MANAGEMENT OF NON-OCCUPATIONAL

POST EXPOSURE PROPHYLAXIS TO HIV (NONOPEP):

SEXUAL, INJECTING DRUG USER OR OTHER EXPOSURES

This is a document from the

EUROPEAN PROJECT ON NON-OCCUPATIONAL

POST EXPOSURE PROPHYLAXIS (EURO-NONOPEP)

FUNDING: European Commission, Directorate-General Health Care and Consumer Protection. Unit G4. Project number 2000CVG4-022.

COORDINATOR CENTRE:

Center for Epidemiological Studies on AIDS in Catalonia (CEESCAT)

Carretera de Canyet, s/n

08 916, Badalona-Barcelona SPAIN

PRINCIPAL INVESTIGATORS: Dr Jordi CASABONA

Dr Jesus ALMEDA

FIELD COORDINATOR: Dr Betty G. SIMON

STEERING COMMITTEE MEMBERS: Dr Michèle GERARD ( Belgium)

Dr Barry EVANS ( United Kingdom)

Dr Dominique REY (France)

Dr Vincenzo PURO (Italy)

PARTICIPANT COUNTRIES: Austria, Belgium, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, The Netherlands, United Kingdom, Slovenia, Spain, Switzerland.

PURPOSE :

To standardize and to assess the feasibility of a guideline on non occupational post-exposure prophylaxis of the HIV infection in Europe.

OBJECTIVES :

MAIN OBJECTIVES:

1- To collect and describe the existing recommendations of non occupational post exposure prophylaxis for HIV in the participant countries.

2- To establish an European prospective registry of potentially HIV non occupational exposure individual, by mean of the national registries.

SECONDARY OBJECTIVES.

1- To describe the knowledge and attitudes of health professional and the groups at high risk of acquiring HIV infection.

2- If it possible, to assess the effectiveness of non occupational post exposure prophylaxis for HIV.

Names and institutions of the participant members of the working group which developed this document:

COUNTRY	NAME	INSTITUTION	E-MAIL
BELGIUM	Michelle GERARD	C.H.U. Saint Pierre, Brussels	maladiesinfectieuses@stpierre-bru.be
ENGLAND	Tania TOMAS	Public Health Laboratory Service, London	ttomas@phls.org.uk
FRANCE	Patricia ENEL	CISIH, Marseille	penel@ap-hm.fr
FRANCE	Dominique REY	ORS PACA, Marseille	rey@marseille.inserm.fr
GREECE	Nikos MANGAFAS	Centre for the Control of AIDS & STDs , Athens	mklazanas@ath.forthnet.gr mangafas@otenet.gr
GERMANY	MARKUS ULRICH	Robert Koch Institut Infektionsepidemiologie, Berlin	MarkusU@rki.de U.Marcus@rki.de
IRELAND	Colm BERGIN	St James Hospital, Dublin	cbergin@stjames.ie
ITALY	Vincenzo PURO	Spallanzani Hospital. Rome	puro@spallanzani.roma.it
PORTUGAL	Carles ALVAREZ	Hospital de S. Joao, Porto	servico.infecciosas@clix.pt amotamiranda@mail.telepac.pt
SLOVENIA	Janez TOMAZIC	Institute of Public Health, Ljubljana	janez.tomazic@kclj.si
SPAIN	Jordi CASABONA	CEESCAT, Badalona	jcasabona@ceescat.hugtip.scs.es
SPAIN	Betty SIMON	CEESCAT, Badalona	bsimon@ceescat.hugtip.scs.es
SPAIN	Jesús ALMEDA	CEESCAT, Badalona	jalmeda@ceescat.hugtip.scs.es
SWITZERLAND	Enos BERNASCONI	Ospedale Civico, Lugano	Enbernasconi@tinet.ch

1- INTRODUCTION AND JUSTIFICATION

Post-exposure prophylaxis (PEP) is now the standard of care when a health care worker (HCW) is exposed by accident to a source patient known to be HIV infected (occupational exposure), but this is not the case for non-occupational exposures (see definition in point 2 below),

Althout there is not scientific data to support its potential efficacy, the non occupational post exposure prophylaxis (NONOPEP) is becoming more repetly used. Faced with a NONOPEP for HIV request, the physicians have to deal with several questions such as the dimension of the real risk exposure or whether prescribe anti-retroviral therapy (ART) or not. In the case of ART, which combination choose? What is the follow-up duration? Which laboratory tests are necessary? NONOPEP demand is no negligible in Europe (1,2,3,4), nor is it in the other continents (5,6,7,8,9,10,11). Curiously, in most of the European countries there are no formal national guidelines for the management of possible sexual, injecting-drug-use, or other non-occupational exposures to HIV(12).

Several factors justify the concept of NONOPEP:

1- The biological plausibility of NONOPEP for HIV infection.

2- Scientific literature on the effectiveness of the ART used for post exposure prophylaxis in animals and occupational exposures in humans.

3- The efficacy of the prevention mother-to-child HIV transmission.

4- Studies on cost-effectiveness and cost-benefit of post exposure prophylaxis for HIV.

1.- One of the characteristics of the pathogenesis of HIV infection is a period of time between the HIV exposure and the replication of the virus in lymph nodes (13,14). In matter of fact, immediately after HIV exposure, there is an infection of dendritic cells at the site of the inoculation. These infected cells will migrate to the regional lymph nodes during around 24-48 hours (15). The beginning of HIV systemic infection is marked by the lymph nodes settlement of the infected dendritic cells. In theory, administering ART, as a prophylaxis, during this period and before the lymph nodes settlement could prevent the establishment of the systemic infection.

2.- The results of different studies showed the plausibility to prevent HIV infection, by administering ART after an exposure to HIV, for animals (16). In 1995, was published the results of a study showing the prevention of SIV infection in Macaques. Administering an antiretroviral compound (PMPA; tenofovir) 24 hours after the inoculation and during 4 weeks, prevented SIV infection in all the macaques. The protection was incomplete if the tenofovir was administrated at 48 or 72 hours after the exposure, or if the duration of the treatment was 3 or 10 days. This suggest that and that the earlier ART is given the more effective is the prevention (17). In 2000, Otten and other published data on a study where macaques received an atraumatic intravaginal inoculum of HIV-2. One group of macaques did not receive any ART, the second group received tenofovir 12h after the exposure, the third at 36 hours and the fourth group 72h after the vaginal exposure. In the first group, all except one of the macaques were infected. None of the macaques of the second and third group were infected, and one over three macaques became infected after 16 weeks in the fourth group. These data confirm that the time elapse between the exposure and the beginning of ART is a important factor which can affect NONOPEP efficacy. The delayed infections further support the need for adequate follow-up period after NONOPEP to monitor for delayed sero-conversions(18).

In a retrospective case control study, AZT given after an HCW occupational percutaneous exposure was associated with a decrease of 81% in the risk of HIV infection. An other issue of this HCW study was the increase of the risk of acquiring HIV when existed some associated factors as: the high size of the injury, visible blood on the device, HIV disease stage of the source person(19)...

3.- Data of human studies on prevention of mother-to-child HIV transmission support also the probability of the efficacy of an HIV post exposure prophylaxis. In a randomized trial, the administration of AZT to HIV-infected pregnant women was associated with a 2/3rd reduction in HIV infections in babies whose mothers had been given AZT pre and intra-partum (and who themselves had received AZT post-partum) versus those randomized to placebo (20). In spite of contact between the child’s blood and the HIV of his/her mother, AZT prevented the infection in the majority of cases.

4.- In 1997, was published an article showing the cost effectiveness of Tri-therapy with Zidovudine, Lamivudine and Indinavir following moderate to high risk occupational exposure for society (21). An other Cost-effectiveness study on post exposure prophylaxis following potential sexual HIV exposure in humans concluded that in the following cases PEP is cost-effective: Receptive anal sex when it is nearly certain that the source person is infected, and receptive vaginal sex only when the source person is know to be HIV positive (22). Assuming that it is not only the cost effectiveness which can predominate in a public health decision, further studies on it are convenient.

Guidelines for the management of occupational HIV exposures exist in the USA and in most of European countries; but on the other hand, very few national guidelines for NONOPEP have been elaborated in Europe (12).

The studies above-mentioned hearten us to propose and standardize this prophylaxis for non occupational exposure despite of the difficulties as: the extrapolation of animals survey data to humans, the specificity of the mother to child transmission, the difference between HCW occupational exposures and the non occupational ones, the difficulty of the risk assessment in non occupational exposure, the reports of PEP failures to prevent HIV infection after occupational exposure in at least 21 instances with different ART (23-29).

An other argument to propose the NONOPEP guidelines is the results of a French study in which the existence of NONOPEP recommendations had an impact on physicians behavior, improving their acceptability, their concern about NONOPEP(30) and probably the risk assessment. Furthermore, a survey has been conducted among European physicians as part of the EURO-NONOPEP project coordinated by the CEESCAT, and presented above. Its results showed clearly that there were significantly more prescriptions after NONOPEP requests(76% vs 61% p=0,007), as well as more ARV emergency start kit available(92% vs 44%, p<0,001), in the countries with national guidelines. In the same way, the exposure risk assessment and the management of NONOPEP request were improved in this group of physicians in comparison with the group without national guidelines.

Finally, as summarized in chapter 3, the probability of HIV transmission by certain non-occupational exposures is estimated higher than the risk of percutaneous occupational exposure. Furthermore, the characteristics of both situations –occupational and non-occupational- are different. In the case of occupational exposures, it is possible to start the ART early, the source HIV status is mostly known, and the follow-up of the exposed person is more feasible. On the contrary, in the case of a non occupational exposure, the time of ART initiation is frequently longer, the chance to get the HIV status of the person source lower, and the rate of lost to follow up surely higher. Hence the need for specific guidelines for these specific situations that are the non-occupational exposures.

One of the main objective of the EURO-NONOPEP project is the elaboration of the communal European recommendations on the management of the non occupational exposure prophylaxis for HIV. In this perspective, the national representatives who attended the first General Workshop of this project, during the 19^th and the 20^th of October 2001, drew up a consensus draft regarding European NONOPEP guidelines, to standardize and homogenize the attitude of the physicians. These recommendations were based on the actual knowledge on NONOPEP, particularly its cost effectiveness and the risk exposure assessment of several types of non occupational exposures. We also made use of the CDC recommendations and reports on the management of occupational and non occupational exposure to HIV. Every country is quite free to adapt these recommendations to its HIV infection epidemiological situation, and its own NONOPEP policies, specially regarding the attitudes indicated as “considered”…

As NONOPEP effectiveness is not established, it is necessary to initiate a National and European surveillance system to collect information about persons who seek medical care after possible non occupational exposure for HIV. This system will assess the viability, the medication toxicity and eventually the effectiveness by gathering the characteristics of the reported exposures, the details of the ART used, the toxicity and the adherence to the ART, and eventual sero-conversions.

2- DEFINITION OF NON-OCCUPATIONAL EXPOSURE

We considered as non occupational exposure for HIV, all accidental and sporadic situations in which contact with blood or other body fluids (semen, vaginal secretions, or other body fluids) potentially at risk for HIV infection takes place, having even taken measures from prevention for it, except the HCW exposure occurring in health care or in the laboratory setting. That is to say: sexual exposure, intravenous drug users (IDUs) sharing material, street accidental needle stick, non occupational HCW exposure, bite wound, mucosal exposure….

Neither tears nor sweat exposures are considered as at risk for HIV.

3-LITERATURE REVIEW OF RISK EXPOSURE ASSESSMENT

Table 1 shows the different risk of HIV transmission by non-occupational exposures, according to a literature review.

Table 1. Summary of HIV transmission risk by type of non-occupational exposure

TYPE OF EXPOSURE (from a source known as HIV positive)	RISK OF HIV TRANSMISSION PER EXPOSURE	REFERENCES
Accidental needle stick	0,2%-0,4%	19
Mucosal membrane exposure	0,1%	31
Receptive Oral Sex	Varied from 0 to 6,6%	32, 33
Insertive vaginal sex	£ 0,1%	34 - 37
Insertive anal sex	£ 0,1%	34 - 37
Receptive vaginal sex	0,01%-0,15 %	34, 36, 38, 39
Receptive anal sex	£ 3%	33, 37, 39
Sharing IDUs needle	0,7%	40
Transfusion	90-100%	41

It is important to remind that these estimates of transmission are not absolute. Every risk exposure depends on the type of exposure, but also on co-factors such as follows:

· Infectivity of the source: High plasma viral load increases the risk (42)

· Genital oral ulcers, STD or bleeding increase the risk a sexual exposure (39)

· For accidental needle stick exposure, fresh blood, a depth injury or intravenous injection increases the risk of HIV transmission.(19)

When the source HIV status is unknown, the risk assessment is based on the type of exposure, on the HIV prevalence estimation in the source HIV group and/or his country HIV prevalence.

4- PEP RECOMMENDATIONS

Facing any non occupational post exposure for HIV, the physicians have to take the following steps into consideration:

1- To evaluate the HIV status and risk behavior history of the reported source of HIV exposure (his belonging to a HIV high risk group or to a country with high HIV prevalence) and, if it is possible, to test the source person for HIV-antibodies.

2- To evaluate the risk for HIV transmission regarding the type of the exposure, as well as the presence of factors that would increase the risk (e.g., precise the presence or not of a condom, details of the exposure as receptive or insertive one, anal or vaginal one, presence of visible genital ulcers …for sexual exposure; sharing material number of persons; depth of any per-cutaneous exposure …for IDUs).

3- To determine the time elapsed between the exposure and the presentation for medical care before deciding to prescribe an antiretroviral therapy. PEP should be given within 72 hours from the time of exposure.

4- All the patients should receive medical evaluation including HIV-antibodies tests at baseline and periodically for at least 6 months after the exposure, as well as the other blood-borne pathogens such as HBV and HCV or tests for sexually transmitted diseases (STD).

5- In the case of prescribing ART, the treatment has to start the earliest possible. Drug toxicity monitoring should include a complete blood count, renal and hepatic chemical function tests at baseline, and periodically until at least 6 months after the exposure.

6- For HIV-sexually exposed women, a pregnant test has to be done, and the result taken in account before any prescription. Consult obstetricians or other experts in the care of HIV infection during pregnancy. Similarly, for children, consult specialist in the care of children HIV infection.

7- The exposed individual should be counseled to prevent additional exposure, an to improve the ART adherence in the case of prescription.

8- NONOPEP should never be considered as a prevention strategy.

A- Sexual exposures:

It should be stated that at risk sexual exposures are “unprotected intercourses”(without condom or with broken or slipped condom).

1- HIV source known as positive:

· Anal Receptive sex …………………………….. PEP is Recommended

· Anal Insertive sex ……………………………… PEP is Considered

· Vaginal Receptive sex …………………………. PEP is Considered

· Vaginal Insertive sex …………………………... PEP is Considered

· Receptive Oral sex with ejaculation …………… PEP is Considered

· Splash of sperm into eye ………………………. PEP is Considered

· Receptive Oral sex without ejaculation ……….. PEP is Discouraged

· Female to female sex ………………………….. PEP is Discouraged

In case of raping or the existence of any high risk factors (for both, source person or exposed individual): High Viral Load of the source partner, menstruations, other bleeding during intercourse, Genital ulcer, STD.

· Insertive Anal sex ……………………………… PEP is Recommended

· Insertive Vaginal sex …………………………... PEP is Recommended

· Receptive Vaginal sex …………………………. PEP is Recommended

· Receptive Oral sex With ejaculation …………... PEP is Recommended

· Female to female vaginal-oral sex …………….. PEP is Considered

2- Unknown source HIV status:

a \ The source person is from a group or from an area of high HIV prevalence (at least 15%).

· Receptive Anal sex ……………………………. PEP is Recommended

· Receptive Vaginal sex ………………………… PEP is Considered

· Insertive Anal sex …………………………….. PEP is Considered

· Insertive Vaginal sex ………………………….. PEP is Considered

· Receptive Oral sex with ejaculation …………... PEP is Considered

· Other Situations ……………………………….. PEP is Discouraged

In case of raping or the existence of any high risk factors (for both: source person or exposed individual): High Viral Load of the source partner, menstruations, other bleeding during intercourse, Genital ulcer, STD.

· Insertive Anal sex ……………………………… PEP is Recommended

· Insertive Vaginal sex …………………………... PEP is Recommended

· Receptive Vaginal sex …………………………. PEP is Recommended

· Receptive Oral sex with ejaculation …………… PEP is Recommended

b \ The source person does not belong to a high risk group or is from an area of low HIV prevalence.

· Receptive Anal sex ……………………………. PEP is Considered

· All Other Situations……………………………. PEP is Discouraged

In case of raping or the existence of any high risk factors (for source person or exposed individual): High Viral Load of the source partner, menstruations, other bleeding during intercourse, Genital ulcer, STD.

· Receptive Anal sex …………………………….. PEP is Considered

· Receptive Vaginal sex …………………………. PEP is Considered

· Insertive Anal sex ……………………………… PEP is Considered

· Insertive Vaginal sex …………………………... PEP is Considered

· Receptive Oral sex with ejaculation …………… PEP is Considered

· All Other Situations ……………………………. PEP is Discouraged

B- IDU exposures:

1- Source known as HIV positive:

· Needle or Syringe Exchange …………………… PEP is Recommended

· Any material* sharing inside IDUs group ……… PEP is Considered

2- Source HIV status is unknown:

· Needle or Syringe Exchange …………………… PEP is Discouraged

· Any material* sharing inside IDUs group ……... PEP is Discouraged

In case of prevalence of HIV infection in concerned IDU population >15%

· Needle, Syringe or any material* Exchange …… PEP is Considered

* Such as: cookers to melt the drug, cotton used as filter, or water to rinse the syringe

C- Other needle exposures:

· Abandoned needle stick ……………………….….. PEP is Discouraged

· Aggression with a needle …………………………. PEP is Discouraged:

If severity factors exist: needle of someone known to be HIV positive, or in “high risk area” (prevalence of HIV infection in the concerned IDU population >15%), injection of blood or deep injury, fresh blood in syringe…

· Aggression with a needle …………………………. PEP is Considered

· Abandoned needle stick with visible fresh blood … PEP is Considered

D- Other expositions

: Non intact skin, mucosal, bite, … :

1- Source is HIV positive, or is from a group or

from an area of high HIV prevalence

(at least 20%).…………………………………… PEP is Considered

2- Source HIV status unknown, or is not from a

group or from an area of high HIV prevalence ….. PEP is Discouraged

5- ANTI-RETROVIRAL PROPHYLAXIS: DRUG SELECTION AND FOLLOW-UP SCHEDULE

A- Drugs selection:

We based our drugs selection on:

a) the antiretroviral drugs approved by the FDA(43);

b) the concept that a combination drugs with activity at different stages in the viral replication cycle have proved superior to mono-therapy regimen, and a three drugs regimen superior to bi-therapy.

Guidelines for the treatment of HIV infection recommend the use of three drugs (44). It is supposed that a three therapy will be also the most effective in the case of NONOPEP, when there is a real risk of HIV transmission.

1- Which Treatment combination?

Triple therapy (treatment with a combination of three drugs belonging to two different classes) is recommended.

Bi-therapy (treatment with two nucleoside reverse transcriptase inhibitors -NRTI- ) may be an option.

2- First line treatment:

Source with unknown HIV status, or HIV positive but not treated, or HIV positive with an efficient first line therapy, the NONOPEP treatment recommended for the patient is as follows:

2 NRTI (a) + PI* (b) or Efavirenz

(a): Zidovudine + Lamivudine;

or Stavudine + Didanosine EC;

or Stavudine + Lamivudine.

(b): Nelfinavir;

or Indinavir;

or Lopinavir/ritonavir.

When there are several possibilities for the same active principle use the simplest pharmaceutical form.

Dual PI is less appropriated.

Do not use Abacavir, or Nevirapine in a 4 weeks regimen, because of potential severe adverse events (45,46).

Only a single initial dose can be used if necessary.

3- Second line prophylaxis:

If the source person is HIV positive and treated by ART with any failure of treatment in his/her history (actual or previous):

Adapt the NONOPEP ART to the drug history and\or to resistance testing if available.

Abacavir may be an option in this case.

If the source person is HIV positive and treated by ART (without treatment failure) with undetectable viral load:

The same ART of the source person can be used.

B- Duration of Treatment:

4 weeks.

C- Patient follow-up:

Laboratory tests Recommended	Baseline	Week 2	Week 4-6	Month 3 and Month 6
HIV Anti body tests	Yes		Yes	Yes
Haematological tests	Yes	Yes	Yes
Creatininemia, Transaminases, Glycaemia, Amylasemia.	Yes	Yes	Yes
Pregnancy test (if patient is a woman)	Yes
Medical visit: Counseling, Compliance assessment, adverse events, clinical seroconversion	Yes	Yes	Yes	Yes

NB: Consider the assessment of other STD (Syphilis, Gonorrhoea, Chlamydia infection) and of Hepatitis B and C.

Remarks:

• Viral load or p24 antigen tests in exposed person are not recommended, except in case of suspected primary HIV infection.

• If it is possible, deliver drugs for no more than a 2 weeks period, to improve the patient follow-up.

• In case of ART prescribed, written informed consent is recommended.

• For pregnant women, Efavirenz and Amprenavir (44,47) are unwise. Anyway, decide on a case by case and consult an experienced specialist. Contr

aindicated

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* Portease inhibitor