Epidemiology and cost of herpes zoster and postherpetic neuralgia among patients treated in primary care centres in the valencian community of Spain

Herpes zoster (HZ) is caused by the reactivation of a latent infection with varicella zoster virus (VZV) after primary chickenpox. HZ is characterized by a localized eruption of vesicular lesions following the trajectory of a sensory nerve, and by the presence of pain and inflammation of the affected nerve root [1].

The most frequent and debilitating complication of HZ is postherpetic neuralgia (PHN), defined as neuropathic pain that appears in the dermatomes affected by the VZV infection. Pain associated with PHN can be very severe and disabling and has a significant impact on a patient's quality of life [2].

Studies carried out in a number of countries have shown that the incidence and severity of both HZ and PHN increase significantly with age. The annual incidence of HZ reported in population-based studies from several countries ranged from 1.2 to 4.8 cases per 1,000 inhabitants/year. The lifetime risk of HZ can be as high as 30% and increases markedly with age, affecting 50% of people living to 85 years of age [3–11]. PHN affects 10-70% of patients with HZ. This wide range is partly due to differences in the definition of PHN used in different studies and to the age range of the study populations from which these estimates were obtained. Thus, in older patients, the prevalence of PHN among patients with HZ is likely to be closer to the upper boundary of that range [12].

In a previous study we reported an annual incidence of HZ of 4.1 per 1,000 persons > 14 years of age (95% confidence interval (CI) = 3.4-4.7) and described the clinical and epidemiological characteristics of HZ in Spain [13]. Our results were consistent with previous findings by other authors in Spain [14, 15], and in other European [16–25] and non-European [8, 10, 11, 26–28] published studies.

Data on the epidemiology of HZ and PHN in Spain, and on the associated costs are scarce; therefore, studies are needed to evaluate the epidemiological and economic impact of HZ and its most common complication, PHN. The present study aimed to estimate the clinical and economic burden of HZ and PHN in the primary health care system in Spain.

No previous study has provided current HZ epidemiological data and a detailed estimate of the associated costs in Spain. It is important to highlight that our study was prospectively designed and patients' symptoms were monitored periodically by phone until PHN resolution. As mentioned above, no medical visits were planned for study purposes in order to allow for a more accurate estimate of healthcare resource consumption associated with HZ management. Moreover, this is the first study in Spain that provides information about the cost of HZ and PHN on an outpatient basis. Others have reported the cost of HZ in patients admitted to hospital [38].

In our study the 1-year incidence of HZ was 4.1 per 1000 persons (95% CI = 3.4-4.7) in those aged > 14 years. The incidence of PHN was 47.6% at 1 month. This percentage was higher than the figures reported in retrospective studies in Europe (14.3% [all ages of subjects] [39] to 19.5% [≥ 50 years of age] [24]) but similar to that in a prospective study (51.2%) recently published in a Mediterranean country [40]. In the USA, a groundbreaking study by Yawn [27] reported that the incidence of HZ in subjects > 22 years in the US was 3.6 per 1000 person-years (95% CI = 3.4-3.7). The incidence of PHN in the same population was 82% when defined as pain of at least 1 month duration. In the case of 3-month PHN (PHN3), our results (14.5%) were similar to those reported in other observational studies in Europe [23, 24, 40], and also to those reported in the USA [4, 27].

Although differences were observed with regard to PHN1 between our study and that of Yawn [27], the incidence of HZ and PHN at 3 months was similar though determined in slightly different populations (> 22 vs. > 14 years). We do not have a reason for the 1-month difference as both study populations showed a similar distribution of age and gender, both of which have an effect on the incidence of PHN. Nevertheless, the different study designs might have an impact in this regard. The study by Yawn [27] was retrospective and the present investigation was prospective to better estimate the occurrence of PHN.

The main risk factor for developing PHN among immunocompetent subjects in our study was age. An increase in 1 year of age yielded a 4.2% increase in the risk of PHN at 1 and 3 months. This finding has been previously observed by other authors [23, 24].

There is controversy as to whether gender can be considered an actual risk factor for PHN as some studies found an association [24, 39] while others did not [23]. Differences between genders, regarding perception and response to pain, may explain the disparities [41], or a higher GP attendance by women may play a part.

In our study the overall percentage of patients treated with antivirals was high, namely 91%, when compared with the proportion of patients (58.8%) in whom treatment was initiated within 72 hours of the onset of rash (following the current treatment recommendations). However, this proportion was not substantially different to that observed in other previously published studies, such as the Oxman study [4]. In that study, the percentage of patients treated with antiviral drugs ranged from 85.7% to 87.3%. Differences in study design might have influenced the small differences between the studies.

In our study the prescription of antiviral therapy was not associated with the occurrence of PHN, although it should be stressed that a high percentage of patients (41.2%) received antivirals beyond 72 hours after rash onset. After adjusting for other co-variates, such as age and presence of chronic illness, it was not found that antivirals would act as a preventive measure for the development of PHN.

This study also provides a recent estimate of the economic burden of HZ and PHN in a developed country. Given that the size of Spanish population age > 14 years in 2007 was 38,443,352 inhabitants, and that the prevalence of HZ was 4.1 cases per 1,000 persons > 14 years (95% CI = 3.4-4.7), we estimate a national cost of €59.6 million per year (95% CI = 49.4-68.3), which represents 0.06‰ of the 2007 gross national product (GNP).

In comparing with other European studies, our investigation found the cost of HZ to be €378 per patient, roughly double the cost reported by Gautier [24] (103 GB Pounds [£] equivalent to €151), but was lower than those reported by Davies [42] (£770, equivalent to €1132), Edmunds [43] (£306 equivalent to €450) and Scott [23] (£524, equivalent to €770). The high cost reported by Davies [42] could be due to the fact that the patients attended a tertiary referral center with a specialist pain clinic. We report a cost per PHN episode of 549 € using the 1-month definition, similar to that reported by Gautier [24] (£341, equivalent to €501). Applying the 3-month PHN definition, we report a total cost equal to €821 per patient while it was of £397 (€584) in Gautier's study [24].

In the USA, the comparable study by Yawn [44] found that the mean HZ-attributable cost was $782 (€531) for those patients in an outpatient setting. In our study (no hospitalizations were recorded) the mean cost was €378, significantly lower than that reported in the Yawn study [44]. For those patients who developed PHN, a mean cost of $4,388 per patient (€3203) was obtained in the Yawn study [44]. Again, this figure was substantially higher than our estimate (€821). Noteworthy in the Yawn's study there were 66 HZ-related hospitalizations, (with a mean length of stay of 5.1 days) compared to none hospitalizations in our study. This could explain, at least partially, the observed differences.

Comparisons between different studies from different countries are controversial due to substantial disparities in economic, demographic, cultural and institutional (health sector) structures [45]. Moreover, the different rate of antiviral prescribing (50% in the Gautier [24] study vs. 91% in the present study) might have accounted for some of the differences in the total cost between the studies. This issue is in contrast with the current recommendations of clinical consensus reports and needs to be studied in detail separately [46].

In line with Gautier's study in Europe [24] and Yawn's study in the USA [44], the most important factor that contributed to the economic burden was medication, followed by general practitioner visits.

HZ and PHN have an important impact for the Spanish Health Service, society and the individual. Current therapies and options do not completely alleviate the acute pain, and fail to prevent PHN, and thus provides preventive measures such as vaccination may be warranted. Zoster vaccine has been shown to reduce the burden of HZ by decreasing the incidence and symptom severity, and it has also been shown to reduce the incidence of PHN compared with placebo [4].

Our study has some limitations. First, those patients with HZ who may have gone to a private practitioner might not be detected in our study, leading to an underestimate of the disease; however, it can be presumed that this proportion of patients would be small given the free health care provision in Spain and the reimbursement of drugs prescribed in public GP offices. In Spain many patients directly attend Accident & Emergency (A&E) departments when they perceive a disease as "serious". This might have underestimated our incidence result. Any way, we consider that this underestimation should not be of considerable importance as in the Valencian Community, usually patients diagnosed by the A&E departments physicians or private specialists, in addition, attend to their primary care GP for prescription and reimbursement of medication, thus being susceptible to be recruited in the study.

Second, our study is not a population-based study but is based on a convenience sample of primary healthcare GP offices, so extrapolation of our results to the general adult population should be made with caution. Finally, in our study the costs related to working time lost showed a wide range of variation as indicated by a high standard deviation, thus making interpretation difficult.

HZ and PHN are prevalent diseases in Spain whose incidence increases with age. HZ and PHN have a significant clinical and economic burden. Randomized controlled trials would be appropriate and necessary to investigate the role of antiviral therapy in preventing PHN when prescribed more than 72 hours after rash onset.