Herpes simplex virus: a new era?

Herpes simplex virus type 2 (HSV-2) causes life-long infection with episodic reactivation. For decades, antiviral drugs, such as guanosine analogues (aciclovir and its prodrug valaciclovir), 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. In The Lancet, Christine Johnston and co-workers provide some clues with three clinical trials (cross-over studies) that assessed the eff ect of antiherpes drugs on HSV-2 genital shedding. Various doses of antiviral drugs were tested for their eff ects on asymptomatic, frequent, short (a few hours), breakthrough episodes of HSV reactivation in 90 patients, who collected genital swabs four times daily. In the fi rst trial, the investigators compared low-dose aciclovir with no medication in symptomatic and asymptomatic HSV-2 seropositive patients. The second trial compared standard-dose valaciclovir with high-dose aciclovir, and the third study compared standard-dose valaciclovir with high-dose valaciclovir, in patients with four or more genital herpes recurrences per year. In trial 1, standard-dose aciclovir reduced HSV-2 shedding, although rare shedding episodes still occurred. The shedding rate was not correlated with drug adherence, which makes it unlikely that shedding was caused by missed doses of antiviral therapy. By contrast, aciclovir or valaciclovir, irrespective of dose, had less eff ect on HSV-2 genital shedding in patients with frequent reactivations. Although highdose valaciclovir reduced the HSV shedding rate by about 50% compared with standard-dose valaciclovir, HSV was still detected on 3·3% of swabs, and the number of breakthrough shedding episodes was the same for both standard-dose and high-dose antiviral medication. Overall, no antiviral regimen fully suppressed short subclinical reactivations of HSV. The fi nding that treatment cannot fully prevent transmission should encourage patients to use condoms and adopt safe sex practices, especially since increase of the treatment dose would not further reduce the risk of transmission to patients’ partners. Furthermore, the study prompts reconsideration of the nature of latency and reactivation of chronic HSV. Chronic HSV-2 infection is characterised by symptomatic reactivations at mucosal sites and by short, frequent breakthrough shedding episodes. Mathematical modelling suggests that HSV replication, instead of being characterised by periods of replicative silence (latency) separated by viral bursts (reactivations), probably occurs almost constantly. According to this model, HSV is continuously released— albeit slowly—by infected neurons in sensory ganglia; about 40–90 virions are produced every day. This release is followed by rapid spread of HSV-2 within the genital tissues, with secondary plaques forming because of cellfree particle propagation. In the model, viral replication and propagation is controlled in situ by CD8 cells with highly localised activity and is probably the major factor for duration and severity of reactivations at mucosal sites; cell density is 70% lower 1 cm away from the lesion. The so-called hide and seek interplay between the virus and its host is not only theoretical; low-level viral replication substantially increases transmission risk and is not easily suppressed by antiherpetic therapies. The complex interactions between herpes viruses and HIV and the confl icting results from trials of the eff ectiveness of interventions to reduce HIV transmission by HSV suppression should be revisited. What should be done to address the ineff ectiveness of antiherpetic therapies for suppression of viral replication? The development of new antiherpetic drugs such as helicase–primase inhibitors is important. Published Online January 5, 2012 DOI:10.1016/S01406736(11)61614-0