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Experience to date with PEP
   Last updated: 19.05.03
 
There have been no formal studies of the effectiveness of PEP for non–occupational exposure to HIV, and so its effectiveness in these circumstances remains unproven. However, its use is expanding in many countries.

Due to the lack of information on efficacy concerning the application of PEP after sexual exposure, the UK Chief Medical Officers' Expert Advisory Group on AIDS (EAGA) does not recommend in favour of, or against its use in such settings.

A study in San Francisco has investigated the safety and acceptability of PEP after possible sexual or IDU exposure to HIV. Individuals who have experienced this type of exposure within the previous 72 hours are offered one month's treatment with AZT and 3TC in the form of one tablet twice a day (also known by the trade name Combivir). Other drugs (ddI and d4T) are being offered in cases where it is believed that a risk may exist of exposure to AZT and/or 3TC-resistant virus (Kahn).

The study collected data on the number of cases, the types of risk exposure, the uptake of PEP, side effects, adherence, the development of drug–resistant HIV strains, and subsequent risk behaviour. The study is not large enough to provide statistically significant evidence of PEP's effectiveness, although it is collecting data on the number of seroconversions.

In total 401 requests for PEP were received between December 1997 and March 1999. 91% of participants were men and the median age was 32 years.
375 of the 401 participants sought PEP because of sexual exposure and only 2% reported sharing of IDU equipment. Receptive anal intercourse was reported in 40% of the exposures.

PEP was supplied within 72 hours of exposure.

Certainty of source partner's HIV positive status was expressed by 174 (43%) of participants. For the majority of participants exposed during sexual activity, the sexual exposure that prompted enrolment represented a lapse in safe sex practices rather than habitual high-risk behaviour.

In total 309 (48%) of participants completed 4 weeks of treatment. Complete adherence to medication in the four days before the clinic visit was reported by 84% to 78% of participants, despite high levels of self-reported side-effects, including; nausea (52%), fatigue (44%), headache (24%) and diarrhoea (15%).

This study is one of the first to provide data on the actual practice of providing PEP after sexual and IDU exposure. It demonstrated that people with sexual exposures will seek PEP. For the majority of individuals, the episode represented a lapse in safer sexual practices. The study demonstrated the feasibility of identifying persons with a sexual exposure to HIV as well as that exposed persons can be reliably and safely treated with a four-week course.

Completion rates were high at 78%. This was most likely due to several factors including, the provision of one-to-one medication adherence counselling, dispensing only a limited supply of medications at each visit which required individuals to make regular contact with staff and finally, the majority of participant took a dual nucleoside analogue regimen which was dose twice daily. Such a regimen is associated with fewer side-effects and greater ease of use than triple combinations including a protease inhibitor.

The study was not designed to evaluate efficacy, though no individuals were observed to develop antibodies to HIV at six months after exposure.

Because persons seeking PEP are highly motivated to avoid infection, they may be in a window period in which education and counselling will have significant influence.

Another pilot feasibility study is underway at six vaccine research recruitment sites in the USA. Men reporting high risk exposure are randomly assigned to receive very rapid access to PEP or information about PEP and referrral to clinicians who will prescribe PEP. The study will assess willingness to enrol and receive PEP, the number of PEP courses sought and received in each study arm, adherence, side effects and subsequent risk behaviour.

In New York, seven patients were enrolled via a 24 hour telephone helpline to receive an individualised antiretroviral regimen. An NNRTI was given alongside AZT and 3TC, and those patients presenting between 48 and 72 hours after exposure were given nelfinavir. One patient discontinued nelfinavir due to elevated lipid levels, otherwise side-effects were limited to GI disturbances and did not require treatment modification or discontinuation. The researchers found that with adequate counselling and support, participants were able to demonstrate excellent adherence (Torres). This was the first nonoccupational post-exposure prophylaxis (PEP) pilot program in New York City and aimed to enroll 120 participants over the first 12 months.

Several other preliminary studies have reported poor rates of adherence and follow-up; for example, only three out of eight sexually exposed patients completed a PEP course at the Chelsea and Westminster Hospital in London (Easterbrook), and only one out of eight returned for all follow-up visits. At St Vincent's Hospital in New York, none of the six individuals who received PEP after sexual assault returned for HIV testing when the course was completed (Opio). It is worth remembering that numbers in these studies are low.

Ethical and practical issues
Providing PEP after sexual or IDU exposures presents different challenges than for occupational or perinatal exposures. Persons exposed to HIV from sexual or IDU activities may not accurately assess their risk for infection and may delay seeking treatment.

Identifying a person's source partner and determining his or her HIV status after sexual exposure may be problematic.

Concerns have been raised that if PEP were provided for sexual or IDU exposure, individuals would experience unacceptable side-effects or would inadequately adhere to the treatment regimen or refuse to return for follow-up HIV testing.
Additionally, there is the concern that PEP would fail to fully suppress the virus and rapidly induce resistance to the drugs used. This risk is greatest, if people take it in the belief that they are HIV negative when in fact they are already HIV positive.

The point has been raised that the availability of PEP for sexual and IDU exposures might paradoxically increase risk behaviour. For this reason the San Francisco study described above included a number of sessions of risk reduction counselling.

At a session discussing PEP during the Eleventh International Conference on AIDS in Vancouver in July 1996, physicians voiced their sense of unease at limiting PEP to health–care workers. As has been pointed out, “The probability of HIV infection due to puncture by a contaminated needle is similar to that estimated for a single episode of unprotected receptive anal or vaginal intercourse with an infected partner or for a single episode of injection–drug use with HIV–contaminated equipment” (Katz). If PEP works, then ethically it should be made available to individuals who are placed at significant risk of infection through other exposure routes.

The American Society of Law, Medicine and Ethics convened an interdisciplinary Working Group on HIV Testing, Counselling, and Prophylaxis After Sexual Assault, which published its recommendations in 1994. At that time the efficacy of PEP was less clearly established, but nevertheless the group concluded that survivors should be provided with information about the availability of PEP to enable them to decide whether or not to use it, “based on a risk assessment of the exposure. The risk assessment should consider available information on the serostatus of the assailant, the type of exposure (anal, vaginal, or oral penetration and ejaculation), the nature of the physical injuries, and the number of assaults”, as well as the potential for drug side–effects (Gostin).

Research amongst a cohort of gay men in four US cities caused researchers to conclude that the per-exposure risk of unprotected receptive anal intercourse was greater than that of a single needlestick injury, and that this level of risk justified offering PEP after such a potential sexual exposure. However, it is worth noting that this research took place between 1992 and 1994, and infectivity may have been altered by the widespread use of HAART (Vittinghof).

It will be difficult to define the boundary between cases of sexual risk which are high enough to justify offering PEP, and those in which the risk of infection is sufficiently low that the financial cost of PEP and the risk of drug side–effects is felt to be unjustifiable. For instance, the CDC guidelines indicate that combination therapy may be reasonable for health–care workers who experience mucosal exposure to semen even where there are only grounds for suspicion, rather than certainty, that the source patient is HIV–positive. How does this differ from the situation of any gay man who gets fucked without a condom in a large city in the UK?

A 1998 review of ethical and clinical implications of PEP for non-occupational exposure concluded that it would be prudent to consider local HIV prevalence rather than relying on per-exposure risks calculated for very high prevalence cities when considering the likely need for PEP (Lurie), although it should be noted that the four city study mentioned above did distinguish between the per-contact risk of receptive anal intercourse with a partner known to be HIV-positive, and one of unknown HIV status.

When used, PEP should be initiated promptly, since animal research suggests that PEP may be ineffective if started later than 24 to 36 hours after exposure. A recent discussion of PEP for non–occupational risks recommends against initiating treatment more than 72 hours after the exposure (Katz), although the CDC guidelines argue that starting even one to two weeks post–exposure may be justified in cases of the highest risk. The protocol used at San Francisco General Hospital notes that “after an exposure, most health–care workers are upset and find that decisions about treatment are very hard to make. We recommend that the exposed person start therapy. Therapy can be stopped later, after the exposed person has had a chance to talk with their clinician and loved ones. Once the immediate crisis has passed, it is usually easier to make the best decision.” (San Francisco General Hospital Epi–Center). If PEP is ever to become a practical option for non–occupational exposure, a new system of 'rapid response' clinic services may be required to provide prompt access to treatment.

According to Guidance from the DoH, PEP following occupational expoure should ideally be started within an hour of exposure. The guidelines recognise that presentation following a non-occupational (sexual or IDU) exposure is unlikely to be sufficiently prompt to derive maximum benefit from PEP. This would imply a need to distribute 'starter packs' in the community, along with education in their proper use. The obvious model for this is the way that pregnant women with HIV are given their first dose of nevirapine to take home and keep for the onset of labour, prior to hospital admission. However, for sexual transmission there would be added costs due to packs that were unused and issues concerning shelf-life and safe storage. An alternative would be to educate GPs, pharmacists, and accident and emergency staff in delivering PEP, to ensure out-of-hours access.

Are British clinics providing PEP for sexual or IDU exposures?
Current practice varies from clinic to clinic, and none has a formal, open policy. Lack of policy is in part a result of the complex issues surrounding non–occupational PEP and the paucity of research supporting its use.

A number of centres state that they treated individuals who report recent unprotected sex with an HIV–positive partner. However, they assess these on a case by case basis. Clinics that prescribe PEP are often anxious not to gain a public reputation for doing so, since this might lead to a significant increase in the number of presenting cases, with resulting cost pressures.

Other clinics report that they do not currently offer PEP for sexual or IDU exposure, citing the lack of proof of efficacy and concern over drug toxicities. They argue that if PEP is to be provided, it should be on the basis of clear public guidelines backed by adequate funding.

Access
Clinics will not automatically offer this form of treatment to everyone who believes they may have been at risk of HIV infection. They may use a number of criteria to decide whether high risk exposure is likely, including:
  • Was your partner known to be HIV-positive?

  • Was your partner in a high risk group?

  • Did ejaculation occur into your body, or were you the active partner?

  • Did you inject a large quantity of blood into your veins if you were sharing needles?

  • Was sexual intercourse violent or traumatic e.g. sexual assault?

  • Where did your partner come from? A metropolitan area with high HIV prevalence or a small town with low prevalence?

  • Are you able to comply with a four week course of treatment which might produce unpleasant side-effects and will require that you take medication according to a strict dosing schedule?


Cost–effectiveness of PEP
A universal policy of prescribing PEP for people who have experienced any significant HIV risk exposure could never be cost–effective, even though at around £750 the cost of a month's triple combination therapy PEP for a single individual seems to compares extremely favourably with the likely life–time costs of treating the same individual should he or she become infected with HIV. The cost–effectiveness of an intervention such as PEP can only be meaningfully calculated in terms of the amount of money that would need to be spent to prevent a single infection. On average, no more than about one out of every three hundred people who have a single episode of unprotected receptive anal sex with an HIV–positive person becomes infected as a result (Katz). So if all 300 came forward for PEP after their risk exposure, 299 would be treated 'unnecessarily', because they would not have become infected regardless of whether or not they received PEP. If doctors have to treat 300 people in order to prevent the one single infection, the cost of preventing that infection would be three hundred times £750, which makes £225,000. In blunt financial terms, this no longer compares so favourably with the life–time costs of medical care.

The cost–effectiveness of PEP could be improved by using fewer or cheaper drugs; for example, if only two nucleoside analogue drugs were used (or if an additional protease inhibitor was reserved only for specific cases of the greatest risk) the cost per course of PEP would be approximately halved. Moreover, PEP would also be more cost–effective if it were delivered only to people whose circumstances meant that they were most at risk of becoming infected (effectively reducing the proportion of recipients who are being treated 'unnecessarily').

Possible criteria for prioritisation might include limiting PEP to cases in which people had a risk encounter with someone who was known for sure to be HIV–positive – even though the US guidelines for occupational use do not carry such a restriction. PEP would also become more cost–effective if offered only to people whose risk had been substantial, such as unprotected receptive anal or vaginal sex or shared drug injecting equipmen. The first study based on public guidelines for non–occupational use of PEP includes receptive oral sex with ejaculation as sufficient grounds for treatment although in practice, few people came forwards for treatment solely on that basis, suggesting that individuals can self-select for treatment, balancing the risks of exposure against the risks and inconvenience of the drugs (Katz & Gerberding). Technology such as viral load testing of the HIV–positive partner might be employed, enabling the prioritisation of cases in which the HIV–positive partner had a high viral load, such as during advanced HIV infection, which might also be expected to increase the risk of transmission. Nevertheless, funding more than the occasional case of PEP for a sexual risk exposure is likely to be beyond the means of most genito–urinary clinic budgets.

Lipodystrophy following exposure to PEP
In April 2003 the first report of what is thought to be the first case of an HIV-negative man developing central adiposity (fat accumulation) after taking HIV post-exposure prophylaxis (PEP) was published.

The case concerned a 32 year old man who was given two courses of PEP after repeated high-risk sex with his HIV-positive partner. PEP consisted of two three-week courses of 300mg efavirenz twice daily, with 40mg of d4t and 150mg of 3TC, both twice daily. The man remained HIV-negative at least four months after the last exposure.

Despite maintaining his usual diet and patterns of physical activity, within six weeks of the second course of PEP the man developed a rapid increase in abdominal girth, with associated bloating and loss of appetite. The doctors describe his body change as resembling “protease paunch”, an indicator of lipodystrophy. However the man’s blood lipids remained normal. Nor did he develop the fat loss which is also seen in people with lipodystrophy. Striking before and after photographs taken between the two courses of PEP, and again eight weeks after the second course of PEP, demonstrate substantial abdominal distention. The fat accumulation persisted for at least four months after the last exposure to antiretrovirals.

Dr Stefan Mauss and colleagues believe that the case casts some light on the causes of lipodystrophy and suggest that “this case report may be a limited proof of principle that the alterations in adipose tissue are caused by antiretroviral combination therapy rather than HIV infection itself.” They conclude that patients receiving PEP should be assessed for evidence of lipodystrophy.

Rhode Island guidelines for non-occupational PEP
In January 2003, guidelines which covered the use of PEP following non-occupational exposure to HIV were published in the Journal of the American Medical Association (JAMA).

The 30-page document, Nonoccupational Human Immunodeficiency Virus Postexposure Prophylaxis Guidelines for Rhode Island Healthcare Practitioners, is online on the websites of the Rhode Island Department of Health (http://www.healthri.org/media/020925a.htm) and the Brown University AIDS Program (BRUNAP) (http://www.brown.edu/Departments/BRUNAP/backnpep.htm).

Seven countries—six European nations and Australia—have adopted HIV non-occupational PEP guidelines. The US Centers for Disease Control and Prevention reviewed the issue in 1998, but has not issued formal guidelines on its use. Currently, California and New York have guidelines for NPEP for victims of sexual assault, but not for people who sustain other types of potential HIV exposure.


A clinical advisory had been issued by the Massachusetts Department of Public Health in October 2000 to medical providers in the state to inform them that HIV-risk assessment and PEP "should be considered for individuals who present within 72 hours of a high-risk sexual or other non–health care related exposure." The department also recommends that clinical settings offering non-occupational PEP establish written protocols that incorporate certain elements regarding assessment, treatment, and follow-up. The advisory can be read online at http://www.state.ma.us/dph/aids/guidelines/exposure_nonwork.htm

The guidelines recommend that clinicians in Rhode Island first assess the risk of HIV exposure. According to the guidance, non-occupational PEP should be offered following possible exposure with a person known to be HIV-positive. It may also be offered after high-risk exposures (such as unprotected sex with a person who has had multiple sexual partners or is an injecting drug user), and may be considered if a person has had a low risk exposure (such as an unprotected sexual contact with a person of no recognised risk behaviours for HIV). When possible, the HIV serostatus of the source should be determined.

The guidelines suggest that, when offered, treatment should be provided within a maximum of 72 hours and preferably within one hour of exposure.

Specific drug regimens are also recommended; following exposure with a person known to be HIV-positive, it is recommended that a triple combination, containing a protease inhibitor be provided for 28 days. Where possible, the clinician responsible for the care of the HIV-positive person should be contacted to obtain details of the contact’s HIV treatment history and known resistance profile.

In all other instances a dual combination should be provided for four weeks. In all cases, people receiving non-occupational PEP should receive information about dosing, potential side-effects, and possible drug interactions. For healthcare professionals, the guidelines include details of which tests should be undertaken on people with possible HIV infection.

The guidelines also include information about appropriate laboratory tests, non-occupational PEP considerations by exposure category (sexual assault, consensual sex, nonoccupational needlestick and sharps injuries, injection drug use, and "unusual" exposures to body fluids (such as amniotic fluid), and sample patient instructions.

The Rhode Island guidelines also indicate that certain groups who might benefit from non-occupational PEP should be informed about the option and arrangements should be made for quick access to medications, should the need arise. Such groups include the uninfected partner in serodiscordant couples, as well as people who may be at higher risk of experiencing a needlestick or sharps injury, including non–health care personnel and caretakers of HIV-infected patients, sanitation workers, and housekeeping and commercial cleaning workers.

The guidelines stress that non-occupational PEP is not a substitute for HIV prevention programmes. Dr Ronald Merchant, one of the authors of the Rhode Island guidelines said: “Primary prevention is very important but we need to find other ways [to prevent HIV]” adding, “HIV non-occupational PEP is not the end-all, but it can be one part of our armamentarium for decreasing the incidence of HIV.”

The US non-occupational PEP registry
Following the US Centers for Disease Control (CDC) issuing specific recommendations concerning occupational PEP. The suggestion was made that PEP should also be offered to people with unanticipated sexual or drug-related exposures.

A recent CDC statement on the management of non-occupational exposures to HIV concluded that since no data exist regarding the efficacy of PEP for non-occupational exposure, recommendations for or against its use cannot yet be made.

In order to collect needed information, the US National non-occupational HIV post-exposure Prophylaxis Registry was created back in 1999. Data presented at XIV International AIDS Conference in Barcelona in July 2002 showed 219 cases in the registry up to March 2001.

US clinicians are invited to provide information on potential HIV exposure within 60 days of the event occuring, so long as the exposure was sexual, or involved drug use or some other known HIV transmission pathway- for example needlestick injury, so long as it did not occur in the occupational setting.

The objectives of the registry are to;
  • determine the characteristics of the exposures for which PEP is prescribed

  • assess the completion rate of prescribed PEP regimens, and to assess the impact of side effects and adverse events on early discontinuations

  • identify differences in PEP practice in different clinical settings (i.e., emergency rooms, private practice)

  • evaluate and compare HIV infection rates between those who sustain exposures and are treated with PEP and those who are exposed but untreated

  • monitor the occurrence of acute retroviral syndrome

  • monitor repeat use of PEP by those receiving an initial course reported to the registry.


The initial report will ascertain patient and provider demographic characteristics; the nature, extent, and timing of the reported exposure; HIV status and risk behaviors of the reported source (if known); whether antiretroviral treatment was offered and accepted; and what treatment (if any) was given.

Follow-up reporting will provide additional information;

  • at 4-6 weeks


At 4-6 weeks following the initial visit, data will be collected to document the HIV status of the patient at the time of exposure, whether treatment (if given) was completed, altered, or discontinued before 28 days, and the HIV status of the patient 4-6 weeks after potential exposure. Information on side-effects and adverse effects of therapy, and any symptoms of acute retroviral syndrome will also be collected.

  • at 6 and 12 months


Information collected at the 6-month and 12-month follow-up will include information about HIV test results and HIV exposures reported since the 4-6 week follow-up visit, and whether or not an additional course of PEP was given.

References


HIV Post Exposure Prophylaxis: Guidance from the UK Chief Medical Officers' Expert Advisory Group on AIDS. Department of Health. July 2000.

Easterbrook P et al. Post-exposure prophylaxis for occupational and sexual exposures to HIV: experience in a London hospital. Twelfth World AIDS Conference, Geneva, abstract 33176, 1998.

Kahn J et al. Feasibility of post-exposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: The San Francisco PEP study. Journal of Infectious Diseases 183; 707-714, 2001.

Katz M et al. Postexposure treatment of people exposed to the human immunodeficiency virus through sexual contact or injection-drug use. New England Journal of Medicine 336: 1097-1100, 1997.

Lurie P et al. Postexposure prophylaxis after nonoccupational HIV exposure: clinical, ethical and policy considerations. Journal of the American Medical Association 280: 1769-1773, 1998.

Mauss S et al. Rapid development of central adiposity after postexposure prophylaxis with antiretroviral drugs: a proof of principle? AIDS 17: 944 – 955, 2003.

Opio G et al. Post-sexual exposure prophylaxis with HAART after sexual assault. Twelfth World AIDS Conference, Geneva, abstract 33174, 1998.

Stephenson J. PEP talk: treating nonoccupational HIV exposure JAMA 289: 287-288, 2003.

Torres R et al. Preliminary report on nonoccupational post-exposure prophylaxis utilizing an NNRTI/NRTI regimen. Thirteenth International AIDS Conference, Durban, abstract TuPeB3204, 2000.

Vittinghoff E et al. Per-contact risk of human immunodeficiency virus transmission between male sexual partners. American J of Epidemiology 150: 306-311, 1999.