Department of Reproductive Health and Research

PROPOSAL FOR

THE INCLUSION OF VALACICLOVIR IN

THE WHO MODEL LIST OF ESSENTIAL MEDICINES

DEPARTMENT OF REPRODUCTIVE HEALTH AND RESEARCH

STI/RTI Team

NOVEMBER 2002

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1.Summary statement of the proposal for inclusion, change or deletion

Valaciclovir is proposed for inclusion in the World Health Organisation (WHO) Model List of Essential Medicines for the management of genital herpes simplex infections.

Herpes simplex virus type 2 (HSV2) infection is the primary cause of genital herpes causing an ulcerative sexually transmitted infection (STI). Control of HSV2 is of paramount importance because of its chronicity, its complications, both physical and psycho-social and its role as cofactor for the acquisition and transmission HIV. It is also an infection that can be vertically transmitted from mother to child. HSV2 is highly prevalent in many parts of the world with a wide geographic variation.

Valaciclovir, which is the L-valyl ester pro-drug of aciclovir, is converted to the antiherpes compound aciclovir and l-valine by hepatic first-pass metabolism following oral administration. It is better absorbed than aciclovir and the bioavailability of aciclovir following oral valaciclovir administration is enhanced three to five-fold compared to oral acyclovir. This renders valaciclovir properties that allow it to be taken on a twice daily dosage compared with aciclovir, which must be administered at four to six hourly intervals.

The efficacy of valaciclovir equals that of acyclovir, and there is no significant difference in adverse events in the two drugs.

Episodic and suppressive therapies have been recommended by WHO for the management of herpes simplex. However, compliance with acyclovir has raised concerns in clinical management settings.

Therefore, valaciclovir, with its high bioavailability, is being proposed for inclusion in the WHO Model List of Essential Medicines.

2.Name of the focal point in WHO submitting or supporting the application

Dr. Francis Ndowa

Department of Reproductive Health and Research (RHR)

STI/RTI Team

3.Name of the organisation(s) consulted and/or supporting the application

World Health Organisation

4.International Nonproprietary Name (INN, generic name) of the medicine

VALACICLOVIR

5.Whether listing is requested as an individual medicine or as an example of a therapeutic group

Valaciclovir, the L-valyl ester pro-drug of aciclovir is extensively converted to the antiherpes compound aciclovir and l-valine by hepatic first-pass metabolism following oral administration.

Aciclovir, the active form of the pro-drug, is highly specific for herpes virus-infected cells. It is selectively is activated by viral thymidine kinase in HSV- and varicella–zoster virus infected cells. In the active form aciclovir acts specifically to inhibit viral replication by acting as a competitive substrate for viral DNA polymerase and as an obligate chain terminator, effectively preventing any further elongation of the viral DNA chain.

This proposal is for inclusion of valaciclovir as a better alternative to acyclovir on account of its improved bioavailability.

6.Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

Herpes simplex infections are among the most frequent human viral infections. Herpes simplex virus type 2 (HSV2) infection is the primary cause of genital herpes causing an ulcerative sexually transmitted infection (STI). The improvement in the management of bacterial causes of genital ulcer diseases has resulted in an increase in the proportion of genital ulcer disease due to HSV2 in developing countries. The public health importance of HSV2 stems mainly from its chronicity, its complications both physical and psycho-social, and its role as cofactor for the acquisition and transmission HIV.

HSV2 is highly prevalent in many parts of the world and varies according to geographic location, age, sex and behavioural practices. Prevalences in adults are low in some parts of Europe (15%), intermediate in the United States (22%), Latin American and South East Asia and high in some population in sub-Saharan Africa (50%).[1], [2]

Prevalences have been shown to be higher among women than among men and increase with increasing age.[3],[4] Prevalence studies have shown that women are infected with HSV2 much earlier in life and that they have more episodes of disease than men. The disparity could be due to women being more biologically susceptible or younger females seeking sexual partners among older males who are more likely to be already infected. Infection has also been associated with younger age at first sex, increased years of sexual activity, lack of circumcision in men and current or recent STI.3,[5], [6], [7].

Neonatal Herpes simplex

Neonatal herpes infection is one of the most serious outcomes of genital herpes in a pregnant woman. Intra-partum contact of the foetus with infected genital tract accounts for approximately 85% of all cases neonatal herpes. Estimates of the incidence of neonatal herpes range from 1 in 2500 to 1 in 20,000,000 live births.[8] Studies have shown that 3% to 4% of gravid women have a known history of recurrent genital HSV infection.[9] To avoid exposure of intrapartum HSV exposure and transmission of infection to the neonate, it has been recommended in some countries that pregnant women with active genital herpes lesions at the time of labour should undergo caesarean delivery. Treatment with aciclovir during late pregnancy has been shown to decrease the frequency of recurrence of HSV disease at delivery.

Natural history of HSV2

Transmission of HSV infection most frequently occurs through sexual contact with a person who is shedding virus in genital or oral secretions. Viral replication occurs locally, usually associated with ulcerations. The virus ascends the peripheral sensory nerves and enters sensory or autonomic nerve root ganglia where latency is established.

The infection follows a sequence of clinical manifestations whose severity is dependent on a number of factors, including the site of the lesion and the immune status of the host. Primary infection may be followed by a clinically apparent first episode. Subsequently, there may be clinical recurrences and/or asymptomatic shedding. The rate of recurrence varies greatly between individuals and over time within the same individual. Recurrences tend to be more frequent in the first months to years after acquisition of the infection.[10] The median recurrence rate after a symptomatic first episode of genital herpes is four to five episodes per year and severe first episodes are associated with even higher recurrence rates.[11], [12]

Asymptomatic shedding, defined as the detection of HSV in the absence of genital lesions is synonymous with subclinical reactivation and subclinical shedding. Studies have shown that HSV asymptomatic shedding does play a role in HSV transmission. Studies have also shown that after lesions have healed a person may continue to shed virus particles for a period of time.[13]Though there is no known cure for genital herpes the course of symptoms can be modified if systemic therapy with aciclovir, or its analogues, is started as soon as possible following the onset of symptoms, either for a short course of five to seven days (episodic treatment) or over a prolonged period of time to prevent recurrences (suppressive treatment).

7.Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostic or treatment facilities and skills)

The main goals of therapy of genital HSV infection are shortening the clinical course of disease, including the frequency of complications of primary infection and decreasing the transmission of the infection. Additionally, strategies are being evaluated to prevent recurrences in individual cases. Treatment methodologies include episodic and suppressive treatments.

Episodic treatment decreases the severity, duration, and viral shedding of the primary episode but has less impact on recurrences.[14]Treatment of recurrent genital herpes reduces the duration of lesions only by a day or two in an immunocompetent person. Its effect is enhanced when treatment is started in the prodrome or within a day of onset of lesions.

Suppressive therapy decreases the frequency and duration of recurrences and viral shedding. Antiviral therapy does not eradicate the latent virus or affect the natural history, frequency, or severity of recurrences after the drugs are discontinued.

Thus, the main benefits of treatment are the clinical and viral shedding benefits during the first episode genital herpes. Recommendations for suppressive therapy take into account a number of criteria (i.e. the number of recurrences in the past 12 months, patient concerns on psycho-sexual and social issues and cost of medication.

In individuals who are HSV2 positive but not HIV infected, reducing the severity and duration of the person’s herpes outbreaks may reduce the risk of acquiring HIV. Conversely, in individuals who are dually infected with HSV2 and HIV reducing the severity and duration of the person’s herpes outbreaks would reduce the risk of transmitting HIV. Finally, irrespective of HIV status, antiviral therapy would reduce the risk of transmission of HSV2 itself among sexual partners.

• Compliance for suppressive therapy may be affected by dosing convenience, understanding asymptomatic transmission and understanding the relationship between HSV and HIV and concern for partner’s health.

WHO Treatment Guidelines for the management of Sexually Transmitted infections 2002[15]

In the updated WHO treatment guidelines due to be published in 2002, a number of new recommendations were made for the management of various STI. The choice of antimicrobials for WHO guidelines is guided by criteria which include:

• Only drugs that have efficacy of 95% or more. Regimens yielding cure rates between 85% may be used with caution but lower cure rates are unacceptable

• Organism resistance is unlikely to develop or likely to be delayed
• Have acceptable toxicity and tolerance.
• Drugs that have oral administration are favoured over parental drugs; this however depends on the above criteria being satisfied.
• Single doses are favoured over multiple dose regimens since this has been shown to improve client compliance and acceptability.
• Drugs that can also be administered during pregnancy and lactation are preferred

In these guidelines valaciclovir is included in the recommendations for the management of the following:

First Clinical episode of genital herpes episode

In first clinical episodes management regimens are follows:

• Aciclovir, 200 mg 5 times daily for 7 days

Or

• Aciclovir, 400 mg 3 times daily for 7 days

Or

• Valaciclovir, 1g 2 times daily for 7 days

Or

• Famciclovir 250 mg 3 times daily for 7 days

Recurrent infections

For recurrent infections regimens are as follows:

• Aciclovir, 200mg orally 5 times daily for 5 days

Or

• Aciclovir 400mg 3 times daily for 5 days

Or

• Aciclovir 800 mg orally twice daily for 5 days

Or

• Famciclovir 125 mg orally twice daily for 5 days

Or

• Valaciclovir 500 mg orally twice daily for 5 days

Or

• Valaciclovir 1000 mg orally once daily for 5 days

Suppressive therapy

For suppressive treatment regimens are as follows:

• Aciclovir, 400mg orally, 2 times daily, continuously

Or

• Famciclovir 250 mg orally twice daily

Or

• Valaciclovir 500mg orally once daily

Or

• Valaciclovir 1000mg orally daily

European Sexually Transmitted Diseases Guidelines [16]

In the European guidelines antiviral therapy is recommended for patients presenting within 5 days of onset of lesions or while lesions are still forming. Aciclovir, famciclovir and valaciclovir are recommended as follows:

For first clinical episodes

• Aciclovir 200mg five times a day,

Or

• Famciclovir 250mg 3 times a day

Or

• Valaciclovir 500mg 2 times day

Choice should be made by individual clinicians taking cost of therapy and likely compliance into account.

For recurrent episodes

• Aciclovir 200mg five times daily

Or

• Valaciclovir 500mg twice daily

Or

• Famciclovir 125ng twice daily, plus supportive measures

For suppressive therapy

The optimal regimens are as follows:

• Aciclovir 800mg daily

Or

• Famciclovir 250mg twice daily

Or

• Valaciclovir 500 mg daily (for patients with less than 10 recurrences per annum)

Or

• Valaciclovir 1000mg daily (for patients with more than 10 recurrences per annum)

Therapy should be discontinued after a maximum one year of continuous antiviral therapy.

Centers for Diseases Control and Prevention’s Sexually Transmitted Diseases Treatment Guidelines 2002[17]

In these treatment guidelines treatment recommendations are as follows:

For the first clinical episode of genital herpes:

• Aciclovir 400mg orally three times a day for 7-10 days

Or

• Aciclovir 200mg orally five times a day for 7-10 days

Or

• Famciclovir 250mg orally three times a day for 7-10 days

Or

• Valaciclovir 1g twice a day for 7-10 days

Treatment may be extended if healing is incomplete after 10 days of therapy.

For Episodic treatment for recurrent episodes:

• Aciclovir 400mg orally three times a day for 5 days,

Or

• Aciclovir five times a day for 5 days

Or

• Aciclovir 800mg twice a day for 5 days

Or

• Famciclovir 125mg orally twice a day for 5 days

Or

• Valaciclovir 500mg orally twice a day for 3-5 days

Or

• Valaciclovir 1.0g orally once a day for 5 days

Suppressive Therapy for recurrent genital herpes

• Aciclovir 400mg orally twice a day

Or

• Famciclovir 250mg orally twice a day

Or

• Valaciclovir 500mg orally once a day

Or

• Valaciclovir 1.0 g orally once a day

Recommended regimen for episodic infection in persons infected with HIV:

• Aciclovir 400mg orally three times a day for 5-10 days

Or

• Aciclovir 200mg orally five times a day for 5-10 days

Or

• Famciclovir 500mg orally twice a day for 5-10 days

Or

• Valaciclovir 1.0g orally twice a day for 5-10 days

Suppressive Therapy for recurrent genital herpes in persons infected with HIV:

• Aciclovir 400-800mg orally twice to three times a day

Or

• Famciclovir 500mg orally twice a day

Or

• Valaciclovir 500mg orally twice a day

8.Summary of comparative effectiveness in a variety of clinical settings:

Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)

Details of literature searches conducted:

The principal data-bases maintained by WHO that were searched were:

The Cochrane Data-base of systematic reviews

The ACP Journal Club reviews published trials

The data-base of reviews of abstracts of reviews of effectiveness (DARE)

The Cochrane controlled trials register (CCTR)

Medline

Clinical Evidence

Searched terms included:

Valaciclovir

Herpes simplex

Randomised controlled trials

Cost effectiveness tolerability safety

Study selection:

Meta-analysis

Systematic reviews

Randomised controlled trials compared with either placebo or aciclovir

Exclusion criteria:

Trials which are not randomised.

Trials with no controls.

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Summary of available estimates of comparative effectiveness

First Episode of genital herpes

The management of the first episode of genital herpes plays an important role in the management of the infection. A meta-analysis has shown that there is a significant difference in the time or frequency of recurrences between people given oral aciclovir and those given placebo.[18] (Table 1)

A systematic review of treatment comparison showed that in a randomised controlled trial of 643 healthy adults with first episode genital herpes there was no significant difference between 1000 mg valaciclovir twice daily and 200 mg of aciclovir 5 times a day for 10 days.[19], [20](Table 1)

Episodic treatment

Studies on episodic treatment revealed that valaciclovir is effective in the management of herpes simplex episodes. In a randomised controlled trial 987 healthy volunteers, who had four or more recurrences per year, were managed on valaciclovir 1000mg twice daily for 5 days (n=368), valaciclovir 500mg twice daily for 5 days (n= 360) or placebo twice daily for 5 days by self initiated treatment (n=259). The results showed a decrease in the median episode length in the treatment arm compared to placebo arm. Healing time was shortened and both valaciclovir dosages reduced the percentage of people with disease episodes (p=0.005). Valaciclovir accelerated the cessation of pain and viral shedding. Adverse effects were similar in all groups. The study concluded that administration of valaciclovir within 24 hours after onset of an episode of herpes genitalis accelerated the time of resolution of the episode and time of lesion healing.[21]

A multi-centre, double–blind, placebo-controlled, randomised parallel-design study of 1200 patients on either 1000 mg valaciclovir twice daily or 200 mg of aciclovir 5 times daily or placebo for 5 days revealed that both drugs were significantly more effective than placebo in speeding resolution of herpes episodes and aborting episodes. The nature, severity and frequency of adverse events did not differ among the 3 treatment groups. Valaciclovir was deemed to be a useful alternative to aciclovir when convenience of dosing and compliance issues are the prime consideration in treatment.[22] A systematic review in HIV infected individuals found no significant difference between aciclovir and valaciclovir.[23] (Table 1)

Suppressive treatment

Three randomised controlled trials (RCT) and 1 open label study demonstrated the efficacy and long-term safety of oral valaciclovir for the suppression of recurrent genital HSV infection. Three thousand and fifty patients (1062 immunocompromised) were enrolled in the studies and 2206 received valaciclovir 250-1000mg/day for up to 1 year. In immunocompetent patients a dose of 500mg or more of valaciclovir in once or twice daily regimens significantly prevented or delayed recurrences compared with placebo and was comparable in efficacy to 400mg aciclovir twice a day.[24]

In a RCT to determine the effect of suppressive therapy in HIV infected individuals 1062 individuals were enrolled and received valaciclovir 500mg twice daily or valaciclovir 1000mg once daily or aciclovir. Valaciclovir was found to be as effective as acyclovir in preventing recurrences. The dosages of 500mg twice daily was found to be more effective than 1000mg daily in preventing recurrences, resulting in 82% versus 71% being recurrence-free at 48 weeks (p<0.05).23

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TABLE 1. Summary of available data (appraisal of quality, outcome measures, summary of results)

Reference / Setting / Design / Drug Dosages / Outcome measures / Adverse event
Tyring SK, Douglas JM Jr, Corey L, Spruance SL, Esman J.
Archives of Dermatology. 134(2):185-1919,1998 / 1200 patients with recurrent genital herpes / A randomised, placebo-controlled comparison of oral valaciclovir and aciclovir in immuno-competent patients with recurrent genital herpes infections / Valaciclovir
100mg twice daily x 5
Aciclovir
200 mg 5 times a day x 5 days / Resolution of symptoms:
Valaciclovir - 4.8days
Aciclovir - 4.8 days
Placebo - 5.9 days
Hazard ratios:
Valaciclovir - 1.66
Aciclovir -1.71 (P=0.001)
Duration of pain:
Valaciclovir - 2 days
Aciclovir - 3 days
Viral shedding:
Valaciclovir - 2.55 faster than placebo
Aciclovir - 2.24 faster than placebo
Aborted episodes
Valaciclovir- 25.9%
Aciclovir- 24.8%
Placebo – 19.8% / No difference for three groups
Tyring SK, Baker D, Snowden W.
The Journal of Infectious Diseases 2002;186 (suppl) : s40-6 / Post- marketing experience.
Systematic review of
patients over 10 years. / Valaciclovir for herpes simplex virus infection: Long-term safety and sustained efficacy after 20 years’ experience with aciclovir. A prospective study of 1175 randomised and double blind in parts aciclovir
3050 valaciclovir / 111 women exposed to valaciclovir (the aciclovir pregnancy registry) no increase in birth defects:
aciclovir – 3.3% risk of birth defect
birth defects in general population 3% -5% / Similar side effects in nature and incidence:
0.2% valaciclovir
0.7% aciclovir

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