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PEP
Further research about PEP after rape and high risk sex
Harrison, Moreira, et all, February 2003

225 Post-Sexual-Exposure Chemoprophylaxis (PEP) for HIV: A Prospective Cohort Study of Behavioral Impact.
L. H. Harrison*, R. F. do Lago, R. I. Moreira, A. B. Mendelsohn, and M. Schechter. Univ. of Pittsburgh, PA and Univ. Federal do Rio de Janeiro, Brazil

Background:There are limited data on effectiveness and behavioral impact of PEP to prevent HIV infection. PEP could increase the risk of HIV infection if its availability resulted in increased high-risk behavior.

Methods:HIV-seronegative subjects from an HIV cohort among homosexual men with an annual HIV incidence of 3.1% were included. Participants were given a 4-day supply of ZDV + 3TC at enrollment and instructed to begin PEP immediately after sexual exposure of a mucous membrane to blood or semen and to report for evaluation within 96 hours. If the exposure was deemed to fulfill study criteria, a further 24-day supply was given. All participants were interviewed bi-annually concerning sexual exposures in the preceding 6 months.
Results:As of September 30, 2000, 202 subjects had been followed for a mean (maximum) of 16 (21) months, respectively (total 3,218 person-months of follow-up, and a 12-month follow-up rate of 96%). The mean age was 28 years.
At enrollment, the mean number of male partners in the previous 6 months was 9.7. The % of participants reporting any anal, oral or vaginal high-risk exposure at baseline and at 12 months were 56.2 and 45.4 (McNemar's test, p = 0.01), 40.5 and 34.6 (p = 0.17), 24.3 and 13.5 (p = 0.003), and 4.8 and 5.9 (p = 0.32), respectively. PEP was initiated 92 times by 65 participants; 83 (90.2%) of exposures were eligible. Although 74% reported at least one side effect, the full PEP course was completed 86% of the time. There were 8 HIV seroconversions, 7 of which were among non-PEP users. The annual seroincidence rates were 3.0% (95% CI: 1.3%, 5.9%), 3.9% (1.6%, 8.1%), and 1.1% (0.03%,6.4%) for the whole cohort, for those who never used PEP and for PEP users, respectively.

Conclusions:The reported behaviors on average improved in this cohort with access to PEP. Although there was a lower HIV seroincidence among PEP users, the limited statistical power of this preliminary analysis and the lack of a randomized controlled trial do not allow us to directly measure PEP efficacy. Future analyses will focus on whether break-through HIV infections are associated with antiretroviral-resistant HIV and on the effectiveness of PEP.

Post-exposure prophylaxis (PEP)

Some hospitals are now offering what is called post-exposure prophylaxis to people no more than 24 to 48 hours after a possible exposure to HIV. This may have the potential to block HIV infection completely if treatment lasts one month. Treatment does not need to continue indefinitely because the aim of treatment is to prevent HIV from entering cells in the body. Infection will either become established or will be aborted within that period.

Two key studies have provided evidence that PEP can prevent HIV infection: one study showed that antiretroviral therapy prevented SIV infection in macaques and a second study found AZT PEP within 24 hours of needlestick exposure reduced this risk of HIV infection among healthcare workers by 80%.

But whether antiretroviral therapy can reduce the risk of HIV transmission following sexual exposure has not yet been proven.
Available data have been collected from ongoing observational cohort studies. These data show that very few cases of HIV transmission have occurred after PEP. In areas of high HIV prevalence, PEP following sexual assault may be able to prevent new cases of HIV. Only one of 500 sexual assault victims in South Africa who were treated within 72 hours of the assault subsequently developed HIV infection (Wulfsohn 2003).

One possible case of transmission following PEP was reported at the 2000 British HIV Association meeting, and in 2002 a health care worker who received antiretroviral prophylaxis was found to be infected with a drug-resistant form of HIV (Beltrami 2002).

Despite the apparent success of PEP, it is difficult to assess the risk of infection associated with each exposure, especially in cases where the serostatus of the source is not known. A emerging trend from current research suggests the uptake of PEP is often quite low and that many people who do accept PEP fail to attend follow-up appointments. (pls remember that this is ONLY in studies among gay men taking PEP after high risk behaviour, studies with women raped, esp in high infection settings like SA show a very high rate of followup returns - 60% and higher depending on study- it is believed, the figure would be higher but many rape survivors are poor and cannot afford taxi fare or transport to the hospital/clinic- Charlene Smith)

Low completion rates may be due to the frequency of side-effects associated with PEP in several studies. For example, six of nine healthcare workers at St Bartholomew's Hospital, London, who commenced AZT/3TC/indinavir did not complete four weeks of indinavir therapy. There were no discontinuations among the five people who received saquinavir (Parkin). Other research is summarised below.

Access

Clinics will not automatically offer this form of treatment to everyone who believes they have been at risk of HIV infection. They may use a number of criteria to decide whether you have been at high risk of infection, such as:
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?

It is essential that this treatment begin no more than 24-48 hours after exposure for it to offer the maximum chances of success.
PEP with nevirapine?

Nevirapine has been proposed as a suitable drug for PEP because it causes less nausea and is less disruptive to everyday life than indinavir, the drug currently recommended in UK guidelines. However, a recent study found that the use of nevirapine for post-exposure prophylaxis may carry a risk of serious adverse effects unless the normal four-week regimen is shortened.

Between 1997-1999, the Camden and Islington Health Authority used d4T/3TC and nevirapine as the standard PEP regimen. Nine percent of those who received a nevirapine-containing regimen experienced serious adverse effects, including severe rash or liver toxicity. A nevirapine-containing regimen was no better tolerated than an indinavir-containing regimen overall, although fewer minor adverse events were seen in the nevirapine group (Benn).

Professor Brian Gazzard, commenting on the findings, suggested that nevirapine-containing PEP might be shortened, since rash tends to occur only after ten to fourteen days.
US authorities recently reported 22 cases of severe or life-threatening side-effects such as rash and liver failure among people taking nevirapine as post-exposure prophylaxis. Some experts have suggested the risk of severe toxicity means that that nevirapine should not be recommended for PEP (see Nevirapine - key research in Drugs used by people with HIV: A to Z of treatments for details).

Key research

Wulfsohn (2003) studied 858 people from the South African province of Gauteng Province who were sexually assaulted between 1999-2001. At presentation, HIV infection was already established in 14% in the first year and 22% in the final year. PEP within 72 hours was taken by 644 survivors, of whom 500 returned for HIV testing at 6 weeks, and 66% of pts returned for repeat HIV testing. Only one seroconversion was reported - in a intellectually disabled girl of 14 years who was thought to have been repeatedly exposed to HIV.

Harrison reported on a study which provided 202 gay men with a 4-day supply of AZT/3TC to take following possible exposure to HIV. The PEP kit was complemented by counselling and additional drug for 24 days. 65 men took PEP on 92 occasions, with 86% completing the PEP course. After 16 months, 8 seroconversions occurred among the group, but only one of those men had taken a course of PEP. Reduced risk-taking was reported among the cohort.

Silbermann conducted a retrospective study of PEP following rape. 111 people commenced PEP, 60% returned for at least one visit and only 18 completed one month of PEP. No seroconversions occurred.

Soussy reported a prospective French study of people who were raped between February 1999-June 2000. 103 people were judged to be candidates for PEP. 5 people refused and 98 were treated within an average of 7.5 hours of exposure. 64% returned at day and 50% returned at one month. 59% interrupted PEP early due to patient choice (37 cases) or HIV-negative perpetrator (17 cases). Of 32% who returned at 3 months, none had seroconverted.

Martin reported 401 individuals, mostly gay men, who took PEP following sexual or other non-occupational exposure. Following PEP, participants became less likely to engage in unsafe sexual behaviour, although 9 people returned for subsequent courses of PEP.

Benaise reported on 2550 women who had been raped were offered PEP within 48 hours of the assault in France. Only 100 women accepted PEP, of whom 25% failed to return for follow-up. Many discontinued therapy and no cases of transmission occurred.
Debab found no cases of HIV transmission among 248 people who received medical advice regarding PEP following exposure to blood or sexual fluids (63.6% occupational, 8% non-occupational and 28% sexual exposure). 68.4% of cases accepted PEP (63.6% within 24 hours, 23.2% within 24-48 hours, 11.6% within 48-72 hours and 5.6% after 72 hours). The source was known to be positive in 21.6% of cases. 76% took triple therapy, 21% dual therapy and 3% monotherapy with 38% completing 28 days of treatment. 27.6% stopped PEP when tests showed the source to be negative. 82% of recipients were fully compliant. Adverse events (AE) were common and 4 people stopped PEP due to AE. After 6 months follow-up for between one third to two thirds of recipients, no seroconversions have occurred.

Correll is conducting an ongoing prospective cohort study of people reporting non-occupational exposure to HIV. 58 exposures were during anal sex, 9 during heterosexual sex and 13 were non-occupational exposure (including 4 assaults with a syringe). In nearly half of the cases, the source was known to be positive. To date, 83 people have received PEP, 60 receiving triple therapy. 45/62 returned for 4 week testing reporting full adherence; none were positive. 75% reported generally mild side effects.

Myles reported on 376 sexual assault survivors assessed for PEP. 3% were positive at baseline. 213 were offered PEP and only 32.4% accepted. Of the third who accepted treatment, only 12% reported for follow-up at day 10. Those most likely to initiate PEP were white, tertiary education men with stable housing and people reporting anal penetration.

Friedman offered 202 men who reported unprotected vaginal, anal or oral receptive sex within the last 48 hours 4 days of PEP withAZT/3TC. 47 initiated prophylaxis.
Prevot found 21% of 95 people with occupational exposure to HIV took PEP as did 63% of 96 people with non-occupational exposure. No cases of HIV transmission occurred.
Katz collected data on 401 people who received PEP in San Francisco and found no instances of HIV transmission. Treatment was started an average 33 hours after exposure and 78% completed the prescribed one month of treatment with dual nucleoside therapy. However, this strategy has been questioned given that 10% of participants returned within six months following another exposure to HIV.

Puro reported findings from the Italian National Registry of PEP on toxicity. 216 received AZT/3TC (group A) and 380 received a triple drug regimen (92% receiving indinavir) (group B). 58% of group A and 66% of group B experienced at least one side effect and 21% in group A and 27% in group B discontinued PEP (18 of 106 in group B discontinued the protease inhibitor initially but subsequently abandoned dual NRTI therapy, while 44 abandoned the PI but completed the PEP course).

Benn reported that a man who received nevirapine-containing PEP after a potential sexual exposure tested HIV-negative after three months but HIV-positive after six months.
References

Beltrami EM et al. Transmission of drug-resistant HIV after an occupational exposure despite postexposure prophylaxis with a combination drug regimen.
Infection Control and Hospital Epidemiology 23(6):345-348, 2002.
Benais JP et al. Treatment of sexual assault. A multicentrique study in emergency medico-legal units in the Paris region. Thirteenth International AIDS Conference, Durban, abstract C314, 2000.
Benn P et al. Prophylaxis with a nevirapine-containing triple regimen after exposure to HIV-1. Lancet 357(9257): 687-8, 2001.
Cardo DM et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. New England Journal of Medicine 337:1485-1490, 1997.
Correll P et al. Non occupational HIV post exposure prophylaxis (PEP) in Australia. Thirteenth International AIDS Conference, Durban, abstract C4420, 2000.
Debab Y et al. HIV post-exposure prophylaxis: influence of the mode of exposure on the compliance and tolerance of the procedure. Thirteenth International AIDS Conference, Durban, abstract C1448, 2000.

Friedman RK et al. Acceptability of post-sexual exposure chemoprophylaxis for the prevention of HIV infection in Brazil. Thirteenth International AIDS Conference, Durban, abstract C315, 2000.
Harrison LH et al. Post-sexual exposure chemoprophylaxis (PEP) for HIV: a prospective cohort study of behavioural impact. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 225, 2001.
Kahn JO et al. Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco PEP Study. Journal of Infectious Diseases 183(5): 707-714, 2001.
Myles JE et al. Postexposure prophylaxis for HIV after sexual assault. Journal of the American Medical Association 284(12):1516-1518, 2000.
Parkin J et al. Tolerability and side-effects of post-exposure prophylaxis for HIV infection. Lancet 355(9205): 722-723, 2000.
Prevot MH. Comparative evaluation over a six months experience of postexposure antiretroviral treatment for occupational (OE) and non-occupational (NOE) exposures to HIV. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract I-156, 1998.
Puro V et al. Short term toxicity and discontinuation of antiretroviral post-exposure prophylaxis. J Biol Regul Homeost Agents 15(3): 238-42, 2002.
Sibermann B et al. Anti-HIV chemoprophylaxis in the context of accidental sexual exposure by rape. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 227, 2001.
Soussy A et al. Post-sexual exposure prophylaxis with HAART after sexual assaults. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 228, 2001.
Tsai CC et al. Prevention of SIV infection in macaques by (r)-9-(2-phosphonylmethoxyprophyl)adenine. Science 270:1197-1199, 2000.
Wulfsohn A et al. Post-exposure prophylaxis after sexual assault in South Africa. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 42, 2003.

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