Can the promotion of post-exposure prophylaxis following sexual exposure to HIV (PEPSE) cause harm?: Response
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《性传输感染》
Many countries are utilising such therapies as one method of HIV prevention
Keywords: post-exposure prophylaxis; HIV; risk; behavioural disinhibition
Richens et al question whether the development of guidelines for the provision of post-exposure prophylaxis following sexual exposure (PEPSE) will cause harm, based on three areas of concern: doubts over efficacy, possible effects on sexual behaviour, and cost.
The efficacy of PEPSE has yet to be determined in a robust fashion. As Richens et al observe, data to support the UK1 (and other) guidelines have been drawn from animal models, vertical transmission studies, retrospective data from healthcare workers exposed to HIV, and prospective (unrandomised) studies in men who have sex with men (MSM),2 and individuals following sexual assault.3 In the latter two case-controlled studies HIV seroconversion in PEPSE recipients was 0.6% and 0% compared to 4.2% and 2.7% in controls, supporting its putative efficacy. It is highly unlikely that a prospective randomised study to address the fundamental question of efficacy would be possible (given the numbers involved to achieve sufficient power) or acceptable from an individual or ethical perspective. Whether the absence of such data should result in a failure to offer a potentially beneficial intervention is questionable. Although we live in an era where evidence based medicine is the holy grail, the majority of medical interventions are not supported by high levels of robust evidence from randomised studies. The provision of PEP to healthcare workers following actual or potential exposure to HIV is open to similar criticisms, but the routine adoption of PEP in this setting is not questioned by Richens et al, nor indeed by UK or other national policies. This is despite a marked difference in risk of transmission involved in comparing these scenarios. For example, the risk to a healthcare worker following a needlestick injury from a homosexual man of unknown HIV serostatus is 0.045%, whereas the risk following receptive anal intercourse from a known HIV positive "donor" is at worst 3%, and from an undetermined source 0.45%. Is it ethical to withhold a potentially beneficial though not "AI" evidence based intervention in one situation (of higher risk) but provide it freely in the other? To do so would seem to challenge the basic biomedical ethical principles of justice and beneficence.
Richens et al quite rightly identify that one of the major concerns regarding the routine provision of PEPSE is the potential for a resulting change in risk behaviour such that individuals will engage in high risk activity in the knowledge that PEPSE is available. However, contrary to these concerns, all available data suggest that this is not the case. In the two studies that have examined behaviour after individuals have taken PEP the opposite appears to occur. In Brazilian MSM, risk behaviour declined over time (in both PEP users and non-users),2 and in San Francisco 73% reported a decrease in high risk sexual acts.4 Clearly, there are limitations to these data. Firstly, it remains to be determined whether such changes in sexual behaviour occur in other settings (such as the United Kingdom). Secondly, these studies have only examined changes in behaviour in individuals who have received PEP and not the wider community. Those studies that have attempted to address the possible effects of availability of PEP have suggested that awareness does not result in an increase in risk taking.5,6 It is well recognised that risk behaviour has increased in MSM (and other groups) in recent years. Possible explanations for this change include treatment optimism,7 easier access to casual sexual partners (for example via the internet),8 and safe sex "burnout."9 None of these factors individually are sufficient to explain behavioural changes, which is likely to result from a complex interplay of individual and societal factors. Within this milieu, it is highly unlikely that the provision of PEPSE will in itself be a significant driver of behavioural change at a population level, though studies to confirm this would be welcomed. In the meanwhile, there exists the opportunity at an individual level not only to provide a further method of HIV prevention, but also to seize this opportunity to screen and vaccinate for other sexually transmitted infections and offer risk reduction advice. Providing PEPSE may well act as a "wake up call" and have a beneficial effect on behaviour rather than a deleterious one.
Richens et al quite rightly raise issues regarding cost and service provision. These have been specifically addressed within the BASHH guidelines. Modelling from the United States10 has suggested that the provision of PEPSE is cost saving following unprotected receptive anal intercourse in men who have sex with men, and is cost effective in all other situations for which PEPSE is recommended within the BASHH guidelines. While the cost of providing PEPSE is not insignificant—￡600–￡1000 per patient—the cost of an individual with HIV infection is ￡0.5–1 million to the healthcare system and society. Richens et al acknowledge that no commissioner of health care was involved in the development of these guidelines. This is hardly unusual for guidelines that are intended for patient management. Surely the role of commissioners is to respond to the view of the medical profession (and allied professionals and service users) rather than to guide clinical decisions? Furthermore, it is of relevance that during a prolonged period of consultation, there has been not a single response to the BASHH guidelines from any purchaser of health care or health promotion. Commissioners will, however, no doubt become involved in the negotiation of funding for levels of service provision to respond to patient and clinical demand—including the increased demand for PEPSE like any other service development. The data on increasing demand from Richens et al is to be welcomed in this respect and ongoing monitoring (such as via the NonoPEP study) remains vital to determine levels of service required, in addition to providing further data on behaviour and efficacy. Previous PEPSE programmes in San Francisco11 and Sydney (Watson R, personal communication) have not resulted in a major demand on service capacity, but obviously the impact in the United Kingdom may be different. Richens et al question whether other individuals (such as heterosexuals) may present for PEPSE in situations where it will not be cost effective. The guidelines are clear in recommending PEPSE only where there is significant risk of the source individual being HIV positive.
Providing PEPSE may well act as a "wake up call" and have a beneficial effect on behaviour rather than a deleterious one
Richens et al question the publicity campaign by non-governmental organisations that accompanied the release of the draft BASHH guidance. It is noteworthy that surveys of those at highest risk of HIV transmission (that is, MSM)12 have shown that only 23% were aware of the possibility of PEPSE. (In this survey, it is also of relevance that only 1% had requested PEP despite this level of awareness.) It would seem difficult to justify maintenance of the current situation where availability of PEPSE is limited to those few who are aware of its existence, as to do so would result in a significant majority of those at risk being denied a potentially beneficial intervention on the grounds of ignorance alone. Furthermore, it should be noted that promotional material is clear that PEPSE remains unproved; is not 100% effective, and should not be used as a routine method of HIV prevention.
Richens et al do not comment on variations of practice in the absence of guidance. A previous study by the British Cooperative Clinical Group demonstrated that provision of PEPSE was highly variable across the United Kingdom.13 The development of national guidelines is therefore entirely consistent with ethical principles of equity and the ethos of a national healthcare system. The absence of any recommendation would result in the maintenance of the status quo—that is, variability of advice/management dependent upon the healthcare setting to which the individual presented.
The recommendations made by BASHH are similar to those made by the United States, France, Spain, and Australia. From a similar, if imperfect, body of evidence many countries—where HIV transmission is ongoing and antiretroviral therapy is available—are utilising such therapies as one method of HIV prevention. The BASHH guidelines state explicitly that the provision of PEPSE is only one strand of HIV prevention and should only be considered as a last measure where conventional and proved methods have failed. Monitoring of uptake and efficacy and research programmes to determine impact on behaviour are essential and guidance should be reviewed in the light of new data. In the interim, to ignore the issue and fail to produce guidance would seem to prolong inequity of service provision, delay the emergence of information to guide clinical decision making, and potentially withhold one extra tool in the battle to prevent new cases of HIV infection.
REFERENCES
Clinical Effectiveness Group . (British Association of Sexual Health, HIV). United Kingdom Guidelines for the use of post-exposure prophylaxis for HIV following sexual exposure. www.bashh.org/guidelines/draft-04/pepse%B1%5D_010404.doc.
Praca Onze Study Team. Behavioural impact, acceptability, and HIV incidence amongst homosexual men with access to postexposure chemoprophylaxis for HIV. J Acquir Immune Defic Syndr 2004;35:519–25.
Schecter M . Occupational and sexual PEP—benefit/risk? 6th International Conference on Drug Therapy in HIV Infection, Glasgow, UK, 2002 (abstract PL 6.1).
Martin JN, Roland ME, Neilands TB, et al. Use of postexposure prophylaxis against HIV infection following sexual exposure does not lead to increases in high-risk behaviour. AIDS 2004;18:787–92.
Waldo CR, Stall RD, Coates TJ. Is offering post-exposure prevention for sexual exposures to HIV related to sexual risk behaviour in gay men? AIDS 2000;14:1035–9.
Van der stratten A, Gomez CA, Saul L, et al. Sexual risk behaviours among heterosexual serodiscordant couples in the era of post-exposure prevention and viral suppressive therapy. AIDS 2000;14:F47–54.
Elford J . HIV treatment optimism and high-risk sexual behaviour among gay men: the attributable population risk. AIDS 2004;18:2216–7.
Elford J, Bolding G, Sherr L. Seeking sex on the Internet and sexual risk behaviour amongst men using London gyms. AIDS 2001;15:1433–4.
Wolitski RJ, Valdiserri RO, Denning PH, et al. Are we headed for a resurgence of the HIV epidemic amongst men who have sex with men? Am J Public Health 2001;91:883–8.
Pinkerton SD, Martin JN, Roland ME, et al. Cost-effectiveness of HIV postexposure prophylaxis following sexual or injection drug exposure in 96 metropolitan areas in the United States. AIDS 2004;18:2065–73.
Kahn JO, Martin JN, Roland ME, et al. Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco study. J Infect Dis 2001;183:707–14.
Sigma Research. Gay men’s sex survey 2003. Accessible at, www.sigmaresearch.org.uk/reports.html.
Giele CM, Maw R, Carne C, et al. Post-exposure prophylaxis for non-occupational exposure to HIV: current clinical practice and opinions in the United Kingdom. Sex Transm Infect 2002;78:130–2.(M Fisher)
Keywords: post-exposure prophylaxis; HIV; risk; behavioural disinhibition
Richens et al question whether the development of guidelines for the provision of post-exposure prophylaxis following sexual exposure (PEPSE) will cause harm, based on three areas of concern: doubts over efficacy, possible effects on sexual behaviour, and cost.
The efficacy of PEPSE has yet to be determined in a robust fashion. As Richens et al observe, data to support the UK1 (and other) guidelines have been drawn from animal models, vertical transmission studies, retrospective data from healthcare workers exposed to HIV, and prospective (unrandomised) studies in men who have sex with men (MSM),2 and individuals following sexual assault.3 In the latter two case-controlled studies HIV seroconversion in PEPSE recipients was 0.6% and 0% compared to 4.2% and 2.7% in controls, supporting its putative efficacy. It is highly unlikely that a prospective randomised study to address the fundamental question of efficacy would be possible (given the numbers involved to achieve sufficient power) or acceptable from an individual or ethical perspective. Whether the absence of such data should result in a failure to offer a potentially beneficial intervention is questionable. Although we live in an era where evidence based medicine is the holy grail, the majority of medical interventions are not supported by high levels of robust evidence from randomised studies. The provision of PEP to healthcare workers following actual or potential exposure to HIV is open to similar criticisms, but the routine adoption of PEP in this setting is not questioned by Richens et al, nor indeed by UK or other national policies. This is despite a marked difference in risk of transmission involved in comparing these scenarios. For example, the risk to a healthcare worker following a needlestick injury from a homosexual man of unknown HIV serostatus is 0.045%, whereas the risk following receptive anal intercourse from a known HIV positive "donor" is at worst 3%, and from an undetermined source 0.45%. Is it ethical to withhold a potentially beneficial though not "AI" evidence based intervention in one situation (of higher risk) but provide it freely in the other? To do so would seem to challenge the basic biomedical ethical principles of justice and beneficence.
Richens et al quite rightly identify that one of the major concerns regarding the routine provision of PEPSE is the potential for a resulting change in risk behaviour such that individuals will engage in high risk activity in the knowledge that PEPSE is available. However, contrary to these concerns, all available data suggest that this is not the case. In the two studies that have examined behaviour after individuals have taken PEP the opposite appears to occur. In Brazilian MSM, risk behaviour declined over time (in both PEP users and non-users),2 and in San Francisco 73% reported a decrease in high risk sexual acts.4 Clearly, there are limitations to these data. Firstly, it remains to be determined whether such changes in sexual behaviour occur in other settings (such as the United Kingdom). Secondly, these studies have only examined changes in behaviour in individuals who have received PEP and not the wider community. Those studies that have attempted to address the possible effects of availability of PEP have suggested that awareness does not result in an increase in risk taking.5,6 It is well recognised that risk behaviour has increased in MSM (and other groups) in recent years. Possible explanations for this change include treatment optimism,7 easier access to casual sexual partners (for example via the internet),8 and safe sex "burnout."9 None of these factors individually are sufficient to explain behavioural changes, which is likely to result from a complex interplay of individual and societal factors. Within this milieu, it is highly unlikely that the provision of PEPSE will in itself be a significant driver of behavioural change at a population level, though studies to confirm this would be welcomed. In the meanwhile, there exists the opportunity at an individual level not only to provide a further method of HIV prevention, but also to seize this opportunity to screen and vaccinate for other sexually transmitted infections and offer risk reduction advice. Providing PEPSE may well act as a "wake up call" and have a beneficial effect on behaviour rather than a deleterious one.
Richens et al quite rightly raise issues regarding cost and service provision. These have been specifically addressed within the BASHH guidelines. Modelling from the United States10 has suggested that the provision of PEPSE is cost saving following unprotected receptive anal intercourse in men who have sex with men, and is cost effective in all other situations for which PEPSE is recommended within the BASHH guidelines. While the cost of providing PEPSE is not insignificant—￡600–￡1000 per patient—the cost of an individual with HIV infection is ￡0.5–1 million to the healthcare system and society. Richens et al acknowledge that no commissioner of health care was involved in the development of these guidelines. This is hardly unusual for guidelines that are intended for patient management. Surely the role of commissioners is to respond to the view of the medical profession (and allied professionals and service users) rather than to guide clinical decisions? Furthermore, it is of relevance that during a prolonged period of consultation, there has been not a single response to the BASHH guidelines from any purchaser of health care or health promotion. Commissioners will, however, no doubt become involved in the negotiation of funding for levels of service provision to respond to patient and clinical demand—including the increased demand for PEPSE like any other service development. The data on increasing demand from Richens et al is to be welcomed in this respect and ongoing monitoring (such as via the NonoPEP study) remains vital to determine levels of service required, in addition to providing further data on behaviour and efficacy. Previous PEPSE programmes in San Francisco11 and Sydney (Watson R, personal communication) have not resulted in a major demand on service capacity, but obviously the impact in the United Kingdom may be different. Richens et al question whether other individuals (such as heterosexuals) may present for PEPSE in situations where it will not be cost effective. The guidelines are clear in recommending PEPSE only where there is significant risk of the source individual being HIV positive.
Providing PEPSE may well act as a "wake up call" and have a beneficial effect on behaviour rather than a deleterious one
Richens et al question the publicity campaign by non-governmental organisations that accompanied the release of the draft BASHH guidance. It is noteworthy that surveys of those at highest risk of HIV transmission (that is, MSM)12 have shown that only 23% were aware of the possibility of PEPSE. (In this survey, it is also of relevance that only 1% had requested PEP despite this level of awareness.) It would seem difficult to justify maintenance of the current situation where availability of PEPSE is limited to those few who are aware of its existence, as to do so would result in a significant majority of those at risk being denied a potentially beneficial intervention on the grounds of ignorance alone. Furthermore, it should be noted that promotional material is clear that PEPSE remains unproved; is not 100% effective, and should not be used as a routine method of HIV prevention.
Richens et al do not comment on variations of practice in the absence of guidance. A previous study by the British Cooperative Clinical Group demonstrated that provision of PEPSE was highly variable across the United Kingdom.13 The development of national guidelines is therefore entirely consistent with ethical principles of equity and the ethos of a national healthcare system. The absence of any recommendation would result in the maintenance of the status quo—that is, variability of advice/management dependent upon the healthcare setting to which the individual presented.
The recommendations made by BASHH are similar to those made by the United States, France, Spain, and Australia. From a similar, if imperfect, body of evidence many countries—where HIV transmission is ongoing and antiretroviral therapy is available—are utilising such therapies as one method of HIV prevention. The BASHH guidelines state explicitly that the provision of PEPSE is only one strand of HIV prevention and should only be considered as a last measure where conventional and proved methods have failed. Monitoring of uptake and efficacy and research programmes to determine impact on behaviour are essential and guidance should be reviewed in the light of new data. In the interim, to ignore the issue and fail to produce guidance would seem to prolong inequity of service provision, delay the emergence of information to guide clinical decision making, and potentially withhold one extra tool in the battle to prevent new cases of HIV infection.
REFERENCES
Clinical Effectiveness Group . (British Association of Sexual Health, HIV). United Kingdom Guidelines for the use of post-exposure prophylaxis for HIV following sexual exposure. www.bashh.org/guidelines/draft-04/pepse%B1%5D_010404.doc.
Praca Onze Study Team. Behavioural impact, acceptability, and HIV incidence amongst homosexual men with access to postexposure chemoprophylaxis for HIV. J Acquir Immune Defic Syndr 2004;35:519–25.
Schecter M . Occupational and sexual PEP—benefit/risk? 6th International Conference on Drug Therapy in HIV Infection, Glasgow, UK, 2002 (abstract PL 6.1).
Martin JN, Roland ME, Neilands TB, et al. Use of postexposure prophylaxis against HIV infection following sexual exposure does not lead to increases in high-risk behaviour. AIDS 2004;18:787–92.
Waldo CR, Stall RD, Coates TJ. Is offering post-exposure prevention for sexual exposures to HIV related to sexual risk behaviour in gay men? AIDS 2000;14:1035–9.
Van der stratten A, Gomez CA, Saul L, et al. Sexual risk behaviours among heterosexual serodiscordant couples in the era of post-exposure prevention and viral suppressive therapy. AIDS 2000;14:F47–54.
Elford J . HIV treatment optimism and high-risk sexual behaviour among gay men: the attributable population risk. AIDS 2004;18:2216–7.
Elford J, Bolding G, Sherr L. Seeking sex on the Internet and sexual risk behaviour amongst men using London gyms. AIDS 2001;15:1433–4.
Wolitski RJ, Valdiserri RO, Denning PH, et al. Are we headed for a resurgence of the HIV epidemic amongst men who have sex with men? Am J Public Health 2001;91:883–8.
Pinkerton SD, Martin JN, Roland ME, et al. Cost-effectiveness of HIV postexposure prophylaxis following sexual or injection drug exposure in 96 metropolitan areas in the United States. AIDS 2004;18:2065–73.
Kahn JO, Martin JN, Roland ME, et al. Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco study. J Infect Dis 2001;183:707–14.
Sigma Research. Gay men’s sex survey 2003. Accessible at, www.sigmaresearch.org.uk/reports.html.
Giele CM, Maw R, Carne C, et al. Post-exposure prophylaxis for non-occupational exposure to HIV: current clinical practice and opinions in the United Kingdom. Sex Transm Infect 2002;78:130–2.(M Fisher)