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High-dose intravenous acyclovir in the treatment of zoster: A double-blind, placebo-controlled trial
Journal of Infection (I983) 6, Supplement I, 31-36
H i g h - d o s e i n t r a v e n o u s acyclovir in the t r e a t m e n t o f zoster: a d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d trial B. E. J u e l - J e n s e n , J. A. K h a n a n d G. P a s v o l
Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford Summary In a randomised, double-blind, controlled trial, 40 patients with zoster of short duration (rash present for less than three days) were given either Io mg/kg acyclovir (2o) or placebo (2o) intravenously three times daily for five days. Pain was reduced in the treatment group both in the acute phase and at follow-up, when compared with the placebo group, but this difference did not reach statistically significant levels. Healing of the lesions was also better, but not significantly so, in the acyclovir group. No complications of the disease were seen in the six cases of ophthalmic zoster given acyclovir whereas, of the four cases in the placebo group, two developed seventh cranial nerve palsies and one secondary glaucoma. No evidence of renal or other major toxicity was detected in the acyclovir group, although three patients developed mild thrombophlebitis. We conclude that acyclovir, given by the route and in the dose and frequency as used in this study, is free from major side effects, but is only of marginal benefit in the treatment of zoster. Introduction Shingles is a c o m m o n and often distressing condition, particularly when it causes incapacitating pain which may last for years. In the specific treatment of zoster, topical idoxuridine (4o per cent) in dimethyl sulphoxide has proved effective. 1 H o w e v e r , topical therapy has limitations, since it cannot be used in motor, or sensory zoster in which m u c o c u t a n e o u s areas such as the m o u t h , bladder, vagina and anorectal regions are involved. M o r e o v e r , it has the theoretical disadvantage that it cannot halt replication of the virus in deep seated structures. Systemic cytarabine is effective, is easily soluble, b u t has unpleasant toxic side effects. ~ Vidarabine is effective in i m m u n o c o m p r o m i s e d patientsfl b u t is relatively insoluble. Acyclovir, which was claimed to have few side effects and i m p r o v e d solubility, seemed a promising drug for systemic use in zoster. Acyclovir m u s t be p h o s p h o r y l a t e d to have antiviral activity. Although acyclovir in vitro is an excellent substrate for the thymidine kinase ( T K ) specified b y herpes simplex virus ( H S V ) I and II, it is only poorly phosphorylated b y mammalian isoenzymes. T h e T K s of varicella zoster virus (VZ) unfortunately, have less avidity for acyclovir than that of H S V . Values in vitro for the 5o per cent inhibitory concentration were o.I #M for H S V I and approximately 3 #M for VZ. ~ Acyclovir has shown great promise in h u m a n H S V infections at a dose of 5 m g / k g eight hourly. 4 W e therefore carried out a randomised placebo-controlled, d o u b l e - b l i n d trial of intravenous acyclovir in zoster using the relatively high dose of IO m g / k g eight hourly. Requests for reprints to B. E. Juel-Jensen.
~I63-4453/83/o3 IO31 ~-06 $02.00/0
© I983 The British Society for the Study of Infection 3-z
32
B.E. JUEL-JENSEN,
J. A. K H A N A N D G. P A S V O L
Patients and methods
F o r t y subjects over the age of 18 with a clinical diagnosis of uncomplicated segmental zoster were entered into the trial and admitted to the infectious disease ward at the Slade Hospital, Oxford. T h e following exclusions were m a d e : patients presenting 72 hours or more after the onset of the rash, patients w h o had received specific recent antiviral therapy, patients with a history of renal insufficiency, and w o m e n of child-bearing age. After giving informed consent, patients received acyclovir IO m g / k g or placebo (dextrose). D r u g or placebo were infused in a 0"5 per cent ( w / v ) solution of normal saline eight hourly for five days. Preliminary pharmacokinetic studies which we had c o n d u c t e d had shown a rise in urea and creatinine when the drug was given as a bolus. Because of potential nephrotoxicity, possibly due to crystalluria,~the drug was given by infusion over the period of an hour. Patients were assessed during their stay in hospital, at an outpatient visit a b o u t two weeks after admission and by post, a b o u t three to five months later. Pain, analgesia requirement, t e m p e r a t u r e and skin lesions were assessed daily; the n u m b e r o f days for crusting to appear, for vesicles to disappear, and whether there was local or distant extension was recorded. R o u t i n e tests for marrow, renal and liver functions were taken on admission and on day three, on discharge and at follow-up outpatient visits. T h e diagnosis o f zoster was confirmed by electron microscopy of vesicle fluid a n d / o r culture of vesicle fluid on fibroblasts, a n d / o r by a rise in complement fixation titre ( C F T ) to VZ in sera taken before treatment and at follow-up. At three to five m o n t h s after discharge all patients were contacted by post. T h e y were asked w h e t h e r they still had pain related to their shingles, and if so, whether analgesics were required. Patients were also requested to rate the discomfort suffered on a nuisance scale from o - I o o . Statistical comparisons b e t w e e n the drug and placebo groups with respect to pain were made using Fisher's exact test (two-tailed). T h e n u m b e r of days during the patients' stay in hospital on which analgesics were taken were compared by Student's t-test. Results
T h e admission characteristics of the 40 patients entered are shown in T a b l e I. T h e two groups were mostly comparable except that the acyclovir group did appear to be at a slightly earlier stage of development of the disease as shown by the stage and extent of the lesions and presence of satellite lesions. Pain, which we consider to be most relevant in such a study rather than the healing of the skin lesions, was favourably b u t not significantly influenced b y the d r u g ( T a b l e II). T h u s , the n u m b e r of days on which analgesia was required, increasing or moderate or severe pain whilst in hospital, moderate or severe pain at the completion of treatment, or pain at the time of the follow-up letter (to which all 4o patients replied), were all marginally in favour o f the drug. H o w e v e r , of those whose discomfort at the time of the follow-up was noticeable (nuisance value > IO), eight were in the placebo group, whilst three had received the drug. Quite noticeable in our patient group was the fact that
Acyclovir in treatment of zoster
33
T a b l e I Admission characteristics of patients with zoster treated with acyclovir or placebo Characteristic
Acyclovir g r o u p
Placebo g r o u p
No. of p a t i e n t s Men Women M e a n age (yr) (range) M e a n d u r a t i o n of pain in days (range) M e a n d u r a t i o n of r a s h in days Localisation Trigeminal
20 9
20 9
Cervical Thoracic Lumbosacral Severity of pain None Mild Moderate Severe Stage o f lesion MP* MPV MPVC E x t e n t of lesions Scanty ( < IO vesicles) P r o f u s e ( > IO vesicles) Semi-confluent Satellite lesions None Present T e m p e r a t u r e (mean) °C
I I
I I
63 (23-84) 3"2 (0---I0) 2.2
65 (28-87) 4"3 (I--I0) 2. 4
6 (all o p h t h a l m i c ) I 6 7
5 (all except one o p h t h a l m i c ) 3 9 3
4 4 6 6
o 5 7 8
Io 9 I
3 II 6
6 8 6
2 II 7
17 3 37"1
13 7 37'2
'~ M = macules, P = papules, V = vesicles, C = crusts.
of the 27 patients with moderate or severe pain on admission, only I3 had taken analgesics. Similarly, of the eleven patients with noticeable discomfort at follow-up, only four were using analgesics either occasionally or on a regular basis, two of these were in the drug group and two in the placebo group. T h e results of the evaluation of the healing of the skin lesions are shown in T a b l e I I I . All patients in the placebo group developed vesicles whereas, in four patients on acyclovir, the lesions regressed w i t h o u t vesicle formation. (In these cases the diagnosis was m a d e clinically and by means of at least a fourfold rise in C F T to VZ.) A further three patients in the acyclovir group w h o developed vesicles failed to develop crusts. At least a fourfold rise in titre to the varicella zoster virus was seen in 18 patients in each of the acyclovir and placebo groups (Table III). In assessing complications of the drug, the only side effects were n a u s e a / vomiting in one patient on acyclovir, in none on placebo, and thrombophlebitis seen in three cases receiving the drug and in one on placebo. O n e patient on acyclovir had a creatinine of I73 #mol/1 on admission; no rise was recorded
34
B.E. JUEL-JENSEN,
J. A. K H A N
A N D G. P A S V O L
Occurrence and severity of pain in patients with zoster treated with acyclovir or placebo
Table II
Characteristic Mean stay in hospital (days) No. of days of analgesia in hospital (mean + standard error) Pain increasing or remaining moderate or severe whilst in hospital Moderate or severe pain at completion of treatment Pain at time of follow-up letter (mean time in months after discharge) Nuisance value > io at time of follow-up letter
Acyclovir group
Placebo group*
6'5 3'3 +0-52
6'4 4"3 + 0"54
2
5
3
6
8 (4'8) 3
Io (4"9) 8
* Statistical comparisons as in methods section: except for no. of days of analgesia in hospital o'o5 < P < o.I, other P-values all > o'I.
Other characteristics of patients with zoster during and after treatment with acyclovir or placebo
Table I I I
Characteristic Skin lesions Vesicles absent By day 3 By discharge After discharge Regression (i.e. no vesicles at all)* Crusting present By day 3 By discharge After discharge Regression (i.e. no crusts at all)t Highest temperature (mean) Highest ESR m m / i s t hour (mean) Greater than fourfold rise in VZ C F T titre Complications of therapy Thrombophlebitis Urea > 9 #mol/l Creatinine > 200 #tool/1 Nausea/vomiting Complications of disease VIIth nerve palsy (ophthalmic cases) Secondary glaucoma * P > o'I (Fisher's exact test). t P < o.I but > 0"05 (Fisher's exact test).
Acyclovir group
Placebo group
I 5 IO 4
o I3 7 o
5 5 3 7
8 7 3 2
37"I9 23 18
37'42 23 18
3 2 o
r o o
I
0
0(6)
2(4)
o
i
Acyclovir in treatment of zoster
35
on treatment or follow-up. In none of the other patients receiving acyclovir did the creatinine rise above I5o #mol/1. Perhaps more remarkable in the assessment of the complications of the disease was the fact that none of the six patients with ophthalmic zoster and on acyclovir developed complications, whereas of the four with ophthalmic zoster on placebo two developed a seventh cranial nerve palsy and one secondary glaucoma. Discussion
T h e efficacy of acyclovir in the treatment of HSV infections has been well documented in double-blind, placebo-controlled trials, for instance in HSV infection of the cornea5 and in the prophylaxis of HSV infection in bone-marrow transplant recipients. 6 Although less sensitive to acyclovir than HSV, VZ was the next logical candidate for antiviral chemotherapy. T h e results of two such double-blind studies in acute zoster have already been published. 7, 8 Both these studies showed a significantly improved rate of healing of the skin lesions and relief of pain in the acute phase of the disease but were unable to demonstrate any beneficial effect on postherpetic neuralgia, which is after all, the main reason for giving a systemic drug in this condition. T h e skin lesions and acute pain of uncomplicated herpes zoster can be quite successfully managed with topical 4o per cent idoxuridine in dimethyl sulphoxide and analgesics, with a significant effect on postherpetic neuralgia. 1 In our present study the effect on pain at long-term follow-up was in favour of the drug but this was not statistically significant. It is possible that much larger numbers of participating patients might have shown a clear difference, but if large numbers are needed the effect of the drug can only be marginal. No significant effects on the healing of skin lesions or acute pain were found in the present trial. In the Aarhus study 7 the lower dose of 5 m g / k g eight hourly was used and no toxic effects of the drug on kidney, liver and haemopoietic function were noted. T h e Minnesota trial 8 used a dose of 5oo m g / m 2 and noted a raised serum creatinine ( > I . o m g / d l (9 r #mol/l) for females and > 1.3 m g / d l ( i i 8 #mol/1) for males with a rise of at least 25 per cent above pretreatment levels) in I I / I 9 recipients of acyclovir. Nausea or vomiting was observed in i o / i I recipients with raised creatinine levels and in three other acyclovir recipients without raised creatinine levels. In our study using comparable dosages, no nephrotoxicity as defined by our criteria (creatinine > 15o #mol/1, or if > I5o #mol/1 a rise of > 25 per cent) was noted. T h u s our study is able to demonstrate the safety of acyclovir at this comparatively high dose but showed only a marginal effect on pain, the most dreaded of the sequelae of uncomplicated segmental zoster. It is possible that the drug was given for an insufficient period. Seventeen of the 4o patients, including Io from the acyclovir group, still had vesicles at the time of discharge. Moreover, the Minnesota study 8documented a recurrence of pain after the cessation of acyclovir. Although the numbers were small, the freedom of complications in our patients with ophthalmic zoster who received active treatment might justify a specific trial of this variant of zoster with its particularly unpleasant complications.
36
B. E. JUEL-JENSEN~ J. A. KHAN AND G. PASVOL
For practical purposes in the outpatient treatment of uncomplicated herpes zoster, acyclovir m u s t obviously be given by the oral r o u t e in doses sufficient to give c o n t i n u o u s l y adequat e blood levels, possibly for a peri od longer t han the five days used in our study. T r i a l s need to be designed so that the p r o j e c t e d n u m b e r o f patients with p o s t h e r p e t i c neuralgia are sufficient to enable assessment o f the value o f such t r e a t m ent . W e h o p e that the e m e r g e n c e o f T K deficient strains of the virus will n o t b e c o m e a p r o b l e m in varicella-zoster infections as has been t he case in infections with H S V . 9 A l t h o u g h n o t clearly showing the benefit o f acyclovir in zoster, our st udy has d e m o n s t r a t e d the f r e e d o m f r o m toxicity o f the d r u g at the relatively high dose o f IO m g / k g given e i g h t - h o u r l y intravenously. T h i s s t u d y t h e r e f o r e provides a logical step in p r o c e e d i n g to the trial o f acyclovir given by m o u t h in an ad eq u at e dose, possibly for the d u r a t i o n o f ten days. (We are grateful to Dr Donald McKendrick of the Wellcome Research Laboratories for providing the drug and placebo and to Dr John Kurtz and Mr Ivor Chinn, of the Virology Laboratory, John Radcliffe Hospital, Oxford, for doing the virological investigations.) References
I. Juel-Jensen BE, MacCallum FO, Mackenzie AMR, Pike MC. Treatment of zoster with idoxuridine in dimethyl sulphoxide. Results of two double-blind controlled trials. Br Med J 197o; iv: 776-780. 2. Simpson G L A comparison of antiviral compounds in the treatment of herpes zoster infection. MSc Thesis, University of Oxford. June I977. 3. Whitley RJ, Soong SJ, Dolin R, et al. (I981) quoted by Dolin R, Reichman RC. Adenine Arabinoside (ara-A) therapy of herpes virus infections in humans. In: Shiota H, Cheng Y-C, Prusoff WH, eds. Herpesvirus clinical, pharmacological and basic aspects. Excerpta Medica. Amsterdam, Oxford, Princeton 1982; I31-132. 4. Elion GB. Mechanism of action, pharmacology and clinical efficacyof acyclovir. In: Shiota H, Cheng Y-C, Prusoff WH, eds. Herpesvirus clinical, pharmacological and basic aspects. Excerpta Medica. Amsterdam, Oxford, Princeton I982; 229-235. 5. Jones BR, Coster DJ, Fison PN, et al. Efficacyof acycloguanosine (Wellcome 248V) against herpes simplex corneal ulcers. Lancet 1979; i: 243-244. 6. Saral R, Burns W, Laskin O, et al. Acyclovir prophylaxis of herpes simplex virus infections. A randomized, double-blind, controlled trial in bone-marrow transplant recipients. New E n g l J Med I98I; 3o5: 63-67. 7- Peterslund NA, Seyer-Hansen K, Ipsen J, et al. Acyclovir in herpes zoster. Lancet I98I ; ii : 827-830. 8. Bean B, Braun C, Balfour HH. Acyclovir therapy for acute herpes zoster. Lancet 1982; ii: II8. 9. Field HI, Wildy P. Clinical resistance of herpes simplex virus to acyclovir. Lancet 1982; i: 1125.
H i g h - d o s e i n t r a v e n o u s acyclovir in the t r e a t m e n t o f zoster: a d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d trial B. E. J u e l - J e n s e n , J. A. K h a n a n d G. P a s v o l
Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford Summary In a randomised, double-blind, controlled trial, 40 patients with zoster of short duration (rash present for less than three days) were given either Io mg/kg acyclovir (2o) or placebo (2o) intravenously three times daily for five days. Pain was reduced in the treatment group both in the acute phase and at follow-up, when compared with the placebo group, but this difference did not reach statistically significant levels. Healing of the lesions was also better, but not significantly so, in the acyclovir group. No complications of the disease were seen in the six cases of ophthalmic zoster given acyclovir whereas, of the four cases in the placebo group, two developed seventh cranial nerve palsies and one secondary glaucoma. No evidence of renal or other major toxicity was detected in the acyclovir group, although three patients developed mild thrombophlebitis. We conclude that acyclovir, given by the route and in the dose and frequency as used in this study, is free from major side effects, but is only of marginal benefit in the treatment of zoster. Introduction Shingles is a c o m m o n and often distressing condition, particularly when it causes incapacitating pain which may last for years. In the specific treatment of zoster, topical idoxuridine (4o per cent) in dimethyl sulphoxide has proved effective. 1 H o w e v e r , topical therapy has limitations, since it cannot be used in motor, or sensory zoster in which m u c o c u t a n e o u s areas such as the m o u t h , bladder, vagina and anorectal regions are involved. M o r e o v e r , it has the theoretical disadvantage that it cannot halt replication of the virus in deep seated structures. Systemic cytarabine is effective, is easily soluble, b u t has unpleasant toxic side effects. ~ Vidarabine is effective in i m m u n o c o m p r o m i s e d patientsfl b u t is relatively insoluble. Acyclovir, which was claimed to have few side effects and i m p r o v e d solubility, seemed a promising drug for systemic use in zoster. Acyclovir m u s t be p h o s p h o r y l a t e d to have antiviral activity. Although acyclovir in vitro is an excellent substrate for the thymidine kinase ( T K ) specified b y herpes simplex virus ( H S V ) I and II, it is only poorly phosphorylated b y mammalian isoenzymes. T h e T K s of varicella zoster virus (VZ) unfortunately, have less avidity for acyclovir than that of H S V . Values in vitro for the 5o per cent inhibitory concentration were o.I #M for H S V I and approximately 3 #M for VZ. ~ Acyclovir has shown great promise in h u m a n H S V infections at a dose of 5 m g / k g eight hourly. 4 W e therefore carried out a randomised placebo-controlled, d o u b l e - b l i n d trial of intravenous acyclovir in zoster using the relatively high dose of IO m g / k g eight hourly. Requests for reprints to B. E. Juel-Jensen.
~I63-4453/83/o3 IO31 ~-06 $02.00/0
© I983 The British Society for the Study of Infection 3-z
32
B.E. JUEL-JENSEN,
J. A. K H A N A N D G. P A S V O L
Patients and methods
F o r t y subjects over the age of 18 with a clinical diagnosis of uncomplicated segmental zoster were entered into the trial and admitted to the infectious disease ward at the Slade Hospital, Oxford. T h e following exclusions were m a d e : patients presenting 72 hours or more after the onset of the rash, patients w h o had received specific recent antiviral therapy, patients with a history of renal insufficiency, and w o m e n of child-bearing age. After giving informed consent, patients received acyclovir IO m g / k g or placebo (dextrose). D r u g or placebo were infused in a 0"5 per cent ( w / v ) solution of normal saline eight hourly for five days. Preliminary pharmacokinetic studies which we had c o n d u c t e d had shown a rise in urea and creatinine when the drug was given as a bolus. Because of potential nephrotoxicity, possibly due to crystalluria,~the drug was given by infusion over the period of an hour. Patients were assessed during their stay in hospital, at an outpatient visit a b o u t two weeks after admission and by post, a b o u t three to five months later. Pain, analgesia requirement, t e m p e r a t u r e and skin lesions were assessed daily; the n u m b e r o f days for crusting to appear, for vesicles to disappear, and whether there was local or distant extension was recorded. R o u t i n e tests for marrow, renal and liver functions were taken on admission and on day three, on discharge and at follow-up outpatient visits. T h e diagnosis o f zoster was confirmed by electron microscopy of vesicle fluid a n d / o r culture of vesicle fluid on fibroblasts, a n d / o r by a rise in complement fixation titre ( C F T ) to VZ in sera taken before treatment and at follow-up. At three to five m o n t h s after discharge all patients were contacted by post. T h e y were asked w h e t h e r they still had pain related to their shingles, and if so, whether analgesics were required. Patients were also requested to rate the discomfort suffered on a nuisance scale from o - I o o . Statistical comparisons b e t w e e n the drug and placebo groups with respect to pain were made using Fisher's exact test (two-tailed). T h e n u m b e r of days during the patients' stay in hospital on which analgesics were taken were compared by Student's t-test. Results
T h e admission characteristics of the 40 patients entered are shown in T a b l e I. T h e two groups were mostly comparable except that the acyclovir group did appear to be at a slightly earlier stage of development of the disease as shown by the stage and extent of the lesions and presence of satellite lesions. Pain, which we consider to be most relevant in such a study rather than the healing of the skin lesions, was favourably b u t not significantly influenced b y the d r u g ( T a b l e II). T h u s , the n u m b e r of days on which analgesia was required, increasing or moderate or severe pain whilst in hospital, moderate or severe pain at the completion of treatment, or pain at the time of the follow-up letter (to which all 4o patients replied), were all marginally in favour o f the drug. H o w e v e r , of those whose discomfort at the time of the follow-up was noticeable (nuisance value > IO), eight were in the placebo group, whilst three had received the drug. Quite noticeable in our patient group was the fact that
Acyclovir in treatment of zoster
33
T a b l e I Admission characteristics of patients with zoster treated with acyclovir or placebo Characteristic
Acyclovir g r o u p
Placebo g r o u p
No. of p a t i e n t s Men Women M e a n age (yr) (range) M e a n d u r a t i o n of pain in days (range) M e a n d u r a t i o n of r a s h in days Localisation Trigeminal
20 9
20 9
Cervical Thoracic Lumbosacral Severity of pain None Mild Moderate Severe Stage o f lesion MP* MPV MPVC E x t e n t of lesions Scanty ( < IO vesicles) P r o f u s e ( > IO vesicles) Semi-confluent Satellite lesions None Present T e m p e r a t u r e (mean) °C
I I
I I
63 (23-84) 3"2 (0---I0) 2.2
65 (28-87) 4"3 (I--I0) 2. 4
6 (all o p h t h a l m i c ) I 6 7
5 (all except one o p h t h a l m i c ) 3 9 3
4 4 6 6
o 5 7 8
Io 9 I
3 II 6
6 8 6
2 II 7
17 3 37"1
13 7 37'2
'~ M = macules, P = papules, V = vesicles, C = crusts.
of the 27 patients with moderate or severe pain on admission, only I3 had taken analgesics. Similarly, of the eleven patients with noticeable discomfort at follow-up, only four were using analgesics either occasionally or on a regular basis, two of these were in the drug group and two in the placebo group. T h e results of the evaluation of the healing of the skin lesions are shown in T a b l e I I I . All patients in the placebo group developed vesicles whereas, in four patients on acyclovir, the lesions regressed w i t h o u t vesicle formation. (In these cases the diagnosis was m a d e clinically and by means of at least a fourfold rise in C F T to VZ.) A further three patients in the acyclovir group w h o developed vesicles failed to develop crusts. At least a fourfold rise in titre to the varicella zoster virus was seen in 18 patients in each of the acyclovir and placebo groups (Table III). In assessing complications of the drug, the only side effects were n a u s e a / vomiting in one patient on acyclovir, in none on placebo, and thrombophlebitis seen in three cases receiving the drug and in one on placebo. O n e patient on acyclovir had a creatinine of I73 #mol/1 on admission; no rise was recorded
34
B.E. JUEL-JENSEN,
J. A. K H A N
A N D G. P A S V O L
Occurrence and severity of pain in patients with zoster treated with acyclovir or placebo
Table II
Characteristic Mean stay in hospital (days) No. of days of analgesia in hospital (mean + standard error) Pain increasing or remaining moderate or severe whilst in hospital Moderate or severe pain at completion of treatment Pain at time of follow-up letter (mean time in months after discharge) Nuisance value > io at time of follow-up letter
Acyclovir group
Placebo group*
6'5 3'3 +0-52
6'4 4"3 + 0"54
2
5
3
6
8 (4'8) 3
Io (4"9) 8
* Statistical comparisons as in methods section: except for no. of days of analgesia in hospital o'o5 < P < o.I, other P-values all > o'I.
Other characteristics of patients with zoster during and after treatment with acyclovir or placebo
Table I I I
Characteristic Skin lesions Vesicles absent By day 3 By discharge After discharge Regression (i.e. no vesicles at all)* Crusting present By day 3 By discharge After discharge Regression (i.e. no crusts at all)t Highest temperature (mean) Highest ESR m m / i s t hour (mean) Greater than fourfold rise in VZ C F T titre Complications of therapy Thrombophlebitis Urea > 9 #mol/l Creatinine > 200 #tool/1 Nausea/vomiting Complications of disease VIIth nerve palsy (ophthalmic cases) Secondary glaucoma * P > o'I (Fisher's exact test). t P < o.I but > 0"05 (Fisher's exact test).
Acyclovir group
Placebo group
I 5 IO 4
o I3 7 o
5 5 3 7
8 7 3 2
37"I9 23 18
37'42 23 18
3 2 o
r o o
I
0
0(6)
2(4)
o
i
Acyclovir in treatment of zoster
35
on treatment or follow-up. In none of the other patients receiving acyclovir did the creatinine rise above I5o #mol/1. Perhaps more remarkable in the assessment of the complications of the disease was the fact that none of the six patients with ophthalmic zoster and on acyclovir developed complications, whereas of the four with ophthalmic zoster on placebo two developed a seventh cranial nerve palsy and one secondary glaucoma. Discussion
T h e efficacy of acyclovir in the treatment of HSV infections has been well documented in double-blind, placebo-controlled trials, for instance in HSV infection of the cornea5 and in the prophylaxis of HSV infection in bone-marrow transplant recipients. 6 Although less sensitive to acyclovir than HSV, VZ was the next logical candidate for antiviral chemotherapy. T h e results of two such double-blind studies in acute zoster have already been published. 7, 8 Both these studies showed a significantly improved rate of healing of the skin lesions and relief of pain in the acute phase of the disease but were unable to demonstrate any beneficial effect on postherpetic neuralgia, which is after all, the main reason for giving a systemic drug in this condition. T h e skin lesions and acute pain of uncomplicated herpes zoster can be quite successfully managed with topical 4o per cent idoxuridine in dimethyl sulphoxide and analgesics, with a significant effect on postherpetic neuralgia. 1 In our present study the effect on pain at long-term follow-up was in favour of the drug but this was not statistically significant. It is possible that much larger numbers of participating patients might have shown a clear difference, but if large numbers are needed the effect of the drug can only be marginal. No significant effects on the healing of skin lesions or acute pain were found in the present trial. In the Aarhus study 7 the lower dose of 5 m g / k g eight hourly was used and no toxic effects of the drug on kidney, liver and haemopoietic function were noted. T h e Minnesota trial 8 used a dose of 5oo m g / m 2 and noted a raised serum creatinine ( > I . o m g / d l (9 r #mol/l) for females and > 1.3 m g / d l ( i i 8 #mol/1) for males with a rise of at least 25 per cent above pretreatment levels) in I I / I 9 recipients of acyclovir. Nausea or vomiting was observed in i o / i I recipients with raised creatinine levels and in three other acyclovir recipients without raised creatinine levels. In our study using comparable dosages, no nephrotoxicity as defined by our criteria (creatinine > 15o #mol/1, or if > I5o #mol/1 a rise of > 25 per cent) was noted. T h u s our study is able to demonstrate the safety of acyclovir at this comparatively high dose but showed only a marginal effect on pain, the most dreaded of the sequelae of uncomplicated segmental zoster. It is possible that the drug was given for an insufficient period. Seventeen of the 4o patients, including Io from the acyclovir group, still had vesicles at the time of discharge. Moreover, the Minnesota study 8documented a recurrence of pain after the cessation of acyclovir. Although the numbers were small, the freedom of complications in our patients with ophthalmic zoster who received active treatment might justify a specific trial of this variant of zoster with its particularly unpleasant complications.
36
B. E. JUEL-JENSEN~ J. A. KHAN AND G. PASVOL
For practical purposes in the outpatient treatment of uncomplicated herpes zoster, acyclovir m u s t obviously be given by the oral r o u t e in doses sufficient to give c o n t i n u o u s l y adequat e blood levels, possibly for a peri od longer t han the five days used in our study. T r i a l s need to be designed so that the p r o j e c t e d n u m b e r o f patients with p o s t h e r p e t i c neuralgia are sufficient to enable assessment o f the value o f such t r e a t m ent . W e h o p e that the e m e r g e n c e o f T K deficient strains of the virus will n o t b e c o m e a p r o b l e m in varicella-zoster infections as has been t he case in infections with H S V . 9 A l t h o u g h n o t clearly showing the benefit o f acyclovir in zoster, our st udy has d e m o n s t r a t e d the f r e e d o m f r o m toxicity o f the d r u g at the relatively high dose o f IO m g / k g given e i g h t - h o u r l y intravenously. T h i s s t u d y t h e r e f o r e provides a logical step in p r o c e e d i n g to the trial o f acyclovir given by m o u t h in an ad eq u at e dose, possibly for the d u r a t i o n o f ten days. (We are grateful to Dr Donald McKendrick of the Wellcome Research Laboratories for providing the drug and placebo and to Dr John Kurtz and Mr Ivor Chinn, of the Virology Laboratory, John Radcliffe Hospital, Oxford, for doing the virological investigations.) References
I. Juel-Jensen BE, MacCallum FO, Mackenzie AMR, Pike MC. Treatment of zoster with idoxuridine in dimethyl sulphoxide. Results of two double-blind controlled trials. Br Med J 197o; iv: 776-780. 2. Simpson G L A comparison of antiviral compounds in the treatment of herpes zoster infection. MSc Thesis, University of Oxford. June I977. 3. Whitley RJ, Soong SJ, Dolin R, et al. (I981) quoted by Dolin R, Reichman RC. Adenine Arabinoside (ara-A) therapy of herpes virus infections in humans. In: Shiota H, Cheng Y-C, Prusoff WH, eds. Herpesvirus clinical, pharmacological and basic aspects. Excerpta Medica. Amsterdam, Oxford, Princeton 1982; I31-132. 4. Elion GB. Mechanism of action, pharmacology and clinical efficacyof acyclovir. In: Shiota H, Cheng Y-C, Prusoff WH, eds. Herpesvirus clinical, pharmacological and basic aspects. Excerpta Medica. Amsterdam, Oxford, Princeton I982; 229-235. 5. Jones BR, Coster DJ, Fison PN, et al. Efficacyof acycloguanosine (Wellcome 248V) against herpes simplex corneal ulcers. Lancet 1979; i: 243-244. 6. Saral R, Burns W, Laskin O, et al. Acyclovir prophylaxis of herpes simplex virus infections. A randomized, double-blind, controlled trial in bone-marrow transplant recipients. New E n g l J Med I98I; 3o5: 63-67. 7- Peterslund NA, Seyer-Hansen K, Ipsen J, et al. Acyclovir in herpes zoster. Lancet I98I ; ii : 827-830. 8. Bean B, Braun C, Balfour HH. Acyclovir therapy for acute herpes zoster. Lancet 1982; ii: II8. 9. Field HI, Wildy P. Clinical resistance of herpes simplex virus to acyclovir. Lancet 1982; i: 1125.