco-prevention It works, if you take your pills PrEP More questions then answers More research necessary Implemention research TASP Proof of concept Real life can be very different then trial situations