YOU ARE HERE:
HIV’s Morning After Pill(s)?
   Last updated: 25.08.04
Will PEP be to HIV what the “morning after” pill is to pregnancy?, asks Gus Cairns

For the past twenty years or so, condoms, safer sex negotiation and – in many countries outside of the UK – abstinence have the been the holy trinity of HIV prevention work. With the unveiling of the first UK guidelines regarding the use of PEP for sexual transmission of HIV, there is now the possibility of a last-ditch attempt to stop HIV taking hold when the other three have failed. But just how effective is PEP, and what does it mean for prevention work as a whole?

What is PEP?
PEP is short for the term Post-Exposure Prophylaxis, which literally means preventing infection after exposure to a pathogen – in this case to HIV. PEP requires a short course of antiretrovirals, although the exact length of time PEP is taken for – and number of drugs given – varies from country to country and even from treatment centre to treatment centre, and is currently under debate.

The concept of PEP has been around almost as long as antiretrovirals themselves, but for many years was used only for healthcare workers who were accidentally exposed to HIV, usually after being unintentionally pricked by a sharp or needle that they had used on someone who was – or was likely to be – HIV-positive. The US term needlestick injury is now the usual phrase for this kind of accident, which may result in occupational exposure to HIV.

More recently, PEP has been used as a way of attempting to prevent HIV infection following possible exposure to HIV through both gay and heterosexual sex, as well as injecting drug use (IDU). This is known as community or non-occupational exposure.

PEP in the UK
The most recent review of prescriptions for non-occupational PEP in the UK covered events in 1999 1. Of 242 requests in that year, 130 people were prescribed PEP. Half of the requests followed sexual exposures between known HIV discordant couples. Requests for PEP were received by 56 of the UK’s 132 GUM clinics (42%). However, just nine clinics received over 60% of all requests, and of the 39 clinics that actually prescribed PEP, just six clinics issued 64% of prescriptions.

Though this could simply reflect supply and demand, it seems much more likely that the reasons for this unequal access are at least partly due to the lack of clear guidance on using PEP in non-occupational settings. The Department of Health’s (DoH) PEP Guidelines 2 deal largely with occupational exposure. Just three of its 20 pages are devoted to sexual exposure, and it makes few specific recommendations.

In fact, a recent survey of UK gay men found that 22% knew someone who had sought PEP, but that only 4% had tried to get it themselves and only 2% had actually taken it. Seventy-one per cent of respondents said they would take PEP if they needed it and it was easily available.3

This summer, PEP should become much more widely available in the UK following the release of detailed guidelines regarding the use of PEP in response to sexual exposure of HIV by the British Association for Sexual Heath and HIV (BASHH). The draft guidelines will be available for consultation online soon, at www.bashh.org

At the same time, the first CHAPS awareness campaign for 2004/5, due to be launched in July, will aim to increase gay men's awareness of PEP and its availability, especially in cities with larger gay scenes, such as Brighton, London and Manchester.

The effectiveness of PEP

Large-scale prospective, placebo-controlled trials have not been carried out for PEP, and so a definitive answer regarding the effectiveness of PEP cannot be given at this time. A much-cited 1997 case control study of health care workers from France, Italy, the UK, and the US came to the conclusion that PEP (in this case AZT monotherapy) reduced the risk of becoming infected with HIV by 48-94%.4. However, there is much less solid data on PEP’s effectiveness after sexual exposure.

One of the more convincing studies was conducted in Brazil and reported two years ago at the 9th Retroviruses Conference in Seattle 5. Here, 202 HIV-negative gay men were enrolled and followed for an average of two years. At the time of enrolment, 57% of the group reported “high-risk behaviour”. PEP, consisting of four weeks of AZT/3TC, was used 100 times by 73 of the participants, 91% of whom completed the course.

There were 11 seroconversions among the group; however, only one occurred in someone who had taken PEP. Analysis of the strain of HIV that infected him despite using PEP showed that it harboured the M184V mutation which is likely to lead to high-level resistance to 3TC. The researchers calculated that PEP reduced the seroconversion rate by 83%, from 4.1 cases per 100 patients a year to 0.7 cases.

Several other interesting findings came from this study. One was that “high-risk” behaviour declined during the study from 56% to 40%. Although it has been suggested from other studies that people reporting declines in risky behaviour may sometimes not be reporting the whole story due, possibly, to guilt at being a ‘study failure’, this finding may help allay fears that the widespread availability of PEP for sexual exposure will cause an increase in condomless intercourse.

Furthermore, 92% of the time, PEP was taken appropriately, i.e. after an exposure that researchers considered “high risk”. This seems to offer a degree of assurance that PEP will not be abused by the ‘worried well’ concerned by very low-risk incidents.

Finally, the study issued people with ‘starter packs’ – ready-wrapped doses of AZT/3TC with instructions that participants should take them immediately following exposure. Other PEP schemes have relied on people reporting to A&E departments after weekend incidents. Since one of the key components to successful PEP is prompt treatment – ideally within 24 hours - this may explain some of the difference between the reported effectiveness rate of 83% in the Brazil study and the 53% rate in the study detailed below.

The cost-effectiveness of PEP

A major concern about PEP is cost. Since the end of ‘ring-fenced’ money for HIV from the Government coffers, lack of funding for prevention work has become, and remains, a major stumbling block. It could be argued that offering everybody anti-HIV drugs as a preventative measure is a lot more expensive than offering condoms. However, it could also be argued that PEP is HIV treatment rather than HIV prevention, and should therefore be paid for out of treatment budgets.

A study published in January 6 attempted to calculate the cost-effectiveness of PEP. Here, Pinkerton and colleagues looked at 401 people who had sought PEP in San Francisco.

The group included men and women who sought PEP for incidents of unprotected anal and/or vaginal intercourse and needle-sharing. The researchers concluded that PEP reduced expected HIV infections by 53% by calculating that, according to types of risk reported by the study participants, an average of 2.36 HIV infections would have been expected: PEP reduced this to 1.1 infections.

This 53% reduction saved 11.74 quality adjusted life years (QALYs). This measurement, frequently used in cost-benefit calculations, means that, for those that used it successfully, PEP should lead to an extra 11.74 years of reasonable health. This in turn, it was calculated, would save a total of US$281,323 in future HIV-related medical costs. When all factors were taken into account, the cost of PEP per QALY saved was US$14,449 – approximately £9,500.

This may sound a lot, but in the US programmes costing $40,000 - $60,000 per QALY are seen as cost-effective.6 By comparison, similar cost-effectiveness studies 7 showed that HIV combination therapy resulted in a cost of US$23,000 per QALY saved. There is no official figure for the UK, but it is thought that the National Institute of Clinical Excellence (NICE), which guides Primary Care Trust spending, considers anything below £30,000 per QALY saved to be cost-effective.

By including a varied population with different risks, this study found that PEP given to the general at-risk population did work out to be much less cost-effective than other HIV prevention methods. One risk-reduction programme for at-risk women8 attending an urban primary health care clinic was successful at increasing condom use and cost about US$260 per client or about US$2,000 per QALY. A similar programme for gay men,9 although costing US$470 per client, was not only cost-effective but also cost-saving: the cost of likely future treatment and care of those infected without the programme outweighed the cost of delivering the programme to the whole group. This compares with an average cost of US$8,607 per QALY saved for PEP for gay men as a whole as reported by Pinkerton. However, when it came to gay men who had been on the receiving end of unprotected anal sex (i.e. ‘bottoms’), the Pinkerton study found that PEP was not merely cost-effective, but actually cost-saving. The cost per infection averted for this group was US$177,293 – which is less than the likely cost of their lifetime HIV treatment if they had not received successful PEP. On the other hand, PEP for gay men on the insertive end of unprotected anal sex (i.e. ‘tops’) was not considered cost-effective.

The variation seen in cost-effectiveness between subgroups of different popuations is not surprising, given that you need to provide PEP to the people most at-risk for it to be cost-effective. As we go to press, the Health Protection Agency (HPA) are attempting to define the risks of HIV transmission in the UK - based on mathematical probability. They are currently estimating that gay men who are the passive partner in unprotected anal intercourse have a 1-in-33 risk of being infected with HIV if they are certain their partner is HIV-positive, but a 1-in-222 risk if they do not know the HIV status of their partner. They estimate that gay men who are the active partner in unprotected anal intercourse have a 1-in-555 risk of being infected with HIV if they are certain their partner is HIV-positive, but a 1-in-11,111 risk if they do not know the HIV status of their partner. However, other factors such as geographical location, STIs, viral load and bleeding may affect the risk estimate, so there is likely to be a range of risk of transmission rather than an exact value.10

In short, if PEP in the UK is offered to gay men who have been the passive partner in unprotected anal intercouse and/or who have known HIV+ partners, PEP could potentially save as much money as providing condoms and safer-sex education, as long as PEP is not routinely relied upon as a substitute for these other safer-sex practices.

What the draft UK guidelines recommend
Last December, HIV prevention experts and community activists met in London to discuss a draft of the BASHH guidelines at a round table session organised by Terrence Higgins Trust (THT). The first guest speaker was Dr. Martin Fisher of Brighton and Sussex University Hospitals, who is lead author of the guidelines writing group.

There was a wide variation in the availability of PEP at STD clinics, he told the meeting. For example, one HIV-negative partner of a serodiscordant couple who sought (and received) PEP at Brighton had been refused by three other clinics.

The guidelines would cover, among other things:
· The scientific basis for recommending PEP
· A guide to calculating the risk of a given exposure
· The pros and cons of PEP as a prevention measure
· Recommended protocols
· Pathways for access
· An emphasis that PEP is only one strand in HIV prevention

The draft recommendations, which are open for discussion, and therefore may be amended, are as follows:


Partner status HIV+ Partner status unknown
Receptive anal intercourse Recommended Recommended if partner high risk
Insertive anal intercourse Recommended Consider if partner high risk
Receptive vaginal Recommended Not recommended
Insertive vaginal Recommended Not recommended



Other factors to consider include whether either partner has a concurrent STI, the viral load in the HIV+ partner, and whether there was sexual assault/trauma.

Draft recommendations for PEP regimens are:

· Combivir (zidovudine, AZT + lamivudine, 3TC)
or
· Zerit (stavudine, D4T) + Epivir (lamivudine, 3TC)
or
· Viread (tenofovir,TDF) + Epivir (lamivudine, 3TC)
plus either
· Viracept nelfinavir
or
· Kaletra (lopinavir/ritonavir)


Although Combivir is suggested as one of the nucleoside components, as Dr. Fisher explains below, this may be ruled out due to high rates of pre-existing HIV strains resistant to both drugs that are currently circulating within the UK. NNRTIs are not recommended because of the likelihood of short-term side-effects: central nervous system problems such as sleep disturbance and depression with efavirenz and liver toxicity with nevirapine. (see The Night Before... on pages 8-9 for more on nevirapine and PEP).

Other draft recommendations include:
· 24-hour access and expertise via A&E
· Baseline HIV test mandatory
· Rapid GUM/HIV clinic referral
· Weekly follow-up during PEP period
· Three- and six-month HIV antibody test
· No limit on repeat requests, but an appointment with a psychologist or health advisor should be mandatory after several repeats.

This last recommendation contrasts with Australia’s ‘three strikes and you’re out’ policy. France and Spain allow a maximum of four and five repeats respectively.

Behavioural implications

Dr. Oliver Davidson, Head of Sexual Health Psychology at London’s Mortimer Market Centre, addressed the possible impact of PEP on subsequent perceptions of risk behaviour.

In the San Francisco study6 reported above, only 10% of people seeking PEP reported an increase in risk behaviour following a PEP consultation. This compares with 74% reporting a decrease in risk behaviour and 16% no change. Consequently, Davidson commented: “Health-related interventions such as PEP may help capitalise on ‘close calls’ to motivate and sustain risk reduction.”

A US survey of gay men in 199811 attending a large Pride festival in Atlanta found that 3% of those surveyed had used PEP, 26% planned to use it, and 74% doubted if they would need to use PEP. Those planning to use PEP were younger, less educated, more likely to have used recreational drugs and have a history of IDU. They were also more likely to have had unprotected receptive anal sex.

As others at the seminar noted, this user profile could be seen either as a problem or as an opportunity. Does the availability of PEP mean that young, drug-using gay men have an ‘excuse’ not to try to maintain safer sex habits? Or, conversely, are they taking a realistic look at their behaviour and its likely risks and seizing upon a technology that may protect them?

Davidson was also concerned about the potential cost (as opposed to cost-effectiveness) of PEP if taken up as a mass prevention measure. One of the implications of the San Francisco study6 is that if the entire annual US HIV prevention budget was used for PEP, it would fund 550,000 treatments and prevent a mere 880 new infections, or 2.2% of the estimated US annual incidence.

Putting PEP into practice

Rod Watson of THT reported on his experience of promoting a PEP programme for gay men in his former capacity as Health Promotion Manager for SE Sydney Health Authority in Australia. The Australian policy on PEP for sexual exposure – the first of its kind – was first written in 1998, although the decision to actively promote PEP as a prevention tool was not taken until June 2000.

The high-risk groups targeted initially were gay men and people in serodiscordant relationships; subsequently, IDUs and sex workers were also targeted.

A phoneline with the number 1-800-PEP-NOW was publicised, posters were placed in community press and information was issued in leaflets and on the web. There were 493 calls for the January-November 2001 duration of the helpline, of which 88% were direct requests for PEP. Sixty-one percent met guidelines for PEP prescription; 28% did not because they were considered low risk, and 11% fell outside the 72-hour time limit.

Interestingly, and contrary to some other surveys, only 7.2% of callers were seeking PEP for exposure with regular partners.

In terms of community awareness of PEP, 64% of those polled in the target groups had not heard of PEP in February 2001. Six months later, 58.5% had heard of PEP. Triple combination therapy was prescribed at the start of the programme, but cost pressure meant that HAART was reduced to the dual nucleoside therapy, AZT/3TC.

Q&A with Dr. Martin Fisher, Chair of the BASHH HIV Special Interest Group
ATU: Are you satisfied that PEP represents an important part of the HIV prevention arsenal?
MF: I certainly think that it’s one part, but it’s only one part – essentially, the last part, when everything else has gone wrong. The problem about when to use it is due to the relative lack of any clear guidelines or consistent message up to now.

ATU: Animal studies have concentrated on, and demonstrated much less effectiveness after, the first 24 hours. Why do the guidelines recommend PEP up to 72 hours after exposure?
MF: The key is not to think that it’s fine up to 72 hours. It’s just that after 72 hours it can be shown to have little or no effect. If people want to consider PEP they need to enquire as early as possible. All the data suggests the earlier the better.

ATU: Why do you recommend triple combination therapy when studies seem to show that dual or single therapy can work?
MF: This is just a draft, and there are a few places where we’ve tried to be a little provocative to generate a reaction and get suggestions. The regimen recommendations are one of those places.

There aren’t any randomised controlled studies of PEP in humans and it’s difficult to imagine how you would design one, from an ethical point of view. Who would be the control group? You have to extrapolate from animal studies, retrospective studies and studies of the prevention of mother-to-child-transmission – which is, after all, HIV prophylaxis by means of drugs – to decide on the best regimen.

We have mainly stuck with the current DoH guidelines. We are flagging up the possibility of tenofovir monotherapy, as this has proved to be 100% effective in some animal studies.12 There are no published studies of tenofovir monotherapy in humans, and we know it’s well tolerated in the short term – the kidney toxicity associated with tenofovir comes from long-term exposure.

The Australian guidelines say there is a role for dual nukes, but we won’t say that. I have concerns, in particular with increasing rates of primary resistance, that AZT/3TC may not be effective, as with the one failure in the Brazil study.

ATU: Why do you recommend PEP for all kinds of sexual intercourse when the partner is known to be HIV+ but only for receptive anal intercourse where their status is unknown?
MF: My guess is some will say we’re being too conservative about this, others too aggressive. We regard receptive anal sex as ‘high risk’, remember, not just because it transmits quite efficiently but because it’s likely to be with a high-risk partner, i.e. a gay man. When the partner’s HIV status is unknown and they are of a low-prevalence population, e.g. a straight non-IDU European man, we might just say ‘consider’ and not ‘recommend’ PEP, even if the risk behaviour is receptive anal intercourse.

ATU: You place no limit on the number of repeat prescriptions. Why?
MF: Because we felt you had to treat each individual instance on its own merits. But if people are repeatedly presenting, then something clearly isn’t working for them, and we’d like them to go to a health adviser or psychologist to explore that.

That being said, it’s very important to note that repeat presentation is not common, and reported incidence of unprotected sex among people who’ve had PEP has usually gone down, not up.

ATU: Cost is clearly a concern. What if raising awareness of PEP proves to be too effective?
MF: Remember ‘cost-effective’ isn’t the same as ‘cost-saving’. Most medical interventions come at a net cost; it’s usually cheaper to do nothing.

All the experience so far – as with with the Australian campaign, for example – indicates that vast numbers of people are not going to come forward and demand PEP as their prevention method of choice. Introducing the “morning after” pill for women has not resulted in it becoming the only form of family planning for women, but it has provided a fallback strategy for some.

The point about increasing awareness is that at present it’s only those who know about PEP and know how to access it that can get it, and that’s not equitable.

My personal preference is that we need to notch up services a bit and find ways of providing PEP so people don’t miss out. It needs to be provided locally. There is a very clear role for the non-statutory sector here. I don’t mean getting your PEP pack from the THT, but I do mean that they could be acting as gatekeepers, filtering out inappropriate requests.

ATU: What about the idea of ‘starter packs’ for weekend incidents, as in the Brazilian study?
MF: It’s something some physicians have done informally before, for instance issuing them to a serodiscordant couple who live a long way from the clinic. The main problem there is one of drug storage: for example, you couldn’t keep your Kaletra on the bathroom shelf for months.

ATU: The ‘starter pack’ idea blurs the distinction between post-exposure prophylaxis and PRE-exposure. You could, after all, take your starter pack before you think you are likely to exposed to HIV. What do you think of pre-exposure prophylaxis, which is currently the subject of some high-profile studies?
MF: If it’s shown to work, then it too is another addition to the arsenal. It could have a particular role in developing countries where condom use simply isn’t possible for some women. Twenty years of HIV prevention has shown there is no magic bullet that will prevent HIV. We have to explore all the options.

References


1. Giele CM et al. STI 78:130-132, 2002
2. DoH, July 2000. see http://www.doh.gov.uk/eaga/pepgu20fin.pdf
3. 2003 Gay Men's Sex Survey, Sigma Research, unpublished
4. Tokars JI et al. Ann Intern Med 118(12):913-919, 1993
5. Schechter M et al. 9th CROI, Seattle, abs 15, 2002
6. Pinkerton SD et al. Arch Intern Med 164:46-54, 2004
7. Freedberg KA et al. NEJM 344:824-831, 2001
8. Holtgrave DR et al. Am J Pub Health 86:1442-1445, 1996
9. Holtgrave DR et al. AIDS & Behavior 1:173-180, 1997
10. HPA personal communication
11. Kalichman SC. Am J Prev Med. 15(2): 120-7, 1998
12. Tsai CC et al. Science 270: 1197-9, 1995