e1-24: Antiviral Chemotherapy

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) being 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 the clinical efficacy of peramivir 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 (oseltamivir 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 (oseltamivir 75 mg orally once daily, zanamivir 10 mg inhaled once daily) for 7 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 as, but more expensive than, oral oseltamivir.

Baloxavir marboxil is a small-molecule prodrug approved for the treatment of uncomplicated influenza and postexposure prophylaxis of influenza A or B. Baloxavir marboxil is hydrolyzed to an active form, baloxavir, which inhibits influenza polymerase acidic endonuclease to halt replication of influenza A and B. With this unique mechanism of action, baloxavir is not influenced by adamantane or neuraminidase resistance. However, resistance to baloxavir has been detected. Baloxavir marboxil is administered as a one-time, weight-based oral dose within the first 48 hours of symptom onset. This medication is approved for adults and pediatric patients aged 12 years or older and weighing 40 kg or more. When administered, baloxavir marboxil should be separated from polyvalent cations, such as calcium, magnesium, iron, etc. In clinical studies, baloxavir marboxil was well tolerated; side effects include diarrhea and bronchitis, rarely. In clinical trials, patients who received baloxavir marboxil showed improvement in symptoms earlier than those patients receiving placebo. Time to symptom improvement was not significantly different between baloxavir marboxil and oseltamivir, but baloxavir marboxil more rapidly decreases the influenza viral load compared with oseltamivir.

Ribavirin aerosol or oral tablets are 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 have been debated. The use of intravenous high-dose ribavirin has been associated with a high rate of anemia, hypomagnesemia, and bradycardia in the treatment of SARS. The medication is teratogenic in animals, and pregnant women should not take care of patients receiving the aerosol. 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.

Remdesivir, a nucleoside analog RNA polymerase inhibitor, was approved for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hospitalized patients (see Chapter 32). In a multinational, randomized trial, hospitalized patients infected with SARS-CoV-2 who received remdesivir showed a significant reduction in the time to recovery compared with those who received placebo; those requiring supplemental oxygen benefited the most from remdesivir treatment. Remdesivir is administered as a once daily intravenous infusion dosed at 200 mg on the first day followed by 100 mg intravenously daily thereafter for adults or children aged 12 years or older weighing at least 40 kg. Common adverse effects include transaminitis and nausea. A slower infusion of 120 minutes may mitigate the risk of hypersensitivity infusion reactions. Molnupiravir also targets viral RNA polymerase, causing significant mutations in viral RNA and ultimately halting viral replication. However, unlike remdesivir, molnupiravir's kinetics show favorable bioavailability and potential utility as an oral SARS-CoV-2 therapeutic. Dosed twice daily, molnupiravir is rapidly absorbed after oral administration and appears to be well tolerated based on preliminary trials. Due to theoretical risk for human DNA mutagenesis and fetal malformations reported in animal studies, some have raised concern about using molnupiravir during pregnancy and lactation. For a full review of remedesivir and other SARS-CoV-2 therapeutics, see Chapter 32.

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 or frequency of recurrence. Oral acyclovir does not significantly reduce the 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.

Oral acyclovir is significantly more efficacious than topical therapy in the treatment of herpes simplex mucocutaneous oral lesions in immunosuppressed patients.

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 3 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 almost 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 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 PCR. 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.

Administration of 900 mg of valganciclovir orally results in serum ganciclovir levels equal to those achieved with an intravenous 5 mg/kg dose of ganciclovir.

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 or oral tablet 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 with other available CMV prophylaxis agents (eg, valganciclovir), letermovir appears to cause little myelosuppression. The most common side effects of letermovir, compared with placebo, are vomiting, edema, and atrial fibrillation or flutter.

For a full review of chronic hepatitis B diagnosis and management, see Chapter 16.

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 after 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 patients who have HIV and hepatitis B coinfection. Similar to adefovir, the primary toxicity associated with tenofovir is nephrotoxicity. An alternative 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 anti–hepatitis 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 with that observed with other nucleoside analogs.

For a full review of chronic hepatitis C diagnosis and management, see Chapter 16.

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, typically treatment-experienced patients who fail interferon-free regimens, 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 list of effective 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, and side effects. Many antivirals used for the treatment of HCV are cytochrome P450 substrates that interact with other drugs, and patients taking these medications should be monitored closely for drug interactions. Regimens for HCV infection typically include a NS5A inhibitor (eg, elbasvir, ledipasvir, pibrentasvir, velpatasvir, daclatasvir) in combination with either a NS5B RNA polymerase inhibitor (eg, sofosbuvir) or NS3/4 protease inhibitor (eg, paritaprevir, simeprevir, voxilaprevir, grazoprevir, glecaprevir).

Vosevi (sofosbuvir, velpatasvir, voxilaprevir), a combination product composed of a NS5B polymerase inhibitor, NS5A inhibitor, and NS3/4A protease inhibitor, is approved for patients with prior treatment failure with a NS5A inhibitor-based regimen for any genotype or genotypes 1 or 3 infection with a sofosbuvir-containing regimen. Vosevi is effective against all HCV genotypes in patients without and with compensated cirrhosis.

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. A combination of ledipasvir and sofosbuvir (Harvoni) is 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. Ledipasvir/sofosbuvir is indicated for hepatitis C genotypes 1, 4, 5, and 6. Sofosbuvir can also be used in combination with daclatasvir as an alternative treatment option for hepatitis C genotypes 1 and 3 in treatment-naïve or treatment-experienced patients. Sofosbuvir with velpatasvir is a first-line choice for treatment-naïve patients regardless of genotype. In addition to sofosbuvir-based regimens, the Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets co-packaged with dasabuvir tablets) is also available to treat patients with chronic HCV genotype 1 infection. Similar to the results associated with Harvoni, 91–100% of participants who received Viekira Pak achieved sustained viral response, but the combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir has been associated with serious hepatotoxicity in patients. Subsequently, elbasvir/grazoprevir (Zepatier), sofosbuvir/velpatasvir (Epclusa), and glecaprevir/pibrentasvir (Mavyret) were approved in the United States. Elbasvir/grazoprevir is a fixed-dosed combination for genotype 1 or 4 in treatment-naïve or treatment-experienced patients. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir are recommended as first-line therapy for all genotypes (1–6) in treatment-naïve adults with or without compensated cirrhosis. In patients with decompensated cirrhosis, ledipasvir/sofosbuvir (genotypes 1, 4, 5, or 6) or sofosbuvir/velpatasvir (genotypes 1–6) are recommended in combination with ribavirin for 12 weeks, if eligible. Patients with decompensated cirrhosis who cannot receive ribavirin require 24 weeks of either ledipasvir/sofosbuvir or sofosbuvir/velpatasvir. Glecaprevir/pibrentasvir allows for a shorter treatment duration of 8 weeks (compared with 12 weeks) for treatment-naïve patients living with HCV who are noncirrhotic or with compensated cirrhosis. Glecaprevir/pibrentasvir can be administered in patients with kidney impairment, including end-stage renal disease, without dose adjustment. However, glecaprevir/pibrentasvir has a high pill burden with three tablets taken together 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 does not interact with HIV protease inhibitors but cannot be used with efavirenz, etravirine, or nevirapine, since these medications decrease the levels of velpatasvir. Ledipasvir/sofosbuvir can be safely coadministered with most antiretrovirals; however, patients on tenofovir-based regimens should have an eGFR of at least 60 mL/min/1.73 m² while taking either ledipasvir/sofosbuvir or sofosbuvir/velpatasvir. Because of the cost and similar efficacy associated with HCV therapies, it is recommended to select the least costly and best tolerated regimen. All direct-acting HCV antiviral medications must include a boxed warning regarding the risk of 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 15-35).