Antiviral treatment doesn't prevent short episodes of genital herpes reactivation

High-dose antiviral treatment does not prevent short, sub-clinical shedding of the genital herpes virus, investigators from the US report in the January 5 edition of The Lancet.

“Our results show that short episodes of subclinical shedding persist with both standard-dose and high-dose aciclovir and valaciclovir,” comment the authors. “These data suggest that novel therapies are needed to completely prevent HSV [herpes simplex virus] reactivation.”

HSV-2 is a common sexually transmitted infection. It can cause painful symptoms and can increase the risk of infection with HIV.

Daily therapy with the antiviral drugs aciclovir or its prodrug valaciclovir reduces the frequency of genital lesions caused by HSV-2 and suppresses shedding of the virus. However, such therapy does not eliminate the risk of sexual transmission of HSV-2. One study showed that daily treatment with valaciclovir reduced the risk by less than 50%. Nor does antiviral treatment reduce the risk of infection with HIV.

Intensive monitoring shows that genital shedding of HSV-2 is much more frequent than previously thought. Many of these episodes are of short duration, typically less than twelve hours. The impact of antiviral treatment on short episodes of HSV-2 is unknown.

Investigators at the University of Washington therefore designed three, complementary randomised studies involving a total of 90 HSV-2 infected but HIV-negative patients.

The first study compared standard-dose aciclovir (400 mg twice daily) with no treatment. The second trial was a comparison of standard-dose valaciclovir (50 mg daily) with high-dose aciclovir (800 mg three times daily). The third study compared standard-dose valaciclovir with high-dose valaciclovir (1 g three times daily).

All three studies had a cross-over design and consisted of two phases. The patients took their allocated medication for between four to seven weeks. This was followed by a one-week “washout” phase, after which the patients switched to regimen.

The patients swabbed their genitals four-times daily and these swabs were analysed for HSV-2 shedding. The primary outcome of all three studies was the impact of the various treatments on shedding. Secondary outcomes were the number of HSV shedding episodes, the duration of shedding and  maximum HSV-2 load during episodes of disease reactivation. Data were also gathered on the rates of adverse events.

Most (54%) of the patients were women, their median age was 43 years, 76% were white and the median duration of infection with HSV-2 was 7.6 years. Treatment was safe, although 30% of patients taking high-dose valaciclovir reported headache.

A total of 23,605 swabs were collected for analysis.

All doses of medication reduced the frequency of HSV detection compared with no medication (no medication vs. standard-dose valaciclovir, p = 0.03; no medication vs. high-dose aciclovir, p = 0.002; no medication vs. high-dose valaciclovir, p < 0.001).

Nevertheless, shedding of HSV occurred with all drug doses.

A total of 344 episodes of HSV reactivation were observed. The incidence of shedding for each treatment regimen was as follows:

·      No treatment = 18%.

·      Standard-dose aciclovir = 1.2%.

·      Standard-dose valaciclovir = 5.8%.

·      High-dose valaciclovir = 3.3%.

The median duration of shedding episodes was 13 hours for those receiving no treatment compared for seven hours for standard-dose aciclovir (p = 0.01). For individuals treated with standard-dose valaciclovir the median duration was ten hours, compared to seven hours for patients treated with the standard dose (p = 0.01). In the study comparing high-dose aciclovir with high-dose valaciclovir the median period of shedding was eight hours for each regimen.

Maximum HSV load was highest among patients who received no therapy (3.3 log₁₀ copies/ml) and lowest among patients treated with standard dose valaciclovir (2.5 log₁₀ copies/ml).

In all study groups, 80% of shedding episodes were without symptoms.

“Our data suggest that anti-HSV therapy, although clinically effective, does not substantially alter the underlying pathobiology of frequent, subclinical HSV-2 reactivation,” write the authors.

“That we could not eliminate or even alter the frequency of shedding episodes with high-dose valaciclovir suggests that the maximum benefit of shedding reduction has probably been reached for currently available antiviral drugs.”

They therefore conclude, “suppressive therapies with greater potency, including antiviral drugs or immunotherapy in the form of therapeutic vaccines, are needed to provide substantial public health benefits.”

Johnston C et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. The Lancet, online edition. DOI: 10.1061/S0140-6736(11)61750-9, 2012.