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WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION
Commentary on proposal to add valaciclovir
for the treatment of genital herpes simplex infections
From WHO Collaborating Center
Discipline of Clinical Pharmacology
Faculty of Medicine and Health Sciences
University of Newcastle
NSW Australia
An application has been lodged by the Department of Reproductive Health, WHO, for
the addition of valaciclovir to the Essential Medicines List, for the treatment of genital
herpes simplex infections. The proposal is that valaciclovir should be included as a
better alternative to acyclovir because it has better bioavailability and can be
administered as a twice daily dose, rather than the 4 to 6 times per day required for
acyclovir. In the treatment of sexually transmitted infections, compliance is a key
issue in ensuring the effectiveness of treatments.
The application presents a comprehensive review of efficacy and safety studies that
compare valaciclovir with acyclovir. The studies compare the two drugs as treatments
for the first clinical episode of genital herpes or as treatment for recurrent infections
or as suppressive therapy. The treatment regimens for each of these conditions are
shown below, based on the WHO treatment guidelines for Sexually Transmitted
Infections and the CDC guidelines (for treatment in HIV).
Table 1. Dosage regimens
First episode
Recurrent
infection
Suppressive
therapy
Episodic
infection
in
HIV
infected
patients
Suppressive
treatment
in
HIV
infected
persons
acyclovir
200mg 5 times daily for 7 days OR
400mg 3 times daily for 7 days
200mg 5 times daily for 5 days OR
400mg 3 times daily for 5 days
200mg twice daily continuously
400mg three times per day for 5-10
days
400-800mg orally twice to three times
per day
valaciclovir
1g twice daily for 7 days
500mg twice daily for 5 days OR
1g once daily for 5 days
500mg once daily OR 1g once daily
continuously
1 gm orally twice a day for 5-10
days
500mg orally twice a day
These treatment recommendations for first episode and recurrent infection are slightly
different from those in the European Guidelines and also different from those in the
CDC guidelines.
The application reviews the randomised controlled trials and reviews that have
examined the comparative effectiveness of valaciclovir and acyclovir. The outcomes
measured in the studies are: time to resolution of symptoms, duration of pain, viral
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shedding, length of episodes, and in chronic infection, time to recurrence. According
to the application, none of the trials show any significant differences between the two
active treatments and both have similar advantages when compared to placebo.
The application makes the argument that compliance is enhanced in the valaciclovir
treatment groups because in some of the trials the treatment regimen for the drug
requires less frequent dosing. However, this is not consistently the case AND none of
the trials actually report compliance or patient preferences as an outcome measure.
To support the argument regarding improved compliance, the application cites two
studies of the use of doxycycline in STIs, where compliance rates with short course
treatment were found to be 24% and 44% respectively. There is no evidence provided
that directly supports the argument that compliance is improved in patients using
valaciclovir compared with those using acyclovir. As the treatment regimens for some
of the indications are suggesting twice daily dosing for both drugs, the proposed
advantages seem to be based on the claims about improved bioavailability only.
Comparative cost and cost-effectiveness
On the basis of the assessment of comparative clinical performance, the appropriate
approach to an economic evaluation would be a cost minimisation evaluation. The
application presents a comparison of the unit costs for acyclovir, valaciclovir and
famciclovir in local currency and USD as well as the cost per course of 5 day
treatment (summarised in Table 2, below). Cost sources are provided. The cost per
course of 5 days treatment with acyclovir ranged from $US 1.46 to $US 31.69. Two
of the lower costs per 5 days ($US 3.15 and $US 4.10) could not be verified given the
information provided in the application. The cost per course of 5 days treatment with
valaciclovir is $US 36.72.
Table 2: Range of costs of acyclovir and valaciclovir
Cost/Pack
Pack Size
Cost/Tablet♦
Cost for 5 Days
Treatment*
($US)
acyclovir
$29.19
$2.42
$10.48
500
30
100
$0.0584
$0.0807
$0.1048
$1.46
$3.15
$4.10
acyclovir (nonproprietary)
$6.60
25
$0.264
$6.60
acyclovir
$9.42
25
$0.3768
$9.42
acyclovir (Zovirax)
$31.59
25
$1.26
$31.69
valaciclovir
$36.72
* assuming dosage of 1000 mg/day
♦
assuming 200 mg tablets
25
$1.47
$36.72
Drug
Comparative cost-effectiveness (presented as range of cost per routine outcome)
The costs of acyclovir and valaciclovir for 5 days of treatment, as presented in Section
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10.1, formed the basis of the cost-effectiveness comparison. No rationale was
provided for the choice of a 5 day course of treatment (first episodes are treated for 7
days, recurrent episodes for 5 days). Only drug costs were included in the comparison
and the resulting costs are those described above.
The only way such a cost differential could be justified in a cost-minimsation
evaluation would be if the inclusion of justifiable other direct and indirect costs (such
as physician visits, hospitalisation, adverse events, productivity losses) associated
with either treatment showed that the non-drugs costs associated with acyclovir are
substantially greater than those with valaciclovir. Based on the clinical trial evidence
provided, this is unlikely to be the case.
The application states that there are no published studies of the cost-effectiveness of
valaciclovir or acyclovir in the treatment of HSV. It states that there is one published
trial comparing the cost-effectiveness of valaciclovir and acyclovir in the treatment of
herpes simplex virus (Grant et al., 1997), that reported that valaciclovir reduced direct
medical costs by an average of 17% ($US 60.01) and indirect medical costs by an
average of 25% ($US 46.54) compared to acyclovir.
The published analysis is actually a cost-consequence analysis rather than a true
cost-effectiveness analysis. The authors of the analysis were employees of Glaxo
Wellcome. As this analysis would be highly system specific, it is not appropriate to
assume that it would necessarily be applicable to other settings even if it were
possible to validate it as an appropriate model.
Based on the evidence provided, there are two possible circumstances where
valaciclovir might be acceptably cost effective. These are:
1) if the price of valaciclovir was reduced to be equal to that of acyclovir
2) if there were evidence to show that compliance with acyclovir were so poor
that it reduced the effectiveness by at least 5 fold. This latter situation is highly
unlikely.
It is therefore recommended that valaciclovir should not be added to the list, but that
acyclovir should become a ‘boxed’ drug for this indication.
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