Antiretrovirals associated with the treatment of human immunodeficiency virus (HIV) are discussed in Chapter 99, HIV infection: antiretroviral therapy.

Acyclovir

Acyclovir, a guanine derivative, has in vitro activity against herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), Epstein–Barr virus (EBV), and cytomegalovirus (CMV), but it is used primarily in HSV and VZV infections. Acyclovir is preferentially taken up by HSV-infected cells and is phosphorylated by HSV thymidine kinase, which is necessary for conversion to the active triphosphate form. It inhibits viral DNA polymerase and causes DNA chain termination when incorporated into replicating DNA. Valacyclovir (discussed later in this chapter) is a prodrug of acyclovir.

Acyclovir may be used for primary episodes of genital herpes to reduce the time of viral shedding and time to healing at a dose of 200 mg orally five times per day for 10 days. It can also be used for treatment of recurrent episodes with 200 mg orally five times a day for 5 days at the first sign of a recurrence. Acyclovir can be used as chronic suppressive therapy to decrease the incidence of recurrent genital herpes at 400 mg orally twice daily. Therapy should be evaluated periodically to reassess the need for chronic suppression. An ointment is available for primary herpes genitalis, but its impact on the natural course of the infection is marginal. Many physicians use acyclovir for the treatment of herpes labialis in a fashion similar to the treatment of genital herpes.

Acyclovir reduces mortality in HSV encephalitis and should be used at high dosages (10–15 mg/kg intravenously [IV] every 8 hours) for 14 to 21 days. Severe mucosal and cutaneous infections in immunocompromised patients may require IV therapy (5 mg/kg every 8 hours) for 7 days. HIV-1-infected patients often require oral suppression to prevent recurrences. Refractoriness to therapy in such patients may indicate the development of acyclovir resistance.

Acyclovir is also active against VZV, but treatment of VZV infections requires higher dosages than treatment of uncomplicated HSV infections. Acyclovir, 800 mg five times daily for 7 to 10 days, should be used in patients with herpes zoster (shingles) to prevent dissemination and in an attempt to shorten the time to healing. In immunocompromised patients, the recommended dose is 10 mg/kg IV every 8 hours for 7 days. Such treatment does not convincingly alter the subsequent development of postherpetic neuralgia, however. Ophthalmic zoster, involving the first branch of the trigeminal nerve, warrants evaluation by an ophthalmologist and immediate therapy, which may be given orally. VZV has also been associated with the syndrome of acute retinal necrosis, which should be treated as a medical emergency.

Acyclovir 800 mg orally every 6 hours for 5 days is effective in the treatment of primary varicella or chickenpox, shortening the duration and severity of illness when begun within 24 hours after the onset of rash. The recommended dose for the treatment of immunocompromised patients is 10 mg IV every 8 hours for 7 to 10 days. Chickenpox in pregnant women may be life threatening, particularly when varicella pneumonia develops. Acyclovir treatment of neonates with VZV or HSV infection is also indicated.

Oral acyclovir, 400 mg five times a day, or IV therapy is effective in preventing mucocutaneous HSV infections in both solid organ and bone marrow transplant patients. It may be given longer term (6 months) to decrease the incidence of VZV infections in bone marrow transplant recipients.

Acyclovir may be of some benefit in EBV-induced lymphoproliferative disease in immunocompromised patients, but it is not clinically useful in EBV disease such as mononucleosis. Incidentally, acyclovir is of no utility in the treatment of chronic fatigue immune dysfunction syndrome (CFIDS)/chronic fatigue syndrome (CFS), because this syndrome has no causal association with EBV infection. Acyclovir is active and has been clinically useful against Herpesvirus simiae, or B virus, an endemic herpesvirus of certain primate species, which, when transmitted to humans has resulted in severe neurologic disease and death.

Pharmacokinetics

Acyclovir has poor water solubility and hence poor oral bioavailability (10%–15%) but good tissue distribution; the low oral bioavailability necessitates frequent administration which is partly resolved by using either the IV formulation or valacyclovir. The serum half-life is 2.5 to 3 hours. Acyclovir is excreted renally and dose adjustment is necessary in patients with impaired renal function.

Major toxicities

Central nervous system (CNS) effects range from confusion to seizures and coma, especially in the settings of renal insufficiency, underlying altered mental status, and old age. Renal failure may occur from precipitation in the renal tubules. When administering high IV doses, it is important to ensure adequate hydration of the patient. Acyclovir is potentially teratogenic, but inadvertent or therapeutic administration during pregnancy has occurred without obvious adverse effects.

Drug interactions

Acyclovir may potentiate or be potentiated by drugs that decrease renal function or compete for active tubular secretion. Coadministration of acyclovir with cimetidine, mycophenolate mofetil, or probenecid may increase acyclovir exposure although dose adjustment is usually not necessary because of the wide therapeutic index of acyclovir. Acyclovir may increase cyclosporine and theophylline exposure.

Adefovir

Adefovir dipivoxil is a nucleotide analog that inhibits reverse transcriptase. It is indicated for the treatment of chronic hepatitis B infection with active viral replication and either elevated serum aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) or histologically active disease. Adefovir competitively inhibits hepatitis B virus (HBV) DNA polymerase, causing DNA chain termination. The recommended dose of adefovir is 10 mg daily. HIV resistance may emerge in chronic hepatitis B patients treated with adefovir but with unrecognized or untreated HIV infection.

Pharmacokinetics

Following oral intake, adefovir dipivoxil is readily converted to adefovir. It is renally excreted by both glomerular filtration and tubular secretion. The dosing interval should be adjusted in patients with renal impairment.

Major toxicities

Associated adverse events include asthenia, headache, abdominal pain, gastrointestinal (GI) upset, pruritus, lactic acidosis, hepatitis, hepatomegaly with steatosis, and nephrotoxicity with prolonged use. An exacerbation of hepatitis can occur when treatment is discontinued.

Drug interactions

Adefovir may potentiate or be potentiated by drugs that decrease renal function or compete for active tubular secretion.

Amantadine

Amantadine hydrochloride (1-adamantanamine hydrochloride) is used to treat Parkinson’s disease and as an antiviral agent that prevents uncoating of influenza A virus after host cell entry. In 2008/2009, it was determined that widespread resistance exists to amantadine, among circulating influenza A strains. It is therefore no longer recommended for prevention or treatment.

Boceprevir

Boceprevir and telaprevir (discussed later) represent the first orally administered direct-acting antivirals (DAA) against hepatitis C virus (HCV). Both are HCV NS3/4A serine protease inhibitors; boceprevir is indicated for patients with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy, including prior null responders, partial responders, and relapsers. When initiating therapy with boceprevir, patients should receive a 4-week lead-in period with pegylated interferon (peginterferon alfa) and ribavirin followed by the addition of boceprevir 800 mg three times daily with food. Treatment is for 24 and 32 weeks in those who are treatment naïve and treatment experienced, respectively. The need for continued peginterferon/ribavirin treatment is then determined by virologic response (response-guided therapy) at week 4 (i.e., after the lead-in period), 8, and 24 as well as prior treatment history, and presence or absence of cirrhosis upon liver biopsy.

Pharmacokinetics

Boceprevir is formulated as a 1:1 mixture of two diastereomers. In plasma, a 2:1 ratio is observed favoring the active diastereomer. It is rapidly absorbed and food increases its exposure. Metabolism of boceprevir is via aldo-keto reductase (AKR) to inactive ketones. The average terminal elimination half-life of boceprevir is 3.4 hours.

Major toxicities

Associated adverse events for the combination of boceprevir, peginterferon, and ribavirin include fatigue, anemia, nausea, headache, and dysgeusia. Patients should be closely monitored for anemia, hypersensitivity, and neutropenia.

Drug interactions

Boceprevir is a substrate and potent CYP3A inhibitor. Coadministration of boceprevir with alfuzosin, cisapride, drospirenone, pimozide, rifampin, St. John’s wort (Hypericum perforatum), ergot derivatives (i.e., dihydroergotamine, ergonovine, ergotamine, or methylergonovine), certain anticonvulsants (i.e., carbamazepine, phenobarbital, or phenytoin), certain HMG-CoA reductase inhibitors (i.e., lovastatin or simvastatin), certain phosphodiesterase type 5 inhibitors when used in the treatment of pulmonary hypertension (i.e., sildenafil and tadalafil), or certain sedative/hypnotics (i.e., oral midazolam or triazolam) is contraindicated. It is not recommended to coadminister boceprevir and the following medications: dexamethasone, rifabutin, salmeterol, inhaled corticosteroids, and certain HIV protease inhibitors (i.e., atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir). The dose of colchicine or phosphodiesterase type 5 inhibitor when used for erectile dysfunction (e.g., sildenafil, tadalafil, or vardenafil) should be adjusted when coadministered with boceprevir.

Cidofovir

Cidofovir is an acyclic nucleoside derivative with antiviral activity. Cidofovir was designed to minimize the resistance that develops in response to nucleoside analogs that require phosphorylation by viral enzymes, such as acyclovir and ganciclovir. Although cidofovir must be diphosphorylated to become active, it does not require phosphorylation by viral kinases. Rather, cidofovir is activated by cellular enzymes. Cidofovir is more active against herpesvirus DNA polymerases than cellular DNA polymerases and thus has selective antiviral activity.

Cidofovir is primarily used for the treatment of CMV retinitis in acquired immunodeficiency syndrome (AIDS) patients. Its use in other CMV infections and in other immunocompromised patients has not been adequately evaluated. Cidofovir has been effective in delaying the progression of CMV retinitis in AIDS patients, including those who have failed ganciclovir or foscarnet therapy. Ganciclovir-resistant strains of CMV, which carry mutations in the UL97 phosphokinase gene, generally remain susceptible to cidofovir. However, other ganciclovir-resistant mutants, especially those carrying mutations in the DNA polymerase gene may be cross-resistant to cidofovir. CMV strains resistant to ganciclovir, foscarnet, and cidofovir have also been described.

Intravenous cidofovir is administered with probenecid to prevent rapid secretion of the drug by the renal tubules. Creatinine clearance should be estimated by calculation or directly measured before initiating therapy with cidofovir. The nephrotoxic potential of cidofovir is such that a creatinine clearance less than 55 mL/min, a serum creatinine greater than 1.5 mg/dL, or 2+ proteinuria is a contraindication to its use. Induction therapy with cidofovir is initiated at a dosage of 5 mg/kg once weekly for 2 weeks, followed by the same dose once every 2 weeks as maintenance therapy. Intravenous saline prehydration with 1 L of normal saline immediately before cidofovir infusion is mandatory to prevent nephrotoxicity. If possible, an additional liter of saline should be administered with and after cidofovir over a 1- to 3-hour period. In addition, great care should be taken to monitor renal function with both urine and serum measurements, and the importance of taking the probenecid should be emphasized. Probenecid is administered as follows: 2 g 3 hours before infusion and 1 g at 2 and 8 hours after infusion.

Pharmacokinetics

Approximately 70% of cidofovir is eliminated unchanged by the kidneys. Its plasma half-life is approximately 2.5 hours, but it has a long-lasting antiviral effect. The latter is the result of the intracellular persistence of its active phosphorylated metabolite.

Major toxicities

As described, the major toxicity of cidofovir is its nephrotoxicity. Neutropenia has occurred in approximately 20% of cidofovir recipients in clinical trials.

Drug interactions

The most important drug interactions are those leading to additional nephrotoxicity. Additive or synergistic nephrotoxic effects with other drugs known to result in nephrotoxicity, such as aminoglycosides or amphotericin B, have not been studied. In addition, the potential for probenecid effects on the metabolism and disposition of other drugs must be considered.

Docosanol

Docosanol is a saturated fatty alcohol that can reduce the duration of cold sores associated with HSV. Its mechanism of action is not entirely known but may involve inhibition of fusion between the viral envelope and human host cell. Docosanol 10% is available over the counter and is applied topically to the cold sore five times a day for up to 10 days. The most commonly reported side effects include headache and local skin irritation.

Entecavir

Entecavir is a nucleoside analog that works by inhibiting HBV polymerase. It is indicated for the treatment of chronic hepatitis B infection in adults with evidence of active viral replication and either persistently elevated serum aminotransferases (ALT or AST) or histologically active disease. For the treatment of chronic hepatitis B infection in adults and adolescents (16 years old or older) who are nucleoside treatment naïve, the dosing is 0.5 mg daily. For patients with hepatitis B viremia also being treated with lamivudine or who have lamivudine and/or telbivudine resistance, the dose is 1 mg daily. Dose adjustment is necessary for patients with decreased renal function. Like adefovir, HIV resistance may emerge in chronic hepatitis B patients treated with entecavir but with unrecognized or untreated HIV infection.

Pharmacokinetics

Entecavir has a bioavailability of 100% following oral administration when the patient is fasting. It is predominantly eliminated by the kidney as unchanged drug. It undergoes both glomerular filtration and tubular secretion.

Major toxicities

Commonly reported side effects include headaches, fatigue, dizziness, and GI upset. Severe acute exacerbations of hepatitis have occurred when treatment has been discontinued.

Drug interactions/precautions

Entecavir may potentiate or be potentiated by drugs that decrease renal function or compete for active tubular secretion.

Famciclovir

Famciclovir, a diacetyl 6-deoxy analog of penciclovir (9-[4-hydroxy-3-hydroxymethylbut-1-yl] guanine), is a nucleoside analog that has a spectrum of activity similar to that of acyclovir. Famciclovir is an inactive prodrug of penciclovir. After oral administration, famciclovir is rapidly metabolized to active penciclovir, which is phosphorylated by viral thymidine kinase and has a mechanism of action similar to acyclovir. Famciclovir is more bioavailable than acyclovir and has a prolonged intracellular half-life, which permits thrice-daily dosing. Famciclovir is approved for treatment of herpes zoster (500 mg three times daily for 7 days) and is similar to acyclovir in ameliorating the course of the acute attack. It is also claimed, on the basis of two studies, that famciclovir shortens the duration of postherpetic neuralgia. It is also indicated for the treatment and suppression of recurrent genital HSV (treatment: 1000 mg every 12 hours for 1 day; suppression: 250 mg every 12 hours for up to 1 year) and recurrent herpes labialis in immunocompetent patients (1500 mg as a single dose). For the treatment of orolabial or genital herpes in HIV-infected patients, it is recommended that famciclovir 500 mg be given every 12 hours for 7 days.

Pharmacokinetics

Famciclovir is excreted renally. The serum half-life is 2.5 to 3 hours, but the intracellular half-life is 10 to 20 times longer. Dose adjustment is necessary in patients with reduced renal function.

Major toxicities

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