Current Strategies to Prevent Vertical HSV Transmission with Antiviral Therapy

[Rajkamal]

Does antiviral drugs cut down the vertical transmission of HSV?

[Olichudhar]

@rajkamal Current strategies to prevent vertical transmission with antiviral therapy have focused on 3 approaches, as follows:

Antiviral suppression for gravidas with first-episode infections during pregnancy

Routine antiviral suppression for gravidas with a history of genital HSV

Identification of seronegative gravidas at risk for primary and nonprimary first-episode genital HSV infections

Antiviral suppression for gravidas with first-episode infections during pregnancy
Recognizing that recurrent infections occur more frequently within the first year after a primary infection, Scott et al randomized 46 gravidas with first genital outbreak during pregnancy to either acyclovir (400 mg tid) or placebo beginning at 36 weeks' gestation. Patients receiving acyclovir experienced a significant reduction in the percentage of HSV recurrences at delivery (36% vs 0%) and cesarean deliveries for HSV (36% vs 0%). However, the reduction in the total number of cesarean deliveries in enrolled women was not statistically significant (40% vs 19%).

No patients in this study had asymptomatic shedding at the time of delivery, and no infant developed neonatal HSV infection or had complications from acyclovir. No attempt was made to distinguish between primary infections, nonprimary first-episode infections, or first-recognized recurrent infections. This study was, however, the first to demonstrate the utility of antiviral suppression in reducing the number of recurrences at the time of delivery.

Routine antiviral suppression for gravidas with a history of genital HSV
In 1998, Brocklehurst et al performed a double-blind placebo-controlled trial that involved 63 women with a history of recurrent HSV infection. [25] These women were randomized to either acyclovir (200 mg qid) or placebo, both beginning at 36 weeks' gestation. Nonsignificant reductions were found in recurrent HSV outbreaks at delivery, cesarean deliveries for HSV, and total cesareans in the acyclovir group. No infant in either group developed neonatal HSV, and no gravida experienced toxicity from acyclovir. The authors concluded that the sample size was too small to demonstrate a significant benefit from acyclovir and recommended that acyclovir be used only in clinical trials.

Since that time, additional randomized clinical studies have been performed, each demonstrating nonsignificant reductions in cesarean deliveries for recurrent HSV outbreaks and no differences in neonatal outcomes.

A 2003 meta-analysis pooled the results of five randomized clinical trials evaluating the use of antenatal suppressive acyclovir in 799 gravidas.
All of the observed outcomes were significantly reduced with suppressive use of acyclovir (no 95% confidence interval included the value of 1). No cases of neonatal herpes were reported in any of the 799 infants in all 5 studies, whether in the acyclovir or placebo group. Owing to the rarity of neonatal HSV infections, far larger numbers of subjects are required to demonstrate a significant difference in this important outcome.

Recommended regimens for suppressive therapy for pregnant women with recurrent genital herpes are as follows:

Acyclovir, 400 mg orally three times per day
Valacyclovir, 500 mg orally twice a day
Identification of seronegative gravidas at risk for primary and nonprimary first-episode genital HSV infections
This approach is the most ambitious of all strategies to prevent vertical transmission. Its logic is based on the observation that most neonatal HSV transmission occurs not in gravidas with a history of genital HSV, but rather in women who have primary or nonprimary first-episode genital infections at the time of labor. If routine serologic screening revealed that a woman was at risk for primary HSV (no antibodies) or nonprimary first-episode infection (either HSV-1 or HSV-2 only), she could be counseled to avoid genital-genital or oral-genital contact in order to prevent new genital infections during the third trimester of pregnancy and, hence, reduce neonatal HSV infections.

An alternative strategy would be to check the serologic status of the sexual partner, as well, and to recommend sexual abstinence only if the woman was at risk and the couple was serologically discordant, which occurs in 15-25% of couples. For example, if a woman was seronegative for HSV-2, and her partner was seropositive for HSV-2, the woman's risk of acquiring HSV-2 during pregnancy would be as high as 20%. Such a couple would, thus, be advised to abstain from sexual activity during pregnancy.

Despite the theoretical appeal of such an approach, no clinical trials have been published that show this approach results in a reduced rate of neonatal HSV infection. Three cost-benefit analyses have yielded conflicting results.

In 2000, Rouse and Stringer performed a decision analysis model to test the value of routine screening of couples for HSV serology during pregnancy. Of 1 million hypothetical women screened, the rate of neonatal HSV-1 transmission would be marginally reduced from 126 to 99, and the rate of neonatal HSV-2 infection would be reduced from 157 to 124. The cost per serious case of neonatal HSV averted would be $891,000. The authors concluded that HSV serology was not a cost-effective strategy to prevent neonatal HSV, predominantly through failure of counseling to prevent horizontal transmission.

Similarly, Thung and Grobman performed a decision analysis comparing current routine care (no serology testing), couple screening for susceptible gravidas with counseling for discordant couples, and counseling for discordant couples plus acyclovir prophylaxis for seropositive women to prevent symptomatic and asymptomatic shedding in labor. Out of 100,000 hypothetical women, serology screening would prevent 2 and 3.8 neonatal deaths or neurologic sequelae for strategies 2 and 3, respectively, with respective costs of 5.8 and 4 million dollars for each adverse sequela prevented.

In contrast, the decision analysis of HSV-2 screening by Baker et al compared no routine serology screening; routine screening, counseling for HSV-negative gravidas about safe sex, and offering acyclovir prophylaxis to HSV-positive women at 36 weeks; and testing the partners of HSV-negative women and offering suppressive therapy for HSV-positive men starting at 15 weeks. These researchers found that the cost of each case of neonatal herpes prevented with strategy 2 was $194,000, while the additional cost of partner screening and suppressive therapy was nearly 5 million dollars for each case of neonatal herpes prevented. They concluded that routine maternal serology screening with acyclovir suppression in seropositive gravidas was cost-effective, while partner screening and suppression was not.

Currently, routine maternal serologic screening is not widespread. Reasons for this include cost considerations; the unproven value of abstinence counseling in susceptible women; and the psychosocial ramifications of discovering a positive serology, as HSV-2 is predominantly a sexually transmitted disease. At this time, the American College of Obstetricians and Gynecologists has not endorsed routine maternal HSV serology screening.