Background: To investigate the temporal associations between Trichomonas vaginalis (TV) diagnoses in women at a large urban sexual health clinic and a major Papanicolaou (Pap) smear screening laboratory in Victoria, Australia with Pap smear screening rates and the introduction of nitroimidazole treatments.
Methods: An ecological analysis of TV diagnosis rates at the Melbourne Sexual Health Centre and the Victorian Cytology Service, Pap smear screening rates and nitroimidazole prescription data.
Results: Diagnoses of TV at the Melbourne Sexual Health Centre peaked in the 1950s at 20% to 30% and then rapidly declined through the 1960s and 1970s to below 1% in 1990. A similar pattern was observed at the Victorian Cytology Service. Metronidazole prescribing and opportunistic Pap smear screening began in Victoria in the 1960s coinciding with declining TV. The availability of tinidazole in 1976 led to further declines in TV in the late 1970s. A national cervical screening program introduced in 1991 was temporally associated with further declines in TV.
Conclusions: Our analyses suggest that the introduction of metronidazole was associated with a large reduction in TV among Victorian women in the 1960s. The subsequent availability of tinidazole and increased Pap smear screening may have contributed to the current low TV prevalence in Victoria.
The introduction of nitroimidazole treatments and Papanicolaou smear screening have contributed to declining Trichomonas vaginalis rates in Australia observed over the last 60 years.
From the *School of Population Health, University of Melbourne; †Melbourne Sexual Health Centre, Victoria; ‡Victorian Cytology Service, Melbourne, Victoria; §Canberra Sexual Health Centre and Academic Unit of Internal Medicine, Australian National University, Australian Capital Territory; ¶Microbiological Diagnostic Unit, University of Melbourne, Victoria; #Sydney Sexual Health Centre; **National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, New South Wales; and ††Key Centre for Women's Health in Society, School of Population Health, University of Melbourne, Victoria, Australia
The authors are grateful to Gillian Phillips and Matthew Cunningham at the VCS for their help with the data extraction; Chris Thomas and Bernard Folley from the MSHC for their advice regarding TV treatment. Thanks also to the DUSC/PBS and VDHS for respectively providing the nitroimidazole and gonorrhoea notification data.
Correspondence: Dr. Jane S. Hocking, Key Centre for Women's Health in Society, The University of Melbourne, Victoria 3010, Australia. E-mail: email@example.com.
Received for publication September 20, 2007, and accepted December 20, 2007.
TRICHOMONAS VAGINALIS (TV) IS ONE OF the most common sexually transmitted infections (STIs) with an estimated 174 million cases worldwide each year.1 It is a serious public health problem, associated with an increased risk of human immunodeficiency virus (HIV) transmission, infertility, pelvic inflammatory disease and complications in pregnancy, including premature rupture of the placental membranes.2–6 In the United States, it has been suggested that the proportion of HIV infections that are attributable to TV may be 20% or more,7 with a conservative direct annual medical cost of 34.2 million (year 2000, United States) dollars.8 TV is asymptomatic in over 50% of cases9 and without active testing, the majority of infections will remain undiagnosed.
TV is particularly common in some US populations; the prevalence of TV among women attending inner city sexually transmitted disease (STD) clinics approaches 25%,10 with very high prevalence estimates reported among black women.7 It is also common in parts of Asia,11 the Pacific,12 Africa,13,14 and among rural or remote Indigenous populations in New Zealand15 and Australia.4,9,16 However, it is rare in urban areas of Australia17 and in parts of Europe.4 In data from Denmark's national surveillance system, the percentage of women diagnosed with TV fell from 19% in 1967 to 2% in 1997.18
It is unclear why TV diagnosis rates have declined in some countries but not in others. Some have suggested that differences in Papanicolaou (Pap) smear screening rates may be responsible for the discrepancy.17 Another suggestion is that TV diagnosis rates have been affected by the increased use of nitroimidazoles (including metronidazole or tinidazole), for the treatment of TV infections or other infections such as giardiasis or bacterial vaginosis.17
Our aim was to investigate the temporal relationship between TV diagnosis rates among women attending a large urban sexual health clinic, women having a Pap smear screened at a major urban laboratory, Pap smear screening (coverage) and the introduction of metronidazole and tinidazole treatments in Australia.
This ecological study utilized data from a number of sources. Our analyses were restricted to TV diagnosis rates among women only, as men were not routinely screened for TV at the Melbourne Sexual Health Centre (MSHC). TV infection in men is usually self-limiting, with a significantly shorter duration of infection compared with women who experience most of the TV associated complications.19
The MSHC is a large publicly funded sexual health clinic in Melbourne, Victoria, Australia, and services a population of approximately 3.7 million. The MSHC has always been located in the central business district and currently provides about 25,000 consultations a year. From 1947 to 2004, it was routine practice to test all symptomatic women for TV by wet preparation and culture, with all asymptomatic women by culture (in all cases using Cysteine Peptone Liver Maltose media),20 unless they were returning for results or review.21 Since 1917, the MSHC has kept a registry of all clients and their diagnoses. The registry, which is in the form of logbooks, includes patient medical record numbers, gender of patients, type of STI tests performed, date of testing, and test results. The number of TV tests conducted on women attending the MSHC and the number of positive test results were extracted for each year from 1947 (when TV was first recorded at the MSHC) to 2005.
Victorian Cytology Service Data
The diagnosis of TV on a Pap smear is well documented with a reported sensitivity of 50% to 60%.2,10,17,22 A national organized cervical screening program was introduced in Australia in 1991.23 As part of this program, the contact details of women are voluntarily placed into a registry that allows for subsequent recall every 2 years and the follow up of any detected abnormalities.23 Currently in Australia, about 60% of women aged 20 to 69 years are screened every 2 years.24 Before 1991, women were opportunistically screened when they presented to their general practitioner, with no formal systems in place for recall or management. The Victorian Cytology Service (VCS) is Australia's largest publicly funded cervical cytology laboratory. It commenced operation in 1965 and currently screens about 50% of Victoria's annual Pap smears. Any TV diagnosed on a Pap smear is entered into the VCS reporting database. The number of Pap smears screened and the number of TV diagnoses were extracted from the VCS database each year for the period from 1965 to 1989. We determined the total number of Pap smears screened annually in Victoria from 2 sources. First, from 1989 to 2005 we used the Victorian Cervical Cytology Registry which has collected this information.25 Second, as no accurate data are available for the total number of Pap smears screened annually in Victoria before 1989, we used the estimated VCS market share of Pap smear screens before 1989 to approximate the total number of Pap smears conducted during this time. The correlation between the TV diagnosis rate at the VCS and the annual Pap smear screening rate in Victoria was examined using simple linear regression. Because of the small number of TV diagnoses and small number of annual pap smears (<5000 per year) before 1968, the linear regression was only performed on data post 1968.
Prescription Pharmaceutical Benefits Scheme Data
A single 2 g dose of either metronidazole or tinidazole has a cure rate of over 90% for TV.26 These nitroimidazoles are available in Australia by prescription only. Two sources of data were used to estimate the number of prescriptions for these 2 nitroimidazoles. First, records of all prescriptions dispensed for metronidazole and tinidazole that have been subsidized by government payments are stored in Australia's Health Insurance Commission records database. Second, a number of pharmacies nationally are involved in an ongoing survey of estimates on the use of nonsubsidized medicines. The Australian governmental body known as the Drug Utilization Sub-Committee of the Pharmaceutical Benefits scheme, combines these national data from both the above mentioned sources and produces estimates of the number of prescriptions dispensed per year for different drugs nationally.27 We used these national estimates as an approximation to the trend of use of metronidazole and tinidazole in the Victorian population. The number of prescriptions dispensed for metronidazole and tinidazole were combined for each year from the earliest electronic records in 1987 to 2005. These data were extracted from the Drug Utilization Sub-Committee database for men and women combined, as it was not possible to obtain separate data for men and women.
Gonorrhoea Notification Data
As there are no cytologic changes diagnostic of gonorrhoea infection, Pap smear screening would be expected to have no effect on gonorrhoea prevalence. Further, effective treatment for gonorrhoea with penicillin has been widely available in Australia since the 1940s28 and as a result, any increases in the annual gonorrhoea notification rate are possibly attributable to changes in sexual risk taking behavior.29To assess whether changes in TV could be explained by changes in sexual behavior, we examined trends in the annual gonorrhoea notification rate among Victorian women from 1948 to 2005 (data were not available for 1947). These data were obtained from the Victorian Department of Human Services. The examined trends were viewed as a surrogate measure of the influence of changes in sexual behavior. For example, if gonorrhoea notifications increased while TV diagnoses decreased, this would suggest that factors other than sexual behavior were influencing TV diagnosis rates.
Ethics approval for this study was obtained from the Alfred Hospital Ethics Committee.
Figure 1 shows the TV diagnosis rates among women diagnosed at the MSHC between 1947 and 2005 and in Pap smears screened at the VCS between 1965 and 2005. Both these data sources show several consistent patterns. First, TV diagnosis rates at the MSHC rose substantially from 1947 to a peak of 28% in 1955. Second, in the 1960s TV diagnosis rates decreased at both the MSHC and the VCS, falling considerably until the 1970s where they remained stable until about 1980. Third, diagnosis rates progressively fell in the 1980s to extremely low levels in the 1990s, to less than 1% at both sites by the early 1990s.
Gonorrhoea notifications among women in Victoria show a different pattern to TV diagnosis rates. The gonorrhoea notification rate increased dramatically during the 1960s to peak at about 50/100,000 in 1972, remaining high during the 1970s at a time when TV diagnoses at the MSHC and the VCS were decreasing considerably. Gonorrhoea notifications then decreased dramatically in the 1980s, coinciding with a decrease in sexual risk taking behavior, possibly in response to the HIV epidemic,29 but have subsequently begun to increase since the early 2000s.
Metronidazole was introduced and licensed for the treatment of TV infections in Australia in the early 1960s30 and was further recommended for the treatment of giardiasis in 1969.31 In the years following this, TV diagnoses at the MSHC began to decline substantially. Tinidazole was introduced in 197632 and a further decline in TV diagnoses was observed at the MSHC in the late 1970s; similar declines around this period were also noted in other Australian states (suggesting a national phenomenon).33 Metronidazole was subsequently recommended for the treatment of bacterial vaginosis in 198134 and this is likely to have further influenced TV infection in Australia.
Data on the annual number of prescriptions dispensed for metronidazole and tinidazole were only available for Australia (unable to obtain Victorian only data), and only available from 1987 to 2005. These data indicate that the number of prescriptions dispensed each year for these nitroimidazoles in Australia rose from 237,978 (2922/100,000) in 1987 to 684,587 (6700/100,000) in 2005. There was also a considerable increase in the number of prescriptions dispensed from <240,000 (<2946/100,000) prescriptions in 1987 to >590,000 (>6721/100,000) prescriptions in 1992, coinciding with the introduction of the national cervical screening program in 1991.23
Figure 2 shows the correlation between TV diagnosis rates at the VCS and annual Pap smear screening rates in Victoria. It shows that once Pap smear screening rates increased above 3% per year in the 1968, there was a significant linear decline in the TV diagnosis rate each subsequent year (P <0.01). Pap smear screening was introduced sporadically in Victoria in the early 1960s, but an organized national screening program did not occur until 1991.23 Annual Pap smear screening rates gradually increased from less than 1% coverage of Victorian women in the early 1960s to about 40% of women by 1994.
To our knowledge, this is the first study to describe the changes in TV prevalence over an almost 60 year period and temporally associate them with Pap smear screening, nitroimidazole prescribing and a surrogate marker for sexual risk taking behavior. Over this period, the TV diagnosis rate at the MSHC declined by more than 200-fold, from more than 20% at its peak in the 1950s, to less than 1% in the early 1990s. The majority of the decline in TV diagnoses occurred in the 1970s at a time when gonorrhoea notifications were increasing. These data suggest that although changes in sexual behavior were influencing the incidence of other STIs (such as gonorrhoea), the increased availability of nitroimidazoles and Pap smear screening may have had a role in the near eradication of TV currently in urban Australia. Although some have suggested that Pap smear screening or antibiotic use may be responsible,17 our study is the first to present data supporting this hypothesis.
TV prevalence remains high in Australian Aboriginal and Torres Straight Islander communities living in remote settings, where the community prevalence in women is about 25%.4,9,16,17 It has been reported that this is most likely the result of limited access to appropriate health care.35 Further, Pap smear coverage in Indigenous communities is also significantly lower (up to 30% less) than in urban settings,36 which may be contributing to a higher TV prevalence in these communities.
TV prevalence continues to remain high in some US populations, with prevalence estimates in clinical and sentinel population settings ranging from 3% among young women attending adolescent health clinics,37 through to over 45% in incarcerated women.38 Further, TV prevalence is disproportionately higher among blacks, ranging from approximately 1.5 to 10 times greater than in other ethnic groups.7,39 A recent population based study in the United States reported a prevalence of 1% among young white women and 10.5% among young black women.39
It is unclear why TV rates are higher in the United States, particularly as Pap smear coverage is high with around 80% of all women and nearly 90% of black women aged 18 to 44 years, having Pap smears every 3 years.40 However, it is apparent that TV is not routinely reported on Pap smears by US laboratories. The Bethesda terminology for reporting results of cervical cytology includes a code for TV diagnosis, but reporting is optional.41 Furthermore, clinicians may not always treat patients on the basis of a Pap smear report.
Another factor that may be contributing to the higher TV rates in the United States is the possibility that many STD clinics are not routinely testing for TV as part of a routine STD screen. A survey of 144 public health diagnostic laboratories showed that only 4 did any testing for TV.42 Other studies investigating the age-specific prevalence of TV in the United States have demonstrated that prevalence increases with age, in contrast with both gonorrhoea and chlamydia where the peak age for prevalence is between 15 and 25 years.10,19 Therefore, because younger age groups are more likely to be targeted for STI screening as a control measure, older people with TV may not be identified, thereby acting as a possible reservoir of infection.10
Increasing reports of metronidazole resistant TV may also be contributing to higher TV rates in the United States.10,43 Until recently, metronidazole was the only effective treatment for TV available in the United States with tinidazole becoming newly available in 2004.44 Other factors that may be contributing to higher TV rates particularly among black women include ready access to health care40,45–47 and douching.48
Our study has a number of limitations. First, this study used an ecological design, one which is inherently weak but is useful for hypothesis forming.
Second, it would have been useful to have had more accurate estimates on the number of Pap smears conducted annually before 1989 and the number of prescriptions dispensed for metronidazole or tinidazole before 1987. We did however, identify when other indications for metronidazole were introduced for common infections in Australia. Metronidazole was first recommended for giardiasis in 196931 and for bacterial vaginosis in 1981.34
Third, our data are retrospective and therefore, it is possible that differences in clinical practice over time may have influenced the TV diagnosis rates or number of gonorrhoea notifications. It is however, unlikely that this would explain such large differences in the noted TV diagnosis rate or number of gonorrhoea notifications. We know that there were no changes in diagnostic methods for TV at the MSHC over the study period and that all women were tested. In addition, the MSHC has an on-site laboratory with negligible delay in wet preparation or cultured samples, both types visually diagnosed for TV by highly trained and experienced laboratory staff. Therefore, it is unlikely that any large variability in the diagnosis of TV exists at the MSHC.
Fourth, we used gonorrhoea notifications as a surrogate marker of changes in sexual risk taking behavior of Victorian women and it is possible that factors other than sexual behavior may have contributed to changes in gonorrhoea notifications. However, it was the only quantifiable means obtainable by the authors to suggest changes in such behavior of Victorian women over the given time span.
Finally, the analysis relating to metronidazole and tinidazole dispensed, may not equate with the actual amount consumed by patients and it is possible that an unquantifiable amount of effective treatment was never consumed by patients or lost in Australia. However, it is reasonable to assume that this may have only occurred in a relatively minor number of cases.
Our analyses suggest that it was the introduction of metronidazole that brought about the initial large reduction in TV prevalence among Victorian women in the 1960s to 1970s. The subsequent availability of other treatments like tinidazole and increased Pap smear screening in the 1980s may have contributed to current TV diagnoses of less than 1% among Victorian women.
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