{"id":11080,"date":"2024-06-09T08:39:23","date_gmt":"2024-06-09T12:39:23","guid":{"rendered":"https:\/\/blogs.nejm.org\/hiv-id-observations\/?p=11080"},"modified":"2024-06-09T08:39:23","modified_gmt":"2024-06-09T12:39:23","slug":"the-mysteries-and-challenges-of-the-rpr-and-a-proposed-clinical-trial","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/the-mysteries-and-challenges-of-the-rpr-and-a-proposed-clinical-trial\/2024\/06\/09\/","title":{"rendered":"The Mysteries and Challenges of the RPR — and a Proposed Clinical Trial"},"content":{"rendered":"
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Detroit, early 20th century. RPRs are the Karius of the day.<\/p><\/div>\n

Last week, we had a real treat for our weekly ID\/HIV clinical conference — a review of controversies in the management of syphilis in adults by Dr. Khalil Ghanem<\/a>, from Johns Hopkins. He’s a well-known expert in the field of sexually transmitted infections, syphilis in particular.<\/p>\n

A highlight of the talk was his dismantling of a particularly confusing aspect of treatment monitoring, which is the serial checking of the RPR to assess the response to treatment, along with retreatment for failure to respond. An abbreviation for rapid plasma reagin<\/em>, the RPR and its oscillations have vexed clinicians and their patients for decades.<\/p>\n

How long? Well, since 1906 — 118 years ago, if his talk (and my math) are correct. To highlight how long ago this was, he showed a slide depicting what people were driving and wearing in 1906. (See photo for approximation. His slide is much funnier.) This is emphatically not<\/em> a new technology. Don’t expect a high degree of accuracy from something that debuted before widespread electrification of homes in our country.<\/p>\n

And the test is very weird. Unlike most antibody tests in infectious diseases, it measures not antibodies directed against the pathogen of interest, Treponema pallidum,<\/em> but to cardiolipin-cholesterol-lecithin antigens; it’s an immunologic response triggered by the infection.<\/p>\n

These antibodies are called “reaginic” antibodies — whatever “reaginic” means. Not surprisingly, the RPR is the quintessential non-specific diagnostic test, with tons of false positives (11% in one study<\/a>), and a very well-known (and paradoxical) cause of false-negatives when the titer is particularly high, called the “prozone” phenomenon.<\/p>\n

Which, trust me, isn’t a zone you want to be in.<\/p>\n

To make matters more confusing, how about those units? Here’s a summary I wrote previously<\/a> trying to explain how RPRs are reported, and what they mean:<\/p>\n

When positive, RPRs are reported in dilutions \u2014 e.g., 1:4 is a one-dilution lower (and a twofold lower) titer than 1:8. Not many of our tests get reported this way (ANA comes to mind as another); in general, it\u2019s only considered a significant change if it\u2019s two dilutions or more \u2014 1:16 goes down to 1:4 after treatment, for example.<\/p><\/blockquote>\n

So what about this fourfold change? As summarized by Dr. Ghanem, the data supporting this notion that this change is necessary for treatment success are weak indeed — in fact, the primary argument for it is that laboratory variability is a twofold change, hence you can’t say anything significant about a titer that goes from 1:16 to 1:8.<\/p>\n

How about the view that if the titer doesn’t drop appropriately, then the patient should at the very least be retreated, with consideration of a CSF examination to diagnose occult CNS disease? Again, data are very weak to support these recommendations, even though I’ve heard some experts strongly advocate this approach.<\/p>\n

In summary, we can legitimately question a strategy of retreatment of syphilis for “serologic non-response”. Even the STI treatment guidelines<\/a> acknowledge this uncertainty.<\/p>\n

Failure of nontreponemal test titers to decrease fourfold within 12 months after therapy for primary or secondary syphilis (inadequate serologic response) might be indicative of treatment failure … Optimal management of persons who have an inadequate serologic response after syphilis treatment is unclear.<\/strong><\/p><\/blockquote>\n

Sounds like the perfect setting for a clinical trial. Indeed, during the question-and-answer period, Dr. Ghanem commented that he’d like to see such a study of syphilis serologic non-response with and without further treatment.<\/p>\n

Inspired by his talk, I offer here a potential study design:<\/p>\n

– Inclusion criteria:\u00a0 Asymptomatic people with treated syphilis who have serologic non-response, defined as a failure of nontreponemal test titers to decrease fourfold within 12 months after therapy
\n– Stratifications:\u00a0 Stage of disease (early vs late), HIV
\n– Exclusion criteria:\u00a0 Suspected reinfection, pregnancy, non-penicillin therapy
\n– Intervention:\u00a0 Randomization to 1) retreatment with penicillin or, 2) ongoing clinical monitoring alone, with assumption that the titer is the patient’s new baseline
\n– Primary endpoint:\u00a0 Clinical manifestations of treatment failure
\n– Secondary endpoints:\u00a0 RPR trajectory, other blood tests, additional testing (such as CSF exams), other treatments, patient satisfaction score, clinician time, costs<\/p><\/blockquote>\n

Would you refer a patient who meets these criteria into such a study? Anyone interested in doing it? Seems right up the alley of the great pragmatic trials run by our ID and sexual health colleagues in the United Kingdom — hope they (or someone else) will give it some thought.<\/p>\n

And though it has nothing to do with syphilis, this UK export certainly makes me laugh every time I watch it.<\/p>\n