Uses
IV acyclovir sodium is used for the treatment of initial and recurrent mucocutaneous herpes simplex virus (HSV-1 and HSV-2) infections and the treatment of varicella-zoster infections in immunocompromised adults and children; for the treatment of severe first episodes of genital herpes infections in immunocompetent individuals; and for the treatment of HSV encephalitis and neonatal HSV infections. Acyclovir is used orally for the treatment of initial and recurrent episodes of genital herpes; for the acute treatment of herpes zoster (shingles, zoster) in immunocompetent individuals; and for the treatment of varicella (chickenpox) in immunocompetent individuals.
For topical uses of acyclovir,
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Mucocutaneous, Ocular, and Systemic Herpes Simplex Virus (HSV) Infections
Acyclovir is considered the drug of choice for the treatment of mucocutaneous herpes simplex virus (HSV) infections in immunocompromised adults, adolescents, and children and also is considered the drug of choice for the treatment of severe HSV infections such as HSV encephalitis and neonatal HSV infections.
Controlled studies of initial and recurrent mucocutaneous HSV-1 and HSV-2 infections (e.g., orofacial, esophageal, genital, nasal, labial) in immunocompromised adults and children have shown that IV acyclovir therapy decreases the duration of viral shedding (time from onset of therapy until the last positive culture), the duration of pain and itching, the time required for crusting and healing of lesions, and the duration of positive cultures. In one study, the median duration of viral shedding was 3 days in acyclovir-treated patients compared with 17 days in placebo-treated patients; pain ceased within 10 days of initiating therapy in acyclovir-treated patients compared with 16 days in placebo-treated patients. The time required for crusting and healing of lesions was 7 and 14 days, respectively, in acyclovir-treated patients compared with 14 and 28 days, respectively, in placebo-treated patients. IV acyclovir was not effective in reducing the frequency or delaying the onset of subsequent recurrent infection with HSV-1, HSV-2, or other herpesviruses or in eliminating an established latent infection.
Acyclovir has been used for the treatment of orolabial HSV infections, including gingivostomatitis, in adults and children; the drug is not effective or is minimally effective for the prevention of recurrence of herpes labialis in immunocompetent individuals.
Oral or IV acyclovir has been reported to be effective in the treatment of eczema herpeticum caused by HSV in several patients with a history of atopic dermatitis; the drug decreased fever and/or the appearance of new lesions, and promoted crusting and healing of lesions.
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HIV-Infected Individuals
Acyclovir generally is considered the drug of choice for the treatment of primary or recurrent mucocutaneous HSV infections in individuals with human immunodeficiency virus (HIV) infection. Mucocutaneous HSV infections in HIV-infected individuals can involve severe lesions that persist longer than those in immunocompetent individuals. Infections often progress to visceral disease and CNS or disseminated HSV may occur. HSV oral lesions in HIV-infected individuals generally are erosive, painful ulcerations that persist for several weeks and can extend to the esophagus. While these lesions may heal spontaneously, initiation of oral acyclovir at the onset of symptoms is recommended since severe pain and local tissue destruction may occur; IV acyclovir may be necessary for severe cases.
In patients with advanced HIV infection, reactivation of HSV frequently occurs and can result in chronic, persistent mucocutaneous disease that may be severe. The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) has established guidelines for the prevention of opportunistic infections in HIV-infected individuals that include recommendations concerning prevention of exposure to opportunistic pathogens, prevention of first disease episodes, and prevention of disease recurrence. The USPHS/IDSA does not currently recommend primary prophylaxis against initial episodes of HSV infection in HIV-infected adults, adolescents, or children. In addition, the USPHS/IDSA does not recommend routine chronic suppressive or maintenance therapy (secondary prophylaxis) against HSV disease in HIV-infected individuals since acute episodes generally can be treated successfully with acyclovir. However, long-term prophylaxis against recurrence of HSV can be considered for adults, adolescents, and children who have frequent or severe recurrences. If secondary prophylaxis of HSV disease is indicated in HIV-infected adults or adolescents, the USPHS/IDSA and other experts recommend use of oral acyclovir, oral famciclovir, or oral valacyclovir as the regimen of choice. If indicated in infants and children, the USPHS/IDSA and other experts recommend oral acyclovir.
HIV-infected patients receiving acyclovir may develop acyclovir-resistant strains of HSV; these infections have been reported most often in patients with advanced HIV infection or those who have received long-term acyclovir therapy. IV foscarnet or IV cidofovir can be used for the management of HSV infections in HIV-infected patients when the HSV infection is known or suspected of being caused by acyclovir-resistant strains. Additional study is needed to determine whether long-term suppression of HSV reduces or facilitates the emergence of drug-resistant strains of the virus and to determine optimal strategies for suppressive therapy of acyclovir-resistant HSV infections. It has been postulated that alternating the use of antiviral agents (e.g., acyclovir, foscarnet) may prevent emergence and subsequent predominance of drug-resistant isolates.
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Ocular HSV Infections
Oral acyclovir (400 mg 5 times daily) has been used for the treatment of HSV keratitis in HIV-infected patients. Long-term antiviral therapy may be necessary to prevent recurrent ocular HSV disease in these patients. Oral acyclovir (400 mg twice daily for 12 months) has been used for the prevention of recurrent ocular HSV disease in immunocompetent adults and children 12 years of age or older who had an episode of ocular HSV disease (blepharitis, conjunctivitis, epithelial keratitis, stromal keratitis, iritis) in one or both eyes within the preceding 12 months. Results of one study in adults indicate that long-term oral acyclovir (400 mg twice daily for up to 18 months) is effective in decreasing the number of HSV recurrences. Oral acyclovir (400 mg twice daily for 6 months) has been used to prevent HSV recurrences in patients undergoing penetrating keratoplasty for herpetic eye disease. The optimum duration of prophylaxis remains to be determined.
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HSV Encephalitis
Controlled studies in adults and children 6 months of age or older have shown that IV acyclovir is effective for the treatment of HSV encephalitis. Many clinicians consider acyclovir the drug of choice for the treatment of HSV encephalitis, and the American Academy of Pediatrics (AAP) and other experts also consider acyclovir the drug of choice for the treatment of neonatal HSV infections involving the CNS.
HSV encephalitis and neonatal HSV infections of the CNS are associated with substantial morbidity and mortality despite antiviral treatment. In one study in patients 6 months to 79 years of age with brain biopsy-proven HSV encephalitis randomized to receive 10 days of IV acyclovir (10 mg/kg every 8 hours) or IV vidarabine (15 mg/kg daily; no longer commercially available in the US), the overall mortality rate at 12 months was 25% in those who received acyclovir versus 59% in those who received vidarabine. Morbidity assessments at 12 months indicated that 32% of patients who received acyclovir were functioning normally or had only mild neurologic sequelae (e.g., decreased attention span); the remaining survivors had moderate (e.g., hemiparesis, speech impediment, seizures) or severe (continuous supportive care required) sequelae. Patients who were younger than 30 years of age and those with less severe neurologic involvement at the time of treatment had the best outcome. Initiation of acyclovir early in the course of the infection (prior to the development of semicoma or coma) may enhance its efficacy.
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Neonatal HSV Infections
The AAP, US Centers for Disease Control and Prevention (CDC), and other experts consider IV acyclovir the drug of choice for the treatment of mucosal, cutaneous, CNS, or disseminated HSV infections in neonates.
Neonatal HSV infection is associated with substantial morbidity and mortality, and approximately 25% of neonates with disseminated HSV disease die despite antiviral therapy. Because the risk of morbidity and mortality increases substantially with systemic (CNS or disseminated) infection compared with mucocutaneous infection, early recognition of neonates with HSV infection confined to the skin, eyes, and mouth and early initiation of antiviral therapy are important. The AAP recommends that IV acyclovir therapy be initiated in all neonates with HSV infection, irrespective of presenting clinical findings. In addition, the AAP states that infants with HSV disease that has ocular involvement should received a topical ophthalmic antiviral agent (e.g., trifluridine, vidarabine) in addition to parenteral therapy.
In one study in infants with neonatal HSV disease who were randomized to receive a 10-day regimen of IV acyclovir (10 mg/kg every 8 hours) or vidarabine (30 mg/kg daily; no longer commercially available in the US), mortality at 1 year in the acyclovir group was 0/54 in those with localized disease (limited to skin, eye, and/or mouth), 5/35 in those with CNS infections, and 11/18 in those with visceral organ involvement such as hepatitis or pneumonitis with or without CNS involvement.
Relapse of neonatal HSV disease involving the skin, eyes, mouth, or CNS can occur after acyclovir therapy is discontinued; however, optimal management of these recurrences has not been established. The safety and efficacy of long-term suppressive or intermittent acyclovir therapy for neonates with HSV disease of the skin, eyes, and mouth are being evaluated.
The care of infants exposed to HSV during delivery depends on the status of the mother's infection and mode of delivery; infants exposed to HSV during birth should be monitored carefully in consultation with a specialist. Most experts recommend that women with recurrent genital herpetic lesions at the onset of labor should deliver by cesarean section to prevent neonatal herpes. However, cesarean section does not completely eliminate the risk for HSV transmission to the infant. Women without symptoms or signs of genital herpes can deliver vaginally. The AAP states that all neonates born to women with active genital HSV lesions, regardless of whether the child was delivered by vaginal or cesarean delivery, should be observed carefully and viral cultures for HSV should be obtained 24-48 hours after birth. Because the infection rate in infants born by vaginal delivery to mothers with recurrent genital herpes infection is low, most experts recommend that these infants not be given empiric acyclovir therapy. These infants should be observed for signs of infection and undergo surveillance cultures. For neonates whose mothers have presumed or proven primary genital herpes infection, some experts recommend empiric acyclovir treatment at birth (despite the fact that data are not available to support the efficacy of such a strategy) because the risk of infection in these neonates may exceed 50%; other experts would only initiate acyclovir therapy if HSV cultures are positive. All infants with neonatal herpes should be evaluated and treated with acyclovir. Symptoms suggestive of neonatal HSV infection include skin or scalp rash (especially vesicular lesions) and unexplained clinical manifestations (such as respiratory distress, seizures, signs of sepsis). The fact that neonatal HSV infection can occur as late as 4-6 weeks after delivery should be considered.
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Hematopoietic Stem Cell Transplant Recipients
The CDC, the Infectious Diseases Society of America (IDSA), and the American Society of Blood and Marrow Transplantation (ASBMT) have established guidelines for preventing opportunistic infections in hematopoietic stem cell transplant (HSCT) recipients. These guidelines recommend that candidates for HSCT whose screening tests before HSCT are seropositive for HSV receive acyclovir to prevent HSV recurrence. Acyclovir prophylaxis is initiated at the beginning of the conditioning regimen and continued until engraftment occurs or mucositis resolves (approximately 30 days after HSCT). Routine prophylaxis for longer than 30 days is not recommended. Prophylaxis is not indicated for HSCT recipients who are seronegative for HSV.
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Genital Herpes
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Treatment of First Episode Infections
Acyclovir is used in the treatment of initial episodes of genital herpes. First episode genital herpes infections occur in patients experiencing their first vesicular or ulcerative lesion of the genitalia and can be either a true primary infection or a non-primary infection. Primary infections frequently are asymptomatic, in which case the first symptomatic episode actually represents a reactivated recurrent infection. Individuals with true primary HSV infections lack antibody to HSV-1 and/or HSV-2 in their serum.
The severity of first episodes of genital herpes may vary from asymptomatic to disabling; however, untreated primary infections are generally characterized by severe and prolonged symptoms (average duration of 14 days) and a large number of lesions (average duration of 24 days). Symptoms of primary genital herpes usually appear 2-20 days (average: 6 days) following sexual contact with an individual who has a symptomatic or asymptomatic genital herpes infection. Untreated non-primary infections are generally less severe, of shorter duration, and involve fewer systemic complications; lesions of non-primary infections are present for an average of 14 days. Viral shedding occurs in both primary and non-primary infections, and usually lasts about 12 days in untreated primary infections and 7 days in untreated non-primary infections.
Because many patients with first episodes of genital herpes present with mild clinical symptoms but later develop severe or prolonged symptoms, the CDC states that most patients with initial genital herpes should receive antiviral therapy. The CDC and some clinicians recommend that first episodes of genital herpes in immunocompetent adults and adolescents should be treated with a regimen of oral acyclovir (400 mg 3 times daily or 200 mg 5 times daily for 7-10 days), oral famciclovir (250 mg 3 times daily for 7-10 days), or oral valacyclovir (1 g twice daily for 7-10 days). Oral acyclovir also can be used for the treatment of first episodes of genital herpes in pediatric patients. Topical antiviral agents are not recommended for the treatment of genital herpes since these agents offer only minimal clinical benefit.
Controlled studies have shown that oral acyclovir is effective for the treatment of first episodes of genital herpes in immunocompetent patients. Several studies have shown that oral acyclovir therapy decreases viral shedding and the time required for crusting and healing of lesions; in some patients, the formation of new lesions and the duration of pain, pruritus, or dysuria were decreased.
IV acyclovir should be used for the initial treatment of genital herpes when the infection is severe or when there are complications that necessitate hospitalization, including disseminated infection, pneumonitis, hepatitis, CNS involvement (e.g., meningitis, encephalitis). Controlled studies of severe first episodes of genital herpes in immunocompetent individuals have shown that IV acyclovir decreases viral shedding (time from onset of therapy until last positive culture) from genital and cervical lesions, the time necessary for crusting and healing of lesions, the duration of positive cultures, the formation of new lesions, the duration of dysuria and abnormal vaginal discharge, and the degree and duration of pain and pruritus. In one study, the duration of viral shedding was 2 days in acyclovir-treated patients compared with 8 days in placebo-treated patients; the time required for healing of lesions was 7 days in acyclovir-treated patients compared with 15 days in placebo-treated patients. No substantial reduction in the duration of pain was noted in acyclovir-treated patients compared with placebo-treated patients.
Oral acyclovir has been used at higher dosages (400 mg 5 times daily) for the treatment of first episodes of herpes proctitis.
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Episodic Treatment of Recurrent Infections
Oral acyclovir is used in the treatment of recurrent episodes of genital herpes in immunocompetent adults and adolescents. Antiviral therapy for recurrent genital herpes can be given episodically to ameliorate or shorten the duration of lesions or can be given continuously as suppressive therapy to reduce the frequency of recurrences. For episodic treatment of recurrent genital herpes in immunocompetent adults and adolescents, the CDC and some clinicians recommend oral acyclovir (400 mg 3 times daily for 5 days, 800 mg twice daily for 5 days, or 800 mg 3 times daily for 2 days), oral famciclovir (125 mg twice daily for 5 days or 1 g twice daily for 1 day), or oral valacyclovir (500 mg twice daily for 3 days or 1 g once daily for 5 days). Episodic antiviral therapy should be initiated within 1 day of lesion onset or during the prodrome that precedes some outbreaks.
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Suppressive Therapy of Recurrent Infections
Oral acyclovir is used for chronic suppressive therapy of recurrent genital herpes in immunocompetent adults and adolescents. Data are not available regarding use of acyclovir for suppressive therapy in children. The CDC states that suppressive antiviral therapy can reduce the frequency of genital herpes recurrences by 70-80% in patients who have frequent recurrences (i.e., 6 or more per year) and many patients report no symptomatic outbreaks during such therapy. Quality of life often is improved in patients who receive suppressive therapy rather than episodic treatment for recurrent genital herpes. For chronic suppressive therapy of recurrent genital herpes, the CDC and some clinicians recommend that immunocompetent adults and adolescents receive a regimen of oral acyclovir (400 mg twice daily), oral famciclovir (250 mg twice daily), or oral valacyclovir (500 mg or 1 g once daily). The CDC states that data suggest that famciclovir and valacyclovir are as effective as acyclovir in terms of clinical outcome, although the 500-mg once-daily valacyclovir regimen might be less effective than the acyclovir regimen or other valacyclovir regimens in patients who have very frequent recurrences (i.e., 10 or more episodes per year).
Controlled studies have shown that prophylactic administration of oral acyclovir for suppressive therapy may reduce the frequency and/or severity of subsequent recurrent genital herpes infections or delay the onset of subsequent episodes in immunocompetent patients and can prevent clinical recurrences of genital herpes infections in a substantial proportion of patients. The efficacy of prophylactic administration of oral acyclovir therapy in patients with recurrent herpes proctitis remains to be established. In a study in patients with frequent recurrences of genital herpes infections (6 or more per year) receiving chronic suppressive therapy (400 mg of oral acyclovir twice daily), 45, 52, and 63% of patients were free of recurrences during the first, second, and third years, respectively; serial analyses of 3-month recurrence rates revealed that 71-87% were recurrence free during each quarter, and the annual frequency of recurrences during the third year of therapy relative to the baseline frequency was reduced in 97% of patients. The proportion of these patients (i.e., those receiving chronic suppressive therapy) who remained recurrence free during the first year of the study was substantially higher than that of another group of patients who received intermittent (initiated within 48 hours of onset of a herpes episode) therapy instead; in addition, approximately 25% of patients who received chronic suppressive therapy for 3 years remained recurrence free during the entire period.
Safety and efficacy of oral acyclovir for suppressive therapy of recurrent genital herpes infections have been established in patients receiving daily therapy for up to 5-6 years. Because the frequency of recurrent episodes diminishes over time in many patients, the manufacturer and CDC recommend that suppressive antiviral therapy be discontinued periodically (e.g., once yearly) to assess the need for continued therapy.
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HIV-Infected Individuals
Immunocompromised individuals may have prolonged or severe episodes of genital, perianal, or oral herpes; HSV lesions are common in those with human immunodeficiency virus (HIV) infection and may be severe, painful, and atypical.
(See Uses: Mucocutaneous Herpes Simplex Virus Infections.) The CDC states that episodic treatment or suppressive therapy with oral antiviral agents often is beneficial in HIV-infected individuals with genital herpes. While the drugs of choice for episodic treatment or suppressive therapy of genital herpes in HIV-infected individuals are the same as those in immunocompetent individuals, higher dosages and/or more prolonged therapy may be necessary. For episodic treatment of recurrences of genital herpes in HIV-infected individuals, the CDC recommends a 5- to 10-day regimen of oral acyclovir (400 mg 3 times daily), oral famciclovir (500 mg twice daily), or oral valacyclovir (1 g twice daily). If chronic suppressive therapy of recurrent genital herpes is used in HIV-infected individuals, the CDC recommends oral acyclovir (400-800 mg 2-3 times daily), oral famciclovir (500 mg twice daily), or oral valacyclovir (500 mg twice daily).
Although rare, clinically important resistance to acyclovir is more likely to occur with prolonged or repeated therapy in severely immunocompromised patients with active lesions. Acyclovir-resistant HSV are resistant to valacyclovir and most strains also are resistant to famciclovir. The potential clinical benefits of acyclovir therapy in immunocompromised patients must be weighed against the potential for selecting resistant HSV strains. If presence of acyclovir-resistant HSV are suspected, specimens should be obtained for in vitro susceptibility testing. Patients whose therapy for the prevention or treatment of recurrence fails because of resistance should be managed in consultation with an expert. IV foscarnet can be used for the management of severe HSV infections known or suspected of being caused by acyclovir-resistant strains; IV foscarnet (40 mg/kg every 8 hours given until clinical resolution is attained) often is effective for the treatment of acyclovir-resistant genital herpes.
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Pregnant Women
Although safe use of acyclovir during pregnancy has not been established, the CDC states that oral acyclovir may be used to treat first episodes of genital herpes or severe recurrent genital herpes in pregnant women and that IV acyclovir may be used to treat severe HSV infection in pregnant women.
The risk for transmission of HSV to the neonate from an infected mother during vaginal delivery is high (30-50%) among women who acquire genital herpes near the time of delivery (primary infections) and low (0-5%) among women with histories of recurrent genital herpes at term or women who acquire genital herpes during the first half of pregnancy. Administration of acyclovir late in pregnancy in women who have recurrent genital herpes decreases the frequency of recurrences at term and reduces the frequency of cesarean sections; many clinicians recommend such treatment. There are no data to support administration of acyclovir to HSV-seropositive women who do not have a history of genital herpes. Because the risk of herpes is high in infants of women who acquire genital herpes in late pregnancy, such women should be managed in consultation with an HSV expert. Some experts recommend acyclovir therapy and/or routine cesarean section in these women to decrease the risk of transmission of HSV to the neonate.
(See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
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Patient Counseling and Management of Sexual Partners
Counseling of infected individuals and their sex partners is critical to management of genital herpes. The goals of such counseling are to help patients understand and cope with the infection and to prevent sexual and perinatal transmission of the virus. Antiviral therapy offers clinical benefit to most symptomatic patients and is the mainstay of management; however, genital herpes is a recurrent, lifelong viral infection. Although antiviral therapy can be used to control the symptoms and signs of genital herpes episodes, it cannot eradicate latent HSV or affect the risk, frequency, or severity of recurrences of genital herpes following discontinuance of antiviral therapy.
The majority of genital herpes infections are transmitted by individuals unaware that they have the infection or by individuals who are asymptomatic when transmission occurs. Patients should be advised that acyclovir is not a cure for genital herpes, and there are no data evaluating whether acyclovir prevents transmission of HSV to others. Because genital herpes is a sexually transmitted disease, patients should be advised to avoid sexual contact with uninfected partners when lesions and/or prodromal symptoms are present. In addition, patients should be advised that sexual transmission of the virus can occur during asymptomatic periods and that suppressive antiviral therapy reduces, but does not eliminate, subclinical viral shedding.
Sex partners of individuals with genital herpes should be advised that they may be infected even if they have no symptoms. Asymptomatic partners of patients with genital herpes should be questioned regarding a history of genital lesions, educated to recognize symptoms of genital herpes, and offered type-specific serologic testing to determine whether risk for HSV acquisition exists. Antiviral therapy is not recommended for sex partners who do not have clinical manifestations of infection, but symptomatic sex partners of individuals with genital herpes should be evaluated and treated.
The risk for neonatal HSV infection should be discussed with all genital herpes patients, including men. Pregnant women and women of childbearing potential who have genital herpes should inform their providers who care for them during pregnancy as well as those who will care for their neonate.
Information to assist patients and clinicians in counseling regarding genital herpes is available at http://www.ashastd.org and http://www.ihmf.org.
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Varicella-Zoster Infections
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Varicella (Chickenpox)
Oral acyclovir is used in the treatment of varicella (chickenpox) in immunocompetent adults and children to reduce the severity and duration of the illness. Use of oral acyclovir therapy (initiated within 24 hours of the onset of rash) in otherwise healthy children, postpubertal adolescents, or adults with varicella can decrease the appearance of new lesions, accelerate vesicle healing (vesicles often progress directly from the maculopapular stage to the crusted or healed stage), reduce new vesicle formation by the second day of treatment, and reduce the frequency, duration, and/or severity of fever, pruritus, and constitutional symptoms (e.g., anorexia, lethargy, coryza). In one study in otherwise healthy children 2-12 years of age, nearly all patients receiving oral acyclovir therapy initiated within 24 hours of the onset of rash developed only mild illness of 3-4 days duration with manifestations characteristic of the infection, whereas untreated children generally developed more severe disease of longer duration and many had progressive cutaneous lesions that persisted for more than 6 days.
Some patients who received oral acyclovir therapy reportedly had decreased numbers of residual hypopigmented lesions 4 weeks after initial appearance of rash, and it has been suggested that this possibly indicates a reduction in cutaneous sequelae. However, the clinical relevance, if any, of this finding remains to be established. There currently is no evidence that acyclovir therapy for acute varicella in immunocompetent patients can affect the frequency and/or severity of early complications associated with the disease, in part because such complications generally are uncommon even in untreated individuals. In addition, there currently is no evidence that such therapy can affect the frequency and/or severity of subsequent herpes zoster (shingles, zoster) later in life. It remains to be established whether acyclovir can affect transmission of varicella within households. Current regimens, in which acyclovir is initiated within 24 hours of the appearance of rash, have not reduced such transmission, possibly because therapy was initiated after the period of greatest infectivity. Many clinicians suggest that amelioration, rather than prevention, of varicella in otherwise healthy household contacts should be the principal goal of therapy since prevention could result in the individual being at ongoing risk of primary infection at an older age when manifestations of the disease generally are more severe.
Oral acyclovir therapy in immunocompetent patients generally does not appear to affect antibody response to varicella-zoster infection when measured 1 month and 1 year following treatment with the drug, although somewhat reduced response occasionally has been observed 1 month following treatment with the drug. However, some theoretical concern persists since use of acyclovir in patients with primary herpes simplex infection may result in decreased humoral and cellular immune responses in some patients.Although these altered responses generally have not been associated with increased rates of recurrence or relapse of herpes simplex, the severity of the first subsequent episode of the disease may be increased. Some clinicians also have raised theoretical concerns that potential pathophysiologic and/or immunologic alterations induced by early treatment of varicella infection may predispose to subsequent development of, or more severe, herpes zoster infection, but such concerns have been questioned and remain to be substantiated. Acyclovir should not be used prophylactically in an attempt to prevent infection or illness in otherwise healthy children exposed to varicella.
Because of the usually benign course of varicella, the current lack of evidence of effect of acyclovir therapy on early and delayed complications of the disease, and the lack of established substantial cost-benefit of such therapy, the role of acyclovir in the treatment of varicella in otherwise healthy patients currently is controversial.Therefore, the AAP and other clinicians state that oral acyclovir should not be used routinely in otherwise healthy children with uncomplicated varicella since administration within 24 hours of rash results in only a modest decrease in symptoms. However, use of oral acyclovir may be considered in certain individual cases when family or clinical circumstances justify the drug's modest benefit and only when the drug can be initiated within the first 24 hours after the onset of rash. The AAP and other clinicians state that use of acyclovir can be considered for otherwise healthy individuals at increased risk of moderate to severe varicella, including those older than 12 years of age, those who contract the disease from siblings or other household contacts, those with chronic cutaneous or pulmonary disorders, those receiving long-term salicylate therapy, and those receiving short, intermittent, or aerosolized courses of corticosteroids. Although it is not known whether children receiving short, intermittent, or aerosolized courses of corticosteroid therapy are at increased risk of complicated or severe varicella, the AAP states that use of acyclovir to minimize the likelihood of severe disease should be considered for these children since no data currently exist to confirm their immunocompetence. Because these children are unlikely to have clinically important immunosuppression, oral acyclovir may used; however, children immunocompromised because of high-dose corticosteroid therapy should receive IV acyclovir therapy. If possible, corticosteroid therapy should be discontinued after known exposure to varicella.
The fact that it may be difficult to recognize varicella and initiate acyclovir therapy soon enough after onset of rash to be of appreciable benefit in many patients, particularly the index case, should be considered. Oral acyclovir provides maximum benefit when initiated as soon as possible after the first manifestation of varicella appears; little if any benefit is apparent if treatment is delayed (e.g., for 48 hours after onset of rash).
IV acyclovir is used for the treatment of varicella in immunocompromised adults and children and many clinicians currently consider IV acyclovir the drug of choice for the treatment of varicella in immunocompromised patients. In immunocompromised adults and children with varicella, IV acyclovir therapy may produce negative viral cultures, decrease the appearance of new lesions, and promote the crusting of lesions; the drug also appears to prevent disseminated, life-threatening infection in some patients. Although limited data suggest that oral acyclovir also may be beneficial in some immunocompromised children with varicella, the AAP states that oral therapy generally is not recommended for these patients because of poor oral bioavailability. However, high dosage of oral acyclovir has been used in highly selected immunocompromised patients perceived to be at lower risk of developing severe varicella, such as HIV-infected patients with relatively normal CD4 T-cell counts and children with leukemia in whom careful follow-up is assured. Acyclovir has been used IV in immunocompetent adults for the treatment of complicated varicella (e.g., pneumonia, encephalitis). IV acyclovir therapy appeared to be effective in the treatment of varicella-zoster pneumonia in at least one immunocompetent adult; however, it could not be conclusively determined that the drug was responsible for resolution of infection. In addition, efficacy of the drug may be reduced substantially if initiation of acyclovir is delayed until the disease has advanced to pneumonitis, particularly in immunocompromised patients; therefore, early initiation of therapy is recommended.
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Herpes Zoster (Shingles, Zoster)
Controlled studies have shown that oral acyclovir is effective for the acute treatment of herpes zoster (shingles, zoster) in immunocompetent adults. Oral acyclovir may prevent the appearance of new lesions, decrease viral shedding, decrease the severity and/or duration of pain, promote healing and crusting of lesions, and reduce the prevalence of localized zoster-associated neurologic manifestations (paresthesia, dysesthesia, or hyperesthesia) in immunocompetent adults with localized herpes zoster, at least when given in high dosages within 2 days of the onset of rash. In these studies, acyclovir was particularly effective in adults 50 years of age or older. In immunocompetent adults, high-dose oral acyclovir therapy also may ameliorate cutaneous manifestations, if initiated within 72 hours of rash onset, and acute pain, and may reduce some anterior inflammatory ocular complications (pseudodendritic keratopathy, stromal keratitis, uveitis), if initiated within 7 days of rash onset, but not early cutaneous and external ocular complications (e.g., lid margin vesiculation, conjunctivitis, corneal hypoesthesia, episcleritis). Longer than usual courses of acyclovir (e.g., 21-day therapy) appear to be associated only with marginal additional benefits with regard to the incidence, duration, and severity of pain during the acute phase of the disease in immunocompetent patients when compared with those receiving a 7-day course of therapy. Therefore, because of cost considerations and insufficient evidence of clinical benefits to support such prolonged use, acyclovir therapies longer than 10 days' duration are not recommended for treatment of acute herpes zoster in immunocompetent individuals.
The effect of oral acyclovir on postherpetic neuralgia remains to be clearly determined. In most studies to date, the drug did not appear to prevent postherpetic neuralgia; however, there is some evidence that high-dose therapy may reduce the occurrence of pain in the second and third months after treatment and the associated local neurologic symptoms 3-6 months after treatment. In a limited number of patients with acute herpes zoster, addition of corticosteroids to acyclovir therapy did not appear to influence incidence or severity of postherpetic neuralgia. In one double-blind, placebo-controlled study in immunocompetent adults older than 50 years of age with localized herpes zoster, patients were randomized to received oral acyclovir (800 mg 5 times daily for 21 days) with oral prednisone (daily dosage of 60 mg for days 1-7, then 30 mg for days 8-14 and 15 mg for days 15-21), oral acyclovir with placebo, oral prednisone with placebo, or 2 placebos. Patients were evaluated for persistence of pain and quality of life (i.e., return to 100% usual activity, return to uninterrupted sleep, cessation of analgesic therapy); acute neuritis was assessed during the first month and chronic pain was assessed for up to 6 months. While patients who received prednisone had a shorter duration of acute pain and improved quality of life during the first month after disease onset compared with those who did not receive the drug, the incidence of pain at 3 or 6 months was similar in all 4 treatment groups.
IV acyclovir is used for the treatment of herpes zoster infections in immunocompromised patients, and some clinicians suggest that IV acyclovir is the preferred antiviral agent for the treatment of primary or disseminated herpes zoster in immunocompromised patients, including HIV-infected patients. IV acyclovir also has been used for the treatment of herpes zoster in immunocompetent patients who have both localized and disseminated infections. In a placebo-controlled study in immunocompromised patients with herpes zoster, reductions in cutaneous and visceral dissemination were greater in those who received IV acyclovir (500 mg/m every 8 hours for 7 days) compared with those who received placebo. In a limited number of immunocompetent adults and immunocompromised adults and children with localized and disseminated herpes zoster infections, IV acyclovir therapy appeared to decrease pain and fever, prevent the appearance of new lesions, produce negative cultures, and promote crusting and healing of lesions; however, the principal therapeutic effect of acyclovir in immunocompromised patients appears to be in preventing progression of disease as manifested by cutaneous or visceral dissemination. IV acyclovir therapy has also produced rapid clinical response in a limited number of immunocompetent and immunocompromised patients with herpes zoster-associated encephalitis. There is no evidence that IV acyclovir prevents postherpetic neuralgia.
Oral acyclovir has been used for the treatment of dermatomal herpes zoster in immunocompromised patients, including transplant recipients and HIV-infected patients.
IV acyclovir (10 mg/kg 3 times daily for 7 days) followed by oral acyclovir (800 mg 3-5 times daily) as maintenance therapy has been used for the treatment of herpes zoster ophthalmicus in HIV-infected patients.
Several cases of acyclovir-resistant varicella-zoster virus infections have been reported in adults and children with acquired immunodeficiency syndrome (AIDS) following chronic suppressive courses of therapy with the drug; because pretreatment isolates were not obtained, it is not known whether the original virus developed resistance or a resistant strain was selected during chronic therapy. Another case of therapeutic failure secondary to resistant varicella-zoster has been reported in an immunocompromised patient; however, limited data to date suggest that resistance of the virus to acyclovir occurs only rarely, but additional study and experience are necessary.
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Cytomegalovirus Infections
Acyclovir generally is ineffective in the treatment of cytomegalovirus (CMV) infections. IV acyclovir therapy reportedly reduced fever, improved radiographic findings of pneumonia, and resulted in negative blood cultures in some immunocompromised patients with pneumonia caused by CMV. However, in one randomized study in HIV-infected patients, there was no evidence that oral acyclovir therapy suppressed CMV excretion in these patients. IV acyclovir therapy produced little clinical improvement in several infants with congenital CMV infection.
Oral acyclovir has been used for the prevention of CMV disease in organ transplant recipients considered at risk for the disease. There are conflicting data concerning the effectiveness of the drug for this use, however, and further study is necessary. There is some evidence that IV acyclovir may be effective for suppression of CMV infections in some immunocompromised patients undergoing bone marrow transplantation. Results of a randomized, double-blind study in bone marrow allograft recipients at risk for developing CMV infection (i.e., CMV-seropositive or -seronegative recipients of bone marrow from a CMV-seropositive donor) indicate that in patients who received acyclovir (IV [given 500 mg/m 3 times daily beginning 5 days before bone marrow transplantation until 30 days after transplantation] followed by either placebo or oral acyclovir [800 mg 4 times daily for 6 months]) the probability of developing CMV infection and delaying its onset was reduced compared with those receiving oral acyclovir (200-400 mg 4 times daily beginning 5 days before bone marrow transplantation until 30 days after transplantation) followed by placebo. If acute CMV infection developed in patients receiving oral acyclovir followed by placebo, it occurred at a median time of 41 days after transplantation while if the infection developed in patients receiving IV acyclovir followed by placebo or oral acyclovir, it occurred at a median time of 54 or 57 days, respectively. In addition, survival rate appeared to be increased in patients receiving IV acyclovir followed by oral acyclovir therapy, compared with those receiving oral acyclovir followed by placebo. While IV acyclovir also has been used in an attempt toprevent CMV disease in patients undergoing autologous bone marrow transplantation, the drug does not appear to be effective for this use. In one retrospective study in CMV-seropositive autologous bone marrow recipients, patients who received IV acyclovir (500 mg/m every 8 hours beginning 5 days before transplantation and continued to day 30) did not have a lower incidence of CMV disease and CMV pneumonia during the first 200 days after transplantation than a control group of CMV-seropositive autograft recipients who did not receive the drug.
There is some evidence that high-dose, oral acyclovir therapy may decrease the incidence of CMV disease in certain renal transplant patients, and results of one study indicate that the drug may decrease the incidence of CMV infection in some liver transplant patients. Although some clinicians recommend use of high-dose, oral acyclovir in renal transplant patients, there is little evidence to date that use of oral acyclovir (with or without concomitant immune globulin IV) is associated with a clinically important effect on CMV infection or disease in patients undergoing heart, lung, liver, or kidney transplantation who are considered at risk. In one randomized study in patients undergoing liver transplantation, acyclovir (10 mg/kg IV every 8 hours from day 1 after transplantation until discharge, then 800 mg orally 4 times daily until day 100) was less effective than ganciclovir (6 mg/kg daily IV from day 1-30 after transplantation, then 6 mg/kg daily 5 days weekly until day 100) in preventing CMV disease in these patients. During the first 120 days after the procedure, CMV infections occurred in 38% of those receiving acyclovir and in only 5% of those receiving ganciclovir.
Acyclovir is not effective in preventing CMV disease in HIV-infected individuals, and the drug is not recommended for this use in such patients.
Acyclovir is not effective in preventing CMV disease in hematopoietic stem cell transplant (HSCT) recipients, and the drug is not recommended for this use in such patients. Ganciclovir is the drug of choice for this indication.
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Epstein-Barr Virus Infections and Disorders
Because acyclovir exhibits in vitro activity against Epstein-Barr virus (EBV), the drug has been used in the treatment of uncomplicated or complicated infectious mononucleosis, chronic infectious mononucleosis, and various disorders (e.g., oral hairy leukoplakia) associated with EBV infections. While the role of acyclovir in EBV infections remains to be more fully elucidated, current evidence suggests that efficacy of the drug is variable and probably depends on the linear or circular state of EBV DNA, clonality of EBV-infected cells, immune responsiveness of the host, and role of ongoing EBV replication in the pathophysiology of the infection.
Although high-dose oral acyclovir or IV acyclovir has transiently inhibited oropharyngeal shedding of EBV in patients with uncomplicated or complicated infectious mononucleosis, therapy with the drug generally has had little clinical benefit in immunocompetent patients with signs and symptoms of infectious mononucleosis or in immunocompromised patients with EBV infections. There are some reports that IV acyclovir may decrease fever and interstitial pneumonitis and improve lymphocyte CD4/CD8 ratio in patients with chronic infectious mononucleosis; however, these effects do not occur in all patients who receive the drug.
In a limited number of HIV-infected patients, oral acyclovir therapy was effective in producing clinical regression of oral hairy leukoplakia (apparently caused by EBV), which recurred following discontinuance of the drug; leukoplakia in patients with acquired immunodeficiency syndrome (AIDS) appeared to be less responsive than in patients whose HIV infection had not progressed to this stage. Some clinicians suggest that, because oral hairy leukoplakia is benign and usually asymptomatic, it may not require treatment. If treatment is required, topical therapy (e.g., topical trichloracetic acid, glycolic acid, podophyllum resin) may be effective; oral acyclovir can be used in severe cases. However, all of these should be considered palliative since the condition recurs when treatment is discontinued. While there is some evidence that oral acyclovir may suppress oral hairy leukoplakia, the benefit of prolonged suppressive therapy with acyclovir is questionable because such use could promote emergence of acyclovir-resistant HSV in HIV-infected patients.
Acyclovir appeared to produce a beneficial response in several patients with an atypical EBV-associated syndrome manifested as fever, interstitial pneumonitis, pancytopenia, and extremely high titers of antibody to replicative antigens of EBV. IV acyclovir has been reported to be effective in some renal allograft recipients for the treatment of the early stages of posttransplant EBV-associated polyclonal B-cell lymphoproliferative disorders; however, the drug does not appear to be effective once the tumor progresses into monoclonal lymphoma.
Because Epstein-Barr virus (EBV) has been suggested as a cause of chronic fatigue syndrome (chronic Epstein-Barr virus syndrome), acyclovir has been used in a limited number of patients for the treatment of this condition. However, in a placebo-controlled study in adults with chronic (average duration of 6.8 years), debilitating fatigue, oral acyclovir therapy (3.2 g daily for 30 days) was no more effective than placebo in ameliorating symptoms of the syndrome and there was no correlation between clinical improvement and reduction in EBV antibody levels.
