- Email: [email protected]
Acyclovir
p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 1 7 8 e1 8 0
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pid
Antimicrobials in Clinical Practice
Acyclovir Parang Mehta Consultant Pediatrician, Surat, Gujarat, India
article info
abstract
Article history:
Acyclovir is one of the oldest antiviral drugs, having been in use for three decades now. It is
Received 19 November 2013
an acyclic guanosine derivative and has activity mainly against herpes virus-1 (HSV-1),
Accepted 29 November 2013
herpes virus-2 (HSV-2), and varicella zoster virus (VZV). It is only weakly active against
Available online 15 December 2013
EpsteineBarr virus (EBV), cytomegalovirus (CMV), and human herpes virus-6 (HHV-6), and not used for these infections.
Keywords:
It acts by inhibition of viral DNA synthesis. Before it can act, it has to be phosphorylated
Acyclovir
by virus-specific thymidine kinase. This step gives it a high therapeutic index, but is also a
Herpes virus
major mechanism of viral resistance.
Guanosine derivative
Copyright ª 2013, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
1.
Pharmacokinetics
Oral absorption is about 20%, and is unaffected by food. This is considered adequate for the treatment of mild and non lifethreatening infections, but serious infections must be treated with intravenous acyclovir. The drug is distributed widely in the body. However, CSF concentration is less than half that of plasma and the brain concentration is probably lower. This is an important consideration when treating viral encephalitis. The drug is excreted unchanged through the kidneys, both by glomerular filtration and tubular secretion. The half life of acyclovir is 2.5e3 h.1 The half life increases in renal impairment.
2.
Uses
Acyclovir is most effective against herpes virus-1 and herpes virus-2. Action against the varicella zoster virus is weaker, but
adequate for clinical use. Against other DNA viruses, acyclovir shows weak in vitro activity, and cannot be used clinically.
3.
Herpes virus
An important use of acyclovir is in encephalitis caused by herpes simplex. This viral disease is rapidly progressive, is fatal in about 70% of untreated cases, and often leaves sequelae in survivors. Acyclovir, given intravenously, is the drug of choice. Early initiation is important; outcomes are poor if the drug is started after patients have slipped into coma. If diagnosis and initiation of acyclovir are swift, mortality can be reduced to less than 20%. Early therapy is especially important in neonates.2 Though acyclovir therapy reduces mortality, many of the survivors have neurological sequelae.3 Other herpes simplex infections also are treated with acyclovir. Skin infections with herpes simplex, including labial and genital herpes, are treated with topical acyclovir (cream).4 Oral acyclovir, if given for the first episode of genital
E-mail address: [email protected]. 2212-8328/$ e see front matter Copyright ª 2013, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved. http://dx.doi.org/10.1016/j.pid.2013.11.004
p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 1 7 8 e1 8 0
herpes, hastens healing and shortens viral shedding. People who have frequent recurrences of labial herpes benefit from long term oral acyclovir (6e12 months). It is effective in treating primary gingivostomatitis in children. Ocular keratitis caused by herpes simplex is treated with acyclovir ophthalmic ointment. However, herpetic keratoconjunctivitis in the newborn is treated with intravenous acyclovir. Similarly the skin lesions of neonatal herpes simplex infection are also treated with intravenous acyclovir, because dissemination and severe disease is likely. Some immunocompromised children are susceptible to severe herpes simplex infections. These children are given prophylactic oral acyclovir over prolonged periods. Resistance is a problem now, especially in children with AIDS. An alternative is foscarnet.
4.
Varicella zoster virus
The varicella zoster virus is also susceptible to acyclovir, and has been tried in chicken pox. If given to otherwise healthy children within 24 h after varicella occurs, it reduces duration of fever, number of skin lesions, and viral shedding by a small amount.5 The drug is not recommended for uncomplicated varicella in immunocompetent children. The drug is recommended in complicated varicella (pneumonia or hepatitis), in adolescents and adults (in whom varicella tends to be more severe), and in children with altered immunity. Immunodeficient children who develop varicella are at risk for severe disease. They should be evaluated swiftly and treated with acyclovir, which prevents the disease from disseminating.6 Neonatal varicella is a condition with a high probability of disseminated disease. Varicella pneumonia, hepatitis, and meningoencephalitis are often seen, and mortality is significant. The disease is treated with intravenous acyclovir for 7e10 days. Babies whose mother develops chicken pox around birth (5 days before to 2 days after) need to be protected against the development of neonatal varicella. The recommended agent is varicella zoster immune globulin (VZIG). Since it is rarely available, acyclovir is used as prophylaxis. If the mother develops varicella more than 5 days before delivery, the risk to the baby is small. Acyclovir is also recommended in shingles (herpes zoster). It is most effective if started within 48 h of the appearance of the rash. Children with altered immunity are likely to have more severe disease; intravenous administration may be needed. Acyclovir can reduce the intensity of acute pain, accelerate the healing of the vesicular rash, and reduce the duration of viral shedding.7,8 Acyclovir also reduces the incidence of post herpetic neuralgia.9 Children with immunodeficiency are usually not given live vaccines, since they may proliferate and cause severe disease. However, since the risks of wild varicella virus are greater, they may be given varicella vaccine. The vaccine virus is susceptible to acyclovir, which can be used if the vaccine induced disease becomes threatening10,11 Acyclovir is used to prevent varicella among contacts. If given after a history of contact, most children will develop no varicella, or mild varicella.12 Acyclovir is effective against primary as well as secondary viremia, and can prevent the
179
disease even if started several days after the contact. This is an important measure in children too young to receive the vaccine. Given the non-availability of varicella zoster immune globulin (VZIG), acyclovir as prophylaxis is important for older children also. Acyclovir is far more affordable than VZIG. Acyclovir is also used long term to prevent VZV infections in immunodeficient children, especially children on immunosuppressive therapy, after HCT, etc.13,14
5.
Other uses
Acyclovir is not useful in the treatment of cytomegalovirus or Ebstein Barr virus infections. It is used as prophylaxis in children with altered immunity and transplant recipients. It has protective efficacy against herpes simplex and VZV infections, but not against cytomegalovirus (CMV) infections.15,16
6.
Dose
The dose of acyclovir depends on what is being treated. Varicella zoster virus is less susceptible to the drug than Herpes simplex viruses and higher doses are sometimes used for the former. For neonatal herpes simplex disease, the dose is 60 mg/kg/ day in three divided intravenous doses. For skin, oral, or eye disease, 14 days is enough. For encephalitis and disseminated disease, 21 days is recommended. Infants, children, and adolescents who have herpes simplex encephalitis are treated with 30 mg/kg/day in three divided doses. For children with immunocompromise who develop varicella, the dose is 1500 mg/square meter body surface per day, in three divided doses, for 7e10 days. Children under one year of age should be given 30 mg/kg/day, in three divided doses.17 Newborns with varicella are treated with intravenous acyclovir 30e60 mg/kg/day in 3 divided doses for 10 days.
7.
Adverse effects
Acyclovir is generally a well tolerated drug. Common side effects are nausea, diarrhea, rash, and headache. Other neurologic toxicity includes tremors, delirium, and seizures. Renal side effects (crystalline nephropathy and interstitial nephropathy) mostly occur when rapid intravenous administration leads to high serum levels. These problems can be avoided by sufficient dilution, adequate hydration, and slow administration. Neurotoxicity is an important accompaniment of acyclovir therapy. It usually manifests as tremors, changes in consciousness, lethargy, confusion, hallucinations, myoclonus, seizures, and extrapyramidal signs. These signs and symptoms are reversible, and subside after cessation of therapy. High dose animal studies have not shown acyclovir to be teratogenic, mutagenic, or carcinogenic. However, safety for use during pregnancy in humans has not been proved.
180
8.
p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 1 7 8 e1 8 0
Drug interactions 6.
Coadministration of zidovudine leads to somnolence. Coadministration of cimetidine or probenecid reduces renal clearance of acyclovir. When coadministered with amphotericin B, the risk of nephrotoxicity is increased. The coadministration of other nephrotoxic drugs such as cyclosporine or amphotericin B increases the occurrence of renal toxicity of acyclovir.
7.
8.
9.
9.
Resistance
Viruses develop resistance through alteration of DNA polymerase or thymidine kinase enzymes. Acyclovir resistant viral infections are a particular problem in immunocompromised hosts, as they often take this drug over prolonged periods as prophylaxis. These infections can be treated with foscarnet, trifluridine, or cidofovir.
10.
11.
12.
Conflicts of interest The author has none to declare.
13.
references 14. 1. Tod M, Lokiec F, Bidault R, De Bony F, Petitjean Y. Aujard and the acyclovir pediatric French group. Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis. Antimicrobial Agents Chemother. 2001;45:150e157. 2. Shah Samir S, Aronson Paul L, Mohamad Zeinab, Lorch Scott A. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics. 2011;128:1153. 3. McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex encephalitis treated wit acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatr. 1997;63:321e326. 4. Spruance Spotswood L, Nett Robert, Marbury Thomas, Wolff Ray, Johnson James, Spaulding Theodore. Acyclovir cream for treatment of herpes simplex labialis: results of two vehicle-controlled, multicenter clinical randomized, doubleblind trials. Antimicrobial Agents Chemother. 2002;46:2238. 5. Klassen Terry P, Belseck Elaine M, Wiebe Natasha, Hartling Lisa. Acyclovir for treating varicella in otherwise
15.
16.
17.
healthy children and adolescents: a systematic review of randomised controlled trials. BMC Pediatr. 2002;2:9. Nyerges G, Meszner Z, Gyarmati E, Kerpel-Fronios S. Acyclovir prevents dissemination of varicella in immunocompromised children. J Infect Dis. 2013;208:309e313. Bruxelle J, Pinchinat S. Effectiveness of antiviral treatment on acute phase of herpes zoster and development of post herpetic neuralgia: review of international publications. Med Mal Infect. 2012;42:53e58. Wood MJ, Shukla S, Fiddian AP, Crooks RJ. Treatment of acute herpes zoster: effect of early (48 h) versus late (48e72 h) therapy with acyclovir and valaciclovir on prolonged pain. J Infect Dis. 1998;178:S81eS84. Wood MJ, Kay R, Dworkin RH, Soong S-J, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis. 1996;22:341e347. Gennery Andrew R, Finn Adam HR, Cant Andrew J. Primary and acquired immunodeficiency. In: Arceci Robert J, Hann Ian M, Smith Owen P, eds. Pediatric Hematology. 3rd ed. Blackwell Publishing Ltd; 2006:425e449. Patel Soonie R, Chisholm Julia C, Heath Paul T. Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am. 2008;55:169e186. Suga S, Yoshikawa T, Ozaki T, Asano Y. Effect of oral acyclovir against primary and secondary viraemia in incubation period of varicella. Arch Dis Child. 1993;69:639e643. Veronique Erard, Guthrie Katherine A, Varley Cara, et al. One-year acyclovir prophylaxis for preventing varicellazoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood. 2007;110:3071e3077. Boeckh Michael, Kim Hyung W, Flowers Mary ED, Meyers Joel D, Bowden Raleigh A. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantationda randomized double-blind placebocontrolled study. Blood. 2006;107:1800e1805. Kanda Y, Mineishi S, Saito T, et al. Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;28:689e692. Kletzmayr Josef, Kolzmann Harald, Popow-Kraupp Theresia, Kovarik Josef, Klauser Renate. Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (cmv) disease in cmv high-risk renal transplant recipients. J Am Soc Nephrol. 1996;7:325e330. Aygun Banu. Supportive care and management of oncologic emergencies. In: Philip Lanzkowsky, ed. Manual of Pediatric Hematology and Oncology. 4th ed. San Diego, USA: Elsevier Academic Press; 2005:716.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pid
Antimicrobials in Clinical Practice
Acyclovir Parang Mehta Consultant Pediatrician, Surat, Gujarat, India
article info
abstract
Article history:
Acyclovir is one of the oldest antiviral drugs, having been in use for three decades now. It is
Received 19 November 2013
an acyclic guanosine derivative and has activity mainly against herpes virus-1 (HSV-1),
Accepted 29 November 2013
herpes virus-2 (HSV-2), and varicella zoster virus (VZV). It is only weakly active against
Available online 15 December 2013
EpsteineBarr virus (EBV), cytomegalovirus (CMV), and human herpes virus-6 (HHV-6), and not used for these infections.
Keywords:
It acts by inhibition of viral DNA synthesis. Before it can act, it has to be phosphorylated
Acyclovir
by virus-specific thymidine kinase. This step gives it a high therapeutic index, but is also a
Herpes virus
major mechanism of viral resistance.
Guanosine derivative
Copyright ª 2013, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
1.
Pharmacokinetics
Oral absorption is about 20%, and is unaffected by food. This is considered adequate for the treatment of mild and non lifethreatening infections, but serious infections must be treated with intravenous acyclovir. The drug is distributed widely in the body. However, CSF concentration is less than half that of plasma and the brain concentration is probably lower. This is an important consideration when treating viral encephalitis. The drug is excreted unchanged through the kidneys, both by glomerular filtration and tubular secretion. The half life of acyclovir is 2.5e3 h.1 The half life increases in renal impairment.
2.
Uses
Acyclovir is most effective against herpes virus-1 and herpes virus-2. Action against the varicella zoster virus is weaker, but
adequate for clinical use. Against other DNA viruses, acyclovir shows weak in vitro activity, and cannot be used clinically.
3.
Herpes virus
An important use of acyclovir is in encephalitis caused by herpes simplex. This viral disease is rapidly progressive, is fatal in about 70% of untreated cases, and often leaves sequelae in survivors. Acyclovir, given intravenously, is the drug of choice. Early initiation is important; outcomes are poor if the drug is started after patients have slipped into coma. If diagnosis and initiation of acyclovir are swift, mortality can be reduced to less than 20%. Early therapy is especially important in neonates.2 Though acyclovir therapy reduces mortality, many of the survivors have neurological sequelae.3 Other herpes simplex infections also are treated with acyclovir. Skin infections with herpes simplex, including labial and genital herpes, are treated with topical acyclovir (cream).4 Oral acyclovir, if given for the first episode of genital
E-mail address: [email protected]. 2212-8328/$ e see front matter Copyright ª 2013, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved. http://dx.doi.org/10.1016/j.pid.2013.11.004
p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 1 7 8 e1 8 0
herpes, hastens healing and shortens viral shedding. People who have frequent recurrences of labial herpes benefit from long term oral acyclovir (6e12 months). It is effective in treating primary gingivostomatitis in children. Ocular keratitis caused by herpes simplex is treated with acyclovir ophthalmic ointment. However, herpetic keratoconjunctivitis in the newborn is treated with intravenous acyclovir. Similarly the skin lesions of neonatal herpes simplex infection are also treated with intravenous acyclovir, because dissemination and severe disease is likely. Some immunocompromised children are susceptible to severe herpes simplex infections. These children are given prophylactic oral acyclovir over prolonged periods. Resistance is a problem now, especially in children with AIDS. An alternative is foscarnet.
4.
Varicella zoster virus
The varicella zoster virus is also susceptible to acyclovir, and has been tried in chicken pox. If given to otherwise healthy children within 24 h after varicella occurs, it reduces duration of fever, number of skin lesions, and viral shedding by a small amount.5 The drug is not recommended for uncomplicated varicella in immunocompetent children. The drug is recommended in complicated varicella (pneumonia or hepatitis), in adolescents and adults (in whom varicella tends to be more severe), and in children with altered immunity. Immunodeficient children who develop varicella are at risk for severe disease. They should be evaluated swiftly and treated with acyclovir, which prevents the disease from disseminating.6 Neonatal varicella is a condition with a high probability of disseminated disease. Varicella pneumonia, hepatitis, and meningoencephalitis are often seen, and mortality is significant. The disease is treated with intravenous acyclovir for 7e10 days. Babies whose mother develops chicken pox around birth (5 days before to 2 days after) need to be protected against the development of neonatal varicella. The recommended agent is varicella zoster immune globulin (VZIG). Since it is rarely available, acyclovir is used as prophylaxis. If the mother develops varicella more than 5 days before delivery, the risk to the baby is small. Acyclovir is also recommended in shingles (herpes zoster). It is most effective if started within 48 h of the appearance of the rash. Children with altered immunity are likely to have more severe disease; intravenous administration may be needed. Acyclovir can reduce the intensity of acute pain, accelerate the healing of the vesicular rash, and reduce the duration of viral shedding.7,8 Acyclovir also reduces the incidence of post herpetic neuralgia.9 Children with immunodeficiency are usually not given live vaccines, since they may proliferate and cause severe disease. However, since the risks of wild varicella virus are greater, they may be given varicella vaccine. The vaccine virus is susceptible to acyclovir, which can be used if the vaccine induced disease becomes threatening10,11 Acyclovir is used to prevent varicella among contacts. If given after a history of contact, most children will develop no varicella, or mild varicella.12 Acyclovir is effective against primary as well as secondary viremia, and can prevent the
179
disease even if started several days after the contact. This is an important measure in children too young to receive the vaccine. Given the non-availability of varicella zoster immune globulin (VZIG), acyclovir as prophylaxis is important for older children also. Acyclovir is far more affordable than VZIG. Acyclovir is also used long term to prevent VZV infections in immunodeficient children, especially children on immunosuppressive therapy, after HCT, etc.13,14
5.
Other uses
Acyclovir is not useful in the treatment of cytomegalovirus or Ebstein Barr virus infections. It is used as prophylaxis in children with altered immunity and transplant recipients. It has protective efficacy against herpes simplex and VZV infections, but not against cytomegalovirus (CMV) infections.15,16
6.
Dose
The dose of acyclovir depends on what is being treated. Varicella zoster virus is less susceptible to the drug than Herpes simplex viruses and higher doses are sometimes used for the former. For neonatal herpes simplex disease, the dose is 60 mg/kg/ day in three divided intravenous doses. For skin, oral, or eye disease, 14 days is enough. For encephalitis and disseminated disease, 21 days is recommended. Infants, children, and adolescents who have herpes simplex encephalitis are treated with 30 mg/kg/day in three divided doses. For children with immunocompromise who develop varicella, the dose is 1500 mg/square meter body surface per day, in three divided doses, for 7e10 days. Children under one year of age should be given 30 mg/kg/day, in three divided doses.17 Newborns with varicella are treated with intravenous acyclovir 30e60 mg/kg/day in 3 divided doses for 10 days.
7.
Adverse effects
Acyclovir is generally a well tolerated drug. Common side effects are nausea, diarrhea, rash, and headache. Other neurologic toxicity includes tremors, delirium, and seizures. Renal side effects (crystalline nephropathy and interstitial nephropathy) mostly occur when rapid intravenous administration leads to high serum levels. These problems can be avoided by sufficient dilution, adequate hydration, and slow administration. Neurotoxicity is an important accompaniment of acyclovir therapy. It usually manifests as tremors, changes in consciousness, lethargy, confusion, hallucinations, myoclonus, seizures, and extrapyramidal signs. These signs and symptoms are reversible, and subside after cessation of therapy. High dose animal studies have not shown acyclovir to be teratogenic, mutagenic, or carcinogenic. However, safety for use during pregnancy in humans has not been proved.
180
8.
p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 1 7 8 e1 8 0
Drug interactions 6.
Coadministration of zidovudine leads to somnolence. Coadministration of cimetidine or probenecid reduces renal clearance of acyclovir. When coadministered with amphotericin B, the risk of nephrotoxicity is increased. The coadministration of other nephrotoxic drugs such as cyclosporine or amphotericin B increases the occurrence of renal toxicity of acyclovir.
7.
8.
9.
9.
Resistance
Viruses develop resistance through alteration of DNA polymerase or thymidine kinase enzymes. Acyclovir resistant viral infections are a particular problem in immunocompromised hosts, as they often take this drug over prolonged periods as prophylaxis. These infections can be treated with foscarnet, trifluridine, or cidofovir.
10.
11.
12.
Conflicts of interest The author has none to declare.
13.
references 14. 1. Tod M, Lokiec F, Bidault R, De Bony F, Petitjean Y. Aujard and the acyclovir pediatric French group. Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis. Antimicrobial Agents Chemother. 2001;45:150e157. 2. Shah Samir S, Aronson Paul L, Mohamad Zeinab, Lorch Scott A. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics. 2011;128:1153. 3. McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex encephalitis treated wit acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatr. 1997;63:321e326. 4. Spruance Spotswood L, Nett Robert, Marbury Thomas, Wolff Ray, Johnson James, Spaulding Theodore. Acyclovir cream for treatment of herpes simplex labialis: results of two vehicle-controlled, multicenter clinical randomized, doubleblind trials. Antimicrobial Agents Chemother. 2002;46:2238. 5. Klassen Terry P, Belseck Elaine M, Wiebe Natasha, Hartling Lisa. Acyclovir for treating varicella in otherwise
15.
16.
17.
healthy children and adolescents: a systematic review of randomised controlled trials. BMC Pediatr. 2002;2:9. Nyerges G, Meszner Z, Gyarmati E, Kerpel-Fronios S. Acyclovir prevents dissemination of varicella in immunocompromised children. J Infect Dis. 2013;208:309e313. Bruxelle J, Pinchinat S. Effectiveness of antiviral treatment on acute phase of herpes zoster and development of post herpetic neuralgia: review of international publications. Med Mal Infect. 2012;42:53e58. Wood MJ, Shukla S, Fiddian AP, Crooks RJ. Treatment of acute herpes zoster: effect of early (48 h) versus late (48e72 h) therapy with acyclovir and valaciclovir on prolonged pain. J Infect Dis. 1998;178:S81eS84. Wood MJ, Kay R, Dworkin RH, Soong S-J, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis. 1996;22:341e347. Gennery Andrew R, Finn Adam HR, Cant Andrew J. Primary and acquired immunodeficiency. In: Arceci Robert J, Hann Ian M, Smith Owen P, eds. Pediatric Hematology. 3rd ed. Blackwell Publishing Ltd; 2006:425e449. Patel Soonie R, Chisholm Julia C, Heath Paul T. Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am. 2008;55:169e186. Suga S, Yoshikawa T, Ozaki T, Asano Y. Effect of oral acyclovir against primary and secondary viraemia in incubation period of varicella. Arch Dis Child. 1993;69:639e643. Veronique Erard, Guthrie Katherine A, Varley Cara, et al. One-year acyclovir prophylaxis for preventing varicellazoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood. 2007;110:3071e3077. Boeckh Michael, Kim Hyung W, Flowers Mary ED, Meyers Joel D, Bowden Raleigh A. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantationda randomized double-blind placebocontrolled study. Blood. 2006;107:1800e1805. Kanda Y, Mineishi S, Saito T, et al. Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;28:689e692. Kletzmayr Josef, Kolzmann Harald, Popow-Kraupp Theresia, Kovarik Josef, Klauser Renate. Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (cmv) disease in cmv high-risk renal transplant recipients. J Am Soc Nephrol. 1996;7:325e330. Aygun Banu. Supportive care and management of oncologic emergencies. In: Philip Lanzkowsky, ed. Manual of Pediatric Hematology and Oncology. 4th ed. San Diego, USA: Elsevier Academic Press; 2005:716.