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The Prevalence of Syphilis From the Early HIV Period Is Correlated With Peak HIV Prevalence at a Country Level

Osbak, Kara K. MD; Rowley, Jane T. PhD; Kassebaum, Nicholas J. MD; Kenyon, Chris Richard MBChB, MPH, BA, MA, FCP(SA), DTMH, CertID(SA), PhD

Sexually Transmitted Diseases: April 2016 - Volume 43 - Issue 4 - p 255–257
doi: 10.1097/OLQ.0000000000000422
Original Study
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Background Could we have predicted national peak HIV based on syphilis prevalence in the 1990s? Earlier studies have shown positive correlations between various sexually transmitted infections at different population levels. In this article, we test the hypothesis that there was a residual variation in the national prevalence rates of syphilis and that these rates could predict subsequent peak HIV prevalence rates.

Methods This analysis uses linear regression to evaluate the country-level relationship between antenatal syphilis prevalence (1990–1999) and peak HIV prevalence. Antenatal syphilis data were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low-risk populations. Peak HIV prevalence was calculated based on data taken from the Global Health Observatory Data Repository of the World Health Organization.

Results A moderately strong association is found for the 76 countries with data available (R2 = 0.53, P < 0.001). The association was weakened but remained significantly positive when we adjusted for the type of syphilis testing used.

Conclusions Syphilis prevalence in the 1990s predicted approximately 53% of the variation in peak HIV prevalence. Populations with generalized HIV epidemics had a higher prevalence of syphilis in the pre-HIV period. This finding provides additional rationale to carefully monitor sexual behavior, sexual networks, and sexually transmitted infection incidence in these populations.

This study found that populations with generalized HIV epidemics had a higher prevalence of syphilis in the pre-HIV period.

From the *HIV/STI Unit, Institute of Tropical Medicine, Antwerp, Belgium; †London, United Kingdom; ‡Institute for Health Metrics and Evaluation, Seattle Children's Hospital, University of Washington, Seattle, WA; and §Division of Infectious Diseases and HIV Medicine, University of Cape Town, Cape Town, South Africa

Conflicts of Interest and Source of Funding: None declared.

Correspondence: Chris Richard Kenyon, MBChB, MPH, BA, MA, FCP(SA), DTMH, CertID(SA), PhD, HIV/STI Unit, Institute of Tropical Medicine, Antwerp, Belgium. E-mail: ckenyon@itg.be.

Received for publication October 30, 2015, and accepted December 10, 2015.

Previous studies have found positive correlations between the prevalence of various sexually transmitted infections (STIs) at different levels of aggregation. At the level of ethnic/racial groups, studies have found a relationship between the prevalence of HIV and syphilis,1,2 herpes simplex virus type 2 (HSV-2),2,3 chlamydia,1 and gonorrhea.1 At a national level, peak HIV prevalence has been found to be correlated with HSV-2 prevalence in women.3 At the world-regional level, HIV prevalence was correlated with the prevalence of HSV-2, gonorrhea, chlamydia, syphilis, and trichomonas, but this relationship was only statistically significant in the case of HSV-2 and gonorrhea.4

In this article, we extend these analyses to assess if the prevalence of syphilis from the early HIV period is correlated with peak HIV prevalence at a country level. We chose syphilis as the widespread testing for syphilis in routine antenatal care means that there are more data available from population-based samples for syphilis in the early HIV period than there is for other STIs.5

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METHODS

Antenatal syphilis data for 1980 to 2010 were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low-risk populations compiled for Global Burden of Disease Study 2010.6 The Institute for Health Metrics and Evaluation data sources included the Joint United Nations Programme on HIV and AIDS epidemiologic fact sheets, UN General Assembly Special Session on Drugs country progress reports, reports from country specific surveillance systems, World Health Organization reports on syphilis epidemiology, and unpublished data from correspondence with Global Burden of Disease Study 2010 collaborators. These were supplemented by a systematic literature review of syphilis seroprevalence (most recent PubMed search was October 2011). To be included, a study needed to provide data on the prevalence of syphilis in populations considered representative of the general population and have a sample size of at least 100. Data from high-risk populations (e.g., men who have sex with men [MSM], sex workers, and STI clinic attendees) were excluded.6–9

For each country, we extracted the studies conducted in antenatal populations between 1990 and 1999 and used the median of these studies as a proxy for the national prevalence of antenatal syphilis (termed the syphilis prevalence variable).

For the adjusted syphilis prevalence, we generated new syphilis prevalence estimates adjusted according to the syphilis-testing algorithm used because different types of testing algorithms influence the estimates of prevalence. Studies that use both a treponemal and a nontreponemal test to diagnose infection are regarded as offering the most accurate measure of active syphilis infection.10 We applied correction factors to different syphilis testing algorithms used based on a systematic review and meta-analysis that estimated the proportion of pregnancies with “probable active syphilis” according to the testing methodology used in the study.5 Studies using only a treponemal test will falsely label persons with old or treated syphilis as having active syphilis; therefore, a correction factor of 0.536 was applied to these prevalence estimates. Studies using only nontreponemal testing will falsely diagnose active syphilis in persons with other inflammatory conditions that lead to biological false-positive reactions in the nontreponemal test. A correction factor of 0.522 was applied to these studies. In addition, the study recommended the use of a correction factor of 0.686 for studies that did not report the type of testing used.5

National peak HIV prevalence was obtained for 149 countries for which HIV prevalence estimates were available from 1990 to 2009 in the Global Health Observatory Data Repository of the World Health Organization (http://apps.who.int/gho/data/node.main.622).11 These estimates are based on population-based testing, antenatal clinical surveillance, and epidemic models.12 From these data, we calculated the peak HIV prevalence variable as the highest HIV prevalence (in 15- to 49-year-olds) that each country obtained between the years 1990 to 2009 (median year, 1998; interquartile range, 1996–2005).11,13 We chose to use peak HIV prevalence rather than HIV prevalence at a defined period after the syphilis prevalence was measured per country, as this has been shown to avoid the HIV introduction time bias which is caused by the widely differing times that national HIV epidemics began.14 Peak HIV prevalence is a composite measure of all the factors that enhance and prevent the spread of HIV in a particular population. Because all national populations have now been exposed to HIV for more than a decade, the peak prevalence of HIV that they attained represents a useful summary measure of how permissive different sexual networks are to the spread of HIV.14 It may also be a useful measure of sexual network susceptibility to other STIs such as syphilis. Because HIV epidemics have been shown to reduce syphilis prevalence both through AIDS mortality15,16 and improved STI treatment,17 it is important to test the association between peak HIV and syphilis prevalence using syphilis prevalence data preceding the peak HIV prevalence. The period 1990–1999 was chosen for syphilis prevalence data because this was the first decade for which sufficient data were available in the data set and the beginning of this period predates the year that most countries attained their peak HIV prevalence. Only 16 countries had data points for the 1980s.

Simple linear regression was used to evaluate the relationship between syphilis prevalence and peak HIV prevalence—unadjusted and adjusted for laboratory testing used. Because the severity and heterogeneity of the HIV epidemics have been greater in sub-Saharan Africa than elsewhere, the analyses were repeated limited to the countries of sub-Saharan Africa. All analyses were performed in STATA 12.0 (StataCorp LP, College Station, TX).

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RESULTS

We found a moderately strong association between syphilis prevalence and peak HIV prevalence for the 76 countries with data available (R2 = 0.53, P < 0.001; Fig. 1). The association was weakened but remained significantly positive when we adjusted for the type of syphilis testing used (R2 = 0.34, P < 0.001). A similar positive association was found when we restricted the analyses to 28 countries of sub-Saharan Africa (R2 = 0.69, P < 0.001, for unadjusted syphilis prevalence vs. peak HIV prevalence).

FIGURE 1

FIGURE 1

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DISCUSSION

This study found a positive association between syphilis prevalence during the period 1990–1999 and peak HIV prevalence at a country level. Syphilis prevalence in the 1990s predicted approximately 53% of the variation in peak HIV prevalence. This same relationship has been found at the levels of individuals,18,19 ethnic/racial groups,1,2 and world regions.4 For example, a study that assessed this relationship at the ethnic group level in the United States and South Africa found a strong positive association between syphilis prevalence (predating peak HIV prevalence) and HIV prevalence.2 However, not all studies have found this positive association.19 That the same positive association has been found between HIV and other STIs at the levels of individuals, ethnic/racial groups, and countries2,4 reduces the chance that this relationship is explained by confounding or is due to an ecological or other form of bias. Rather, this association suggests that syphilis played a significant role in the spread of HIV and/or that both are determined by the same or similar factors.

There are a number of limitations with this type of retrospective study; chief among these is the quality of the syphilis prevalence data. Peak HIV data were only reported for 149 countries, and we only had combined HIV and syphilis data for 76 countries. Of the countries with data, prevalence estimates were based on relatively small or somewhat selected samples that may not be representative of the general population. Specifically, many of the studies are from urban areas and are studies of women presenting for antenatal care. It would also would have been optimal to have had an earlier range syphilis prevalence estimates because some countries started attaining their peak HIV prevalences in the early/mid 1990s, such as Uganda, where HIV peaked in 1991. We cannot exclude the possibility that the association between HIV and syphilis is due to unmeasured confounders. In certain countries, intravenous drug use has been the major mode of HIV transmission, and in these countries, one would expect to find HIV prevalences to be disproportionately elevated vis-à-vis syphilis. We have also not considered the role that the endemic trepanematoses may have played in giving false-positive syphilis results. The effect of each of these data and methodological limitations would dilute the strength of an association between syphilis and peak HIV prevalence.

A syphilis testing regime correction factor was also included in the analysis, and when this factor was applied, the association between syphilis and HIV was weakened. This could be explained by the fact that syphilis prevalences were overestimated in the studies that only use antibody testing which cannot distinguish reinfections from previous infections. The correction factors have not been validated in separate studies, and hence, they may lead to inaccurate prevalence estimates which is an alternative explanation for the observed attenuation in HIV/syphilis association. A number of countries experienced considerable decreases or increases in the prevalence of syphilis in the 1990s.7,20 Our measure of syphilis prevalence was the median value for the 1990s, and our prevalence estimates may not have captured these changes.

There is increasing evidence that AIDS mortality played a role in the marked decline of syphilis prevalence in general populations in Southern and Eastern Africa16,17,20 and MSM populations in North America.15 In high-income countries, the widespread availability of antiretroviral therapy has led to a decline in AIDS mortality, and partly as a result, MSM sexual networks are returning toward a high-risk pre-AIDS structure with a concomitant increase in syphilis and other STIs.21,22 It is important to appreciate that populations with generalized HIV epidemics had a higher prevalence of other STIs such as syphilis in the pre-HIV period,2 as this provides an additional rationale to carefully monitor sexual behavior, sexual networks, and STI incidence in these populations to allow for the early detection of any return toward to a pre-HIV risk configuration.16

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