Post exposure prophylaxis following exposure to HIV. Paul Benn Mortimer Market Centre, Camden PCT HIVPA study day Tuesday 18 th November 2008 SOAS

Transcription

1 Post exposure prophylaxis following exposure to HIV Paul Benn Mortimer Market Centre, Camden PCT HIVPA study day Tuesday 18 th November 2008 SOAS

2 Overview Hypothesis PEP? Awareness & uptake PEP/PEPSE Ensuring appropriate and timely PEP/PEPSE Tolerability & completion PEP/PEPSE Current guidelines Special circumstances: cases Effect of PEPSE on sexual behaviour? Future surveillance/research

3 Dynamics following exposure to HIV

4 The risk of HIV transmission Type of exposure X Risk source is HIV+

5 Risk of exposure Type of exposure Needle-stick injury Sharing injecting equipment Mucous membrane exposure Receptive anal intercourse Receptive vaginal intercourse Insertive vaginal intercourse Insertive anal intercourse Receptive oral sex Estimated risk of HIV transmission 0.3% 0.67% 0.09% 0.1 3% % % 0.06% %

6 Calculating the risk of HIV transmission Needle stick injury HIV positive 100% X 0.3% = 3/1000

7 The risk of HIV transmission Infectiousness of source Susceptibility of individual

8 Other factors: occupational Exposure characteristics Source characteristics Viral factors

9 Other factors: occupational Exposure characteristics - Depth Visible blood Vessel Type of fluid Source characteristics - HIV status if unknown load Primary infection/aids Known resistance Plasma viral

10 Other factors: occupational AZT 0.2 AIDS 6.4 Vessel 5.1 Visible blood 5.2 Deep OR Cardo DM et al. N. Engl. J Med 1997; 337:1485

11 Other factors: sexual (infectiousness of source) Viral factors Circumcision STI s

12 Other factors: sexual (susceptibility of host) Genetic PEP & PrEP Microbicides Genital tract

13 Does PEP work? Animal studies Human studies Vertical transmission

14 Does PEP work? Individual Population

15 Time to initiation and duration of PEP Tenofovir PEP in macaques Time to PEP (hours) Duration of PEP (days) Number protected /4 (100%) /4 (50%) /4 (25%) /4 (0%) /4 (50%) /4 (100%) Tsai CC et al. J Virol 98; 72:

16 Evidence human: Occupational exposure AZT 0.2 AIDS 6.4 Vessel 5.1 Visible blood 5.2 Deep OR Cardo DM et al. N. Engl. J Med 1997; 337:1485

17 Failures of PEP & PEPSE?

18 Occupationally acquired HIV (2002) USA Europe (UK) Rest of world Documented cases HIV (5) 14 Possible cases HIV (14) 14 PEP failures : late presentation, insufficient duration/dose, resistant virus

19 Seroconversion following non-occupational PEP against HIV 7/702 (1%, 95% CI 0.4 2%) Unprotected receptive anal intercourse Late presentation; poor adherence Ongoing risk behaviour M E Roland et al. CID 2005:41;

20 What is the awareness & uptake of PEP & PEPSE?

21 Postal survey awareness PEP among junior doctors 1998 (n=350) M Y Chen et al. Sex Trans Infec 2001; 77: /273 (93%) had heard of PEP 23/273 (8%) could name the specific drugs 89/273 (33%) PEP should be initiated < 1 hour 208/273 (76%) reported at least one potential exposure 49/273 (18%) had sought advice about PEP

22 HPA: Occupational exposure to HIV infected source 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% N= PEP No PEP Unknown

23 PEP following occupational exposure to HIV Mortimer Market Centre No Occupational Sexual Non occupational Not specified

24 Awareness of PEPSE among MSM 2003 (n=14,000) Ford Hickson: Sigma Research % Heard of PEP Sought PEP Taken PEP

25 THT/CHAPS PEP Campaigns July 2004 Promote PEP MSM Brighton/London Information Self assessment tool Pathways November 2006 BME

26 Increase in awareness of PEPSE among MSM (n=16,000) Ford Hickson: Sigma Research % Heard of PEP Sought PEP Taken PEP

27 PEP following sexual exposure to HIV Mortimer Market Centre No Occupational Sexual Non occupational Not specified

28 Ensuring appropriate and timely PEP & PEPSE?

29 Avoiding exposure- universal precautions Safe handling sharps and needles Gloves Protective eyewear Education and training

30 Factors contributing to accidental exposures Equiptment related HCW related Procedure related Patient related Non compliance with UP %

31 Preventable exposures No % preventable Ward A&E ITU Theatre After procedure Other

32 Time to initiation of PEP 2005 (n=189) 6% 5% 34% 55% < 1 hour 1-24 hours hours >72 hours

33 Duration of PEP when source tests HIV negative (n=82) day 2-7 days 8 or more days 10

34 Avoiding PEP: POCT HIV tests EIA Ora quick & EIA p 1/1/03 10/7/03 11/7/03 31/12/03 Number HCW exposures Number of pep doses taken 3.8 (0-6) 1.2 (0-3) Cost per exposure N/A (USD) Landrum ML et al. Infect Control Hosp Epidemiol. 2005; 26(9):

35 Ensuring appropriate and timely PEP Awareness Trust policy/care pathways 24 hour access Training Use of POCT

36 Pilot POCT at MMC for MSM requesting PEP following sexual exposure to HIV n=198 Use of Abbott Determine and INSTI HIV POCT 9/198 (4.5%) positive at baseline confirmed by HIV Ag/Ab avoided unnecessary PEP 1/198 (0.5%) false reaction INSTI

37 Tolerability & completion PEP/PEPSE

38 PEP following occupational exposure Parkin J M et al (Lancet 2000, 355; 29: 722-3) 28 HCWs 15/28 (53.6%) completed 4 weeks 6/19 (31.6%) indinavir-based regimen required more than 2 weeks off work

39 Patients prescribed PEP at the MMC 1/97-11/99 Benn P et al (Lancet, 2001; 357: 687-8) occupational (n=44) sexual (n=40) median time to PEP (hours): completion rates: 2 (range 1-48) 23 (range 9-192) 19/40 (48%) 24/39 (62%)

40 Completion rates 4 weeks PEP (%) % completing nevirapine protease inhibitor AZT/3TC n=57 n=19 n=7

41 Adverse Events (%) % of PEP recipients nevirapine protease inhibitor AZT/3TC minor AE major AE

42 Risk:Benefit Analysis Risk of transmission Risk of PEP

43 NONOPEP study Prospective descriptive study of the use PEP following non-occupational exposure to HIV infection 10 centres November June 2005 Follow-up 6/12 N=333 (93% followed sexual exposure)

44 NONOPEP Median time to initiation of PEP Median time hours (range) Sexual n=309 Mucous membrane n=10 Needle-stick n=14 24 (0.3-72) 21 ( ) 4 (1-63)

45 NONOPEP Completion and adherence to PEP (n=333) % completed 28/7 % % missed at least 1 dose 32% LTFU Completed 100% adherence Completed missed at least 1 dose Completed adherence data missing Stopped early LTFU

46 NONOPEP Completion rates (%) among individuals returning for F/U according to PEP regimen % AZT/3TC/NFV D4T/3TC/NFV Other* N=

47 NONOPEP Tolerability of PEPSE 132/225 (59%) reported at least 1 side effect 50/189 (27%) required at least one day off work, mean 7 days (range 1 30). 137/201 (68%) reported some degree of psychological disturbance while receiving PEP.

48 Guidelines

49 International guidelines US (CDC) Europe UK Australia When? 72 hours 72 hours 72 hours 72 hours What? 2 or 3 drugs 3 drugs 3 drugs 2 or 3 drugs How long? 28 days 28 days 28 days 28 days Who? Source HIV+ or from risk group Source HIV+ or from risk group Source HIV+ or from risk group Source HIV+ or from risk group

50 UK guidelines: Situations in which PEP would be considered Exposure Source HIV+ Source Prevalence high (>10%) Source Prevalence low Receptive anal sex R R C Insertive anal sex R C Receptive vaginal sex R C Insertive vaginal sex R C Fellatio with ejaculation C C Fellatio without ejaculation Splash semen into eye C Cunnilingus

51 UK guidelines: Situations in which PEP would be recommended Exposure Source HIV+ Source Prevalence high (>10%) Source Prevalence low Receptive anal sex R 3 /100 R 3 /1000 C Insertive anal sex R 1/1000 C Receptive vaginal sex Insertive vaginal sex Fellatio with ejaculation R R C 1/1000 1/1000 C C C Fellatio without ejaculation Splash semen into eye C Cunnilingus

52 UK guidelines: Situations in which PEP would be considered Exposure Source HIV+ Source Prevalence high (>10%) Source Prevalence low Receptive anal sex R R C Insertive anal sex Receptive vaginal sex R R C C 1/ /10000 Insertive vaginal sex R C 1/10000 Fellatio with ejaculation C 4 /10000 C 1/10000 Fellatio without ejaculation Splash semen into eye C Cunnilingus

53 Previous DoH & BASHH guidelines DOH 2/04: AZT/3TC/Nelfinavir 28/7 BASHH 04: TI # + PI (boosted PI)* 28/7 # AZT/3TC or D4T/3TC or TDF/3TC or TDF/FTC Nelfinavir, Lopinavir, Fosamprenavir or Saquinavir

54 Previous DoH & BASHH guidelines DOH 2/04: AZT + 3TC + rpi 28/7 BASHH 04: TI # + PI (boosted PI)* 28/7 # AZT/3TC or D4T/3TC or TDF/3TC or TDF/FTC Lopinavir, Fosamprenavir or Saquinavir

55 Pan London PEP/SE regimens units using three different regimens 5 different durations of starter packs (range 1-7) Some trusts using longer 28 days?discarding additional medication Variation in cost from 517 to 745 per PEP/SE course

56 Current DoH & BASHH guidelines DOH 2008: Truvada & Lopinavir 28/7 BASHH 04: TI # + PI (boosted PI)* 28/7 # AZT/3TC or D4T/3TC or TDF/3TC or TDF/FTC Lopinavir, Fosamprenavir or Saquinavir

57 Key changes DoH guidelines in 2008 Truvada and kaletra: 28/7 Testing source: result available within 8 hours (max 24) Cut off 72 hours Follow up testing at 3 months after completion of PEP

58 Pan London approach in 2008? Standardised regimen Standardised cost Central packaging (blister packs) Standardised patient information sheet

59 Key considerations for which regimen? Individualise Potency Pill burden Tolerability Standardise Starter packs Storage Anxiety Adherence Drug-drug interactions Drug penetration Medical conditions Resistance

60 Key considerations for which regimen? Individualise Potency Pill burden Tolerability Adherence Drug-drug interactions Drug penetration Medical conditions Resistance

61 Female Genital Tract Exposure (percent of blood plasma) Dumond et al. Abstract 129, 13 th CROI 0 200% 400% 600% ddi (100%) IDV (200%) 3TC (400%) FTC (600%) SQV(ND) ZDV (200%) TDF (400%) EFV (0.6%) ABC (150%) d4t (4%) RTV (20%) DLV (20%) ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) TI PI NTI

62 Female Genital Tract Exposure (percent of blood plasma) Dumond et al. Abstract LB 135, 14 th CROI 0 200% 400% 600% ddi (100%) IDV (200%) 3TC (400%) FTC (600%) SQV(ND) ZDV (200%) TDF (400%) EFV (0.6%) ABC (150%) d4t (4%) RTV (20%) DLV (20%) MVC (400%) ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) CCR5 TI PI NTI

63 Other considerations for which regimen? 4 case studies

64 Case 1 MSM attended A&E 1/7 ago following an episode of UPRAI with a known HIV+ partner. Diagnosed 10 years ago and has taken several combinations ART previously Started standard regimen of Truvada Kaletra What do you want to know?

65 Case 1 (2) CD4? Viral load? Which regimen? Resistance profile?

66 Case 1 (3) CD4 600 Viral load Previous regimens 3200 copies/ml CBV EFV Resistance profile RT 184V K103N PI Nil Do you change his PEP?

67 Case 1 (4) CD4 600 Viral load Previous regimens Resistance profile 3200 copies/ml Triple class experienced Extensive triple class resistance Do you change his PEP?

68 Resistance Undiagnosed prevalence 5-10% Untreated (check baseline resistance test) On treatment (majority will have VL < 50) On treatment with known resistant virus

69 % UK Surveillance Resistance N= 4454 Treatment naïve (316 recently infected) Dunn et al. AIDS 2007; 21(8): N= Any TI NTI PI

70 Resistance Undiagnosed prevalence 5-10% Untreated (check baseline resistance test) On treatment (majority will have VL < 50, resistance unlikely) On treatment with known resistant virus chase result

71 Case 2 MSM attended A&E 1/7 ago following an episode of UPIAI with a known HIV+ partner. Diagnosed 10 years ago and is taking ART Started standard regimen of Truvada Kaletra What do you want to know?

72 Case 2 (2) CD4? Viral load? Previous regimen? Resistance profile? Adherence?

73 Case 2 (3) CD4 920 Viral load What is his risk of acquiring HIV? < 50 copies/ml Previous regimen Atripla Should he continue PEP? Resistance profile Adherence Wild type Excellent

74 Viral load < 50 Viral load does not = non infectious? Usually plasma VL proportional to genital tract VL Impact of STIs? Impact of non/poor adherence? Overall risk VERY SMALL

75 Viral load < 50? Exposure Source HIV+ Source Prevalence high (>10%) Source Prevalence low Receptive anal sex R 3 /1000? R 3 /10000? C Insertive anal sex R 1/10000? C Receptive vaginal sex Insertive vaginal sex Fellatio with ejaculation R R C 1/10000? 1/10000? C C C Fellatio without ejaculation Splash semen into eye C Cunnilingus

76 Viral load < 50 Viral load does not = non infectious Usually plasma VL proportional to genital tract VL Impact of STIs? Impact of non/poor adherence? Overall risk VERY SMALL

77 Case 3 29 year old female nurse is referred to your clinic following a needle stick injury from a man on HDU with severe pneumonia, recently moved from S. Africa. What do you want to do next?

78 Case 3 (2) Test source with his consent Sexual, PMH, DH of nurse Test nurse with consent Risk of pregnancy positive high risk partner negative 6/52 pregnant Would you give PEP? If so what?

79 Pregnancy Pregnancy not a contraindication to taking PEP Risk vs benefit analysis Combivir & kaletra

80 Case 4 (1) 43 year old MSM presents to your clinic following UPRAI with several men at least one is known to be HIV + 24 hours ago On further questioning he has taken PEP four times this year Should you offer him PEP?

81 Impact of PEPSE upon sexual behaviour? Individual

82 Impact of PEPSE upon sexual behaviour? Negative impact: people who use seat-belts drive faster 1 Or? Positive impact: access to sexual health care and wake-up call 2

83 Summary of impact of PEPSE upon sexual behaviour (NONOPEP study)? High risk group Majority of people report reduction or no change in risk taking behaviour compared to baseline in short to medium term - number of partners in 3/12 - number of additional HIV exposures

84 Impact of PEPSE upon sexual behaviour?? Population

85 Multiple requests for PEP among MSM following sexual exposure to HIV 1/98 to 12/06 Mortimer Market Centre 30/794 (3.8%) Brighton 7/118 (5.9%) St Thomas 10/609 (1.6%)

86 Case 4 (2) Very high risk of acquiring HIV Case by case analysis of risk vs benefit Involve health advisor & psychology teams

87 Case 4 (3) He reports that he has been taking PEPSE from St elsewhere for two weeks and has another 14 days left What do you do?

88 Future research and surveillance Occupational exposures Voluntary reporting system to HPA Non-occupational exposures No surveillance system PEP BASHH HIV SIG- KC60 codes Web based enhanced surveillance RCT Maraviroc vs Kaletra + Truvada

89 Conclusions Risk HIV acquisition is small/risk assessment key Awareness & easily accessible PEP/PEPSE may reduce delays in initiation Guidelines and POCT ensure appropriate use of PEP/PEPSE Which PEP regimen? Poor tolerability & follow up rates Majority individuals taking PEPSE report reduction risk taking behaviour short/medium term Future surveillance/studies

90 Acknowledgments MRC grant NONOPEP study Co-investigators NONOPEP study Fortune Ncube HPA Sarah Tomkins HPA