Treating Genital Herpes Today, and Tomorrow

Summarized by Robert W. Griffith, MD
May 27, 2002 (Reviewed: April 19, 2004)

Introduction

Genital herpes, one of the most common sexually transmitted diseases (STDs), is usually caused by the herpes simplex virus type 2 (HSV-2); however, HSV-1 infections, normally expressed as fever blisters or cold sores, are becoming more frequently recognized as the cause of genital herpes. Risk factors include female sex, being African-American, married, multiple sex partners, and city dwelling. Antibodies to HSV-2 are most common in female prostitutes (75%) and male homosexuals (5%).

Spread of the disease is encouraged by the fact that many cases are asymptomatic, or go unrecognized. Patients without genital lesions may be classified as: A. having recognizable symptoms; B. having unrecognized symptoms; and C. having no symptoms. With good education, class B patients can usually be converted to class A. Treatment of the patient must be directed at providing relief for the individual patient, and reducing the spread of the virus in the community. A recent review article from Belgium has covered the present and future status of HSV therapy from these viewpoints.

Present Treatments

The antiviral agent acyclovir was first described 25 years ago, and it has been used for treating genital herpes for almost 20 years. Its oral bioavailability is poor (about 20%) so that it has to be given 5 times a day for first episodes of HSV infection. Two similar agents with improved bioavailability have been introduced -- valaciclovir (twice a day) and famciclovir (3 times daily).

Frequency of administration can be reduced for treating recurrent episodes, and to prevent their return - twice daily with all 3 agents for recurrences, while for prophylaxis it's twice daily with acyclovir and famciclovir, and once daily with valaciclovir.

The duration of treatment is normally 5-10 days for first episodes, and 5 days for recurrences. Frequency and duration of therapy are important factors in determining compliance with, and hence the success of, treatment.

There has been a report of the use of a 2-day regimen of acyclovir, given 3 times a day, for treating recurrences of HSV-2, with efficacy clearly superior to placebo.¹ Both famciclovir and valaciclovir have been shown to suppress or delay recurrences using once- to twice-daily dosing during remission. All three antivirals reduce viral shedding when given during remission periods.

Topical acyclovir (cream, ointment) is available for treating HSV episodes. It must be applied 4 to 6 times a day, for up to 10 days. It is considered to offer less clinical benefit than oral acyclovir. Topical penciclovir is approved for treating cold sores, but not for genital herpes; it must be applied every 2 hours.

Resistant forms of HSV can develop in immuno-compromised patients (transplant recipients, cancer patients given chemotherapy, and AIDS patients). Acyclovir-resistant disease must be managed with 'second-line therapy', i.e. using drugs that are able to attack the virus but carry greater risk of adverse effects. They include foscarnet (oral), cidofovir (intravenous or topical), and trifluridine (topical only). Fortunately, resistant HSV forms are rare in non-immuno-compromised patients.

Future treatments

There are several new approaches to treating genital herpes, apart from improved candidates and new dosage forms likely to be developed within the acyclovir-type class of antivirals.

Antivirals are under investigation that attack the viral replication cycle at different points. Resimiquimod is an immuno-modulatory quinidine derivative; used as a gel applied 2-3 times a week over a 6 month period, it was found to lengthen the mean time between remissions in patients from 57 days to 169 days.

One particular opportunity is presented by identification of a thymidine kinase that is not required for replication in dividing cells, but is necessary in reactivating the latent virus. A drug candidate based on this approach is in development.

Vaccination against HSV infection has been investigated, but results to date are disappointing. The many sorts of vaccines studied include attenuated HSV vaccines, replication-limited HSV vaccines, inactivated HSV vaccines, and vaccines containing viral components or subunits. The problem lies in the nature of the disease process -- there is either local pathology, or retreat of the virus to nerve tissue, so that there is no real viremia phase. Thus plasma antibodies would be relatively ineffective against mucosal infection or the latent virus.

Reducing spread of the disease

Any form of treatment for genital herpes must include specific instructions regarding the steps the patient should take to minimize the risk of infecting someone else with the virus. Sometimes such steps may include the use of what have been termed 'microbicides' -- agents of different classes that are applied to the genital areas. These may be detergents (e.g. nonoxynol-9), surfactants (e.g. poly[sodium-4-styrene sulfonate]), non-penetrant gels, or pH regulators. Obviously condoms, when used correctly, offer one of the best means of controlling spread of the condition. However, total abstinence if either partner has any symptoms of genital herpes is the safest solution. It's important to remind patients that acyclovir treatment will not prevent the spread of the virus to others.

The necessity for the careful management of genital herpes in pregnant women cannot be over-emphasized, in view of the risks of infection to the fetus, both in utero and during delivery. Untreated neonatal herpes has a mortality rate of up to 60%, and severe developmental deficits are found in survivors.

Source

• New treatments for genital herpes. R. Snoeck, E. De Clercq, Curr Opin Infect Dis, 2002, vol. 15, pp. 49--55

Footnotes
1. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. A. Wald, D. Carrell, M. Remington,  et al., Clin Infect Dis , 2002, vol. 34, pp. 944--948

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