Reconstruction of human immunodeficiency virus (HIV) sub-epidemics in Italian regions

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1 International Epidemiological Association 1999 Printed in Great Britain International Journal of Epidemiology 1999;28: Reconstruction of human immunodeficiency virus (HIV) sub-epidemics in Italian regions S Barcherini, M Cantoni, P Grossi and A Verdecchia Background The spread of human immunodeficiency virus (HIV) infections is likely to consist of sub-epidemics in local areas and/or risk groups. Small-area risk group specific analyses may thus be a suitable means of better understanding and controlling the epidemic course. Methods An age, period, and cohort back-calculation method was used to reconstruct region-specific epidemics of HIV infection. The HIV infection incidence rates were estimated for individual Italian regions by using as denominator the specific risk category population (i.e. intravenous drug user population [IDU], homosexual/ bisexual population [MSWM], and Italian general population for heterosexual contacts [HST]). Incidence rates obtained in this way represent the risk of HIV infection conditional to belonging to the specific sub-group of the population. Results The HIV epidemic is heterogeneous in terms of gender, risk category and region. The highest risk of HIV infection has been estimated in the Lombardia region (North-West area) among men belonging to the IDU category in In recent years, a trend of decrease in HIV has been estimated, especially among IDU and MSWM. For the HST category, some regions have shown trends of great increase, particularly on the island of Sardegna and the regions of Puglia and Sicilia (Southern Italy). In 1987, most HIV infections were observed among IDU (39 90%), while in 1992 the MSWM and HST categories made the greatest contribution to the HIV epidemic. Conclusions The results stress the idea of sub-epidemics rather than a single epidemic affecting the entire country. Some Southern regions emerge as areas in which the spread of HIV infections, although still at a rather low level, should cause considerable concern, particularly the trend of new infections by heterosexual transmission involving the general population. Detailed information on levels and trends of HIV infection epidemics at the local level are essential for surveillance purposes and for planning health care facilities, and can highlight areas in which preventive measures can be effective. Keywords AIDS, geographical heterogeneity, risk categories, HIV infections Accepted 9 April 1998 In a previous paper, 1 we discussed the benefits of describing the acquired immunodeficiency syndrome (AIDS) epidemic in Italy as several smaller-area sub-epidemics which vary in terms of composition of risk groups and temporal trends. The idea is generally plausible, particularly for Italy, where most HIV infections have been observed among intravenous drug users (IDU) and men who have sex with men (MSWM) (i.e. sub-groups of the population with majority of contacts most likely occurring within the specific group rather than outside). Spread of HIV Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome, Italy. Reprint requests to: Dr Arduino Verdecchia. infection is expected to present fairly heterogeneous patterns in other countries as well and the analyses we are proposing could be a useful model for detailed surveillance analyses. Age at onset of HIV infection, mode of transmission, and size of the population at risk for HIV infection may vary among different geographical areas and may indicate targets for specific preventive measures. Unbiased comparisons among heterogeneous areas require that populations at risk be taken into account and that proper adjustment for different age structures be done. When referred to group-specific population, incidence rates may represent the actual risk of HIV infection for individuals belonging to the subgroup and may provide a more meaningful picture of the epidemics which greatly differ from any conventional analysis based on HIV or AIDS counts. 122

2 HIV SUB-EPIDEMICS IN ITALY 123 Figure 1 Age-standardized acquired immunodeficiency syndrome (AIDS) incidence rates per population in the Italian regions in 1992, by using the Italian population as standard Information on place of residence is essential for any geographical analysis of HIV/AIDS epidemics. In Italy, both place of residence and place of diagnosis are recorded on AIDS notifications. Studying HIV incidence and prevalence levels and trends at the local level may help local authorities in better controlling the epidemics, highlighting areas where intervention programmes could be of potential use. The objective of the present study was to reconstruct the incidence and prevalence of HIV infection for each of Italy s 20 geographical regions by gender and by mode of transmission. To this end, a back-calculation method, which incorporates age at onset of HIV infection and susceptible population, was used. Geographical and temporal analysis of past HIV infection incidence is presented. The analysis can be considered as a model for similar regional analyses to be performed in other countries in which the HIV epidemic is expected to be heterogeneous. Materials and Methods Basic data on age, gender, geographical area, and mode of transmission for people with AIDS were available from the Italian National AIDS Registry. The data collected, corrected for reporting delay according to the method described in Brookmeyer and Liao, 2 refer to AIDS cases reported from 1 January 1983 to 30 June 1995, 3 as based on CDC 1987 AIDS case definition up to 1992 and 1993 European revision of AIDS definition thereafter. 4 Paediatric AIDS cases (i.e. 14 years) were excluded from the analysis because of the different nature of the infection in this group. As of 30 June 1995, the total number of cases reported in Italy was : (79.3%) males and 6009 (20.7%) females. The map in Figure 1 shows the age-standardized AIDS incidence in Italian regions in 1992, obtained using the Italian resident population as standard. We considered the 20 Italian regions as the smallest geographical unit in the analysis. Small regions with few AIDS cases were grouped with bordering regions to produce more reliable estimates of HIV incidence and prevalence; specifically, the following regions were combined: Piemonte and Valle d Aosta, Veneto and Friuli Venezia Giulia, Umbria and Marche, Abruzzi and Molise, and Campania and Basilicata, resulting in a total of 15 regions out of an original 20. The 15 regions were also grouped, as an intermediate level, into four broad geographical areas: North-West (Lombardia, Liguria, Piemonte, Valle d Aosta), North-East (Veneto, Trentino Alto Adige and Friuli Venezia Giulia), Centre (Emilia Romagna, Toscana, Lazio, Umbria and Marche and Sardegna), and South (Abruzzi, Molise, Campania, Basilicata, Calabria, Puglie and Sicilia). The AIDS cases were classified by mode of transmission according to the following criteria: intravenous drug users (IDU) (i.e. individuals who had injected drugs at least once since 1979); men who have sex with men (MSWM) (i.e. men who had sexual intercourse with homosexual/bisexual male at least

3 124 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY once since 1979); and heterosexual transmission category (HST), meeting at least one of the following criteria: (1) sexual intercourse with a partner belonging to known risk group, (2) sexual intercourse with an HIV-positive partner, (3) infected through sexual intercourse but information on partner(s) not available, (4) undetermined mode of transmission (i.e. none of the risk factors reported above). The AIDS cases classified as undetermined mode of transmission are cases periodically revised by the Italian AIDS Registry and they are reclassified according to appropriate mode of transmission. The cases who definitely remain undetermined are expected to be individuals infected through a heterosexual contact with people not apparently belonging to known risk categories. The expanded HST category definition adopted here is then expected to represent a suitable classification which accounts for the whole heterosexual contact mode of transmission. The size of the IDU population was derived from a previous empirical estimate based on regression analysis on data of impact of drug addiction on justice, policy, health care system and so on. It totalled ( males and females), as usually accepted in the epidemiological literature with reference to Italy. 5 8 Age structure was taken from the IDU component of the Italian multicentre seroconversion study, 9 validated by using data from an epidemiological study on IDU in Milan (Lombardia). 10 Table 1 reports the percentage of the total regional population represented by IDU and the estimated size of the IDU population by region. The MSWM population was estimated to consist of individuals, constituting 1.9% of the Italian male population, with the same age structure as the total male population. 5 For the HST population the Italian general population was used as reference. 11,12 The HIV incidence rates were estimated in each region using as denominator the population of the specific risk category (i.e. IDU population, MSWM population, and the general population for HST population). These incidence rates represent the actual risk of HIV infection for the specific category. To evaluate temporal trends and to make comparisons among the regions, age-standardized annual incidence rates 13 were calculated using the 1990 resident population in Italy as standard. Incidence rates are presented per population. Mortality data by region were provided by the Italian National Bureau of Statistics (ISTAT). The risk of death for IDU living in Milan 10 was quoted as around 20 times the mean value of that of the general population of the same age and sex in the period. The death rate due to AIDS in the same period accounted for about half of the total death risk for IDU. We assumed the competitive pre-aids risk of death for IDU (the mortality from overdose and other non-aids causes) remained stable at about 10 times (18 times for women) that of the general population, as reported in a previous epidemiological investigation conducted in Rome, Central Italy. 14 The back-calculation procedure used is a generalization of standard methods for estimating and projecting the dimension of the HIV/AIDS epidemics. Age at onset of HIV infection, age and calendar time dependent incubation time distribution, susceptible population, and competitive non-aids mortality rates for infected people are included in the estimation process. The incidence of new HIV infections is assumed to be represented by a continuous function which is chosen from the polynomial Table 1 Estimated intravenous drug user (IDU) population in the Italian regions, per cent of total regional population (%) and size (N) functions family of age, period and birth cohort, in the logistic scale, and as the one giving the best fit of the age and period distribution of notified AIDS cases. This method is described in detail in a previous paper, 5 along with a description of its application for reconstructing the HIV infection epidemic on a national scale in Italy. 15 Incubation time distribution was derived from the Italian seroconversion cohort study 9 involving 19 clinical centres throughout the country, with the majority of cases represented by IDU and MSWM. The distribution of incubation times, from seroconversion to AIDS, was found to be strongly influenced by the age of the subjects at onset of HIV infection. 16 Median incubation times were estimated to be 12.5 years for ages 25, 9.1 years between 25 and 34 years and 7.4 years for people aged 35 or more. 5 Results IDU Male IDU Female Regions % N % N North-West Lombardia Piemonte + Val d Aosta Liguria North-East Veneto + Friuli V. G Trentino Alto Adige Centre Toscana Emilia Romagna Lazio Umbria + Marche Sardegna South Abruzzi + Molise Campania + Basilicata Calabria Puglie Sicilia Figures 2a and 2b show the trend of the estimated HIV incidence by gender for the four broad geographical areas. The overall incidence among males was approximately four times that among females. For both genders, incidence peaked in , with more than 9000 HIV infections in males and approximately 2000 in females (29 per population and 7 per population, respectively). The highest incidence rates were found in the North-West and the Centre. An overall trend of decrease in incidence was estimated for the years following 1986, although the decline is much more evident for males than for females. Despite this general trend of decrease, women in the South showed a trend of increase. Following the idea of AIDS sub-epidemics, 1 we performed separate analyses for HIV infection by sex, risk category and

4 HIV SUB-EPIDEMICS IN ITALY 125 Figure 2 Estimated human immunodeficiency virus (HIV) incidence cases by geographical areas among (A) males and (B) females region, within each geographical area. Figures 3, 4, and 5 show the estimated age-adjusted HIV incidence rates per population by region and for the entire country among the IDU, MSWM, and HST populations, respectively. The HIV incidence peaked in for IDU and MSWM and in for the HST population in almost all regions. Although trends of general decrease of HIV incidence were estimated after peaking for almost all regions and risk categories, some differently shaped trends merit further discussion and are addressed below. For IDU in the North-West area (Figures 3a, 3b) and in the Lazio region (Figures 3e, 3f), and for male IDU in the region of Sicilia (Figure 3g), the age-adjusted HIV incidence rate was higher than the average incidence rate for the entire country. In particular, the 1985 HIV incidence rate among male IDU in Sicilia (approximately one infection for every 10 male IDU) was similar to that for the Lombardia region, which has always been the region with the highest HIV incidence in Italy. The epidemic curves for the North-West regions anticipated those of the other regions; it was particularly evident for the Lombardia region, denoting that the HIV epidemic started earlier and developed faster in these regions. Since 1990, the HIV incidence rate among IDU was estimated generally as decreasing and approaching zero in recent years, although with large confidence intervals. Only a few exceptions occurred for women in Central and Southern Italy (Figure 3). For the HST population the trend of HIV incidence (Figure 4) was very similar among regions in each of the four broad geographical areas; thus only one region representing each of these areas is presented. The regions in the North-West had higher incidence than Italy as a whole, for both sexes, as shown by the Lombardia region. Conversely, the North-East, as shown by the Veneto region, had generally lower levels. In the Central area, the epidemic curve for the island of Sardegna differs from the general trend as reflected by the Lazio region, with the epidemic course for Sardegna being delayed for both sexes and with a lower incidence for males but not for females. Southern regions, here represented by the island of Sicilia, had levels of HIV incidence lower than the overall national levels. The epidemic curve for the HST population did not peak as dramatically as it did for IDU, in any of the regions or in Italy as a whole. For MSWM (Figure 5), as for the HST population, only one region in each broad area is presented, since similar levels and trends were found in each area. The regions of Lazio and Lombardia showed the highest age-adjusted HIV incidence rates among MSWM, with levels twice as high as the national average. The combined region of Veneto and Friuli Venezia Giulia (North-East area) showed rather high levels of HIV infection incidence among MSWM, but low incidence for both the IDU and HST categories. The Southern regions showed very low incidence levels among MSWM. The decrease in HIV incidence among IDU and MSWM in recent years has greatly changed the composition by risk group affected by new infections and it is expected to accordingly change the composition of AIDS notifications for the coming years. In 1987, most HIV infections were reported among IDU. In 1992, the contribution of IDU to HIV incidence generally decreased, while increasing for the other risk categories. In most of the Central and Southern regions, HST became the primary risk category in Table 2 shows the 1992 prevalence of HIV-infected individuals who had not developed AIDS, by region, risk category, and gender. The prevalence proportion presented in the Table refers to the resident population in each region, thus representing the risk for people living in the region of potentially having contact with prevalent infected IDU, MSWM and HST. Discussion We reconstructed HIV sub-epidemics in individual regions by sex and risk category, demonstrating a great variability in terms of levels and trends of incidence. We had previously analysed variability of notified AIDS cases in Italy, 1 yet trends of HIV incidence provide far more information on changes in the infection risk. Describing the pattern of spread of HIV infections in situations in which AIDS surveillance shows geographical heterogeneity, empowers the potential of surveillance by being able to detect early low level areas causing great concern. Before drawing firm conclusions, the assumptions involved in the estimation process are addressed. Individual regions were used as the statistical unit for our analysis, and regions

5 126 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Figure 3 Age-standardized human immunodeficiency virus (HIV) incidence rates per people among intravenous drug user (IDU) category by gender and geographical area with very few notified AIDS cases were combined with bordering regions, thus assuming similarity of levels and trends. Regarding the four broad geographical areas, the island of Sardegna was included in the Central area, which is somewhat similar to Sardegna in terms of incidence; however, most geographical analyses have included Sardegna in the Southern area. Furthermore, regions correspond to administrative districts with no relevance to the risk of HIV infection, other than the fact that the Italian health care system is regionally based. Risk categories for AIDS cases are assigned on the basis of available information and their classification can be arbitrary when there are multiple categories or a lack of information. For

6 HIV SUB-EPIDEMICS IN ITALY 127 Figure 4 Age-standardized human immunodeficiency virus (HIV) incidence rates per people among heterosexual transmission (HST) category by gender and geographical area Figure 5 Age-standardized human immunodeficiency virus (HIV) incidence rates per people among men sex with men (MSWM) category by gender and geographical area the HST category, we combined the heterosexual category and that of undetermined mode of transmission, which, by excluding any known risk behaviour, actually represents transmission through heterosexual contact among the general population. The HST category accounts for all transmissions through heterosexual contact, whether the partner is or is not known to be infected with, or at risk for, HIV infection. Results obtained by risk category, although based on partially uncertain classification, are expected to be indicative of levels and trends of HIV infection risk in different strata of the population. It has been estimated that the 1993 revision of the AIDS case definition resulted in an earlier AIDS diagnosis for only approximately 5% of infected individuals, potentially influencing estimates given for In a companion paper, 17 we report that the effect of the revised definition is limited to a moderate excess in estimated incidence and that this excess is uniformly distributed among regions, thus, in principle, not affecting geographical differences. Trends in more recent years may be more consistently affected by this phenomenon, as well as by the well known uncertainty of back-calculation estimates for recent years. For this reason, the presentation of results was truncated at December Back-calculation methods are highly sensitive to uncertainty in the incubation distribution. In this application, we used an estimate of the incubation time obtained from a multicentre cohort study in Italy; incubation time was found to be dependent on age at seroconversion rather than risk category and sex. 5,16 Methods that do not consider an age-dependent incubation time for AIDS may give rise to biased estimates when referring to sub-groups of the population in which the age distribution is different from the one from which the incubation time was estimated. We assumed size and age structure of IDU and MSWM populations. Particularly for IDU, the assumption is critical as it may affect the results. It has been shown 5 that using the general population as reference for IDU can lead to distortion of estimates (overestimation), by not allowing for possible saturation of HIV infections in particular age classes at high risk for HIV infection. Although not exactly known, assuming an IDU population should be regarded as a better approximation than none at all. Reference to specific sub-populations allows us to consider incidence as the risk of HIV infection conditional to belonging to the specific population sub-group, thus improving the interpretability of the results. Comparisons between risk groups and areas may also provide more meaningful results in terms of incidence rates with reference to group-specific and area-specific sub-populations, than can be obtained simply by comparing counts. Reference to regional and group-specific populations provided results for IDU that were somewhat unexpected on the basis of previous observations. In particular, we found for the Sicilia region almost the same level of peak incidence as the Lombardia and Lazio regions, which are known to have the highest epidemic levels. The IDU population in the Lombardia region is almost seven times larger than in the Sicilia region, and HIV infection, estimated in 1985, affected one out of every 10 male IDU in both regions. Overall incidence of HIV infection in Italy has been estimated to have peaked in , with almost new infections (20 per popluation). The distribution of HIV infections does not follow a clear North-to-South pattern, being highest in North-West and Central areas, but lower in North- East and Southern regions. While North-West and Central regions, with high levels of HIV infection incidence in past years, have had generally low rates in recent years, the increasing trends for Southern regions, in which the epidemic started later and progressed at a lower rate of increase, particularly for the heterosexual category and for women, should be cause for great concern.

7 128 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Table 2 Estimated number (N) and proportion (P) of human immunodeficiency virus (HIV) infected people (non-acquired immunodeficiency syndrome [AIDS]) in the Italian regions by risk categories, 1992 IDU a HST b MSWM c Total Male Female Male Female Male Female Regions N P d N P d N P d N P d N P d N P d N P d North-West e Lombardia Piemonte + Val d Aosta Liguria North-East e Veneto + Friuli V. G Trentino Alto Adige Centre e Toscana Emilia Romagna Lazio Umbria + Marche Sardegna South e Abruzzi + Molise Campania + Basilicata Puglie Calabria Sicilia Italy f a Intravenous drug user. b Heterosexual transmission. c Men sex with men. d Number of HIV prevalent/resident population of the region * e Values obtained as sum of regional estimates. f Values obtained as independent estimates. The estimated number of HIV prevalent infected individuals in each region is presented in Table 2 and may be useful for determining current and future needs in terms of health care facilities. Since prevalence represents the cumulative incidence, it strongly depends on the past epidemic course and only slightly reflects trends of HIV infection in recent years. Higher prevalence proportions are thus estimated in the Northern and Central regions, where high levels of HIV infection have been reported in the past; Southern regions have a lower prevalence proportion, despite the apparently increasing risk of infection, particularly through heterosexual contact. Our results show that regional HIV epidemics greatly differ in composition as well as in levels and trends. For instance, in the Northern regions homosexual behaviour has been the leading cause of HIV infection in recent years. In the Central and Southern regions, the spread of HIV infection has mainly been through heterosexual contact. Effective preventive measures are expected to differ according to the specific HIV epidemic. Surveillance and health care planning should also take into account the different regional composition of the HIV epidemic. The health care system in Italy is regionally based and we expect our analysis to be appropriate for planning purposes. National estimates, which are useful from a general epidemiological perspective, are not specific enough to be effective at the local level for specific actions. References 1 Cantoni M, Cozzi Lepri A, Grossi P, Rezza G, Verdecchia A. Use of AIDS surveillance data to describe subepidemic dynamics. Int J Epidemiol 1995;24: Brookmeyer R, Liao L. The analyses of delays in disease reporting: Methods and results for the acquired immunodeficiency syndrome. Am J Epidemiol 1990;132: Centro Operativo AIDS (COA). Aggiornamento dei casi AIDS notificati in Italia al 30 Giugno Notiziario dell Istituto Superiore di Sanità. Agosto 1995;8(Suppl.3). 4 Centers for Disease Control and Prevention revised classification system for HIV infection and expanded surveillance casedefinition for AIDS among adolescents and adults. MMWR 1992;41: Verdecchia A, Mariotto.B. A back-calculation method to estimate the age and period HIV infection intensity, considering the susceptible population. Stat Med 1995;14: Perucci CA, Michelozzi P, Abeni DD et al. Riflessioni sull epidemia di infezioni da HIV e di AIDS. Epidemiol Prev 1991;48 49: Perucci CA, Forastiere F, Rapiti E, Davoli M, Abeni DD. The impact of intravenous drug use on mortality of young adults in Rome, Italy. Br J Addict 1992;87: Iannelli M, Loro R, Milner F, Pugliese A, Rabbiolo E. An AIDS model with distributed incubation and variable infectiousness: applications to i.v. drug users in Latium, Italy. Eur J Epidemiol 1992;8:

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