Several compounds can influence viral replication and the development of viral disease.
Agents for Influenza and Other Respiratory Viral Infections
Amantadine (and rimantadine) are active against influenza A (but not influenza B) and previously have been effective both as prophylaxis and therapy. However, the high rate of emerged influenza resistance has resulted in amantadine (and rimantadine) no longer recommended in the treatment of influenza. Yearly immunization against influenza is the primary intervention for disease prevention.
Neuraminidase inhibitors, including zanamivir inhalation and oseltamivir tablets, are effective in the prevention and treatment of influenza A and B and are also active against the avian influenza virus. Peramivir is an intravenous neuraminidase inhibitor approved for the treatment of influenza. Insufficient data exist to evaluate peramivir’s clinical efficacy against influenza B. The majority of influenza A H1N1 viruses tested for drug resistance have been susceptible to oseltamivir, zanamivir, and peramivir but resistant to the adamantanes (amantadine, rimantadine). Thus, choices for oral therapy center upon oseltamivir and zanamivir. To date, all oseltamivir-resistant isolates have been zanamivir-susceptible. As with amantadine and rimantadine, the neuraminidase inhibitors must be administered soon (within 48 hours) after the onset of symptoms to be effective. Zanamivir inhalers are difficult to use for some patients, especially those with asthma and chronic obstructive pulmonary disease, in whom bronchospasm has been reported. Gastrointestinal adverse events are the most commonly observed side effects with oseltamivir. In addition, while cause and effect are not well-established, neuropsychiatric disorders, including suicidal ideation, have been associated with oseltamivir. Both medications are administered twice daily (oseltamavir, 75 mg orally; zanamivir 10 mg inhalation) for 5 days when used for therapy; however, up to 150 mg of oseltamivir twice daily has been recommended for more severe disease. Both agents reduce the duration of symptoms by only 1 day and viral shedding by 2 days. However, treatment of critically ill patients initiated within 5 days after symptom onset has been associated with decreased mortality. Both agents also effectively prevent disease in household contacts when administered prophylactically (oseltamavir 75 mg orally once daily, zanamavir 10 mg inhaled once daily) for 10 days. Critically ill patients, in most instances, are unable to receive antiviral agents via the oral or inhaled route of administration. Peramivir, an intravenous antiviral is available as a single-dose. It is as effective, but more expensive, than oral oseltamavir.
Ribavirin aerosol is used in the treatment of respiratory syncytial virus infections in bone marrow transplant patients. It is not known whether the addition of immune globulin provides additional benefit. Intravenous ribavirin (compassionate use availability only) can significantly lower the fatality rate of Lassa fever and has been used for hantavirus; however, the benefit is unclear. While used in some patients in the treatment of severe acute respiratory syndrome (SARS), its value and tolerability has been debated. During the SARS outbreak in Toronto, the use of high-dose ribavirin was associated with a high rate of anemia, hypomagnesemia, and bradycardia. The medication is teratogenic in animals, and pregnant women should not take care of patients receiving the aerosol. Oral ribavirin is used in combination with interferons to treat chronic hepatitis C infections (see Chapter 16). The combination of oral ribavirin and interferon or peginterferon has been found to be superior to monotherapy with interferon. As an alternative to the inhaled preparation, oral ribavirin is effective and well-tolerated for the treatment of upper and lower respiratory syncytial virus infections (with or without immune globulin) in immunocompromised patients.
Agents for Herpesviruses and Cytomegalovirus
Acyclovir is active against herpes simplex virus and varicella-zoster virus. In herpes-infected cells, it is selectively active against viral DNA polymerase and thus inhibits virus proliferation. Given intravenously (15 mg/kg/day in three divided doses), it is useful in the treatment of mucocutaneous herpes simplex in immunocompromised patients. It can reduce pain, accelerate healing, and prevent dissemination of herpes zoster and varicella in immunocompromised patients. The usual dosage for serious varicella-zoster infections is greater, ie, 30 mg/kg/day intravenously in three equal doses. The medication has no effect on establishment of latency, frequency of recurrence, or incidence of postherpetic neuralgia. Acyclovir (30 mg/kg/day intravenously in three equal doses) is the medication of choice for herpes encephalitis. Intravenous or oral acyclovir is effective prophylaxis against recurrent mucocutaneous and visceral herpes infections in transplant and other severely immunosuppressed patients. Prophylactic intravenous or oral acyclovir is effective in preventing cytomegalovirus (CMV) disease in some transplant settings (kidney and perhaps bone marrow) but not in others (liver).
Oral acyclovir, 400 mg three times daily for 7–10 days, is effective in primary genital herpes simplex infections. Oral acyclovir at a dose of 800 mg three times a day for 2 days for recurrent genital herpes reduces viral shedding and symptoms. Suppressive therapy (400 mg twice daily) for 4–6 months reduces the frequency and severity of recurrent genital herpetic lesions. Acyclovir minimally affects symptoms or viral shedding in recurrent herpes labialis and is not generally used for this disease. However, in a dose of 400 mg twice daily, it is effective in preventing recurrent herpes labialis in those with frequent relapses and in preventing sun-induced relapses.
Other uses of oral acyclovir include (1) acceleration of healing of herpes zoster in immunocompetent patients if initiated within 48 hours after onset (800 mg five times daily for 7 days), (2) more rapid healing of rash and lessened clinical symptoms of primary varicella in adults and children if instituted within 24 hours after onset of rash and continued for 5–7 days, (3) prevention of herpes simplex and CMV infections in transplant recipients (in doses of 800 mg four or five times daily), and (4) prophylaxis against varicella in susceptible household contacts.
Topical 5% acyclovir ointment can shorten the period of pain and viral shedding in herpes simplex mucocutaneous oral lesions in immunosuppressed patients but not in patients with normal immunity. In contrast, acyclovir cream or penciclovir ointment (see famciclovir, below) appears to reduce the duration of pain and viral shedding by approximately 1 day in immunocompetent patients. Oral acyclovir is significantly more efficacious than topical therapy for this indication.
The absolute oral bioavailability of acyclovir is 10–30%. Famciclovir and valacyclovir (see below) are significantly better absorbed than oral acyclovir and can be administered less frequently. Dosage reduction in kidney disease is required. Since hemodialysis reduces serum levels significantly, the daily dose should be given after hemodialysis.
Acyclovir is relatively nontoxic. Precipitation of medication in renal tubules has been described with intravenous acyclovir and can be avoided by maintaining adequate hydration and urine flow. Resistance has been described, usually in immunosuppressed patients who have received multiple courses of therapy.
Famciclovir is a prodrug of penciclovir. After oral administration, 75–80% is absorbed and deacetylated in the intestinal wall to the active drug, penciclovir. Penciclovir, like acyclovir, inhibits viral replication by interfering with viral DNA polymerase. Acyclovir-resistant strains of herpes simplex and varicella-zoster virus are also resistant to famciclovir. Famciclovir in a dose of 500 mg three times daily for 7 days accelerates healing of lesions in acute herpes zoster if started within 72 hours after the onset of rash. At a dose of 125 mg twice daily for 5 days, famciclovir is effective therapy of recurrent genital herpes; at a dose of 500 mg twice daily, it is effective as chronic suppressive therapy.
Valacyclovir is a prodrug of acyclovir that has significantly increased oral bioavailability when compared with acyclovir. After absorption, it is converted to acyclovir and serum levels are three to five times higher than those achieved with acyclovir. Valacyclovir at a dosage of 1 g three times daily for 7–10 days is effective therapy for herpes zoster when started within 72 hours after onset of rash and is slightly more effective than acyclovir in relieving zoster-associated pain. It shortens the course of initial episodes of genital herpes (1 g twice daily for 7–10 days), can be used to treat recurrent genital herpes (500 mg twice daily for three days), and is effective prophylaxis for recurrent genital herpes when given as a single 1-g daily dose. Valacyclovir prophylaxis (500 mg daily) reduces the rate of viral shedding and transmission of herpes in discordant monogamous couples. At doses of 2 g four times daily, valacyclovir is more effective than placebo in preventing CMV infections in seronegative recipients of a kidney from a seropositive donor. The adverse effect profile of valacyclovir is comparable to that of acyclovir.
Foscarnet (trisodium phosphonoformate) is a pyrophosphate analog that inhibits viral DNA polymerase of human herpesviruses (CMV, herpes simplex, varicella-zoster) and the reverse transcriptase of HIV. The medication is much less well tolerated than acyclovir and ganciclovir and more difficult to administer. Therefore, its use is limited to patients who do not respond to or cannot tolerate ganciclovir or acyclovir. Isolates of ganciclovir-resistant CMV and acyclovir-resistant herpes simplex and varicella-zoster usually are susceptible to foscarnet. Oral absorption is poor, and the medication must be given intravenously. The half-life is 3–5 hours, and this is prolonged with kidney disease. The usual induction dose is 60 mg/kg/dose every 8 hours, and the dose for maintenance therapy is 120 mg/kg once daily. Adjustments are required for even minimal impairment in kidney function (see package insert).
Foscarnet can cause severe phlebitis, thus central intravenous administration is generally used. Nephrotoxicity, which is dose-dependent and reversible, is the major toxicity. Prehydration with 2.5 L of 0.9% saline reduces nephrotoxicity. Foscarnet binds divalent cations, and hypocalcemia, peripheral neuropathy, seizures and arrhythmias, hypomagnesemia, and hypophosphatemia can occur. Monitoring of electrolytes and kidney function is required during therapy. Anemia (20–50%) and nausea and vomiting (20–30%) are other common adverse effects.
Cidofovir is a nucleotide analog that is active against most all human herpesviruses and poxviruses. The medication has a prolonged pharmacokinetic intracellular half-life, allowing for administration every 1–2 weeks. Strains of CMV, herpes simplex virus, and herpes zoster virus that are resistant to ganciclovir or acyclovir often are susceptible to cidofovir. However, the least likely cross-resistance is between foscarnet and cidofovir. Cidofovir delays progression of CMV retinitis in newly diagnosed disease (5 mg/kg weekly for 2 weeks, followed by maintenance of 3–5 mg/kg every other week) and is effective therapy in relapsed disease or in patients who are intolerant of traditional therapy (5 mg/kg every other day). The medication is ineffective or only marginally effective in the treatment of AIDS-associated progressive multifocal leukoencephalopathy. Cidofovir is associated with a high incidence of nephrotoxicity, sometimes severe. To avoid this complication, probenecid, an inhibitor of active tubular secretion, and intravenous saline must be administered with each dose. Ocular toxicity, including uveitis and iritis, is another complication reported with cidofovir.
Ganciclovir is an analog of acyclovir with similar antiviral activity, including activity against CMV. The addition of intravenous immunoglobulin or CMV immune globulin to ganciclovir may improve outcomes associated with CMV pneumonitis in bone marrow transplant patients. Ganciclovir is frequently used in solid organ and stem cell transplant patients in the treatment and prevention of infection. However, there is no uniformity of opinion about the duration of therapy or the route of administration. Before the availability of oral valganciclovir (see below), which results in serum levels equivalent to those achieved with intravenous medication, ganciclovir was frequently administered intravenously and in the immediate posttransplant period for 1–2 weeks. Depending on the type of transplant (bone marrow transplant patients are at greater risk for developing CMV disease than solid organ transplant patients) and the serologic status of the donor and recipient (seronegative recipients who receive solid organ transplants from seropositive donors are at greatest risk for developing disease), various antiviral agents are used to prevent infection. Acyclovir, valacyclovir, ganciclovir, and valganciclovir have been used in the prevention of CMV in stem cell transplant patients. With the availability of oral valganciclovir, high-risk patients can benefit from prophylaxis without relying on the use of the intravenous route. In addition, because tests to detect early infection with CMV are very sensitive, the strategy for prevention has shifted from one of universal prophylaxis to one of preemptive therapy. At many institutions, high-risk patients are routinely screened for CMV DNA in blood by antigen detection or polymerase chain reaction. A positive test results in subsequent preemptive therapy with intravenous ganciclovir or oral valganciclovir.
The major adverse effect is neutropenia, which is reversible but may require the concomitant use of colony stimulating factors. Thrombocytopenia, nausea, rash, and phlebitis occur less commonly.
Oral ganciclovir is no longer marketed, and it has been replaced by valganciclovir, an esterification product of ganciclovir that is significantly better absorbed. Administration of 900 mg of valganciclovir orally results in serum ganciclovir levels equal to that achieved with an intravenous 5 mg/kg dose of ganciclovir. In CMV retinitis in AIDS patients, oral valganciclovir is as efficacious as intravenous ganciclovir therapy.
Letermovir is a CMV DNA terminase complex inhibitor approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients up to 100 days posttransplant. Compared with placebo, letermovir therapy results in significantly fewer CMV infections within 6 months of allogeneic hematopoietic stem cell transplantation. Letermovir is administered as an intravenous infusion at 480 mg once daily. As an inhibitor of CYP3A, letermovir can increase concentrations of CYP3A substrates such as amiodarone, HMG-CoA reductase inhibitors, and immunosuppressants such as cyclosporine, tacrolimus, and sirolimus. Letermovir also induces CYP2C9 and 2C19 as well as inhibits hepatic organic anion transporters that are responsible for uptake of certain medications. Since letermovir is also a substrate of many drug enzymes, including CYP3A4, letermovir concentrations can be affected by CYP inducers/inhibitors (eg, cyclosporine, rifampin). A dose reduction from 480 mg to 240 mg once daily is recommended if cyclosporine is coadministered with letermovir. Patients receiving letermovir should be closely evaluated for drug interactions. Compared to other available CMV prophylaxis agents (eg, valganciclovir), letermovir appears to cause little myelosuppression. The most common side effects of letermovir, compared to placebo, are vomiting, edema, and atrial fibrillation or flutter.
Lamivudine (3TC), a well-tolerated oral antiviral nucleoside analog used in treatment of HIV infection, is effective against hepatitis B. Once-daily therapy (100 mg) results in clinical, serologic, and histologic improvement in approximately 50% of patients. While lamivudine is useful, development of resistance is common with long-term therapy. Therapy post–liver transplantation is associated with a reduced risk of reinfection with hepatitis B. Unlike the combination of ribavirin and interferon, lamivudine does not improve the outcome seen with interferon monotherapy.
Adefovir is an antiviral agent with activity against hepatitis B. It is as effective against lamivudine-susceptible and lamivudine-resistant isolates. While previously used higher doses have been associated with substantial nephrotoxicity, this complication is rare with the lower doses (10 mg/day) used to treat hepatitis B. The antiretroviral tenofovir disoproxil fumarate is at least as effective as adefovir and is particularly useful in the treatment of HIV- and hepatitis B–coinfected patients. Similar to adefovir, the primary toxicity associated with tenofovir is nephrotoxicity. A new formulation of tenofovir, tenofovir alafenamide, is noninferior to tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection with favorable effects on bone mineral density and kidney function.
Entecavir is a nucleoside analog medication that has selective antihepatitis B virus (HBV) activity against both lamivudine-susceptible and lamivudine-resistant isolates. For patients with chronic hepatitis B who are beginning treatment for the first time (nucleoside-naïve patients), the recommended dosage of entecavir is a single 0.5-mg tablet taken once daily on an empty stomach; for those patients infected with lamivudine-resistant isolates, a single 1-mg tablet is taken once daily. While entecavir is useful for lamivudine-resistant isolates, cross-resistance has been observed among HBV nucleoside analogs. In cell-based assays, entecavir was associated with an 8- to 30-fold less inhibition of replication of HBV that contained lamivudine-resistant mutations than of wild-type virus. Adverse events are similar to those of other hepatitis B agents and include severe, acute exacerbation of hepatitis B after discontinuation as well as headache, abdominal pain, diarrhea, fatigue, and dizziness.
Telbivudine is also active against both lamivudine-susceptible and lamivudine-resistant isolates and comparative trials demonstrate clear superiority over lamivudine. The advantages over lamivudine include both viral suppression as well as normalization of ALT. Combination therapy with telbivudine and lamivudine does not offer any advantages over monotherapy with telbivudine. It is well absorbed by the oral route and food has no impact upon bioavailability. Telbivudine is administered once daily and patients with moderate to severe kidney disease require dosage adjustment. The adverse effect profile is comparable to that observed with other nucleoside analogs.
Human interferons have been prepared from stimulated lymphocytes and by DNA recombinant technology. These agents have antiviral, antitumor, and immunoregulatory properties. The most common uses of these agents include therapy of chronic hepatitis due to hepatitis B, C, and D (see Chapter 16). A long-acting preparation of interferon, peginterferon, in combination with oral ribavirin is superior to conventional interferon for therapy of hepatitis C virus (HCV). Relapse of the underlying disease after cessation of therapy is common but usually responds to reinstitution of medications. Adverse effects are common and include an influenza-like illness with fever, chills, nausea, vomiting, headache, arthralgias, and myalgias. Bone marrow suppression, especially with high-dose interferon therapy, also occurs. Considering the poor tolerability of interferon, only a minority of patients infected with hepatitis C are actually candidates for the combination therapy.
The serine protease inhibitors boceprevir and telaprevir represented an advance in the treatment of hepatitis C. However, while these agents are extremely effective in the treatment of this disease, they are associated with substantial toxicity. They have limited efficacy in hepatitis C infections other than genotype 1 and the requirement to administer these antiviral agents concomitantly with interferon greatly limits their utility.
Fortunately, an extensive pipeline of new agents exists, including direct-acting antiviral agents and host-targeting antiviral agents. These agents all differ in terms of efficacy, breadth of genotypic coverage, probability of drug resistance, side effects, and drug-drug interactions. First-line regimens for HCV infection typically include a NS5A inhibitor (eg, elbasvir, ledipasvir, pibrentasvir, velpatasvir) in combination with either a NS5B RNA polymerase inhibitor (eg, sofosbuvir) or NS3/4 protease inhibitor (eg, grazoprevir, glecaprevir). Vosevi (sofosbuvir, velpatasvir, voxilaprevir), a combination product composed of a NS5B polymerase inhibitor, NS5A inhibitor, and NS3/4A protease inhibitor, was approved in 2017 for patients with prior treatment failure with a NS5A inhibitor-based regimen. Vosevi is effective against all HCV genotypes.
Sofosbuvir represented the first therapeutic advance over boceprevir and telaprevir, in that it does not require coadministration with interferon and may be curative in certain patients. However, the initial cost of this agent was high, and a combination of ledipasvir and sofosbuvir (Harvoni) is now available and recommended over monotherapy with sofosbuvir. Sustained virologic response can be achieved in more than 95% of patients with chronic hepatitis C virotype with few adverse events. In addition to ledipasvir/sofosbuvir, the Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets co-packaged with dasabuvir tablets) is also available to treat patients with chronic hepatitis C virus genotype 1 infection. Similar to the results associated with Harvoni, 91–100% of participants who received Viekira Pak achieved sustained viral response. In contrast to Harvoni, the combination of ombitasvir, paritaprevir, and ritonavir with dasabuvir has been associated with serious hepatotoxicity in patients. Subsequently, elbasvir/grazopravir (Zepatier), sofosbuvir/velpatasvir (Epclusa), and glecaprevir/pibrentasvir (Mavyret) were approved within the United States. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir are fixed-dose combinations recommended as first-line therapy for genotypes 1 through 6. Glecaprevir/pibrentasvir allows for a shorter treatment duration of 8 weeks (compared to 12 weeks) for noncirrhotic, treatment-naïve HCV-infected patients and it can be administered in patients with kidney impairment, including end-stage renal disease, without dose-adjustment. However, this regimen has a high pill burden since glecaprevir/pibrentasvir must be administered as three tablets taken at the same time once daily. Sofosbuvir/velpatasvir is a fixed-dose combination product administered as one pill once daily for 12 weeks regardless of cirrhosis status. For HIV coinfected patients, sofosbuvir/velpatasvir has few drug interactions with HIV antiretrovirals, including HIV protease inhibitors. Sofosbuvir/velpatasvir should not be used in combination with efavirenz, etravirine, and nevirapine; however, ledipasvir/sofosbuvir can be safely coadministered with these antiretrovirals as well as most others. Ledipasvir/sofosbovir still retains a place in therapy for genotypes 1a, 1b, 4, 5, and 6. Elbasvir/grazoprevir is recommended for genotypes 1a, 1b, and 4. The wholesale acquisition cost associated with the most widely used HCV therapies ranges from $27,000 (Mavyret) to $94,000 (Harvoni). All direct-acting HCV antiviral medications must include a boxed warning regarding the risk of hepatitis B virus (HBV) reactivation. Patients should be screened for current or past HBV infection before starting treatment with a direct-acting HCV antiviral and monitored for HBV reactivation during and following treatment (see Chapter 15).
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