Viruses are obligate intracellular parasites. They lack both a cell wall and a cell membrane, and they do not carry out metabolic processes. Viruses use much of the host’s metabolic machinery, and few drugs are selective enough to prevent viral replication without injury to the infected host cells. Therapy for viral diseases is further complicated by the fact that the clinical symptoms appear late in the course of the disease, at a time when most of the virus particles have replicated. At this stage of viral infection, administration of drugs that block viral replication has limited effectiveness. However, some antiviral agents are useful as prophylactic agents. The few virus groups that respond to available antiviral drugs are discussed in this chapter. To assist in the review of these drugs, they are grouped according to the type of infection they target.
Antiviral Drugs: TREATMENT OF RESPIRATORY VIRAL INFECTIONS
Focus topic: Antiviral Drugs
Viral respiratory tract infections for which treatments exist include influenza A and B and respiratory syncytial virus (RSV). [Note: Immunization against influenza A is the preferred approach. However, antiviral agents are used when patients are allergic to the vaccine or outbreaks occur.]
A. Neuraminidase inhibitors
The neuraminidase inhibitors oseltamivir [os-el-TAM-i-veer] and zanamivir [za-NA-mi-veer] are effective against both type A and type B influenza viruses. They do not interfere with the immune response to influenza vaccine. Administered prior to exposure, neuraminidase inhibitors prevent infection and, when administered within 24 to 48 hours after the onset of symptoms, they modestly decrease the intensity and duration of symptoms.
- Mechanism of action: Influenza viruses employ a specific neuraminidase that is inserted into the host cell membrane for the purpose of releasing newly formed virions. This enzyme is essential for the virus life cycle. Oseltamivir and zanamivir selectively inhibit neuraminidase, thereby preventing the release of new virions and their spread from cell to cell.
- Pharmacokinetics: Oseltamivir is an orally active prodrug that
is rapidly hydrolyzed by the liver to its active form. Zanamivir is
not active orally and is administered via inhalation. Both drugs are
eliminated unchanged in the urine.
- Adverse effects: The most common adverse effects of oseltamivir are gastrointestinal (GI) discomfort and nausea, which can be alleviated by taking the drug with food. Irritation of the respiratory tract occurs with zanamivir. It should be used with caution in individuals with asthma or chronic obstructive pulmonary disease, because bronchospasm may occur.
- Resistance: Mutations of the neuraminidase enzyme have been identified in adults treated with either of the neuraminidase inhibitors. These mutants, however, are often less infective and virulent than the wild type.
B. Adamantane antivirals
The therapeutic spectrum of the adamantane derivatives, amantadine [a-MAN-ta-deen] and rimantadine [ri-MAN-ta-deen], is limited to influenza A infections. Due to widespread resistance, the adamantanes are not recommended in the United States for the treatment or prophylaxis of influenza A.
- Mechanism of action: Amantadine and rimantadine interfere with the function of the viral M2 protein, possibly blocking uncoating of the virus particle and preventing viral release within infected cells.
- Pharmacokinetics: Both drugs are well absorbed after oral administration. Amantadine distributes throughout the body and readily penetrates into the central nervous system (CNS), whereas rimantadine does not cross the blood–brain barrier to the same extent. Amantadine is primarily excreted unchanged in the urine, and dosage reductions are needed in renal dysfunction. Rimantadine is extensively metabolized by the liver, and both the metabolites and the parent drug are eliminated by the kidney.
- Adverse effects: Amantadine is mainly associated with CNS adverse effects, such as insomnia, dizziness, and ataxia. More serious adverse effects may include hallucinations and seizures. Amantadine should be employed cautiously in patients with psychiatric problems, cerebral atherosclerosis, renal impairment, or epilepsy. Rimantadine causes fewer CNS reactions. Both drugs cause GI intolerance. They should be used with caution in pregnant and nursing mothers.
- Resistance: Resistance can develop rapidly, and resistant strains can be readily transmitted to close contacts. Resistance has been shown to result from a change in one amino acid of the M2 matrix protein. Cross-resistance occurs between the two drugs.
Ribavirin [rye-ba-VYE-rin], a synthetic guanosine analog, is effective against a broad spectrum of RNA and DNA viruses. For example, ribavirin is used in treating immunosuppressed infants and young children with severe RSV infections. Ribavirin is also effective in chronic hepatitis C infections when used in combination with interferon-α.
- Mechanism of action: Ribavirin inhibits replication of RNA and DNA viruses. The drug is first phosphorylated to the 5′-phosphate derivatives, the major product being the compound ribavirin triphosphate, which exerts its antiviral action by inhibiting guanosine triphosphate formation, preventing viral messenger RNA (mRNA) capping, and blocking RNA-dependent RNA polymerase.
- Pharmacokinetics: Ribavirin is effective orally and by inhalation. An aerosol is used in the treatment of RSV infection. Absorption is increased if the drug is taken with a fatty meal. The drug and its metabolites are eliminated in urine.
- Adverse effects: Side effects of ribavirin include dose-dependent transient anemia. Elevated bilirubin has also been reported. The aerosol may be safer, although respiratory function in infants can deteriorate quickly after initiation of aerosol treatment. Therefore, monitoring is essential. Ribavirin is contraindicated in pregnancy
Antiviral Drugs: TREATMENT OF HEPATIC VIRAL INFECTIONS
Focus topic: Antiviral Drugs
The hepatitis viruses thus far identified (A, B, C, D, and E) each have a pathogenesis specifically involving replication in and destruction of hepatocytes. Of this group, hepatitis B (a DNA virus) and hepatitis C (an RNA virus) are the most common causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma and are the only hepatic viral infections for which therapy is currently available. [Note: Hepatitis A is a commonly encountered infection caused by oral ingestion of the virus, but it is not a chronic disease.] Chronic hepatitis B may be treated with peginterferon-α-2a, which is injected subcutaneously once weekly. [Note: Interferon-α-2b injected intramuscularly or subcutaneously three times weekly is also useful in the treatment of hepatitis B, but peginterferon-α-2a has similar or slightly better efficacy with improved tolerability.] Oral therapy for chronic hepatitis B includes lamivudine, adefovir, entecavir, tenofovir, or telbivudine. The preferred treatment for chronic hepatitis C is the combination of peginterferon-α-2a or peginterferon-α-2b plus ribavirin, which is more effective than the combination of standard interferons and ribavirin. For genotype 1 chronic hepatitis C virus (HCV), an NS3/4A protease inhibitor (such as boceprevir or telaprevir) should be added to pegylated interferon and ribavirin.
Interferons [in-ter-FEER-on] are a family of naturally occurring, inducible glycoproteins that interfere with the ability of viruses to infect cells. The interferons are synthesized by recombinant DNA technology. At least three types of interferons exist—α, β, and γ. One of the 15 interferon-α glycoproteins, interferon-α-2b has been approved for treatment of hepatitis B and C, condylomata acuminata, and cancers such as hairy cell leukemia and Kaposi sarcoma. In “pegylated” formulations, bis-monomethoxy polyethylene glycol has been covalently attached to either interferon-α-2a or -α-2b to increase the size of the molecule. The larger molecular size delays absorption from the injection site, lengthens the duration of action of the drug, and also decreases its clearance.
- Mechanism of action: The antiviral mechanism is incompletely understood. It appears to involve the induction of host cell enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA.
- Pharmacokinetics: Interferon is not active orally, but it may be administered intralesionally, subcutaneously, or intravenously. Very little active compound is found in the plasma, and its presence is not correlated with clinical responses. Cellular uptake and metabolism by the liver and kidney account for the disappearance of interferon from the plasma. Negligible renal elimination occurs.
- Adverse effects: Adverse effects include flu-like symptoms, such as fever, chills, myalgias, arthralgias, and GI disturbances. Fatigue and mental depression are common. These symptoms subside with continued administration. The principal dose-limiting toxicities are bone marrow suppression, severe fatigue and weight loss, neurotoxicity characterized by somnolence and behavioral disturbances, autoimmune disorders such as thyroiditis and, rarely, cardiovascular problems such as heart failure. Interferon may also potentiate myelosuppression caused by other bone marrow–suppressive agents.
This cytosine analog is an inhibitor of both hepatitis B virus (HBV) and human immunodeficiency virus (HIV) reverse transcriptases (RTs). Lamivudine [la-MI-vyoo-deen] must be phosphorylated by host cellular enzymes to the triphosphate (active) form. This compound competitively inhibits HBV RNA-dependent DNA polymerase. As with many nucleotide analogs, the intracellular half-life of the triphosphate is many hours longer than its plasma half-life. The rate of resistance is high following long-term therapy with lamivudine. Lamivudine is well absorbed orally and is widely distributed. It is mainly excreted unchanged in urine. Dose reductions are necessary when there is moderate renal insufficiency. Lamivudine is well tolerated, with rare occurrences of headache and dizziness.
Adefovir dipivoxil [ah-DEF-o-veer die-pih-VOCKS-ill] is a nucleotide analog that is phosphorylated by cellular kinases to adefovir diphosphate, which is then incorporated into viral DNA. This leads to termination of chain elongation and prevents replication of HBV. Adefovir is administered once a day and is renally excreted via glomerular filtration and tubular secretion. As with other agents, discontinuation of adefovir may result in severe exacerbation of hepatitis. Nephrotoxicity may occur with chronic use, and the drug should be used cautiously in patients with existing renal dysfunction. Adefovir may raise levels of tenofovir through competition for tubular secretion, and concurrent use should be avoided.
Entecavir [en-TECK-ah-veer] is a guanosine nucleoside analog for the treatment of HBV infections. Following intracellular phosphorylation to the triphosphate, it competes with the natural substrate, deoxyguanosine triphosphate, for viral RT. Entecavir is effective against lamivudine-resistant strains of HBV and is dosed once daily. The drug is primarily excreted unchanged in the urine and dosage adjustments are needed in renal dysfunction. Concomitant use of drugs with renal toxicity should be avoided.
Telbivudine [tel-BIV-yoo-dine] is a thymidine analog that can be used in the treatment of HBV. Telbivudine is phosphorylated intracellularly to the triphosphate, which can either compete with endogenous thymidine triphosphate for incorporation into DNA or be incorporated into viral DNA, where it serves to terminate further elongation of the DNA chain. The drug is administered orally, once a day. Telbivudine is eliminated by glomerular filtration as the unchanged drug. The dose must be adjusted in renal failure. Adverse reactions include fatigue, headache, diarrhea, and elevations in liver enzymes and creatine kinase.
F. Tenofovir (see tenofovir under Section VI – NRTIs)
G. Boceprevir and telaprevir
Boceprevir [boe-SE-pre-vir] and telaprevir [tel-A-pre-vir] are the first oral direct-acting antiviral agents for the adjunctive treatment of chronic HCV genotype 1. These HCV NS3/4A serine protease inhibitors covalently and reversibly bind to the NS3 protease active site, thus inhibiting viral replication in host cells. Both drugs are potent inhibitors of viral replication; however, they have a low barrier to resistance and, when used as monotherapy, resistance quickly develops. Therefore, boceprevir or telaprevir should be used in combination with peginterferon alfa and ribavirin in order to improve response rates and reduce the emergence of viral resistance. Boceprevir is administered with food to improve absorption. The absorption of telaprevir is enhanced when it is administered with non–low-fat food. The metabolism of boceprevir and telaprevir occurs via CYP450 isoenzymes. Because both drugs are strong inhibitors of CYP3A4/5 and are also partially metabolized by CYP3A4/5, they have the potential for complex drug interactions. Common adverse events with boceprevir include anemia and dysgeusia. Telaprevir is associated with rash, anemia, and anorectal discomfort.
Antiviral Drugs: TREATMENT OF HERPESVIRUS INFECTIONS
Focus topic: Antiviral Drugs
Herpes viruses are associated with a broad spectrum of diseases, for example, cold sores, viral encephalitis, and genital infections. The drugs that are effective against these viruses exert their actions during the acute phase of viral infections and are without effect during the latent phase.
Acyclovir [ay-SYE-kloe-veer] (acycloguanosine) is the prototypic antiherpetic therapeutic agent. Herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), and some Epstein-Barr virus–mediated infections are sensitive to acyclovir. It is the treatment of choice in HSV encephalitis. The most common use of acyclovir is in therapy for genital herpes infections. It is also given prophylactically to seropositive patients before bone marrow transplant and post–heart transplant to protect such individuals from herpetic infections.
- Mechanism of action: Acyclovir, a guanosine analog, is monophosphorylated in the cell by the herpesvirus-encoded enzyme thymidine kinase. Therefore, virus-infected cells are most susceptible. The monophosphate analog is converted to the di- and triphosphate forms by the host cell kinases. Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and is itself incorporated into the viral DNA, causing premature DNA chain termination.
- Pharmacokinetics: Acyclovir is administered by intravenous (IV), oral, or topical routes. [Note: The efficacy of topical applications is questionable.] The drug distributes well throughout the body, including the cerebrospinal fluid (CSF). Acyclovir is partially metabolized to an inactive product. Excretion into the urine occurs both by glomerular filtration and tubular secretion. Acyclovir accumulates in patients with renal failure. The valyl ester, valacyclovir [val-a-SYE-kloe-veer], has greater oral bioavailability than acyclovir. This ester is rapidly hydrolyzed to acyclovir and achieves levels of the latter comparable to those of acyclovir following IV administration.
- Adverse effects: Side effects of acyclovir treatment depend on the route of administration. For example, local irritation may occur from topical application; headache, diarrhea, nausea, and vomiting may result after oral administration. Transient renal dysfunction may occur at high doses or in a dehydrated patient receiving the drug intravenously.
- Resistance: Altered or deficient thymidine kinase and DNA polymerases have been found in some resistant viral strains and are most commonly isolated from immunocompromised patients. Crossresistance to the other agents in this family occurs.
Cidofovir [si-DOE-foe-veer] is approved for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. [Note: CMV is a member of the herpesvirus family.] Cidofovir is a nucleotide analog of cytosine, the phosphorylation of which is not dependent on viral or cellular enzymes. It inhibits viral DNA synthesis. Slow elimination of the active intracellular metabolite permits prolonged dosage intervals and eliminates the permanent venous access needed for ganciclovir therapy. Cidofovir is administered intravenously. Intravitreal injection (injection into the vitreous humor between the lens and the retina) of cidofovir is associated with risk of hypotony and uveitis and is reserved for extraordinary cases. Cidofovir produces significant renal toxicity, and it is contraindicated in patients with preexisting renal impairment and in those taking nephrotoxic drugs. Neutropenia and metabolic acidosis also occur. Oral probenecid and IV normal saline are coadministered with cidofovir to reduce the risk of nephrotoxicity. Since the introduction of highly active antiretroviral therapy (HAART), the prevalence of CMV infections in immunocompromised hosts has markedly declined, as has the importance of cidofovir in the treatment of these patients.
Unlike most antiviral agents, foscarnet [fos-KAR-net] is not a purine or pyrimidine analog. Instead, it is a phosphonoformate (a pyrophosphate derivative) and does not require activation by viral (or cellular) kinases. Foscarnet is approved for CMV retinitis in immunocompromised hosts and for acyclovir-resistant HSV infections. Foscarnet works by reversibly inhibiting viral DNA and RNA polymerases, thereby interfering with viral DNA and RNA synthesis. Mutation of the polymerase structure is responsible for resistant viruses. Foscarnet is poorly absorbed orally and must be injected intravenously. It must also be given frequently to avoid relapse when plasma levels fall. It is dispersed throughout the body, and greater than 10% enters the bone matrix, from which it slowly leaves. The parent drug is eliminated by glomerular filtration and tubular secretion. Adverse effects include nephrotoxicity, anemia, nausea, and fever. Due to chelation with divalent cations, hypocalcemia and hypomagnesemia are also seen. In addition, hypokalemia, hypo- and hyperphosphatemia, seizures, and arrhythmias have been reported.
Ganciclovir [gan-SYE-kloe-veer] is an analog of acyclovir that has greater activity against CMV. It is used for the treatment of CMV retinitis in immunocompromised patients and for CMV prophylaxis in transplant patients.
- Mechanism of action: Like acyclovir, ganciclovir is activated
through conversion to the nucleoside triphosphate by viral and cellular
enzymes. The nucleotide inhibits viral DNA polymerase and
can be incorporated into the DNA resulting in chain termination.
- Pharmacokinetics: Ganciclovir is administered IV and distributes throughout the body, including the CSF. Excretion into the urine occurs through glomerular filtration and tubular secretion. Like acyclovir, ganciclovir accumulates in patients with renal failure. Valganciclovir [val-gan-SYE-kloe-veer], an oral drug, is the valyl ester of ganciclovir. Like valacyclovir, valganciclovir has high oral bioavailability, because rapid hydrolysis in the intestine and liver after oral administration leads to high levels of ganciclovir.
- Adverse effects: Adverse effects include severe, dose-dependent neutropenia. Ganciclovir is carcinogenic as well as embryotoxic and teratogenic in experimental animals.
- Resistance: Resistant CMV strains have been detected that have lower levels of ganciclovir triphosphate.
E. Penciclovir and famciclovir
Penciclovir [pen-SYE-kloe-veer] is an acyclic guanosine nucleoside derivative that is active against HSV-1, HSV-2, and VZV. Penciclovir is only administered topically. It is monophosphorylated by viral thymidine kinase, and cellular enzymes form the nucleoside triphosphate, which inhibits HSV DNA polymerase. Penciclovir triphosphate has an intracellular half-life much longer than acyclovir triphosphate. Penciclovir is negligibly absorbed upon topical application and is well tolerated. Famciclovir [fam-SYE-kloe-veer], another acyclic analog of 2′-deoxyguanosine, is a prodrug that is metabolized to the active penciclovir. The antiviral spectrum is similar to that of ganciclovir, and it is approved for treatment of acute herpes zoster, genital HSV infection, and recurrent herpes labialis. The drug is effective orally. Adverse effects include headache and nausea.
Trifluridine [trye-FLURE-i-deen] is a fluorinated pyrimidine nucleoside analog that is structurally similar to thymidine. Once converted to the triphosphate, the agent is believed to inhibit the incorporation of thymidine triphosphate into viral DNA and, to a lesser extent, lead to the synthesis of defective DNA that renders the virus unable to replicate. Trifluridine is active against HSV-1, HSV-2, and vaccinia virus. It is indicated for treatment of HSV keratoconjunctivitis and recurrent epithelial keratitis. Because the triphosphate form of trifluridine can also incorporate to some degree into cellular DNA, the drug is considered to be too toxic for systemic use. Therefore, the use of trifluridine is restricted to a topical ophthalmic preparation. A short half-life necessitates that the drug be applied frequently. Adverse effects include a transient irritation of the eye and palpebral (eyelid) edema.
Antiviral Drugs: OVERVIEW OF THE TREATMENT FOR HIV INFECTION
Focus topic: Antiviral Drugs
Prior to approval of zidovudine in 1987, treatment of HIV infections focused on decreasing the occurrence of opportunistic infections that caused a high degree of morbidity and mortality in AIDS patients. Today, the viral life cycle is understood, and a combination of drugs is used to suppress replication of HIV and restore the number of CD4 cells and immunocompetence to the host. This multidrug regimen is commonly referred to as “highly active antiretroviral therapy,” or HAART. There are five classes of antiretroviral drugs, each of which targets one of the four viral processes. These classes of drugs are nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, and the integrase inhibitors. The preferred initial therapy is a combination of two NRTIs with a PI, an NNRTI, or an integrase inhibitor. Selection of the appropriate combination is based on 1) avoiding the use of two agents of the same nucleoside analog; 2) avoiding overlapping toxicities and genotypic and phenotypic characteristics of the virus; 3) patient factors, such as disease symptoms and concurrent illnesses; 4) impact of drug interactions; and 5) ease of adherence to the regimen. The goals of therapy are to maximally and durably suppress HIV RNA replication, to restore and preserve immunologic function, to reduce HIV-related morbidity and mortality, and to improve quality of life.
Antiviral Drugs: NRTIS USED TO TREAT HIV INFECTION
Focus topic: Antiviral Drugs
A. Overview of NRTIs
- Mechanism of action: NRTIs are analogs of native ribosides (nucleosides or nucleotides containing ribose), which all lack a 3′-hydroxyl group. Once they enter cells, they are phosphorylated by cellular enzymes to the corresponding triphosphate analog, which is preferentially incorporated into the viral DNA by RT. Because the 3′-hydroxyl group is not present, a 3′,5′-phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA chain cannot be formed, and DNA chain elongation is terminated. Affinities of the drugs for many host cell DNA polymerases are lower than they are for HIV RT, although mitochondrial DNA polymerase γ appears to be susceptible at therapeutic concentrations.
- Pharmacokinetics: The NRTIs are primarily renally excreted, and all require dosage adjustment in renal insufficiency except abacavir, which is metabolized by alcohol dehydrogenase and glucuronyl transferase.
- Adverse effects: Many of the toxicities of the NRTIs are believed to be due to inhibition of the mitochondrial DNA polymerase in certain tissues. As a general rule, the dideoxynucleosides, such as didanosine and stavudine, have a greater affinity for the mitochondrial DNA polymerase, leading to toxicities such as peripheral neuropathy, pancreatitis, and lipoatrophy. When more than one NRTI is given, care is taken to avoid overlapping toxicities. All of the NRTIs have been associated with a potentially fatal liver toxicity characterized by lactic acidosis and hepatomegaly with steatosis.
- Drug interactions: Due to the renal excretion of the NRTIs, there are not many drug interactions encountered with these agents except for zidovudine and tenofovir.
- Resistance: NRTI resistance is well characterized, and the most common resistance pattern is a mutation at viral RT codon 184, which confers a high degree of resistance to lamivudine and emtricitabine but, more importantly, restores sensitivity to zidovudine and tenofovir. Because cross-resistance and antagonism occur between agents of the same analog class (thymidine, cytosine, guanosine, and adenosine), concomitant use of agents with the same analog target is contraindicated (for example, zidovudine and stavudine are both analogs of thymidine and should not be used together).
B. Zidovudine (AZT)
Zidovudine [zye-DOE-vyoo-deen], the pyrimidine analog, 3′-azido-3′-deoxythymidine (AZT), was the first agent available for the treatment of HIV infection. AZT is approved for the treatment of HIV in children and adults and to prevent perinatal transmission of HIV. It is also used for prophylaxis in individuals exposed to HIV infection. AZT is well absorbed after oral administration. Penetration across the blood–brain barrier is excellent, and the drug has a half-life of 1 hour with an intracellular half-life of approximately 3 hours. Most of the drug is glucuronidated by the liver and then excreted in the urine. AZT is toxic to bone marrow and can cause anemia and neutropenia. Headaches are also common. Both stavudine and ribavirin are activated by the same intracellular pathways and should not be given with AZT.
C. Stavudine (d4T)
Stavudine [STAV-yoo-deen] is an analog of thymidine approved for the treatment of HIV. The drug is well absorbed after oral administration, and it penetrates the blood–brain barrier. The majority of the drug is excreted unchanged in the urine. Renal impairment interferes with clearance. Stavudine is a strong inhibitor of cellular enzymes such as the DNA polymerases, thus reducing mitochondrial DNA synthesis and resulting in toxicity. The major and most common clinical toxicity is peripheral neuropathy, along with headache, rash, diarrhea, and lipoatrophy.
D. Didanosine (ddI)
Upon entry of didanosine [dye-DAN-oh-seen] (dideoxyinosine, ddI) into the host cell, ddI is biotransformed into dideoxyadenosine triphosphate (ddATP) through a series of reactions that involve phosphorylations and aminations. Like AZT, the resulting ddATP is incorporated into the DNA chain, causing termination of chain elongation. Due to its acid lability, absorption is best if ddI is taken in the fasting state. The drug penetrates into the CSF but to a lesser extent than does AZT. Most of the parent drug appears in the urine. Pancreatitis, which may be fatal, is a major toxicity with ddI and requires monitoring of serum amylase. The dose-limiting toxicity of ddI is peripheral neuropathy. Because of its similar adverse effect profile, concurrent use of stavudine is not recommended.
E. Tenofovir (TDF)
Tenofovir [te-NOE-fo-veer] is a nucleotide analog, namely, an acyclic nucleoside phosphonate analog of adenosine 5′-monophosphate. It is converted by cellular enzymes to the diphosphate, which is the inhibitor of HIV RT. Cross-resistance with other NRTIs may occur. Tenofovir has a long half-life, allowing once-daily dosing. Most of the drug is recovered unchanged in the urine. Serum creatinine must be monitored and doses adjusted in renal insufficiency. GI complaints are frequent and include nausea and bloating. The drug should not be used with ddI due to drug interactions. Tenofovir decreases the concentrations of the PI atazanavir such that atazanavir must be boosted with ritonavir if these agents are given concurrently.
F. Lamivudine (3TC)
Lamivudine [la-MI-vyoo-deen] (2′-deoxy-3′-thiacytidine, 3TC) inhibits the RT of both HIV and HBV. However, it does not affect mitochondrial DNA synthesis or bone marrow precursor cells, resulting in less toxicity. It has good bioavailability on oral administration, depends on the kidney for excretion, and is well tolerated.
G. Emtricitabine (FTC)
Emtricitabine [em-tri-SIGH-ta-been], a fluoro derivative of lamivudine, inhibits both HIV and HBV RT. Emtricitabine is well absorbed after oral administration. Plasma half-life is about 10 hours, whereas it has a long intracellular half-life of 39 hours. Emtricitabine is eliminated essentially unchanged in urine. It has no significant interactions with other drugs. Headache, diarrhea, nausea, and rash are the most common adverse effects. Emtricitabine may also cause hyperpigmentation of the soles and palms. Withdrawal of emtricitabine in HBVinfected patients may result in worsening hepatitis.
H. Abacavir (ABC)
Abacavir [a-BA-ka-veer] is a guanosine analog. Abacavir is well absorbed orally. It is metabolized to inactive metabolites via alcohol dehydrogenase and glucuronyl transferase, and metabolites appear in the urine. Common adverse effects include GI disturbances, headache, and dizziness. Approximately 5% of patients exhibit the “hypersensitivity reaction,” which is usually characterized by drug fever, plus a rash, GI symptoms, malaise, or respiratory distress. Sensitized individuals should never be rechallenged because of rapidly appearing, severe reactions that may lead to death. A genetic test (HLA-B*5701) is available to screen patients for the potential of this reaction.
Antiviral Drugs: NNRTIS USED TO TREAT HIV INFECTION
Focus topic: Antiviral Drugs
NNRTIs are highly selective, noncompetitive inhibitors of HIV-1 RT. They bind to HIV RT at an allosteric hydrophobic site adjacent to the active site, inducing a conformational change that results in enzyme inhibition. They do not require activation by cellular enzymes. These drugs have common characteristics that include cross-resistance with other NNRTIs, drug interactions, and a high incidence of hypersensitivity reactions, including rash.
A. Nevirapine (NVP)
Nevirapine [ne-VYE-ra-peen] is used in combination with other antiretroviral drugs for the treatment of HIV infections in adults and children. Due to the potential for severe hepatotoxicity, nevirapine should not be initiated in women with CD4 cell counts greater than 250 cells/mm3 or in men with CD4 cell counts greater than 400 cells/mm3. Nevirapine is well absorbed orally. The lipophilic nature of nevirapine accounts for its wide tissue distribution, including the CNS, placenta (transfers to the fetus), and breast milk. Nevirapine is metabolized via hydroxylation and subsequent glucuronide conjugation. The metabolites are excreted in urine. Nevirapine is an inducer of the CYP3A4 isoenzymes, and it increases the metabolism of a number of drugs, such as oral contraceptives, ketoconazole, methadone, quinidine, and warfarin. The most frequently observed adverse effects are rash, fever, headache, and elevated serum transaminases and fatal hepatotoxicity. Severe dermatologic effects have been encountered, including Stevens-Johnson syndrome and toxic epidermal necrolysis. A 14-day titration period at half the dose is mandatory to reduce the risk of serious epidermal reactions and hepatotoxicity.
B. Delavirdine (DLV)
Delavirdine [de-LA-vir-deen] is not recommended as a preferred or
alternate NNRTI in the current HIV guidelines due to its inferior antiviral
efficacy and inconvenient (three times daily) dosing.
C. Efavirenz (EFV)
Efavirenz [e-FA-veer-enz] is the preferred NNRTI. Following oral administration, efavirenz is well distributed, including to the CNS. It should be administered on an empty stomach to reduce adverse CNS effects. Most of the drug is bound to plasma albumin at therapeutic doses. A half-life of more than 40 hours accounts for its recommended once-a-day dosing. Efavirenz is extensively metabolized to inactive products. The drug is a potent inducer of CYP450 enzymes and, therefore, may reduce the concentrations of drugs that are substrates of the CYP450. Most adverse effects are tolerable and are associated with the CNS, including dizziness, headache, vivid dreams, and loss of concentration. Nearly half of patients experience these complaints, which usually resolve within a few weeks. Rash is another common adverse effect. Efavirenz should be avoided in pregnant women.
D. Etravirine (ETR)
Etravirine [et-ra-VYE-rine] is a second-generation NNRTI active against many HIV strains that are resistant to the first-generation NNRTIs. HIV strains with the common K103N mutation that are resistant to the first-generation NNRTIs are fully susceptible to etravirine. Etravirine is indicated for HIV treatment–experienced, multidrugresistant patients who have evidence of ongoing viral replication. The bioavailability of etravirine is enhanced when taken with a high-fat meal. Although it has a half-life of approximately 40 hours, it is indicated for twice-daily dosing. Etravirine is extensively metabolized to inactive products and excreted mainly in the feces. Because etravirine is a potent inducer of CYP450, the doses of CYP450 substrates may need to be increased when given with etravirine. Rash is the most common adverse effect.
E. Rilpivirine (RPV)
Rilpivirine [ril-pi-VIR-een] is approved for HIV treatment-naïve patients in combination with other antiretroviral agents. It is administered orally once daily with meals and has pH-dependent absorption. Therefore, it should not be coadministered with proton pump inhibitors and requires dose separation from H2-receptor antagonists and antacids. Rilpivirine is highly bound to plasma proteins, primarily albumin. Rilpivirine is a substrate of CYP3A4, and coadministration with other medications that are inducers or inhibitors of this isoenzyme may affect levels of the drug. Rilpivirine is mainly excreted in the feces. Cross-resistance to other NNRTIs is likely after virologic failure and development of rilpivirine resistance. The most common adverse reactions are depressive disorders, headache, insomnia, and rash.