Based on the results of several studies [1–5], national guidelines for HIV post-exposure prophylaxis (PEP) were issued in France for occupational settings (1995) and for non-occupational exposure (1998) [6,7]. Guidelines on non-occupational exposure were followed by an increase in prescriptions; most events carried a low risk of exposure to HIV .
By 1998, five European countries (Austria, Germany, Luxembourg, Switzerland and France) had guidelines for PEP after sexual exposure. However, France was the only country to recommend PEP even when the HIV serostatus of the partner was unknown .
In 1998, US guidelines on non-occupational PEP neither recommended nor discouraged PEP. In 2005, updated guidelines recommended PEP only for individuals seeking care less than 72 h after exposure to blood or genital secretions of an individual known to be HIV infected [10,11].
The cost-effectiveness of PEP remains controversial [12–16]. Modelling studies concluded that PEP was only cost effective in specific circumstances [17–19]. An empirical study found that a PEP programme that targeted higher risk groups was cost effective . The aim of this study was to assess the cost effectiveness of the French PEP programme in which there appears to have been a shift towards prescribing for less risky exposures after guidelines were developed.
We conducted a cost-effectiveness analysis, from a societal perspective, based on a decision tree (TreeAge Data Pro software; TreeAge Software, Inc., Williamstown, Massachusetts, USA). We compared the PEP programme and a ‘no PEP’ alternative to estimate the number of infections averted and the number of quality adjusted life-years (QALY) saved and to evaluate the cost of PEP per QALY saved during 1999–2003. Future savings in averted HIV-related medical care costs and QALY benefits were discounted at a 3% annual rate and expressed in 2002 €. As parameters vary according to the exposure risks, a separate decision tree was built for each type of exposure event. The outcomes (costs and effectiveness) of each decision tree were multiplied by the numbers of individuals who were exposed to the given event and received PEP, and then summed up to obtain the total cost-effectiveness of the French programme.
Post-exposure prophylaxis programme
PEP treatment is free of charge and is initiated in hospitals. Guidelines recommend PEP initiation within 48 h after potential exposure. Patients are evaluated by a clinician and given PEP ‘if necessary’, based on the risk of exposure, including the mode of exposure and the knowledge or likelihood that the source was infected.
When treatment is initiated by an emergency clinician, PEP reference physician's validation is required within 48 h. Clinicians may prescribe the drugs of their choice, usually a tri-therapy containing a protease inhibitor. At the first visit, HIV and hepatitis B and C serology, pregnancy test in women, and other laboratory tests are performed. Three follow-up visits are scheduled at days 15, 30 and 90 after exposure. Laboratory tests are scheduled at day 15. HIV and hepatitis serology is repeated at 30 (end of treatment), 120 and 180 days . The PEP physician provides the patient with a 4-week supply of antiretroviral drugs and counselling at each visit.
A national hospital-based voluntary surveillance of the PEP programme for both occupational and non-occupational exposure was set up in 1999. Information on patients' characteristics, risk of exposure, treatments prescribed, serology and potential adverse effects were recorded by clinicians during follow-up visits, and entered in an anonymous database at the National Public Health Surveillance Institute (Institut de Veille Sanitaire).
Number of HIV infections averted
The number of HIV infections averted by the PEP programme was estimated by subtracting the estimated number that occurred among individuals receiving PEP from the estimated number of infections that would have occurred among those individuals had they not received PEP (i.e. in the absence of the programme). For a given exposure event, the risk of infection is A = απpE, where α is the per-contact HIV transmission risk; π is the probability that the partner (or the biological source) is infected; p is the probability that the patient will complete the 4-week PEP regimen (compliance) and E is the efficacy of PEP. These parameters are listed in Tables 1 and 2. In the case of sexual exposure, only one contact was taken into account. Per-contact HIV transmission risks were derived from the literature [18,21,22]. Two types of occupational exposure were considered. The per-contact HIV transmission risk after percutaneous exposure to blood (defined as deep injury) was based on an healthcare worker cohort (HCW) study . The per-contact HIV transmission risk for mucous membrane exposure (defined as other injury) was obtained from US guidelines for the management of occupational exposures to HIV . When the source is known to be HIV positive, parameter π is equal to 1. In other cases we used HIV prevalence obtained in national surveys for the relevant population subgroups. For men who have sex with men (MSM), a prevalence of 14% was estimated from two studies of self-reported HIV infection among readers of gay magazines in 1997 and 2000 . A prevalence rate of 16% was used for injecting drug users (IDU), as reported in 1999 by the French monitoring centre for drugs and drug addiction . We used a prevalence of 0.5% for heterosexual individuals, a value based on free and anonymous HIV counselling sessions in France in 2000 . As the efficacy of a three-drug PEP regimen is unknown, we used a value (80%) based on a case–control study of exposed HCW treated with zidovudine .
Compliance values were derived from the PEP database, specific rates were assumed for each type of exposure (Table 2). Overall, 42% of the patients were known to have attended the one-month follow-up visit at the end of the treatment and data on their compliance was available; 5% were known to be lost to follow-up (we assumed that their compliance was zero), and the remaining 53% had no follow-up information available in the PEP database. According to a panel of PEP clinicians, these missing data were more likely to result from non-reporting rather than non-compliance of patients. For each exposure group, two compliance values were estimated. In the base-case, we applied the same compliance for patients without follow-up information as that observed for patients with available information. Minimum compliance was estimated by assuming that all patients without follow-up information were non-compliant.
Post-exposure prophylaxis costs
PEP costs included the costs of drugs, four physician consultations and laboratory tests except costs of hepatitis serology, which were not considered in this analysis. Drug costs were estimated from the 8958 PEP treatment prescribed during 1999–2003. A total of 15 drugs were used in various two-drug (9%), three-drug (90%) and four-drug (1%) combinations. The price of each regimen was calculated using the public sale prices . The average price was €745 for a one-month treatment. Physicians costs were calculated from the sum per visit reimbursed in the pubic sector, i.e. €20 per visit (€80 for four visits). The average costs of laboratory studies during the recommended 6-month follow-up period for a patient on PEP were calculated according to the French price scale , giving an average amount of €163. In total, the cost of PEP was €988 per patient. Partial PEP was estimated to cost half as much as complete PEP, and was considered to be ineffective. We did not take into account the economic costs of adverse drug effects or their consequences.
We assumed that an uninfected individual would live in full health until the age of 65 years. The mean age of individuals requesting PEP was 31 years in this study. Therefore, an uninfected individual would be expected to live 34 years in full health, or to have a quality adjusted life expectancy (QALE) of 34 years, corresponding to a discounted QALE of 21.13 years.
To estimate life expectancy after primary HIV infection, we used a model described by Longini et al. , which we adapted to account for the effects of HAART on delaying disease progression (Table 3). The model includes seven irreversible stages of HIV infection based on declining CD4 cell counts. To each stage corresponds a monthly progression rate (i.e. hazard) λk. To account for HAART effects, we used the relative hazards of progression to AIDS and death for individuals on HAART, by disease stage, as estimated by Egger et al. and multiplied stage-specific progression rates by these relative hazards for patients with CD4 cell counts below 500 cells/μl. In France in 1999, HAART was recommended for patients with CD4 cell counts lower than 350 cells/μl, and was considered for those with counts between 350 and 500 cells/μl . We obtained a mean life expectancy of 22.57 years after HIV primary infection.
Perceived health-related quality of life of HIV-infected individuals by disease stage was obtained from Holtgrave and Pinkerton . The QALE of an infected individual is obtained by the formula
where yi represents the number of years spent in a given stage i and qi is the quality of life in that stage. This adds up to a QALE of 17.11 years, which corresponds to a discounted QALE of 12.79 years. The number of QALY saved by preventing an HIV infection after an at-risk event would therefore be 21.13 minus 12.79, or 8.34.
Lifetime costs of care of an HIV-infected patient with antiretroviral therapy
The only published French study of the lifetime costs of treatment of an HIV-infected patient involved a cohort of 1232 patients , and monthly costs were calculated for the following disease stages: HIV infection without AIDS according to the CD4 cell count; AIDS-defining events; and the month before death (Table 4). These costs expressed in 1998 € were inflation adjusted and were converted to 2002 € . Monthly costs were multiplied by the number of months spent in each disease stage, which were then summed to obtain the total cost of treating an HIV-infected individual in France. This total cost was €373 325, or €252 768 after discounting.
The cost-effectiveness ratio was calculated as (C − AT)/AQ, where C is the cost of the PEP programme, A is the total number of infections averted, T is the HIV-related medical costs saved per case of HIV infection averted and Q is the number of QALY saved per case of HIV infection averted .
Threshold and sensitivity analysis
For the overall PEP programme, one-way sensitivity analyses were performed on compliance according to the low estimation of the compliance (Table 2) and on life-expectancy of HIV-infected individuals according to the higher value of life expectancy and the higher lifetime HIV cost resulting from longer survival (Table 1). These values were obtained using the estimated higher boundary of the confidence interval of disease progression to AIDS and death for individuals under HAART .
A threshold analysis was also performed for some exposures, minimum values of prevalence, per-contact HIV transmission or compliance required to achieve the cost-saving threshold (€0 per QALY saved) or the cost-effective threshold (€50 000 per QALY saved) were estimated.
From July 1999 to December 2003, among 12 551 individuals who sought PEP, treatment was prescribed for 8958 (71%). Of those, 6812 (76%) had a sexual exposure event, 2092 (23.4%) an occupational exposure event (68.9% of these individuals were HCW); and 54 (0.6%) were exposed through sharing drug injection equipment. In the sexual exposure group, 2546 individuals (28.4%) were MSM and 4266 (47.6%) were heterosexual. The source was known to be HIV infected for 2413 individuals (27%). Compliance was higher when the source was known to be HIV infected (89%) than when it was unknown (86%). A total of 1597 (17.8%) underwent the 6-month HIV serology test after exposure. Five individuals became HIV infected during follow-up. Two were considered as PEP failures through receptive anal intercourse (RAI) in a gay man and a woman, respectively, 171 and 102 days after PEP initiation. For the three remaining patients (all MSM), the physicians considered that the seroconversions resulted from high-risk sexual behaviour after the PEP treatment.
On the basis of our model, we estimated that among the 8958 treated individuals, 12 cases of HIV infections would have occurred if none had received PEP, and 4.3 cases would have occurred if all had received PEP.
The cost of the PEP programme, i.e. the cost of providing PEP to 8958 individuals, was estimated at €7 670 002, and the cost-effectiveness ratio at €996 104 per infection averted. Taking the cost of HIV/AIDS management into account, the total cost of the programme including the cost of caring for the estimated 4.3 cases of HIV infections that occurred among the 8958 treated individuals, was €3 035 075. By comparison, the cost of caring for the estimated 12 cases of HIV infections that would have occurred without the PEP programme was €8 752 150. The estimated marginal cost was thus €5 717 075 and the cost-effectiveness ratio was €88 692 per QALY saved (Table 5). Therefore, according to international standards that use US$50 000 per QALY saved as a threshold, the French PEP programme appears not be a cost-effective intervention.
There were, however, major differences in the cost-effectiveness ratio according to the type of exposure. PEP after receptive anal intercourse with an HIV-infected individual was cost saving in men and in women, with a negative ratio of €22 141 and €22 031 per QALY saved, respectively. PEP prescribed for an IDU having shared needles with an HIV-infected individual is also a cost-saving intervention, with a negative ratio of €1141 per QALY saved. These three exposures accounted for 4.4% of the prescriptions. PEP was cost effective (< €50 000 per QALY saved) for HCW after percutanaeous exposure to material from an HIV-infected patient and for MSM having had RAI with a partner of unknown HIV status. These two exposures accounted for 11.3% of the prescriptions. Altogether, these five exposures accounted only for 15.7% of the prescriptions. In most instances, PEP was not considered cost effective: 72% of prescriptions concerned exposures with a cost-effectiveness ratio higher than €200 000 per QALY saved and the ratio exceeded €2 million per QALY saved in 52% of cases.
Sensitivity analysis was performed for the overall programme using the estimated minimum compliance (Table 2) while keeping the other parameters fixed at their base-case values. In this case, the programme would prevent 3.8 infections and save 31.7 QALY at a marginal cost of €5 087 344, resulting in a cost-effectiveness ratio of €160 382 per QALY saved. As in the base-case, PEP prescribed for RAI with an HIV-infected individual would remain cost saving (−€17 788 and −€18 860 per QALY saved for MSM and heterosexual women, respectively). In contrast, providing PEP to an IDU having shared needles with an HIV-infected individual would still be cost effective (€18 445 per QALY saved) but no longer cost saving.
The overall cost-effectiveness ratio of the programme was also estimated using both higher values of the QALY estimates (16.82 QALY) and the lifetime cost of an HIV-infected individual (€331 869). According to this scenario, the overall programme would prevent 33.3 QALY at a marginal cost of €5 105 998, resulting in a cost-effectiveness ratio of €153 241 per QALY saved. The programme would thus be less cost effective than in the base-case analysis. Nevertheless, the three exposure risks with a negative ratio in the base-case analysis would remain under this scenario cost saving with higher cost ratios (€61 179, €60 966 and €20 552 per QALY saved for MSM in the case of RAI with an HIV-infected individual, heterosexual women having had RAI with an HIV-infected partner, and IDU having shared needles with an HIV-infected individual, respectively).
Threshold analyses were performed for exposures with cost-effectiveness ratios under €200 000 per QALY saved. PEP for MSM after RAI with a partner of unknown HIV status would be cost saving for a per-contact HIV transmission risk at least equal to 0.0411 or an HIV prevalence of at least 0.208. After needle sharing with an individual of unknown serostatus, to achieve cost effectiveness (€50 000 per QALY saved) the compliance should be equal at least to 0.92 with both highest values of the prevalence (0.21) and of the per-contact transmission risk (0.0092). For vaginal RUI with an HIV-infected partner, a per-contact HIV transmission risk equal to 0.0208 would allow the cost-effectiveness ratio to be reached.
The majority (72%) of PEP courses in the French programme have a cost-effectiveness ratio higher than €200 000 per QALY, whereas only 15.7% can be considered cost effective. With an overall cost-effectiveness ratio equal to €88 692 per QALY saved, the PEP programme is less cost effective than other French prevention or screening programmes such as the prophylaxis of HIV-related opportunistic infections (cost-effectiveness ratio €18 700 per QALY saved), breast cancer screening (€20 852 per year of life saved) or varicella vaccination of 15 year olds (€55 100 per year of life saved) [37–39]. This programme also appears to be less cost effective than the San Francisco PEP programme [US$14 449 (€13 632) per QALY saved] . The main difference between these two programmes is their target populations. In San Francisco, most PEP recipients (81%) are MSM, whereas in France, most are exposed through heterosexual intercourse. Nonetheless, the cost-effectiveness ratios for each exposure category and population subgroup are consistent in the two countries. PEP after RAI with an HIV-infected partner among men is cost saving in both programmes.
Overall, the cost-effectiveness ratio of PEP after unprotected heterosexual intercourse exceeded €200 000 per QALY saved, because of the low prevalence (0.5%) in heterosexuals and the high proportion (79%) of PEP prescriptions after exposure to partners of an unknown HIV status. French guidelines recommend that clinicians take into account the patient's perception of risk. A study of physicians' experiences showed that PEP prescriptions were based more on the patient's request and a safety-first attitude rather than on proper risk assessment, especially as clinicians had limited time to evaluate the source, given the need to initiate treatment within 48 h. Also, it is noteworthy that the proportion of PEP prescriptions after exposure to a known HIV-infected source fell from 78% in 1997 to 41% in 1999 . The efficiency of the PEP programme could thus be improved if the source's serostatus could be ascertained. This knowledge could also guide the choice of PEP drugs when the source is already treated, and avoid treatment and toxicity when the source is found to be HIV seronegative [40,41]. A similar situation applied for occupational exposure, as the status of the source was unknown for 65% of PEP prescriptions. Whereas it should be relatively simple to determine the source's HIV status in the hospital setting, it may be rather difficult in other occupational settings. The serostatus of the source was known for 51% of prescriptions to HCW but for only 10% of other individuals consulting after occupational exposure. It is noteworthy that PEP compliance was better in the occupational exposure group than in the other groups, suggesting that PEP given in a professional context is better accepted or at least better followed.
Providing PEP for an IDU having shared needles with an HIV-infected individual appears to be a cost-saving intervention. A US study has shown that syringe exchange programmes can be cost effective . IDU accounted for only a small proportion of PEP prescriptions in our study (0.6%). The harm reduction policy implemented in France since the late 1980s led to a substantial fall in the incidence of HIV infection among IDU . A study among 166 IDU involved in prevention programmes has showed that only 39% were aware of the PEP programme .
This study has several limitations. We had to make several initial assumptions. To overcome this limitation, we conducted sensitivity analyses. Compliance could only be estimated for 47% of PEP prescriptions, as a result of missing data. Overall, compliance was estimated to be 0.75, in keeping with values obtained in French hospital-based studies [45,46]. Any overestimation of compliance would tend to improve the cost-effectiveness ratio, as shown in the sensitivity analysis using a low estimation of compliance. Also, because no data were available on the lifetime cost of HIV/AIDS patient management in France, we had to estimate this parameter. The discounted cost of €252 768 is consistent with the US$223 072 (€209 688) estimated in a recent cost-effectiveness analysis of PEP . Our model did not include the possibility that some patients seeking PEP after sexual exposure may continue at-risk behaviour. However, risk reduction counselling given before PEP prescription may play a part in the patients' education and thus influence their behaviour. Furthermore, it has been reported that PEP prescription does not lead to increased at-risk behaviour .
Likewise, we did not consider PEP adverse effects. However, 65% of 2138 treated patients in the French PEP programme had clinical adverse events, and 8% presented with biological abnormalities [48,49]. Several publications have underlined the problem of antiretroviral toxicity, including its economic consequences [50,51]. Taking adverse effects into account would further reduce the cost-effectiveness ratio of the overall PEP programme.
As controlled trials of PEP are ethically unacceptable, modelling approaches are necessary to evaluate the cost effectiveness of PEP programmes. The number of HIV infections predicted by our model (4.3 infections) is higher than that observed and considered to be PEP failures (two infections). However, as HIV serology 6 months after PEP initiation was only available for 18% of patients, the true number of PEP failures may be higher.
For the efficient use of public health resources, PEP use in France should target high-risk exposure events. To achieve this goal, national guidelines should provide more precise treatment indications, taking into account the type of exposure and the serostatus of the source. This would relieve the pressure from clinicians to prescribe PEP to individuals with a very low risk of HIV infection. However, to avoid any apparent contradiction with current HIV/AIDS prevention messages, PEP guidelines must be revised by consensus with the health authorities, physicians and patients' organizations involved in HIV prevention.
The authors acknowledge all the clinicians participating in the French PEP surveillance and Ms Betty Basselier for technical assistance. They are indebted to Dr Yazdan Yazdanpanah for his helpful comments on the manuscript.
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