Introduction
In September 2001, the European Commission funded a project for a standardised
management of healthcare worker (HCW) occupational exposures to HIV and
other bloodborne infections in European countries, including antiretroviral
post-exposure prophylaxis (PEP). The main objective of the project was
to develop a set of common recommendations, based on a review of the literature
and of national management strategies.
Nine European countries participated in the project: Croatia, Denmark,
France, Germany, Portugal, Spain, Switzerland, the United Kingdom, and
Italy (as coordinating centre).
The recommendations that follow were discussed during 2002 with representatives
of participating countries, and approved. The final consensus document
therefore represents the opinion of experts in the field of bloodborne
pathogens transmission prevention and PEP. Scientific evidences appearing
in the literature after the consensus meeting were included in this document.
The complete rationale and a full list of references used to support the
present recommendations can be consulted at http://europa.eu.int/comm/health/ph_projects/2000/com_diseases/comdiseases_project_2000_sum_en.htm
Recommendations
All preventive efforts should be made to reduce the risk of occupational
exposures (i.e. development of educational programs, implementation
of standard precautions and safer procedures, provision of safety devices
and personal protective equipment).
All HCWs should be made aware of how to report an exposure. The availability
of PEP should be publicly advertised so that it is immediately and readily
accessible 24 hours/day and initiated as soon as possible following
an occupational exposure.
WHEN TO OFFER OCCUPATIONAL PEP?
The application of PEP should be evaluated following an occupational
exposure with the potential for HIV transmission, based on the route
of exposure, the materials involved, and the evaluation of the source
patient (TABLE).
Efforts should be made to assure 'immediate' results in order to prevent
unnecessary initiation of PEP. Rapid HIV-antibody testing could be useful
for the diagnosis of HIV infection in the source patient, facilitating
the prompt beginning of PEP in the exposed HCW and limiting unnecessary
treatment [1-3].
The possibility of 'serologic window' of infection in the source patient
should be considered on individual case assessment.
TIMING OF STARTING PEP AND DURATION
PEP should be initiated as soon as possible following an occupational
exposure and administered for 4 weeks [4-6].
PEP should be discouraged more than 72 hours after exposure [7, 8].
CHOICE OF REGIMEN
Any combination of antiretrovirals approved for the treatment of HIV-infected
patients can be used in PEP regimens at the recommended dose.
· Triple combination, two class regimen is recommended
as first line PEP.
· Nevirapine (NVP) is not indicated for a full course
of PEP because of the reported severe hepatotoxicity. [9]
· Dual Nucleoside Reverse Transcriptase Inhibitor (NRTI)
combination therapy could be considered an option on a case by case
evaluation (i.e. pregnancy).
Available clinical information about stage of infection, CD4+ T cell
count, viral load testing, current and previous antiretroviral therapy,
and results of any previously available genotypic or phenotypic viral
resistance testing should be collected for consideration in choosing
the most appropriate PEP regimen [10]. If this information is not immediately
available, initiation of PEP, if indicated, should not be delayed; changes
in the PEP regimen can be made after PEP has been started, as appropriate.
Ad hoc genotypic and/or phenotypic resistance tests are not recommended
[11].
Check for any existing medical conditions and any medications that an
exposed HCW may be taking, in order to prevent toxicity and drug interactions.
A simplified regimen should be used whenever possible to increase adherence
by reducing number of pills and frequency of dosing.
If reported constitutional adverse reactions can be controlled through
the administration of symptomatic drugs, this could enhance adherence
to the prescribed regimen with the ultimate goal of achieving treatment
completion in the exposed HCW.
PEP IN PREGNANCY
Pregnancy per se should not preclude the use of HIV PEP. However, the
decision to use any antiretroviral drug during pregnancy should involve
discussion with the exposed HCW regarding the potential benefits and
risks to her and her baby, to help her to make an informed decision
about the use of PEP.
Women should be asked about the possibility of pregnancy. If pregnancy
cannot be excluded, a pregnancy test should be performed.
· The use of efavirenz should be avoided in pregnant women.
· The need for a combination of d4T and ddI should be
carefully evaluated.
· Because of the observed association with hyperbilirubinaemia,
indinavir should not be administered shortly before delivery.
FOLLOW UP SCHEDULE
All HCWs occupationally exposed to HIV should receive appropriate counselling
and clinical follow up regardless of whether or not they have received
PEP. A first HIV test should be performed within a few days after exposure.
Psychological support should be offered at any time during follow up.
[12]
HCWs should be strongly encouraged to report signs and symptoms promptly,
and should be counselled in order to prevent secondary transmission
during the follow up period.
Follow up visits and HIV testing are recommended at 6-8 weeks and three
months post exposure [3]. The routine use of direct virus assay (HIV
p24 antigen or tests for HIV-RNA) to detect infection in exposed HCW
is not recommended. [13]
Adherence to PEP and tolerance must be monitored. Complete blood cell
count, ALT, AST, creatinine, glucose, amylase blood levels and urine
test at baseline and at 15 days can be performed on a case by case basis,
and according to the toxicity profiles of the drugs included in the
PEP regimen.
The HCW should be tested for HIV at least once more, 6 months post exposure.
Testing the HCW at one year post exposure should be considered in cases
when the source patient is coinfected with HIV and HCV. [14]
Conclusions
About 100 documented and 200 possible cases of HIV infection in HCWs
have been reported worldwide [15]. The risk of transmission has been
estimated on average to be 0.3% after a percutaneous exposure to HIV
infected blood, and 0.09% after a mucous membrane exposure; the risk
can be higher following an exposure to a large volume of blood or to
a high titre of HIV [14].
A convergence of indirect evidence suggests that PEP administered soon
after occupational exposure to HIV in HCWs decreases the risk of infection.
Most information derives from animal experiments [4-6] and studies on
vertical transmission of HIV infection [7,8]; additional data derives
from studies in exposed persons.
Although recommendations on the use of PEP have been issued in a number
of European and non-European countries [14,16], differences exist and
several issues remain controversial. The present document aims to harmonise
the recommendations at the European level, and must be considered as
being dynamic: recommendations may change in the future with further
research and scientific information. Updated information on available
combinations of antiretrovirals, and on their pattern of resistance,
interactions and toxicity profiles, including their use in pregnancy,
are available at http://www.aidsinfo.nih.gov/guidelines/default_db2.asp?id.
Currently, the main issues on the agenda are represented by the increasing
prevalence of HIV strains resistant to antiretroviral drugs and PEP
toxicity concerns. Both these issues relate to the choice of an appropriate
regimen.
Indeed, recent studies have demonstrated the emergence of HIV mutations
associated with resistance to antiretroviral agents from source patients
involved in occupational exposure [10,11]. Moreover, the more recent
cases of PEP failure reported in the literature occurred after exposure
to source patients harbouring resistant HIV strains [17,18].
In fact, the ideal regimen for PEP is not fully defined. When it has
been decided that the characteristics of the exposure indicate the initiation
of PEP, clinicians should choose the drug combination only after careful
assessment of source patient's characteristics, including treatment
history. When available, data from genotyping or phenotyping resistance
tests should be considered. However, because of the time needed to perform
drug resistance tests and the necessity of a prompt initiation of PEP,
ad hoc testing for antiretroviral resistance mutations is not applicable
in this setting [12,13].
Others have supported the HIV fusion inhibitor enfuvirtide for post-exposure
prophylaxis (PEP) [19], but the complex modality of administration and
the frequent local injection site reactions could make enfuvirtide poorly
acceptable for PEP [20].
Furthermore, clinicians should choose the drug combination after a careful
assessment of the HCW's characteristics, including existing medical
conditions and medications. For example, since hepatotoxicity may be
more common in persons with chronic viral hepatitis, caution should
be used in the choice of the regimen when the healthcare worker is chronically
infected with hepatitis B or hepatitis C virus. Protease inhibitors
and non-nucleoside reverse transcriptase inhibitors interact with oral
contraceptives, so that alternative or additional methods should be
used to avoid pregnancy. Several antihistamine, cardiac or psychotropic
drugs should not be used with these antiretrovirals, and plasma concentrations
of anticoagulants and anticonvulsants might be decreased by coadministration
with ritonavir.
Drug intolerance and regimen complexity are factors affecting adherence
to PEP and causing interruption in approximately 50% of HCWs. For example,
simplicity and tolerability of the regimen induced the New York State
Department of Health to recommend zidovudine, lamivudine and tenofovir
as a first line PEP regimen [21]. Although the use of regimens easier
to assume and proven to be well tolerated is obviously recommended,
further information should be gathered on the efficacy of a one class
regimen. For example, disappointing data about the efficacy of all-nucleoside
regimens were recently presented [22].
Concerns about PEP safety arise because of its wide and increasing use
following occupational and non-occupational exposures. Many adverse
effects of PEP, most frequently gastrointestinal symptoms, can be controlled
by symptomatic interventions, but in case of severe toxicity it could
be necessary to stop one or all the drugs of a combination regimen.
Toxicity usually has an early onset and promptly reverses when the drugs
are stopped. Some antiretroviral drugs can cause alterations of the
glucidic and/or lipidic metabolism, even if it seems unlikely that these
alterations could lead to irreversible consequences during PEP. Cases
of PEP-associated ototoxicity, galactorrhoea and hyperprolactinemia,
acute cholestatic hepatitis have been described anecdotally. More recently,
a case of rapid development of central adiposity [23], and a case of
reversible multiorgan failure have been reported [24].
ARV-induced hepatotoxicity seems rare, often mild to moderate, and always
reversible [25].
However, nevirapine (NVP) during PEP was associated with cases of life-threatening
hypersensitivity (Stevens-Johnson syndrome), myositis, and hepatitis,
mostly rash-associated [26]. Efavirenz could also determine increased
transaminase levels and rash, though usually milder; however, severe
rashes (Stevens-Johnson syndrome) have been reported [27]. Hypersensitivity
reactions which could be fatal have been reported following the use
of abacavir [28].
Some studies suggest that adverse effects and discontinuation of PEP
are more common among persons taking protease inhibitor containing PEP
regimens, compared with those taking two NRTI [14]. Other studies seem
to demonstrate that the difference in the proportion of individuals
developing adverse effects and discontinuing PEP between the two regimens
is not very significant [29].
Although the incremental benefit of a triple, two class combination
of drugs active at different stages of the viral replication cycle as
PEP is speculative at present, neither the prevalence of resistant strains
in the sources nor the rate of side effects and PEP discontinuation
seem to justify per se the initial use of a potentially less potent
regimen.
*Panel of experts participating in the European Occupational Post-Exposure
Prophylaxis Study Group
Croatia
Slavko Schonwald, Josip Begovac, Rok Civljak, Dr F Mihaljevic
University Hospital for Infectious Diseases, Zagreb
Denmark
Ulla Balslev, Department of Infectious Diseases, Hvidovre Hospital,
Copenhagen
Suzanne Lunding, Department of Infectious Diseases, Rigshospitalet,
Copenhagen
France
Florence Lot, Christine Larsen
Institut de Veille Sanitaire, Unité des Maladies Infectieuses
Sida, Saint-Maurice
Germany
Ulrich Marcus
Robert Koch Institut, Infektionsepidemiologie AIDS/STD, Berlin
Portugal
José Luis Boaventura, Alvaro A Pereira, Francisco Antunes
Servicio de Doenças Infecciosas, Hospital de Santa-Maria, Lisbon
Spain
Magda Campins Martí, Hopital de val d'Hebron, Servicio de Medicina
Preventiva, Barcelona
Switzerland
Enos Bernasconi, Ente Ospedaliero Cantonale, Ospedale Civico, Lugano
Patrick Francioli, Centre Hospitalier Universitaire Vaudois, Division
des Maladies Infectieuses, Lausanne
United Kingdom
Tania Thomas, Barry Evans, Health Protection Agency, Communicable Disease
Surveillance Centre, HIV and STI Division, London, England
Fiona Genasi, Scottish Centre for Infection and Environmental Health,
Glasgow, Scotland
Acknowledgements
The European Occupational Post-Exposure Prophylaxis Study Group wishes
to thank the personnel working at the Coordinating Centre: Francesca
Mattioli and Zlatan Lazarevic for data collection and management, Yohanka
Alfonso Contreras for secretarial support, Lorena Fiorentini for administrative
support.
Funded by the European Commission Directorate-General for Health and
Consumer Protection. Unit F4. Project 2000/SID/107, grant no. SI2.322294.
Supported in part by the Italian Ministry of Health- AIDS Research ISS
grant 30D.66, and Ricerca Corrente IRCCS.
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