PostExposure Prophylaxis an evidencebased review

1
Post-Exposure Prophylaxisan evidence-based review

• Christopher Behrens, MD
• Hillary Liss, MD
• Northwest AIDS Education
• Training Center
• University of Washington

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Post-Exposure Prophylaxis (PEP)

• The use of therapeutic agents to prevent
  infection following exposure to a pathogen
• Types of exposures include percutaneous
  (needlestick), splash, bite, sexual
• For health-care workers, PEP commonly considered
  for exposures to HIV and Hepatitis B

3
Hepatitis B PEP

• Prevalence of chronic hepatitis B infection in
  U.S. relatively low
• Most health-care workers vaccinated against
  hepatitis B
• Hepatitis B PEP immunization HBIG (hepatitis B
  Immune Globulin)
• HBIG effective up to one week following exposure

Grady GF et al. JID 1978138625-38.
4
HIV PEP

• Exposures common
• 56 documented cases of health care workers
  contracting HIV from exposures 138 other
  possible cases
• Area of considerable concern but little data

MMWR June 29, 2001 / 50(RR11)1-42
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Case Presentation

• 27 yo medical exam assistant (MA) presents to
  Urgent Care for evaluation of needlestick injury
  2 days ago from a diabetic lancet
• Source patient (SP) 35 yo male, known HIV
• Would you offer her PEP?

6
Case Presentation continued

• What is her risk for contracting HIV?
• Are there factors that might affect this risk?
• How effective is PEP?
• Is it too late to start PEP?
• What are the drawbacks of starting PEP?
• Which regimen(s) should be considered?
• What follow-up should be arranged?

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What is her risk of contracting HIV?

• What factors affect this risk?

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Risk of HIV Transmission Following Percutaneous
(Needlestick) Exposure

• Pooled analysis of prospective studies on health
  care workers with occupational exposures suggests
  risk is approximately 0.3 (95 CI, 0.2 - 0.5)1
• Presence or absence of key risk factors may
  influence this risk in individual exposures

1. Bell DM. Am J Med 1997102(suppl 5B)9-15.
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Risk Factors for Seroconversion Following
Needlesticks

• CDC-sponsored case-control study
• 33 cases, 665 controls with needlesticks from
  confirmed HIV SPs
• Zidovudine (AZT) monotherapy as PEP

Cardo DM et al. NEJM 19973371485-90
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Risk Factors for Seroconversion
plt0.01 for all
Cardo DM et al. NEJM 19973371485-90
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Other Likely Risk Factors

• Viral load
• Glove use
• 50 decrease in volume of blood transmitted1
• Hollow bore vs solid bore
• Large diameter needles weakly associated with
  increased risk (p 0.08)2
• Drying conditions
• tenfold drop in infectivity every 9 hours3

1. Mast ST et al. JID 1993168(6)1589-92. 2.
Cardo DM et al. NEJM 19973371485-90 3. Resnick
L et al, JAMA 1986255(14)1887-91.
3.
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How effective is PEP?
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Evidence of Efficacy of PEP

• Animal models high level of protection when
  started within 24 hours1
• OR 0.19 for zidovudine use in case-control
  study2
• Two drugs, three drugs
• No direct evidence that more effective than 1
  drug
• Cases of seroconversion despite 3-drug PEP imply
  efficacy less than 1003,4

1. Tsai C-C et al. J Virol 1998724265-73. 2.
Cardo DM et al. NEJM 19973371485-90. 3.
Jochinsen EM et al. Arch Int Med
19991592361-3. 4. MMWR June 29, 2001 /
50(RR11)1-42
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What are the drawbacks of PEP?
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Tolerability of HIV PEP in Health Care Workers
Incidence of Common Side Effects
Percent of HCWs
Wang SA. Infect Control Hosp Epidemiol
2000231780-5.
16
HIV Postexposure ProphylaxisSerious Adverse
Events Associated with Nevirapine
22 Serious Adverse events - 12 hepatotoxicity
- 2 cases of liver failure - 14 dermatologic
Number
Year
MMWR 200149(51)1153-6.
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When should PEP be started?
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When should PEP be started?

• Efficacy of PEP thought to wane with time
• At what point is PEP no longer worth it?

benefits of PEP
risks of PEP
time
exposure
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Timing of PEP whats the evidence?

• Animal models and animal PEP studies suggest
  substantially less effective beyond 24 - 36
  hours1,2
• Case-control study most subjects in each group
  received PEP within 4 hours3
• Analysis of PEP failures does not suggest a clear
  cut-off4

1. Tsai C-C et al. J Virol 1998724265-73. 2.
Shih CC et al. JID 1991. 3. Cardo DM et al. NEJM
19973371485-90. 4. MMWR June 29,
200150(RR11)1-42.
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Timing of PEP An Anecdote

• 13 yo girl in Italy transfused with one unit of
  blood from donor who was acutely infected with
  HIV but not yet HIV-antibody positive
• Seroconversion risk estimated to be virtually
  100
• 3-drug PEP initiated 50 hours post-transfusion,
  continued for 9 months
• No evidence of HIV infection 15 months later

Ann Int Med 200013331-4.
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Timing of PEP CDC Guidelines

• PEP should be initiated as soon as possible,
  preferably within hours rather than days of
  exposure.
• Interval after which there is no benefit for
  humans is not known
• Obtain expert advice when interval has exceeded
  24-36 hours

MMWR 200554(No. RR-9).
22
How Long Should PEP be Administered?

• N 24 macaques inoculated with SIV intravenously
• PEP initiated 24 hours post-inoculation
• PEP administered for 3, 10, or 28 days

Tsai C-C et al. J Virol 1998724265-73.
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Duration of PEP

• In animal model, 28 days more effective than 10
  days or 3 days of PEP1
• 4 weeks (28 days) used in case-control study2 and
  recommended by CDC guidelines3

1. Tsai C-C et al. J Virol 1998724265-73. 2.
Cardo DM et al. NEJM 19973371485-90. 3. MMWR
June 29, 200150(RR11)1-42.
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Back to the Case

• 27 yo Medical Assistant presents to Urgent Care
  for evaluation of needlestick 2 days ago from a
  diabetic lancet
• Source patient (SP) 35 yo male, known HIV
• What other questions do you have for her?

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Back to the Case

• According to the MA, the SP has never received
  treatment for his HIV. She does not know his VL
  or CD4 count, but he looks pretty healthy.
• The lancet was visibly bloody and stuck her
  through her glove, causing her to bleed
• Exam pinpoint puncture wound on thumb
• What are your PEP recommendations?

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Which PEP regimen should be considered?
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PEP Regimens Basic regimens

• Two NRTIs
• Simple dosing, fewer side effects
• Preferred basic regimens
• zidovudine (AZT) OR tenofovir (TDF)
• plus
• lamivudine (3TC) OR emtricitabine (FTC)
• Alternative basic regimens
• stavudine (d4T) OR didanosine (ddI)
• plus
• lamivudine (3TC) OR emtricitabine (FTC)

MMWR 200554(No. RR-9).
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Expanded PEP Regimens

• Basic regimen plus a third agent
• Rationale 3 drugs may be more effective than 2
  drugs, though direct evidence is lacking
• Consider for more serious exposures or if
  resistance in the source patient is suspected
• Adherence more difficult
• More potential for toxicity

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Expanded PEP Regimens

• Preferred Expanded Regimen
• Basic regimen plus lopinavir/ritonavir (Kaletra)
• Alternate Expanded Regimens
• Basic regimen plus one of the following
• Atazanavir /- ritonavir
• Fosamprenavir /- ritonavir
• Indinavir /- ritonavir
• Saquinavir (hgc Invirase) ritonavir
• Nelfinavir
• Efavirenz

MMWR 200554(RR-9)
Atazanavir requires ritonavir boosting if used
with tenofovir
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Adverse Effects Basic vs Expanded Regimens
of individuals
Puro V et al. 9th CROI, February 2002, Abstract
478-M
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Other Antiretrovirals

• ARVs to be considered only with expert
  consultation
• Enfuvirtide (Fuzeon T-20)
• ARVs not generally recommended for PEP
• Delavirdine
• Zalcitabine
• Abacavir
• Nevirapine

MMWR 200554(No. RR-9).
32
0
MMWR 200554(No. RR-9).
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Back to the Case

• After extensive counseling, she decides to take
  zidovudine lamivudine (Combivir) basic regimen
• You write the prescription and arrange for
  follow-up, but before the patient leaves, the
  triage nurse informs you that she has finally
  tracked down the SPs Primary Care Provider

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Back to the Case, continued

• The SPs PCP tells you the following
• His CD4 count was 450 cells/mm3 two months ago,
  his CD4 nadir is 280 cells/mm3, he has never had
  an OI.
• SP is not naïve to therapy for the past year he
  has been on AZT/3TC/RTV/IDV (1st regimen).
• Viral load 2 months ago was around 60,000
  copies/mL.
• What do you do with this information?

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HELP!

• Expanded regimens and expert advice indicated for
  severe exposures or when resistance is suspected
• Northwest AETC
• Hillary Liss [phone] pager
• Chris Behrens [phone] pager
• National Clinicians Post-Exposure Prophylaxis
  Hotline (PEPline)
• (888) HIV-4911

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Case PEP options

• Source patients high-level VL despite ART
  suggests that he is either not taking his
  medications, or that he has developed resistance
  to his regimen
• Turn-around time for a resistance assay too long
  for this to be a useful tool in designing her PEP
  regimen Must make best guess about patterns of
  anticipated resistance to SPs regimen
• If resistance has developed, would suspect
  resistance to lamivudine, zidovudine, and
  possibly ritonavir/indinavir
• Cross-resistance considerations would suggest
  that resistance to stavudine and abacavir may
  also exist resistance to tenofovir and
  didanosine also possible but less likely

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Case PEP options

• Given concerns over efficacy of a 2-NRTI regimen,
  would recommend a 3 or 4 drug PEP regimen
• Resistance to PIs difficult to estimate, but PI
  resistance generally evolves less rapidly than
  does resistance to the NRTI components of typical
  ART regimens
• Would not expect any resistance to NNRTI class
• One reasonable PEP regimen tenofovir d4T
  (efavirenz OR lopinavir/ritonavir)
• Notes
• Efavirenz is contraindicated in pregnancy
• Combining ddI tenofovir efavirenz no longer
  recommended in ART regimens

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CDC Post-Exposure Prophylaxis Guidelines

• MMWR 200554(No. RR-9).
• http//www.aidsinfo.nih.gov

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CDC Post-Exposure Prophylaxis Guidelines
MMWR 200554(No. RR-9).
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CDC Post-Exposure Prophylaxis Guidelines
MMWR 200554(No. RR-9).
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Situations for which expert consultation for
HIVpostexposure prophylaxis (PEP) is advised
Either with local experts or by contacting the
National Clinicians Post-Exposure Prophylaxis
Hotline (PEPline), 888-448-4911.
MMWR 200554(No. RR-9).
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Follow-up of health-care personnel (HCP) exposed
to known or suspected HIV-positive sources
0

• Exposed HCP should be advised to use precautions
  (e.g., avoid blood or tissue donations,
  breastfeeding, or pregnancy) to prevent secondary
  transmission, especially during the first 612
  weeks post-exposure.
• For exposures for which PEP is prescribed, HCP
  should be informed regarding
• need for monitoring
• possible drug interactions
• the need for adherence to PEP regimens.
• Consider re-evaluation of exposed HCP 72 hours
  post-exposure, especially after additional
  information about the exposure or SP becomes
  available.

MMWR 200554(No. RR-9).
43
Follow-up HIV Testing

• CDC recommendations HIV Ab testing for 6 months
  post-exposure (e.g., at 6 weeks, 3 months, 6
  months)
• Extended HIV Ab testing at 12 months is
  recommended if health care worker contracts HCV
  from a source patient co-infected with HIV and
  HCV
• VL testing not recommended unless primary HIV
  infection (PHI) suspected

MMWR 200554(No. RR-9).
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Case 2 Non-occupational exposure

• 34 yo woman presents to ED after being sexually
  assaulted by someone that she says is
  HIV-infected
• Physical exam reveals perineal bruising, shallow
  vaginal lacerations
• What is her level of risk?
• Should PEP be considered?
• Are there guidelines that cover this situation?

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Exposure Risks (average, per episode, involving
HIV-infected source patient)
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Is PEP effective for non-occupational exposures?

• Brazilian non-randomized trial of PEP following
  sexual assault rate of HIV transmission was
  2.7 in control subjects compared with 0 in
  those who received PEP (P lt .05).
• Buenos Aires study involving MSM HIV
  transmission occurred in 4.2 of 131 men who did
  not receive PEP, compared with 0.6 of 66 men who
  received PEP (P lt .05).

Schechter M. Program and abstracts of the Sixth
International Congress on Drug Therapy in HIV
Infection November 17-21, 2002 Glasgow.
Abstract PL6.1.
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Guidelines???
48
(No Transcript)
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Non-occupational PEP Evaluation Treatment
Algorithm
MMWR January 21, 2005, Vol 54, No. RR-2
50
Non-occupational PEP Regimens
MMWR January 21, 2005, Vol 54, No. RR-2
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Does Offering Non-occupational PEP Encourage
High-Risk Behavior?

• N 401 participants receiving PEP following
  unprotected sexual or IDU exposure to HIV
• 379 sexual exposures 336 involved MSM
• Most MSM reported decrease in risky behaviors on
  followup questioning
• By 12 months of follow-up, 17 of MSM had
  received PEP for one or more repeat exposures

Percentage of participants
Change in Risky Behavior
Martin J et al, 8th CROI, February 2001, Abstract
224.
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Case Number 3 Splash!

• 24 yo dental technician splashed in the eye
  during dental procedure 3 hours ago
• Source patient 33 yo male, co-infected with HIV
  and HCV
• What else do you want to know?

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Which fluids are potentially infectious for HIV?

• blood?
• saliva?
• sweat?
• feces?

• spinal fluid?
• pleural fluid?
• pus?
• urine?

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Which fluids are potentially infectious for HIV?

• blood
• saliva
• sweat
• feces

• spinal fluid
• pleural fluid
• pus
• urine

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Case number 3 continued

• Saliva was visibly bloody - in fact, it was
  mostly blood that splashed her
• She rinsed out her eye immediately
• Source patient has never taken antiretrovirals,
  has a CD4 count of about 500 and a viral load
  of 20,000 last time it was checked
• The technician is 8 weeks pregnant

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Case number 3 continued

• What is her risk of contracting HIV?
  Of HCV?
• What are your PEP recommendations?
• How does her pregnancy affect your decision
  making?

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Case 3 continued

• Risk of HIV from mucous membrane exposures 0.09
  (95 CI 0.006 -0.5)1
• Risk of HCV in this circumstance unknown thought
  to be higher than HIV, because risk of HCV in
  percutaneous exposures of 1.8,2-4 is higher than
  that for HIV

1. Ippolito G et al. Arch Int Med
19931531451--8. 2. Lanphear BP et al. Infect
Control Hosp Epidemiol 199415745-50. 3. Puro V
et al. Am J Infect Control 199523273-7. 4.
Mitsui T et al. Hepatology 1992161109-14.
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PEP in Pregnancy

• Most antiretrovirals are pregnancy class B or C
• Antiretroviral Pregnancy Registry has not
  detected increased teratogenic risk for ARVs in
  general, nor specifically for AZT and 3TC, in the
  first trimester1
• Avoid efavirenz (anacephaly in monkeys),
  amprenavir (ossification defects in rabbits), and
  indinavir in late term (hyperbilirubinemia)
• Theoretically higher risk of vertical
  transmission with primary HIV infection

1. Garcia et al. ICAAC, December 2001, Abstract
1325.
59
Case 3 continued

• You jointly decide on AZT/3TC/nelfinavir
• 3 days later she calls complaining of headache,
  an itchy rash, and URI symptoms
• What do you do?

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Case 3 continued

• Exam
• VS - T 99.0 R 14 P 78 BP 134/76
• Gen - alert, tired-appearing, no acute distress
• HEENT - nasal congestion, otherwise benign
• Neck - 3 ant cervical lymph nodes
• Lungs, cardiac, abdomen - benign
• Neuro - nonfocal
• Skin - urticarial rash on trunk and legs

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Case 3 continued

• What could be responsible for her symptoms?
• How would you manage her?

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Could she have Primary HIV Infection?

• Most patients who contract HIV are symptomatic
  with seroconversion1
• Flu-like or mono-like illness often accompanied
  by a rash2
• Onset typically 2-6 weeks following exposure, but
  high variability1
• Treatment of PHI with antiretroviral therapy may
  have significant long-term benefit3

1. Schacker T et al. Ann Int Med
1996125257-64. 2. Kahn JO, Walker BD. N Engl J
Med. 199833933-39. 3. Walker B. State of the
Art Lecture and Summary. 8th CROI, Session 37.
63
Primary HIV Infection Common Signs Symptoms
N 160 patients with PHI in Geneva, Seattle and
Sydney
of patients
Vanhems P et al. AIDS 2000 140375-0381. 
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Primary HIV Infection Other Signs Symptoms
of patients
Kahn JO, Walker BD. N Engl J Med. 199833933-39.
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PHI Diagnostic Testing
1 mil
HIV RNA
100,000

HIV RNA
HIV-1 Antibodies
_
10,000
Ab
1,000
Exposure
100
Symptoms
10
0
20
30
40
50
Days
66
Could She Have Primary HIV Infection?

• Several features of her current illness make
  primary HIV infection unlikely
• Only three days since the exposure
• Presence of nasal congestion
• Rash is urticarial
• However, would not be unreasonable to check an
  HIV viral load to rule out PHI

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Hepatitis C Exposure

• Average risk of seroconversion from percutaneous
  exposure 1.81-3
• Same risk factors as for HIV thought to apply
• Gamma globulin not recommended4
• Early recognition and treatment of chronic HCV
  infection may substantially improve odds of
  eradication5

1. Lanphear BP et al. Infect Control Hosp
Epidemiol 199415745-50. 2. Puro V et al. Am J
Infect Control 199523273-7. 3. Mitsui T et al.
Hepatology 1992161109-14. 4. Alter MJ. Infect
Control Hosp Epidemiol 199415742-4. 5. Jaeckel
E et al. N Engl J Med 2001 3451452-1457.
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Hepatitis C follow-up testing

• CDC guidelines follow-up HCV Ab and ALT at 4-6
  months1
• Consider periodic HCV RNA screening (monthly?) if
  earlier detection desired
• Note that unlike acute HIV infection, most
  patients are not symptomatic with acute HCV
  infection2

1. MMWR June 29, 2001 / 50(RR11)1-42. 2.
Mandell Principles and Practice of Infectious
Diseases, 5th ed., p. 1279.
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Post-Exposure Prophylaxis Core Principles

• Evidence is limited
• Balancing of risks vs benefits
• Timing the sooner the better, but interval
  beyond which there is no benefit is unclear

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Post-Exposure Prophylaxis Core Principles

• Optimal duration unclear, 28 days is recommended
• Decision making can become very complex when drug
  resistance in the SP is suspected
• Offering non-occupational PEP is indicated for
  risky exposures, and does not appear to increase
  unsafe sexual behavior for most recipients

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• National Clinicians Post-Exposure Prophylaxis
  Hotline (PEPLine)
• A Joint Program of UCSF/SFGH CPAT/EPI Center
  supported by HRSA and CDC
• PI Ron Goldschmidt

http//www.ucsf.edu/hivcntr
(888) HIV-4911