Here we present a comprehensive longitudinal study, including the observation of clinical manifestation, diagnosis and treatment, based on a concurrent Syphilis/HIV infection identified during window period. The main purpose of this longitudinal study is to evaluate whether the diagnostic power (efficiency) of different test methods (both serological and nucleic-acid tests) is compromised in Syphilis/HIV co-infected donors before and after clincal treatment.
Disease progression may be altered in co-infected or post-treatment individuals. Previous research has shown that, in addition to functional defects of macrophages, HIV–induced breakdown of cell-mediated and humoral immunity alters the course of syphilis progression. The progression of syphilis is usually faster in HIV patients than in those not infected by this virus . In addition, ART usually modulates host immunity, by a series of mechanisms that are not fully understood. Although the median length of time from the initial infection to a positive syphilis serological test is 10 days (4–60 days), this median time can increase up to 32 days in individuals where an initial ELISA test is negative .
Different tests vary in sensitivity. In this case report, the length of time between the ulceration of the external genitalia (identified at the 28th DBD) to a positive serological test was 0, 6 and 10 DAD using anti-TP reagent 1, anti-TP ECLIA and anti-TP reagent 2 tests, respectively. These data values were within the ranges observed in mono-infected syphilis patients . These results indicated that HIV/syphilis co-infection does not compromise the diagnostic power (efficiency) of different test methods for the detection of syphilis. However, syphilis treatment usually has a lower response rate in HIV-infected individuals as shown by slower decrease in non-treponemal titers . In our case, we observed that both IgG and IgM levels were decreased following syphilis treatment and a successful serological response was obtained at the 80th DAD. This data demonstrate that HIV/Syphilis co-infeceted individuals respond well to syphilis treatment although we are not quite sure whether HIV-infection weakens the response rate or not.
A positive response to syphilis treatment requires monitoring of nontreponemal antibody titers, with more than 4-fold decline and/or seroreversion to non-reactive titers. As reported, 15–25% of patients treated during the primary stage revert to serologically non-reactive after 2–3 years . The majority of HIV-negative patients with early syphilis failed to have seroreversion at 12 months . Seroreversion at six months after treatment appears to be similar among all primary syphilis patients . In our study, a successful serological response to syphilis treatment was reached ~ 80th DAD. Our data is in agreement with previous findings that timely treatment of syphilis is highly effective, even in co-infection patients . Some previous studies have also evaluated the association of HIV status with serologic outcomes, after syphilis treatment, by comparing patients with and without HIV infection [16, 17]. Unfortunately, the results of these particular studies are inconsistent, so it remains unclear whether HIV-infected individuals are less likely to achieve serologic clearance of syphilis. At least in part, these contrasting results might be related to (i) the variability in the stages of syphilis and HIV infection status, and (ii) an inconsistent definition of serological non-response.
Identificaiton of the WP infections is difficult. As recommended by the UK national guidelines, the 4th generation of HIV laboratory tests for HIV p24 detection is more applicable for shorter WP as compared to rapid tests and 3rd generation ELISA, which typically reduces WP to 1.56 and 5.32 days, respectively [18, 19]. According to BASHH/EAGA Position Statement on HIV Window Period (November 2014), a negative result of the 4th generation testing obtained four weeks after exposure is highly likely to exclude HIV infection. However, based on our current study, the window period appears to be longer in HIV/syphilis co-infected individual.
In this case study, the 4th generation anti-HIV ELISA and CLIA platform provided a positive signal at the 6th DAD. It had been nearly six weeks since the last high-risk exposure of the 41st and 35th DBD. We speculate that one possible reason for this longer WP might be that syphilis infection affects the progression of humoral response to HIV. Moreover, the behavior of an insertive anal intercourse could lead to a lower concentration of receptive virus, affecting the HIV dynamics and immune response.
In 2015, the ART guidelines from the World Health Organization (WHO) recommended treatment only after HIV infection was detected [20, 21]. In addition, the early initiation of ART following infection may limit the viral burden in the presence of HIV . Qualitative HIV DNA tests are preferred for confirmation at a later stage. As shown in Table 1, we observed that, after early ART treatment, the test signal from the 4th generation anti-HIV ELISA and CLIA showed slightly declining although no apparent reduction was detected by both 3rd G anti-HIV ELISA and HIV Rapid Test. This data demonstrates that, although the 4th generation ELISA was the most sensitive test to detect AHI prior to ART, the 3rd generation approach was the most sensitive during treatment . Furthermore, this co-infected donor responds well to ART as shown by the declined HIV viral loads until reaching undetectable levels at the 246th DAD although HIV-1 DNA was detectable by the 403rd DAD (Table 1). Therefore, in accordance with previous work, our data illustrates the critical role of early stage treatment for HIV. This data also indicates that HIV DNA can still be detected, as virus reservoir, after co-infection.
According to the background information, this blood donor presented one genital ulcer (chancre) at the 28th DBD. Previous research has shown that chancres typically appear 10–90 days after exposure . The window period whereby the humoral response to syphilis develops is between 1 to 4 weeks after the chancre forms in primary syphilis . Apparently, co-infection appears to have limited effect towards this length of time.
Although this is a comprehensive longitudial follow-up study, our report also faces some limitations. First, the patient had two high-risk behaviors but, due to the lack of follow-up data, the specific infection time could not be determined. Second, this study is mainly focused on testing and treatment, the molecular mechanism(s) related to the effect of coinfection towards the immune system remains in-depth investigation. Nevertheless, based on this rare case study, we strongly believe that our current data will serve as an useful background information for future research.