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We conducted an observational cohort study of people prescribed NPEP in the Eastern states of Australia between 1998 and 2004.
In Australia, prescription of antiretroviral medication is limited to HIV specialist medical practitioners and to a relatively small number of other medical practitioners who are registered as antiretroviral prescribers. In 1998, all registered prescribers in NSW were included in the study. Prescribers in Queensland were included from 1999, and those in Victoria and the Australian Capital Territory from 2001 as NPEP became available in each jurisdiction.
Eligibility criteria for NPEP were based on the New South Wales guidelines until 2001  and the national guidelines from 2001 , as follows.
The participant reported unprotected anal or vaginal sexual intercourse, or condom-protected intercourse where the condom had broken or slipped off, or reported sharing injecting equipment, or other mucous membrane or trans-cutaneous exposure to HIV.
The source person was known to be HIV positive, or was a person who had a risk factor for HIV infection.
The participant presented within 72 h of the initial exposure.
Participants were eligible for this study whether or not they elected to take NPEP.
The national guidelines recommended two-antiretroviral-drug NPEP in most situations. Under the guidelines, three-drug NPEP was reserved for high-risk exposures to known HIV-positive sources when the source was known to have advanced HIV disease, or had an HIV viral load greater than 20 000 HIV-1 RNA copies/mL, or had known antiretroviral drug resistance to drugs from at least two classes .
The study was approved by the University of New South Wales Human Research Ethics Committee and by local area health authority ethics committees.
Prescribers completed data collection forms at the time of initial presentation, and at 4 weeks and 6 months later.
At the initial presentation, information collected included participant demographics, previous HIV test results, history of previous NPEP prescription and whether or not a baseline HIV test was performed. Details of the exposure included whether contact had been anal, vaginal, oral or other sexual exposure. Condom use was recorded, and whether or not breakage or slippage had occurred. Information was collected on percutaneous exposures including the reuse of injecting equipment and the depth of skin penetration. Information on the source, as reported by the patient, included gender, HIV serostatus and prior HIV infection risk behaviour. At 4 weeks after the exposure, another HIV antibody test was recommended, and adherence and side effects were assessed at the clinic visit. At 6 months after the exposure, results of all available HIV antibody tests since the exposure were collected.
To ascertain the proportion of all NPEP prescriptions that were included in the study, data from administrative records concerning drug cost reimbursement were obtained from 11 area health services in New South Wales between April 2001 and March 2002, and from all areas of Queensland between June 2000 and October 2002, and compared with numbers of NPEP prescriptions recorded through the study in the corresponding areas and time periods.
Original data were coded and entered into an Oracle8 database. Statistical analysis was performed using stata version 8.0 (Stata Corp., College Station, TX, USA). All P-values are two-tailed.
Four-week and 6-month follow-ups were defined as a visit at least 26 and 165 days after the initial consultation, respectively. The number of HIV infections expected in the study population was estimated by taking the sum over all participants of the product of the per-contact transmission probability, based on the reported type of exposure, multiplied by the probability that the source was HIV positive. The per-contact transmission probabilities were based on published estimates from prospective studies conducted in industrialized countries. Estimates from modelling or cross-sectional studies were not considered. These estimates were 0.82% [95% confidence interval (CI) 0.24–2.76%] for the receptive partner in unprotected anal intercourse (UAI) , 0.1% for both male and female partners in unprotected vaginal intercourse (95% CI 0.05–0.17%) , 0.0% (95% CI 0.0–0.04%) for receptive fellatio , 0.29% (95% CI 0.13–0.70%) for needle stick injury , and 0% (95% CI 0–0.28%) for mucosal exposure . As there are no published estimates of risk of insertive anal intercourse with a known HIV-positive partner, we assumed that the transmission probability was the same as for the insertive partner in vaginal intercourse.
The probability of the source being HIV positive was taken as 100% when the source was reported as positive by the participant. In all other cases, published estimates of HIV seroprevalence in appropriate populations were used. For male-to-male sex, the prevalence of HIV infection among gay men was based on self-reported HIV status as recorded in Australian community-based cross-sectional studies in 2003–2005 [17–20]. These estimates were 5.1% in Canberra, 6.4% in Brisbane, 9.1% in Melbourne and 14.2% in Sydney. Average seroprevalence weighted for state of residence was calculated. For heterosexual contacts, the estimated prevalence of HIV infection in 15–49-year-olds (0.2%)  was assumed. For injecting drug user sources, the prevalence of 1.1% measured among attendees at needle and syringe exchange programmes was used .
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In Australia, use of NPEP has become widespread, but remains highly targeted towards homosexual men, with little prescription outside this group. This usage reflects the epidemiology of HIV in Australia . The vast majority of prescriptions occurred after high-risk exposures which qualified for NPEP according to local guidelines . Side effects were common but were generally mild to moderate and none was irreversible. Although 10 people were newly diagnosed with HIV infection, seven were men found to be HIV positive at baseline. The other three seroconverted more than 4 weeks after their exposure, and ongoing risk behaviour after the completion of NPEP was reported in all these cases. It appears that no new HIV infections related to NPEP failure occurred. We estimate that 1–9 HIV infections were prevented by the provision of NPEP.
As nearly three-quarters of eligible study participants did not return for follow-up at 6 months after exposure, our data cannot be seen as definitive evidence of the efficacy of NPEP. However, there are three reasons suggesting that it is unlikely that we missed NPEP failures. First, all the 850 people who had an HIV test at 4 or more weeks after exposure were HIV negative at that time, and the sensitivity of the HIV serological test is such that the vast majority of NPEP failures would have been detected then. Secondly, those who returned for the 4-week follow-up tended to be at higher risk than those lost to follow-up (data not shown). Thirdly, homosexual men in Australia report frequent testing for HIV, and testing is most frequent in high-risk men , so it is likely that they would have re-presented for testing to their doctors, and been notified to the study, had they seroconverted.
This study represents one of the largest population-based studies of NPEP. Australia was among the first countries in the world to recommend the use of NPEP, and awareness of the availability of NPEP among homosexual men in 2004 ranged from 46 to 66% in cross-sectional studies in Eastern State capitals . In an ongoing observational community-based cohort study of HIV-negative homosexual men in Sydney, 2–7% of men used NPEP each year . Levels of use of NPEP among at-risk individuals in Australia, and the impact of NPEP on the epidemic, are probably as high as anywhere in the world. It was therefore disappointing that only 1–9 infections were potentially prevented. However, as only about half of those who received NPEP in the study region were enrolled, it might be that twice that number were actually prevented by NPEP. Also, if the exposures were of higher than average risk, as a result of the presence of transmission risk cofactors such as high viral load and sexually transmissible infections, or if a higher than average proportion of sources were HIV positive, then it is possible that we have underestimated the number of infections averted. However, to put the number of infections possibly averted in perspective, surveillance systems in the areas covered by this study reported 3768 new HIV diagnoses and 1138 newly acquired HIV infections during the study period .
There were at least three major contributions to the relatively limited population-level impact of NPEP in this population. First, the HIV status of the source was known in only 32% of participants, suggesting that a relatively large number of NPEP prescriptions were unnecessary. In other reports of use of NPEP, the reported proportion of sources who were known to be HIV positive was similarly low, ranging from 30 to 47% [1,2,25]. In a Swiss study, a policy of active contacting and HIV testing of source persons reduced exposure to unnecessary NPEP by 73% amongst those whose source person could be contacted and tested . However, in our study, 33% of the contacts were reported as anonymous and an additional 44% casual, so it is unlikely that active contact tracing could have had a large effect in reducing NPEP prescribing. Secondly, only 15% of exposures, but 68% of prevented infections, were related to the highest risk exposure, receptive UAI with a known HIV-positive partner. This raises the question of whether NPEP prescription after anal intercourse between homosexual men should be restricted to the receptive partner or to cases in which the partner is known to be HIV positive. In fact, in our data, there already appears to have been a degree of selection towards presentation after receptive intercourse. Of all UAI episodes that led to NPEP, nearly one in five (18%) episodes were after receptive UAI with a known HIV-positive partner. In contrast, in a community-based cohort study of HIV-negative homosexual men in Sydney, only 6% of all reported UAI episodes that could have led to HIV transmission were reported to be receptive with a known HIV-positive partner . Whether this selection towards prescription of NPEP after receptive intercourse with an HIV-positive partner occurred because men were more likely to present to their doctor after such an event, or whether doctors were more likely to reserve NPEP for such a situation, is unknown. Thirdly, because of the relatively low transmission probabilities for HIV, even for the highest risk exposures, the great majority of NPEP prescriptions will always be for people who would not have become HIV infected anyway.
In a setting where so few HIV infections were prevented, safety is of paramount importance. Although the majority of NPEP recipients (66%) reported side effects, only a small number of side effects were reported as severe. The occurrence of side effects was more common in those prescribed three or more drugs, suggesting that the safety of NPEP could be improved by reserving three-drug prescriptions for highest risk exposures. However, a triple-nucleoside regimen with much improved safety and tolerability has recently been described . The occurrence of severe side effects, in particular the cases of Stevens–Johnson syndrome associated with nevirapine and nephrolithiasis associated with indinavir, highlights the imperative to balance the risk of HIV infection against the potential toxicity of the individual antiretroviral agents. The frequent occurrence of subjective drug-related toxicities in this study confirms the need to restrict the prescription of NPEP to those only at high risk of HIV infection after exposure.
The relatively small population-level impact of NPEP that we have estimated should not be seen as an argument against NPEP availability. An NPEP programme is but one part of a comprehensive HIV infection prevention programme , and the provision of NPEP offers an opportunity for HIV infection prevention counselling to high-risk individuals. The lack of identified cases of HIV infection attributable to NPEP failure after NPEP use suggests that NPEP may be an effective preventive intervention against HIV infection at an individual level.
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The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health and Ageing. GlaxoSmithKline and the NSW Health Department provided additional financial support for this project.
The authors would like to acknowledge the work of research assistants Patty Correll, Belinda O'Sullivan and Wei Zheng. We would also like to thank the participants who consented to the collection of information.
We also wish to acknowledge the following medical practices, doctors and research nurses who enrolled participants for the study, and completed the data forms.
In New South Wales: 16 Oxford Street, Darlinghurst (Anthony Tedesco); 229 Oxford St, Darlinghurst (Marilyn McMurchie, Mark Kelly, Michael Kidd and Craig Rodgers); 407 Bourke Street, Darlinghurst (David Baker, William Genn, Janet Kidd, Robert Macfarlane, Hugh Macleod and Ankita Roy); 5 Bligh Street, Tamworth (Miriam Grotowski and Pam Rooney); 66 Oxford St, Darlinghurst (Ben Hanson); Albion Street Clinic, Surry Hills (Fraser Drummond, Brian Hughes, Harry Michelmore and Don Smith); Bigge Park Centre, Liverpool (Rodney Lovett, John Quin and Ruhand Steele); Burwood Road Practice, Burwood (Nicholas Doong); Coffs Harbour Sexual Health (David Ellis); Darlinghurst Medical Centre (Dennis Rhodes); Hawkesbury Sexual Health Services (Deborah Couldwell); Holden Street Sexual Health Centre, Gosford (Deborah Allen, Kym Collins and Cheryn Palmer); Holdsworth House General Practice (David Austin, Kate Bessey, Mark Bloch, Andrew Gowers and Dick Quan); John Hunter Hospital Byrne House (Michael Boyle); Kirketon Road Centre, Darlinghurst (Melanie Andromas, Marianne Jauncey, John Kearley, Tim Shortus and Hester Wilce); Livingstone Road Sexual Health, Marrickville (Damian Conway); Lismore SHAIDS (Steven Davies, Brian Mulhall and Gillian Smith); Nepean Sexual Health Clinic (Tong Liang); Paramatta Sexual Health (Katrina Lagios and John Moran); Port Kembla Sexual Health (Simon Marlton); Prince of Wales Hospital (Jeff Post); Quay Street Medical Centre (Ben Anderson); Royal North Shore Hospital, Clinic 16 (Derek Chan, David Crawford, Archie Darbar, Linda Dyan, Elizabeth Hamlyn, Ann Hofmeyer, George Kotsiou, Catriona Ooi, Claudia Whyte and Sebastian Van Hal); Royal Prince Alfred Hospital (Louise Evans); Sydney Sexual Health Centre (Chris Bourne, Ellen Chan, Marcus Chen, Damien Conway, Basil Donovan, Rene Francia, Janine Haran, Jo Lusk, Anna McNulty, Heidi Spillane, Julia Trayer, Catriona Ooi and Nathan Ryder); St George Hospital (Chris Carmody and Pam Konecy); Taylor Square Private Clinic, Darlinghurst (Neil Bodsworth, Rachel Burdon, John Byrne, John Ewan, Samuel Hay, Robert Finlayson, George Nisyrios, Cathy Pell, Ross Price, Matthew Routley, Matt Shields, Louise Tomlins, Emmanuel Vlahakis and John White); St Vincent's Hospital, Darlinghurst (David Cooper, Andrew Carr, Fraser Drummond and John McAllister).
In Queensland: 38 Gladstone Road (Leonie Todhunter); AIDS Medical Unit (Elizabeth Christensen, Ken Clare, John Patten and Hugo Ree); Blackall Terrace Clinic, Nambour (David Sowden); Brisbane Sexual Health Clinic (Gale Bearman, Natalie Edmiston, Bella George, Margaret Mobbs, David Orth, Diane Rowling and Tracy Schrader); Brunswick Street Medical Centre (Kate Evans, Graham Lister and Dominique Wells); The Doll's House Clinic, Cairns (David Bradford); Nambour Sexual Health (David Sowden); Gold Coast Sexual Health (John Chuah, Sally Jacobs and Maree O'Sullivan); Princess Alexandra Hospital Sexual Health Clinic (David Jardine and Jackie Mein); Townsville General Hospital (Robert Norton); Toowoomba Health Clinic (John Hooper).
In the Australian Capital Territory: Canberra Sexual Health (Frank Bowden, Sarah Martin, Vanita Parekh and Alexandra Tyson); Interchange General Practice (Janelle Hamilton, Tuck Meng Soo and Claire Willington).
In Victoria: Alfred Hospital (Kate Cherry, Ben Cowie, Suzanne Crowe, Anne Drake, Phillip du Cros, Lloyd Eisendal, Beng Eu, Andrew Fuller, Margaret Hellard, Ben Howden, Jenny Hoy, Stephen Kent, Chris Lemoh, Sharon Lewin, Lyn-Li Lim, Graeme Maclaren, Anne Mijch, John Mills, Richard Moore, Norman Roth, Joe Sasadeusz, Kasha Singh, Denis Spelman, John Spicer, Ivan Straton, Alan Street, Irani Therarajan, Olga Vukovic, Steven Wesselingh, Ian Woolley and Edwina Wright).