RECENT STUDIES HAVE REPORTED an increasing rate of syphilis among men having sex with men in an era in which highly active antiretroviral therapy (HAART) has become available in industrialized countries.1–3 This increase may be attributable to the decrease in mortality in human immunodeficiency virus (HIV)-infected patients associated with HAART,4 and to an increase in high-risk sexual behavior resulting from treatment-induced optimism.5,6 Furthermore, a study has demonstrated that virological and immunologic improvement with the use of HAART increased the level of unprotected sex among HIV-infected patients.7
However, there is little information about whether the duration of receiving HAART influences syphilis incidence or whether immunologic improvement through HAART is related to the incidence of syphilis in HIV patients.8 An understanding of the effect of HAART on the incidence of syphilis may have great implications for controlling HIV transmission as well as syphilis itself in HIV-infected patients; one reason is that syphilis may increase the risk of HIV transmission by causing genital ulcers.9
In this study, therefore, we aimed to evaluate the incidence of early syphilis as a function of the time after the start of HAART in HIV-infected patients.
Methods
The study included all HIV patients (>15 years old) who started HAART at Seoul National University Hospital (Seoul, Republic of Korea) from 1998 through 2006. The hospital is a 1600-bed, university-affiliated teaching hospital, and it is the largest referral center for HIV/acquired immune deficiency syndrome in South Korea; a quarter of all HIV patients in South Korea are seen at this hospital. HAART is defined as the use of at least 3 antiretroviral drugs, including protease inhibitors or nonnucleoside reverse transcriptase inhibitors, for at least 1 month.
In these patients, the first event of early (primary or secondary) syphilis was identified from 0 to 4 years after the start of HAART. Early syphilis was diagnosed with clinical symptoms and the reactive Venereal Disease Research Laboratory (VDRL) test and fluorescent treponemal antibody-absorption tests. Early latent syphilis was not included in the event of early syphilis because the patients did not receive regular monitoring for syphilis. Infections in patients with a history of previously treated syphilis were diagnosed when they showed a documented 4-fold or greater increase in VDRL test titers.
Baseline CD4 lymphocyte count and HIV RNA level were the test results obtained closest to the time of initiation of HAART (less than 90 days before initiation). CD4 cell counts and HIV RNA levels at the time of the syphilis diagnosis were taken as the averages of all measurements recorded within a window around the time of syphilis diagnosis ±2 months. Clinical categories were defined by the 1993 Centers for Disease Control and Prevention classification criteria.10
Statistical Analysis
The confidence intervals (CIs) of the incidence rates of early syphilis were estimated by Poisson distribution 95% confidence limits, and trends of event rates according to the time after starting HAART were evaluated by Poisson regression after adjustment for the calendar year. Statistical analyses were performed with SPSS software (version 12.0) and SAS (version 9.1); the P value was considered significant at 0.05.
Results
Of the 539 patients who met the eligibility criteria, all except 6 patients were Korean, the median age was 38 years [interquartile range (IQR), 32–46], and 91% were men, 42% of whom were men having sex with men. Median follow-up duration per person was 2.9 years (IQR: 1.4–4.0). Among them, 56 (10.4%) patients were diagnosed with early syphilis, 17 (3.2%) with primary syphilis, 39 (7.2%) with secondary syphilis, and 9 (16.1%) had previous syphilis infections. The baseline characteristics of these patients at the start of HAART are shown in Table 1. Thirty-nine (69.6%) patients received protease inhibitors as their HAART regimen, and 17 (30.4%) received nonnucleoside reverse transcriptase inhibitor. The median titer of the VDRL tests at time of syphilis diagnosis was 1:64 (IQR, 1:32–1:128).
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TABLE 1: Baseline Characteristics of 56 HIV Patients With Early Syphilis During Highly Active Antiretroviral Therapy
The overall incidence rate of early syphilis for 4 years after the start of HAART was 4.57 per 100 person-years (95% CI, 3.45–5.93). The period-specific incidence rate of early syphilis was 3.42 per 100 person-years (95% CI, 1.82–5.85) in the first year after starting HAART, 3.51 per 100 person-years (95% CI, 1.81–6.13) in the second year, 6.19 per 100 person-years (95% CI, 3.67–9.79) in the third year, and 6.10 per 100 person-years (95% CI, 3.25–10.43) in the fourth year. The incidence rate of early syphilis significantly increased in proportion to the years after the start of HAART after adjustment by the calendar year (P <0.001) (Fig. 1).
Fig. 1: Period-specific incidence of early (primary or secondary) syphilis in 539 HIV patients according to time after start of highly active antiretroviral therapy (HAART). The data include only the first event of early syphilis in each patient after HAART initiation. P value is obtained by Poisson regression after adjustment by calendar year. PY, person-year.
Median CD4 cell count was 165/mm3 (IQR, 70–250) at the start of HAART and 365/mm3 (IQR, 221–480) at the time of syphilis diagnosis (Table 1). The median increased level of CD4 cell counts from baseline at the time of syphilis diagnosis was 174/mm3 (IQR, 66–330).
In 33 (63%) of 52 patients with available data, HIV viral load was not detected (<400 copies/mL) at the time of syphilis diagnosis. Among patients with early syphilis, the proportion with undetected viral load at the time of syphilis was 69% in the first year after HAART initiation, 56% in the second year, 71% in the third year, and 54% in the fourth year.
Discussion
Several previous studies have suggested an association between HAART and sexually transmitted diseases (STD) other than HIV infection.7,11–13 Some reported that the incidence of STD in HIV patients in the HAART era increased compared with the era preceding HAART introduction.7,13 However, the association between syphilis and HAART may just reflect the increased prevalence of syphilis in general population or men having sex with men. Therefore, we tried to minimize the effect of a secular trend in the population by adjusting the calendar year in Poisson regression model.
This study demonstrated that the incidence of new syphilis in HIV patients increased in proportion to the duration of HAART therapy even after adjustment by calendar year. This finding strongly supports the association between HAART and the increased incidence of syphilis in HIV patients.
The effect of HAART on the incidence of syphilis can be explained in both physical and psychological aspects. Successful HAART therapy results in a better physical condition, which may be related to increased sexual activity, including unprotected sexual behavior. Concurrently, HIV patients may believe that HAART reduces the risk of transmission and negates the need for safer sex practices.14 These physical and psychological changes may be factors in the increased incidence of syphilis.
Although baseline CD4 cell counts were diverse according to the time from start of HAART to early syphilis, CD4 cell counts at the time of syphilis diagnosis were over 200/mm3 in more than 80% patients. These findings suggest that CD4 cell count may be a useful marker for defining the risk group for syphilis during HAART. A previous study demonstrated that higher CD4 cell count at time of acquired immune deficiency syndrome diagnosis was associated with increased risk of acquiring a STD.11
The increase in the incidence of early syphilis after HAART initiation may raise concerns about HIV transmission because an increased syphilis incidence reflects a high rate of risky sexual behavior in HIV patients; in addition, syphilis may increase the risk of HIV transmission through genital ulcers.9,15 Our data showed that in about 40% of patients with early syphilis, HIV viral load was not fully suppressed. Although there are limited data regarding whether a syphilis outbreak among HIV patients increases HIV incidence,16 our findings draw special attention to HIV transmission from HIV patients receiving HAART.
This study has some limitations. First, syphilis may present with nontypical features in HIV patients.17 Furthermore, we did not include latent syphilis in this study. Therefore, we might have underestimated the incidence of early syphilis in HIV patients. Second, recent studies reported that syphilis may decrease CD4 cell counts and increase HIV viral load.18,19 For this reason, values from the time of syphilis diagnosis might not exactly reflect the immunologic or virological state of the HIV patients. To minimize this discordance, we took CD4 counts and viral loads as averages of all measurements recorded within a window around the time of syphilis diagnosis. Third, incidence of STD may be influenced by risk-reduction counseling in clinics.20 The study hospital did not have a counseling program to prevent STD in HIV patients. The results in the HIV clinics with that situation might be different from ours.
In summary, this study demonstrated that the incidence of early syphilis in HIV patients increased in proportion to the time after the start of HAART. Our findings suggest that more intensive risk-reduction counseling and routine periodic screening for syphilis in HIV patients who initiate HAART should be encouraged with attention to the time passed since HAART initiation.
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