In their interesting report, Buchacz and coworkers  claim that novel syphilis infection is significantly linked to an increase in viraemia and a drop in the CD4 lymphocyte count, in their series of 52 HIV-infected men with primary of secondary syphilis, but an antiretroviral treatment rate limited to 58% of cases. Although statistically significant or tending to statistical significance, the mean variations in log10 HIV-RNA copies/ml observed before and after syphilis were limited to a very restricted range, from +0.22 to −0.10, and the modification of the mean absolute CD4 cell count ranged from −62 to +33 cells/μl, respectively, before and after the concurrent syphilitic infection . These limited variations in laboratory data are known to be of nearly negligible clinical value, especially when considering the retrospective, non-controlled study design, laboratory data evaluated by different hospital facilities, and the natural evolution of HIV disease, particularly when a substantial rate of affected patients (42%) did not take advantage of antiretroviral drugs , and for the remaining 52% of patients detailed data on HAART administration and efficacy are lacking . Therefore, we strongly believe that generalizations cannot be made on the grounds of the presented data only.
After the recent concerns about the increase in sexually transmitted diseases among HIV-infected individuals [2–4], a prospective observational survey was undertaken at our reference centre in a homogeneous cohort of over 1000 HIV-infected patients followed since the year 2001. Thirty-eight patients (25 homo–bisexual men, and 13 heterosexuals) were identified as novel cases of syphilis (secondary syphilis in 31 episodes), according to clinical features and standardized laboratory testing, received appropriate treatment, and were followed up for 18 consecutive months. Virological and immunological testing were available for 36 patients (33 men and three women, aged 29–58 years), including at least the 6 months preceding the diagnosis of syphilis, and the 9 months after disease treatment (Table 1). Only five out of the evaluable 36 did not take any antiretroviral therapy, but it was not indicated according to current international guidelines ; all other subjects received various combinations of HAART containing at least three drugs, and therapy was adjusted according to the present recommendations in this field . As summarized in Table 1, no statistically significant trend of both virological and immunological parameters was observed among the HIV–syphilis co-infected patients, using either a plain Student t-test, Wilcoxon rank sum test, or more sophisticated statistical analysis.
Although the reciprocal relationship between syphilis and HIV has not been extensively investigated from an immunological and especially a virological point of view, it is well known that the HIV-associated quantitative and functional impairment of cell-mediated immune response, could possibly affect the course of syphilis during HIV disease, as suggested by appropriate animal models and ex-vivo studies [6,7]. Impaired cellular immunity and blunted cytokine networks were clearly demonstrated during the different stages of syphilis, leading to altered migration and clearance mechanisms [7,8].
On the other hand, it is quite difficult to expect that a non-opportunistic occurrence such as syphilis superinfection may trigger potent pathogenetic pathways, able to influence the course of HIV disease significantly, especially when an effective control of immune recovery can be obtained by HAART administration. The data presented by Buchacz et al.  are also confusing, because 42% of their patients did not receive HAART, and the authors did not explain who and why. The last, large patient group might have experienced a greater worsening of their HIV disease course during and after syphilis . As a consequence, the entire evaluation of laboratory markers of HIV progression in this case series becomes absolutely unpredictable, and the perceived, minimal variations in the mean CD4 lymphocyte count or mean viral load cannot, in our opinion, be attributed to an incidental syphilitic infection. Another relevant bias may stem from the confounding definition of laboratory examinations obtained ‘during’ syphilis, which included determinations performed from 6 months before to 2 months after (an overall duration of up to 8 months ‘around’ the syphilis episode) . In our series, a single determination was made during the diagnosis and treatment of syphilis, so that more affordable laboratory analyses were performed during previous and subsequent quarterly examinations.
Whereas we completely agree with the authors' concerns regarding the recent outbreaks of sexually transmitted diseases in patients with HIV disease or exposed to HIV [2–4], their arguments related to a possible, aspecific activation of the immune system during concurrent infections, which might be lead to enhanced viral replication, were commonly claimed for the majority of HIV-associated opportunistic disorders (i.e. cytomegalovirus, Epstein–Barr virus, tuberculosis, atypical mycobacteriosis, haematological malignancies, and so on), but cannot be extrapolated to syphilis, because neither updated literature data (all reported quotations are 10–15 years old), nor pathogenetic hypotheses are still available. On the other hand, there is recent, mounting evidence that syphilis is involved in immune dysfunction [8,9], as well as in the apopotosis of lymphoid cells , instead of their presumed activation.
Although healthcare givers have to take into careful account all sexually transmitted diseases in patients having HIV or at risk of being HIV infected [3,4], at this time only extensive, prospective, case–control studies, matched according to the use and effectiveness of antiretroviral therapy, might answer some questions regarding the eventual existence of bidirectional pathogenetic interactions between HIV infection and syphilis.
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. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS 2004; 18:2075–2079.
2. Centers for Disease Control and Prevention. Trends in primary and secondary syphilis and HIV infection in men who have sex with men – San Francisco and Los Angeles, California, 1998–2002. MMWR
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