Antivirals

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[edit] Antivirals

Michael Katzman

A chapter devoted to antivirals was unnecessary in early textbooks of primary care medicine because few antiviral agents were available. Viral infections were diagnosed clinically, patients were told they “had a virus,” and symptomatic treatment was provided. Often, antibacterial agents were prescribed to treat possible bacterial infection, in hopes of preventing superinfection, or to appease the patient. Clinicians now have the tools, however, to diagnose and treat many viral infections. The number of antiviral agents increases each year, and indications for established agents continue to expand (Fig. 28-1 and Table 28-1). This chapter discusses antiviral drugs that primary care physicians are most likely to use, with a focus on typical outpatient situations. Comprehensive reviews and package inserts should be consulted for more details.^[1]

Figure 28-1 Cumulative number of antiviral agents. An anti-HIV drug available by an expanded-access program was included in 1999 data. Each major new formulation (e.g., topical, oral, intravenous, subcutaneous/intramuscular) was counted separately; thus the final number differs from that in Table 28-1. Data were derived from drug-approval dates obtained from the U.S. Food and Drug Administration (FDA) and other sources.

Table 28-1 Currently Available Antiviral Agents

✢IV, Intravenous; SC, subcutaneous;IM, intramuscular; IL, intralesional;GCs, gelatin capsules.

†Not all forms are active for all types of infection. FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency virus; HSV, herpes simplex virus;VZV, varicella-zoster virus; CMV, cytomegalovirus; Hep, hepatitis; KS, Kaposi's sarcoma (due to human herpes virus-8); CA, condylomata acuminata (due to human papillomavirus);RSV, respiratory syncytial virus.

‡Not FDA approved but available by expanded access program.

[edit] GENERAL PRINCIPLES

[edit] Role of Primary Care Physician

The decision to begin therapy with an antiviral drug often must be made quickly (e.g., within hours for influenza virus or herpesvirus), and the primary care physician is in the best position to determine and initiate such therapy. In other situations the physician may manage patients with chronic viral infections (e.g., hepatitis, human immunodeficiency virus [HIV]), sometimes following an initial referral to a specialist. Even when the physician is not directly responsible for the long-term management of a chronic infection, patients may ask about possible adverse reactions or may seek general advice. In practice, simply knowing the names of the various antiviral agents is helpful (and often sufficient), whereas a working familiarity is required only for a limited number of drugs.

[edit] Goals of Therapy

Prevention is the most important way to limit morbidity and mortality from viral infections, through public health measures, infection control practices, personal hygiene, appropriate sexual practices, or vaccination. Viruses will continue to infect humans, however, and physicians will need to prescribe pharmacologic agents to treat such infections. Because infections with most ribonucleic acid (RNA) viruses (e.g., influenza) are acute and self-limited, the goal of a short course of antiviral therapy in these patients is to speed recovery and limit complications.

In contrast, the herpesviruses cause lifelong infections that intermittently reactivate. Although many of the manifestations of herpes infections also are self-limited, short courses of therapy can hasten recovery, such as for initial or recurrent episodes of genital herpes. With herpes encephalitis, recovery is unlikely without antiviral therapy. Immunocompromised patients are at risk for dissemination and death from herpes infections unless treatment is provided. Antiviral agents may be used chronically to prevent clinical recurrences, such as for genital herpes. With HIV infection, combinations of antiviral drugs are given indefinitely to suppress virus replication and thereby protect the patient's immune system from deterioration. Physicians must be aware that some approved therapies offer only marginal benefits, which must be weighed against the cost and toxicity of particular regimens.

[edit] Mechanisms and Resistance

Successful antiviral agents must target specific steps in virus replication while limiting toxicity to human cells. This ideal is difficult to achieve because viruses, as intracellular parasites, depend on cellular machinery for replication. Viruses vary tremendously in size and shape, may or may not have a surrounding envelope, and may have a single-stranded or double-stranded RNA or deoxyribonucleic acid (DNA) genome. The replication of all viruses at the cellular level, however, depends on three basic steps: (1) entry of viral genetic information into the infected cell, (2) replication of that genetic information, and (3) assembly and release of new infectious viral particles. Only two antiviral drugs (amantadine and rimantadine) act at the first step. The vast majority of antiviral agents resemble the building blocks of nucleic acid and interfere with the second step, whereas interferon alfa and inhibitors of the HIV protease enzyme act later in replication.

When antiviral agents are used repeatedly or for long times, the development of drug resistance must be considered. Sensitivity testing is not generally available for antiviral agents but will likely play a role in the management of viral infections in the future.

[edit] INFLUENZA

Influenza is a major public health problem responsible for tens of thousands of unnecessary deaths and significant morbidity during most winters. The role of vaccination in the prevention of influenza and associated deaths cannot be overemphasized.^[2] Antiviral drugs have an important role when vaccination has not been provided or is inadequate. Amantadine and rimantadine are inexpensive agents that are effective for the prevention and treatment of influenza type A. Neither has activity against influenza B. Amantadine is approved for the treatment and prophylaxis of adults and children aged 1 year and older. Rimantadine currently is approved for the treatment and prophylaxis of adults, but only for prophylaxis in children (Table 28-2). The major differences between these drugs are the route of elimination, incidence of side effects, and cost. Oral or inhaled neuraminidase inhibitors, which are active against influenza A and influenza B, will likely be available in the future.

Table 28-2 Treatment and Prophylaxis of Influenza A

✢Doses are oral. Single or twice-daily doses with either agent are reasonable. Treatment should be started within 48 hours and limited to 3-5 days; see text for duration of prophylaxis.

†Reduce dose for impaired renal function as follows: for creatinine clearance 30-50 ml/min/1.73m²: 200 mg then 100 mg qd; 15-29 ml/min/1.73m²: 200 mg, then 100 mg every other day; <15 ml/min/1.73m²: 200 mg once a week.

‡Rimantadine is FDA approved for prophylaxis but not treatment in children.

§Reduce dose to 100 mg qd if severe hepatic dysfunction or creatinine clearance ≤10 ml/min.

∥Use 100 mg qd in elderly nursing home residents or if side effects develop at 200 mg qd.

[edit] Amantadine and Rimantadine

Amantadine (Symmetrel) and rimantadine (Flumadine) are symmetric tricyclic amines that interfere with an early step in virus replication. They act to block uncoating of the influenza virus genome, perhaps by increasing the pH within the lysosomes of cells. The target of this action is the M2 matrix protein of influenza A. Resistance to either of these agents is caused by single amino acid substitutions in the transmembrane portion of the M2 protein. These oral agents are well absorbed and achieve good levels within nasal secretions. They have relatively long half-lives (about 12 to 18 hours for amantadine and 24 to 36 hours for rimantadine), permitting once-daily dosing,^[3] although some sources recommend two doses per day.^[4] Amantadine is not significantly metabolized and is highly dependent on renal excretion. In contrast, rimantadine is extensively metabolized in the liver and is not as renal dependent.

The most common side effects are nausea and anorexia (3% of patients), insomnia, nervousness, anxiety, difficulty concentrating, and lightheadedness. The central nervous system effects are more common with amantadine (13%) than rimantadine (6%), compared with a 4% incidence in placebo recipients.^[2] Both drugs are relatively free of serious adverse effects, except for seizures in patients with a seizure history, delirium in those with psychiatric disorders, or delirium in association with high drug levels when dosage adjustments are not made for renal function or age. Both drugs are teratogenic in animals and should not be used during pregnancy.^[4]

The cost of a 5-day course of amantadine is less than $10, and the cost of a similar regimen of rimantadine is less than $30. This price difference is likely to be significant only in institutional settings or when the drugs are used prophylactically for several weeks.

[edit] Prophylactic Use.

Both amantadine and rimantadine are 70% to 90% effective in preventing clinical disease from influenza A when taken by healthy adults or children before and during an epidemic period.^[2][3] After influenza A has entered a community, unvaccinated individuals at high risk for complications of influenza or caring for high-risk persons can begin either drug. Chemoprophylaxis should be continued for 2 weeks if concomitant vaccination is performed, by which time healthy adults should have a protective antibody response to the vaccine. Children who are receiving influenza vaccine for the first time (and who thus require a second dose of vaccine) should receive prophylaxis until 2 weeks after the second vaccination. Chemoprophylaxis can be continued for the duration of peak influenza A activity (typically 4 to 8 weeks) if vaccine is not administered because of patient refusal or allergy to vaccine components or if the vaccine is known to lack effectiveness against the circulating strain. Chemoprophylaxis can also be continued in individuals expected to have a poor antibody response to vaccination because of immunodeficiency.

When outbreaks occur in institutions with patients at high risk for complications from influenza, either of these drugs should be given to all residents, whether or not they were vaccinated that season, and offered to unvaccinated staff. Prophylaxis in this setting should be continued until 1 week after the outbreak ends.^[2] Postexposure prophylaxis in household settings has not been effective when the index case was treated concurrently. In one study approximately 35% of households had secondary cases whether rimantadine or placebo was used, and drug-resistant viruses were recovered from cases in treated households.^[5] This fact emphasizes the need to limit contact between influenza patients and susceptible individuals. Dosing recommendations are provided in Table 28-2.

[edit] Therapeutic Use.

Many studies have shown that amantadine and rimantadine decrease the duration of fever and symptoms from influenza A by 1 to 2 days if started within 48 hours of symptom onset.^[3] Institution of empiric antiviral therapy is appropriate when a patient has a compatible clinical illness and influenza A is documented in the community; it is not appropriate for undocumented influenza or for influenza B. Because studies generally excluded patients with symptoms longer than 48 hours, it may be incorrect to conclude that these drugs are ineffective if started after 48 hours; however, a major benefit is unlikely to occur by that point in such a self-limiting illness.

Although no data show that treatment prevents the complications of influenza, the benefits of these drugs on the usual course of the flu are sufficient to justify wider use. Because resistant viruses have spread within households of treated patients,^[5] however, therapy should be limited to 3 to 5 days or 24 to 48 hours after the disappearance of signs and symptoms.^[2] Although the effectiveness of these drugs for infections of the lower respiratory tract is unproved, instituting therapy with either agent may be appropriate for any hospitalized patient who may have primary influenza pneumonia. Dosing recommendations are provided in Table 28-2.

[edit] HERPES SIMPLEX AND VARICELLA-ZOSTER

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) cause a wide range of clinical syndromes, many of which respond to timely administration of antiviral therapy. Intravenous (IV) acyclovir is the drug of choice for treatment of serious infections caused by HSV or VZV. Three other antivirals (valacyclovir, penciclovir, famciclovir) are also available for outpatient therapy of clinical problems. Acyclovir or related drugs may be the most important antiviral agents available to primary care physicians. Antivirals that are active against cytomegalovirus are also effective for some HSV and VZV infections (see later discussion).

[edit] Acyclovir

Acyclovir (Zovirax) is a deoxyguanosine analog that blocks viral DNA synthesis. Within infected cells, the drug is phosphorylated to a monophosphate by the viral thymidine kinase enzyme and further phosphorylated by cellular enzymes to the active triphosphate form, which inhibits the viral DNA polymerase and acts as a chain terminator when incorporated into viral DNA. The most common type of resistance results from loss of viral thymidine kinase activity so that acyclovir monophosphate is not produced. Although thymidine kinase–deficient viruses are less virulent in animal models, such viruses have caused severe mucocutaneous disease, especially in patients with acquired immunodeficiency syndrome (AIDS).

Acyclovir is most active against HSV types 1 and 2, slightly less active against VZV, less active against Epstein-Barr virus, and only minimally active against cytomegalovirus. Acyclovir is available for topical, oral, and IV use. Given its poor bioavailability (only 10% to 20% of an oral dose), plasma levels from oral formulations are much lower than those achieved by the IV route. The drug distributes throughout body water, including cerebrospinal fluid and vaginal secretions, but levels in saliva are only about 10% of those in plasma. The plasma half-life is approximately 3 hours in patients with normal renal function. Acyclovir is minimally metabolized and is excreted by the kidneys. IV dosing should be reduced if the creatinine clearance is 50 ml/min/1.73 m² or less; oral doses do not need adjustment unless renal function is severely impaired.

Acyclovir is generally well tolerated but can cause nausea, diarrhea, rash, or headache. Renal toxicity can occur from crystallization within the kidneys if patients are dehydrated, and neurotoxicity (including encephalopathy and seizures) can occur in patients with renal insufficiency and high plasma levels, which is rare after oral administration. High levels of acyclovir cause chromosomal damage in some in vitro assays; however, a pregnancy registry has not revealed any increase in the incidence of birth defects from exposure during the first trimester.^[4]

The cost of oral acyclovir ranges from approximately $30 for a 5-day course of 200 mg five times a day (e.g., recurrent genital herpes) to more than $100 for a 7-day course of 800 mg five times a day (e.g., shingles).

Acyclovir as a 5% ointment is approved for limited non-life-threatening mucocutaneous HSV disease in immunocompromised patients and for initial episodes of herpes genitalis. It is not useful for orolabial herpes in nonimmunocompromised persons or for recurrent genital herpes. The oral form of acyclovir is approved for acute treatment of chickenpox, herpes zoster, and initial and recurrent episodes of genital herpes and for suppression of recurrent genital herpes. IV acyclovir is approved for initial and recurrent mucosal and cutaneous HSV or VZV infections in immunocompromised patients, for herpes encephalitis in patients over 6 months of age, and for severe initial episodes of herpes genitalis (although the oral form is most often used). In practice, acyclovir is used for an even larger spectrum of herpes infections (Tables 28-3 and 28-4).

Table 28-3 Treatment for Herpes Simplex Virus Infections

✢Doses are oral unless indicated otherwise; see text for dosing in renal dysfunction.

†Should be started within 1 hour of onset.

‡Not FDA approved for this indication.

§Should be started within 24 hours of onset and as soon as possible to maximize benefits.

∥An ophthalmologist should be consulted.

✢Trifluridine (Viroptic) is preferred to idoxuridine (Herplex) or vidarabine (Vira-A).

Table 28-4 Treatment for Varicella-Zoster Virus Infections

✢Doses are oral unless indicated otherwise; see text for comments on dosing in renal dysfunction.

†See Box 28-1 for treatment recommendations.

‡See Box 28-2 for treatment recommendations and the text for the role of steroids.

§Some physicians would use one of the oral regimens in AIDS patients with localized zoster.

∥Not FDA approved for this indication.

[edit] Valacyclovir

Valacyclovir (Valtrex) is an oral prodrug (the l-valyl ester) of acyclovir. After oral administration, valacyclovir is rapidly absorbed and almost completely converted to acyclovir in the intestinal wall and liver, yielding a bioavailability greater than 50%. The resulting serum levels of acyclovir are several times higher than with oral acyclovir and approach those obtained with IV acyclovir. Dosage does not need to be adjusted unless renal function is severely impaired (creatinine clearance less than 30 ml/min) or the maximum dose of 3 gm/day is indicated and renal function is moderately impaired (creatinine clearance less than 50 ml/min). Valacyclovir carries a warning that thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, sometimes fatal, has occurred in bone marrow or renal transplant recipients or patients with advanced AIDS who received 8 gm/day, suggesting a unique toxicity for the prodrug. That dose, however, is more than twice the currently recommended maximum dose. The price of valacyclovir is comparable to that of acyclovir. Valacyclovir is approved for treatment of herpes zoster and treatment and suppression of genital herpes, including initial episodes (see Tables 28-3 and 28-4).

[edit] Penciclovir

Penciclovir (Denavir) is structurally related to acyclovir and has a similar spectrum of activity. As with acyclovir, it must be phosphorylated by viral thymidine kinase and host enzymes. Although penciclovir triphosphate is less potent than acyclovir triphosphate in inhibiting viral DNA polymerase, it is present at higher concentrations and for longer times in infected cells. Penciclovir is available as a 1% cream and is approved for topical treatment of recurrent herpes labialis (cold sores). The cost to the pharmacist for a 2-gm tube is $21.^[6]

[edit] Famciclovir

Famciclovir (Famvir) is an oral prodrug of penciclovir. After oral administration it is rapidly absorbed and almost completely converted to penciclovir in the intestinal wall and liver, yielding a bioavailability greater than 70%. Because penciclovir has a longer intracellular half-life than acyclovir, it can be dosed less frequently. Doses must be adjusted if the creatinine clearance is less than 40 ml/min (when the typical regimen is indicated) or less than 60 ml/min (when the high-dose regimen is indicated for herpes zoster). Famciclovir is generally well tolerated but can cause headache, nausea, and diarrhea. The price of low-dose regimens of famciclovir is comparable to that of acyclovir, but high dose or long-term regimens can be almost twice as expensive. Famciclovir is approved for treatment of herpes zoster and treatment or suppression of recurrent genital herpes, as well as for treatment of recurrent mucocutaneous HSV infections in HIV-infected patients (Tables 28-3 and 28-4).

[edit] Antiherpes Agents in Specific Clinical Situations

[edit] Herpes Labialis.

In healthy individuals, orolabial infections with HSV, often referred to as cold sores or fever blisters, are self-limited. Although topical acyclovir ointment may diminish viral shedding, it offers no clinical benefit in terms of duration, pain relief, or size of the lesion.^[7] Recently, topical penciclovir was approved for recurrent oral herpes, based on statistically significant but marginal clinical benefits. In two large studies of patients with frequent herpes labialis, patients were instructed to begin application within 1 hour of the first sign of a recurrence and to repeat the application every 2 hours while awake (about nine times per day) for 4 days. Compared with placebo, the time to pain resolution was decreased from 4 days to 3.3 days and the time to healing from 5.4 days to 4.6 days.^[6]

No oral agents are approved for treatment of recurrent oral herpes in healthy individuals, although one group reported that oral acyclovir at 400 mg five times daily had a minor benefit in pain resolution and loss of hard crusts (by about 1 day compared with placebo) when started within 1 hour of symptom onset.^[8] In contrast, oral acyclovir can suppress frequent recurrences (six or more episodes per year) of herpes labialis by about 50% and can prevent sun-induced outbreaks.^[9] In addition, topical, oral, or IV acyclovir (see Table 28-3) speeds recovery in immunocompromised patients with mucocutaneous HSV infections. In particular, oral acyclovir reduced the duration of various clinical end points by 5 to 13 days in bone marrow transplant recipients.^[10]

[edit] Herpes Genitalis.

Initial episodes of genital herpes may be associated with severe local and systemic symptoms, and antiviral therapy can provide significant benefit (see Table 28-3). Treatment with oral acyclovir or valacyclovir (and probably famciclovir) can reduce symptoms and time to healing by several days; treatment also decreases viral shedding but not recurrences. Although prompt institution of therapy is most effective, the benefit for acyclovir was demonstrated when patients started treatment at a mean of 3½ days (and up to 6 days) from onset.^[11] Recurrent episodes of genital herpes, although often troublesome, are associated with less severe symptoms. Rapid institution of therapy with acyclovir, valacyclovir, or famciclovir can decrease duration of symptoms and time to healing by ½ to 2 days. These benefits can be maximized by institution of therapy during the prodromal symptoms heralding an outbreak of lesions. When any of the three antivirals is used for chronic suppression, frequent recurrences (six or more episodes per year) can be significantly reduced; 80% or more of patients will benefit, with 50% of patients free of recurrences at 1 year.^[12]

[edit] Herpes Encephalitis and Other HSV Infections.

Encephalitis from HSV is the most common cause of fatal sporadic encephalitis in the United States, and high-dose IV acyclovir dramatically reduces mortality.^[13] Primary care physicians must be aware of the benefits of therapy, since the patient's level of consciousness and prompt initiation of treatment influence the outcome. Similarly, it is important to know that herpetic keratitis can be treated with topical agents. Moreover, one study showed that long-term acyclovir therapy reduced recurrent ocular disease (including sight-threatening deep infections) from 32% to 19% at 1 year.^[14] Anecdotal evidence also supports use of acyclovir for herpetic whitlow (see Table 28-3).

[edit] Chickenpox (Primary Varicella).

When started within 24 hours of onset of rash, acyclovir can shorten the duration of fever by about 1 day and reduce new lesions and total lesions in children, adolescents, and adults.^[15][16] Treatment has not been shown to affect the rate of complications, spread of infection, or duration of absence from school, although adults can be expected to return to work sooner. The clinical significance of some benefits may be marginal (e.g., reduction in median lesion number from 386 to 277), and theoretic and economic concerns surround treating millions of young children with acyclovir. Thus the American Academy of Pediatrics^[17] recommends treatment of chickenpox only in certain situations (Box 28-1). Universal childhood vaccination against varicella should diminish the need to face this clinical decision.

Although treatment of adults within 24 hours of onset of lesions is reasonable, some guidelines do not recommend routine treatment even in this setting.^[18] Significantly, no benefit of treatment was noted when adults started treatment 25 to 72 hours from onset.^[16] Some guidelines do not recommend treatment of uncomplicated varicella during pregnancy,^[17] whereas others suggest that the risk of pneumonitis during the latter half of pregnancy justifies treatment of women beyond the twentieth week who present within 24 hours of onset of chickenpox.^[19] Data are limited on the efficacy of treatment for viral-mediated complications of primary varicella, such as pneumonia or encephalitis, but high-dose IV acyclovir is recommended for such patients, even pregnant women.

[edit] Shingles (Herpes Zoster).

The use of pharmacologic agents, including antivirals and steroids, in the treatment of zoster has long been a controversial topic. Conflicting results have been published, both for effects on acute symptoms and for influencing postherpetic neuralgia; the latter complication is a common and at times debilitating problem that is especially frequent in those over age 50. Acyclovir started within 72 hours of onset of rash has been shown to shorten the time to full crusting by 1 to 2 days and to decrease the severity of acute pain. Valacyclovir appears at least as effective for these end points, and famciclovir was shown to accelerate lesion healing but not to affect duration of acute pain before healing.^[20][21] A recent meta-analysis concluded that treatment with acyclovir can reduce the number of patients who have any pain in the distribution of the rash at 6 months by 46%.^[22] Famciclovir was reported to shorten the duration (but not reduce the incidence) of postherpetic neuralgia in those over age 50.^[21] Another study found a lower incidence of postherpetic neuralgia when famciclovir, as compared with acyclovir, was started within 48 hours of rash onset.^[23] A different study reported that the incidence of neuralgia at 6 months was reduced to 20% in those treated with valacyclovir for 7 days, compared with 26% for those who received acyclovir (p=0.08).^[20] Overall the three oral antiherpes drugs are unlikely to be dramatically different for acute or long-term end points. For some patients the less frequent dosing required for the newer agents may be an advantage.

The role of steroids in preventing postherpetic neuralgia is even more controversial. In an attempt to settle the issue, a large study of more than 300 patients compared 7 vs. 21 days of acyclovir, with or without oral prednisolone (starting at 40 mg/day and tapered over 3 weeks). Only minor differences were found acutely, with no difference in the incidence of postherpetic neuralgia.^[24] The authors concluded that treatment should consist of 7 days of acyclovir without steroids. Interestingly, they thought that a true placebo group was unethical given the previously reported benefits of acyclovir during the acute phase. A subsequent report compared 21 days of acyclovir alone, prednisone alone (60 mg daily for the first week, 30 mg daily for the second week, 15 mg daily for the third week), acyclovir plus prednisone, or neither drug in the treatment of zoster.^[25] Notably, the incidence of postherpetic neuralgia was no different at 3 to 6 months between any of the four groups. However, the combined treatment group had accelerated time to total crusting and healing and an improved quality of life (return of uninterrupted sleep, return to usual activities, discontinuation of analgesic agents) compared with the double-placebo group. Both drugs contributed to the beneficial effects. Assessing the safety of this relatively expensive regimen is limited by the exclusion of patients with osteoporosis, diabetes, or hypertension from the study. The data also demonstrated that the severity of pain at baseline and the number of lesions at enrollment were predictive of outcome. Box 28-2 summarizes recommendations on these issues.^[26]

[edit] OTHER VIRAL INFECTIONS

[edit] Epstein-Barr Virus

Infectious mononucleosis is most often caused by Epstein- Barr virus (EBV), a herpesvirus. In a small trial of IV acyclovir (10 mg/kg every 8 hours) for young adults with infectious mononucleosis and respiratory obstruction or dehydration severe enough to warrant hospitalization, modest benefit was demonstrated only when several parameters (fever, weight loss, sore throat, tonsillar swelling, self- assessment) were combined.^[27] Benefit in mild cases or with an oral regimen is even less likely; a placebo-controlled study with 120 patients failed to demonstrate any clinical benefit from oral acyclovir.^[28] Thus antiviral therapy is not recommended for this EBV syndrome. The routine use of steroids also is not recommended, since no clinical benefit was found in a double-blind study that compared acyclovir plus prednisolone with placebo.^[29] However, many would prescribe steroids for certain complications, such as respiratory obstruction, thrombocytopenia, hemolytic anemia, myocarditis, pericarditis, or neurologic involvement. One infection associated with EBV infection does seem to respond to antiviral treatment. Oral acyclovir often causes resolution of oral hairy leukoplakia in AIDS patients, although relapse can be expected after treatment.^[30]

[edit] Cytomegalovirus

Cytomegalovirus (CMV) can cause a self-limited mononucleosis syndrome in healthy adults but is most significant for the variety of illnesses it causes in immunocompromised patients. Ganciclovir (Cytovene), foscarnet (Foscavir), and cidofovir (Vistide) are IV drugs used to treat the CMV-related retinitis or gastrointestinal inflammation that is common in such patients. An oral form of ganciclovir is also available and is approved for prevention of CMV disease in patients with advanced HIV infection, for maintenance treatment of CMV retinitis in immunocompromised patients (although not as effective as the IV form), and for prevention of CMV disease in solid organ transplant recipients. Although the drug has very poor bioavailability (less than 10%), it can cause significant neutropenia or thrombocytopenia and is carcinogenic, mutagenic, and teratogenic. The usual dose is 1000 mg three times daily with food, with a reduction in dose if creatinine clearance is less than 70 ml/min.

[edit] Respiratory Viruses

Ribavirin (Virazole) administered as a continuous aerosol for 12 to 18 hours daily is approved for treatment of high-risk infants and hospitalized young children with respiratory syncytial virus (RSV) infection. The benefits of therapy in these patients (now considered questionable), however, are not relevant to adult patients. Because oral ribavirin (Rebetol) has become available for therapy of hepatitis C, future controlled studies may describe use of this toxic but broad-spectrum antiviral for adults with serious respiratory infections from RSV and other viruses.

[edit] Viral Hepatitis

Intramuscular or subcutaneous administration of recombinant interferon alfa-2b (Intron-a) can induce remissions in some patients with chronic hepatitis B infection. Oral lamivudine (Epivir), which was originally approved for HIV infection, was also recently approved for treatment of chronic hepatitis B. In addition, recombinant interferon alfa-2b, alfa-2a (Roferon-a), or alfacon-1 (Infergen) and lymphoblastoid interferon alfa-n1 (Wellferon) can be used to treat chronic hepatitis C infection, although the combination of interferon alfa-2b and oral ribavirin (packaged together as Rebetron) is more effective (see Chapter 104 ). Interferons typically cause a flulike syndrome. Depression and suicidal behavior, cardiovascular toxicity, and other serious side effects may also occur. Table 28-5 lists antiviral uses of interferon.

Table 28-5 FDA-Approved Antiviral Uses for Interferon

✢Administered by the subcutaneous or intramuscular route unless stated otherwise.

[edit] Human Immunodeficiency Virus

Many antiviral drugs are now available to treat HIV infection. When used in combination regimens referred to as highly active antiretroviral therapy (HAART), these drugs can have a dramatic clinical effect on morbidity and mortality (Table 28-6; see Chapter 32 ).

Table 28-6 Anti-HIV Drugs

[edit] EVIDENCE-BASED MEDICINE

Medline entries from 1991 to early 1999 were searched by using a strategy that identified systematic reviews, practice guidelines, and controlled clinical trials for influenza, herpes labialis, herpes genitalis, chickenpox, zoster, and mononucleosis. All entries since 1996 related to therapy or drug therapy for these syndromes also were identified.

[edit] REFERENCES