Preventing Sexual Transmission of Genital Herpes

Table 1.

	Per-contact Probability in the HIV-1-Susceptible Partner
HIV-1 Plasma RNA in Source Partner (copies/mL)	HSV-2 positive	HSV-2 negative
<1700	0.0001	0.00004
1700-12,499	0.0023	0.0005
12,500-38,499	0.0018	0.0002
≥ 38,500	0.0036	0.0007

Table 1. Per-contact Probability of HIV-1 Infection in HSV-2-Seropositive and HSV-2-Seronegative Partners of HIV-1-Seropositive (Source) Subjects, Stratified by Plasma HIV-1 RNA Level of the Source Partner*^[13]

*None of the source partners were treated with antiretroviral therapy.

Table 2.

	Women	Men	Total
Number of Patients Sampled*	132*	70	202
Number of days sampled	9098	4402	13,500
Median percent of days HSV detected (range)	16.6 (0-94.4)	12.1 (0-92)	15.0 (0-96.4)

Table 2. Frequency of HSV Reactivation as Measured by PCR Among Immunocompetent Men and Women^[15]

* Persons sampled for > 30 days.

Table 3.

	Valacyclovir (N = 743)	Placebo (N = 741)	Total	Hazard Ratio (95% CI)	P
	No. (%)
Acquisition of symptomatic HSV-2 infection	4 (0.5)	16 (2.2)	20	0.25 (0.08, 0.75)	.008
Overall acquisition of HSV-2 infection	14 (1.9 )	27 (3.6)	41	0.52 (0.27, 0.99)	.04
Acquisition of HSV-1 or HSV-2 infections	14 (1.9)	31 (4.2)	45	0.45 (0.24, 0.84)	.01

Table 3. Acquisition of HSV Infection Among Susceptible Partners, According to the Source Partner's Treatment Assignment*^[19]

*P values were calculated using the log-rank test. CI denotes confidence interval.

Table 4.

	Hazard Ratio (95% CI)
Risk	Univariate	Adjusted*
Risk for each additional sex act per week	1.16 (1.05, 1.28)	1.16 (1.03, 1.30)
Condom use > 25% vs ≤ 25%	0.38 (0.11, 1.30)	0.25 (0.07, 0.88)
Sex when lesions present vs no sex when lesions present	2.01 (0.78, 5.18)
Acyclovir use by partner vs no acyclovir use	0.64 (0.24, 1.73)

Table 4. Effect of > 25% Condom Use on HSV-2 Acquisition^[21]

*Adjusted estimates are from a model stratified by sex and adjusted for age, condom use, and sex acts per week.
CI, confidence interval; HR, hazard ratio; HSV-2, herpes simplex virus type 2

Table 5.

	Hazard Ratio (95% CI)	P	Adjusted Hazard Ratio* (95% CI)	P
Condom use during study, ≤ 65% vs > 65% of sex acts	0.56 (0.33, 0.97)	.039	0.57 (0.33, 0.96)	.035

Table 5. Effect of > 65% Condom Use on HSV-2 Acquisition^[22]

*Adjusted for age, race, and frequency of sexual activity.

Table 5.

	Hazard Ratio (95% CI)	P	Adjusted Hazard Ratio* (95% CI)	P
Condom use during study, ≤ 65% vs > 65% of sex acts	0.56 (0.33, 0.97)	.039	0.57 (0.33, 0.96)	.035

Table 5. Effect of > 65% Condom Use on HSV-2 Acquisition^[22]

*Adjusted for age, race, and frequency of sexual activity.

Global epidemiology of genital herpes and the interaction of herpes simplex virus with HIV. In: Corey L, ed. HERPES: the Journal of the IFHM. . 2004;11(Suppl 1).
Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 1997;337:1105-1111. Abstract
Armstrong GL, Schillinger J, Markowitz L, et al. Incidence of herpes simplex virus type 2 infection in the United States. Am J Epidemiol. 2001;153:912-920. Abstract
Chen CY, Ballard RC, Beck-Sague CM, et al. Human immunodeficiency virus infection and genital ulcer disease in South Africa: the herpetic connection. Sex Transm Dis. 2000;27:21-29. Abstract
Ballard R, Htun Y, Dangor Y, et al. HIV and genital ulcer disease — determinants of HIV shedding from lesions and consequences of therapy. Program and abstracts from the International Society for Sexually Transmitted Diseases Research 1999; Denver, Colorado. Abstract 055.
Beyrer C, Jitwatcharanan K, Natpratan C, et al. Molecular methods for the diagnosis of genital ulcer disease in a sexually transmitted disease clinic population in Northern Thailand: predominance of herpes simplex virus infection. J Infect Dis. 1998;178:243-246. Abstract
Risbud A, Chan-Tack K, Gadkari, et al. The etiology of genital ulcer disease by multiplex polymerase reaction and relationship to HIV infection among patient attending sexually transmitted disease clinics in Pune India. Sex Transm Dis. 1999;26:55-62. Abstract
Mertz GJ, Trees D, Levine WC, et al. Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group. J Infect Dis. 1998;178:1795-1798. Abstract
Corey L, Wald A. Genital herpes. In: Holmes KK, Sparling PF, Mardh PA, eds. Sexually Transmitted Diseases. New York, NY: McGraw-Hill Inc.; 1999: 285-312.
Wasserheit J. Epidemiological synergy. Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis. 1992:19:61-77. Abstract
Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2 seropositive persons: a meta-analysis. J Infect Dis. 2002;185:45-52. Abstract
Buve A, Carael M, Hayes RJ, et al. The multicenter study of factors determining the differential spread of HIV in four African cities: summary and conclusions. AIDS. 2001;15(suppl 4):S127-S131. Abstract
Gray RH, Wawer MJ, Brookmeyer R, et al; Rakai Project Team. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet. 2001;357:1149-1153. Abstract
Reynolds SJ, Risbud AR, Shepherd ME, et al. Recent herpes simplex virus type 2 infection increases HIV incidence: a prospective study in rural Tanzania. J Infect Dis. 2003;187:1513-1521. Abstract
Mertz GJ, Benedetti J, Ashley R, et al. Risk factors for the sexual transmission of genital herpes. Ann Intern Med. 1992;116:197-202. Abstract
Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med. 2002;347:1654-1661.
Wald A, Corey L, Cone R, et al. Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J Clin Invest. 1997;99:1092-1097. Abstract
Wald A, Zeh J, Barnum G, et al. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996;124:8-15. Abstract
Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350:11-20. Abstract
Corey L, Langenberg AG, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. JAMA. 1999;282:331-340. Abstract
Wald A, Langenberg AG, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA. 2001;385:3100-3106.
Wald A, Langenberg A, Kexel E, Izu A, Ashley R, Corey L. Condoms protect men and women against herpes simplex virus type 2 (HSV-2) acquisition. Program and abstracts from the 2002 National STD Prevention Conference; March 4-7, 2002; San Diego, California. Abstract B9E.
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Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic HSV-2 seropositive persons. N Engl J Med. 2000;342:844-850. Abstract
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Genital Herpes: A Worldwide Epidemic

Genital herpes is perhaps the most common sexually transmitted infection in the world. Herpes simplex virus type 2 (HSV-2) seroprevalence has significantly increased in the last 20 years: in almost all parts of the world, 20% to 60% of sexually active adult men and women have antibodies to HSV-2 (Figure 1).^[1] In the United States, population-based studies have indicated that 22% of adults have antibodies to HSV-2 and that an estimated 1.6 million new cases of HSV-2 infection occur each year.^[2,3] Further, with the advent of polymerase chain reaction (PCR) testing, it has become apparent that HSV-2 is the most frequent cause of genital ulcer disease in all regions of the world. Studies in India, the Republic of South Africa, Tanzania, and Thailand have shown that HSV-2 may be the cause of up to 80% of all genital ulcerations.^[4-7] In the United States and Western Europe, the prevalence of HSV-2 as a cause of genital ulcerations may be even higher.^[8]

Figure 1.

Enlarge

HSV-2 prevalence among women.^[1]

Over the past decade, studies of the natural history of genital herpes have brought increasing recognition that HSV-2 causes chronic infection characterized by frequent reactivations in genital mucosa and the attendant risk of sexual transmission of infection. Significantly, both symptomatic and asymptomatic reactivations have been shown to result in sexual transmission of HSV-2.^[9] Genital herpes reactivations have also been linked with the sexual transmission of other sexually transmitted infections, including human immunodeficiency virus type 1 (HIV-1) infection.

Mounting data describe an epidemiologic synergism between HSV-2 and HIV-1. HSV-2 prevalence appears to influence HIV incidence and vice versa.^[10] A meta-analysis of data from more than 30 studies recently determined that the relative risk for HIV acquisition among persons with HSV-2 infection was 2.1 (95% confidence interval [CI], 1.4-3.2); using this estimate, the authors calculated the population-attributable risk percent (ie, the percentage of HIV infections attributable to genital herpes infection) to be 19% in populations with 22% HSV-2 prevalence, and 47% in populations with 80% HSV-2 prevalence -- a level existing in many parts of sub-Saharan Africa.^[11] Similarly, a study of factors associated with differences in HIV transmission in cities with high and low HIV prevalence showed that high HSV-2 seroprevalence and low circumcision rates were major risk factors for the spread of HIV.^[12] The most direct and compelling data regarding the link between HSV-2 infection and HIV-1 transmission were yielded by a retrospective analysis of factors associated with new HIV infections among HIV discordant couples in Rakai, Uganda.^[13] This study found that a higher viral load in the HIV-infected partner and genital ulceration in the susceptible partner were the main determinants of HIV transmission. Specifically, HSV-2 seropositivity of the susceptible partner was found to increase the risk of HIV acquisition by 5- to 8-fold per sexual contact, regardless of the HIV viral load of the HIV infected partner ( Table 1 ). In fact, the per-contact sexual transmission rate from an HIV-positive partner with an HIV-1 RNA level of < 1500 RNA copies/mL to an HIV uninfected, HSV-2 seropositive partner was equal to that from an HIV-seropositive person with a viral load > 37,000 copies/mL to an HIV-negative, HSV-2-seronegative partner. In light of the widespread prevalence of HSV-2 infection, these findings illustrate, on a population basis, the dramatic effect that HSV-2 seropositivity has upon the spread of HIV.

These findings have brought about a fundamental shift in the medical establishment regarding the importance of preventing genital herpes infections, especially in populations at risk for HIV-1 infection.^[14] This shift has finally placed the concerns of physicians and health officials in concert with those of patients with known genital herpes infections, a majority of whom for years have identified transmission of the infection to others as their chief concern regarding the disease.

Almost all new cases of genital herpes, however, are transmitted among persons who are unaware of their having HSV-2 infection, unaware of the importance of subclinical reactivation in the transmission of disease, and unaware of the mild clinical symptoms of HSV-2 and the attendant frequent reactivations that occur with HSV-2 seropositivity.^[15] Table 2 depicts a compilation of data showing the frequency of HSV-2 reactivation as measured by PCR in various populations. While there is a wide range of variability between individuals, the median frequency of reactivation is quite high and illustrates the reason for the widespread epidemic of HSV-2 that is occurring worldwide.

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Preventing HSV-2 Transmission

Genital Herpes: A Worldwide Epidemic
Preventing HSV-2 Transmission
Conclusions

References

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Table 1.

Table 2.

Table 3.

Table 4.

Table 5.

Table 5.

Clinical Tools for Preventing Sexual Transmission of Genital Herpes

Genital Herpes: A Worldwide Epidemic

Figure 1.

Table of Contents

Table 1.

Table 2.

Table 3.

Table 4.

Table 5.

Table 5.

References

Faculty and Disclosures

Clinical Tools for Preventing Sexual Transmission of Genital Herpes

Genital Herpes: A Worldwide Epidemic

Figure 1.

Table of Contents