Herpes simplex virus type 2 and HIV infection among US military personnel: implications for health prevention programmes

Abstract

US military personnel are routinely screened for HIV infection. Herpes simplex virus type 2 (HSV-2) is a risk factor for HIV acquisition. To determine the association between HSV-2 and HIV, a matched case-control study was conducted among US Army and Air Force servicemembers with incident HIV infections (cases) randomly matched with two HIV-uninfected servicemembers (controls) between 2000 and 2004. HSV-2 prevalence was significantly higher among cases (30.3%, 138/456) than among controls (9.7%, 88/912, P < 0.001). HSV-2 was strongly associated with HIV in univariate (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 3.1–5.8) and multiple analyses (adjusted [OR] = 3.9, 95% CI = 2.8–5.6). The population attributable risk percentage of HIV infection due to HSV-2 was 23%. Identifying HSV-2 infections may afford the opportunity to provide targeted behavioural interventions that could decrease the incidence of HIV infections in the US military population; further studies are needed.

Keywords

HSV-2 HIV herpes co-infection military epidemiology United States

INTRODUCTION

Herpes simplex virus type 2 (HSV-2) is the major cause of genital ulcer disease and the most prevalent sexually transmitted disease (STD) in the USA and worldwide.^1,2 HSV-2 infection has been reported as a significant risk factor for HIV acquisition and transmission.^3–5 Recent epidemiological studies have highlighted the complex synergistic interactions between these two viral infections, both of which are acquired through sexual contact.⁶ Some literature presents the possibility that control of HSV-2 infection may reduce the incidence of HIV infections.^7–9

Since 1998, the annual incidence of HIV in the US military population has remained relatively stable with approximately 0.2 cases per 1000 person-years (PYs),¹⁰ whereas the HSV-2 incidence rate, based on clinically apparent infections associated with a health-care encounter in the military medical system, increased from 1.25 in 1998 to 1.94 cases per 1000 PYs in 2004.¹¹ Currently, there is limited information on the burden of infection with HSV-2 in the US military population and to date the association between HSV-2 and HIV infection has not been examined in this population. Existing literature has been limited to a report on the correlation between HSV-2 and human herpes virus-8 among HIV-infected US military men,¹² and a report of high HSV-2 incidence among female active duty personnel deployed in support of Operation Iraqi Freedom/Operation Enduring Freedom.¹³

Current expert opinion suggests that HSV-2 serological testing may be considered as part of a comprehensive evaluation for STDs among persons with multiple sex partners and those at increased risk for HIV acquisition.¹⁴ Including HSV-2 testing in clinical practice may afford opportunities for counselling regarding treatment options and risk reduction. In the US military, there is no routine or mandatory HSV-2 screening program. Rather, HSV-2 screening is currently based on clinical indicators. The aim of this matched case-control study was to determine the association between HSV-2 and HIV infection in the US military population.

MATERIALS AND METHODS

Medical surveillance systems in the US military

The Defense Medical Surveillance System (DMSS) is the central repository of medical surveillance data for the US armed forces.¹¹ This system contains historical and up-to-date disease data, medical event data and longitudinal data on servicemembers. The Department of Defense Serum Repository (DoDSR) is a central archive of sera that remain after routine HIV antibody testing. All military members have HIV antibody testing performed at entry into military service, periodically every 2–5 years, and before and after major deployments. Similarly, the Air Force Institute of Operational Health Epidemiological Surveillance Laboratory, Brooks City Base, TX (referred to here as Air Force Central HIV Testing Service) performs Air Force HIV testing and epidemiological analysis of HIV tests on active-duty and reserve Air Force personnel and civilian employees, and coordinates archiving activities with the DoDSR.

Study population

All US Army and Air Force servicemembers with incident HIV infection between June 2000 and February 2004 were initially considered as potential cases. Only those cases with archived demographic data (age, sex, self-identified race, educational level, marital status, geographic home region of residence/record, branch and component of military service) and a cryopreserved HIV screening serum specimen available for testing from the DMSS and the DoDSR or the US Air Force Central HIV Testing Service were selected as eligible cases for the study. Two HIV-uninfected servicemember controls were randomly matched to each case by sex and by a blood sample that was collected within 30 days of the date of the case's first HIV-positive test.

Serological analysis

HIV seropositivity was determined by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot assay using freshly collected sera.¹⁰ HIV screening test history data were obtained from the DMSS.¹¹ HSV-2 seropositivity was determined by ELISA (HerpeSelect 2, Focus Technology, Cypress, CA, USA). A cut-off optical density value ≥3.5 was used to improve assay specificity.¹⁵

Study approvals

The study protocol ‘Sero-epidemiologic case-control study of HIV-1 infected and non-infected US military servicemembers’ (Walter Reed Army Institute of Research [WRAIR] #1109, RV #161) was approved by the institutional ethical review board and scientific review committee at the WRAIR, Silver Spring, Maryland.

Statistical analysis

To detect an odds ratio (OR) (association) of 2.0, with a power of 80%, a significance level of 95%, an exposure rate of 5–50%, and two controls per case, the estimated sample size was 492 cases and 984 controls. Age and geographic region or residence (home of record) were categorized based on medians and US Census Bureau guidelines, respectively. Frequencies were compared by chi-square or Fisher's exact test. Conditional logistic regression was used to estimate crude and adjusted ORs. The impact of HSV-2 on HIV infection was assessed by estimating the population attributable risk percent and its confidence intervals were estimated using logit-transformed estimators.¹⁶ Statistical analyses were performed using STATA version 9.0 (Stata Corporation, College Station, TX, USA).

RESULTS

Study population

A total of 525 incident HIV infections were identified between June 2000 and February 2004 among Army and Air Force servicemembers. Of these, 456 (87%) HIV cases with demographic data and serum available were included in this study. Among HIV-positive cases, 57% were ≥30 years old (mean age, 32 years), 59% were African Americans, 72% had less than or equal to a high school education and 58% were single. Among HIV-negative controls, 55% were <30 years old (mean age, 30 years), 72% were white and 55% were married. Significant demographic differences between cases and controls were found for age group, race and marital status (P < 0.001).

HSV-2 prevalence

The overall prevalence of HSV-2 infection among cases was 30.3% (95% confidence interval [CI] = 26.1–34.7%) and was significantly higher than among controls (9.7%, 95% CI = 7.8–11.8%, P < 0.001). Among HIV-positive cases, the highest HSV-2 prevalences were observed among women (48%), African Americans (35%), servicemembers with home of record in the South (34%), those in the Reserves (33%) and married personnel (32%). HSV-2 prevalence was highest among servicemembers ≥30 years old (34%). Among controls, the highest HSV-2 prevalences were observed among single servicemembers (14%), servicemembers from the Midwest (13%), those in the Reserves (11%) as well as among African Americans (11%) and men (10%). In every demographic subgroup analysis, HSV-2 prevalence was significantly higher among cases than among controls (P < 0.05, Table 1).

Table 1

Herpes simplex virus-2 (HSV-2) prevalence and conditional logistic regression analysis among cases and controls

	Cases*		Controls^†		Univariate analysis			Multiple analysis
Feature	HSV-2 %^‡	(n/N)	HSV-2 %	(n/N)	OR	(95% CI)	P value	AOR	(95% CI)	P value
Overall	30.3	(138/456)	9.7	(88/912)	4.2	(3.1–5.8)	<0.001	3.9	(2.8–5.6)	<0.001
Sex
Female	48.1	(13/27)	1.9	(1/54)	26.0	(3.4–198.8)	0.002	31.6	(3.0–338.9)	0.004
Male	29.1	(125/429)	10.1	(87/858)	3.8	(2.8–5.3)	<0.001	3.6	(2.5–5.2)	<0.001
Age group (years)
17–29	25.0	(49/196)	11.1	(56/505)	3.1	(1.7–5.8)	<0.001	2.9	(1.5–5.9)	0.001
>30	34.2	(89/260)	7.9	(32/407)	5.4	(3.0–9.5)	<0.001	6.6	(3.3–11.1)	<0.001
Race
White	25.0	(39/156)	9.3	(61/657)	3.0	(1.7–5.4)	<0.001	3.1	(1.6–5.8)	0.001
Black	34.5	(92/267)	11.4	(20/176)	3.5	(1.7–7.3)	0.001	3.4	(1.5–7.6)	0.003
Other	21.2	(7/33)	8.9	(7/79)	Undef.			Undef.
Education
>High school	30.7	(38/124)	9.6	(26/272)	6.1	(2.1–18.1)	0.001	6.6	(1.8–24.1)	0.004
<High school	29.8	(96/322)	9.4	(58/620)	4.1	(2.7–6.4)	<0.001	3.7	(2.2–6.1)	<0.001
Marital status
Married	32.3	(50/155)	6.8	(34/498)	5.4	(2.6–10.8)	<0.001	5.8	(2.6–13.1)	<0.001
Single	29.0	(76/262)	13.6	(50/369)	3.2	(1.8–5.7)	<0.001	3.0	(1.5–5.9)	0.001
Other	27.8	(10/36)	9.5	(4/42)	2.0	(0.2–22.1)	0.571	Undef.
Region (home)
West	30.6	(11/36)	8.6	(10/116)	Undef.			Undef.
Midwest	30.0	(18/60)	12.7	(17/134)	3.6	(0.4–35.8)	0.267	3.7	(0.3–42.9)	0.299
Northeast	24.3	(9/37)	10.1	(11/109)	Undef.			Undef.
South	33.9	(72/221)	9.0	(26/288)	3.3	(1.8–6.0)	<0.001	2.7	(1.4–5.5)	0.005
Unknown/other	24.5	(25/102)	9.1	(24/265)	2.5	(0.8–7.1)	0.101	3.1	(0.8–11.5)	0.093
Service component
Reserve (National Guard/Reserve)	32.5	(63/194)	11.1	(38/342)	5.0	(2.4–10.5)	<0.001	4.6	(2.0–10.6)	<0.001
Active duty	28.6	(75/262)	8.8	(50/570)	4.0	(2.4–6.8)	<0.001	4.3	(2.3–7.9)	<0.001
Service component
Air Force	25.3	(25/99)	8.8	(28/317)	3.2	(1.2–8.3)	0.016	3.2	(1.1–10.0)	0.041
Army	31.7	(113/357)	10.2	(60/589)	4.5	(3.0–6.7)	<0.001	4.2	(2.7–6.7)	<0.001

*HIV-1 positive individuals; ^†HIV-1 negative individuals; AOR, adjusted odds ratio by age, race, and marital status; CI, confidence interval; Undef; undefined odds ratio, zero or infinity

West (Montana, Wyoming, Colorado, New Mexico, Idaho, Utah, Arizona, Nevada, Washington, Oregon, California, Alaska, and Hawaii); Midwest (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Ohio, Nebraska, North Dakota, South Dakota, and Wisconsin); Northeast (Maine, New Hampshire, Vermont, Massachusetts, Rhode Island, Connecticut, New York, New Jersey, and Pennsylvania); South (Florida, Georgia, North Carolina, South Carolina, Virginia, West Virginia, Maryland, Washington, DC, Delaware, Alabama, Kentucky, Mississippi, Tennessee, Arkansas, Louisiana, Oklahoma, and Texas)

^‡For all demographic data, the prevalence of HSV-2 was significantly higher among cases than among their controls (P < 0.05 by chi-square or Fisher's exact test)

Risk factor analyses

In univariate analysis, HSV-2 was significantly associated with HIV infection (OR = 4.2, 95% CI = 3.1–5.8, P < 0.001). This strong association remained after adjusting for age, race and marital status in multiple conditional logistic regression analysis (adjusted OR [AOR] = 3.9, 95% CI = 2.8–5.6) (Table 1). Higher significant adjusted associations of HSV-2 with HIV infection were observed among servicemembers who were women (AOR = 31.6), who were ≥30 years old (AOR = 6.6), who had greater than a high school education (AOR = 6.6), who were married (AOR 5.8) and who were in the reserve components (AOR = 4.6). The population attributable risk percentage of HIV infection due to HSV-2 was 23% (95% CI = 18–28%).

DISCUSSION

We found a high HSV-2 prevalence among HIV-infected individuals and a strong and significant association between HSV-2 and HIV in this military population. This study represents the first evaluation of the relationship between HSV-2 and HIV among US military servicemembers, a unique study population that consists primarily of young, healthy, employed and racially diverse men. Twenty-three percent of HIV infection could be attributable to HSV-2, suggesting that methods to prevent and/or control HSV-2 infections would have a measurable impact on HIV incident infections.

Servicemembers with HIV infections were four times more likely to have HSV-2 than our HIV-negative control group, a finding similar to a summary estimate from 22 case-control and cross-sectional studies.¹⁷ In some subgroups, however, this effect size was even greater. Among women, for example, the association between these two viral infections was nearly nine times higher than among men. This may be explained by a differential effect between HSV-2 and HIV by sex. Women are more likely than men to acquire HSV-2 infections, likely due to anatomical differences including the lack of an intact stratum corneum in much of the female genital tract.¹⁸ This difference may also be explained by the greater probability of HSV-2 transmission from men to women than women to men.¹⁹ It may be noted that our study had a limited number of females.

Age was also associated between HSV-2 and HIV. A greater number of total lifetime sexual partners has been associated with an increased risk of becoming HSV-2 infected.²⁰ Thus, if age is considered as a crude surrogate measure for potential total number of lifetime partners in HIV-positive individuals this could explain the high association observed in those aged 30 years or more. We noted that a higher educational level had a stronger association between HSV-2 and HIV. In the United States, a higher HSV-2 prevalence has been reported among individuals with a lower educational level.¹ This finding is in contrast to that found in our study, where the risk of HIV infection in HSV-2 seropositive individuals with greater than a high school education was nearly twice as high as among servicemembers with less than or equal to a high school education. This association between educational level and risk for both HSV-2 and HIV is unclear and warrants further study. Reserve component servicemembers are typically called to active duty for short periods (up to 30 days), have access to military health care only during those periods of activation, and are expected to maintain the same military medical readiness as that of active duty servicemembers. The high association of HSV-2 with HIV observed in this group may be partially explained by more limited access to health care and to health promotion programmes.

Based on our findings, and given the recent advances in understanding the complex relationship between HSV-2 and HIV, we present a number of opportunities for prevention and public health approaches to reduce the burden of HSV-2 and also prevent new HIV infections in the US military population. At military health-care facilities that provide care for patients with STDs, HSV-2 testing could be offered to servicemembers who report high-risk sexual behaviours. Screening should be performed with the most current technologies for HSV-2 testing, which provide both high sensitivity and specificity; such tests include those based on type-specific glycoprotein G ELISA (HerpeSelect^®).²¹

Servicemembers diagnosed with HSV-2 should undergo HIV testing given the synergistic interaction between these two viral infections and the strong association found in our study. Recent incident HSV-2 infections are associated with the highest risk of HIV acquisition.²² Personnel that present with primary genital herpes should receive personalized counselling and education regarding sexual behaviour modification, which includes information on the risk and knowledge of transmission of HSV-2 and the correct use of condoms particularly during symptomatic periods of the disease.²³ In addition, information concerning the relationship between HSV-2 and HIV infection should be provided.

HSV-2 positive servicemembers could be offered either episodic or suppressive antiviral therapy, such as with valacyclovir, to suppress genital herpes outbreaks and reduce the risk of transmission of genital herpes.²⁴ A prior study demonstrated that once-daily suppressive compared with twice-daily episodic HSV-2 therapy was associated with increased patient satisfaction and a lower frequency of recurrences.²⁵

HIV-positive servicemembers should be considered for HSV-2 testing. Asymptomatic HSV-2 infections may be associated with increased transmission and acquisition of HIV infection.^3–5 Servicemembers dually infected with HIV and HSV-2 could receive antiherpetic therapy with valacyclovir in order to reduce their risk of HIV transmission. Two previous studies reported that valacyclovir significantly reduced genital shedding and plasma levels of HIV RNA in HIV/HSV-2-coinfected individuals.^7,8 Unfortunately, data from two recent clinical trials among women in Africa and men who have sex with men in the US and Peru showed that HSV-2 suppression with acyclovir was ineffective at reducing their risk of HIV transmission.^26,27 The potential benefit of herpes suppression on HIV infections among heterosexual men remains unclear. Beyond HIV prevention, some data indicate that HSV-2 may accelerate the course of HIV disease by increasing HIV plasma viral loads.⁹ More prospective studies are required to determine the effect of HSV-2 replication on HIV progression. For now, it is unknown whether antiherpetic therapy could be recommended among HIV-positive persons for either public health reasons or their own health.

This study has limitations. First, behavioural data (i.e. sexual practices) are not collected in the DMSS and could not be evaluated. Further research is required to better understand how sexual behaviours influence the risk of HSV-2 and/or HIV infection in this population. Second, our data are limited by the small number of HIV-infected women in the military service; further studies regarding the impact of HSV-2 on HIV infections among women are needed.

In summary, this is the first research study to document the epidemiology of HSV-2 among HIV-infected US military servicemembers. The findings of this study, the high HSV-2 prevalence found among HIV-infected individuals and the strong observed association between these two viral infections suggests that interventions to reduce the occurrence of HSV-2 may have an impact on reducing new HIV infections among US military servicemembers.

Footnotes

ACKNOWLEDGEMENTS

The authors would like to thank all the laboratory personnel at the US Military HIV Research Program, Rockville, MD for sample processing, Warren B. Sateren for comments on this manuscript and A. Sebastian for technical assistance.

Disclaimer: This study has been approved and reviewed by the Walter Reed Army Institute of Research. There is no objection to its publication. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the Department of the Army, Navy, Air Force or the Department of Defense, or any other organization listed.

Financial support: The US Military HIV Research Program at the Walter Reed Army Institute of Research has supported this study.

Data were presented at the Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract MOAC101, Sydney, 2007.

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