Herpes simplex virus type 2 (HSV-2) causes life-long infection with episodic reactivation. For decades, antiviral drugs have been used to treat or prevent frequent and painful episodes. One outstanding question about HSV is why transmission is not stopped by these suppressive treatments. Some clues are provided from three clinical trials (cross-over studies) published in the Lancet that assessed the effect of antiherpes drugs on HSV-2 genital shedding.
The three separate but complementary open-label cross-over studies conducted at the University of Washington Virology Research Clinic enrolled HSV-2-seropositive, HIV-seronegative subjects. They compared:
• No medication with aciclovir 400 mg twice daily (standard-dose aciclovir)
• Valaciclovir 500 mg daily (standard-dose valaciclovir) with aciclovir 800 mg three times daily (high-dose aciclovir)
• Standard-dose valaciclovir with valaciclovir 1g three times daily (high-dose valaciclovir).
Study periods lasted 4 to 7 weeks, separated by 1 week wash-out. Participants collected genital swabs four times daily for quantitative HSV DNA PCR. The primary endpoint was within-person comparison of shedding rate in each study group.
Of 113 participants randomised, 90 were eligible for per protocol analysis of the primary endpoint. The following findings were reported:
• Participants collected 23,605 swabs; 1272 (5.4%) were HSV-positive.
• The frequency of HSV shedding was significantly higher in the no medication group (n=384, 18.1% of swabs) than in the standard-dose aciclovir group (25, 1.2%; incidence rate ratio [IRR] 0.05, 95% CI 0.03 to 0.08).
• High-dose aciclovir was associated with less shedding than standard-dose valaciclovir (198 [4.2%] vs. 209 [4.5%]; IRR 0.79, 95% CI 0.63 to 1.00).
• Shedding was less frequent in the high-dose valaciclovir group than in the standard-dose valaciclovir group (164 [3.3%] vs. 292 [5.8%]; 0.54, 0.44 to 0.66).
• The number of episodes per person-year did not differ significantly for standard-dose valaciclovir (22.6) vs. high-dose aciclovir (20.2; p=0.54), and standard-dose valaciclovir (14.9) vs. high-dose valaciclovir (16.5; p=0.34), but did for no medication (28.7) and standard-dose aciclovir (10.0; p=0.001).
• Median episode duration was longer for no medication than for standard-dose aciclovir (13 vs. 7 hours; p=0.01) and for standard-dose valaciclovir than for high-dose valaciclovir (10 vs. 7 hours; p=0.03), but did not differ significantly between standard-dose valaciclovir and high-dose aciclovir (8 vs. 8 hours; p=0.23).
• Likewise, maximum log10 copies of HSV detected per mL was higher for no medication than for standard dose aciclovir (3.3 vs. 2.9; p=0.02), and for standard-dose valaciclovir than for high-dose valaciclovir (2.5 vs. 3.0; p=0.001), but no significant difference was recorded for standard-dose valaciclovir vs. high-dose aciclovir (2.7 vs. 2.8; p=0.66).
• 80% of episodes were subclinical in all study groups.
• Except for a higher frequency of headaches with high-dose valaciclovir (n=13, 30%) than with other regimens, all regimens were well tolerated.
The researchers conclude “short bursts of subclinical genital HSV reactivation are frequent, even during high-dose antiherpes therapy, and probably account for continued transmission of HSV during suppressive antiviral therapy. More potent antiviral therapy is needed to eliminate HSV transmission.”
An accompanying Comment article discusses the findings and what should be done to address the ineffectiveness of antiherpetic therapies for suppression of viral replication.