DILEMMA

• An 18-year-old male with uncomplicated herpes zoster infection

presenting with dermatomal distribution of multiple vesicular lesions
associated with pain, within <72hours after onset.
• Treatment of Herpes Zoster Infection includes giving antivirals.
• Pain is the most debilitating feature of herpes zoster. The majority of
patients suffer pain immediately before and during the acute rash
phase, but a more important clinical challenge is the need to prevent
or reduce the possibility of persistent pain.
• Postherpetic neuralgia is the most common complication that
reduces quality of life of patients.
• Which drug (Valaciclovir vs Acyclovir) is more efficient in terms
of reducing the risk for postherpetic neuralgia?
EVALUATING DIRECTNESS

• Does the study provide a direct enough answer to your clinical question in terms of
patient (P), examination (E) used and disease or outcome (O) being diagnosed?

Clinical Question:

Among adult patients with uncomplicated herpes zoster infection, is

Valcyclovir more efficient than Acyclovir in reducing the risk for
postherpetic neuralgia?
EVALUATING DIRECTNESS
P – adult patients with
uncomplicated Herpes Zoster
infection
“Patients 50 years of age or older with
clinically diagnosed, localized herpes zoster
presenting within 72 h after the onset of
rash…”
“The clinical diagnosis of herpes zoster was
based on the presence of the unilateral
dermatomal rash.”
E – Valacyclovir and Acyclovir
“Patients were randomized (1:1:1) according
to a computer-generated code to receive
treatment with valaciclovir at 1,000 mg three
times daily for 7 days, valaciclovir at 1,000 mg
three times daily for 14 days, or acyclovir at
800 mg five times daily for 7 days. All patients
received study medication for 14 days.
Patients randomized to 7 days of treatment
with valaciclovir or acyclovir received
placebo during days 8 to 14.”
O – decreased duration of
postherpetic neuralgia
“Patients were defined as achieving complete
cessation of pain if they were pain-free for at
least 28 days and had no subsequent
recurrence of pain during the 24-week
observation period.”
“Because there is no universally accepted
definition of postherpetic
neuralgia, the duration of postherpetic
neuralgia was evaluated by using two
definitions: pain that persisted after
rash healing and pain that persisted for
more than 30 days from the time of
enrollment. For analyses of postherpetic
neuralgia, patients who did not develop
postherpetic neuralgia were assigned a
duration of postherpetic neuralgia equal to 0
days.”
EVALUATING DIRECTNESS

Based in the assessment of PEO in both the

clinical scenario and journal article, the study
can provide direct answer to the clinical
question.
APPRAISING VALIDITY

Question 1: Were patients randomly assigned to treatment groups?

YES.
“Overall, 384 patients were randomized to treatment with valaciclovir for 7 days,
381 were randomized to treatment with valaciclovir for 14 days, and 376 were
randomized to treatment with acyclovir for 7 days.”
APPRAISING VALIDITY

Question 2: Was allocation concealed?

YES.
Patients were randomized (1:1:1) according to a computer-generated code to
receive treatment with valaciclovir at 1,000 mg three times daily for 7 days,
valaciclovir at 1,000 mg three times daily for 14 days, or acyclovir at 800 mg five
times daily for 7 days. All patients received study medication for 14 days. Patients
randomized to 7 days of treatment with valaciclovir or acyclovir received placebo
during days 8 to 14.
 APPRAISING VALIDITY
Question 3: Were baseline characteristics similar at
the start of the trial?
YES.
Demographic and baseline characteristics were
similar in all three treatment groups (Table 1).
Overall, there were 648 females (56.8%) and 493 males
(43.2%), mostly white (94.7%)
and ranging in age from 49 to 99 years (mean, 68
years).
Approximately 60% of patients presented within 48 h of
the appearance of the herpes zoster rash; the
proportion was comparable in all treatment groups. The
proportions of patients reporting prodromal pain (>80%)
and the severity of pain at presentation were also
similar in the three groups.
 APPRAISING VALIDITY
Question #4: Were patients blinded to treatment assignment?
YES.
"Patients 50 years of age or older with clinically diagnosed, localized
herpes zoster presenting within 72 h after the onset of rash were enrolled in the
multicenter, randomized, three-arm, double-blind, double-dummy study described
here.”
“All patients received study medication for 14 days. Patients randomized to 7 days of
treatment with valaciclovir or acyclovir received placebo during days 8 to 14.”
APPRAISING VALIDITY

Question #5: Were caregivers blinded to treatment assignment?

Cannot be determined.
The study did not mention how the drugs were being given to patients
or if they have caregivers/physicians giving their assigned medications
and taking care of them.
 APPRAISING VALIDITY
Question #6: Were outcome assessors blinded to treatment assignment?
YES.
Patients were assigned to keep track of their pain severity assessment hence blinded.
“To evaluate pain, patients kept a diary to record daily (days 1 to 30) and then weekly (to
week 24) assessments of the severity of pain or burning and abnormal sensations such as
allodynia, paresthesia, dysesthesia, or hyperesthesia.”
“Pain severity and unpleasantness were scored in native English-speaking subjects by using
the Gracely scales (9, 10). “
 APPRAISING VALIDITY
Question #7: Were all patients analysed in the groups to which they were originally
randomized?
YES.
“A total of 1,141 patients were enrolled at 107 study centers in 13 countries. All 1,141 enrolled patients
were included in the intent-to-treat analysis.

“Thirty-one patients with no prior history of renal impairment commenced treatment but were
subsequently found to have had low estimated creatinine clearance and elevated serum
creatinine values at presentation. In 22 patients, treatment with the study medication was
stopped prematurely when evidence of renal impairment at presentation became known. The
remaining nine patients (creatinine clearance, 20 to 35 ml/min; serum creatinine level, 124 to
194 mmol/liter) completed the treatment course. All 31 patients were included in all safety
and efficacy analyses.”
 APPRAISING VALIDITY
Question #8: Was follow-up rate adequate?

YES.
“A total of 1,141 patients were enrolled at 107 study centers in 13 countries.”
“All 1,141 enrolled patients were included in the intent-to-treat analysis. Of
these, 946 (82.9%) completed the 24-week study according to the study protocol.
Of the 195 patients who did not complete the study as planned, the most common
reasons were protocol violation (71 patients), adverse experiences (38 patients),
withdrawal of consent (30 patients), and lost to follow-up (24 patients); the
reasons were similarly distributed across the three treatment groups.”
APPRAISING THE RESULTS

One of the outcomes being measured in this study is a dichotomous variable

of “Duration of postherpetic neuralgia” among three groups: Valacyclovir 7
days; Valacyclovir 14 days; Acyclovir 7 days.
 APPRAISING THE RESULTS
Question #1: How large was the effect of treatment?

Treatment % patients who had neuralgia

Valacyclovir, 7 days 79

Valacyclovir, 14 days 80

Acyclovir, 7 days 85
 APPRAISING THE RESULTS
Question #1: How large was the effect of treatment?

Treatment Presence of Headache

Valacyclovir, 7 days 11%

Valacyclovir, 14 days 14%

Acyclovir, 7 days 13%

APPRAISING THE RESULTS

Question #2: How precise was the estimate of the treatment effect?

At 95% level of confidence, there is a 1.07 reduction in risk of having postherpetic

neuralgia in patients treated with Valacyclovir instead of Acyclovir with a confidence
interval of 1.04-1.48 with P=0.01
 ASSESSING APPLICABILITY

• a. Are there biologic issues that may affect accuracy of the

test? (Consider the influence of sex, comorbidity, race, age,
and pathology)
 ASSESSING APPLICABILITY

• Age: In this study, the age of the patient is significant as it includes patient from the adult
age group (range, 49 to 99 years). Although in our case, the patient is 18 years old, the
study generalized the age by mentioning immunocompetent adults which still includes our
patient.
 ASSESSING APPLICABILITY

• Sex: In the study, the patients were prospectively randomized so there is a mix of male
and female patients making this applicable to the patient.
 ASSESSING APPLICABILITY

• Co-morbidities: In patients with uncomplicated herpes zoster infection, the important

factors to consider are the underlying co morbidities. The study was not able to mention
any co-morbidity of the included subjects.
• The patient does not have any co-morbidity.
 ASSESSING APPLICABILITY

• Race: The patients in the study are from United Kingdom. They may have a different built
with our patient who is an Asian.
 ASSESSING APPLICABILITY

• Pathology: The study’s coverage also include presence of the unilateral dermatomal rash
which was the same with what our patient manifests.
 ASSESSING APPLICABILITY

• b. Are there socio-economic issues that may affect the accuracy of the
test?
Yes, especially financially since the patient belongs to a low class
family with monthly income almost enough for their daily needs only.
Additional medications that are expensive may affect the patient’s compliance
to the medication.
 INDIVIDUALIZING RESULTS

Step 1: Estimate your individual patient’s risk for an event without treatment (Rc)
Step 2: Estimate the RR using the study results.
Step 3: Estimate your individual patient’s risk for an event with treatment (Rt).
Step 4: Estimate the individualized absolute risk reduction (ARR)
Step 5: Estimate the individualized number needed to treat (NNT) or number needed to harm (NNH)
 INDIVIDUALIZING RESULTS

Step 1. Estimate your individual patient's risk for an event without treatment
Treatment showing benefit: An 18-year-old male with uncomplicated herpes zoster infection has a
risk of pain persisting after rash healing occurs in more than 50% of untreated patients lasting at
least 6 months. (Beutner, K.)
Treatment showing harm: An 18-year-old male with uncomplicated herpes zoster infection has a
risk for headache of 14% (Beutner, K.)
 INDIVIDUALIZING RESULTS
Step 2. Estimate the RR using the study results
Treatment showing benefit: If we use Valacyclovir for 7 days, we can reduce the
risk for postherpetic neuralgia. RR= 1.07
Rc=85%
Rt=79%
RR= 0.85/0.79=1.07
Treatment showing harm: If we use Valacyclovir for 7 days, we increase the risk
of headache. RR= 0.78
INDIVIDUALIZING RESULTS

Step 3. Estimate individual patient’s risk for an event with treatment (Valacyclovir)
Treatment showing benefit: Rt = 79%
Treatment showing harm: Rt = 10.92%
 INDIVIDUALIZING RESULTS
Step 4. Estimate the individualized absolute risk reduction (ARR)
Valacyclovir
Treatment showing benefit: ARR = 0.85 – 0.79 = 0.06 = 6%
Treatment showing harm: ARR = 14 - 10.92 = 3.08 %
INDIVIDUALIZING RESULTS
Step 5. Estimate the individualized number needed to treat (NTT) or
number needed to harm (NNHA)
Treatment showing benefit: NNT = 100/6= 16.7
Treatment showing harm: NNT = 100/3.08= 32.5 or NNH = -32.5
Conclusion

The appraisal showed that Valacyclovir is not beneficial than

Acyclovir for the patient in reducing the risk of postherpetic neuralgia.
 REFERENCES

Karl R. Beutner, David J. Friedman, Christine Forszpaniak, Paul L. Andersen,4† And

Martin J. Wood. Valaciclovir Compared with Acyclovir for Improved Therapy for
Herpes Zoster in Immunocompetent Adults. Department of Dermatology, University of
California at San Francisco, San Francisco, California; Roger Williams Medical Center, Providence, Rhode
Island; Clinical Pharmacology Investigations Division, Diagnostic Services, Inc., Naples, Florida;
Marselisborg Hospital, Århus, Denmark4; and Birmingham Heartlands Hospital, Birmingham, United
Kingdom