One Dose versus Three Weekly Doses of Benzathine Penicillin G for Patients Co-Infected with HIV and Early Syphilis: A Multicenter, Prospective Observational Study

Abstract

BackgroundOne dose of benzathine penicillin G (BPG) has been recommended for HIV-infected patients with early syphilis (primary, secondary, and early latent syphilis) in the sexually transmitted diseases treatment guidelines, but clinical data to support such a recommendation are limited.MethodsWe prospectively observed the serological response to 1 or 3 weekly doses of BPG in HIV-infected adults who sought treatment of early syphilis at 8 hospitals around Taiwan. Rapid plasma reagin (RPR) titers were followed every 3–6 months after treatment. The serological response was defined as a 4-fold or greater decline in RPR titers at 12 months of treatment. The missing values were treated by following the last-observed-carried-forward principle. We hypothesized that 1 dose was non-inferior to 3 weekly doses of BPG with the non-inferiority margin for the difference of serological response set to 10%.ResultsBetween 2007 and 2012, 573 patients completed at least 12 months of follow-up: 295 (51.5%) receiving 1 dose of BPG (1-dose group) and 278 (48.5%) 3 doses (3-dose group). Overall, 198 patients (67.1%; 95% confidence interval [CI], 61.4–72.5%) in the 1-dose group achieved serological response at 12 months, as did 208 patients (74.8%; 95% CI, 69.3–79.8%) in the 3-dose group (one-sided 95% CI of the difference, 15.1%). In the multivariate analysis, secondary syphilis (adjusted odds ratio [AOR], 1.90; 95% CI 1.17–3.09), RPR titer ≥32 (AOR, 1.93; 95% CI, 1.38–2.69), and 3 doses of BPG (AOR, 1.68; 95% CI, 1.20–2.36) were independently associated with a serological response. The time to the first episode of treatment failure was 1184 (standard deviation [SD], 70.5) and 1436 (SD, 80.0) days for 1- and 3-dose group, respectively.ConclusionsSingle-dose BPG resulted in a higher serological failure rate and shorter time to treatment failure than 3 weekly doses of BPG in the treatment of early syphilis in HIV-infected patients.

Syphilis

“…Notably, the 101 HIV-infected patients enrolled in the trial responded less well serologically, but due to loss to follow up the study was underpowered to detect a two-fold difference in standard versus enhanced treatment in HIV co-infected patients. Furthermore, a large ( n =573) prospective observational study in Taiwan found no difference between single-dose benzathine penicillin G and enhanced treatment in a per-protocol analysis 199 . However, using a last-observed-carried-forward analysis to account for missing data, the authors concluded that 67.1% of those who received one dose responded serologically compared with 74.8%who received the enhanced treatment, a statistically significant difference ( P =0.044) 199 .…”

Benzathine penicillin G for the management of early syphilis among HIV co-infected persons: A systematic review

“…Of note, however, was the finding by Yang et al, which suggested a possible benefit of three doses of BP-G by reporting a longer time to serologic treatment failure in this group (37). However, the authors described a number of limitations to the study that could potentially explain the difference in their findings relative to other studies: 1) the study was not a RCT; 2) the decision to use one vs three doses was made by physicians assessing the patients; 3) 25% had missing RPR titres on followup testing; 4) the researchers could not definitely differentiate between re-infection and treatment failure; and, 5) the majority of patients were men who have sex with men (MSM) which limited the generalizability of their findings to other populations.…”

“…In the included studies, serologic response was commonly defined as ≥4 fold reduction in RPR titres at 12 months. The time to the first episode of serological failure appeared shorter in the group that received one dose: 1,184 (40 months) days for one-dose group and 1,436 days (almost 48 months) in the three-dose group, suggesting benefit from a three-dose regimen (37). In the same study, a Kaplan-Meier survival plot model showed a statistically significant longer mean time to failure in the group that received three-dose regimen (p=0.03) (37).…”

“…The participants in the studies were predominantly male. In four studies, the intervention was one or three doses of BP-G (37,(39)(40)(41). A single study compared one dose of BP-G with two or more doses of BP-G (38) ( Table 1).…”

“…The lack of adjustment for HIV treatment /status (anti-retroviral therapy and CD4 count) further limits the ability to extrapolate results to the clinical setting. These are known and significant associations (37) but the included publications were not analyzed with a stratified or multivariate approach (37,(39)(40)(41). Studies were not representative of the entire population at risk for syphilis and HIV co-infection.…”