Updates By Carol A. Kemper, MD, FACP
By Carol A. Kemper, MD, FACP, Section Editor: Updates, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.
An old disease returns: Syphilis in North America
Syphilis is making a resurgence in the U.S. and Canada, especially in urban areas, where the rates of newly diagnosed infection have soared, especially in men-who-have-sex-with-men (MSM). The problem has begun "spilling over" into the heterosexual community. This epidemic may be largely attributed to the availability of internet hook-ups and networking mobile smartphone apps, such as Grindr, the increased use of methamphetamines, as well as what is termed "prevention fatigue." San Francisco County has recorded spikes in all STDs for six straight years and the number of early syphilis cases rose from 659 in 2010 to 682 in 2011 (the last year for which unofficial numbers are available). It is estimated that each new cases of syphilis results, on average, in exposure to 10 additional people.
Grindr is a gay social networking application launched in 2009 and available worldwide it runs on the iPhone, blackberry and Android. The app allows users to meet other men within close proximity who are interested and available for whatever specified sexual activity using the phones mobile location services. We tried it in our Santa Clara county HIV clinic the other day and someone was available and interested in having sex not more than 75 feet away they were in the same building!
Some public health officials are now recommending syphilis screening of high-risk individuals every 3-6 months. This might make good sense in our HIV clinic, we routinely screen on an annual basis but based on these figures, screening at shorter intervals makes sense.
Syphilis in Africa
Dionne-Odom J, et al. Syphilis treatment response among HIV-discordant couples in Zambia and Rwanda. Clin Infect Dis 2013: 1829-1837.
One of the toughest problems with managing syphilis is discerning the adequacy of therapy, and deciding when ≥ someone is "serofast" or failing to respond to therapy. Generally, I've believed, the longer someone has been RPR-positive, the longer they take to respond, and true failures of therapy are uncommon. In a recent prospective clinical trial involving 465 HIV-negative adults treated for early syphilis, 79% were considered responders and 21% were serofast at 6 months of treatment (response was a negative RPR or at least a ≥ 4-fold drop in RPR titer; and serofast was defined as a ≤ 2-fold decrease in titer or persistent titers).1 There were no treatment failures. Serologic response was associated with younger age, fewer sexual partners, higher baseline antibody titers, and earlier syphilis stage.
Over the years, concern has been expressed that HIV-infection may increase the risk of treatment failure for early syphilis. These authors retrospectively examined the frequency of syphilis infection in HIV-discordant couples cohorts, and compared the frequency and predictors of response to therapy between those who were HIV-positive versus -negative. Two large HIV-discordant couples cohorts in Zambia and Rwanda formed the basis for this investigation. Originally, 6,688 individuals were enrolled in the project between 2002-2008, 6016 of whom had at least one follow-up visit. At one site, RPR testing was performed at baseline, at every 3 months of follow-up for 3 years, and then annually for 3 years, while at the other site, RPR testing was performed every 6 months for the first 3 years of the study, and annually thereafter. The presence of an RPR ≥ 1:2 was considered a positive, and persons with a positive test were offered a single dose of 2.4 million units of benzathine PCN IM, although a few patients with positive RPR's at baseline were treated with 2 to 3 weekly doses of benzathine PCN (n= 68 people). Responses were defined as at least a 4-fold fall in RPR titer.
A total of 1,810 episodes of syphilis were treated in 1,321 individuals during the study period. A positive RPR was found at entry to the study in 18% of patients in Zambia and 9% of patients in Rwanda. At entry to the study, the prevalence of a positive RPR in women was higher than men (20% vs 15%), and the RPR prevalence in HIV-positive individuals was higher than in HIV-negative individuals (16% vs 10%). In total, 35% of RPR-positive participants had an RPR positive spouse, although RPR-positive men were more likely to have an RPR-positive wife (45%), than RPR-positive women, whose male partners were positive 27% of the time.
The difference in the responses seen between genders did not remain significant in multivariate analysis when adjusted for other factors.
The rates of serofast titers were 20% for those with newly diagnosed disease during study, and 33% of those diagnosed with syphilis on entry to study. This difference may, in part, reflect the differences in response to therapy for someone with early primary disease vs. latent disease but, additionally, individuals with more long-standing infection are at greater risk for persistent antibody production and a serofast titer, despite cure. The association between serologic response and a higher RPR titer (≥ 1:4) may also reflect whether a patient was newly diagnosed, or may have had a previously treated, low-grade, positive serofast titer. But it becomes difficult to know for certain whether a serofast titer represents residual disease burden or persistent antibody production. As is often the case, many of the individuals in this study with persistent positive RPR titers received repeated injections of penicillin. While undiagnosed neurologic infection could be an explanation for persistent serofast titers in some individuals, detection of neurosyphilis by lumbar puncture could not, unfortunately, readily be done in this study.
1. Sena AC, et al. Predictors of serological cure and serofast state after treatment in HIV negative persons with early syphilis. Clin Infect Dis 2011; 53(11): 1092-9.
United States HIV prevention stance
Moyer, V, et al. Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2013;159: 51-60; and accompanying editorial: Das M. Bringing the end in sight: Consensus regarding HV screening strategies. Ann Intern Med 2013;159:63-4.
When the U.S. Preventive Services Task Force (USPSTF) last issued guidelines for HIV screening in 2005, the committee expressed concern about the psychological ramifications and social stigmatization of testing HIV- positive, and cautiously focused their screening recommendations on persons at risk and pregnant women. Broad-based screening of the population was given non-committal consideration (a "C" rating).
In 2006, the CDC took a step towards universal screening by recommending what has been framed as an "opt-out" approach persons aged 13 to 64 years could be offered HIV testing with an new emphasis on testing in sites where screening had previously been discouraged, such as emergency rooms, and screening of all pregnant women.
The USPSTF has finally taken the next step and, in the new 2013 U.S. HIV Screening Guidelines, recommends universal HIV screening for all adolescents and adults ages 15 to 65 years of age. Their recommendations were based on several important factors: An estimated 20% of the HIV-infected population in the U.S. (approximately 236,000 people) is unaware of their HIV infection. While 11% of existing infections are attributed to heterosexual sexual contact, 25-27% of newly diagnosed HIV infections are attributed only to heterosexual sex, including many young Hispanic and black women. In addition, nearly half of all STDs occur in adolescents putting them at increased risk for HIV. Many younger people are at risk for HIV infection but do not necessarily enter into the health care system in an established way that provides them testing. If these individuals are going to be tested at all, it must occur when they present for the occasional sore throat, STD, trauma, or pregnancy.
In addition, the USPSTF recognized the significant benefit of HIV treatment on reducing the risk of progression to AIDS, opportunistic infection and death, although they spent several paragraphs attempting to discuss the optimal timing of antiretroviral therapy (early initiation of antiretroviral therapy has previously been vigorously debated and has now been accepted as standard of care). They also acknowledged that while HIV treatment is associated with some risk, including long-term side effects, numerous clinical trials demonstrate a clear benefit-risk ratio. And while the psychological impact of finding out you are positive is a negative the chance of earlier treatment and longer-term survival seems like a better bet. The Task Force also acknowledged that both conventional and rapid HIV testing provide sensitive and specific test results, with a relatively low rate of false-positives. Even in a low-risk population, conventional HIV testing may result in 1 false positive test in 250,000 tests.
An important consideration in favor of universal screening is the concept of "community HIV viral load" effectively, the burden of unrecognized/untreated HIV disease in a community is fueling the occurrence of new infections. Simply put, if we could find that 20% of people who are unaware of their HIV infection, and get them into treatment, they would be less likely to transmit infection to others.
The Task Force recommends continued emphasis on screening in higher risk areas such as STD clinics, homeless shelters, TB clinics, and adolescent health clinics that treat STDs. Persons younger than 15 or older than 65 years of age who engage in risky activities should also be tested.
All pregnant women should continue to be screened with every pregnancy, regardless of the appearance of no risk. Women with risk factors should have repeated screening in the third trimester. This affords the opportunity to confirm HIV infection and provide effective therapy during pregnancy, which is highly effective at reducing transmission to the infant. All women should continue to be screened in subsequent pregnancies. Particular emphasis is given to peri-partum testing in women presented to labor and delivery who have not been previously tested recognizing that the small risk of a false-positive test may result in unnecessary treatment and some limited risk.
The premise here and I believe it's a good one is anyone who has sex is at risk for HIV, and risk behaviors may not be recognized or acknowledged. Screening people for HIV, in addition to hepatitis C, should become the norm. Physicians should make an effort to screen all teenagers, young adults, and even older adults at least once and I make a habit of HIV testing anyone who comes in with a new STD as well as all new ID consults in the hospital, even if the presenting problem is not clearly related to HIV (e.g., MRSA abscess).
A question not well answered by this document, however, is how often re-testing should occur. The Task Force suggested that a reasonable approach might be to screen individuals at "very high risk" every year, and those at "increased risk" every 3 to 5 years. I'm not sure I understand the distinction between these two groups, but presumably the task force is referring to MSM and injection drug users as high risk. Once again, clinicians who are treating these individuals may be changing practice ahead of the published guidelines it is not unusual for MSM in our area who engage in unprotected sex with multiple partners to be screened every 3 to 6 months (Remember, sex is a great multiplier it was estimated above that one new case of syphilis may result, on average, in 10 new cases.) Recent 2013 data examining the risk of HIV-infection in young, largely black women in 10 high risk urban areas within the U.S. identified an annual incidence of HIV-infection of 0.32% comparable to adults living in sub-Saharan Africa. The only way we are going to stem this "tide" is by identifying people who are positive and getting them into care and on treatment.