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Prevalence and Determinants of Herpes Simplex Virus Type 2 Infection in a Cohort of HIV-Positive Individuals in Italy



Background Herpes simplex virus type 2 (HSV-2) infections may be a risk factor for the transmission of HIV. Data on the prevalence of HSV-2 infection among HIV-positive individuals are scarce.

Goal The goal was to study the seroprevalence of and risk factors for HSV-2 infection among a cohort of Italian HIV-positive individuals.

Study Design This was a cross-sectional study. HSV-2 serologic testing was performed for individuals with known date of HIV seroconversion, on the serum specimen obtained on the date closest to the estimated date of seroconversion. Antibodies to HSV-2 (anti-HSV-2) were detected by a gG2-specific ELISA.

Results A total of 380 HIV-positive individuals were tested for anti-HSV-2; 126 (33.2%) of them were positive. Older age at HIV seroconversion and homosexuality were significantly associated with HSV-2 infection in the multivariate analysis.

Conclusions These data stress the need for including anti-HSV-2 testing and therapy in the management of HIV positivity, especially for reducing the risk of transmission of HIV through herpetic lesions.

The high prevalence of herpes simplex virus type 2 (HSV-2) infection, especially among homosexual men, stresses the need for including anti-HSV-2 testing and therapy in the management of HIV positivity, especially for reducing the risk of transmission of HIV through herpetic lesions.

From the *Reparto AIDS e MST, Istituto Superiore di Sanità, Rome; †Dipartimento di Sanità Pubblica, Università di Roma Tor Vergata, Rome; and Ist. Clinica Dermatologica, Ospedale Maggiore, Milan, Italy

The authors thank Mark Kanieff for editorial assistance.

The Italian Seroconversion Study Group includes the following individuals and centers: Giovanni Rezza, Patrizio Pezzotti, Maria Dorrucci (Istituto Superiore di Sanità, Rome); Alessandro Sinicco (University of Turin); Roberto Zerboni (IRCCS Osp. Maggiore, Milan); Gioacchino Angarano (University of Bari); Adriano Lazzarin (San Raffaele Hospital, Milan); Fernando Aiuti (“La Sapienza” University of Rome); Mauro Zaccarelli (Spallanzani Hospital, Rome); Bernardino Salassa (Amedeo Di Savoia Hospital, Turin); Francesco Castelli (University of Brescia); Francesco Alberici (Ospedale Civile, Piacenza); Giovanni Mazzarello (University of Genova); Mauro Barbanera (Livorno Hospital); Vincenzo Colangeli (University of Bologna); Luigi Ortona (Catholic University, Rome); Raffaele Pristerà (Bolzano Hospital); Maria A. Ursitti (Santa Maria Nuova Hospital, Reggio Emilia); Umberto Tirelli (Centro Riferimento Oncologico, Aviano); and Massimo Giuliani (Ospedale S. Gallicano, Rome).

Supported by a grant from Progetto Ricerca AIDS, Ministero della Sanità, Istituto Superiore di Sanità, 1998.

Reprint requests: Barbara Suligoi, MD, Reparto AIDS e MST, Istituto Superiore di Sanità, V.le Regina Elena 299, 00161 Rome, Italy. E-mail:

Received for publication October 17, 2001,

revised January 23, 2002, and accepted January 25, 2002.

GENITAL HERPES, which is caused by herpes simplex virus (HSV) type 1 and, more often, by HSV type 2, is the most commonly reported ulcerative sexually transmitted disease (STD) in western countries. Many studies have pointed out that genital ulcers, including genital herpes, are important risk factors for both acquiring and transmitting HIV. 1 Moreover, several studies have shown that HIV-induced immunologic impairment results in severe, persistent, and recurrent genital herpes, 2 and HIV-positive individuals are four times more likely than HIV-negative individuals to have subclinical reactivation of the infection (revealed by shedding of the virus through genital mucosa) and are thus more likely to transmit HSV-2. 3

Nonetheless, data on the prevalence of HSV-2 infection among HIV-positive individuals are scarce. Some studies have shown the proportion of HIV-positive individuals with a history of genital herpes, yet they are limited by recall bias and misdiagnosis. 4 Very few studies have investigated the proportion of HSV-2-infected persons among HIV-positive individuals by measuring HSV-2 seroprevalence, and the results have greatly varied with the specific geographic area considered. 5–8

We studied seroprevalence of and risk factors for HSV-2 infection among a cohort of Italian HIV-positive individuals.

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We analyzed data derived from a prospective cohort of HIV seroconverters belonging to different HIV exposure categories (the Italian Seroconversion Study). Details of the methods have been reported elsewhere. 9 None of the participants had AIDS upon enrollment in the study. Individuals who reported both homosexual behavior and intravenous drug use were classified as intravenous drug users (IDUs).

Serologic testing was performed on specimens still available from the sera repository of the cohort study (21.4% of the cohort). Testing was performed on the stored serum specimen that had been obtained on the date closest to the estimated date of HIV seroconversion.

To detect antibodies to HSV-2, all samples were tested with a commercially available kit (Gull/Meridian HSV-2-specific gG-2-based immunoglobulin G enzyme-linked immunoabsorbent assay [ELISA]; Meridian Diagnostics, Cincinnati, OH) that has been approved by the US Food and Drug Administration. The test is based on an ELISA in which the monoclonal antibody–selected gG-2 native protein is bound to plate wells, and it is intended for qualitative and quantitative detection of the gG-2-specific immunoglobulin G. Compared with Western blotting, this test has a sensitivity of 90% and a specificity of 100%. 10 Positive samples were not confirmed with Western blotting.

The prevalence of HSV-2 infection and the relative 95% confidence intervals were calculated. We determined descriptive statistics on the basis of main demographic characteristics (gender and age at HIV seroconversion) and by HIV exposure category (IDUs, homosexuals, and heterosexuals). The chi-square test was applied to evaluate whether HSV-2 serostatus was significantly associated with individual demographic characteristics and exposure category. Univariate and multiple logistic regression models were applied to evaluate which variables were predictive of HSV-2 seropositive status in the study population. We performed multivariate analysis, entering all of the above-mentioned variables in the same logistic model.

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The study population consisted of 380 individuals who seroconverted for HIV between 1983 and 1995. The median age at serum collection was 28 years (range: 16–66 years). The majority of participants were males (77.7%). With regard to HIV exposure category, 153 (40.3%) were IDUs, 172 (45.3%) were homosexuals, and 55 (14.4%) were non-drug-using heterosexuals. The estimated prevalence of HSV-2 was 33.2% (95% CI: 28.4%–38.1%).

Table 1 shows the HSV-2 seroprevalence of the 380 study participants by demographic characteristics and HIV exposure category. Seroprevalence was higher among males; however, when homosexual men were excluded, seroprevalence was higher, although not significantly, among females (17.4% versus 13.9%).



HSV-2-positive individuals were older than HSV-2-negative individuals (median age of 33 years versus 26 years). The HSV-2 seroprevalence tended to increase with increasing age at HIV seroconversion (P < 0.001 by chi-square test for trend). In analysis of HIV exposure category, homosexuals were more likely to be HSV-2-positive than non-homosexuals (IDUs and heterosexuals combined; 54.7% versus 15.4%;P = 0.001 by chi-square test).

The crude and adjusted odds ratios (ORs) of HSV-2 seropositivity are also shown in Table 1. In univariate analysis, male gender, older age at HIV seroconversion, and homosexuality were significantly associated with HSV-2 seropositivity, whereas in multivariate analysis, only older age at HIV seroconversion and homosexuality showed a significant association.

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The 33.2% HSV-2 seroprevalence observed among our study population is higher than that reported among HIV-negative low-risk populations in Italy 11 yet lower than that among HIV-positive populations in Slovakia, Zimbabwe, the United States, and Europe, 5–8 possibly because of a lower circulation and prevalence of HSV-2 in the Italian general population than in other countries or a different distribution of risk factors in these populations.

We found a significantly lower HSV-2 seroprevalence among females than males, whereas most investigators have found a higher seroprevalence among females and have interpreted this finding as being indicative of a greater risk of acquiring the infection. However, the high proportion of homosexual males in our population accounts for this difference, given that this group had the highest HSV-2 seroprevalence. This is confirmed by the finding that the OR for HSV-2 seropositivity, which was higher for males in the univariate model, changed directions with adjustment for exposure category and became higher for females. A high HSV-2 seroprevalence among homosexuals has also been observed in other studies conducted among HIV-positive and HIV-negative homosexual men. 7,12

The finding that HSV-2 seroprevalence increased with older age simply reflects a higher probability of acquiring HSV-2 infection with increasing duration of exposure to infectious agents and confirms data reported from other surveys. 6,11

The results of the multivariate analysis showed that older age and being homosexual were independently associated with HSV-2 seropositivity among HIV-positive individuals and confirm that the high HSV-2 seroprevalence among men was attributable to the high proportion of HSV-2-positive homosexual men.

Unfortunately, we were not able to determine the proportion of symptomatic HSV-2-infected participants, because information on self-reported genital herpes or on clinical evidence of genital herpes at enrollment and at follow-up visits was presumably not complete. A high frequency and severity of clinical manifestations of genital herpes, increased HSV-2 asymptomatic viral shedding, and the possible development of acyclovir-resistant HSV-2 strains 2 have been reported to constitute the most important features of HSV-2 infection in HIV-positive individuals.

In conclusion, we found a high prevalence of HSV-2 infection, especially among homosexual men. This finding stresses the need for including anti-HSV-2 testing and therapy in the management of HIV positivity, especially for reducing the risk of transmission of HIV through herpetic lesions.

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