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Unite de Virologie Medicale, Unite d'Hygiene Hospitaliere et Service des Maladies Infectieuses, Hpital Robert Debre, Centre Hospitalo-Universitaire de Reims, and IFR-53/EA-3798, Faculte de Medecine de Reims, Reims
Unite de Virologie Medicale et Service d'Immunologie Clinique, Hpital Europeen Georges Pompidou
Centre Medical de l'Institut Pasteur, Paris, France
ABSTRACT
Using commercially available herpes simplex virus (HSV) type-specific serological diagnostic tests, HSV type 2 (HSV-2) antibody prevalence was assessed in two parallel prospective studies including 534 human immunodeficiency virus type 1 (HIV-1)-infected outpatients living in two areas of northern France. In the first cohort of 434 subjects, 223 (51%) individuals demonstrated a positive HSV-2 serological status while 66 (66%) of 100 subjects in the second cohort were seropositive for HSV-2 (51 versus 66%; P = 0.08). Among the 223 HSV-2-seropositive subjects identified in the first study cohort, only 22 (10%) had suffered from recurrent anogenital lesions during the past 12 months while 154 (69%) had no clinical history of herpesvirus infection. Our findings demonstrate high proportions of subclinical and undiagnosed HSV-2 infection in HIV-1-infected individuals and suggest that HSV type-specific serological testing in the French HIV-1-infected subpopulation could be an efficient strategy to diagnose clinically asymptomatic HSV-2 infections.
TEXT
Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus that is the most common cause of genital ulceration worldwide (9-11). Transmission is facilitated by the frequent recurrence of infectious episodes of subclinical viral shedding (9). Undiagnosed and untreated genital herpesvirus infection in pregnant women can lead to vertical transmission from mother to newborn, causing infant morbidity and mortality (10). Moreover, there is increasing evidence that HSV-2 infection could significantly enhance the rates of sexual transmission and acquisition of human immunodeficiency virus (HIV) in developing countries (11). The seroprevalence of HSV-2 antibodies varies considerably by population, and it has been shown that the prevalence of HSV-2 antibodies in both developed and developing countries has increased markedly over the past few years (5). In German HIV type 1 (HIV-1)-infected subpopulations, the seroprevalence of HSV-2 has been reported to be 47.9%, suggesting that genital secretions of European HIV-HSV-coinfected patients may be a common source of horizontal or vertical HSV transmission (13). Moreover, European HIV-1-HSV-2-coinfected individuals may constitute subpopulations at high risk for HIV transmission to HIV-negative exposed individuals (10). At the present time, the significance of HSV-2 infection in European HIV-1-infected subpopulations remains to be assessed. In this study, we evaluated for the first time HSV seroprevalence and risk factors for HSV-2 infection in French HIV-1-infected outpatients.
In the present study, 534 HIV-1-infected outpatients were prospectively enrolled in two hospital settings for routine follow-up. The first prospective study included a cohort of 434 consecutive outpatients (324 men [mean age, 38 years] and 110 women [mean age, 43 years]) attending the Reims University Medical Center and associated hospitals in the Champagne-Ardennes and Picardie provinces (northeastern France). The second prospective study included a cohort of 100 outpatients (63 men [mean age, 45 years] and 37 women [mean age, 39 years]) attending the Service d'Immunologie Clinique of the Hpital Europeen Georges Pompidou, Paris, France. Among the 534 study outpatients, 507 (95%) were European Caucasians and 27 (5%) were from Africa or Asia, where they had initially acquired HIV-1 infection. Signed informed consent was obtained from each study patient, and an institutional review board approved the two parallel clinical investigations. HSV-1 and HSV-2 type-specific serologic tests were carried out using two commercially available enzyme-linked immunosorbent assays (Champagne-Ardennes and Picardie provinces, SeroHSV-1 and SeroHSV-2 [BMD Diagnostics, Marne-la-Vallee, France]; Paris, HerpeSelect HSV-1 and HSV-2 [Focus Technologies, Eurobio, Courtaboeuf, France]) (1, 6).
Statistical analysis was performed using STATA version 7 Software (STATA Inc.). Comparison of quantitative variables was performed using Student's t test or the nonparametric Mann-Whitney U test when necessary. Chi-square or Fisher's exact tests were used for comparison of the discrete data, and the odds ratio (OR) and 95% confidence interval (CI) were also calculated. P values under or equal to 0.05 were considered significant. All the variables demonstrating a P value under or equal to 0.05 by univariate statistical analyses were then included in a forward stepwise logistic regression analysis, allowing the calculation of independent risk factors.
Among the 534 study subjects, the overall rates of HSV-1 and HSV-2 antibody prevalence were 86% and 59%, with 52% HSV-1-HSV-2 coinfection; HSV-1 and HSV-2 antibody seroprevalences were similar between males and females (92% versus 80% for HSV-1, P = 0.09; 62% versus 57% for HSV-2, P = 0.78, respectively). In the first cohort of 434 subjects, 223 (51%) individuals demonstrated a positive HSV-2 serological status while 66 (66%) of 100 subjects in the second cohort were seropositive for HSV-2 (51 versus 66%; P = 0.08). Among the 434 subjects from the Champagne-Ardenne and Picardie provinces, we conducted a case-control study focusing on demographic features and possible sexual risk factors for HSV-2 seropositivity (Table 1). In a univariate analysis, two variables were significantly associated with HSV-2 seropositivity, including an age above 45 years and high-risk sexual behavior. In a multivariate analysis, the variables age above 45 years and high-risk sexual behavior appeared as two independent risk factors for HSV-2 seropositivity (OR = 1.68, 95% CI = 1.13 to 2.49, P = 0.010, and OR = 1.93, 95% CI = 1.13 to 3.31, P = 0.016, respectively) (Table 1).
Among the 223 HSV-2-seropositive subjects identified in the first study cohort, only 22 (10%) had suffered from recurrent anogenital lesions during the past 12 months while 154 (69%) had no clinical history of herpesvirus infection and were totally unaware of their herpesvirus infection. Only 6 (3%) had suffered from another diagnosed sexually transmitted infection during the 12-month period before inclusion, whereas 12 (5%) of the 221 HSV-2-seronegative patients had suffered from clinically and biologically proven sexually transmitted diseases during the same period (3 versus 5%; P > 0.5). Among the 20 HSV-2-seropositive patients demonstrating genital or anal herpes lesions at the time of inclusion, herpes outbreaks appeared not to be associated with lack of antiretroviral therapy or with CD4 T-lymphocyte counts in peripheral blood (data not shown).
In the present serological survey, nearly two-thirds of the selected HIV-1-infected adults living in Paris and northeastern France were seropositive for HSV-2 infection. Similar rates of seroprevalence had been previously reported in American, African, and Asian HIV-1-infected subpopulations (5, 11). HSV-2 antibody prevalence has been reported to be 17% in the French general adult population (4) and to range from 4 to 24% in other, similar, European populations (5, 8). Our HSV-2 antibody prevalence appeared to be statistically significantly higher than that previously reported by Malkin et al. (4) in the French general population (17.2% of 12,735 subjects), even after the values were adjusted according to age or gender (P < 0.001). Taken together, our findings showed high rates of HSV-2 antibody prevalence in two cohorts of French HIV-1-infected outpatients, suggesting that HSV-2 infection may be markedly associated with HIV-1 infection in France. Two previous studies had reported that the seroprevalence rates of HSV-2 infection were 48% and 75% in U.S. and German HIV-1-infected subpopulations, respectively (3, 5). A further HSV seroepidemiological survey including a representative number of French cohorts of HIV-1-infected outpatients is needed to confirm our present findings.
In the present study, only 22 (10%) of 223 HSV-2-HIV-1-coinfected outpatients from the first study cohort had a clinical history of genital herpes at the time of inclusion or within the 12-month period before. By contrast, the majority of HSV-2-seropositive patients (69%) were totally unaware of their genital infection at the time of inclusion whereas the remaining 47 patients (21%) were aware of their HSV-2 status by a history of past genital herpes outbreaks. These findings demonstrate an unexpectedly high proportion of subclinical and undiagnosed HSV-2 infection in HIV-1-infected individuals. In addition, the occurrence of HSV-2 outbreaks in the study population appeared not to be associated with lack of antiretroviral treatment or with circulating CD4 T-lymphocyte counts, suggesting that HSV-2 recurrences may be poorly or not influenced by antiretroviral treatment, as previously reported (7). Interestingly, multivariate statistical analysis revealed that HIV-1-infected subjects aged more than 45 years or with high-risk sexual behavior were more likely to be infected with HSV-2. These findings are consistent with results reported in several previous seroepidemiological studies which identified sexual behavior and age as risk factors for HSV-2 seropositivity (12). This likely reflects the association of risk of HSV-2 acquisition with the cumulative increase in the number of sexual partners and the duration of sexual activity in the context of the chronic nature of HSV-2 infection, particularly in association with unprotected sexual intercourse (9, 10).
High rates of HSV-2 seroprevalence in the HIV-1-infected subpopulation could have major consequences for the risk levels of transmission and acquisition of HSV-2 or HIV-1 infection via sexual intercourse and consequently could have major implications for the medical care of HSV-2-HIV-1-coinfected patients. Indeed, genital herpes is now considered one of the major cofactors increasing the rate of HIV-1 transmission by the sexual route (12). Coinfected individuals appeared to be subject to high levels of asymptomatic HSV-2 genital infection, which could increase their genital infectivity for HIV-1 and therefore the rates of HIV transmission to potentially exposed HIV-1-negative sexual partners (10). Such a situation could be particularly critical in discordant heterosexual or homosexual couples in which one of the two partners is HIV-1-HSV-2 coinfected while the other is not infected with HIV-1 (2, 3, 10).
In conclusion, the results of the present study demonstrate high proportions of subclinical and undiagnosed HSV-2 infection in French HIV-1-infected outpatients. Moreover, our findings suggest that HSV type-specific serological testing in the French HIV-1-infected subpopulation could be an efficient strategy to diagnose clinically asymptomatic HSV-2 infections and therefore to reduce the risk of HSV-2 and HIV-1 sexual transmission by convenient prophylactic counseling against unprotected intercourse.
ACKNOWLEDGMENTS
This study was independently conducted by the University Medical Center of Reims and was supported by GlaxoSmithKline Laboratory (Marly-le-roi, Paris, France) and by the Faculty of Medicine of Reims (IFR53/EA-3798) for clinical research. We acknowledge BMD diagnostics (Marne-la-Vallee, France) and Eurobio (Courtaboeuf, France) for providing HSV-2 type-specific enzyme-linked immunosorbent assay kits.
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