Lunding, Suzanne MD, PHD*; Katzenstein, Terese L. MD, DM.Sc.†; Kronborg, Gitte MD, DM.Sc.‡; Lindberg, Jens Å. MD§; Jensen, Janne MD¶; Nielsen, Henrik I. MD, DM.Sc.∥; Pedersen, Court MD, DM.Sc.**; Jørgensen, Louise B. MSc, PHD††
The risk of HIV transmission after a single sexual act with exposure to HIV is relatively small but serious. The risk after insertive vaginal intercourse is 0.05% to 0.15%, whereas the risk after receptive anal intercourse is 0.8% to 3.2%.1
Clinical randomized studies to document the effect of postexposure prophylaxis (PEP) after HIV exposures are not feasible. However, a case–control study among health care workers indicated a significant effect of PEP on the risk of HIV transmission.2 Animal studies have indicated that PEP initiated up to 72 hours after sexual exposure to HIV reduce the risk of HIV infection considerably but with the preventive effect declining with increasing time to initiation.3,4 This is in line with the finding from analyses from prevention of mother-to-child experiences, were efficacy has been shown also in cases were only the infant part of the regimen has been given. Furthermore, it was shown that the preventive effect was related to the timing of treatment initiation.5 Guidelines recommending PEP in case of sexual or occupational exposure to HIV in Denmark was introduced in 1998. There has been concerns that PEP might be used as a kind of morning-after pill leading to more unsafe sex and that it would be difficult to control the increase in the number of PEP requests or to ensure prescriptions based on reasonable indications. PEP is associated with frequent adverse effects,6–10 the efficacy is not documented and it only seems to be cost-effective in certain situations.11–13 If the HIV-status of the source is unknown PEP is only cost-effective in case of receptive anal intercourse.11–13 It is therefore important to restrict the use to persons with a reasonable risk of acquiring HIV infection. Some countries have experienced a considerable increase in the number of PEP requests over the years9,14 and in some countries with widespread availability, a significant part of PEP is prescribed to low risk sexual acts in which the HIV-status of the source is unknown.7,9,13
As opposed to many countries, PEP in Denmark can only be prescribed by physicians from 1 of the 8 Infectious Disease clinics treating HIV-patients. The indications for PEP is frequently discussed both within and between the clinics to ensure a uniform practice.
To ensure knowledge of the epidemiology and results of PEP use in Denmark, we initiated the Danish PEP registry with participation of all clinics prescribing PEP. Based on the nationwide data from this registry, this manuscript describes the incidence of the indications for, and the compliance with PEP use after sexual exposure to HIV in Denmark from the introduction in 1998 up till 2006.
MATERIALS AND METHODS
Denmark has a population of 5.3 million people. The estimated overall prevalence of HIV is 0.1% and 5% among men who have sex with men (MSM). It is estimated that a total of 5000 persons are HIV-infected in Denmark of which approximately 39% are MSM, 45% heterosexuals, and 9% intravenous drug abusers.15
In 1998 the Danish National Board of Health issued national guidelines that recommended PEP following occupational blood exposure to HIV. Data on PEP in these cases will be described elsewhere. Likewise, in 1998 the Danish Infectious Diseases Society recommended PEP after sexual exposure to HIV. PEP after sexual exposure is recommended if the overall risk of HIV transmission is comparable with that of a needlestick exposure i.e., 0.3%16 and the patient is seen within 24 hours of sexual exposure to HIV, though initiation with later presentation can be relevant and is evaluated in each case. PEP after vaginal intercourse is generally only indicated if the source is known to be HIV infected. In case of receptive anal intercourse the risk is potentially so high that PEP should be considered even if the HIV-status of the source is unknown. Factors like local HIV-prevalence, coexisting sexually transmitted infections etc. should be included in the risk assessment. The decision to prescribe PEP should, however, always be based on an individual risk assessment. In Denmark, the guidelines do not specifically address other nonoccupational exposures such as HIV-exposure due to rape, sharing of needles in intravenous drug abusers or community acquired needlestick injuries. PEP is, however, eligible and prescribed in these cases as well after individual risk assessment, based on the existing guidelines for PEP.
PEP and antiretroviral medicine for HIV in general can only be prescribed by doctors in 1 of 8 clinics treating HIV-patients. All patients requesting PEP are referred to these centers. This is feasible within a short time since Denmark is a geographically a small country. In a few places where transport by car to a HIV-treatment clinic will take more than 1 hour, starter packets are available at the local hospital, and PEP can be initiated after consulting with an Infectious Disease specialist at one of the treating centers. PEP is given free of charge.
The recommended PEP regimen in Denmark has always been 3 drugs, (2 NRTI's and 1 PI or boosted PI) for 4 weeks. The regimens have changed over time and the treatment can be individualized in case of i.e., knowledge of resistance in the source or adverse effects.
Data Collection and Analysis
The Danish PEP registry collect data from all cases of PEP after blood or sexual exposure to HIV. All clinics in Denmark prescribing PEP participated. The registry has collected data for PEP after sexual HIV-exposure from 1998 and onward.
Data were collected by use of a structured questionnaire. Until 2003 all data were collected retrospectively based on data from the medical records. Since 2003 the majority of data have been collected prospectively using the questionnaire.
In some cases exact information about time from the exposure to initiation of PEP was not given but could be estimated to be within 12, 18, 24, 36, 48, or 72 hours, respectively. Unless otherwise indicated, cases with unavailable data were included in frequency analyses. Source patients were considered belonging to a high risk group if they were men having sex with men (MSM), were intravenous drug users, originated from a high endemic area or if there was information that the source in other ways had a significant documented increased risk of being HIV-infected.
Data were analyzed using the SPSS 11.5 for windows. Comparisons between groups were analyzed using χ2 test for categorical variables.
Exposure and Time to Initiation
A total of 374 patients received PEP, 78% men (293/374) and 22% women (81/374). The median age was 30.5 years (range 14–73). The HIV-status of the source was unknown in 153 (41%) of the cases of whom 90% belonged to a high risk group. Further characteristics of the patients and exposures are illustrated in Tables 1 and 2.
HIV-test of sources with unknown status was performed in only 17 of 153 cases (11%). None were found HIV-positive. A total of 133 (87%) were not tested while data were missing in 3 cases (2%). The reasons for not testing were that the source was anonymous 66% (88/133), could not be contacted 5% (7/133), refused testing 6% (8/133), not attempted to test 3% (4/133), other reasons 2% (3/133), or missing data 17% (23/133). In 32 cases (9%), the patient had been raped. The HIV-status the assailant was unknown in 31 of 32 cases, while 1 assailant was known to be HIV-positive.
There was no significant difference in the proportion of PEP given to patients exposed to a source of unknown HIV-status or the proportion of patients who had had unprotected sex between each year of observation (χ2 test).
A total of 322 of 340 (95%) for whom the time from exposure to PEP was reported or could be estimated received PEP within 24 hours after the exposure. For cases where the exact time to initiation was indicated (n = 225), median time to initiation of PEP was 11.0 hours (range 0.5–60.0).
The number of PEP prescriptions increased over time, from 5 cases in 1998 to 87 cases in 2006 (Fig. 1). The relative proportion of PEP given to MSM is indicated. PEP was prescribed more than once to 23 patients (6%), 12 MSM and 10 heterosexuals (data on the sex of the source was not available in 1 case). Of the 23, 18 received PEP twice, 3 received PEP 3 times, and 2 received PEP 4 and 5 times, respectively.
Nine of 87 patients (10%) who received PEP in 2006, 6 MSM and 3 heterosexuals had received PEP previously. However, only 2 (2%) of these patients had had PEP more than once during that year.
PEP Regimen and Compliance
The initial PEP-regimens prescribed were zidovudine + lamivudine + lopinavir/ritonavir (52%), zidovudine + lamivudine + indinavir (35%), zidovudine + lamivudine + efavirenz (3%), zidovudine + lamivudine + nelfinavir (2%) or other regimens (7%).
PEP was completed by 65% (244/374), interrupted by 9% (35/374) while data on completion was missing in 25% of the cases (95). Of the 279 persons for whom compliance data were available, 87% completed PEP as planned. In 19 cases (7%) the regimen was changed during the 28 days treatment period among these were 3 cases of dose reductions.
The reasons for stopping PEP were a negative HIV-test of the source 29% (10/35), adverse effects in 40% (14/35), or other reasons 23% (8/35).
PEP was completed by 41% (13/32) of rape victims, interrupted by 13% (4/32) while data were missing for 47% (15/32).
Adverse Effects and Follow-Up
Adverse effects were experienced by 58% (218/374), whereas 17% (65/374) had no adverse effects and data were missing for 24% (91/374). Among 218 patients with adverse effects the majority had gastrointestinal complaints 85% (186/218), fatigue 34% (75/218), or headache 8% (18/218).
Only 51% (191/374) and 20% (75/374) complied with HIV-testing after 3 and 6 months respectively. Among rape victims only 34% (11/32) and 13% (4/32) were tested for HIV after 3 and 6 months, respectively. It is, however, possible that some of the patients have been tested elsewhere more convenient to them.
There was 1 case of seroconversion at 3-months follow-up. However, careful investigation revealed that this could not be attributed to PEP failure, but was probably due to repeated exposures during and after completion of PEP.
We found a steady but modest increase in the use of PEP over time to a maximum of 87 cases in 2006. From 2005 to 2006 there was a marked increase in PEP use especially among MSM. However, PEP was also used by a significant proportion of heterosexuals reflecting the distribution of sexual orientation in general among HIV-positives.15
In general PEP was given according to recommended guidelines. Among the 41% that were exposed to a source of unknown HIV-status, the majority had had high risk exposures typically receptive anal intercourse with a source belonging to a high risk group. The proportion of sources with unknown HIV status in countries where PEP can be prescribed by a wider range of physicians, was 73% in France,13 75% in Amsterdam,7 68% in Australia,6 and 57% in San Francisco.10
Our study demonstrate a PEP prescription practice that seems rational and targeted toward high risk exposures. However, an increased effort to test sources with unknown HIV-status would probably avert a significant number of PEP cases.17
Animal studies have shown that the time to initiation of PEP as well as duration of PEP is crucial for the preventive effect.3,4 Despite the fact that PEP is accessible only in few centers, the time to initiation of PEP was low as compared with other studies.6,7,10 One explanation can be a high degree of knowledge of PEP among Danish patients, especially MSM and discordant couples and health care workers as well as short distances to treatment centers. A Danish survey in 2006 among 3141 MSM found that 33% had practiced unsafe sex at least once within a year.18 Hence, the majority of MSM with potential HIV-exposure do not seek PEP. In a survey in 2000 75% of MSM were aware of the possibility of getting PEP after unsafe sex.19 This is higher than in many studies.20,21 A lack of knowledge about the possibility to get PEP does therefore not seem to be the cause. Accessibility to PEP does not seem to be a limitation either, since the time to initiation of PEP was relatively short. It is possible, that the majority of persons practising unsafe sex take a calculated risk, while the persons that requests PEP either as an exception had had unsafe sex or a condom tear or have obtained knowledge or suspicion that the source is HIV-positive. The frequency of repeated PEP courses were comparable with a recent study from Amsterdam7 but low compared with studies from Australia6 (14% in 5½ year) and San Francisco22 (17% in a year).
The rate of completion of PEP among participants was comparable with what has been found in other studies.6,13 It is worrisome, however, that a substantial proportion of the patients failed to complete the PEP treatment. Studies investigating the reasons behind and modes to improve this are needed. The proportion of rape cases that completed PEP was low as seen by others23,24 and in accordance with previous Danish data.25
It is noteworthy, that while our findings are relevant to the situation in most western countries, they are not directly applicable to the situation in high prevalence countries. Many western countries are characterized by a low background HIV prevalence, a population that is well educated, easy access to health care and access to PEP after HIV exposure through consensual sex as well as following rape.26,27 Given the low background prevalence of HIV it is very important to ensure a careful and rational risk assessment to avoid a high degree of unnecessary treatment.
In contrast, in a high HIV prevalence like South Africa PEP is, apart from occupational exposure, almost exclusively offered to rape victims.28,29 These patients are very vulnerable in many ways, often minors, and are often likely to present late. The risk of HIV transmission even in the absence of knowledge of the assailants HIV-status is so high that PEP is justified in any case. Giving PEP in these conditions is far more challenging but studies have shown that with the right approach it is possible to obtain a reasonable rate of compliance and time to initiation.29
There are some limitations in our study that need to be considered. The retrospective nature of a large part of the data as well as a high percentage of missing data are important to consider when interpreting the results. Efforts should be made to improve compliance with follow-up and to collect data on follow-up when this is done in other settings. We unfortunately do not have data on the total number of requests for PEP or the reasons to decline PEP.
In conclusion this nationwide study showed a steady but moderate increase in the use of PEP following sexual HIV-exposure from 1998 to 2006. Time to initiation of PEP was low and the PEP prescription practice was targeted toward high risk exposures.
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