Herpes simplex virus (HSV)-1 and HSV-2 infections are widely prevalent among people infected with HIV. Seroprevalence studies have estimated that 63% to 96% of HIV-infected individuals are also infected with HSV-1, HSV-2, or both.1–5 Although many of these HSV infections are clinically silent, HSV morbidity is common. For example, HSV infection was clinically recognized in 30% of a cohort of HIV-infected military personnel.6 HIV may cause more frequent and severe HSV disease,7 and HSV is associated with increased HIV transmission and viral load.8–11
Given the high prevalence of HSV among people with HIV and the recognized synergistic interactions between these viruses, the Centers for Disease Control and Prevention (CDC) recommends consideration of routine serologic testing for HSV-2 in persons with HIV.12 Antiviral medications prescribed for herpes simplex infection are well tolerated and may be given to treat a single episode of HSV, or as suppressive therapy, which prevents most recurrence, shortens the length of breakthrough episodes, and reduces asymptomatic viral shedding.13,16,17 The CDC recommends that health care providers take into account the frequency and severity of HSV recurrence, risk of HSV-2 transmission, and the potential for increased HIV viral load when considering routine suppressive therapy for HSV.12 The necessity of routine suppressive therapy for HSV in people with HIV has been the subject of ongoing discussion.
The seroprevalence of HSV in persons infected with HIV has been described in a number of studies,3,14,18,19 but the clinical burden of HSV, including the frequency of clinical diagnosis and use of suppressive treatment, has not been characterized in a civilian population. Secular trends in HSV diagnosis and severe infections have also not been examined.
MATERIALS AND METHODS
Data were abstracted from medical records of a dynamic cohort of HIV-infected persons followed by the Adult/Adolescent Spectrum of HIV Disease Project (ASD). This longitudinal study represented a collaboration between CDC and state and local health departments and operated in 11 US metropolitan areas between 1989 and 2004. HIV-infected patients aged ≥13 years were selected from >100 hospitals and clinics participating in the study. Minority groups, that is, women and people of color, were oversampled at some study sites. Study sample selection and methods for the ASD have been described in detail elsewhere.20 Paper and electronic medical records from outpatient visits, hospitalizations, and emergency department visits were reviewed by trained data abstractors. Data regarding patient demographics, mode of HIV exposure, health conditions, prescribed treatments, and laboratory results were captured on a standardized data collection tool. Data were abstracted for the year before the date of initial study entry, and in subsequent 6-month intervals until death of the study subject, relocation, loss to follow-up, or the end of the study. Age was not reported by one of the study sites. CDC and each participating metropolitan area submitted the project for review and received Institutional Review Board exemption or approval to ensure that ethical standards were followed in the conduct of the project.
In 1998, the study data collection form was revised, and prescriptions of valacyclovir and famciclovir and HSV treatment modality, for example, episodic or suppressive, were added.
For the purpose of this analysis, an HSV diagnosis was considered to be present when any HSV episode or recurrence was documented in the clinical notes or laboratory test results, including antibody screening, viral culture, and viral polymerase chain reaction. HSV may have been documented as HSV, HSV-1, or HSV-2, and site of recurrence was recorded as oral, genital, or other. The method of diagnosis (i.e., clinical vs. laboratory diagnosis) was not captured. HSV medication prescription was defined as any prescription for acyclovir, valacyclovir, or famciclovir. These medications are indicated only for treatment and suppression of HSV and herpes zoster infection. To prevent potential misclassification, antiviral medication prescription recorded for intervals with recorded herpes zoster diagnoses were not included in the analysis. Person-time contributed to the study was calculated in months and counted from the first date recorded in the study until the last date of contact.
Descriptive statistics and rates of HSV diagnosis were calculated for the period 1990–2003. Study sites initiated and ended data collection over time; the first and last years of the study (1989 and 2004) contained significantly less person-time and therefore were excluded from the analyses.
To determine whether patient or clinical characteristics were associated with the prescription of suppressive antiviral therapy for HSV, a multivariate analysis was conducted. Gender, race (white vs. nonwhite), sexual orientation (men who have sex with men [MSM] vs. non-MSM), time since HIV diagnosis, ever prescribed highly active antiretroviral therapy (HAART), ever diagnosed with AIDS, and study site were included in the analysis. Variables, which were significant (P < 0.05) or changed the odds ratio of another variable by 10% or more were kept in the multivariate analysis.
Data were managed with and analyzed using SAS version 8.02 (SAS Institute, Cary, NC).
Between 1990 and 2003, 61,299 people were enrolled in the ASD study and contributed 187,686 person-years (PY) of follow-up. A median of 13,682 PY were contributed annually between 1990 and 2003. The average length of follow-up was 3.0 years (range, 0–17.6 years). At the study end, 15,111 people had died (25%). Demographic characteristics of the study population are presented in Table 1.
During the study period, 12,160 people (20%) ever had a recorded HSV diagnosis (Table 2). The rate of HSV diagnosis during the study was 10 per 100 PY. The most common site of HSV recurrence was genital (13%), followed by oral (5%) and other sites (4%). HSV as an AIDS-defining opportunistic infection was diagnosed in 2% of the study population.
Overall, 32% of the study population (19,732 people) received prescriptions for antiviral medications active against HSV, for a treatment rate of 22 per 100 PY.
Diagnosis and treatment of HSV became more common as time since HIV diagnosis increased. Among people followed for 7 or more years, a quarter (25%) were ever diagnosed with HSV compared with just 9% of people diagnosed with HIV in the past year (Fig. 1). Prescriptions for HSV similarly increase with time since HIV diagnosis; 41% of people followed for 7 or more years received a prescription compared with 15% of people followed for 1 year or less.
The average annual rate of HSV diagnosis declined from 14.4 per 100 PY in the first 5 years of the study (1990–1994) to 5.8 per 100 PY in the last 5 years (Fig. 2), a 30% decrease.
The rate of HSV diagnosis decreased by approximately 30% for all lesion sites (genital, oral, and other) between 1990 and 2003 (Fig. 2). Comparing the rate of diagnosis by site for the first 5 years of the study with the last 5 years, the rate of genital HSV decreased from 8.4 to 4.0 per 100 PY, HSV at other sites from 2.1 to 0.9 per 100 PY, and oral HSV from 2.8 versus 0.9 per 100 PY. HSV recurrences meeting the definition of an opportunistic infection also declined substantially throughout the study period, from 14.5 to 1.9 per 1000 PY in the first and last 5 years of the study, respectively (Fig. 3).
Data regarding treatment mode were available for records after 1997. Between 1998 and 2003, of the 26,911 people followed in ASD, 7463 or 28% received a prescription for HSV antiviral medication. Episodic treatment was more common and was prescribed for 5523 people or 21% of the study population. Suppressive treatment was prescribed for 2999 patients (11%). Some patients received both episodic and suppressive therapy in this time period. The mean yearly incidence of episodic therapy was 9.8 per 100 PY and essentially stable from 1998 to 2003 (range, 8.5–11.4). Suppressive therapy incidence was also stable at 8.0 per 100 PY (range, 7.1–10.1).
Patients with white race, who were MSM, receiving HAART, or diagnosed with AIDS were more likely to be given prescriptions for suppressive HSV therapy (Table 3). Significant variation was also present by study site.
To date, this represents the largest study of HSV diagnosis and treatment in a population of people receiving care for HIV. HSV infection is commonly observed in this population, and the percentage of patients followed by ASD who were diagnosed with HSV (20%) is consistent with that observed in other reports.1,3,5,6,21 However, point prevalence of symptomatic HSV may underestimate the burden of clinical HSV disease in people with HIV. In this population, a higher proportion of patients received prescriptions for antiviral treatment for HSV than were diagnosed, suggesting underascertainment of HSV diagnosis in medical records. Over time, an increasing percentage of HIV-infected patients experienced clinical HSV disease and may benefit from treatment.
The frequency of HSV diagnosis swiftly declined concurrent with the widespread use of HAART. Although a decrease was observed in diagnosis of HSV at all lesion sites, there was a greater impact on genital and other sites of lesions compared with oral HSV. Without serological data from this population, it is not possible to determine to what extent these trends are due to secular trends in HSV-1 and HSV-2 seropositivity.22 HAART-mediated improved immune function likely also played a role, resulting in less frequent recurrences and clinical recognition.15 The decrease in clinically recognized HSV may also be due in part to suppressive therapy for HSV.16
Prescriptions for suppressive antiviral medications were more common for patients who are MSM, white, ever treated with HAART, and ever diagnosed with AIDS. Health care providers may be more likely to recommend HSV suppression once AIDS has been diagnosed. Pill burden is a common concern regarding HSV suppressive medication for people with HIV. This analysis showed that people on HAART were actually more likely to be prescribed HSV suppressive therapy. These patients may be more frequently in care and more accepting of daily medication regimens. The association between suppressive therapy and MSM status and race/ethnicity may be due to health care provider's perception of risks or these may be proxy measures for other factors. There is also a significant variation in prescription patterns by study site. This may represent geographic differences in prescription patterns, differences in the patient population, which were not captured in the model (i.e., insurance status), or variation in data recording and abstraction.
This study has several limitations. We utilized an existing surveillance data set, rather than collecting data specific to the research questions examined here. Medical data were abstracted in 6-month intervals during which patients may have had any number of medical visits. Although HSV was a common clinical problem for patients in the ASD population, the costs and health care utilization associated with HSV could not be estimated as ASD neither collected chief complaint information for each visit nor numbers of HSV episodes during each abstraction period.
HSV serology was not available for the patients, and the basis for health care provider's diagnosis of HSV is not documented. Diagnostic methods likely varied among medical providers and were based on one or more of the following: HSV serology or culture, physical exam, or patient history. This may have led to under- or overascertainment of the disease burden according to the sensitivity and specificity of the diagnostic modality used. Differences in provider practice by geographical location and over time may account for some of the variation in HSV diagnosis and treatment observed here.
These data were collected from a convenience sample of people infected with HIV who were in care in selected geographic regions. This limits our ability to generalize these findings; however, the number of patients, facilities, and regions included in this study likely improved the representativeness of the cohort. Medical records from facilities that were not participating in the ASD study were not available unless copies were posted in the record of an ASD site; thus health data are missing for many patients who sought care from providers outside of the participating facilities. Finally, medical records and the data abstracted from them are prone to error, predominantly nondifferential underascertainment, which may have affected the study outcomes by underestimating the clinical burden of the disease and the frequency of antiviral prescriptions. The larger numbers of patients prescribed therapy relative to receiving an HSV diagnosis support underascertainment of HSV.
Despite these limitations, this study confirms that HSV is a common clinical occurrence for people with HIV infection. HSV diagnoses frequently result in episodic and suppressive antiviral treatment. Providers can expect that a significant proportion of their patients with HIV will require therapy for HSV disease. Given the frequency of clinical HSV disease, suppressive therapy may be underutilized, particularly in nonwhite patients. Provider education regarding the clinical burden of disease and effectiveness of suppressive therapy may be beneficial. Further research is needed to identify barriers to HSV suppressive treatment and to estimate the health care costs associated with this common coinfection.
1. Ramaswamy M, Sabin C, McDonald C, et al.. Herpes simplex virus type 2 (HSV-2) seroprevalence at the time of HIV-1 diagnosis and seroincidence after HIV-1 diagnosis in an ethnically diverse cohort of HIV-1 infected persons. Sex Transm Dis 2006; 33:96–101.
2. Romanowski B, Myziuk L, Walmsley S. Seroprevalence and risk factors for herpes simplex virus infection in a population of HIV-infected patients in Canada. Sex Transm Dis 2009; 36:165–169.
3. Ameli N, Bacchetti P, Morrow RA, et al.. Herpes simplex virus infection in women in the WIHS: Epidemiology and effect of antiretroviral therapy on clinical manifestations. AIDS 2006; 20:1051–1058.
4. Des Jarlais DC, Hagan H, Arasteh K, et al.. Herpes simplex virus-2 and HIV among noninjecting drug users in New York City. Sex Transm Dis 2007; 34:923–927.
5. Meyer JL, Crosby RA, Whittington WL, et al.. The psychosocial impact of serological herpes simplex virus 2 testing in an urban HIV clinic. Sex Transm Infect 2005; 81:309–315.
6. Bautista C, Singer D, O'Connell R, et al.. Herpes simplex virus type 2 and HIV infection among US military personnel: Implications for health prevention programmes. Int J STD AIDS 2009; 20:634–637.
7. Ramaswamy M, Geretti AM. Interactions and management issues in HSV and HIV coinfection. Expert Rev Anti Infect Ther 2007; 5:231–243.
8. Horbul JE, Schmechel SC, Miller BRL, et al.. Herpes simplex virus-induced epithelial damage and susceptibility to human immunodeficiency virus type 1 infection in human cervical organ culture. PLoS One 2011; 6:e22638.
9. Sobngwi-Tambekou J, Taljaard D, Lissouba P, et al.. Effect of HSV-2 serostatus on acquisition of HIV by young men: Results of a longitudinal study in Orange Farm, South Africa. J Infect Dis 2009; 199:958–964.
10. Barnabas RV, Wasserheit JN, Huang Y, et al.. Impact of herpes simplex virus type 2 on HIV-1 acquisition and progression in an HIV vaccine trial (the Step Study). J Acquir Immun Defic Syndr 2011; 57:238–244.
11. Barnabas RV, Webb EL, Weiss HA, et al.. The role of coinfections in HIV epidemic trajectory and positive prevention: A systematic review and meta-analysis. AIDS 2011; 25:1559–1573.
12. Centers for Disease Control and Prevention. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Morb Mortal Wkly Rep 2009; 58 (RR04):1–198.
13. Schacker T, Hu H, Koelle DM, et al.. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons: A double-blind, placebo-controlled trial. Ann Intern Med 1998; 128:21–28.
14. Schacker T, Zeh J, Hu H, et al.. Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men. J Inf Dis 1998; 178:1616–1622.
15. Posavad CM, Wald A, Kuntz S, et al.. Frequent reactivation of herpes simplex virus among HIV-1 infected patients treated with highly active antiretroviral therapy. J Inf Dis 2004; 190:693–696.
16. DeJesus E, Wald A, Warren T, et al.. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis 2003; 188:1009–1016.
17. Ioannidis JP, Collier AC, Cooper DA, et al.. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: A meta-analysis of randomized individual patient data. J Infect Dis 1998; 178:349–359.
18. Corey L, Wald A, Celum CL, et al.. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: A review of two overlapping epidemics. J Acquir Immun Defic Syndr 2004; 35:435–445.
19. Kim HN, Meier A, Huang M, et al.. Oral herpes simplex virus type 2 reactivation in HIV-positive and -negative men. J Infect Dis 2006; 194:420–427.
20. Farizo KM, Buehler JW, Chamberland ME, et al.. Spectrum of disease in persons with human immunodeficiency virus infection in the United States. JAMA 1992; 267:1798–1805.
21. Jameson DR, Celum CL, Manhart L, et al.. The association between lack of circumcision and HIV, HSV-2, and other sexually transmitted infections among men who have sex with men. Sex Transm Dis 2010; 37:147–152.
22. Smit C, Pfrommer C, Mindel A, et al.. Rise in seroprevalence of herpes simplex virus type 1 among highly sexual active homosexual men and an increasing association between herpes simplex virus type 2 and HIV over time (1984–2003). Eur J Epidemiol 2007; 22:937–944.