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Guideline Summary
Guideline Title
UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011).
Bibliographic Source(s)
Benn P, Fisher M, Kulasegaram R, BASHH, PEPSE Guidelines Writing Group Clinical Effectiveness Group. UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011). Int J STD AIDS. 2011 Dec;22(12):695-708. PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Fisher M, Benn P, Evans B, Pozniak A, Jones M, Maclean S, Davidson O, Summerside J, Hawkins D, Clinical Effectiveness Group (British Association for Sexual Health and HIV). UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure. Int J STD AIDS 2006 Feb;17(2):81-92. [84 references]

Scope

Disease/Condition(s)

Human immunodeficiency virus (HIV) infection

Guideline Category
Counseling
Evaluation
Management
Prevention
Risk Assessment
Treatment
Clinical Specialty
Emergency Medicine
Family Practice
Infectious Diseases
Internal Medicine
Preventive Medicine
Psychology
Intended Users
Advanced Practice Nurses
Health Care Providers
Health Plans
Hospitals
Nurses
Pharmacists
Physician Assistants
Physicians
Psychologists/Non-physician Behavioral Health Clinicians
Public Health Departments
Social Workers
Utilization Management
Guideline Objective(s)
  • To ensure the appropriate use of post-exposure prophylaxis (PEP) following potential sexual exposure (PEPSE) to human immunodeficiency virus (HIV) as a potential method of preventing HIV infection
  • To offer updated recommendations on the potential use of PEPSE, the circumstances in which it may be recommended, the treatment regimens that may be recommended and the appropriate use of subsequent diagnostic tests to measure individual outcomes
Target Population

Patients in the United Kingdom at risk for human immunodeficiency virus (HIV) infection due to unprotected potential sexual exposure to HIV

Interventions and Practices Considered
  1. Risk assessment to determine whether post-exposure prophylaxis (PEP) following potential sexual exposure (PEPSE) is appropriate
    • Assessment of method of exposure
    • Assessment of source HIV status  
  2. PEPSE combination regimens implemented as soon as possible after the exposure
    • Triple agent antiretroviral treatment (ART) that may use nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and newer classes of drugs
    • Modification of PEP ART in relation to drug history or resistance testing, if available, if source has a current or past history of treatment failure
    • Assessment for potential drug-drug interactions
    • Duration of treatment
  3. Management of treatment side-effects
  4. HIV testing prior to and shortly after initiation of PEPSE and at 12 weeks
  5. Evaluation as early as possible by a clinician or team experienced in the management of ART and with expertise in HIV testing and transmission
  6. Referral to a health advisor (or appropriately experienced health care worker)
  7. Providing information regarding PEPSE to individuals diagnosed with HIV infection, particularly if in a serodiscordant relationship
  8. Regular medical follow-up and patient encouragement
  9. Comprehensive screening for other sexually transmitted diseases (STIs)
  10. Consideration of hepatitis B vaccination (and immunoglobulin)
  11. Risk reduction counselling
  12. Counselling of repeat users of PEPSE
Major Outcomes Considered
  • Transmission of human immunodeficiency virus (HIV) infection following unprotected exposure
  • Transmission of drug-resistant HIV
  • Other sexually transmitted infections (STIs) in patients exposed to HIV
  • Side effects of treatment
  • Treatment failure rate
  • HIV seroconversion rate despite post-exposure prophylaxis (PEP)
  • Rate of repeat presentation for PEP following potential sexual exposure (PEPSE)
  • Cost-effectiveness of PEPSE

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

A literature search using the terms 'post-exposure prophylaxis', 'HIV' and 'antiretroviral therapy' since the last guideline in 2005 was undertaken. This included review of databases (PubMed, Cochrane and Medline) and conference abstracts (Conference on Retroviruses and Opportunistic Infections, British HIV Association [BHIVA], British Association for Sexual Health and HIV [BASHH], International AIDS Society, International Society for Sexually Transmitted Diseases Research, International Union against Sexually Transmitted Infections [IUSTI] and the Health Technology Assessment programme). The following journals (AIDS, HIV Medicine, International Journal of STD & AIDS, Journal of Acquired Immune Deficiency Syndrome, Sexually Transmitted Diseases and Sexually Transmitted Infections) were hand searched for relevant articles.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus
Rating Scheme for the Strength of the Evidence

Levels of Evidence

Level Type of Evidence
Ia Evidence obtained from meta-analysis of randomized controlled trials
Ib Evidence obtained from at least one randomized controlled trial
IIa Evidence obtained from at least one well-designed controlled study without randomization
IIb Evidence obtained from at least one type of well-designed quasi-experimental study
III Evidence obtained from well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies
IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The development of this guideline included a writing group with representatives from British Association for Sexual Health and HIV (BASHH), British HIV Association (BHIVA), Expert Advisory Group on AIDS (EAGA), Society of Sexual Health Advisers (SSHA), HIV Pharmacy Association (HIVPA), Health Protection Agency (HPA), the HIV and Sexual Health Group of the British Psychological Association, the Terrence Higgins Trust (THT) and the National AIDS Trust (NAT). Patients' perspectives were considered by involvement of THT, NAT and discussion at a stakeholder group organized by THT and the Community HIV and AIDS Prevention Strategy (CHAPS) conference.

The guideline is based upon a comprehensive review of the literature pertaining to post-exposure prophylaxis (PEP) following potential sexual exposure (PEPSE). The recommendations are based upon a combination of biological plausibility, cohort studies, data from PEP in other settings, and expert opinion. The recommendations are the result of a series of meetings of the writing committee and the input from the consultation process. Consensus opinion was reached in the event of disagreement.

Rating Scheme for the Strength of the Recommendations

Grades of Recommendation

Grade Recommendation
A
(Evidence levels Ia, Ib)
Requires at least one randomized controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation
B
(Evidence levels IIa, IIb, III)
Requires availability of well-conducted clinical studies, but no randomized clinical trials on the topic of recommendation
C
(Evidence level IV)
Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates absence of directly applicable studies of good quality
Cost Analysis

There are no conclusive data regarding the cost-effectiveness of post-exposure prophylaxis (PEP) following potential sexual exposure (PEPSE). It has been argued that the cost of providing PEP may be effectively spent on other prevention initiatives. However, while the drug cost of a full 28-day course of PEP is approximately £677.50 (British National Formulary [BNF] price October 2010), the lifetime costs of treatment for an HIV positive individual are estimated to be between £280,000 and £360,000. A retrospective cost analysis of the San Francisco PEPSE programme has shown it to be cost-effective when used in high-risk exposures and potentially cost-saving when used after receptive anal intercourse in men who have sex with men (MSM). Subsequent modelling utilizing data from many United States cities and Australia suggests similar levels of cost-effectiveness provided that PEPSE is targeted to high-risk exposures consistent with those recommended within these guidelines. This is in general accordance with the recent review by the Health Technology Assessment.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

Prior to publication the final draft was placed on the British Association for Sexual Health and HIV (BASHH) website and copies were circulated to the Terrence Higgins Trust (THT), the British HIV Association (BHIVA), and the Department of Health for comment and peer review. After a period of three months, any comments received were reviewed by the guideline authors, and acted upon appropriately, before final authorization by the Clinical Effectiveness Group (CEG) was given and publication was undertaken. Feedback was also obtained from emergency medicine specialists and specialists managing victims of sexual assault.

Recommendations

Major Recommendations

Levels of evidence (I-IV) and grades of recommendation (A-C) are defined at the end of the "Major Recommendations" field.

Recommendations for Prescribing Post-Exposure Prophylaxis (PEP) Following Potential Sexual Exposure (PEPSE)

The writing committee feels it is crucial to consider PEPSE as only one strategy in preventing human immunodeficiency virus (HIV) infection and, as such, it should be considered as a last measure where conventional, and proven, methods of HIV prevention have failed (IIb, grade B).

A risk versus benefit analysis should be undertaken for every individual presenting following an exposure and the decision to initiate PEP made on a case-by-case basis. This should consider both the risk of transmission according to exposure (as in Table 2 in the original guideline document) and the risk of the source being HIV-positive (as in Table 1 in the original guideline document) as well as the viral load in the source if known (IV, grade C). The situations when PEPSE should be considered are shown in the table below. The writing committee recommends that PEPSE is indicated when the estimated transmission risk is 1 in 1000 or greater (IV, grade C).

Table: Situations When Post-exposure Prophylaxis (PEP) Is Considered (IV, grade C)

  Source HIV Status
  HIV-positive    
  Viral Load Detectable Viral Load Undetectable Unknown from High Prevalence Group/Area* Unknown from Low Prevalence Group/Area*
Receptive anal sex Recommend Recommend Recommend Not recommended
Insertive anal sex Recommend Not recommended Consider† Not recommended
Receptive vaginal sex Recommend Not recommended Consider† Not recommended
Insertive vaginal sex Recommend Not recommended Consider† Not recommended
Fellatio with ejaculation‡ Consider Not recommended Not recommended Not recommended
Fellatio without ejaculation‡ Not recommended Not recommended Not recommended Not recommended
Splash of semen into eye Consider Not recommended Not recommended Not recommended
Cunnilingus Not recommended Not recommended Not recommended Not recommended
Sharing of injecting equipment Recommend Not recommended Consider Not recommended
Human bite§ Not recommended Not recommended Not recommended Not recommended
Needlestick from a discarded needle in the community     Not recommended Not recommended

*High prevalence groups within this recommendation are those where there is a significant likelihood of the source individual being HIV-positive. Within the United Kingdom (UK) at present, this is likely to be men who have sex with men and individuals who have immigrated to the UK from areas of high HIV prevalence (particularly sub-Saharan Africa).
†More detailed knowledge of local prevalence of HIV within communities may change these recommendations from consider to recommended in areas of particularly high HIV prevalence.
‡PEP is not recommended for individuals receiving fellatio, i.e., inserting their penis into another's oral cavity
§A bite is assumed to constitute breakage of the skin with passage of blood.

Unprotected receptive anal intercourse with someone of unknown HIV status from a high HIV prevalent group or area is included in the 'recommend' category, even though the risk may be less than 1 in 1000, given that this is the major route of HIV transmission within the UK. Similarly unprotected insertive anal intercourse with someone known to be HIV-positive with a detectable viral load is included in the 'recommend' category, despite having a slightly lower risk estimate, for simplicity and in light of the recent data.

Where the estimated transmission risk is between 1 in 1000 and 1 in 10,000 PEP may be considered. The writing committee feels that when the exposure is classified as 'consider', PEPSE should only be prescribed if there are additional factors that may increase the likelihood of transmission, i.e., following sexual assault, in the presence of an sexually transmitted infections (STI) (i.e., where the source is known to have an STI or the exposed individual has symptoms or signs suggesting an STI) or where the source is suspected to have acute HIV infection. Awareness of the local seroprevalence of HIV in the potential source clearly should be factored into local protocols. In the absence of additional factors PEPSE should not be prescribed when the exposure is classified as 'consider'.

Where the estimated transmission risk is below 1 in 10,000, PEP is not recommended (IV, grade C). These thresholds are similar to those used in the Australian non-occupational PEP guidelines and broadly correlate to circumstances where PEP is likely to be cost-effective (see the "Cost Analysis" field).

Consideration should be given to the possibility of the presenting individual having already been infected with HIV, and the ability to adhere to and tolerate the proposed antiretroviral drug regimen. The potential exposure to other STIs and appropriate management for this needs to be considered alongside consideration of provision of PEPSE. The wishes of the individual should be considered at all times (IV, grade C).

Situations in Which PEPSE Would Be Considered

The use of PEPSE following potential sexual exposure to HIV is only recommended where the individual presents within 72 hours of exposure (IIb, grade B). Within that time frame, it is recommended that PEPSE (if given) should be administered as early as possible. All recommendations are for either unprotected sexual exposure or where condom failure has occurred. Recommendations regarding fellatio are where the partner giving fellatio is presenting for PEPSE.

Source Individual Is Known to Be HIV-Positive

In this scenario attempts should be made at the earliest possible stage to determine the viral load, resistance profile and treatment history in the source individual. Where the viral load is undetectable it is assumed that the risk of transmission will be significantly reduced. The majority of supporting evidence is derived from heterosexual discordant couples although there are some data among men who have sex with men (MSM). There are anecdotal reports of transmission where the source is thought to have an undetectable plasma viral load. In light of this evidence the writing committee has therefore downgraded the recommendation from the previous guidelines for PEP where the source is known to be HIV-positive with an undetectable plasma viral load to 'not recommend' with the exception of unprotected receptive anal intercourse, which in the absence of further data remains 'recommended' (see the table above) (IV, grade C).

Source Individual Is of Unknown Status

Attempts should be made, where possible, to establish the HIV status of the source individual (according to appropriate guidance on HIV testing and consent) as early as possible (III, grade B). There is growing evidence to suggest that significant cases of PEP can be averted through assertive HIV testing of the source individual. It is therefore recommended that strong efforts be made to encourage the individual to notify their partner where possible, and for the clinic to arrange urgent HIV testing of that partner, with appropriate guidance on HIV testing and consent, as early as possible.

If the source is from a group or area of high HIV prevalence then PEP is recommended following receptive anal sex only. Where the source is not from a group or area of high HIV prevalence then PEP is not recommended (see the table above) (IV, grade C).

Other Circumstances

Sexual Assault

It is believed that transmission of HIV is likely to be increased following aggravated sexual intercourse (anal or vaginal), such as that experienced during sexual assault. Clinicians may therefore consider recommending PEPSE more readily in such situations. While the routine recommendation of PEPSE is likely to be appropriate in high prevalence situations, it is likely that the strength of recommendation and subsequent uptake will be lower in UK settings unless the 'assailant' is perceived to be from a high-prevalence group (IV, grade C).

Needlestick Injuries in the Community

It is not uncommon for individuals to request PEP following a needlestick injury from a discarded needle in the community. In general, PEP is not recommended following these exposures as it is usually not possible to determine: (i) whether the needle has been used or not and for what purpose; (ii) the HIV status of the source and; (iii) the interval between the needle being used and the exposure (III, grade B). Once blood has dried, HIV 'dies' within a couple of hours. Nonetheless, viable HIV has been shown to persist in syringes and needles up to 30 days depending on temperature and the size of syringe/needle: however, there are no data on the transmissibility of this virus. In studies where only small amounts of blood are in the syringe viable HIV cannot be detected after 24 hours.

Human Bites

Requests for PEP following human bites have been reported. In general PEP is not recommended following these exposures as although the risk of transmission following a bite is unknown it is likely to be extremely small (IV, grade C). Further guidance regarding the management of human bites is available at: http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1194947350692 External Web Site Policy.

Other Factors Which May Alter the Strength of Recommendation

Where factors are present which are believed to influence the probability of HIV transmission - presence of concurrent STI, seroconversion in the source or circumcision status, the strength of these recommendations may be increased or decreased as appropriate.

Considerations for Which Drug Regimens to Use for PEP

The choice of drugs to be used for PEP is drawn from those used in established infection. These include the nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

In established HIV infection, combination drug therapy with at least three drugs is more effective than monotherapy or dual drug regimens. It is thus recommended, when there is considered to be a significant risk of HIV transmission following risk assessment, that a triple agent regimen be advised. Theoretical considerations to support the recommendation of three drugs include the later presentation of patients for PEPSE and giving drugs with different resistance patterns as any resistant virus in the source may be unknown.

If there is evidence that the source patient has current or past history of treatment failure, the PEP antiretroviral treatment (ART) should be modified in relation to the drug history and/or to resistance testing, if available. Expert advice should be sought.

Individuals who are already well informed regarding the safety, tolerability and efficacy profiles of individual antiretroviral agents may have their own individual perspective on which agents they would prefer to take. Such choices should, where possible, be respected but may be affected by the composition of 'starter packs', the possible resistance 'history' of the source, local HIV primary resistance rates, and must involve consideration of toxicity profiles in the uninfected (as outlined above).

Nucleoside Reverse Transcriptase Inhibitors

Zidovudine (an NRTI) is the only drug to date which has been studied and for which there is evidence of reduction of risk of HIV transmission following occupational exposure. However, this agent is frequently poorly tolerated, which is likely to contribute to non-adherence/completion. Studies suggest that other NRTIs including stavudine, tenofovir and emtricitabine either given in combination with PIs or given as triple nucleoside/-tide analogue regimens, are better tolerated.

The improved tolerability of Truvada (a fixed dose combination of tenofovir and emtricitabine) is a key factor for its inclusion within the recommended PEP regimen (see below) (IIb, grade B). In addition, tenofovir (TDF) and emtricitabine (FTC) have been shown to have activity as pre-exposure prophylaxis (PrEP) and PEP in animal models of sexual exposure and are currently being evaluated in high-risk populations as monotherapy or in combination for PrEP.

Both TDF and FTC have been shown to penetrate the genital tract and rectal tissue well in animal models, reaching peak levels within 24 hours of dosing and maintaining high levels for up to seven days, characteristics which hypothetically may be advantageous for PrEP and PEP. TDF and FTC have also both been shown to penetrate the human male and female genital tract well. Truvada has also been shown to reduce acquisition of HIV when used as PrEP in MSM.

The routine use of abacavir is not recommended. A hypersensitivity reaction is reported in up to 8% of patients with established infection. Although the risk has not been assessed in HIV-negative individuals, it is recommended that abacavir be used in exceptional circumstances only.

Non-nucleoside Reverse Transcriptase Inhibitors

Nevirapine has in the past been used for PEP but is now known to be associated with significant toxicity. In one study, almost 10% of individuals receiving a nevirapine-based PEP regimen experienced a grade 3 or 4 elevation in transaminases with or without a rash. Furthermore, two health-care workers in the United States of America (USA) developed fulminant hepatitis, and one required liver transplantation following a nevirapine-based PEP regimen (III, grade B).

Efavirenz has a lower incidence of rash; however, it may be associated with significant central nervous system disturbance at a time when individuals may be anxious, which may make it less suitable for use for PEP (IV, grade C).

Newer NNRTIs (TMC125, etravirine; TMC278, rilpivirine) may also be suitable agents for PEP regimens. Side-effects of both agents include hepatitis and rash. Stevens-Johnson syndrome has been reported with etravirine.

Protease Inhibitors

Although PIs act at a stage of the HIV life cycle post-integration, it is anticipated that they will still add benefit in this indication since it is likely that PEP is 'aborting' rather than prophylaxing against infection and that part of this activity will be achieved by rendering new virions uninfective. Indinavir and nelfinavir have both been used for PEP; however, these combinations have often been poorly tolerated. In one study 6/19 (31.6%) of health-care workers taking an indinavir-based regimen for PEP required more than two-weeks off work.

PIs have been associated with metabolic abnormalities, lipid abnormalities, insulin resistance and diabetes mellitus in addition to gastrointestinal side-effects. Kaletra (lopinavir/ritonavir co-formulation) is the recommended PI for inclusion with PEP regimens. Kaletra frequently causes diarrhoea and other gastrointestinal disturbances and patients may benefit from proactive management of side-effects by the inclusion of antidiarrhoeal and antiemetic medication. The availability of ritonavir tablets now facilitates the inclusion of other boosted PIs such as atazanavir or darunavir within starter packs, both of which may be less likely to cause diarrhoea than Kaletra. However, a recent randomized controlled trial (RCT) comparing the use of Kaletra versus boosted atazanavir in combination with Combivir (zidovudine/lamivudine co-formulation) for 28 days demonstrated high rates of adverse events in both arms with similar discontinuation rates.

Other Drug Classes

Newer classes of drugs available for the treatment of chronic infection may have a role to play in PEP. Tolerability data in established infection and use for PEP may in the future support the use of raltegravir (an integrase inhibitor) or maraviroc (a CCR5 inhibitor) in PEP regimens in preference to PIs. Recent data also suggest that raltegravir and maraviroc may also penetrate the genital tract well in humans, with maraviroc also achieving very high levels in the rectal mucosa following oral administration; such characteristics may also make these agents suitable for both PrEP and PEP. However, the current cost of these agents would preclude their routine use and this should currently be restricted to those where multidrug-resistant virus is known to be present in the source or if tolerability issues arise during PEP that would otherwise result in discontinuation.

Recommended Combinations for PEP

The recommended combinations for PEP are shown in the table below.

Table: Recommended Combinations for PEP

Recommended combination Truvada (tenofovir disoproxil fumarate 245 mg, emtricitabine 200 mg) one tablet once daily*
plus
Kaletra†‡ (lopinavir 200 mg, ritonavir 50 mg) two tablets twice daily or four tablets once daily for 28 days
*Alternative nucleoside reverse transcriptase inhibitors analogues Stavudine 30 or 40 mg twice daily (according to weight)§
OR
Zidovudine 250 mg twice daily**
plus
Emtricitabine 200 mg once daily
OR
Lamivudine 300 mg once daily**
†Alternative protease inhibitors Atazanavir 300 mg once daily plus ritonavir 100 mg once daily
OR
Darunavir 800 mg once daily plus ritonavir 100 mg once daily
‡Alternative to protease inhibitors e.g., in cases with significant drug–drug interactions Stavudine 30 or 40 mg twice daily (according to weight)
OR
Zidovudine 250 mg twice daily
OR
Raltegravir 400 mg twice daily

*Truvada is the preferred agent due to pharmacokinetic considerations, tolerability and the evidence base of efficacy based on animal models for the components, i.e., tenofovir and emtricitabine
§Weight >60 kg = 40 mg stavudine; <60 kg = 30 mg stavudine
**Zidovudine plus lamivudine is available as Combivir; one tablet twice daily

Starter Packs

As with the guidelines for occupational exposure (see http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_088185 External Web Site Policy), it may be helpful to use a starter pack. Starter packs are pre-prepared packages including 3–5 days of antiretroviral, antiemetic and antidiarrhoeal medications. The use of starter packs allows timely provision of PEP. This PEPSE regimen can be continued or modified at initial review within five days, depending on further information about the source virus and the patient's tolerance of the medication (IV, grade C).

Duration of Treatment

The optimal duration of PEP is unknown. However, animal studies and a case-controlled study of healthcare workers suggest that 28 days are required to minimize the potential for HIV transmission. It is recommended therefore that four weeks of PEP should be utilized in the sexual exposure setting (unless source-testing after initiation of PEPSE determines that the 'source' is HIV-negative) (III, grade B).

Side-Effects

Any of the antiretroviral drugs may have side-effects and appear to be less well tolerated in HIV-negative patients receiving PEP than in HIV-positive individuals starting treatment. Many of these can be managed symptomatically, for example the use of antinausea and antidiarrhoeal medication when taking PIs. Although proximal renal tubular dysfunction and Fanconi's syndrome are well reported in patients receiving long-term Truvada therapy, this has not yet been reported in the setting of PEP but monitoring is still required. In individuals reporting significant intolerance to one or more PEP agents an alternative agent(s) should be selected from the table above (IV, grade C).

Ensuring Appropriate Use of PEPSE: Service Provision

Given that, for optimal efficacy, PEPSE should be commenced as soon as possible after exposure (III, grade B), 24-hour access should be available. As with PEP following occupational exposure, it is recommended that local policies and pathways be established to enable this within a geographical network.

It is therefore likely that emergency medicine departments (or other urgent care providers) will be expected to assume significant responsibility for provision of PEPSE, with the need for support and training from areas of local expertise. Such areas are likely to be Departments of genitourinary (GU) medicine/sexual health, HIV medicine, infectious diseases or virology/microbiology. The training issues are essentially those outlined comprehensively in the Department of Health/Expert Advisory Group on acquired immunodeficiency syndrome (DH/EAGA) guidance on HIV PEP.

It is recommended that individuals presenting for PEPSE should be referred and seen as early as possible by a clinician or team experienced in the management of ART and with expertise in HIV testing and transmission - whether or not PEPSE is offered or accepted. PEPSE should not be withheld until such expertise is available. In situations where early referral to an experienced team is not feasible, access to advice from an experienced HIV clinician or team is essential. It is recommended that local policies should include 24-hour access to advice from an experienced HIV clinician, particularly for cases where the PEPSE regimen may need to be adjusted to reflect possible drug resistance in the 'source' (IV, grade C).

Ensuring Appropriate Use of PEPSE: Awareness

It is important that individuals potentially at risk for acquiring HIV are aware of PEP. There is evidence that levels of awareness of PEP are low among individuals with HIV as well as among MSM and that publicity campaigns can increase awareness among at-risk groups. A study undertaken in a community cohort of HIV-negative MSM in Australia showed that despite there being high levels of awareness PEP was sought only for a minority of high-risk exposures. Seeking PEP following some exposures and not others appears to be related to whether the episode was 'unusual' or a 'one off' and influenced by factors such as characteristics of the sexual partner(s), the venue where the exposure took place and the use of alcohol and/or recreational drugs. Sexual assault referral centres (SARCs) should ensure that clients and police officers are aware of PEP, and the need for a risk assessment of HIV transmission in each case.

It is recommended that information regarding PEPSE should be proactively provided to individuals diagnosed with HIV infection, particularly if in a serodiscordant relationship (IV, grade C). Furthermore, uninfected individuals with potential for future exposure to HIV should be provided with information regarding PEPSE in addition to full discussion of other proven risk-reduction strategies. This should include information regarding the indications for PEP and that the time to initiation of PEP is crucial to ensure appropriate uptake. It is recognized that community based organizations will have a large part to play in providing this information. Consideration should be given to provision of 24-hour helpline access to enable individuals to establish whether presentation to hospital services for PEPSE is appropriate (IV, grade C).

Assessment and Initial Management of the Individual Presenting for PEPSE

It is essential that an appropriate risk assessment is performed to enable provision of PEPSE according to the recommendations outlined above.

At presentation, and prior to administration of PEPSE, the following issues must be discussed with the individual:

  • The rationale for PEPSE
  • The lack of conclusive data for the efficacy of PEPSE
  • The potential risks and side effects of PEPSE
  • The arrangement for early follow-up with an HIV/GU medicine clinician

The use of a consent form is not considered essential, but documentation must demonstrate that these issues have been discussed.

It is mandatory that individuals for whom PEPSE is provided to undertake an HIV test (with rapid result) prior to, or shortly after initiating therapy (IV, grade C). This recommendation reflects the possibility of undiagnosed HIV infection, which would significantly alter the risk-benefit balance of short-course ART. It may be possible for service providers to obtain results more rapidly by considering newer technologies, such as point-of-care tests (POCTs), although caution must be given to both the higher possibility of false-positive results and the possibility of false-negative results during early seroconversion. If a POCT is reactive, this should be confirmed with a fourth generation serological test as soon as possible and PEP should not be deferred for a significant length of time. Testing should follow the conventional norms of informed consent (IV, grade C).

Those presenting for PEPSE must be seen in a GU medicine/sexual health/HIV department at the earliest opportunity. Where this is not feasible expert advice should be sought. It is recommended that the individual be referred to a health adviser (or appropriately experienced health-care worker), where the following issues can be addressed:

  • Pre-test discussion (if HIV status as yet unknown)
  • The need to continue with a further four-week course of PEPSE if the baseline result is negative
  • The need to have a follow-up HIV test 12 weeks post-completion of PEP
  • The side-effects of the drugs and the support available in the clinic and in the community to help adherence
  • The need to utilize generic social support over the following four months
  • The need for safer sex for the following four months
  • Issues around disclosure
  • Coping strategies
  • For patients concerned about sexual risk-taking health advisers can offer ongoing risk reduction work or referral to psychology if appropriate

It has been shown that individuals presenting for PEPSE are at higher risk of future acquisition of HIV, although it is unlikely that this was acquired during the presenting episode, and therefore PEPSE presenters should be encouraged to attend for future regular sexual health check-ups and consideration of onward referral for risk-reduction services (IV, grade C).

Follow-Up Arrangements for Individuals Presenting for PEPSE

Regular medical follow-up is necessary for individuals receiving PEPSE to monitor tolerability and possible toxicity of the medications. Close follow-up and encouragement has been shown to improve adherence and completion of PEP. Laboratory monitoring (see Table 6 in the original guideline document) is recommended at baseline and part-way through the PEP regimen and some clinicians also undertake this at completion of PEP. Although uncommon with current PEP combinations, if any laboratory abnormalities are identified these should be monitored until they resolve and modification of the PEP regimen may be required (IV, grade C).

It is recommended that all individuals presenting for PEPSE be comprehensively screened for other STIs at an appropriate time point, in accordance with the guidelines on screening for STIs (accessible at www.bashh.org External Web Site Policy). It is essential that hepatitis B vaccination (and immunoglobulin) be considered in addition to PEP in accordance with existing guidance. Additionally, the opportunity should be taken for appropriate risk-reduction discussion with individuals presenting for PEPSE (IV, grade C).

It is recommended that all individuals who receive PEPSE (and those who decline but have had significant risk of exposure to HIV) be re-tested for HIV antibody/antigen at 12 weeks post-exposure or post-completion of PEP if taken (IV, grade C).

Special Scenarios

Pregnancy

Pregnancy is not a contraindication for PEP. Expert advice should be sought.

Skin Rash/Flu-Like Symptoms During or After PEP

Individuals experiencing a skin rash or flu-like illness while or after taking PEP should be advised to attend for urgent review to exclude an HIV seroconversion illness (IV, grade C).

Discontinuation of PEP Prior to Day 28

Individuals missing doses of PEP should be counselled according to the number of missed doses and the time elapsed from the last administered dose. Persistence of PEP drugs at therapeutic levels will depend on the pharmacokinetic properties of the individual agents used in the PEP regimen. The half-life of Kaletra (and other PIs) is relatively short such that levels of this agent will be subtherapeutic 24 hours after a missed dose and largely undetectable by 48 hours. In contrast, both tenofovir and emtricitabine (co-formulated as Truvada) are agents with significantly longer intracellular half-lives and have been shown to persist at therapeutic concentrations in tissue for at least 72 hours after dosing. The implications for the effectiveness of PEP are unknown (III, grade B).

Owing to the complex pharmacology of these agents and their differential persistence in tissues, recommendations on whether and when to discontinue PEP after missed doses is largely empirical, based on biological and pharmacological rationales as well as expert opinion (IV, grade C) (see the table below).

If discontinuation of PEP less than 72 hours since the last missed dose is related to intolerance of one or more ART agents, re-start PEP with an alternative agent(s) (see the table 'Recommended Combinations for PEP' above).

Table: Guidance on Missed Doses and Intolerance of PEP Agents (IV, grade C)

Scenario Recommendation Comments
Missed Doses
<24 hours elapsed since missed dose Take missed dose immediately and subsequent doses at usual time Reinforce the importance of adherence and re-evaluate the motivation to continue PEP
24–72 hours elapsed since missed dose Re-start PEP Reinforce the importance of adherence
Re-evaluate motivation of recipient to continue PEP
>72 hours elapsed since missed dose Recommend discontinuation of PEP  

Further High-Risk Sexual Exposures While on PEP

Individuals reporting further high-risk sexual exposures while receiving PEP do not need to extend the course of PEP beyond the initial 28 days. Tenofovir and emtricitabine have been shown to prevent acquisition of infection when used as PrEP in animal models and to reduce acquisition among MSM (IV, grade C).

Management of Individuals Who Repeatedly Present for PEPSE or with Ongoing High-Risk Behaviour

There is a theoretical concern regarding repeat users of PEPSE. However, once again, there are few data suggesting that a significant number of individuals will utilize PEPSE repeatedly, perhaps due to the aversive nature of the medications. It is therefore recommended that individuals be considered for repeat courses of PEPSE according to the risk of HIV acquisition at the time of presentation, particularly if their circumstances suggest this to be appropriate (commercial sex workers, serodiscordant couples, inability to control the preventive behaviour of their partners). However, it is also recommended that repeat attenders be strongly encouraged to discuss these issues with a health adviser and/or psychologist (IV, grade C).

Individuals who present more than once a year for PEPSE, who do not otherwise have prevailing circumstances for doing so, are of greater concern. PEPSE should still be considered and provided on the basis of the advice set out in the table 'Situations When Post-Exposure Prophylaxis (PEP) Is Considered' above but it should be made clear that in such cases the provision of PEPSE is fully integrated into a course of advice and counselling around safer sex strategies (IV, grade C). It is recommended that in light of the National Institute of Health and Clinical Excellence (NICE, 2007) recommendations, these individuals are offered one-to-one structured discussions around a model of behaviour change theory which can address factors that can help reduce risk-taking and improve self-efficacy and motivation.

Definitions:

Levels of Evidence

Level Type of Evidence
Ia Evidence obtained from meta-analysis of randomized controlled trials
Ib Evidence obtained from at least one randomized controlled trial
IIa Evidence obtained from at least one well-designed controlled study without randomization
IIb Evidence obtained from at least one type of well-designed quasi-experimental study
III Evidence obtained from well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies
IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

Grades of Recommendation

Grade Recommendation
A
(Evidence levels Ia, Ib)
Requires at least one randomized controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation
B
(Evidence levels IIa, IIb, III)
Requires availability of well-conducted clinical studies, but no randomized clinical trials on the topic of recommendation
C
(Evidence level IV)
Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates absence of directly applicable studies of good quality
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of evidence supporting the recommendations is specifically stated for selected recommendations (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Prevention of infection with human immunodeficiency virus (HIV) following unprotected potential sexual exposure to HIV

Potential Harms

Side Effects of Antiretroviral Drugs

  • Any of the antiretroviral drugs may have side effects, which appear to be less well tolerated in human immunodeficiency virus (HIV)-negative patients receiving post-exposure prophylaxis (PEP) than HIV-positive individuals starting treatment. Many of these can be managed symptomatically, for example the use of antinausea and antidiarrhoeal medication when taking protease inhibitors (PIs).
  • Although proximal renal tubular dysfunction and Fanconi's syndrome are well reported in patients receiving long-term Truvada therapy, this has not yet been reported in the setting of PEP but monitoring is still required.
  • Side-effects of newer non-nucleoside reverse transcriptase inhibitors (NNRTIs: TMC125, etravirine; TMC278, rilpivirine) include hepatitis and rash. Stevens-Johnson syndrome has been reported with etravirine.
  • Efavirenz has a lower incidence of rash; however, it may be associated with significant central nervous system disturbance at a time when individuals may be anxious, which may make
    it less suitable for use for PEP.
  • PIs have been associated with metabolic abnormalities, lipid abnormalities, insulin resistance and diabetes mellitus in addition to gastrointestinal side-effects.

Drug-Drug Interactions

  • When prescribing PEP it is essential to ensure that the potential for drug–drug interactions is considered. Clinicians are advised to liaise with an HIV specialist pharmacist and/or use online tools such as http://www.hiv-druginteractions.org/ External Web Site Policy for this purpose. Examples of relevant drug–drug interactions between PIs and other medications are shown in Appendix A of the original guideline document.
  • Of particular note is the interaction of ritonavir with some statins, resulting in the elevation of those statins (in particular simvastatin or lovastatin) to dangerously high levels, leading to an increased risk of rhabdomyolysis. In this case switching to an alternative statin for a short while, e.g., atorvastatin (area under the curve [AUC] also increased 5-fold) or pravastatin, stopping the statin for the duration of PEP, or using an alternative third (non-PI) agent may be necessary.

Adherence

Poor adherence to PEP regimens theoretically may result in the acquisition of a drug-resistant virus, should the individual become HIV-infected. This has been suggested as a risk for subsequent seroconversion in a retrospective analysis of post-exposure prophylaxis following potential sexual exposure (PEPSE) failures.

Potential Behavioural/Psychological Implications of Offering PEPSE

There are concerns that the availability of PEPSE will reduce commitment to primary prevention strategies and consequently result in more frequent high-risk behaviour. Some studies provide evidence that the availability of PEPSE increases risk behaviour. While most men who have sex with men (MSM) in the USA may not intend to use PEPSE, younger, less-educated MSM may report greater intentions to use PEPSE, especially if they had engaged in high-risk sexual behaviour and had a history of injecting drug use. However, other studies provide evidence that there may be no increase in risk behaviour.

Contraindications

Contraindications

See Appendix A of the original guideline document for drug contraindications in combination with Kaletra (lopinavir and ritonavir) and commonly used medication, or where interactions are significant and potentially dangerous.

Qualifying Statements

Qualifying Statements
  • The recommendations in this guideline may not be appropriate for use in all clinical situations. Decisions to follow these recommendations must be based on the professional judgement of the clinician and consideration of individual patient circumstances and wishes. It should be acknowledged that use of any antiretroviral agent in this setting is an unlicensed indication.
  • All possible care has been undertaken to ensure the publication of the correct dosage and route of administration. However, it remains the responsibility of the prescribing physician to ensure the accuracy and appropriateness of the medication they prescribe.
  • This guideline offers recommendations on the potential use of post-exposure prophylaxis following potential sexual exposure (PEPSE), the circumstances in which it may be recommended, the treatment regimens that may be recommended and the appropriate use of subsequent diagnostic tests to measure individual outcomes. This guideline is intended to be complementary to the existing Department of Health (DH)/Expert Advisory Group on AIDS (EAGA) guidance on PEP.

Implementation of the Guideline

Description of Implementation Strategy

The provision of post-exposure prophylaxis following sexual exposure (PEPSE) requires consideration of appropriate pathways of care between genitourinary medicine/sexual health/human immunodeficiency virus (HIV) clinicians and those providing access to emergency and primary care, including sexual assault referral centres, in order to ensure PEPSE is administered both appropriately and in a timely fashion. This will require local interpretation of this guideline and will most likely involve a degree of organizational change and provision of additional resources.

Implementation Tools
Audit Criteria/Indicators
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Staying Healthy
IOM Domain
Effectiveness
Patient-centeredness
Timeliness

Identifying Information and Availability

Bibliographic Source(s)
Benn P, Fisher M, Kulasegaram R, BASHH, PEPSE Guidelines Writing Group Clinical Effectiveness Group. UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011). Int J STD AIDS. 2011 Dec;22(12):695-708. PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2006 Feb (revised 2011 Dec)
Guideline Developer(s)
British Association for Sexual Health and HIV - Medical Specialty Society
Source(s) of Funding

No specific or external funding was sought or provided in the development of this guideline.

Guideline Committee

Guidelines Writing Group

Composition of Group That Authored the Guideline

Authors: P Benn MBChB FRCP, Camden Provider Services, Central and North West London NHS Foundation Trust, London; M Fisher MBBS FRCP, Department of HIV/Genitourinary Medicine, Brighton and Sussex University Hospitals NHS Trust, Brighton; R Kulasegaram LRCP MRCS FRCP, Department of Genitourinary Medicine, Guy's and St Thomas' NHS Foundation Trust, London

British Association for Sexual Health and HIV (BASHH) PEPSE Guidelines Writing Group: Yusef Azad (representing NAT); Valerie Delpech, HIV and STI Department, Centre for Infections, HPA; Julie Fox, Consultant in GU Medicine, Guy's and St Thomas' NHS Foundation Trust; James Hardie, Health Adviser, Chelsea and Westminster Hospital (representing SSHA); David Hawkins, Consultant in GU Medicine, Chelsea and Westminster Hospital; Barbara Hedge, Consultant Clinical Psychologist (representing British Psychological Society); Keith Radcliffe, Consultant in GU Medicine, Whittall Street Clinic, Birmingham (representing Expert Advisory Group on AIDS); Claire Richardson, Pharmacist, Brighton and Sussex University Hospitals NHS Trust (representing HIVPA); Stephen Taylor, Consultant in Sexual Health and HIV Medicine, Birmingham Heartlands Hospital, Consultant Adviser to HM Armed Forces

Clinical Effectiveness Group (CEG) Members: Dr Keith Radcliffe (Chair) (BASHH); Dr David Daniels (BASHH NAG); Dr Mark FitzGerald (BASHH); Dr Margaret Kingston (BASHH); Dr Neil Lazaro (RCGP); Dr Gill McCarthy (BASHH); Dr Ann Sullivan (BASHH)

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Fisher M, Benn P, Evans B, Pozniak A, Jones M, Maclean S, Davidson O, Summerside J, Hawkins D, Clinical Effectiveness Group (British Association for Sexual Health and HIV). UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure. Int J STD AIDS 2006 Feb;17(2):81-92. [84 references]

Guideline Availability

Electronic copies: Available from the British Association for Sexual Health and HIV Web site External Web Site Policy.

Availability of Companion Documents

Auditable outcome measures are provided in the original guideline document External Web Site Policy.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on June 9, 2008. The information was verified by the guideline developer on August 13, 2008. This summary was updated by ECRI Institute on January 4, 2010 following the U.S. Food and Drug Administration advisory on Lexiva (fosamprenavir). This summary was updated by ECRI Institute on January 12, 2011 following the U.S. Food and Drug Administration advisory on Invirase (saquinavir). This NGC summary was updated by ECRI Institute on March 22, 2012. his summary was updated by ECRI Institute on August 13, 2012 following the FDA advisories on Statin drugs and Statins and HIV or Hepatitis C drugs.

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