Sentinel hospital surveillance of HIV infection in Quebec - Europe PMC

Sentinel hospital surveillance of HIV infection in Quebec Michel Alary,*t MD, PhD; Jean R. Joly,*t MD, MSPH, FRCPC; Raymond Parent,t MSc; Micheline Fauvel,: MSc; Marc Dionne,§ MD, MPH, FRCPC; and the Quebec Sentinel Hospital HIV-Seroprevalence Study Groupil Objective: To measure the HIV seroprevalence rate in a surrogate sample of the general population in the province of Quebec, using a network of sentinel hospitals. Design: Anonymous unlinked sentinel surveillance study. Setting: Outpatient surgery units in 19 acute care hospitals throughout Quebec. Participants: All patients attending the outpatient surgery units from November 1990 to October 1992. A total of 61 547 plasma samples were obtained from leftover blood samples collected for cell counts. Fifty samples were excluded because of an insufficient amount of plasma and one because of an indeterminate result. Intervention: HIV antibody testing with enzyme-linked immunosorbent assay; positive results confirmed with radioimmunoprecipitation assay. Outcome measures: HIV antibody status, sex, year of birth and area of residence. Results: The crude seroprevalence rate among the subjects aged 15 years or more was 0.4 per 1000 population (95% confidence interval [CI] 0.2 to 0.7) among the women and 3.6 per 1000 population (95% CI 2.8 to 4.4) among the men (p < 0.001). The rate after adjustment for age, sex and geographic distribution of the study population was 2.3 per 1000 population (95% CI 1.9 to 2.7). The seroprevalence rate among the male patients in the City of Montreal was much higher than the rates elsewhere in the province. It increased progressively during each of the four 6-month intervals of the study: 8.1, 8.7, 13.9 and 18.3 per 1000 respectively (X2 linear trend = 4.76; p = 0.029). No similar trends were observed outside Montreal for the male patients. There were too few seropositive female patients to draw any solid conclusion. Conclusions: Despite the possible drawbacks of a nonrandomized sampling scheme, this study suggests that in the male population the HIV seroprevalence rate is increasing in Montreal and is stable in all other areas of the province. The continued surveillance of HIV infection through anonymous unlinked studies is useful to monitor trends.

Objectif: Mesurer le taux de seroprevalence du VIH dans un echantillon de convenance represantant le mieux possible la population generale de la province de Quebec a l'aide d'un reseau d'hopitaux-sentinelles. Conception : Surveillance sentinelle a l'aide d'une etude anonyme non liee. Contexte : Unites de chirurgie d'un jour dans 19 hopitaux de soins aigus du Quebec. Participants: Tous les patients ayant consulte dans les unites de chirurgie d'un jour entre novembre 1990 et octobre 1992. On a obtenu au total 61 547 echantillons de plasma From the *Groupe de recherche en epidemiologie de l 'Universite' Laval, Centre de recherche, Hdpital du Saint-Sacrement, Quebec, Que.; the tCentre de sante publique de la region de Quebec, Quebec; the 4Laboratoire de sante publique du Quebec, Sainte-Anne-de-Bellevue, Que.; and the §Direction generale de la sante' publique, Ministere de la sante et des services sociaux du Quebec, Quebec

IMembers: Charlotte Kerlucke, Centre hospitalier re'gional de l 'Outaouais, Hull; Re'jean Fraser, Centre hospitalier Rouyn-Noranda, RouynNoranda; Serge Pilon, H6tel-Dieu de Saint-Jr6me, Saint-J'r6me; Dr. Celine Laferriere, Centre hospitalier Pierre Boucher, Longueuil; Dr. Lucie Mailloux-C&at, H6pital du Haut-Richelieu, Saint-Jean; Dr. Gilbert Cerat, Cite' de la Sante', Laval; Jeanne Grimard, H6pital du Sacre-Coeur de Montr&al, Montreal; Michael Condrom, Royal Victoria Hospital, Montreal; Giovanni D'Angelo, Hopital MaisonneuveRosemont, Montreal; Dr. Gilles Richer, Hopital Notre-Dame, Montreal; Dr. Andre Dascal, Sir Mortimer B. Davis-Jewish General Hospital, Montreal; Dr. Jacques Dubois, Hotel-Dieu de Sherbrooke, Sherbrooke; Dr. Andre' Poirier, Centre hospitalier Saint-Joseph de Trois Rivieres, Trois Rivieres; Carmen O'Grady, Hopital du Saint-Sacrement, Quebec; Marie-Marthe Proteau, Hopital de l'Enfant-Jesus, Quebec; Dr. Andre' Vincent, HBtel-Dieu de Levis, Uvis; Dr. Roger Savard, Hopital de Chicoutimi, Chicoutimi; Gisee Otis, Centre hospitalier re'gional de Rimouski, Rimouski; Armande Jasmin, Hdpital de Sept-Iles, Sept-Iles Reprint requests to: Dr Michel Alary, Centre de recherche, Hopital du Saint-Sacrement, 1050, chemin Sainte-Foy, Quebec, QC GIS 4L8 v- For prescribing information see page 1083

CAN MED ASSOC J 1994; 151 (7)

provenant de sang non utilise recueilli pour fin de numeration globulaire. Cinquante echantilIons ne contenant pas assez de plasma et un autre presentant un resultat indetermine ont ete exclus de l'analyse. Intervention: Evaluation de la presence d'anticorps contre le VIH 'a l'aide d'une methode immuno-enzymatique. Les resultats positifs ont ete confirmes par radioimmunoprecipitation. Mesures des resultats: Presence d'anticorps du VIH, sexe, annee de naissance et region de

residence. Resultats: Le taux brut de seroprevalence chez les sujets de 15 ans ou plus a ete de 0,4 par 1 000 habitants chez les femmes (intervalle de confiance [IC] 95 % de 0,2 a 0,7) et de 3,6 par 1 000 habitants chez les hommes [IC 95 % de 2,8 a 4,4) (p < 0,001). Apres corrections pour l'age, le sexe et la repartition geographique de la population etudiee, le taux s'est etabli 'a 2,3 par 1 000 habitants (IC 95 % de 1,9 'a 2,7). Le taux de seroprevalence chez les patients de sexe masculin residant a Montreal ete beaucoup plus eleve qu'ailleurs dans la province. Il a augmente progressivement 'a chacun des quatre intervalles de 6 mois de l'etude: 8,1; 8,7; 13,9; et 18,3 par 1 000 habitants respectivement (tendance lineaire X2 = 4,76; p = 0,029). On n'a observe aucune tendance semblable 'a l'exterieur de Montreal chez les patients masculins. Il y a eu trop peu de patientes seropositives pour qu'on puisse tirer des conclusions solides 'a propos des tendances chez les femmes. Conclusions: Malgre les inconvenients possibles d'un plan d'echantillonnage non aleatoire, la presente etude semble indiquer que le taux de seroprevalence du VIH dans la population masculine de Montreal augmente mais qu'il est stable dans toutes les autres regions de la province. La surveillance constante des cas d'infection par le VIH 'a l'aide d'etudes anonymes non liees est utile pour connaitre les tendances.

ecause AIDS surveillance through mandatory case reporting only reflects the epidemiologic features of HIV transmission a few years earlier,! new strategies have been developed to implement methods for the surveillance of HIV infection. In North America anonymous unlinked seroprevalence studies, using leftover blood samples obtained through routine collection from which personal identifiers are removed, have been widely used for the surveillance of HIV infection since 1987.2-1 Indeed, that same year in the United States an anonymous survey of neonatal blood spots resulted in an estimated HIV seroprevalence rate of 2.1 per 1000 among childbearing women in Massachusetts. Following this successful study, the US Centers for Disease Control and Prevention (CDC), Atlanta, implemented a number of anonymous unlinked HIV seroprevalence surveys involving civilian applicants for military service, childbearing women, ambulatory patients, Job Corps entrants, inmates in federal prisons, patients attending clinics for sexually transmitted diseases (STDs) and sentinel hospitals.54 Combining data from these surveys and from back-calculation models, the CDC has estimated that between 800 000 and 1 200 000 Americans were infected by HIV in 1989.5 In 1988 the Royal Society of Canada recommended anonymous HIV seroprevalence surveys to assess the actual picture in Canada.6 In response, the Federal Centre for AIDS prepared guidelines on the ethical aspects of such studies,7 and the National Health Research and Development Program (NHRDP) provided funds for studies meeting these guidelines. Since then, data on HIV seroprevalence rates among childbearing women in four Canadian provinces have been published.' -I The rate was much higher in Quebec' than in Ontario,9 British

B

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CAN MED ASSOCJ 1994: 151 (7)

Columbia"' and Manitoba" (6.1, 2.8, 2.7 and 1.1 per 10 000 respectively). In addition, data on the HIV antibody status of patients attending STD clinics in Manitoba" and Nova Scotia' have been reported. In the context of this NHRDP program, we conducted sentinel hospital surveillance of HIV infection in Quebec to estimate the HIV seroprevalence rate. We selected patients attending a network of 19 sentinel hospitals as a proxy for the general population. Reported here are the results of the first 2 years of data collection.

Methods Selection of patients and collaborating hospitals People attending outpatient surgery services of 19 collaborating institutions formed the study population. Information on age, sex, surgical procedure, and primary and secondary diagnoses of these patients were obtained from the Quebec provincial database on hospital discharges (Med-Echo). Outpatients were chosen because both sexes and all age groups are well represented, and the surgical procedures do not appear to be related to HIV infection. Indeed, most of the women undergo minor gynecologic procedures and most of the men minor orthopedic interventions. Minor surgery for ear, nose and throat or ophthalmologic problems are also relatively frequent in both sexes. Outpatients undergoing bronchoscopy do not attend the outpatient surgery services but are rather referred to the pneumology units. Finally, in most hospitals blood samples required for preoperative tests are collected by only a small number of nurses, thus decreasing the possibility of missing eligible patients. The use of this population was successful in a piLE Ior OCTOBRE 1994

lot study, and we decided to retain it for the full-scale study. To select collaborating hospitals we used statistics from Med-Echo. This database provides information on the number of patients attending the outpatient surgery service of most hospitals in Quebec. Collaborating centres were selected to cover all administrative regions of the province governing health and social services and to provide a proportion of plasma samples from each area corresponding approximately to the actual geographic distribution of the province's population. To fulfill these requirements, 19 sentinel hospitals were selected, and all agreed to participate.

Information to the population and ethical considerations This study was in full agreement with the federal ethical guidelines for anonymous unlinked HIV seroprevalence studies.7 At the onset of the study a press release was distributed to major newspapers and radio and television stations in the province to announce the study. In addition, in the waiting rooms attended by eligible subjects, a poster was displayed announcing and explaining the study. A more detailed information sheet was available through the hospital staff if requested by patients. To our knowledge, only two of these information sheets were given out during the study period, and no patient came forward to refuse to participate. The study protocol was approved by a special ethics review board convened by the Centre quebecois de coordination sur le SIDA to examine all anonymous unlinked seroprevalence surveys to be performed in Quebec. The ethics review boards of the collaborating hospitals also approved the project.

transformed into a new variable to correspond to broader geographic areas with the use of a customized computer program. This division of the province corresponded to all of Quebec's administrative regions governing health and social services except Montreal, which was subdivided into three areas: downtown Montreal (i.e., territories covered by the community health departments of the Montreal General Hospital and Hopital Saint-Luc), the City of Montreal (which included downtown Montreal) and metropolitan Montreal (which included the City of Montreal and most suburban areas).

Identification ofduplicate samples Plasma samples obtained from HIV-positive patients with the same year of birth, the same sex and the same first three digits of the postal code and collected during the same study year were considered duplicates for the estimation of the adjusted seroprevalence rate. However, for the time-trend analysis, plasma samples obtained within the same 6-month period and from subjects with the same year of birth, sex and first three digits of the postal code were considered duplicates. For seronegative subjects the Med-Echo database was examined to identify the number of patients consulting the outpatient clinics of the different hospitals more than once during a given year.

Laboratory procedures

HIV antibody testing was done with the use of an automated enzyme-linked immunosorbent assay (Genetic Systems Co., Seattle). Samples that yielded a positive result were tested again in duplicate. Those that were reactive at least two out of three times underwent confirmatory testing by means of radioimmunoprecipitation assay, in a manner similar to the algorithm used in Data collection the province of Quebec since 1986 to confirm HIV inFrom November 1990 to October 1992 nurses col- fection.'3 lecting plasma samples from surgical outpatients in the 19 collaborating centres identified eligible samples with Statistical analysis a sticker. Unlinkage was performed at the laboratory. Crude HIV seroprevalence rates were computed for The month and year of sampling, the year of birth, the patient's sex, the first three digits of the postal code or the study population overall and by age, sex and geothe telephone area code and the first three digits of the graphic distribution. The exact binomial distribution was telephone number were recorded on a form with a used to calculate 95% confidence intervals (CIs) around unique number; these numbers were so designed that seroprevalence rates, and X2 or Fisher's exact test was each collaborating centre could be identified. A sticker used to compare proportions. The X2 test for trend was with the same number identified the plasma sample. The used to examine time trends in the seroprevalence rate forms were sent to the Community Health Department over the study period. Adjusted seroprevalence rates were computed with of the Hopital du Saint-Sacrement, Quebec City, and the plasma samples were refrigerated and sent once a week the use of the actual age, sex and geographic distribution to the Laboratoire de sante publique du Quebec, Sainte- of the population in the province according to the 1986 Anne-de-Bellevue, where serologic tests were per- census. The normal approximation was used to calculate formed. Test results were periodically sent to Quebec 95% CIs for these adjusted rates; the weight given to City and linked to the information form through the their different components was taken into account for unique number. Postal codes or phone numbers were variance computation. OCTOBER 1, 1994


977

Trends in the HIV seroprevalence rates

Results

Samples from seven subjects (all males) were considered potential duplicates and were thus excluded from A total of 61 547 plasma samples were collected. this analysis. Seroprevalence rates for samples collected Of these, 50 were excluded mostly because of an insuffi- in each of the four 6-month periods were analysed by cient amount of plasma. Another sample gave an am- sex, age and area of residence. Among the men the serobiguous result despite repeated assays and thus was also prevalence rate increased over all four periods in the excluded. The area of residence was known for 98.5% of City of Montreal; a similar trend was observed in metrothe subjects (60 560/61 496). When the geographic dis- politan Montreal (Table 3). In other parts of the province tribution of the study population was compared with that the rate was stable. The number of seropositive women of the province's total population, no important differ- was too small for the trend analysis. ences were noted. For example, 29.0% of the study population and 31.1% of the provincial population lived in Adjusted seroprevalence rates metropolitan Montreal. The figures for the Quebec City When evaluating the adjusted seroprevalence rates area were 9.8% and 9.5% respectively. All of the other geographic areas were proportionally well represented in we had to take into account the large increase in infecthe study population. The area of residence was un- tion rates in the Montreal area. Because of this, the adknown for 936 samples; distribution of the hospitals of justed seroprevalence rate among the male patients in origin of these samples was compared with that of the the City of Montreal was calculated only on the basis of remaining samples, but no major discrepancies were ob- the data obtained during the last year of the study, served. The age distribution of the study population was whereas the rates among the other male patients and compared with that of the provincial population. All age among the women were based on the data obtained durgroups were represented in the study group (Table 1). ing both study years. Potential duplicate samples (as defined in the Methods section) were excluded on a yearly For 407 of the patients, age or sex was unknown. basis, leading to the exclusion of 13 seropositive subHIV antibody test results jects. Analysis of the Med-Echo database, to identify duplicate seronegative samples, showed that 7.4% of all Of the analysed samples 7087 were from children the patients had previously consulted the selected clinics less than 15 years of age (4184 males and 2903 females). (7.1 % during the first year of the study and 7.8% during None was seropositive, and thus further analysis was re- the second). Once the denominators were adjusted acstricted to the older subjects. Of the remaining samples cordingly, the HIV seroprevalence rate among the sub95 were HIV positive. Of these, 80 were from men and jects aged 15 years or more was estimated to be 2.3 per 14 from women; sex was unknown in one case. The age 1000 population (95% CI 1.9 to 2.7). and sex distribution of the seropositive patients is presented in Table 2. Most of the seropositive patients were Discussion 25 to 44 years of age. The area of residence was unknown for one seropositive man. Data on the seroprevalence of HIV type 1 (HIV-1) infection have been collected through numerous types of studies.2'458-1'14-33 Pre-eminent among these have been ITable 1: Sex-specific age distribution of the Quebec pop- anonymous unlinked studies.24-X The main advanIulation and of a sample of surgical outpatients in 1 9 tage offered by this design is the elimination, or at least acute care sentinel hospitals in the province" the reduction, of the selection bias that occurs in voluntary testing programs.4 When performed in sentinel hospitals, subjects of both sexes, all age groups and dif~~~~~~~Ay~~~~~~~~~~ tat r,'. ferent risk groups are thought to be well represented. a. r f- p. .,u -.a Our results are consistent with observations of a IC~~~~~~~~~~~~~~~~~concentration of HIV-infected people in large metropolitan areas in many other developed countries.293' 3- Indeed, the prevalence rate of HIV infection was more than five times higher in metropolitan Montreal and 20 times higher in downtown Montreal than in other parts 35 of the province. Similar discrepancies were reported by St. Louis and associates29 for a network of sentinel hospitals in the United States. As in other developed countries, men between 25 and 44 years of age accounted for well over 50% of the

Study sample

)

'i

...

978


LE lcr OCTOBRE 1994

seropositive patients in our study. This is consistent with the pattern of HIV infection in North America, where the male homosexual population has been the most severely affected.36'37 In addition, we observed an important and steady increase in the prevalence rate of infection in the male population of metropolitan Montreal. No similar increase was observed in the male population outside of that area. This increase could be either real or spurious. Indeed, the observed prevalence rate may reflect a real increase in seroprevalence. Since it was confined to the male population, one could suspect that new cases occurred mainly in homosexual men. Previous studies have shown that young homosexual men are generally not adopting adequate preventive measures.3839 We were unable to detect any significant change in seroprevalence when we stratified the subjects by age group (less than 25 years v. 25 years or more) because the number of seropositive patients was small. Relapses in unsafe sexual practices have been observed in older homosexual men, and this could explain the absence of changes in the differential seroprevalence rate among younger and older male subjects." Another explanation is the recently observed increase in the HIV seroprevalence rate among intravenous drug users in Montreal,' about 75% of whom are male.45

The observed increase in the HIV seroprevalence rate in metropolitan Montreal could also be spurious. Indeed, medical procedures related to HIV infection are possibly being performed more commonly now than at the beginning of the study period. To explore this possibility, we interviewed the infectious diseases specialists at the collaborating hospitals in Montreal. We could not identify any important change in the medical practices of these physicians relative to the treatment of HIV-positive patients. We also examined the Med-Echo database to see whether any procedure (e.g., resection of anogenital warts) was more common in the latter part of the study period. Again, no significant changes were observed. It is possible that another, as yet unknown, selection bias was responsible for this increase. In a previous study, involving newborns in Quebec,8 the HIV seroprevalence rate among childbearing women was similar to the one in our study: 0.61 per 1000 (95% CI 0.44 to 0.83) and 0.44 per 1000 (95% CI 0.24 to 0.74) respectively. When restricted to women of reproductive age (those 15 to 44 years old) the prevalence rate in our study was nearly identical (0.61 per 1000 population). However, the previous study involved only women, and given that the burden of the epidemic is on the male homosexual population in developed

Table 2: Crude HIV seroprevalence rates by age and sex of subjects* Sex; rate per 1000 population Age, yr

Male

15-24 25-34 35-44 45-54 55-64 . 65

1.3 (4/3 043) 6.7 (31/4 601) 7.0 (30/4 297) 3.6 (12/3 314) 0.6 (2/3 104) 0.2 (1/4 063)

0.3 (1/3 559) 1.3 (11/8 157) 0.0 (0/7 385) 0.0 (0/4 317) 0.0 (0/3 037) 0.4 (2/5 125)

0.8 (5/6 602) 3.3 (42/12 758) 2.6 (30/11 682) 1.6 (12/7 631) 0.3 (2/6 141) 0.3 (3/9 188)

Total

3.6 (80/22 422)

0.4 (14/31 580)

1.7 (94/54 002)

Female

Overall

Table 3: HIV seroprevalence rates in 6-month intervals from November 1990 to October 1992 among male patients aged 15 years or more by area of residence*

Interval; rate per 1000 population Area of residence Downtown Montreal City of Montrealt Metropolitan Montreal§ Province of Quebec, excluding metropolitan Montreal

Nov 1990 Apr 1991 17.7 (5/282) 8.1 (8/988) 5.2 (9/1727)

May 1991 Oct 1991 15.1 (4/265) 8.7 (8/915)

4.8 (8/1672)

Nov 1991 Apr 1992 14.6 (5/342) 13.9 (14/1007) 8.6 (16/1870)

May 1992 Oct 1992 33.3 (9/270) 18.4 (15/817) 9.8 (15/1534)

X2 valuet 1.37 4.76 3.57

p value 0.242 0.029 0.059

0.35 0.552 2.0 (7/3437) 1.5 (6/4026) 1.3 (5/3840) 1.5 (6/4016) *Seropositive women were excluded from the trend analysis because their numbers were too few. The total number of seropositive male patients was 72. This number excludes seven patients with duplicate samples (see Methods section for explanation) and one for whom area of residence was unknown. The trend analysis was conducted on crude rates, since the age distribution in each geographic area was stable over time. tMantel-Haenszel X' for linear trend. tlncludes downtown Montreal. §1ncludes the City of Montreal and most suburban OCTOBER 1, 1994

areas.


979

countries, the rate was certainly underestimating the actual rate in the general population. If the adjusted seroprevalence rate among surgical outpatients is a good estimate of the true prevalence in the general population aged 15 years or more, 11 685 people in Quebec have HIV infection (95% CI 9653 to 13 470). This is in close agreement with the number reported by Remis46 with the use of back-calculation methods (between 7600 and 14 500 [most probably 11 200]). It is reassuring that our rates are extremely close to those reported by Hankins and collaborators8 for women and Remis46 for the general population. This suggests that our sampling scheme was adequate and that the true HIV seroprevalence rate in Quebec is close to these figures. However, because our study sample was not a random sample of the population, a systematic bias may have been included inadvertently. From the beginning of the AIDS epidemic until January 1994, 2806 cases were reported to public health officials in Quebec.47 As in other developed countries, there will be an increase in the number of patients requiring AIDS-related therapy. Continued surveillance should be seriously considered to monitor trends in HIV seroprevalence and should include surgical outpatients in judiciously selected sentinel hospitals. This work was supported by grant 6605-3434-AIDS from the National Health Research and Development Program (NHRDP), Health Canada, and by additional funding from the Laboratory Centre for Disease Control, Ottawa, and the Centre quebecois de coordination sur le SIDA, Montreal. Dr. Alary is supported by a National Health Research scholarship (6605-4157-48A) from the NHRDP and a grant (930073-103) from the Fonds de la recherche en sante du Quebec.

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31. Tappin DM, Girdwood RWA, Follett EAC et al: Prevalence of maternal HIV infection in Scotland based on unlinked anonymous testing of newborn babies. Lancet 1991; 337: 1565-1567 32. Ippolito G, Costa F, Stegagno M et al: Blind serosurvey of HIV antibodies in newborns in 92 Italian hospitals: a method for monitoring the infection rate in women at time of delivery. J Acquir Immune Defic Syndr 1991; 4: 402-407 33. Ades AE, Parker S, Berry T et al: Prevalence of maternal HIV-1 infection in Thames regions: results from anonymous unlinked neonatal testing. Lancet 1991; 337: 1562-1565 34. Hull HF, Bettinger CJ, Gallagher MM et al: Comparison of HIVantibody prevalence in patients consenting to and declining HIVantibody testing in an STD clinic. JAMA 1988; 260: 935-938 35. Fehrs U, Fleming D, Foster LR et al: Trial of anonymous versus confidential human immunodeficiency virus testing. Lancet 1988; 2: 379-382 36. Curran JW, Jaffe HW, Hardy AM et al: Epidemiology of HIV infection and AIDS in the United States. Science 1988; 239: 610-616 37. Winkelstein W, Lyman DM, Padian N et al: Sexual practices and risk of infection by the human immunodeficiency virus: the San Francisco Men's Health Study. JAMA 1987; 257: 321-325 38. Kays RB, Kegeles SM, Coates TJ: High HIV risk-taking among young gay men. AIDS 1990; 4: 901-907 39. Schechter MT, Boyko WJ, Douglas B et al: The Vancouver Lymphadenophathy-AIDS Study: 6. HIV seroconversion in a cohort of homosexual men. Can Med Assoc J 1986; 135: 1355-1360

~~uux,w u~~~~~~~~~~m

40. McCusker J, Stoddard AM, Mcdonald M et al: Maintenance of behavioral change in a cohort of homosexually active men. AIDS 1992; 6: 861-868 41. Ekstrand ML: Safer sex maintenance among gay men: are we making any progress? AIDS 1992; 6: 875-877 42. Joseph KM, Adib SM, Joseph JG et al: Gay identity and risky sexual behavior related to AIDS threat. J Community Health 1991; 16: 287-297 43. De Wit JBF, van den Hoek AR, Sandfort TGM et al: Increase in unprotected anogenital intercourse among homosexual men. Am J Public Health 1993; 83: 1451-1453 44. Lamothe F, Bruneau J, Coates R et al: Seroprevalence of and risk factors for HIV- 1 infection in injection drug users in Montreal and Toronto: a collaborative study. Can Med Assoc J 1993; 149: 945-951 45. Coates RA, Rankin JG, Lamothe F et al: Needle sharing behaviour among injection drug users (IDUs) in treatment in Montreal and Toronto, 1988-1989. Can J Public Health 1992; 83: 38-41 46. Remis R: Rapport sur la situation du SIDA et de l'infection ai VIH au Quebec, 1992. Resultats de la pemiere annie du mandat: I fe'vrier 1991 au 31 mars 1992, Centre d'etudes sur le SIDA, DSC Hopital General de Montreal, Montreal, 1992 47. Surveillance des cas du syndrome d'immunodeficience acquise (SIDA), Que'bec, Cas cumulatifs 1979-1994, Centre quebecois de coordination sur le SIDA, Montreal, Jan 1994

occurred, usually developed early in the course of therapy, was self limiting and required discontinuation of CYTOTEC in less than 2% of the patients. The incidence of diarrhea can he minimized by adjusting the dose of CYTOTEC, hy adminisfering after food, and hy avoiding co-administration of CYTOTEC with magnesium-containing antacids. Gynecological: Women el: Teewrnosignificant (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmeno *.N & yaso g o le,cm dfencsithsatyprofile of CYTOTEC in approximately 500 alc ou arketing surveillance fptent pared with younger patients. Confusion has heen reported in a small nu reaction of CYTOTEG. Incidence greater than 1%: In clinical trials, t flowing y more than 1% pobe he (2.4%), dyspepsia the dr sea (3.2% of the suhjects receiving CYTOTEC and may he causally re wre n erences between the Ily signit (2.0%), vomiting (1.3%) and constipation (1.1% Howeve incidences of these events for CYTOTEC and pI meddautol TONTnh DOAEM meddautol DM ISRTNTrtnf:h DOAEND AMIST 800 pg a day dosage of CYTOTEC misoprostol) for t sric ulc AI-id ention tMen sche scribed in divided doses. N IDs sho appropriate, physi t ordin ken afteTh8 reComnCYTOTEC and NSAID asiu shoe sly.0 TEC 0 pg enal LI weeks in two or four mended adult oral dTC (mi hetm with food. Antacids dos 0pg qid or 40 equally divided do o a total of 4 weeks unless pi. et sh as needed for (aluminum baesd exm n thhro aients who may not have healin 'Iles by end bendcumnented f f r4wek.Uein Elderly and Renally afte conti fu eks, therapy with CYTOTEC dusmn: Ph ona tets with varying degrees of renal impairkneti I r la orlto owda hrsa beo affected. oprdtIoras In both the In AU su and pharmacokinetics may irmen't jects xvfae endegree ent groups ifcant. No routine dosage adjustment is recommended in cokinetic changes are not clinic oei o oeae.I nee be h sa m ptetswtaenli awrne(0pgODisecm ntgDoae may0 toID nd. gtbesaewiet f-ht,soe,hxgnlwt ERE16 CTT 100 tablets. CYTOTEC 500 n one side availbe in pg tablets are white to off-white, round s120and en d on one side and CYTOTEC on the other available in buff les of1100 tablets. tabl EREe

isoprostoU ~~~~~~~~~~~

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THERAPEUTIC CLASSIFICATION Mucosal Protective Agent INDICATIONS CYTOTEC (misoprostol) is indicated for the prevention of NSAID-induced gastric ulcers. Patients at high risk of developing NSAID-induced complications and who may require protection include: Patients with aprevious history of ulcer disease or a significant gastrointestinal event. * Patients over 60 years of age. * Patients judged to he at risk because of general poor health, severe concomitant medical disease, or patients who are poor surgical risks. * Patients disabled hy joint symptoms (e.g., HAG Disability Index Score >1.5) or those with severe systemic manifestations of arthritis. o Patients drugs known to damage or exacerhate damage to the gastrointestinal tract such as corticosteroids or anticoagtaking other ulants. o Patients taking a high dosage or multiple NSAIDs, including those available Over-The-Counter. The risk of NSAIDinduced complications may he highest in the first three months of NSAID therapy. CYTOTEC is also indicated for the treatmeet of NSAID-induced gastric ulcers (defined as . 0.3 cm in diameter) and for the treatment of duodenal ulcers. CONTRAINDICATIONS Known sensitivity to prostaglandins, prostaglandin analogues, or excipients (microcrystalline and hydroxypropyl methyIcellulose, sodium starch glycolate and hydrogenated castor oil). Contraindicated in pregnancy. (See CLINICAL PHARMACOLOGY.) Women should he advised not to become pregnant while taking CYTOTEC (misoprostol). If pregnancy is suspected, use of the product should be discontinued. WARNINGS Women of childbearing potential should employ adequate contraception i.e., oral contraceptives or intrautermne devices) while receiving CYTOT1EC (misoprostol). (See CONTRAINDICATIONS.) rsin Mohers It is unlikely th th CYTOTEC is excreted in human milk since it is rapidly metabolized throughout the body. However, it is not kno active metabolite (misoprostol acid) is excreted in human milk. Therefore, CYTOTEC should not be administer ri mothers because the potential excretion of misoprostol acid could cause significant diarrhea in nursing URe: Safety and effectiveness in patients below the age of 18 have not been established. olPRECAUTIONS SeleciongofPatients: Caution should be used when using symptomatology as th Mlow-up procedure, since CYTOTEC (misoprostol) has not been shown to have an effect I"pin cu ga hul fort. Before treatment is undertaken, a positive diagnosis of duodenal ulcer or NSAI 50 ymost b The general health of the patient should be considered. Misoprostol is rapidly Str al or h metabolites. Nevertheless, caution should be exercised when patiients have 400 Iroquois Shore Road tin ParaPatient Insert. Ontairio CLINICAL PHARMACOLOGY: Pharmacokinetics.) Diarrhea: Rare instances an L dbOakville, aleading or those t W 1M5 tion have been reported. Patients with an underlying condition s eyL6H irr fprscribed. tion, were it to occur, would be dangerous, should be mo rnces: 1. Ellioff OP. Annals of Pharmacotherapy 1990;24:954-957. 2. Agrawal NW, et al. Annals of Internal Medicine D may be n t h 1 ;115(3):195-200. 3. Cryer B, Feldman M. Arch Intern Med June 1992;152:1145-1153. 4. Fries JF. J of ents ts rotine is.rc Dsge (10 Msculoskeletal Medicine 1991;2:21-28. 5. Gabriel SE, et al. Annals of Internal Medicine 1991;115(10):787-796 na ih Neeo ofmiso- 6. CYTOTEC' Product Monograph, Searle Canada Inc. 7. Graham DY, Agrawal NM, Roth SH. The Lancet 1988;2:1 277-1280. f tlac rum prti pg OlD) is recommended. Drug Interactions: PA tz ari,n propra- Product Monograph available upon request. ine, dion, prostol) was not affected by: indomethacin, iccaid (300 an chlorot minoh rofen, chlorpr nolol, triamterene, cimetidi giiatsnce the no co cln ior om8%t52 pg/mL) lowered the pro hrt. Ilaoa nimination half-lIf tdes, misoprostol has binding of misopr tin oxidase system, and therefore should - linked hepatic mi th shown no signif oftepynie not affect the m normally metabolized by this system. No zodiazepines or0h e CLINICAL PHARMACOLOGY.) Some een obsere tda ibta tmioros dru t ati i 9 I 7 1 i t c i i ) yn results~~ not produced hypotension at dosages effective in promoting the Into date indicate that CYTO healingoPOIc ith caution in the presence of disease states where hypotension vrtheless, CYTOTEC should r disease or coronary artery disease. Epileptic seizures have mih rcp re complications, e.g., cerebr es administered by routes other than oral. Therefore, misobeen reported staglandins and prostaglandin a eptic only when their epilepsy is adequately controlled and then only when used in know prostol tablets o

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mtmatic responses to CYTOTEC do not preclude the presence of gastric expected benefit trials, the most frequent gastrointestinal adverse events were diarrhea, abdominal pain and flatulence. The average xncidences of these events were 11.4%, 6.8% and 2.9%, respectively. In clinical trials using a dosage regimen of 400 pg bid,

the incidence of diarrhea was 12.6%. The events were usually transient and mild to moderate in severit. Diarrhea, when it

OCTOBER 1, 1994

(m isoprostol)

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