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11 December 2002
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
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
1
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 psychosocial, 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
2
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.
3
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
4
Or

Or

Or

Or

Aciclovir 800 mg orally twice daily for 5 days
Famciclovir 125 mg orally twice daily for 5 days
Valaciclovir 500 mg orally twice daily for 5 days
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)
5
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
6
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.
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
7
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
8
TABLE 1. Summary of available data (appraisal of quality, outcome measures, summary of results)
Reference
Setting
Design
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, placebocontrolled comparison of
oral valaciclovir and
aciclovir in immunocompetent patients with
recurrent genital herpes
infections
Tyring SK, Baker D,
Snowden W.
The Journal of Infectious
Diseases 2002;186
(suppl) : s40-6
Postmarketing
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
Drug
Dosages
Valaciclovir
100mg twice
daily x 5
Aciclovir
200 mg 5
times a day x
5 days
Outcome measures
Adverse event
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%
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%
No difference for three
groups
Similar side effects in
nature and incidence:
0.2% valaciclovir
0.7% aciclovir
9
Table 1 contd. Summary of available data (appraisal of quality, outcome measures, summary of results)
Reference
Weller S, Blum MR,
Doucette M, BurnetteT,
Cederberg DM, de
Miranda P, Smiley ML.
Clin Pharmacol Ther
1993 Dec; 54(6): 595605
Spruance SL, Tyring SK
DeGregorio B, Miller C,
Beutner K and the
Valaciclovir HSV study
group. Arch Intern Med.
1996 Aug 12/26; 156:
1729-35
Setting
987 healthy
volunteers
with one
episode of
recurrent
herpes
Design
Pharmacokinetics of the
aciclovir pro-drug
valaciclovir after escalating
single- and multiple-dose
administration to normal
volunteers.
Phase 1 trial
A large scale placebo
controlled dose-ranging
trial of per oral valaciclovir
for episodic treatment of
recurrent herpes genitalis
Drug
Dosages
739 patients
with history
of recurrent
genital
herpes
1000 mg
valaciclovir
twice daily x
5 days
500 mg
valaciclovir
twice daily x
5 days
Valaciclovir versus
aciclovir in patient initiated
treatment of recurrent
genital herpes:
a randomised, double blind
clinical trial
Adverse event
Bioavailability of valaciclovir
Three to five fold of bioavailability
of aciclovir
placebo twice
daily x 5 days
Bodsworth N.J, Crooks
RJ, Borelli S, Veilsgaard
et al.
Geniturin Med. 1997;
73: 110-116
Outcome measures
Valaciclovir
500 mg twice
daily
Aciclovir 200
mg five times
daily
Median episodes length
Lower doses- 4.0 days
Placebo - 5.0 days
Hazard ratio 1.94 (p=0.001)
Healing time
Lower dose 4.1days
Placebo- 6.0 days
Percentage of episodes
Lower dose - 69%
Placebo - 79% p=0.005
Valaciclovir accelerated cessation of
pain. Hazard ratio 1.8%
Viral shedding HR 2.8%
No significant difference between
valaciclovir and aciclovir hazard
ratio 0.93 ( 95% CI 0.79, 1.08)
p = 0.34
Duration of episode 4.7 and 4.6 days
Lesion healing valaciclovir 4.4 and
4.5 days (Hazard ratio 0.96)
No significant difference in
prevention of ulceration
No significant difference in virus
shedding
Similar in all groups
Similar in both
groups
Valaciclovir 9%
Aciclovir 8.6%
10
TABLE 1 contd. Summary of available data (appraisal of quality, outcome measures, summary of results)
Reference
Patel R, Bodsworth NJ,
Woolley P, Peters B et
al. Genitourin. Med.
1997: 73: 105-109
Wald A Clinical
Evidence Issue 7, 2002
Wald A Clinical
Evidence Issue 7, 2002
Kimberlin DF, Weller S,
Whitley RJ, et al. Am J
Obstet Gynecol October
1998, volume 179,
Number (4)846-851
Setting
382 healthy
volunteers
with a
history of
recurrent
herpes
(eight
recurrences
per year)
Systematic
review of
randomised
control
trials
(RCT)
643
volunteers
Systematic
review of
randomised
control
trials
2 RCT
Design
Valaciclovir for the
suppression of recurrent
genital HSV infection: a
placebo controlled study of
once daily therapy
Drug Dosages
Valaciclovir
500mg once
daily
Placebo
Outcome measures
Median time for first recurrence
Placebo - 20 days
Valaciclovir - 112 days
Adverse event
Systematic review:
What are the effects of
antiviral treatment in
people with a first episode
of genital herpes?
Valaciclovir
1000 mg twice
daily
for 10 days
Aciclovir
200mg 5
times daily for
10 days
Aciclovir
200mg 5 times
daily x 5 days
Valaciclovir 1g
twice daily for 5
days
Valaciclovir
1000mg once
daily
No significant difference
Similar to
acyclovir:
Headaches and
nausea
No significant difference between
the two drugs in recurrence rates
Recurrences less likely with
valaciclovir 500mg twice daily
Similar to
acyclovir:
Headache and
nausea
Systematic review
What are the effects of
treatments in people with
genital herpes and HIV
infection?
Pharmacokinetics of oral
valaciclovir and aciclovir in
late pregnancy.
Safe in pregnancy
11
A randomised controlled trial comparing patients on antiviral suppressive therapy
(valaciclovir 1000 mg daily, valaciclovir 500 mg daily, valaciclovir 250 mg twice daily
and aciclovir 400 mg twice daily) to placebo revealed that the herpes specific quality of
life was improved in the treatment arms.25 It was concluded that suppressive therapy was
an effective strategy for the improvement of quality of life of patients with recurrent
herpes. This was sustained over time and thus indicating the value of long-term
management of the diseases.
9. Summary of comparative evidence on safety:
Estimate of total patient exposure to date
It is estimated that aciclovir and valaciclovir have been prescribed for more than 80
million persons for a different range of indications. The clinical development programme
for valaciclovir has involved over 10,000 patients in clinical trials of up to 1-year
duration.24
Use in pregnancy
The risk of transmission of HSV2 from an infected mother to a neonate is between 30%
and 50% in women who acquire herpes around the time of delivery, but the risk is low
(<1%) in women with recurrent genital herpes. Management of genital herpes in
pregnancy includes antiviral therapy, caesarean section or both.
Aciclovir has been used for the management of HSV2 in pregnancy. The Aciclovir
Registry established in 1984 reported that 1207 pregnancies were exposed to aciclovir
during pregnancy. The observed risk of birth defects was 3.3%. This did not exceed that
expected in the general population and the type of defects did not differ from those in
untreated women. 24
In a phase 1 trial, maternal valaciclovir therapy resulted in higher plasma aciclovir levels
with significantly higher peak concentrations, than did aciclovir therapy. Aciclovir and
valaciclovir were found to be effective in reducing recurrences. Both aciclovir and
valaciclovir were well tolerated by patients with no evidence of significant drug toxicity
to mother or foetus.26 There is no evidence that aciclovir is carcinogenic in humans and
no embryonic or fetotoxic effects were demonstrated in animal studies.27
The Aciclovir Pregnancy Registry has documented pregnancy outcomes in 111 women
exposed to valaciclovir. There was no increase in the number of birth defects compared
with the general population and no consistent pattern or uniqueness that would suggest a
common cause.24
Aciclovir has been found in breast milk after systemic administration. The amount of
aciclovir in the breast milk after valaciclovir administration is considerably less (2%)
than that used in therapeutic dosing of neonates and should, therefore, be compatible with
breast-feeding.28 Manufacturers suggest that physicians use it with caution.29
12
Summary of comparative safety against comparators
Description of adverse effects/reactions
Most studies reviewed reported similar adverse events in nature and incidence, for
valaciclovir, aciclovir and placebo. 19, 23, 24,26 There was no apparent relationship between
the total daily exposure to valaciclovir and the nature, severity or frequency of the
common adverse events. The most common side effect for immunocompetent patients
receiving aciclovir and valaciclovir were headache and nausea. For HIV infected
individuals the most common adverse events were diarrhoea, nausea and the onset of
some infectious illnesses. Long-term valaciclovir therapy did not result in haemotologic
or clinical chemistry abnormalities.24 Severe adverse events attributable to valaciclovir
occurred in 0.2% compared to 0.7% in immunocompetent individuals taking aciclovir. In
HIV infected individuals 1.1% of patients on valaciclovir experienced severe adverse
effects compared to 0.7% of aciclovir recipients. In three randomised controlled trials
valaciclovir was discontinued due to adverse effects in only 0.3% of patients in
immunocompetent individuals and 0.4% in HIV infected individuals.24
Manifestations resembling thrombotic microangiopathy have been reported in clinical
trials with high doses of valaciclovir (8000mg/day) administered over long periods. 30
However, there were no such reports in 4 trials evaluating 3050 patients for suppression
of recurrent genital herpes using standard doses. It has been concluded that the
occurrence of thrombotic microangiopathy is restricted to severely immunocompromised
persons receiving higher valaciclovir dosages (e.g. prophylaxis for CMV) than the
standard doses required to control HSV infections.24
Drug interactions
Although some interactions which affect the extent of conversion of valaciclovir to
aciclovir and reduce the renal tubular secretion of aciclovir have been noted with
cimetidine and probenecid, these interactions are not expected to have clinical
consequences regarding the safety of valaciclovir.31 There is no clinically significant
interaction when valaciclovir and digoxin are co-prescribed.32
Bioavailability and compliance
Aciclovir was the first specific effective orally bioavailable antiherpes agent. However,
its limited oral bioavailability of 10%-20% requires dosing regimens of up to 5 times a
day to achieve efficacy in a range of indications. In a phase 1 placebo–controlled trial in
normal volunteers, which included a single dose study with doses from 100 to 1000 mg
(single cohort) and a multiple–dose investigation with doses from 250 to 2000 mg (for
separate cohorts), valaciclovir was rapidly and extensively converted to aciclovir. This
resulted in significantly greater bioavailability approximately threefold to fivefold
(i.e. bioavailability is greater than or equal to 50% in adults) compared to that historically
observed with high-dose (800 mg) oral aciclovir.33 In one study the plasma aciclovir
exposure obtained following oral administration of valaciclovir was similar to that
achieved with doses of intravenous aciclovir and was effective in the treatment and
suppression of the less susceptible herpes viral diseases.34
Compliance in STI management has been one factor that affects the cure rate of patients
receiving management for STI. Non-compliance in STI patients for short course
treatments has been shown to be as low as 24%. In one study 44% of patients attending
13
an STI clinic on a twice daily dose of treatment for five days interrupted their treatment
on at least 2 occasions for intervals of more than 24 hours.35, 36 In long-term treatment
this tends to be even worse.
10. Summary of available data on comparative cost1 and costeffectiveness within the pharmacological class or therapeutic
group:
TABLE 2. Range of costs of the proposed medicine
Drug
Unit cost
Cost per
course of
5 days in
local
currency
$1.46
Cost per
course of
5 days in
USD
Source
Aciclovir
500 Tab
package price 29.19
unit price 0.0584/Tablet
$1.46
(International Dispensary
Association) IDA
$3.15
$3.15
Tender price 100 Tab 10.48
Unit price 0.1048 /Tablet
$4.10
$4.10
Tablets, aciclovir 200 mg,
net price 25-tab pack = £4.23
£4.23
$6.60
British National Formulary
BNF29
200 mg, net price 25-tab pack = £6.03;
400 mg, 56-tab pack = £22.19;
800 mg, 35-tab pack = £22.29.
200 mg, 25-tab pack = £20.22;
400 mg, 56-tab pack = £74.17;
£6.03;
$9.42
BNF29
£20.22
$31.69
BNF29
500 mg, net price 10-tab pack =
£23.50,
42-tab pack = £98.50.
£23.50
$36.72
BNF29
Famciclovir 125 mg, net price 10-tab
pack = £28.12;
250 mg, 15-tab pack = £84.35,
21-tab pack = £118.08;
56-tab pack = £314.90;
500 mg, 14-tab pack = £157.47,
30-tab pack = £337.34,
56-tab pack = £629.89;
750 mg, 7-tab pack = £112.72.
£28.12
$43.94
BNF29
30 Tab
package price (30) 2.4200
Unit price 0.0807/Tablet
Aciclovir
(Nonproprietary)
Aciclovir
Zovirax ®
(GSK)
aciclovir
Valtrex ®
(GSK)
Tablets, f/c,
valaciclovir
Famvir ®
(Novartis)
ECHO (International Health
Services Limited)
BDS ( Barbados drug
service) International Drug
Price Indicator Guide
14
Comparative cost-effectiveness presented as range of cost per routine
outcome (e.g. cost per case, cost per cure, cost per month of
treatment, cost per case prevented, cost per clinical event prevented,
or, if possible and relevant, cost per quality-adjusted life year gained)
The cost per five-day course of patented valaciclovir (Valtrex) is US$36.72 and the cost
per course of aciclovir ranged from US$1.42 to US$31.69. Thus, for a five-day course of
treatment, valaciclovir is between 5 to 25 fold more expensive than aciclovir (Table 2).
No cost-effectiveness studies were found to evaluate valaciclovir in the management of
HSV2. However cost-effectiveness studies of valaciclovir for the management of
varicella zoster and cytomegalovirus infections, which require long-term treatment, have
use of valacyclovir to be cost-effective.37 This latter situation differs from genital herpes
as there are usually no chronic hospitalisation requirements with it.
11. Summary of regulatory status of the medicine (in country of
origin, and preferably in other countries as well)
Valaciclovir is licensed in the United Kingdom of Britain for herpes zoster and herpes
simplex infection (initial and recurrent treatment) as Valtrex.
It has also been licensed in United States of America, Spain and Canada.
12. Availability of pharmacopoieal standards (British
Pharmacopoeia, International Pharmacopoiea, United States
Pharmacopoeia)
Not found in British, European, International or United States Pharmacopoeias.
13. Proposed (new/adapted) text for the WHO Model Formulary
General Information
Valaciclovir is an antiherpes drug used in the management of human herpes viruses
including HSV1 and HSV 2. It is the L-valyl ester pro-drug of acyclovir. After oral
administration it provides a bioavailability of aciclovir three to five times compared to
oral aciclovir.
In HSV- and varicella–zoster virus infected cells aciclovir is selectively activated by viral
thymidine kinase enzyme. 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.
Indications for use:
Treatment of first episode and suppression of recurrent herpes simplex infections of the
genitals, skin and mucous membranes
15
Dosage and administration:
First Clinical episode of genital herpes episode
In first clinical episodes management regimens are as follows:
 Oral valaciclovir, 1g twice daily for 7 days
Recurrent infections
For recurrent infections regimens are as follows:
 Oral valaciclovir 500 mg orally twice daily for 5 days
Or
 Oral valaciclovir 1000 mg orally once daily for 5 days
Suppressive therapy
For suppressive treatment regimens are as follows:
 Oral valaciclovir 500mg orally once daily
Or
 Oral Valaciclovir 1000mg orally daily
The benefits of episodic treatment of recurrent infections are minimal in
immunocompetent persons. Decisions to treat should be made on individual cases
taking into account cost and compliance issues.
Contraindications
Valaciclovir is contraindicated in patients with known hypersensitivity or intolerance to
valaciclovir, aciclovir and or any component of its formulation.
Caution
Thrombocytopenic purpura or haemolytic anaemia have been observed in patients with
advanced HIV disease and recipients of allogenic transplants receiving high dose
valaciclovir of 8g/day.
Use in Pregnancy and lactation
Valaciclovir should be used in pregnancy only if the potential benefits justify the risk to
the foetus.
Adverse Effects
The adverse effects are nausea, vomiting, abdominal pain and diarrhoea.
Precautions
Patients should be adequately hydrated during the course of treatment.
Drug interactions
No clinical drug interactions have been found at the doses used in the management of
herpes simplex infections.
16
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