Acyclovir


Article Author:
Michael Taylor


Article Editor:
Valerie Gerriets


Editors In Chief:
Chaddie Doerr


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/20/2019 9:04:33 PM

Indications

Acyclovir is an agent used to treat infections caused by the herpes simplex virus (HSV). It is FDA approved to treat genital herpes and HSV encephalitis. Non-FDA approved indications are mucocutaneous HSV, herpes zoster (shingles), and varicella-zoster (chickenpox).[1][2] Acyclovir is the first-line treatment for HSV encephalitis. Currently, there are no other medications indicated for the treatment of this condition.[3]

Despite the long term use of acyclovir to treat HSV encephalitis, there has not been a systematic review regarding the efficacy of this disease/treatment combination. Current systematic reviews to address its safety and efficacy are currently ongoing, with the primary outcome being mortality rate. A secondary outcome measure is the quality of life.[4]

HSV keratitis has been shown to respond to oral acyclovir and topical steroids in pediatric patients.[5]

In patients with human immunodeficiency virus (HIV), acyclovir is sometimes used to treat eczema herpeticum. It is also used to prevent infections of the skin, eyes, nose, and mouth. Eczema herpeticum is rare but rapidly progressive if untreated. Those with extensive involvement, systemic symptoms, or decreased oral intake should undergo admission for intravenous acyclovir treatment.[6] Also, acyclovir treats oral hairy leukoplakia.[7][8]

Acyclovir has been proven useful in treating myelopathy secondary to varicella-zoster infection. In a small case series, researching patients from 1994 to 2014 with laboratory-confirmed varicella-zoster virus (VZV) and MRI confirmed myelopathy, marked improvement of symptoms was the outcome in most patients within 2 months.[9]

Brachial plexus neuritis secondary to VZV infection and visceral disseminated VZV infection (characteristic features are abdominal and absence of skin lesions) has also responded to acyclovir, alleviating all symptoms.[10]

In recipients of hematopoietic stem cell transplantation, herpes simplex virus and varicella-zoster reactivation may respond to treatment with acyclovir prophylaxis. Prophylactic use of acyclovir should be considered in HSV-1 and HSV-2-seropositive organ recipients as well.[11] Diseases from such viruses have decreased secondary to this intervention. However, a breakthrough infection may occur. Not surprisingly, HSV and VZV infection is not uncommon in patients that have discontinued acyclovir prophylaxis.[12]

Another form of prophylactic acyclovir use is juvenile-onset recurrent respiratory papillomatosis. In a prospective observational study involving 21 patients, oral acyclovir was a postoperative adjuvant. It was shown to decrease the recurrence of papillomas and thus decrease the need for successive surgeries and associated operative risks.[13]

VZV infections have many complications, including cerebellitis. Treating the source infection has been shown to decrease the complication burden as well. A 2019 case report, for instance, describes a patient presenting with truncal ataxia. After intravenous acyclovir treatment, the patient was free of neurologic disability and his cerebellitis. [14] Similarly, paresis secondary to dermatomal herpes zoster infections has been shown to respond to oral acyclovir; this is a rare complication of herpes zoster when the virus affects motor nerve fibers in addition to/instead of the dorsal root ganglion.[15]

Mechanism of Action

Acyclovir is an antiviral agent that incorporates itself into viral DNA. It inhibits DNA synthesis and viral replication after it is converted to acyclovir triphosphate by cellular enzymes. Acyclovir is a synthetic purine nucleoside analog that demonstrates in vitro and in vivo inhibitory activity against both herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus.[16]

Administration

Acyclovir administration may be oral or intravenous.

For limited mucocutaneous lesions, acyclovir administration can be via the oral route. In cases in which there is disseminated, visceral, or CNS involvement, the acyclovir administration should be intravenous.[11]

When taken orally, acyclovir may be taken with or without food 2 to 5 times a day for 5 to 10 days as well as up to 12 months to prevent outbreaks of genital herpes.

Intravenous administration should be done via IV infusion only, over 1 hour at a constant rate to prevent renal damage. Medication should be in a diluted D5W solution or 0.9% NaCl to a final concentration of less than or equal to 7 mg/mL.

Adverse Effects

Most commonly, patients experience malaise.

Less commonly, patients experience inflammation or phlebitis at the infusion site, nausea, vomiting, transaminitis, and rash (including Steven-Johnson syndrome) when taken intravenously. Rotating infusion sites and decreasing final infusion concentration less than 10 mg/mL can help prevent inflammation/phlebitis at the infusion site.[17][18]. Patients also may experience nausea, vomiting, diarrhea, headache when taken orally.

Least commonly, patients experience abdominal pain, aggression/confusion, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, disseminated intravascular coagulation (DIC), dizziness and fatigue.

In certain pediatric patients, acyclovir has been shown to decrease hemoglobin levels and the absolute neutrophil count.

Contraindications

The only absolute contraindication to acyclovir is hypersensitivity.

Cautions include renal failure/impairment, immunocompromised host, potential risk of thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS)).

Regarding pregnancy and lactation, acyclovir has been shown to cross the placenta. Acyclovir's manufacturer recommends caution with use during pregnancy as well as only using it when necessary and indicated, as there have only been a few studies conducted. Specifically, cases of HSV hepatitis have received treatment during pregnancy. Although rare, this condition can become disseminated and fatal in pregnant patients. Although all 56 patients studied had transaminitis, only 18.2% had a vesicular rash. For patients that were treated with acyclovir empirically, it conferred no risks to the fetus.[19] Acyclovir also has been shown to enter breast milk but is generally considered compatible with breastfeeding.[20] 

Monitoring

Patients should be monitored for adverse effects such as malaise, inflammation or phlebitis at infusion site, nausea, vomiting, rash (including Steven-Johnson syndrome), transaminitis, nausea, vomiting, diarrhea, headache, abdominal pain, aggression/confusion, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, disseminated intravascular coagulation (DIC), dizziness and fatigue.

Toxicity

Acute kidney injury (AKI) is the most significant side effect from parenteral acyclovir administration. The incidence of AKI is comparable to other nephrotoxic medications such as aminoglycosides. Patients with CKD are at higher risk. Dose adjustment of acyclovir for ideal body weight and baseline renal function is imperative.[21] A study regarding the pharmacokinetics of acyclovir demonstrated that a patient's glomerular filtration and tubular secretion contribute to its renal excretion.[22]

Also, a recent retrospective case-control study over four years showed a statistically significant association between obesity and nephrotoxicity (odds ratio 3.2, 95% CI 1.19 to 8.67). Similarly, and not surprisingly, researchers observed a similar association between those receiving concomitant vancomycin (odds ratio 4.73, 95% CI, 1.57 to 14.25). Appropriate cautions are necessary when administering intravenous acyclovir to such higher-risk patients.[23]

Enhancing Healthcare Team Outcomes

Administering intravenous acyclovir requires interdisciplinary effort and communication. It is not a benign drug, having potential side effects such as phlebitis, hypersensitivity, and AKI. Therefore, pharmacists, physicians, and nurses must work together to achieve adequate and non-toxic dosing. Physicians (MDs, DOs, NPs, PAs) will make the initial decision to use acyclovir. Dose adjustments for ideal body weight and baseline renal function are necessary, and the pharmacist should coordinate this with nursing for inpatients. Also, patients must undergo monitoring for signs/symptoms of hypersensitivity and phlebitis, specifically at the infusion site; this is where nursing will be best positioned to inform the rest of the healthcare team should there be any issues of concern. Interprofessional teamwork between each healthcare provider for a patient can help minimize and prevent the adverse effects of intravenous administration of acyclovir.[21] [Level V]


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Acyclovir - Questions

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A 41-year-old G5P4004 at 38 weeks, 0 days pregnant presents for late prenatal testing. She is found to have IgM positive antibodies for HSV-2. The patient desires to deliver vaginally. Which of the following statements is correct regarding the treatment of choice for this patient's condition?



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A 44-year-old female with no significant past medical history presents to the emergency department in status epilepticus. After being stabilized, a CT scan of the head is obtained showing temporal lobe encephalitis. Which of the following is true regarding the medication used to treat this condition?



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A 54-year-old female with a history of anxiety, depression, and hypertension presents to the emergency department in status epilepticus. After being stabilized, a CT scan of the head is obtained showing diffuse inflammation of the temporal lobe. The appropriate antiviral medication is started. For which condition is the oral form of this antiviral effective?



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A 32-year-old female with a history of hyperlipidemia and hypertension presents with a 6-month history of "bumps around my private parts." She says that she has noticed that she has low-grade fever and malaise before the "bumps" appear. On exam, there are several vesicular lesions on the vulva. Which enzyme is needed for the effectiveness of the treatment of choice?



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A 17-year-old female with no significant past medical history presents with a 6-month history of recurring "bumps around my vagina." She says that she has noticed that she has flu-like symptoms before the "bumps" appear. On exam, there are several vesicular lesions on the vulva. What is the appropriate treatment?



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A male with a history of asthma presents to his primary care provider for a two-day history of painful penile lesions. He has a history of unprotected sex. The physical exam is remarkable for multiple vesicular lesions on his penis. What should the patient be taught regarding the correct ointment needed for his condition?



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A 54-year-old female with no significant past medical history presents with a 6-month history of recurring "cold sores on my mouth." On exam, there are several vesicular lesions on her lips. A 5% concentration of the antiviral ointment is administered. Regarding this antiviral ointment, it is important to teach the patient which one of the following?



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A 28-year-old male presents to the emergency department with fever, neck pain and altered mental status. Lumbar puncture results are significant for leukocytosis with a lymphocytic predominance, above normal protein count, normal glucose level. Which of the following is the brand name for the appropriate intravenous medication for this condition?



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A 10-day old male presents to the emergency department with fever. Lumbar puncture results are significant for leukocytosis with a lymphocytic predominance, above normal protein count, and normal glucose level. The patient is started on the appropriate intravenous medication. Which of the following is a significant potential side effect of this medication?



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A 22-year-old female with a history of diabetes mellitus type 2, well controlled, presents with vaginal lesions that were preceded by a prodrome of chills and malaise. The patient claims only occasional condom use and four sexual partners in the past six months. The lesions are painful. On exam, the lesions appear vesicular, and there is no inguinal lymphadenopathy. She receives a prescription. In addition to her presenting condition, which condition is also treatable with the medication she received?



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Acyclovir - References

References

Ryan L,Heed A,Foster J,Valappil M,Schmid ML,Duncan CJA, Acute kidney injury (AKI) associated with intravenous aciclovir in adults: Incidence and risk factors in clinical practice. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2018 Sep;     [PubMed]
Ahronowitz I,Fox LP, Herpes zoster in hospitalized adults: Practice gaps, new evidence, and remaining questions. Journal of the American Academy of Dermatology. 2018 Jan;     [PubMed]
Ljubojevi? Had�avdi? S,Kova?evi? M,Skerlev M,Zekan �, Genital Herpes Zoster as Possible Indicator of HIV Infection. Acta dermatovenerologica Croatica : ADC. 2018 Dec;     [PubMed]
Le A,Patel S, Extravasation of Noncytotoxic Drugs: A Review of the Literature. The Annals of pharmacotherapy. 2014 Jul;     [PubMed]
Charlier C,Le Mercier D,Salomon LJ,Ville Y,Kermorvant-Duchemin E,Frange P,Postaire M,Lortholary O,Lecuit M,Leruez-Ville M, [Varicella-zoster virus and pregnancy]. Presse medicale (Paris, France : 1983). 2014 Jun;     [PubMed]
Gori N,Caldarola G,de Simone C,Moretta G,Peris K, Annular elastolytic giant cell granuloma following Herpes Zoster infection. Journal of the European Academy of Dermatology and Venereology : JEADV. 2019 Apr 13;     [PubMed]
Kukhanova MK,Korovina AN,Kochetkov SN, Human herpes simplex virus: life cycle and development of inhibitors. Biochemistry. Biokhimiia. 2014 Dec;     [PubMed]
Frimpong P,Amponsah EK,Abebrese J,Kim SM, Oral manifestations and their correlation to baseline CD4 count of HIV/AIDS patients in Ghana. Journal of the Korean Association of Oral and Maxillofacial Surgeons. 2017 Feb;     [PubMed]
Yorulmaz A,Sahin EB,Sener M,Kulcu Cakmak S, Acyclovir-induced bullous reaction in a patient with metastatic breast cancer. Cutaneous and ocular toxicology. 2017 Mar;     [PubMed]
Stahl JP,Mailles A, Herpes simplex virus encephalitis update. Current opinion in infectious diseases. 2019 Jun     [PubMed]
Wang W,Ji M, Efficacy of acyclovir for herpes simplex encephalitis: A protocol for a systematic review of randomized controlled trial. Medicine. 2019 Apr     [PubMed]
Bodack MI, Case Series: Pediatric Herpes Simplex Keratitis. Optometry and vision science : official publication of the American Academy of Optometry. 2019 Mar     [PubMed]
Ozcan A,Kahale K,Nguyen D, An 8-Month-Old Girl With Vesicular Rash. Global pediatric health. 2019     [PubMed]
Farhat N,Daoud S,Hdiji O,Sakka S,Damak M,Mhiri C, Myelopathy after zoster virus infection in immunocompetent patients: A case series. The journal of spinal cord medicine. 2019 Apr 23     [PubMed]
Lee S,Tsukasaki H,Yamauchi T, Visceral disseminated varicella zoster virus infection with brachial plexus neuritis detected by fluorodeoxyglucose positron emission tomography and computed tomography. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2019 Mar 14     [PubMed]
Lee DH,Zuckerman RA, Herpes simplex virus infections in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Mar 12     [PubMed]
Dadwal SS, Herpes Virus Infections Other than Cytomegalovirus in the Recipients of Hematopoietic Stem Cell Transplantation. Infectious disease clinics of North America. 2019 Jun     [PubMed]
Mitra S,Das A,Ghosh D,Sengupta A, Postoperative Systemic Acyclovir in Juvenile-Onset Recurrent Respiratory Papillomatosis: The Outcome. Ear, nose, & throat journal. 2019 Jan     [PubMed]
Cross CP,English SW,Krause MA,Zalewski NL, Acute truncal ataxia in a healthy adult with varicella zoster virus cerebellitis: A case report and literature review. Journal of the neurological sciences. 2019 May 15     [PubMed]
Yu YH,Lin Y,Sun PJ, Segmental zoster abdominal paresis mimicking an abdominal hernia: A case report and literature review. Medicine. 2019 Apr     [PubMed]
McCormack AL,Rabie N,Whittemore B,Murphy T,Sitler C,Magann E, HSV Hepatitis in Pregnancy: A Review of the Literature. Obstetrical & gynecological survey. 2019 Feb     [PubMed]
de Miranda P,Whitley RJ,Blum MR,Keeney RE,Barton N,Cocchetto DM,Good S,Hemstreet GP 3rd,Kirk LE,Page DA,Elion GB, Acyclovir kinetics after intravenous infusion. Clinical pharmacology and therapeutics. 1979 Dec     [PubMed]
Barber KE,Wagner JL,Stover KR, Impact of Obesity on Acyclovir-Induced Nephrotoxicity. Open forum infectious diseases. 2019 Apr     [PubMed]

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