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A systematic review and critical appraisal of famciclovir treatment of herpes zoster Bassett, Kenneth, 1952-; Green, C. J. (Carolyn Joanne), 1956-; Wright, James M. Sep 30, 1998

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Centre for Health Servicesand Policy ResearchA systematic review andcritical appraisal of famciclovirtreatment of herpes zosterBCOHTA 98:11J        September 1998British Columbia Office of Health Technology AssessmentJoint Health Technology Assessment SeriesU N I V E R S I T Y  O F  B R I T I S H  C O L U M B I ABritish Columbia Office of Health Technology AssessmentJoint Health Technology Assessment SeriesA systematic review andcritical appraisal of famciclovirtreatment of herpes zosterKen Bassett, MD PhDSenior Medical Consultant, BC Office of Health Technology AssessmentAssociate Professor, Department of Family PracticeUniversity of British ColumbiaCarolyn J. Green, BSc(PT) MScResearch Associate, BC Office of Health Technology AssessmentUniversity of British ColumbiaJames M. Wright, MD PhDClinical Director, Therapeutics InitiativeAssociate Professor, Department of Pharmacology and TherapeuticsUniversity of British ColumbiaBCOHTA 98:11J September 1998BC Office of Health Technology AssessmentCentre for Health Services and Policy ResearchS-184 Koerner Pavilion, 2211 Wesbrook MallThe University of British ColumbiaVancouver BC   V6T 1Z3CanadaiiiiiForewordThe British Columbia Office of Health Technology Assessment (BCOHTA) was established onDecember 1, 1990 by a grant to The University of British Columbia from the Province, to promote andencourage the use of assessment research in policy, planning and utilization decisions by government,health care executives, and practitioners.  It is important to note that the role of the Office is to appraisethe scientific evidence only, without involvement in actual policy development for the requesting agency.Assessments are performed in response to requests from the public sector such as hospitals, physicians,professional associations, health regions, government; private sector groups such as manufacturers; andindividuals from the general public.  One or more of the following criteria are used to determine thepriority of an assessment and the level of analysis:  (1) number of users and potential change in quality oflife; (2) acquisition and operating costs to the health care system; (3) potential to influence provider andconsumer behavior as a result of a review; and (4) availability of accurate information and appropriateresearch skills.Electronic bibliographic databases and fugitive literature (that is, literature not indexed or distributedpublicly) are searched using predefined inclusion and exclusion criteria based on the specific searchstrategy.  The critical appraisal of the retrieved evidence includes the formulation of logical anddefensible conclusions about the technology under study.Health Technology Assessment projects are conducted by faculty and staff who are expert in systematicreview methodology.  Reports are reviewed internally, and then sent to experts from a variety ofacademic or clinical disciplines for external review.  Comments and suggestions are considered before afinal document is produced.  Distribution of the reports is by request from the Office or through inclusionon our mailing list.The strength of BCOHTA’s method of systematic review lies in the process of explicitly detailing themethodology and criteria used to produce recommendations which are based solely on the researchevidence.  This transparent and reproducible assessment process allows readers to review the evidenceobjectively for themselves.  The ensuing reports are available for public distribution.Arminée Kazanjian, Dr. Soc.Principal Investigator, BCOHTACopies may be obtained from:B.C. Office of Health Technology AssessmentCentre for Health Services & Policy ResearchS-184 - Koerner Pavilion, 2211 Wesbrook Mall Tel.:  (604) 822-7049The University of British Columbia Fax:  (604) 822-7975Vancouver, B.C.   V6T 1Z3 http://www.chspr.ubc.caivvTable of ContentsABSTRACT ......................................................................................................................................................  viiiINTRODUCTION .......................................................................................................................................... 1METHODS .................................................................................................................................................... 3RESULTS ...................................................................................................................................................... 4TABLES 1 & 2 ........................................................................................................................................ 7DISCUSSION ............................................................................................................................................... 8SUMMARY AND CONCLUSION ..................................................................................................................  10REFERENCES ...................................................................................................................................................  11viSources of FundingBritish Columbia Office of Health Technology Assessmentis funded under a Government of British Columbia Ministry of Health & Ministry Responsible forSeniors grant, through the Office of the Coordinator of Health Sciences at The University of BritishColumbia.Therapeutics Initiativeis funded through a 5 year grant to The University of British Columbia from the Government of BritishColumbia Ministry of Health & Ministry Responsible for Seniors.viiIntroduction to the SeriesThe Joint Heath Technology Assessment Series reports on projects initiated by the British ColumbiaOffice of Health Technology Assessment (BCOHTA) and evidence-based medicine programs in BC.Dedicated to producing unbiased, systematic reviews of clinical efficacy and effectiveness evidence forhealth care providers, administrators, policy makers, and the general public, these programs currentlyinclude:· Therapeutics Initiative (TI), Department of Pharmacology and Therapeutics, Faculty of Medicine, University ofBC, Vancouver· Technology Assessment Committee, Capital Health Region, Victoria· Drug Benefit Committee, Pharmacare, and ad hoc Health Technology Assessment Committees, the Ministry ofHealth and Ministry Responsible for Seniors, Victoria· Technology Assessment Committee, Workers' Compensation Board of BC, Richmond· Population Testing Programs, Boundary Health Unit, South Fraser Health Unit, Surrey· BC Research Institute for Child and Family Health, BC Women’s and Children’s Hospital, Vancouver· Centre for Clinical Epidemiology and Evaluation, Vancouver Hospital and Health Sciences Centre, Vancouver· Public Health Nursing, Boundary Health Unit, South Fraser Health Unit, SurreyTopics reflect initiative and institutional needs.  Priority is given to topics with significant impact onpatient health and health care costs, and with issues in more than one context.  The goal of the Series isboth to demonstrate systematic review and critical appraisal skills, and to co-ordinate research effortswithin contexts that are geographically separate and institutionally diverse.The Series addresses two different types of evidence-based medicine issues:1. Uncertainty regarding new technology;2. Discrepancy between evidence and practice for established technology.The Joint HTA Series will produce scientifically valid systematic reviews, supported by key individualsin each receptor site.  These individuals are able to present and defend the systematic review conclusionsduring ongoing committee debates.  This is an essential step if health policy and funding decisions are tobe connected to the available efficacy and effectiveness evidence.viiiABSTRACTObjective: to determine the efficacy and effectiveness of famciclovir versus placebo for thetreatment of herpes zoster.Design: systematic review and critical appraisal of randomised trials comparing the efficacy offamciclovir with placebo in adults with herpes zoster.Setting: outpatient clinics in the United States, Canada, and Australia.Subjects: adults with uncomplicated herpes zoster.Interventions: famciclovir 500 mg & 750 mgMain outcome measure: incidence, severity and patient-days of post herpetic neuralgia.Results: The one published report which met the inclusion criteria was of poor methodologicalquality.  Data analysis was incomplete and incongruous.  Famciclovir increased the incidence ofpost herpetic neuralgia from 38% in the placebo arm to 44% in the famciclovir 500 mg and 50%in the famciclovir 750 mg arms respectively.  The difference was statistically significant(p<0.004) in the group of patients over age 50 in the famciclovir 750 mg arm.  Patients over age50 also had similar patient-days of neuralgia: 3689 days (35%) placebo versus 2867 days (27%)famciclovir 750 mg.  This non-statistically significant 8% difference in patient-days contrastswith the dramatic 50% reduction in post herpetic neuralgia duration reported in the publishedstudy.Conclusion: Evidence that famciclovir provides a therapeutic advantage over placebo fortreatment of herpes zoster is incomplete, and inconclusive.  The results demonstrate theimportance of careful critical appraisal of published trial reports before acceptance, and the needfor further trials in this area.BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster1INTRODUCTIONThe clearest and most clinically significant therapeutic benefit from treating herpes zosterwith currently available antiviral medications - acyclovir, valacyclovir (a recent prodrug form ofacyclovir) and famciclovir would be a reduction in the incidence of neuralgic pain.  Post herpeticneuralgia, defined in this trial and elsewhere as "pain after (skin lesion) healing" 1 is known tocause significant immediate disability lasting months, and sometimes an intractable chronic painsyndrome lasting years.2  Acyclovir has not been found to reduce the incidence of neuralgiaversus placebo.3-5  Valacyclovir has no published clinical trial evidence establishing its benefitversus placebo for any parameter of neuralgia, including incidence.  Clinical evidence supportingvalacyclovir consists of one published trial comparing it with acyclovir.6  This trial, which wassubjected to critical appraisal and reported elsewhere 7 concluded that valacyclovir did notinfluence the incidence of post herpetic neuralgia.Significantly reducing neuralgic pain severity would confer almost as much therapeuticbenefit as reducing its occurrence (incidence) altogether.  In contrast to duration, discussedbelow, evidence that neuralgic pain severity is reduced would confer therapeutic benefitindependent of pain duration, assuming that duration was not increased.  No published reports todate have claimed that acyclovir  5 or alacyclovir 8 educe the severity of neuralgic pain.  In fact,study authors have concluded that acyclovir has no effect on pain severity.9Neuralgic pain duration is the weakest and most problematic measure of treatmnt effect.First, clinical interpretation of pain duration, however measured, depends on knowledge of painseverity.  For example, treatment effect to shorten the duration of neuralgia may or may not bedesirable if pain intensity is increased.BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster2While duration of neuralgia is a controversial outcome measure, Tyring et al 10 make astriking efficacy claim for famciclovir in the treatment of patients over age 50 with herpes zoster:The median times to resolution of post herpetic neuralgia in these olderpatients [over age 50] were 63 days for the 500mg famciclovir group, 61days for the 750mg famciclovir group, and 163 days for the placebogroup....  No benefit was seen for patients younger than 50 years.<10 p.92>If post herpetic neuralgia is actually reduced in the treatment group as much as thequotation suggests, then famciclovir treatment of herpes zoster would clearly be justified.However, before clinicians accept that famciclovir provides a clinically significant benefit topatients with herpes zoster, several important questions need to be addressed:  What is theinfluence of famciclovir on other parameters of post herpetic neuralgia beyond its duration, mostnotably its incidence and severity?  In particular, clinicians need to note that a 50% reduction induration of post herpetic neuralgia averaged over an entire treatment group may not translate intoany reduction in patient suffering if the incidence doubles.In addition, clinicians also require assurance that trial results are valid, gener lisable andreplicable.  Has this trial been repeated, with results confirmed by other investigators?BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster3METHODSThe following electronic bibliographic databases were searched from 1993 to Jan 1998:MEDLINE, Current Contents, EMBASE, Cochrane Controlled Trials Registry, Life SciencesCollection, OCLC FirstSearch(Article1st), and Outcomes Activities Database.  Key search termsused were "famciclovir” and "herpes zoster".  The Current Contents database was searched toDecember 1997.  The reference lists from retrieved articles were scanned.  No data were obtainedfrom the manufacturer of famciclovir despite repeated requests.  Studies were selected thatrandomized patient allocation, blinded patients and clinicians, and included famciclovir andplacebo treatment arms.The methodology of Chalmers TC et al 11 was used to critically appraise trial quality.  Inaddition, various numerators and denominators were extracted from the published results tocalculate incidence.  Calculated post herpetic neuralgia incidence was then combined withduration of post herpetic neuralgia to form a 'patient-day' unit.  A patient-day unit has anadvantage over the "median duration of post herpetic neuralgia" unit, because it measures postherpetic neuralgia in relation to all patients in the treatment arm.  In contrast, for post herpeticneuralgia duration the denominator is the sub-group of patients with post herpetic neuralgia.A Standard Pearson Chi-Square test for categorical data was used for tests ofsignificance.BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster4RESULTSOne published report, Tyring et al 10, met the inclusion criteria: 419 patients wererandomized into one of three treatment arms: famciclovir 500 mg, famciclovir 750 mg or placebothree times a day for 7 days.  Tyring et al 10 provide the only published efficacy evidence, from arandomized control trial, supporting famciclovir treatment of herpes zoster versus placebo (oneearlier trial compared famciclovir to acyclovir, but did not include a placebo treatment group 12 ).Key critical appraisal findingsLoss of blindingThe validity of this study's claims regarding post herpetic neuralgia depends onmaintenance of blinding as to patient allocation.  Loss of blinding is strongly suggested in Tyringet al 10 by close scrutiny of the intention to treat versus efficacy evaluable groups described inrelation to assessment of acute pain <10 .91-92>.  The intention to treat group is defined aspatients who took at least one dose of study medication, the efficacy evaluable group is definedas patients who completed 80% of the study protocol.  While the subgroup of patients withsevere rash ( >50 vesicles) in the famciclovir 500 mg and 750 mg arms maintained exactly thesame median duration of pain resolution in moving from intention to treat to the efficacyevaluable calculations (remaining at 20 and 27 days respectively), the median duration of acutepain resolution nearly doubled for the placebo group (from 30 to 53 days).  This difference inpain duration suggests a selective loss of less severely afflicted patients from the placebo group.The importance of the shift from intention to treat to efficacy evaluable groups becomes clearwhen it is appreciated that adding as few as 12 mildly afflicted individuals to the placebo groupwould result in the same median duration of post herpetic neuralgia as found in the famciclovirgroups, by itself negating the authors' most substantive efficacy claim.BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster5Re-analysis of reported findingsThe validity of this study's claim that famciclovir shortens the duration of post herpeticneuralgia cannot be interpreted without knowledge of incidence and pain severity.Incidence of post-herpetic neuralgia:The incidence of post herpetic neuralgia was calculated from the published trial results(Table 1).  The calculation suggests that famciclovir increased the incidence of post herpeticneuralgia from 38% placebo to 44% in the famciclovir 500 mg arm and 50% in the famciclovir750 mg arms respectively.  Furthermore, it suggests that the higher the dose of famciclovir, thehigher the incidence of post herpetic neuralgia.  The difference becomes statistically significant(p<0.004), comparing patients over age 50 in the famciclovir 750 mg versus placebo groups,arguably the age group of greatest clinical concern due to higher risk of severe post herpeticneuralgia.2Total patient-days of neuralgiaIn total, 22192 patient days of data is available from the Tyring et al 10 trial (Table2).Patients in the famciclovir 750 mg group experienced 4148 (20%) patient-days of neuralgiacompared to 6664 (30%) in the placebo group.  In the over 50 age group a total of 10640 patient-days of data are available.  Patients in the famciclovir 750 mg group experienced 2867 (27%)patient-days of neuralgia compared to 3689 (35%) in the placebo group.These values, while showing an 8% absolute reduction in post herpetic neuralgia patient-days for the famciclovir 750 mg group, should be viewed skeptically owing to an incongruousvalue found in the text<10 p.92> and Table 4.  The authors report the "median duration" of postherpetic neuralgia in patients over age 50 in the placebo group as 163 days.  This total, 163 days,exceeds the total defined post herpetic neuralgia study period by 11 days.Assuming that the discrepancy regarding median duration of post herpetic neuralgia in theplacebo group can be explained, the best clinicians can hope for is that, at the end of 6 months,BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster6patients over age 50 treated within 72 hours of onset of herpes zoster rash with famciclovir 750mg three times a day for 7 days will have 8% fewer days of post herpetic neuralgia.  This meansthat for every 100 days that patients taking placebo have post herpetic neuralgia, patients takingfamciclovir 750 mg will have 92.  The point is not to present these values as conclusive.  Rather,it is to contrast a non-statistically, and arguably non-clinically, significant 8% difference inpatient-days with the dramatic 50% reduction in post herpetic neuralgia duration reported byTyring et al. 10Pain severityWith remarkably similar patient-days of suffering in the famciclovir  750 mg treatmentarm, pain intensity becomes crucial for interpreting trial findings.  Tyring et al 10 repo t painseverity at trial onset, albeit measured using a four point scale that has not been validated.  Theauthors incongruously do not report post herpetic neuralgia severity for the remainingassessments during the study.  The drug manufacturer refused repeated requests to supply thiscrucial data.  Therefore, there is no way of knowing whether patients receiving famciclovir750 mg had more painful as well as more frequent post herpetic neuralgia.BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster7Table 1.   Incidence of post-herpetic neuralgia calculated from the raw data reported byTyring et al10 1995Treatment arm OverallincidenceSubgroupanalysisIncidence in subgroupover age 50Placebo: 56/146 = 38% over age 50: 31/70= 44%famciclovir 500 mg:61/138 = 44% over age  50: 41/69 = 59%famciclovir 750 mg:68/135 = 50% over age  50: 47/69 = 68%The top line of Table 4 <10 p.93>  provides the (intention to treat) numerator: 61 (famciclovir 500 mg), 68(famciclovir 750 mg), and 56 (placebo) patients developed post herpetic neuralgia.  The top line of Table 1<10p.91> provides the denominator: 138 (famciclovir 500 mg), 135 (famciclovir 750 mg), 146 (placebo).  Thesetables also provide data for people over age 50.Table 2.   Total patient-days of neuralgia calculated from the raw data reported byTyring et al10 1995Treatment arm Calculation of total patient daysPlacebo56 patients x 119 days (median duration PHN) = 6664 patient-days = 6664/22192 total = 30% patient-daysover age 50 = 31 x 119 = 3689/10640  = 35% patient-daysfamciclovir 750 mg:68 patients x 61 days (median duration PHN)  = 4148 patient-days = 4148/20520(total) = 20% patient-daysover age 50 = 47 x 61 = 2867/10488  = 27%  patient-daysThe total number of days in the "post-herpetic" neuralgia period was taken as 5 months (approximately 152 days)based on the stated study definition: "After the lesions had healed, patients were assessed for the presence of postherpetic neuralgia for an additional 5 months"<10 p.90 >.  This sample calculation is inaccurate because only"median" as opposed to "mean" duration of post herpetic neuralgia data was available (Tables 1 and 4).BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster8DISCUSSIONAs detailed above, famciclovir, if anything, increases the incidence of neuralgia forpatients over age 50, arguably the patients of greatest clinical concern.  Furthermore,Tyring et al 10 did not report on the influence of famciclovir on pain severity.  Instead, Tyring etal 10 limit their discussion of treatment effect to an analysis of post herpetic neuralgia duration.The problem with using neuralgic pain duration to assess treatment effect is that itsmeasurement remains controversial. 2,8  Many studies, starting with the early studies of acyclovir,measured post-herpetic neuralgia, that is, pain after a certain period of time (i.e. 30 days), usuallycorresponding to skin lesion healing.  Neuralgic pain before lesion healing was termed acutephase pain and considered clinically distinct from post herpetic neuralgia.  However,distinguishing between acute phase pain and post herpetic neuralgia has no pathophysiologicalbasis and can lead to bias.  For example, exclusively assessing patients with post herpeticneuralgia is a sub-group analysis of non-randomised groups of patients.Some authors have argued for measuring all herpes zoster pain together, that is,combining acute phase pain with post herpetic neuralgia.1  T rmed zoster associated pain, thismeasurement method, in contrast to post herpetic neuralgia, keeps almost all patients in theanalysis of treatment effect, since almost all patients have some degree of pain, at least in theacute phase.  As demonstrated above in the patient-day calculation of famciclovir, this type ofapproach does provide some sense of the overall population treatment effect, lost by post herpeticneuralgia duration calculations.Authors have made several claims and counter-claims r garding the effect of antiviralmedications on the duration of neuralgia.  None, however, has related their duration claims tovalid assessments of pain severity and/or incidence.  The study comparing valacyclovir toacyclovir, for example, claimed that valacyclovir reduces zoster associated pain versus acyclovir,41 and 51 days (median), respectively.8  This measure is not interpretable, as the authors do notBC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster9report on pain severity.  Tyring et al 10 similarly reported on a reduction of post herpetic neuralgiaduration without discussing pain severity.  In addition, Tyring et al 10 give clinicians and patientsthe unwelcome decision whether to opt for treatment with famciclovir, which may increase theirchance of developing post herpetic neuralgia, but when it does occur may decrease the durationof pain.BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster10SUMMARY AND CONCLUSIONTyring et al 10 provide the only published efficacy evidence that famciclovir treatment ofherpes zoster benefits patients versus placebo.  Shortcomings in the methodology andconclusions of this single randomized clinical trial, and evident omissions in its report are notedhere with concern.  Critical appraisal and re-analysis of this trial report demonstrate that theefficacy claims of these authors are questionable.  The sub-group analysis of patients over age 50demonstrating an increased incidence of post herpetic neuralgia with famciclovir is not meant asconclusive.  In fact, it is equally possible that famciclovir does or does not actually providepatient benefit.The purpose of this critical appraisal is to draw attention to the limitation of the originaltrial report, and to fuel debate as to whether currently published trial evidence is sufficient tosupport use of this drug for the treatment of herpes zoster.  The results demonstrate theimportance of careful critical appraisal of published trial reports before acceptance, and the needfor further trials in this area.BC Office of Health Technology AssessmentFamciclovir treatment of herpes zoster11REFERENCES1. Wood MJ.  How should we measure pain in herpes zoster?  Neurology 1995;45 (Suppl 8):S61-62.2. Loeser JD.  Herpes zoster and post herpetic neuralgia.  Pain 1986;25:149-164.3. Schmader KE.  Are current therapies useful for the prevention of post herpetic neuralgia?  J ofGen Int Med, 1989:4:83-89.4. Huff JC, Drucker JL, Clemmer A, Laskin OL, Connor JD, Bryson YJ, Balfour HH.  Effect oforal acyclovir on pain reduction in herpes zoster: A re-analysis.  J Med Vir 1993;Sup1:93-99.5. Willox MH, Finch RG.  Is oral acyclovir effective in preventing postherpetic neuralgia?Infectious Diseases Newsletter 1990;9:9.6. Beutner KR, Friedman DJ, Forszpaniak C, Anderson Pl, and Wood MJ.  Valaciclovircompared with acyclovir for improved therapy for herpes zoster in immunocompetent adults.Antimic Agents and Chemotherapy 1995;39:1546-1553.7. Therapeutics Initiative. Therapeutics Letter 17. New Drugs II. Famciclovir and Valacyclovir.January,1997; http://www.interchg.ubc.ca/janca.8. Dworkin RH et al.  Assessment of pain in herpes zoster: lessons learned from antiviral trials.Antiviral Research 1997;33:73-859. Wood MJ, Ogan PH, McKendric MW, Care CD, McGill JI, Webb EM, Efficacy of oralacyclovir treatment of acute herpes zoster.  Amer J Med 1988;85(2A):79-83.10. Tyring S, Barbarash RA, Nahlik JE, Cunningham A, Marley J, Heng M et al. Famciclovir forthe treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. Arandomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:89-96.11. Chalmers TC, Smith H, Blackburn B. A method for assessing the quality of a randomizedcontrol trial. Control Clin Trials 1981;2:31-49.12. Degreef H. Famciclovir Herpes Zoster Clinical Study Group.  Famciclovir, a new oralantiherpes drug: results of the first controlled clinical study demonstrating its efficacy and safetyin the treatment of uncomplicated herpes zoster in immunocompetent patients.  Int J AntimicAgents 1994;4:241-246.

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