Australian Herpes Management Forum

Short Course Therapy for Recurrent Herpes Simplex

*

Compiled by the Board of the Australian Herpes Management Forum

Introduction

Genital herpes, which can be caused by either Herpes Simplex Virus (HSV) type 1 or 2, is a common sexually transmissible infection (STI). Its manifestations range from asymptomatic shedding to a severe viraemic illness. Antiviral therapy has been available for 25 years. It has been used for the treatment of acute primary episodes (usually for 5-10 days), as intermittent episodic therapy (5 days) for recurrences, or as continuous daily suppressive therapy. However, it is only relatively recently that consideration has been given to short course therapy.¹

Biology

HSV is transmitted by skin-to-skin contact, entering the epithelium via skin or mucosal abrasions. Following initial infection virions access subdermal neurons and migrate along axons to neural nuclei where replication continues. Recent studies have demonstrated that there is no true latent viral state. The virus constantly migrates along and is released from neural axons. Subdermal lymphocytes are, in the main, able to control virions before they are released through the epidermis. When these lymphocytes fail to achieve this the virus may be shed asymptomatically or there may be epidermal lesions.^2,3

Both HSV types 1 and 2 can infect the genital area and cause a spectrum of disease ranging from mild excoriation to extensive genital ulceration, and both are associated with asymptomatic shedding. Genital HSV-1 infection is usually acquired through oral-genital contact and is far less frequently associated with shedding or recurrences than HSV-2. A significant proportion of the population is infected with HSV 1 (80% of Australians are HSV 1 seropositive by age 25).

In contrast, genital HSV-2 infection commonly recurs and viral shedding, either asymptomatically or with associated symptoms, is a significant source of transmission to new partners.^{3, 4, 5}

Epidemiology

Studies using type specific serology have shown that HSV-2 infection is extremely common in Australia with 1 in 8 Australian adults over the age of 25 having antibodies to HSV-2.⁴ The prevalence in women (16%) is twice as high as in men (8%) and the rural population has a lower prevalence (9%) than metropolitan (13%). Finally indigenous populations have a higher prevalence (18%) than non-indigenous (12%). Other studies have shown an HSV-2 seroprevalence of 65% in heterosexual men attending an STI Clinic, 28% in HIV negative gay men and 61% in HIV positive gay men.^7,8 The majority of those infected have no signs or symptoms of genital herpes. In Australia, the majority of genital herpes cases are caused by HSV-2. However, an increasing percentage of new cases of genital herpes are caused by HSV-1 While associated with fewer recurrences, less shedding and a lower probability of transmission, the manifestations of genital HSV-1 can still be traumatic for the individual.

Clinical Manifestations

Primary herpes infections can be quite severe with both local and systemic features including fever and widespread genital ulceration. These local lesions can take three weeks or more to heal without treatment.

Recurrent genital herpes is most commonly due to infection with HSV-2. Many people experience prodromal symptoms including burning, itching and tingling at the site where the recurrence occurs. The lesions themselves usually heal within 4 -7 days.

About 20% of those HSV-2 antibody positive have a history of recognized genital ulceration, 60% have symptoms they have not recognized as being cause by herpes and the remaining 20% are truly asymptomatic. Virtually all patients infected with HSV-2 shed the virus in the absence of symptoms and such “shedding” occurs in over 20% of days.¹⁰

Antiviral Therapy

Three antiviral agents are available for treating genital herpes: aciclovir, famciclovir and valaciclovir. Aciclovir (ACV) was introduced into Australia in 1983. It is an acyclic nucleoside analogue that is a substrate for HSV-specified thymidine kinase. Aciclovir is selectively phosphorylated by HSV-infected cells to ACV-monophosphate. Cellular enzymes then phosphorylate ACV-monophosphate to ACV-triphosphate which inhibits viral DNA polymerase. This results in termination of the viral DNA chain.

Although effective and safe, aciclovir has poor oral bioavailability (20% or less) and hence multiple doses throughout the day are required.

Famciclovir was the first pro drug in this class to be introduced into Australia in 1995. Famciclovir is rapidly converted to penciclovir once consumed. Penciclovir like aciclovir is an analogue of the nucleoside guanosine and also requires tri-phosphorylation. It has a bioavailability of over 70%.

Valaciclovir is an ester of aciclovir. It is rapidly converted to aciclovir by intestinal and hepatic enzymes, increasingly bioavailability to above 50%.

Treatment Regimens

Primary herpes is usually treated for 5-10 days.

Recurrences can be treated with intermittent therapy (treating each episode) or suppressive therapy (treating patients with continuously over a period of months to prevent episodes).

For intermittent therapy the approved regimens in Australia have until recently, all been for a 5-day period.

In recurrent infections, viral replication reaches its peak within the first 24-48 hours of the onset of symptoms and is, in fact, usually terminated within 2 days of commencing anti-viral therapy.¹⁰ After viral replication ceases, healing then depends on normal wound-healing process. For therapy to be effective it would thus make sense to commence it as early as possible, after the onset of symptoms. This knowledge has prompted investigation of short-course therapies for recurrent genital herpes.

In the United States (US) valaciclovir 500mg bd for 3 days was shown to be equivalent to the same dose over 5 days, and this shorter regimen has been approved by the US FDA¹² and a separate study demonstrated that acyclovir 800mg tds for 2 days was effective, superior to placebo and able to abort lesions.¹³ However neither dosage regimen is approved in Australia.

Recently, short-course (2 day) famciclovir has been approved for use for the treatment of episodic genital herpes in Australia. The FaST study (Famciclovir Short-course Herpes Therapy Study) was a randomized, double-blind, non-inferiority, multi-centre study which involved multiple sites in Australia and Canada. It compared the standard regimen of famciclovir 125 mg bd for 5 days (total 1250mg) to a 2 day short course of famciclovir 500 mg stat then 250 mg every 12 hours for the next three doses (total 1250mg) in the treatment of adult patients with recurrent genital herpes. A total of 1038 recurrences in 616 patients were evaluated. Treatment was initiated by patients within 12 hours of development of a lesion or onset of symptoms. Patients attended for assessment within 24 hours and again 5.5 days following commencement of treatment.

The primary endpoint was the estimated probability of being not lesion-free at 5.5 days after patient self-initiation of therapy. The two treatment regimens were equivalent and thus non-inferiority was confirmed.

The study concluded that the 2-day famciclovir regimen was equivalent to the 5-day regimen in the treatment of adult patients with recurrent genital herpes.¹⁴

Recently even shorter courses have been shown to be effective. First, valaciclovir 1000mg twice daily for one day has been found to be effective in aborting or resolving lesions.¹⁵ Second, famciclovir 1000mg twice daily (patient-initiated) commenced within 6 hours of onset of symptoms or signs of recurrent genital herpes was also shown to be effective at aborting lesions, and reduced time to healing when compared with placebo.¹⁶

Patient-Initiated Therapy

As viral replication peaks within the first 24 hours of the onset of lesions the efficacy of short course treatment depends upon the patient commencing therapy as soon as any symptoms are felt. Studies have demonstrated that patient-initiated therapy reduces the duration of lesions and shortens the time in which virus can be isolated from lesions. Prompt anti-viral therapy is also associated with increased rate of aborted lesions.

Conclusion

In Australia, the recent availability of two-day famciclovir treatment for the episodic management of genital herpes will be of considerable benefit to many patients with recurrent genital herpes.

References

1. Patel, Raj and Rutland, Emma. Has Episodic Treatment of Recurrent Genital Herpes Come of Age? Int Journal of STD & AIDS 2007; 18: 437-439
2.  Corey L, Wald A. Genital Herpes in Holmes KK, Sparling PF, Stamm W et al Sexually Transmitted Diseases 4th Edition (2008) McGraw Hill Medical Publications
3.  Denham I M. Antiviral Management of Genital Herpes. Medicine Today; July 2004
4.  Cunningham et al. Prevalence of infection with herpes simplex virus types 1 and 2 in Australia: a nationwide population survey. STI 2006; 82; 164-168
5.  Haddow et al. Increase in rates of herpes simplex virus type 1 as a cause of anogenital herpes in western Sydney, Australia, between 1979 and 2003. STI 2006; 82: 255-259
6.  Mindel A, Taylor J, Tideman R et al. Neonatal Herpes Prevention; a minor public health problem in some communities. Sex Transm Inf 2000; 76: 287-291
7.  Bassett I et al. Herpes simplex virus type 2 infection of heterosexual men attending a Sexual Health Centre. MJA 1994, 160:697-700
8.  Russell D et al. Seroprevalence of herpes simplex virus types 1 & 2 in HIV-infected and uninfected homosexual men in a primary care setting. Journal of Clinical Virology 2001, 22 (3): 305-313
9.  Tran T, Druce J D, Catton, M C, Kelly H, Birch C J. Changing epidemiology of genital herpes simplex virus infection in Melbourne, Australia, between 1980 and 2003. Sex Transm Infect 2004; 80: 277-279
10.  Corey L. The current trend in genital herpes. Progress in Prevention. Sexually Transmitted Diseases. 1994, 21: 38-44
11.  Novartis data on file (Famvir dossier: First-Episode GH & Recurrent GH: p. 24 (Critical Evaluation); p. 132)
12.  Leone PA, Trottier S, Miller KM. Valacyclovir for episodic treatment of genital herpes: a shorter 3-day treatment course compared with 5-day treatment. Clin Inf Diseases 2002; 34: 958-62
13.  Wald A, Carrell D, Remington M, Kexel E, Zeh J, Corey L. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin Inf Dis 2002; 34: 944-8
14.  Bloch MT, Heley S, Agnew J, on behalf of the FaST Study Group. Short-course famciclovir as episodic treatment of recurrent genital herpes—results of the FaST study. 13th Annual Meeting of the IHMF, Prague, Czech Republic, 27-29 October 2006 (abstract P04)
15. Spruance SL, Jones TM, Blatter MM et al. Oral valaciclovir for the treatment of herpes labialis: two trials of early, high-dose, short-course therapy. The Fifteenth International Conference on Antiviral Research. Prague, Czech Republic. Abstract only. Antiviral Research 2002: 53 (3); A35-A84
16.  Aoki FY, Tyring S, Diaz-Mitoma F, Gross G, Gao J, Hamed K. Single-day patient initiated famciclovir therapy for recurrent genital herpes: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2006; 42: 8-13
17.  Spruance SL, Bodsworth N, Resnick H, et al. Single-dose, patient-initiated famciclovir: a randomized, double-blind, placebo-controlled trial for episodic treatment of herpes labialis. J Am Acad Dermatol 2006; 55: 47-53
18.  Centers for Disease Control and Prevention. STD Treatment Guidelines 2006. [www.cdc.gov/STD/treatment/2006/genital-ulcers.htm#genulc3] Accessed 24 September 2008

 Disclaimer

The AHMF have made considerable efforts to ensure the information upon which this guideline is based reproduces the evidence as accurately as possible. Users of this guideline are strongly recommended to confirm that the information contained within it, especially drug indications, is correct by way of independent sources, as this guideline does not indicate an exclusive course of action or serve as a standard of medical care. The AHMF accepts no responsibility for any inaccuracies, information perceived as misleading, or success of any treatment regime detailed in this guideline.