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.

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Preventing HSV-2 Transmission

Prevention strategies for reducing the sexual transmission of HSV-2 include (1) vaccination, (2) behavior modification with a focus on the use of condoms, and (3) the use of chronic, daily antiviral therapy. Two of these approaches are clinically practicable at this time. At present, although several vaccine candidates are under development, no HSV-2 vaccine is currently licensed for clinical use. Recent clinical trials suggest partial efficacy of a candidate vaccine in HSV-2 seronegative women; confirmatory trials are ongoing.^[16] Even under the best of circumstances, however, it will take 4-6 years to find out whether this potential vaccine will provide a useful public health control measure for preventing new HSV-2 infections. As such, interventions at present must rely on the use of condoms, the use of antiviral therapy, or, as discussed below, both.

Use of Antivirals to Prevent the Transmission of Genital Herpes

Although the use of chronic, daily antiviral therapy has been shown for nearly 2 decades to reduce the frequency of clinical reactivation of genital herpes infections, only more recently has it been shown that daily antiviral therapy also reduces the frequency of subclinical reactivations and the amount of HSV-2 that is shed, subclinically, on genital mucosal surfaces, the principal source of transmitted infections.^[17,18] These effects provided the rationale for a large multicenter study that demonstrated the effectiveness of once-daily valacyclovir therapy in reducing the risk of sexual transmission of genital herpes.^[19]

This randomized, placebo-controlled trial involved the study of nearly 1500 immunocompetent, heterosexual, monogamous couples who were serologically discordant for HSV-2 infection. HSV-2-seropositive partners were randomized in a 1:1 ratio to receive valacyclovir 500 mg once daily or matching placebo.^[19] Condoms were provided free of charge to all participants in the trial throughout the study, and all couples received counseling about the effective use of condoms. HSV-2-seronegative, susceptible partners were evaluated monthly for 8 months for clinical and laboratory evidence of HSV-2 infection. New infections were diagnosed on the basis of isolation of HSV-2 from culture or HSV-2 seroconversion. Of 1498 couples at 96 centers worldwide, 1159 completed the study. During the study period, a total of 41 HSV-2 infections occurred among susceptible partners: 20 were clinically symptomatic and 21 were diagnosed on the basis of HSV-2 seroconversion only ( Table 3 ).

Of the 20 symptomatic infections, 16 occurred among the 741 partners of placebo recipients (2.2%) and 4 occurred among the 743 partners of valacyclovir recipients (0.5%) (relative risk, 0.25; 95% CI, 0.08-0.74; P = .01) (Figure 2). The time to development of symptomatic first episodes of genital herpes was significantly longer among the partners of valacyclovir recipients than among the partners of placebo recipients. In all 41 cases of HSV-2 acquisition that were evaluated, HSV-2 had been acquired by 27 of the susceptible partners of placebo recipients (3.6%) compared with 14 of the susceptible partners of valacyclovir recipients (1.9%) (hazard ratio [HR], 0.52; 95% CI, 0.27-0.99; P = .04) (Figure 2).

Consistent with the findings of other studies of HSV-2 transmission, more female partners than male partners of placebo-treated patients acquired HSV-2 infection (7.4% vs 1.8%).^[19] No evidence of a significant difference in treatment effect of valacyclovir was seen between susceptible female or male partners. There were several significant factors that influenced the effectiveness of the medication, however. Valacyclovir-treated persons who had genital herpes for less than 2 years were nearly 3 times more likely to transmit than those who had genital herpes for more than 2 years. Similarly, those who were in a monogamous relationship of less than 2.5 years' duration were also 3 times more likely to transmit infection. Interestingly, past HSV-1 infection was not a factor in protecting against the acquisition of HSV-2.

Condom use data were collected during the course of the trial.^[19] Couples were classified, on a monthly basis, as those who never used condoms, sometimes used condoms (1% to 90% of sexual contacts), and nearly always used condoms (> 90% of sexual contacts). In the study population as a whole, frequent condom use was found to reduce the acquisition rate of genital herpes infections. Of interest, the effect of valacyclovir was similar among all frequencies of condom use. While the numbers were small, there was no evidence of transmission among couples who used condoms very frequently (> 90%) and also received valacyclovir (Figure 3); the study was not powered, however, to confirm that utilization of both modalities was 100% effective.

Condoms for Prevention of HSV-2

The effectiveness of using condoms for preventing transmission of HSV-2 infection has been difficult to demonstrate. There have been no prospective studies specifically designed to evaluate the efficacy of condom use in this regard. Retrospective analyses of data from a prospective cohort study of incident genital herpes^[20] have been useful in defining the fact that condoms are effective in reducing the transmission of HSV-2 from men to women and, more recently, from women to men. The effect is incomplete at best, however, with protection rates of only 40% to 50% being observed.^[21,22] The most useful available data on the effectiveness of condom use for preventing genital herpes are shown in Table 4 and Table 5 .

It should be noted that in this analysis^[21] -- the first to document the effectiveness of condoms with specific regard to preventing HSV-2 infection -- when data were examined by sex, condoms appeared to be highly protective for women (adjusted HR, 0.085; 95% CI, 0.011-0.67) but not for men (HR, 2.02; 95% CI, 0.32-12.5). In a second analysis of the same study population, the authors reported that a higher frequency of condom use (ie, > 65% of sex acts) afforded equal and significant protection to heterosexual women, heterosexual men, and men who have sex with men ( Table 5 ).^[22]

The reasons for the less-than-perfect efficacy of condom use are of interest. Subclinical shedding studies have shown that perirectal shedding and asymptomatic vulvar shedding from microscopic lesions are common in both men and women.^[23,24] Thus, one could hypothesize that skin to skin contact that occurs prior to putting on the condom may be a factor in the continued transmission of genital herpes. Differences in the degree of protection provided by condoms in women and heterosexual men may also be explained in this way, as viral shedding studies have indicated that penile skin is the most common site of HSV-2 shedding in men.^[24]