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A double-masked, placebo-controlled trial of acyclovir cream in immunocompetent patients with herpes zoster
Journal of Infection (I988) I7, 57-63
A double-masked, placebo-controlled trial o f acyclovir cream in i m m u n o c o m p e t e n t patients with herpes zoster B. K. Mandal,* E. M. Dunbar,* M. E. Ellis,* Joanne Ellis* and Pauline Dowdt
* Regional Department of Infectious Diseases and Tropical Medicine, Monsall Hospital, Manchester and t Wellcome Research Laboratories, Beckenham, Kent, U.K. Accepted for publication I I January I988 Summary Sixty-four patients with herpes zoster were entered into a randomised double-masked, placebo-controlled trial of 5 % acyclovir cream applied five times daily for 5 days. Of these patients, 56 were included in the final analysis (26 acyclovir, 30 placebo). Significant and objective differences in either progression of the rash, severity of acute pain or incidence of post-herpetic neuralgia were not observed. Although significantly more rashes involuted in the acyclovir group, this isolated finding cannot be explained. Twenty-two patients (I2 acyclovir, IO placebo) experienced erythema or desquamation or both during treatment with the cream. The similar incidence of skin reactions in both groups suggests that they were related to the cream base rather than the acyclovir.
Introduction H e r p e s zoster is a c o m m o n disease, mainly of the elderly, often associated with severe and protracted pain. Its course, especially progression of the rash and the severity of acute pain, has been shown to be beneficially influenced b y intravenous acyclovir in doses of 5 m g / k g b o d y weight or greater, 8 hourly for 5 day s.1-4 M o s t i m m u n e - c o m p e t e n t patients who develop herpes zoster, however, do not otherwise require to be in hospital. W e therefore decided to evaluate the treatment of herpes zoster with acyclovir administered b y an alternative route and chose its topical application to the affected dermatome. T w o different topical formulations of acyclovir have been developed for treating m u c o c u t a n e o u s herpes infections. An ointment containing 5 % acyclovir with polyethylene glycol as solvent, developed in the U . S . A . , has been s h o w n to have a significant antiviral effect in primary episodes of genital h e r p e s ) '6 Results in patients with recurrent genital herpes, however, were disappointing, v-9 An alternative dermal formulation was therefore developed in the U . K . containing 5 % acyclovir in a modified aqueous cream base which includes 4o % propylene glycol as the solvent and 1 % pluronic as a stabiliser. This cream p r o v e d superior to acyclovir ointment for treating Herpes simplex virus infections in guinea-pigs. 1° It has also been shown to have antiviral activity in first episodes of genital herpes. 11'12 T h e acyclovir cream was therefore chosen for evaluation in a doublemasked, placebo-controlled trial designed to determine the effect of its topical application on the duration and s y m p t o m s of herpes zoster in elderly patients. oi63-4453/88/o4oo57 + 07 $02.00/0
© I988 The British Society for the Study of Infection
58
B.K. MANDAL
ET
AL.
Methods
I m m u n e - c o m p e t e n t patients of either sex, over 5o years of age, presenting with a clinical diagnosis of herpes zoster w e r e included in the study. Patients were excluded from the trial if the rash was m o r e than 72 h duration; if they had received other antiviral therapy, or if they were k n o w n to have renal insufficiency. Approval b y the appropriate ethical committee was obtained before the study began and all patients gave informed consent. T h e trial started with inpatients b u t after recruitment of the first ~6 patients changed to being mainly domiciliary so as to allow an increase in the n u m b e r of patients. After referral by their general practitioners, patients were seen b y the research nurse w h o entered t h e m into the study and initiated treatment. Patients were examined soon afterwards b y one of the principal investigators w h e n the diagnosis and suitability of the patient for the study were confirmed. T h e trial was d o u b l e - m a s k e d and randomised. Patients were allocated to receive 5 % acyclovir in a modified aqueous cream base or the base alone. T h e cream was applied five times a day for 5 days b y gently r u b b i n g it for 2 minutes into the rash and into healthy skin surrounding it. T h e cream was applied by hospital staff to inpatients, or, for patients at home, by a m e m b e r of the patient's household. Patients were assessed daily for at least 5 days at approximately the same time of day b u t not immediately after the cream had been applied. Surveillance was continued at I, 2 and 4 weeks after each patient's entry into the trial and thereafter at m o n t h l y intervals if pain persisted. O n entering the trial, patients were assessed for their general condition, the duration o f p r o d r o m a l s y m p t o m s and rash. At each assessment the approximate n u m b e r of discrete lesions in the affected d e r m a t o m e were recorded. Particular attention was paid to the loss of vesicles, crusting of lesions and d e v e l o p m e n t o f n e w lesions. In addition, the appearance of lesions in other dermatomes (satellite, distant, disseminated) was recorded. T h e severity of pain was noted at each visit b y the patient b y marking a linear analogue scale ranging from none to very severe and continuous. This was done without access to previous records and was then transcribed to the record sheet as a score of 0-4, with o = no pain, I = mild pain ( < 25 ~o), 2 = m o d e r a t e pain (25-50 %), 3 = severe pain (51-99 %) and 4 = very severe and continuous pain (~oo %). T h e nature, dose and frequency o f any prescribed analgesics were also recorded. A n y patient with herpes zoster affecting the ophthalmic division of the trigeminal nerve who developed involvement o f the eye was treated with acyclovir eye ointment administered five times a day. T h e patients remained in the trial. Statistical methods
T h e times to : the first day w i t h o u t vesicles; first and full crusting of lesions; the last day of n e w lesions appearing in the d e r m a t o m e ; the last day with n e w disseminated lesions and the last day of all n e w lesions were analysed b y means of the M a n t e l - C o x (log-rank) test. Persistence of the rash in each patient was
Acyclovir cream for treating herpes zoster
59
estimated by the Kaplan-Meier technique for survival curves. T h e proportions of patients in the two groups whose rash was arrested were compared by use of the Pearson X2 test and the changes in the number of lesions were analysed by standard t-tests. Changes in the scores relating to severity of pain between day o (pretreatment) and day 5 (end of treatment) were examined by standard ttests. Scores of the distribution of pain on day 5 and the percentage of patients with decrease in pain from day o in the two groups were compared by means of the Pearson X2 test. As well as analysing the records of all patients in the trial as already described, separate analyses were made for patients who had a moderate or severe rash on entry ( > 25 discrete lesions on day o) and for patients with a rash of ~< 48 hours' duration before cream was first applied. All the statistical tests were two-tailed. Results
Of a total of 64 patients who entered the trial, 56 were included in the analysis. Reasons for exclusion included: alternative diagnosis made (two having had placebo, one having had acyclovir), missing proforma (three having had acyclovir), failure to complete the trial, reason unknown (one having had acyclovir) and failure to fulfil the entry criteria (one patient with cancer of the stomach, received acyclovir.) Initial a s s e s s m e n t
T h e r e were slightly more female patients in the placebo group on entry. T h e remaining initial features assessed were comparable between the two groups (Table I). Approximately half the patients had mild rashes with less than 25 discrete lesions while general symptoms were usually scored as absent or mild. Most patients had either moderate or severe pain at entry requiring the use of analgesia. Efficacy
(I) Progression of the rash T h e results of analysing the progression of the rash are summarised in Table II. Statistically significant differences between the two treatment groups were not observed for any of the features recorded. Separate analyses of patients who entered the trial with rashes of ~< 48 h duration and patients with more extensive rashes ( > 25 discrete lesions) also failed to reveal any significant differences between the two treatment groups (Table III). T h e proportions of patients whose rash was arrested are shown in Table IV for all patients combined, for those with a rash of ~< 48 h duration and for those with > 25 discrete lesions. For all the patients combined and for patients with > 25 discrete lesions with difference between the acyclovir and the placebo group was significant (P = 0.02 and P = 0"03 respectively).
(2) Acute pain Significant differences in the average daily pain scores between the two groups were not observed. Furthermore, the proportion of patients still taking
B.K. MANDAL ET AL.
60
T a b l e I Details of patients entering the trial
Sex: Male Female Age : Mean (years) Range (years) Affected dermatome : Trigeminal nerve (all divisions) Other Duration of prodrome (h) < 48 48-96 > 96 Duration of rash (h) 0-24 25-48 49-72 Number of discrete lesions : 25
26-50 5 I-IOO
> IOO Missing values Pain score: 0 (none) I (mild) 2 (moderate) 3 (severe) 4 (very severe) Use of analgesics : Analgesics not used Analgesics used
Acyclovir, n = 26
Placebo, n = 30
iI 15
9 2I
67"4 5o--87
68"4 5o-89
6
9
20
2I
5 12 9
7* 13 9
II
13
IO
IO
5
7
12
14 5
5 5
5
4 --
4 I
i 5 6 12 2
i 5 II 9 4
8 18
6 24
* One observation missing. a n a l g e s i c s at t h e e n d o f t h e r a p y w a s a l m o s t i d e n t i c a l (65 % o f t h e a c y c l o v i r g r o u p , 67 % o f t h e p l a c e b o g r o u p ) . (3) Post-herpetic pain F o r t h e p u r p o s e o f this s t u d y , p o s t - h e r p e t i c p a i n w a s d e f i n e d as p a i n p e r s i s t i n g f o r m o r e t h a n I m o n t h a f t e r e n t r y i n t o t h e trial. T h e p a i n r e c o r d i n g s at 3 w e e k s a n d I m o n t h are t h e r e f o r e t a k e n to r e p r e s e n t t h e e n d o f t h e p h a s e o f a c u t e p a i n . A f t e r t h e a s s e s s m e n t s at I m o n t h , p a t i e n t s w e r e n o t a c t i v e l y f o l l o w e d u n l e s s t h e y w e r e e x p e r i e n c i n g p a i n . E v e n so, as m a n y p a t i e n t s as p o s s i b l e w e r e c o n t a c t e d a f t e r 6 m o n t h s . 2k t o t a l o f 44 p a t i e n t s ( z I h a v i n g h a d a c y c l o v i r , 23 h a v i n g h a d p l a c e b o ) w e r e s e e n at this t i m e . O f t h e s e , 7/21 (33"3 % ) a c y c l o v i r r e c i p i e n t s a n d 9 / 2 3 ( 3 9 " 1 % ) p l a c e b o r e c i p i e n t s w e r e still e x p e r i e n c i n g s o m e
Acyclovir cream for treating herpes zoster
6i
T a b l e II Progression of rash Acyclovir
Placebo
n
Mean
n
Mean
P-value
T i m e to loss of vesicles (days)
26
6-0
29
5"8
0-83
T i m e to first crust (days)
16
3"4
22
3"5
0"92
T i m e to complete crusting (days)
23
6-0
27
6"I
0"83
T i m e to last day with new lesion forming in the dermatome (days)
I2
2"8
20
2"I
0"39
5
2"4
9
3 .2
o'96
14
2"7
21
2"5
o'96
Time to last day of disseminated lesion forming (days) T i m e to last day of all new lesions (days)
Table
III
P-Values for patients entered within 48 h of onset of rash and for patients with > 25 discrete lesions Duration of rash ~<48h
No. of discrete lesions >25
T i m e to loss of vesicles
0.38
0.79
T i m e to first crust
0.92
0'78
T i m e to complete crusting
0.72
0.29
Table
IV
Proportion of patients whose rash was arrested Duration of rash All patients ACV
Normal progression of rash (no. of patients) Arrested rash (no. of patients) % arrested P-Value
PCB
> 25 discrete lesions
~< 48 h ACV
PCB
ACV
PCB
5
*5
4
9
2
8
21
15
17
14
IZ
7
50 %
81 To
61 To
86 %
8i %
* (P < 0"05). ACV, acyclovir; PCB, placebo.
0.02*
o. 14
47 % 0"03*
62
B.K. M A N D A L E T A L .
pain although for most of them it was very mild and, in approximately half the patients, it was intermittent. T h e scores for pain between the acyclovir and placebo groups were not significantly different at any of the subsequent monthly assessments. A d v e r s e effects
Twenty-two patients (I2 acyclovir and ten placebo recipients) experienced adverse reactions to the cream. These consisted of either erythema, desquamation of the skin or both. T h e similar incidence of these skin reactions in the two groups suggests that the reactions were to the cream base rather than to the acyclovir. In none of the patients were the adverse events so severe as to require therapy to be stopped. Discussion
T h e results of this study did not demonstrate any significant differences in respect of objectively measurable features between patients receiving treatment with acyclovir cream and those receiving placebo. Only one somewhat subjective assessment was statistically significant (P = o'02) in favour of acyclovir. This was the proportion of patients with a fully or partially arrested rash (full = no crusting, partial = minimal crusting only). In a separate analysis of patients with more than 25 lesions on entering the study, the percentage of acyclovir recipients with arrested rashes was also significantly higher (P = 0"o3). This result, however, is contrary to expectations since, in the subgroup of patients entering the study within 48 h of the rash developing, this feature failed to achieve significance because of a higher rate of apparently arrested rashes in the placebo group. Even so, the early application of acyclovir would be expected to increase the chances of altering the course of the disease. Furthermore, a recent placebo-controlled study of oral acyclovir (8oo mg five times daily) with many more patients failed to show any significant effect on rashes partially or fully arrested although other features of the rash were significantly improved in the acyclovir-treated group, x~ It is possible that higher concentrations of acyclovir in the lesion as a result of topical application may more favourably affect this feature. In our study, application of acyclovir cream did not have a significant effect on the severity of acute pain or on the development or the rate of disappearance of post-herpetic neuralgia. T h e only published study of topically applied acyclovir for treating herpes zoster infections was performed in immunocompromised patients with the ointment formulation. 14 In a placebo controlled trial, 5 % acyclovir was applied to the rash four times daily for Io days. T h e time to healing was significantly less but pain was not alleviated significantly and virus titres were not significantly lower. T h e greater severity of mucocutaneous varicella-zoster infections in immunocompromised patients may lead to increased absorption .of drugs applied topically. This may be why Levin et al. x4 demonstrated significant benefit whereas in this trial none was observed. T h e median time to full crusting in the current trial was very short, thereby suggesting that the infections may have been milder than in the study of oral acyclovir which
Acyclovir cream for treating herpes zoster
63
showed efficacy. 13 If m o r e severe infections were to be studied, benefit from acyclovir cream might be shown. It is m o r e likely, however, that systemic administration of acyclovir would be preferred. ( D r A. M . G i l b e r t a n d M r D . A. J o n e s , W e l l c o m e R e s e a r c h L a b o r a t o r i e s , B e c k e n h a m , K e n t , U . K . c o l l a b o r a t e d in t h i s s t u d y . )
References
I. Bean B, Braun C, Bfilfour H H . Acyclovir therapy for acute herpes zoster. Lancet I982; i i : 118--121.
z. McGill JI, Hiscott C, Worstman T , Larkin M. T h e use of acyclovir in the treatment of herpes zoster ocular infections. In Sundmache R, ed. Herpetische Augener Warlungen. Munich: J F Bergmann, I 9 8 I : 461-464. 3- McGill JI, MacDonald R, Fall C, McKendrick G D W . Intravenous acyclovir in acute herpes zoster infection. J Infect I983: 6: I 5 7 - I 6 I . 4. Peterslund NA, Seyer-Hansen U, Ipsen J, Esmann V, Schonheyder H, Juhl H. Acyclovir in herpes zoster. Lancet I98I ; ii: 827-83o. 5- Corey L, Nahmias AJ, Guinan ME, Benedetti JK, Critchlow CW, Holmes K K . A trial of topical acyclovir in genital herpes simplex virus infections. New Engl J Med I983 ; 3o6: I x 6--I 19.
6. Thin RN, Nabarro JM, Davidson Parker J, Fiddian AP. Topical acyclovir in the treatment of initial genital herpes. Br J Vener Dis I983 ; 59 : I i 6 - i I9. 7. Corey L, Beneditti JK, Critchlow C W et al. Double-blind controlled trial of topical acyclovir in genital herpes simplex virus infections. A m J Med I93 ; 73 (IA): 326-334. 8. Reichman RC, Badger GJ, Guinan M E et al. Topically administered acyclovir in the treatment of recurrent herpes simplex genitalis. A controlled trial. J Infect Dis I983 ; I47: 366-340. 9. L u b y JP, Gnann JW, Alexander WJ et al. A collaborative study of patient initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J Infect Dis I984; I50 : I-6.
io. Collins P, Oliver N M . Acyclovir treatment of cutaneous herpes in guinea-pigs and herpes encephalitis in mice. A m J Med I982 ; 73 (IA): 96-99. 1 I. K i n g h o m GR, T u r n e r EB, Barton I G , Potter CW, Burke CA, Fiddian AP. Efficacy of topical acyclovir cream in first and recurrent episodes of genital herpes. Antiviral Res I983 ; 3 : 29I-3OI-
I2. Fiddian AP, K i n g h o m GR, Goldmeier D et al. Topical acyclovir in the treatment of genital herpes; a comparison with systemic therapy. J Antimicrob Chemother 1983; IZ (Suppl B): 67-77. I3. McKendrick M W , McGill JI, White JE, Wood MJ. Oral acyclovir in acute herpes zoster. Br M e d J I986; z93: I529-I532. I4. Levin MJ, Zaiai JA, Hershey et al. Topical acyclovir treatment of herpes zoster in immunocompromised patients. J A m Acad Dermatol I985; I3: 590-596.
A double-masked, placebo-controlled trial o f acyclovir cream in i m m u n o c o m p e t e n t patients with herpes zoster B. K. Mandal,* E. M. Dunbar,* M. E. Ellis,* Joanne Ellis* and Pauline Dowdt
* Regional Department of Infectious Diseases and Tropical Medicine, Monsall Hospital, Manchester and t Wellcome Research Laboratories, Beckenham, Kent, U.K. Accepted for publication I I January I988 Summary Sixty-four patients with herpes zoster were entered into a randomised double-masked, placebo-controlled trial of 5 % acyclovir cream applied five times daily for 5 days. Of these patients, 56 were included in the final analysis (26 acyclovir, 30 placebo). Significant and objective differences in either progression of the rash, severity of acute pain or incidence of post-herpetic neuralgia were not observed. Although significantly more rashes involuted in the acyclovir group, this isolated finding cannot be explained. Twenty-two patients (I2 acyclovir, IO placebo) experienced erythema or desquamation or both during treatment with the cream. The similar incidence of skin reactions in both groups suggests that they were related to the cream base rather than the acyclovir.
Introduction H e r p e s zoster is a c o m m o n disease, mainly of the elderly, often associated with severe and protracted pain. Its course, especially progression of the rash and the severity of acute pain, has been shown to be beneficially influenced b y intravenous acyclovir in doses of 5 m g / k g b o d y weight or greater, 8 hourly for 5 day s.1-4 M o s t i m m u n e - c o m p e t e n t patients who develop herpes zoster, however, do not otherwise require to be in hospital. W e therefore decided to evaluate the treatment of herpes zoster with acyclovir administered b y an alternative route and chose its topical application to the affected dermatome. T w o different topical formulations of acyclovir have been developed for treating m u c o c u t a n e o u s herpes infections. An ointment containing 5 % acyclovir with polyethylene glycol as solvent, developed in the U . S . A . , has been s h o w n to have a significant antiviral effect in primary episodes of genital h e r p e s ) '6 Results in patients with recurrent genital herpes, however, were disappointing, v-9 An alternative dermal formulation was therefore developed in the U . K . containing 5 % acyclovir in a modified aqueous cream base which includes 4o % propylene glycol as the solvent and 1 % pluronic as a stabiliser. This cream p r o v e d superior to acyclovir ointment for treating Herpes simplex virus infections in guinea-pigs. 1° It has also been shown to have antiviral activity in first episodes of genital herpes. 11'12 T h e acyclovir cream was therefore chosen for evaluation in a doublemasked, placebo-controlled trial designed to determine the effect of its topical application on the duration and s y m p t o m s of herpes zoster in elderly patients. oi63-4453/88/o4oo57 + 07 $02.00/0
© I988 The British Society for the Study of Infection
58
B.K. MANDAL
ET
AL.
Methods
I m m u n e - c o m p e t e n t patients of either sex, over 5o years of age, presenting with a clinical diagnosis of herpes zoster w e r e included in the study. Patients were excluded from the trial if the rash was m o r e than 72 h duration; if they had received other antiviral therapy, or if they were k n o w n to have renal insufficiency. Approval b y the appropriate ethical committee was obtained before the study began and all patients gave informed consent. T h e trial started with inpatients b u t after recruitment of the first ~6 patients changed to being mainly domiciliary so as to allow an increase in the n u m b e r of patients. After referral by their general practitioners, patients were seen b y the research nurse w h o entered t h e m into the study and initiated treatment. Patients were examined soon afterwards b y one of the principal investigators w h e n the diagnosis and suitability of the patient for the study were confirmed. T h e trial was d o u b l e - m a s k e d and randomised. Patients were allocated to receive 5 % acyclovir in a modified aqueous cream base or the base alone. T h e cream was applied five times a day for 5 days b y gently r u b b i n g it for 2 minutes into the rash and into healthy skin surrounding it. T h e cream was applied by hospital staff to inpatients, or, for patients at home, by a m e m b e r of the patient's household. Patients were assessed daily for at least 5 days at approximately the same time of day b u t not immediately after the cream had been applied. Surveillance was continued at I, 2 and 4 weeks after each patient's entry into the trial and thereafter at m o n t h l y intervals if pain persisted. O n entering the trial, patients were assessed for their general condition, the duration o f p r o d r o m a l s y m p t o m s and rash. At each assessment the approximate n u m b e r of discrete lesions in the affected d e r m a t o m e were recorded. Particular attention was paid to the loss of vesicles, crusting of lesions and d e v e l o p m e n t o f n e w lesions. In addition, the appearance of lesions in other dermatomes (satellite, distant, disseminated) was recorded. T h e severity of pain was noted at each visit b y the patient b y marking a linear analogue scale ranging from none to very severe and continuous. This was done without access to previous records and was then transcribed to the record sheet as a score of 0-4, with o = no pain, I = mild pain ( < 25 ~o), 2 = m o d e r a t e pain (25-50 %), 3 = severe pain (51-99 %) and 4 = very severe and continuous pain (~oo %). T h e nature, dose and frequency o f any prescribed analgesics were also recorded. A n y patient with herpes zoster affecting the ophthalmic division of the trigeminal nerve who developed involvement o f the eye was treated with acyclovir eye ointment administered five times a day. T h e patients remained in the trial. Statistical methods
T h e times to : the first day w i t h o u t vesicles; first and full crusting of lesions; the last day of n e w lesions appearing in the d e r m a t o m e ; the last day with n e w disseminated lesions and the last day of all n e w lesions were analysed b y means of the M a n t e l - C o x (log-rank) test. Persistence of the rash in each patient was
Acyclovir cream for treating herpes zoster
59
estimated by the Kaplan-Meier technique for survival curves. T h e proportions of patients in the two groups whose rash was arrested were compared by use of the Pearson X2 test and the changes in the number of lesions were analysed by standard t-tests. Changes in the scores relating to severity of pain between day o (pretreatment) and day 5 (end of treatment) were examined by standard ttests. Scores of the distribution of pain on day 5 and the percentage of patients with decrease in pain from day o in the two groups were compared by means of the Pearson X2 test. As well as analysing the records of all patients in the trial as already described, separate analyses were made for patients who had a moderate or severe rash on entry ( > 25 discrete lesions on day o) and for patients with a rash of ~< 48 hours' duration before cream was first applied. All the statistical tests were two-tailed. Results
Of a total of 64 patients who entered the trial, 56 were included in the analysis. Reasons for exclusion included: alternative diagnosis made (two having had placebo, one having had acyclovir), missing proforma (three having had acyclovir), failure to complete the trial, reason unknown (one having had acyclovir) and failure to fulfil the entry criteria (one patient with cancer of the stomach, received acyclovir.) Initial a s s e s s m e n t
T h e r e were slightly more female patients in the placebo group on entry. T h e remaining initial features assessed were comparable between the two groups (Table I). Approximately half the patients had mild rashes with less than 25 discrete lesions while general symptoms were usually scored as absent or mild. Most patients had either moderate or severe pain at entry requiring the use of analgesia. Efficacy
(I) Progression of the rash T h e results of analysing the progression of the rash are summarised in Table II. Statistically significant differences between the two treatment groups were not observed for any of the features recorded. Separate analyses of patients who entered the trial with rashes of ~< 48 h duration and patients with more extensive rashes ( > 25 discrete lesions) also failed to reveal any significant differences between the two treatment groups (Table III). T h e proportions of patients whose rash was arrested are shown in Table IV for all patients combined, for those with a rash of ~< 48 h duration and for those with > 25 discrete lesions. For all the patients combined and for patients with > 25 discrete lesions with difference between the acyclovir and the placebo group was significant (P = 0.02 and P = 0"03 respectively).
(2) Acute pain Significant differences in the average daily pain scores between the two groups were not observed. Furthermore, the proportion of patients still taking
B.K. MANDAL ET AL.
60
T a b l e I Details of patients entering the trial
Sex: Male Female Age : Mean (years) Range (years) Affected dermatome : Trigeminal nerve (all divisions) Other Duration of prodrome (h) < 48 48-96 > 96 Duration of rash (h) 0-24 25-48 49-72 Number of discrete lesions : 25
26-50 5 I-IOO
> IOO Missing values Pain score: 0 (none) I (mild) 2 (moderate) 3 (severe) 4 (very severe) Use of analgesics : Analgesics not used Analgesics used
Acyclovir, n = 26
Placebo, n = 30
iI 15
9 2I
67"4 5o--87
68"4 5o-89
6
9
20
2I
5 12 9
7* 13 9
II
13
IO
IO
5
7
12
14 5
5 5
5
4 --
4 I
i 5 6 12 2
i 5 II 9 4
8 18
6 24
* One observation missing. a n a l g e s i c s at t h e e n d o f t h e r a p y w a s a l m o s t i d e n t i c a l (65 % o f t h e a c y c l o v i r g r o u p , 67 % o f t h e p l a c e b o g r o u p ) . (3) Post-herpetic pain F o r t h e p u r p o s e o f this s t u d y , p o s t - h e r p e t i c p a i n w a s d e f i n e d as p a i n p e r s i s t i n g f o r m o r e t h a n I m o n t h a f t e r e n t r y i n t o t h e trial. T h e p a i n r e c o r d i n g s at 3 w e e k s a n d I m o n t h are t h e r e f o r e t a k e n to r e p r e s e n t t h e e n d o f t h e p h a s e o f a c u t e p a i n . A f t e r t h e a s s e s s m e n t s at I m o n t h , p a t i e n t s w e r e n o t a c t i v e l y f o l l o w e d u n l e s s t h e y w e r e e x p e r i e n c i n g p a i n . E v e n so, as m a n y p a t i e n t s as p o s s i b l e w e r e c o n t a c t e d a f t e r 6 m o n t h s . 2k t o t a l o f 44 p a t i e n t s ( z I h a v i n g h a d a c y c l o v i r , 23 h a v i n g h a d p l a c e b o ) w e r e s e e n at this t i m e . O f t h e s e , 7/21 (33"3 % ) a c y c l o v i r r e c i p i e n t s a n d 9 / 2 3 ( 3 9 " 1 % ) p l a c e b o r e c i p i e n t s w e r e still e x p e r i e n c i n g s o m e
Acyclovir cream for treating herpes zoster
6i
T a b l e II Progression of rash Acyclovir
Placebo
n
Mean
n
Mean
P-value
T i m e to loss of vesicles (days)
26
6-0
29
5"8
0-83
T i m e to first crust (days)
16
3"4
22
3"5
0"92
T i m e to complete crusting (days)
23
6-0
27
6"I
0"83
T i m e to last day with new lesion forming in the dermatome (days)
I2
2"8
20
2"I
0"39
5
2"4
9
3 .2
o'96
14
2"7
21
2"5
o'96
Time to last day of disseminated lesion forming (days) T i m e to last day of all new lesions (days)
Table
III
P-Values for patients entered within 48 h of onset of rash and for patients with > 25 discrete lesions Duration of rash ~<48h
No. of discrete lesions >25
T i m e to loss of vesicles
0.38
0.79
T i m e to first crust
0.92
0'78
T i m e to complete crusting
0.72
0.29
Table
IV
Proportion of patients whose rash was arrested Duration of rash All patients ACV
Normal progression of rash (no. of patients) Arrested rash (no. of patients) % arrested P-Value
PCB
> 25 discrete lesions
~< 48 h ACV
PCB
ACV
PCB
5
*5
4
9
2
8
21
15
17
14
IZ
7
50 %
81 To
61 To
86 %
8i %
* (P < 0"05). ACV, acyclovir; PCB, placebo.
0.02*
o. 14
47 % 0"03*
62
B.K. M A N D A L E T A L .
pain although for most of them it was very mild and, in approximately half the patients, it was intermittent. T h e scores for pain between the acyclovir and placebo groups were not significantly different at any of the subsequent monthly assessments. A d v e r s e effects
Twenty-two patients (I2 acyclovir and ten placebo recipients) experienced adverse reactions to the cream. These consisted of either erythema, desquamation of the skin or both. T h e similar incidence of these skin reactions in the two groups suggests that the reactions were to the cream base rather than to the acyclovir. In none of the patients were the adverse events so severe as to require therapy to be stopped. Discussion
T h e results of this study did not demonstrate any significant differences in respect of objectively measurable features between patients receiving treatment with acyclovir cream and those receiving placebo. Only one somewhat subjective assessment was statistically significant (P = o'02) in favour of acyclovir. This was the proportion of patients with a fully or partially arrested rash (full = no crusting, partial = minimal crusting only). In a separate analysis of patients with more than 25 lesions on entering the study, the percentage of acyclovir recipients with arrested rashes was also significantly higher (P = 0"o3). This result, however, is contrary to expectations since, in the subgroup of patients entering the study within 48 h of the rash developing, this feature failed to achieve significance because of a higher rate of apparently arrested rashes in the placebo group. Even so, the early application of acyclovir would be expected to increase the chances of altering the course of the disease. Furthermore, a recent placebo-controlled study of oral acyclovir (8oo mg five times daily) with many more patients failed to show any significant effect on rashes partially or fully arrested although other features of the rash were significantly improved in the acyclovir-treated group, x~ It is possible that higher concentrations of acyclovir in the lesion as a result of topical application may more favourably affect this feature. In our study, application of acyclovir cream did not have a significant effect on the severity of acute pain or on the development or the rate of disappearance of post-herpetic neuralgia. T h e only published study of topically applied acyclovir for treating herpes zoster infections was performed in immunocompromised patients with the ointment formulation. 14 In a placebo controlled trial, 5 % acyclovir was applied to the rash four times daily for Io days. T h e time to healing was significantly less but pain was not alleviated significantly and virus titres were not significantly lower. T h e greater severity of mucocutaneous varicella-zoster infections in immunocompromised patients may lead to increased absorption .of drugs applied topically. This may be why Levin et al. x4 demonstrated significant benefit whereas in this trial none was observed. T h e median time to full crusting in the current trial was very short, thereby suggesting that the infections may have been milder than in the study of oral acyclovir which
Acyclovir cream for treating herpes zoster
63
showed efficacy. 13 If m o r e severe infections were to be studied, benefit from acyclovir cream might be shown. It is m o r e likely, however, that systemic administration of acyclovir would be preferred. ( D r A. M . G i l b e r t a n d M r D . A. J o n e s , W e l l c o m e R e s e a r c h L a b o r a t o r i e s , B e c k e n h a m , K e n t , U . K . c o l l a b o r a t e d in t h i s s t u d y . )
References
I. Bean B, Braun C, Bfilfour H H . Acyclovir therapy for acute herpes zoster. Lancet I982; i i : 118--121.
z. McGill JI, Hiscott C, Worstman T , Larkin M. T h e use of acyclovir in the treatment of herpes zoster ocular infections. In Sundmache R, ed. Herpetische Augener Warlungen. Munich: J F Bergmann, I 9 8 I : 461-464. 3- McGill JI, MacDonald R, Fall C, McKendrick G D W . Intravenous acyclovir in acute herpes zoster infection. J Infect I983: 6: I 5 7 - I 6 I . 4. Peterslund NA, Seyer-Hansen U, Ipsen J, Esmann V, Schonheyder H, Juhl H. Acyclovir in herpes zoster. Lancet I98I ; ii: 827-83o. 5- Corey L, Nahmias AJ, Guinan ME, Benedetti JK, Critchlow CW, Holmes K K . A trial of topical acyclovir in genital herpes simplex virus infections. New Engl J Med I983 ; 3o6: I x 6--I 19.
6. Thin RN, Nabarro JM, Davidson Parker J, Fiddian AP. Topical acyclovir in the treatment of initial genital herpes. Br J Vener Dis I983 ; 59 : I i 6 - i I9. 7. Corey L, Beneditti JK, Critchlow C W et al. Double-blind controlled trial of topical acyclovir in genital herpes simplex virus infections. A m J Med I93 ; 73 (IA): 326-334. 8. Reichman RC, Badger GJ, Guinan M E et al. Topically administered acyclovir in the treatment of recurrent herpes simplex genitalis. A controlled trial. J Infect Dis I983 ; I47: 366-340. 9. L u b y JP, Gnann JW, Alexander WJ et al. A collaborative study of patient initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J Infect Dis I984; I50 : I-6.
io. Collins P, Oliver N M . Acyclovir treatment of cutaneous herpes in guinea-pigs and herpes encephalitis in mice. A m J Med I982 ; 73 (IA): 96-99. 1 I. K i n g h o m GR, T u r n e r EB, Barton I G , Potter CW, Burke CA, Fiddian AP. Efficacy of topical acyclovir cream in first and recurrent episodes of genital herpes. Antiviral Res I983 ; 3 : 29I-3OI-
I2. Fiddian AP, K i n g h o m GR, Goldmeier D et al. Topical acyclovir in the treatment of genital herpes; a comparison with systemic therapy. J Antimicrob Chemother 1983; IZ (Suppl B): 67-77. I3. McKendrick M W , McGill JI, White JE, Wood MJ. Oral acyclovir in acute herpes zoster. Br M e d J I986; z93: I529-I532. I4. Levin MJ, Zaiai JA, Hershey et al. Topical acyclovir treatment of herpes zoster in immunocompromised patients. J A m Acad Dermatol I985; I3: 590-596.