Antiviral agents

Acyclovir, valacyclovir, and famciclovir are the most commonly used agents for treating HSV infections. Potent inhibitors of HSV-induced DNA polymerases, these medications act on viral replication by causing chain termination of the viral DNA once it inactivates the viral DNA polymerase. They have no effect on host cells.

Famciclovir has a longer half-life with higher intracellular concentrations. Acyclovir and valacyclovir have a greater affinity for the target protein, HSV DNA polymerase. While all three drugs decrease the duration and severity of illness and viral shedding, they have no effect on nonreplicating viruses, nor do they eliminate the virus from the ganglia. All three agents appear to have equivalent clinical efficacy. 

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In addition to receiving treatment during acute episodes, patients infected with HSV-1 and HSV-2 should be given oral therapy to suppress clinical outbreaks and reduce asymptomatic shedding. To maximize benefits, oral antiviral drugs should be given on a continuous basis to patients with frequent relapses. There is no diminished efficacy with long-term suppressive use and no evidence that viral resistance results from this regimen. Episodes of subclinical shedding are reduced 90% with suppressive therapy, but such treatment does not eliminate all asymptomatic shedding. Prophylaxis should be individualized for each patient based on frequency and severity of recurrence as well as concerns about taking medication on a daily basis.

Patients should be given the option of no prophylaxis, selective prophylaxis (such as at times of stress or when a recurrence would be most inconvenient), or continuous prophylaxis.

Previously, topical use of the antiviral agents penciclovir and acyclovir had been largely supplanted by their oral administration because the latter appeared to have greater efficacy. Oral agents reach peak tissue levels 1.5 hours after administration, preferentially enter virus-infected cells, and potentially attack the HSV before it reaches the skin surface. Nevertheless, studies showed that topical agents speed healing and may decrease shedding of the virus; some patients preferred topical remedies. In short, there is a distinct group of herpes patients who may well be better served with topical therapies, which is appreciated by understanding the bimodal temporal distribution of herpes, discussed below. For a discussion on agents to augment topical therapy, see “Augmenting topical antiviral agents.”

Recent research has resulted in two new compounds, BILS 179 BS and BAY 57-1293, which act on the enzymes helicase and primase. These enzymes are part of an enzyme complex that the herpesvirus needs to untwist from its double-stranded DNA to form single strands and then prime the strands for replication into new viral DNA. The cost of developing the two new compounds appears to be prohibitive (it is estimated that getting a new oral drug through the FDA costs $802 million) in light of the fact that these new drugs would offer only slight advantages over present therapies.

Bimodal temporal distribution of herpetic reactivation

Present dogma suggests that a recurrent herpetic infection occurs only when the virus descends from its latent state along the peripheral nerve to the cutaneous, or mucosal, surface. However, it fails to explain the bimodal temporal distribution of herpetic reactivation. In short, if the lips of patients with sun-induced herpes labialis are exposed to UV radiation, approximately 20%-25% of tested individuals develop lesions within 24 hours; the remaining 80%-75% have lesions that do not surface until three to five days after light exposure. The immediate peak at one day is from activation of HSV localized solely within the epidermal cells, while the delayed eruption at four days is a result of virus ascending from the dorsal root ganglion.7 There is evidence that these same percentages also apply to herpes genitalis.7 

HSV-1 and HSV-2 that are reactivated from the dorsal root ganglia are easily controlled with current oral modalities. However, reactivation of HSV localized within the epidermal cells, which occurs in 20%-25% of infected individuals, is much more recalcitrant to current suppressive oral therapies.7 Clinically, this subgroup of herpes infections does not demonstrate prodromal sensations prior to its outbreaks and also has unsatisfactory results on oral therapies. A different treatment approach, such as the addition of topical antiviral therapy, seems to be more beneficial to this group of patients.

Further in support of this bimodal temporal distribution of herpes is the detection of herpesvirus by PCR within the epidermis in vivo and in human keratinocytes cultured in vitro. Clinically, continuous prophylactic administration of acyclovir does not rid the epidermis of the virus. Herpesvirus within the epidermis can be shed frequently without any necessary trigger, explaining, in part, the high transmission of herpes when infected individuals are asymptomatic.

Recurrence rate

Patients generally begin to notice a significant reduction in recurrence rates of clinical lesions seven years after initial infection. Regardless of therapy, the frequency of herpetic recurrences diminishes over time. As a result, lifelong use of suppressive antiviral agents may not be required.

Is HSV actually advantageous?

Herpes may not be 100% villainous to humans. It makes some sense that the body retains the virus in various locations for a reason. A dominant theme in the history of life has been the evolutionary innovations of cooperative symbiosis among organisms. Thus, although the herpesvirus can act as a pathogen, causing serious disease, the virus also appears to offer benefit to its host as well. Being similar to a symbiote, it works with the immune system and is controlled by it as well.

The herpesvirus appears to offer its human host oncolytic, immune-stimulating, and antitumor properties. The virus thrives in many types of cancer cells and shows selective damage to and initiation of an immunologic response to these cells. Indeed, herpesviruses genetically engineered to not replicate in normal tissue have shown promise in the treatment of several types of cancer. The frequent presence of the virus at sites of potential or existent cancer, such as cervical, ovarian, and squamous cell of the airways, may reflect this beneficial trait for the host.

Certainly herpes offers many more avenues of study clinically and therapeutically, and further research is warranted.

Dr. Burkhart is clinical professor of dermatology at Medical University of Ohio at Toledo and clinical assistant professor of dermatology at Ohio University College of Osteopathic Medicine in Athens.


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