InternalMed_Harrison

InternalMed_Harrison. Immunofluorescence, hemadsorption, and hemagglutination assays for antiviral antibodies are labor-intensive and have been replaced by enzyme-linked immunosorbent assays (ELISAs), which generally use the specific viral proteins most frequently targeted by the antibody response. The proteins are purified from virus-infected cells or produced by recombinant DNA technology and are attached to a solid phase, where they can be incubated with serum, washed to eliminate nonspecific antibodies, and allowed to react with an enzyme-linked reagent to detect human IgG or IgM antibody specifically adhering to the viral antigen. The amount of antibody can then be quantitated by the intensity of a color reaction mediated by the linked enzyme. ELISAs can be sensitive and automated. Western blots can simultaneously confirm the presence of antibody to multiple specific viral proteins. The proteins are separated by size and transferred to an inert membrane, where they are incubated with serum antibodies.


InternalMed_Harrison

InternalMed_Harrison. confirm the presence of antibody to multiple specific viral proteins. The proteins are separated by size and transferred to an inert membrane, where they are incubated with serum antibodies. Western blots have an internal specificity control because the level of reactivity for viral proteins can be compared with that for cellular proteins in the same sample. Western blots require individual evaluation and are inherently difficult to quantitate or automate.


InternalMed_Harrison

InternalMed_Harrison. Isolation of virus in tissue culture depends on infection and replication in susceptible cells. Growth of virus in cell cultures can frequently be identified by effects on cell morphology under light microscopy. For example, HSV produces a typical cytopathic effect in rabbit kidney cells within 3 days. Other viral cytopathic effects may not be as diagnostically distinctive. Identification usually requires confirmation by staining with virus-specific monoclonal antibodies. The efficiency and speed of virus identification can be enhanced by combining short-term culture with immune detection. In assays with “shell vials” of tissue culture cells growing on a coverslip, viral infection can be detected by staining with a monoclonal antibody to a specific viral protein expressed early in viral replication. Thus, virus-infected cells can be detected within hours or days of inoculation, whereas several rounds of infection would be required to produce visible cytopathic effects.


InternalMed_Harrison

InternalMed_Harrison. Isolation of virus in tissue culture also depends on the collection of specimens from appropriate sites and the rapid transport of these specimens in appropriate medium to the virology laboratory (Chap. 150e). Rapid transport maintains viral viability and limits bacterial and fungal overgrowth. Enveloped viruses are generally more sensitive to freezing and thawing than nonenveloped viruses. The most appropriate site for culture depends on the pathogenesis of the virus in question. Nasopharyngeal, tracheal, or endobronchial aspirates are most appropriate for the identification of respiratory viruses. Sputum cultures generally are less appropriate because bacterial contamination and viscosity threaten tissue-culture cell viability. Aspirates of vesicular fluid are useful for isolation of HSV and VZV. Nasopharyngeal aspirates and stool specimens may be useful when the patient has fever and a rash and an enteroviral infection is suspected. Adenoviruses can be cultured from the urine of


InternalMed_Harrison

InternalMed_Harrison. HSV and VZV. Nasopharyngeal aspirates and stool specimens may be useful when the patient has fever and a rash and an enteroviral infection is suspected. Adenoviruses can be cultured from the urine of patients with hemorrhagic cystitis. CMV can frequently be isolated from cultures of urine or buffy coat. Biopsy material can be effectively cultured when viruses infect major organs, as in HSV encephalitis or adenovirus pneumonia.


InternalMed_Harrison

InternalMed_Harrison. The isolation of a virus does not necessarily establish disease causality. Viruses can persistently or intermittently colonize normal human mucosal surfaces. Saliva can be positive for herpesviruses, and normal urine samples can be positive for CMV. Isolations from blood, cerebrospinal fluid (CSF), or tissue are more often diagnostic of significant viral infection. Another method aimed at increasing the speed of viral diagnosis is direct testing for antigen or cytopathic effects. Virus-infected cells from the patient may be detected by staining with virus-specific monoclonal antibodies. For example, epithelial cells obtained by nasopharyngeal aspiration can be stained with a variety of specific monoclonal antibodies to identify the specific infecting respiratory virus. Antigen and serologic assays can be multiplexed to detect multiple analytes simultaneously by coupling of reagents to color-coded beads for each analyte and detection by flow cytometry.


InternalMed_Harrison

InternalMed_Harrison. Nucleic acid amplification techniques bring speed, sensitivity, and specificity to diagnostic virology. The ability to directly amplify minute amounts of viral nucleic acids in specimens means that detection no longer depends on viable virus and its replication. For example, amplification and detection of HSV nucleic acids in the CSF of patients with HSV encephalitis is a more sensitive detection method than culture of virus from CSF. The extreme sensitivity of these tests can be a problem, because subclinical infection or contamination can lead to false-positive results. Detection of viral nucleic acids does not necessarily indicate virus-induced disease.


InternalMed_Harrison

InternalMed_Harrison. Measurement of the amount of viral RNA or DNA in peripheral blood is an important means for determining whether a patient is at increased risk for virus-induced disease and for evaluating clinical responses to antiviral chemotherapy. Nucleic acid technologies for RNA quantification are routinely used in AIDS patients to evaluate responses to antiviral agents and to detect viral resistance or noncompliance with therapy. Virus-load measurements are also useful for evaluating the treatment of patients with HBV and HCV infections. Nucleic acid testing or direct staining with CMV-specific monoclonal antibodies to quantitate virus-infected cells in the peripheral blood (CMV antigenemia) is useful for identifying immunosuppressed patients who may be at risk for CMV-induced disease.


InternalMed_Harrison

InternalMed_Harrison. Multiple steps in the life cycles of viruses can be effectively targeted by antiviral drugs (Chaps. 215e and 216). Nucleoside and nonnucleoside reverse transcriptase inhibitors prevent HIV provirus synthesis, whereas protease inhibitors block maturation of the HIV and HCV polyprotein after infection of the cell. Enfuvirtide is a small peptide derived from HIV gp41 that acts before cell infection by preventing a conformational change required for initial fusion of the virus with the cell membrane. Raltegravir is an integrase inhibitor that is approved for use with other anti-HIV drugs. Amantadine and rimantadine inhibit the influenza M2 protein, preventing release of viral RNA early during infection, whereas zanamivir and oseltamivir inhibit the influenza neuraminidase, which is necessary for the efficient release of mature virions from infected cells.


InternalMed_Harrison

InternalMed_Harrison. Viral genomes can evolve resistance to drugs by mutation and selection, by recombination with a drug-resistant virus, or (in the case of influenza virus and other segmented RNA viral genomes) by reassortment. The emergence of drug-resistant strains can limit the efficacy of antiviral therapy. As in antibacterial therapy, excessive and inappropriate use of antiviral therapy can select for the emergence of drug-resistant strains. HIV genotyping is a rapid method for identifying drug-resistant viruses. Resistance to reverse transcriptase or protease inhibitors has been associated with specific mutations in the reverse transcriptase or protease genes. Identification of these mutations by polymerase chain reaction amplification and nucleic acid sequencing can be clinically useful for determining which antiviral agents may still be effective. Drug resistance also can arise in herpesviruses but is a less common clinical problem.


InternalMed_Harrison

InternalMed_Harrison. Viral vaccines are among the outstanding accomplishments of medical science. Smallpox has been eradicated except as a potential weapon of biological warfare or bioterrorism (Chap. 261e). Poliovirus eradication may soon follow. Measles can be contained or eliminated. Excess mortality due to influenza virus epidemics can be prevented, and the threat of influenza pandemics can be decreased by contemporary killed or live attenuated influenza vaccines. Mumps, rubella, and chickenpox are well controlled by childhood vaccination in the developed world. Reimmunization of mature adults can be used to control herpes zoster. New rotavirus vaccines can have a major impact on this leading cause of gastroenteritis and prominent cause of childhood death worldwide. Widespread HBV vaccination has dramatically lowered the frequency of acute and chronic hepatitis and is expected to lead to a dramatic decrease in the incidence of hepatocellular carcinoma. The HPV vaccine was the first vaccine


InternalMed_Harrison

InternalMed_Harrison. dramatically lowered the frequency of acute and chronic hepatitis and is expected to lead to a dramatic decrease in the incidence of hepatocellular carcinoma. The HPV vaccine was the first vaccine specifically licensed to prevent virus-induced cancer. Use of purified proteins, genetically engineered live-virus vaccines, and recombinant DNA–based strategies will make it possible to immunize against severe infections with other viruses. The development of effective HIV and HCV vaccines is complicated by the high mutation rate of viral RNA polymerase and reverse transcriptase, the population-based and individual divergence of HIV or HCV genomes, and repeated high-level exposure in some populations. Concerns about the use of smallpox and other viruses as weapons necessitate maintenance of immunity to agents that are not encountered naturally.


InternalMed_Harrison

InternalMed_Harrison. Viruses are being used experimentally to deliver biotherapeutic agents or novel vaccines. Foreign genes can be inserted into viral nucleic acids, and the recombinant virus vectors can be used to infect the patient or the patient’s cells ex vivo. Retrovirus integration into the cell genome has been used to functionally replace the abnormal gene in T cells of patients with severe combined immunodeficiency, thereby restoring immune function. Recombinant adenovirus, AAV, and retroviruses are being explored for use in diseases due to single-gene defects, such as cystic fibrosis and hemophilia. AAV carrying a lipoprotein lipase gene is now being used in Europe to treat a rare lipid-processing disease and is the first gene therapy approved for clinical use. Recombinant poxviruses, adenoviruses, and influenza viruses are also being used experimentally as vaccine vectors. Viral vectors are being tested experimentally for the expression of cytokines that can enhance immunity against tumor cells


InternalMed_Harrison

InternalMed_Harrison. influenza viruses are also being used experimentally as vaccine vectors. Viral vectors are being tested experimentally for the expression of cytokines that can enhance immunity against tumor cells or for the expression of proteins that can increase the sensitivity of tumor cells to chemotherapy. HSV deficient for replication in resting cells is being used to selectively kill proliferating glioblastoma cells after injections into CNS tumors. For improved safety, nonreplicating viruses are frequently used in clinical trials. Potential adverse events associated with virus-mediated gene transfer include the induction of inflammatory and antiviral immune responses. Instances of retrovirus-induced human malignances have raised concerns about the safety of retroviral gene therapy vectors.


InternalMed_Harrison

InternalMed_Harrison. Medical Virology Antiviral Chemotherapy, Excluding Antiretroviral Drugs Antiviral Chemotherapy, Excluding Antiretroviral Drugs Lindsey R. Baden, Raphael Dolin The field of antiviral therapy—both the number of antiviral drugs and our understanding of their optimal use—historically has lagged behind 215e that of antibacterial treatment, but significant progress has been made in recent years on new drugs for several viral infections. The development of antiviral drugs poses several challenges. Viruses replicate intracellularly and often use host cell enzymes, macromolecules, and organelles for synthesis of viral particles. Therefore, useful antiviral compounds must discriminate between host and viral functions with a high degree of specificity; agents without such selectivity are likely to be too toxic for clinical use.


InternalMed_Harrison

InternalMed_Harrison. Significant progress has also been made in the development of laboratory assays to assist clinicians in the appropriate use of antiviral drugs. Phenotypic and genotypic assays for resistance to antiviral drugs are becoming more widely available, and correlations of laboratory results with clinical outcomes are being better defined. Of particular note has been the development of highly sensitive and specific methods that measure the concentration of virus in blood (virus load) and permit direct assessment of the antiviral effect of a given drug regimen in that host site. Virus load measurements have been useful in recognizing the risk of disease progression in patients with viral infections and in identifying patients for whom antiviral chemotherapy might be of greatest benefit. As with any in vitro laboratory test, results are highly dependent on and likely vary with the laboratory techniques used.


InternalMed_Harrison

InternalMed_Harrison. Information regarding the pharmacodynamics of antiviral drugs, and particularly the relationship of concentration effects to efficacy, has been slow to develop but is also expanding. However, assays to measure concentrations of antiviral drugs, especially of their active moieties within cells, are still primarily research procedures not widely available to clinicians. Thus, there are limited guidelines for adjusting dosages of antiviral agents to maximize antiviral activity and minimize toxicity. Consequently, clinical use of antiviral drugs must be accompanied by particular vigilance for unanticipated adverse effects.


InternalMed_Harrison

InternalMed_Harrison. Like that of other infections, the course of viral infections is profoundly affected by interplay between the pathogen and a complex set of host defenses. The presence or absence of preexisting immunity, the ability to mount humoral and/or cell-mediated immune responses, and the stimulation of innate immunity are important determinants of the outcome of viral infections. The state of the host’s defenses needs to be considered when antiviral agents are used or evaluated.


InternalMed_Harrison

InternalMed_Harrison. As with any therapy, the optimal use of antiviral compounds requires a specific and timely diagnosis. For some viral infections, such as herpes zoster, the clinical manifestations are so characteristic that a diagnosis can be made on clinical grounds alone. For other viral infections, such as influenza A, epidemiologic information (e.g., the documentation of a community-wide influenza outbreak) can be used to make a presumptive diagnosis with a high degree of accuracy. However, for most of the remaining viral infections, including herpes simplex encephalitis, cytomegaloviral infections other than retinitis, and enteroviral infections, diagnosis on clinical grounds alone cannot be accomplished with certainty. For such infections, rapid viral diagnostic techniques are of great importance. Considerable progress has also been made in recent years in the development of such tests, which are now widely available for a number of viral infections.


InternalMed_Harrison

InternalMed_Harrison. Despite these complexities, the efficacy of a number of antiviral compounds has been clearly established in rigorously conducted and controlled studies. As summarized in Table 215e-1, this chapter reviews the antiviral drugs that are currently approved or are likely to be considered for approval in the near future for use against viral infections other than those caused by HIV. Antiretroviral drugs are reviewed in Chap. 226. (SEE ALSO CHAPS. 223 AND 224) ZANAMIVIR, OSELTAMIVIR, PERAMIVIR, AND LANINAMIVIR


InternalMed_Harrison

InternalMed_Harrison. Zanamivir and oseltamivir are inhibitors of the influenza viral neuraminidase enzyme, which is essential for release of virus from infected cells and for its subsequent spread throughout the respiratory tract of the infected host. The enzyme cleaves terminal sialic acid residues and thus destroys the cellular receptors to which the viral hemagglutinin attaches. Zanamivir and oseltamivir are sialic acid transition-state analogues and are highly active and specific inhibitors of the neuraminidases of both influenza A and B viruses. The antineuraminidase activity of the two drugs is similar, although zanamivir has somewhat greater in vitro activity against influenza B virus. Zanamivir may also be active against certain strains of influenza A virus that are resistant to oseltamivir. Both zanamivir and oseltamivir act through competitive and reversible inhibition of the active site of influenza A and B viral neuraminidases and have relatively little effect on mammalian cell enzymes.


InternalMed_Harrison

InternalMed_Harrison. Oseltamivir phosphate is an ethyl ester prodrug that is converted to oseltamivir carboxylate by esterases in the liver. Orally administered oseltamivir has a bioavailability of >60% and a plasma half-life of 7–9 h. The drug is excreted unmetabolized, primarily by the kidneys. Zanamivir has low oral bioavailability and is administered orally via a hand-held inhaler. By this route, ~15% of the dose is deposited in the lower respiratory tract, and low plasma levels of the drug are detected. The toxicities most frequently encountered with orally administered oseltamivir are nausea, gastrointestinal discomfort, and (less commonly) vomiting. Gastrointestinal discomfort is usually transient and is less likely if the drug is administered with food. Neuropsychiatric events (delirium, self-injury) have been reported in children who have been taking oseltamivir, primarily in Japan. Zanamivir is orally inhaled and is generally well tolerated, although exacerbations of asthma may occur. An IV


InternalMed_Harrison

InternalMed_Harrison. have been reported in children who have been taking oseltamivir, primarily in Japan. Zanamivir is orally inhaled and is generally well tolerated, although exacerbations of asthma may occur. An IV formulation of zanamivir is under development and is available from GlaxoSmithKline as part of clinical trials.


InternalMed_Harrison

InternalMed_Harrison. Inhaled zanamivir and orally administered oseltamivir have been effective in the treatment of naturally occurring, uncomplicated influenza A or B in otherwise healthy adults. In placebo-controlled studies, illness has been shortened by 1.0–1.5 days of therapy with either of these drugs when treatment is administered within 2 days of onset of symptoms. Pooled analyses of clinical studies of oseltamivir suggest that treatment may reduce the likelihood of hospitalizations and of certain respiratory tract complications associated with influenza, and observational studies suggest that oseltamivir may reduce mortality rates associated with influenza A outbreaks (Chap. 224). Once-daily inhaled zanamivir or once-daily orally administered oseltamivir can provide prophylaxis against laboratory-documented influenza A– and influenza B–associated illness.


InternalMed_Harrison

InternalMed_Harrison. Resistance to the neuraminidase inhibitors may develop by changes in the viral neuraminidase enzyme, by changes in the hemagglutinin that make it more resistant to the actions of the neuraminidase, or by both mechanisms. Isolates that are resistant to oseltamivir—most commonly through the H275Y mutation, which leads to a change from histidine to tyrosine at that residue in the neuraminidase—remain sensitive to zanamivir. Certain mutations impart resistance to both oseltamivir and zanamivir (e.g., I223R, which leads to a change from isoleucine to arginine). Because the mechanisms of action of the neuraminidase inhibitors differ from those of the adamantanes (see below), zanamivir and oseltamivir are active against strains of influenza A virus that are resistant to amantadine and rimantadine.


InternalMed_Harrison

InternalMed_Harrison. Appropriate use of antiviral agents against influenza viruses depends on a knowledge of the resistance patterns of circulating viruses. As of this writing, currently circulating influenza A/H1N1 and H3N2 viruses (2013–2014) were sensitive to zanamivir and oseltamivir, with a few exceptions for oseltamivir. Up-to-date information on patterns of resistance to antiviral drugs is available from the Centers for Disease Control and Prevention (CDC) at www.cdc.gov/flu. Influenza A and B: treatment Influenza A: treatment Influenza A and B: prophylaxis Influenza A: prophylaxis Varicella: immunocompetent host Varicella: immunocompromised host Oral IV IV IV Adults: 75 mg bid × 5 d Children 1–12 years: 30–75 mg bid, depending on weight,a × 5 d Adults and children ≥7 years: 10 mg bid × 5 d Adults: 100 mg qd or bid × 5–7 d Children 1–9 years: 5 mg/kg per day (maximum, 150 mg/d) × 5–7 d Adults: 75 mg/d Children ≥1 year: 30–75 mg/d, depending on weighta


InternalMed_Harrison

InternalMed_Harrison. Adults: 100 mg qd or bid × 5–7 d Children 1–9 years: 5 mg/kg per day (maximum, 150 mg/d) × 5–7 d Adults: 75 mg/d Children ≥1 year: 30–75 mg/d, depending on weighta Adults and children ≥5 years: 10 mg/d Adults: 200 mg/d Children 1–9 years: 5 mg/kg per day (maximum, 150 mg/d) 5 mg/kg bid × 14–21 d; then 5 mg/kg per day as maintenance dose 900 mg bid × 21 d; then 900 mg/d as maintenance dose 60 mg/kg q8h × 14–21 d; then 90–120 mg/kg per day as maintenance dose 5 mg/kg once weekly × 2 weeks, then once every other week; given with probenecid and hydration 330 mg on days 1 and 15 followed by 330 mg monthly as maintenance 20 mg/kg (maximum, 800 mg) 4 or 5 times daily × 5 d


InternalMed_Harrison

InternalMed_Harrison. Children 2–18 years: 20 mg/kg tid (not to exceed 1 g tid) × 5 d 20 mg/kg q8h × 14–21 d When started within 2 d of onset in uncomplicated disease, zanamivir and oseltamivir reduce symptom duration by 1.0–1.5 and 1.3 d, respectively. Their effectiveness in prevention or treatment of complications is unclear, although some analyses suggest that oseltamivir may reduce the frequency of respiratory tract complications and hospitalizations. Oseltamivir's side effects of nausea and vomiting can be reduced in frequency by drug administration with food. Zanamivir may exacerbate bronchospasm in patients with asthma. Amantadine and rimantadine are not recommended for routine use unless antiviral susceptibilities are known because of widespread resistance in A/H3N2 viruses since 2005–2006 and in pandemic A/H1N1 viruses in 2009–2010. Their efficacy in treatment of uncomplicated disease caused by sensitive viruses has been similar to that of neuraminidase inhibitors.


InternalMed_Harrison

InternalMed_Harrison. Prophylaxis must be continued for the duration of exposure and can be administered simultaneously with inactivated vaccine. Unless the sensitivity of isolates is known, neither amantadine nor rimantadine is currently recommended for prophylaxis or therapy. Use of ribavirin is to be considered for treatment of infants and young children hospitalized with RSV pneumonia and bronchiolitis, according to the American Academy of Pediatrics. Ganciclovir, valganciclovir, foscarnet, and cidofovir are approved for treatment of CMV retinitis in patients with AIDS. They are also used for colitis, pneumonia, or “wasting” syndrome associated with CMV and for prevention of CMV disease in transplant recipients. Valganciclovir has largely supplanted oral ganciclovir and is frequently used in place of IV ganciclovir. Foscarnet is not myelosuppressive and is active against acyclovirand ganciclovir-resistant herpesviruses.


InternalMed_Harrison

InternalMed_Harrison. Foscarnet is not myelosuppressive and is active against acyclovirand ganciclovir-resistant herpesviruses. Fomivirsen has reduced the rate of progression of CMV retinitis in patients in whom other regimens have failed or have not been well tolerated. The major form of toxicity is ocular inflammation. Treatment confers modest clinical benefit when administered within 24 h of rash onset. A change to oral valacyclovir can be considered once fever has subsided if there is no evidence of visceral involvement. Results are optimal when therapy is initiated early. Some authorities recommend treatment for 21 d to prevent relapses. Serious morbidity is common despite therapy. Prolonged oral administration after initial IV therapy has been suggested because of long-term sequelae associated with cutaneous recurrences of HSV infection. Genital herpes simplex, primary: treatment Genital herpes simplex, recurrent: treatment Genital herpes simplex, recurrent: suppression


InternalMed_Harrison

InternalMed_Harrison. Genital herpes simplex, primary: treatment Genital herpes simplex, recurrent: treatment Genital herpes simplex, recurrent: suppression Mucocutaneous herpes simplex in immunocompromised host: treatment Mucocutaneous herpes simplex in immunocompromised host: prevention of recurrence during intense immunosuppression Herpes simplex orolabialis, recurrente Herpes zoster: immunocompetent host Acyclovir 125 mg bid × 5 d, 1000 mg bid × 1 d, or 500 mg once, then 250 mg PO bid × 3 doses 800 mg bid 5 mg/kg q12h 500 mg to 1 g bid or tid 500 mg bidc 1.0% cream applied q2h during waking hours × 4 d 1 drop of 1% ophthalmic solution q2h while awake (maximum, 9 drops daily) 0.5-in. ribbon of 3% ophthalmic ointment 5 times daily 800 mg 5 times daily × 7–10 d The IV route is preferred for infections severe enough to warrant hospitalization or with neurologic complications.


InternalMed_Harrison

InternalMed_Harrison. The oral route is preferred for patients whose condition does not warrant hospitalization. Adequate hydration must be maintained. Topical use—largely supplemented by oral therapy—may obviate systemic administration to pregnant women. Systemic symptoms and untreated areas are not affected. Valacyclovir appears to be as effective as acyclovir but can be administered less frequently. Famciclovir appears to be similar in effectiveness to acyclovir. The clinical effect is modest and is enhanced if therapy is initiated early. Treatment does not affect recurrence rates. Suppressive therapy is recommended only for patients with at least 6–10 recurrences per year. “Breakthrough” occasionally takes place, and asymptomatic shedding of virus occurs. The need for suppressive therapy should be reevaluated after 1 year. Suppression with valacyclovir reduces transmission of genital HSV among virus-discordant couples.


InternalMed_Harrison

InternalMed_Harrison. The choice of the IV or oral route and the duration of therapy depend on the severity of infection and the patient's ability to take oral medication. Oral or IV treatment has supplanted topical therapy except for small, easily accessible lesions. Foscarnet is used for acyclovir-resistant viruses. Treatment is administered during periods when intense immunosuppression is expected— e.g., during antitumor chemotherapy or after transplantation—and is usually continued for 2–3 months. Treatment shortens healing time and symptom duration by 0.5–1.0 d (versus placebo). Therapy begun at earliest symptom reduces disease duration by 1 d. Therapy begun within 1 h of prodrome decreases time to healing by 1.8–2.2 d. Application at initial symptoms reduces healing time by 1 d. Therapy should be undertaken in consultation with an ophthalmologist.


InternalMed_Harrison

InternalMed_Harrison. Application at initial symptoms reduces healing time by 1 d. Therapy should be undertaken in consultation with an ophthalmologist. Valacyclovir may be more effective than acyclovir for pain relief; otherwise, it has a similar effect on cutaneous lesions and should be given within 72 h of rash onset. The duration of postherpetic neuralgia is shorter than with placebo. Famciclovir showed overall efficacy similar to that of acyclovir in a comparative trial. It should be given ≤72 h after rash onset. Acyclovir causes faster resolution of skin lesions than placebo and provides some relief of acute symptoms if given within 72 h of rash onset. Combined with tapering doses of prednisone, acyclovir improves quality-of-life outcomes. Antiviral Chemotherapy, Excluding Antiretroviral Drugs


InternalMed_Harrison

InternalMed_Harrison. Antiviral Chemotherapy, Excluding Antiretroviral Drugs Herpes zoster: immunocompromised host 1 million units per wart (maximum of 5) thrice weekly × 3 weeks 250,000 units per wart (maximum of 10) twice weekly × up to 8 weeks 100 mg/d × 12–18 months; 150 mg bid as part of therapy for HIV infection 0.5 mg/d × 48 weeks (1 mg/d if HBV is resistant to lamivudine) 1.5 μg weekly × 48 weeks 1.5 μg/kg weekly (IFN)/ 800–1400 mg daily (ribavirin) × 24–48 weeks 9–15 μg thrice weekly × 6–12 months Effectiveness in localized zoster is most marked when treatment is given early. Foscarnet may be used for acyclovir-resistant VZV infections. Treatment reduces ocular complications, including ocular keratitis and uveitis. Intralesional treatment frequently results in regression of warts, but lesions often recur. Parenteral administration may be useful if lesions are numerous. HBeAg and DNA are eliminated in 33–37% of cases. Histopathologic improvement is also seen.


InternalMed_Harrison

InternalMed_Harrison. HBeAg and DNA are eliminated in 33–37% of cases. Histopathologic improvement is also seen. ALT levels return to normal in 39% of patients, and histologic improvement occurs in 38%. Lamivudine monotherapy is well tolerated and effective in reduction of HBV DNA levels, normalization of ALT levels, and improvement in histopathology. However, resistance develops in 24% of recipients when lamivudine is used as monotherapy for 1 year. A return of ALT levels to normal is documented in 48–72% of recipients and improved liver histopathology in 53–64%. Adefovir is effective in lamivudine-resistant hepatitis B. Renal function should be monitored. Normalization of ALT is seen in 68–78% of recipients and loss of HBeAg in 21%. Entecavir is active against lamivudine-resistant HBV.


InternalMed_Harrison

InternalMed_Harrison. Normalization of ALT is seen in 68–78% of recipients and loss of HBeAg in 21%. Entecavir is active against lamivudine-resistant HBV. HBV DNA is reduced by >5 log10 copies/mL along with normalization of ALT levels in 74–77% of patients and improved histopathology in 65–67%. Resistance develops in 9–22% of patients after 2 years of therapy. Elevated CPK levels and myopathy may occur. ALT levels return to normal in 68–76% of patients, and liver histopathology improves in 72–74%. Resistance is uncommon with up to 2 years of therapy. SVRs are noted in 20–30% of patients. Normalization of ALT levels and improvements in liver histopathology are also seen. Combination therapy results in SVR in up to 40–50% of recipients.


InternalMed_Harrison

InternalMed_Harrison. SVRs are noted in 20–30% of patients. Normalization of ALT levels and improvements in liver histopathology are also seen. Combination therapy results in SVR in up to 40–50% of recipients. The slower clearance of pegylated IFNs than of standard IFNs permits once-weekly administration. Pegylated formulations appear to be superior to standard IFNs in efficacy, both as monotherapy and in combination with ribavirin, and have largely supplanted standard IFNs in treatment of hepatitis C. SVRs were seen in 42–51% of patients infected with HCV genotype 1 and in 76–82% of those infected with genotype 2 or 3. Doses of 9 and 15 μg are equivalent to IFN-α2a and IFN-α2b doses of 3 million units and 5 million units, respectively. HCV genotypes 1, 4, 5, and 6: 400 mg qd with daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) and weekly pegylated IFN for 12 weeks. Genotypes 2 and 3: 400 mg qd with daily weight-based ribavirin for 12 and 24 weeks, respectively


InternalMed_Harrison

InternalMed_Harrison. Alternative regimen for genotypes 1 and 4: 150 mg qd for 12 weeks plus daily ribavirin and weekly pegylated IFN for 24 weeks and for 24–48 weeks, respectively Sofosbuvir is generally well tolerated, and most common side effects have been attributable to concomitantly administered IFN and ribavirin. Sofosbuvir is recommended in triple combination with pegylated IFN and ribavirin as first-line therapy for genotypes 1, 4, 5, and 6, with SVRs in 89–97% of treatment-naïve patients, and in double combination with ribavirin for genotypes 2 and 3.


InternalMed_Harrison

InternalMed_Harrison. Simeprevir has supplanted the first-generation protease inhibitors boceprevir and telaprevir. Its metabolism by cytochrome CYP3A can result in interactions with other drugs. Photosensitivity and reversible hyperbilirubinemia are associated toxicities. Testing for the Q80K-resistant variant should be carried out since this variant is present in one-third of HCV genotype 1a infections. Triple combinations with pegylated IFN and ribavirin result in SVRs in 80% of genotype 1 infections without Q80K. Chronic hepatitis D IFN-α2a or IFN-α2b SC 9 million units thrice weekly × 12 The overall efficacy and the optimal regimen months and duration of therapy are not fully established. Pegylated IFN-α2b SC Sustained SVRs have been seen in 25–30% of 1.5 μg weekly × 48 weeks IFN-α.


InternalMed_Harrison

InternalMed_Harrison. IFN-α. aFor detailed weight recommendations and for children <1 year of age, see www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. bAmantadine and rimantadine are not recommended for routine use because of widespread resistance in currently circulating A/H3N2 and pandemic A/H1N1 viruses. Their use may be considered if sensitivities become reestablished. cNot approved for this indication by the U.S. Food and Drug Administration (FDA). dApproved by the FDA for treatment of HIV-infected individuals. eAcyclovir suspension (15 mg/kg PO, to a maximum of 200 mg per dose) given for 7 d has been reported to be effective in treatment of primary herpetic gingivostomatitis in children. fActive ingredient: benzyl alcohol. Available without prescription. gConsult www.hcvguidelines.org for recommendations regarding treatment of null or partial responders to IFN regimens or of patients ineligible to receive IFN.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: ALT, alanine aminotransferase; CMV, cytomegalovirus; CPK, creatine phosphokinase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; IFN, interferon; RGT, response-guided therapy; RSV, respiratory syncytial virus; SVR, sustained virologic response; VZV, varicella-zoster virus. Zanamivir and oseltamivir have been approved by the U.S. Food and Drug Administration (FDA) for treatment of influenza in adults and in children (those ≥7 years old for zanamivir and those ≥1 year old for oseltamivir) who have been symptomatic for ≤2 days. Oseltamivir is approved for prophylaxis of influenza in individuals ≥1 year of age and zanamivir for those ≥5 years of age (Table 215e-1). Guidelines for the use of oseltamivir in children <1 year of age can be accessed through the CDC website, as noted in the footnote to Table 215e-1.


InternalMed_Harrison

InternalMed_Harrison. Peramivir is an investigational neuraminidase inhibitor that can be administered intravenously to patients for whom such an intervention is considered necessary. It has been approved in Japan, China, and South Korea but not in the United States, where it has been available in clinical trials through BioCryst Pharmaceuticals. Oseltamivir-resistant viruses generally exhibit reduced sensitivity to peramivir. Laninamivir octonoate is an investigational neuraminidase that has been approved in Japan. It is the prodrug of laninamivir, which is administered by oral inhalation and has a prolonged half-life of ~3 days. In limited studies, it has been investigated as single-dose therapy for influenza; its effects were similar to those obtained with multiple dosing of zanamivir or oseltamivir.


InternalMed_Harrison

InternalMed_Harrison. Amantadine and the closely related compound rimantadine are primary symmetric amines that have antiviral activity limited to influenza A viruses. Amantadine and rimantadine have a long history of efficacy in the prophylaxis and treatment of influenza A infections in humans. However, high frequencies of resistance to these drugs were noted among influenza A/H3N2 viruses in the 2005–2006 influenza season and continued to be seen in 2013–2014. The pandemic A/H1N1 viruses that circulated in 2009–2010 were also resistant to amantadine and rimantadine, and circulating influenza A/H1N1 viruses in the 2013–2014 season were largely resistant. Therefore, these agents are no longer recommended unless the sensitivity of the particular isolate of influenza A virus is known, in which case their use may be considered. Amantadine and rimantadine act through inhibition of the ion channel function of the influenza A M2 matrix protein, on which uncoating of the virus depends. A substitution of a single


InternalMed_Harrison

InternalMed_Harrison. be considered. Amantadine and rimantadine act through inhibition of the ion channel function of the influenza A M2 matrix protein, on which uncoating of the virus depends. A substitution of a single amino acid at critical sites in the M2 protein can result in a virus that is resistant to amantadine and rimantadine.


InternalMed_Harrison

InternalMed_Harrison. Amantadine and rimantadine have been shown to be effective in the prophylaxis of influenza A in large-scale studies of young adults and in less extensive studies of children and elderly persons. In such studies, efficacy rates of 55–80% in the prevention of influenza-like illness were noted, and even higher rates were reported when virus-specific attack rates were calculated. Amantadine and rimantadine have also been found to be effective in the treatment of influenza A infection in studies involving predominantly young adults and, to a lesser extent, children. Administration of these compounds within 24–72 h after the onset of illness has resulted in a reduction of the duration of signs and symptoms by ~50% compared with that in placebo recipients. The effect on signs and symptoms of illness is superior to that of commonly used antipyretic-analgesic agents. Only anecdotal reports are available concerning the efficacy of amantadine or rimantadine in the prevention or treatment of


InternalMed_Harrison

InternalMed_Harrison. illness is superior to that of commonly used antipyretic-analgesic agents. Only anecdotal reports are available concerning the efficacy of amantadine or rimantadine in the prevention or treatment of complications of influenza (e.g., pneumonia).


InternalMed_Harrison

InternalMed_Harrison. Amantadine and rimantadine are available only in oral formulations and are ordinarily administered to adults once or twice daily, with a dosage of 100–200 mg/d. Despite their structural similarities, the two compounds have different pharmacokinetics. Amantadine is not metabolized and is excreted almost entirely by the kidneys, with a half-life of 12–17 h and peak plasma concentrations of 0.4 μg/mL. In contrast, rimantadine is extensively metabolized to hydroxylated derivatives and has a half-life of 30 h. Only 30–40% of an orally administered dose of rimantadine is recovered in the urine. The peak plasma levels of rimantadine are approximately half those of amantadine,


InternalMed_Harrison

InternalMed_Harrison. Antiviral Chemotherapy, Excluding Antiretroviral Drugs but rimantadine is concentrated in respiratory secretions to a greater extent than amantadine. For prophylaxis, the compounds must be administered daily for the period at risk (i.e., duration of the exposure). For therapy, amantadine or rimantadine is generally administered for 5–7 days.


InternalMed_Harrison

InternalMed_Harrison. Although these compounds are generally well tolerated, 5–10% of amantadine recipients experience mild central nervous system side effects consisting primarily of dizziness, anxiety, insomnia, and difficulty in concentrating. These effects are rapidly reversible upon cessation of the drug’s administration. At a dose of 200 mg/d, rimantadine is better tolerated than amantadine; in a large-scale study of young adults, adverse effects were no more frequent among rimantadine recipients than among placebo recipients. Seizures and worsening of congestive heart failure have also been reported in patients treated with amantadine, although a causal relationship has not been established. The dosage of amantadine should be reduced to 100 mg/d in patients with renal insufficiency—i.e., a creatinine clearance rate (CrCl) of <50 mL/min—and in the elderly. A rimantadine dose of 100 mg/d should be used for patients with a CrCl of <10 mL/min and for the elderly.


InternalMed_Harrison

InternalMed_Harrison. Ribavirin is a synthetic nucleoside analogue that inhibits a wide range of RNA and DNA viruses. The mechanism of action of ribavirin is not completely defined and may be different for different groups of viruses. Ribavirin-5′-monophosphate blocks the conversion of inosine-5′-monophosphate to xanthosine-5′-monophosphate and interferes with the synthesis of guanine nucleotides as well as with that of both RNA and DNA. Ribavirin-5′-monophosphate also inhibits capping of virus-specific messenger RNA in certain viral systems.


InternalMed_Harrison

InternalMed_Harrison. Ribavirin administered as a small-particle aerosol to young children hospitalized with respiratory syncytial virus (RSV) infection has been clinically beneficial and has improved oxygenation in some studies (7 of 11). Although ribavirin has been approved for treatment of infants hospitalized with RSV infection, the American Academy of Pediatrics has recommended that it be considered on an individual basis rather than used routinely in that setting. Aerosolized ribavirin has also been administered to older children and adults (including immunosuppressed patients) with severe RSV and parainfluenza virus infections and to older children and adults with influenza A or B infection, but the benefit of this treatment, if any, is unclear. In RSV infections in immunosuppressed patients, ribavirin has been given in combination with anti-RSV immunoglobulins.


InternalMed_Harrison

InternalMed_Harrison. Orally administered ribavirin has not been effective in the treatment of influenza A virus infections. IV or oral ribavirin has reduced mortality rates among patients with Lassa fever; it has been particularly effective in this regard when given within the first 6 days of illness. IV ribavirin has been reported to be of clinical benefit in the treatment of hemorrhagic fever with renal syndrome caused by Hantaan virus and as therapy for Argentinean hemorrhagic fever. Oral ribavirin has also been recommended for the treatment and prophylaxis of Congo-Crimean hemorrhagic fever. Use of IV ribavirin in patients with hantavirus pulmonary syndrome in the United States has not been associated with clear-cut benefits.


InternalMed_Harrison

InternalMed_Harrison. Oral administration of ribavirin reduces serum aminotransferase levels in patients with chronic hepatitis C virus (HCV) infection; because it appears not to reduce serum HCV RNA levels, the mechanism of this effect is unclear. The drug provides added benefit when given by mouth in doses of 800–1200 mg/d in combination with interferon (IFN) α2b or α2a (see below), and the triple combination of ribavirin, IFN, and sofosbuvir or simeprevir has been approved for the treatment of patients with chronic HCV infection (see below). Recent data suggest that oral ribavirin may be beneficial in resolution of chronic hepatitis E infection associated with organ transplantation. Large oral doses of ribavirin (800–1000 mg/d) have been associated with reversible hematopoietic toxicity. This effect has not been observed with aerosolized ribavirin, apparently because little drug is absorbed systemically. Aerosolized administration of ribavirin is generally well tolerated but occasionally is associated


InternalMed_Harrison

InternalMed_Harrison. been observed with aerosolized ribavirin, apparently because little drug is absorbed systemically. Aerosolized administration of ribavirin is generally well tolerated but occasionally is associated with bronchospasm, rash, or conjunctival irritation. It should be administered under close supervision—particularly in the setting of mechanical ventilation, where precipitation of the drug is possible. Health care workers exposed to the drug have experienced minor toxicity, including eye and respiratory tract irritation. Because ribavirin is mutagenic, teratogenic, and embryotoxic, its use is generally contraindicated in pregnancy. Its administration as an aerosol poses a risk to pregnant health care workers. Because clearance of ribavirin is primarily renal, dose reduction is required in the setting of significant renal dysfunction.


InternalMed_Harrison

InternalMed_Harrison. DAS181 is an investigational antiviral agent with activity against influenza A and B and parainfluenza viruses. It is a sialidase linked to a respiratory epithelium–anchoring domain. This agent cleaves the terminal sialic acid residues on human respiratory cells, reducing the binding of the aforementioned respiratory viruses. DAS181 is administered by oral inhalation and is being evaluated in the treatment of parainfluenza type 3 infections in recipients of lung and stem cell transplants.


InternalMed_Harrison

InternalMed_Harrison. Acyclovir is a highly potent and selective inhibitor of the replication of certain herpesviruses, including herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). It is relatively ineffective in the treatment of human cytomegalovirus (CMV) infections; however, some studies have indicated effectiveness in the prevention of CMV-associated disease in immunosuppressed patients. Valacyclovir, the l-valyl ester of acyclovir, is converted almost entirely to acyclovir by intestinal and hepatic hydrolysis after oral administration. Valacyclovir offers pharmacokinetic advantages over orally administered acyclovir: it exhibits significantly greater oral bioavailability, results in higher blood levels, and can be given less frequently than acyclovir (two or three rather than five times daily).


InternalMed_Harrison

InternalMed_Harrison. The high degree of selectivity of acyclovir is related to its mechanism of action, which requires that the compound first be phosphorylated to acyclovir monophosphate. This phosphorylation occurs efficiently in herpesvirus-infected cells by means of a virus-coded thymidine kinase. In uninfected mammalian cells, little phosphorylation of acyclovir occurs, and the drug is therefore concentrated in herpesvirus-infected cells. Acyclovir monophosphate is subsequently converted by host cell kinases to a triphosphate that is a potent inhibitor of virus-induced DNA polymerase but has relatively little effect on host cell DNA polymerase. Acyclovir triphosphate can also be incorporated into viral DNA, with early chain termination.


InternalMed_Harrison

InternalMed_Harrison. Acyclovir is available in IV, oral, and topical forms, while valacyclovir is available in an oral formulation. IV acyclovir is effective in the treatment of mucocutaneous HSV infections in immunocompromised hosts, in whom it reduces time to healing, duration of pain, and virus shedding. When administered prophylactically during periods of intense immunosuppression (e.g., related to chemotherapy for leukemia or transplantation) and before the development of lesions, IV acyclovir reduces the frequency of HSV-associated disease. After prophylaxis is discontinued, HSV lesions recur. IV acyclovir is also effective in the treatment of HSV encephalitis.


InternalMed_Harrison

InternalMed_Harrison. Because VZV is generally less sensitive to acyclovir than is HSV, higher doses of acyclovir must be used to treat VZV infections. In immunocompromised patients with herpes zoster, IV acyclovir reduces the frequency of cutaneous dissemination and visceral complications and—in one comparative trial—was more effective than vidarabine. Acyclovir, administered at oral doses of 800 mg five times a day, had a modest beneficial effect on localized herpes zoster lesions in both immunocompromised and immunocompetent patients. Combination of acyclovir with a tapering regimen of prednisone appeared to be more effective than acyclovir alone in terms of quality-of-life outcomes in immunocompetent patients over age 50 with herpes zoster. A comparative study of acyclovir (800 mg PO five times daily) and valacyclovir (1 g PO three times daily) in immunocompetent patients with herpes zoster indicated that the latter drug may be more effective in eliciting the resolution of zoster-associated pain.


InternalMed_Harrison

InternalMed_Harrison. and valacyclovir (1 g PO three times daily) in immunocompetent patients with herpes zoster indicated that the latter drug may be more effective in eliciting the resolution of zoster-associated pain. Orally administered acyclovir (600 mg five times a day) reduced complications of herpes zoster ophthalmicus in a placebo-controlled trial.


InternalMed_Harrison

InternalMed_Harrison. In chickenpox, a modest overall clinical benefit is attained when oral acyclovir therapy is begun within 24 h of the onset of rash in otherwise healthy children (20 mg/kg, up to a maximum of 800 mg, four times a day) or adults (800 mg five times a day). IV acyclovir has also been reported to be effective in the treatment of immunocompromised children with chickenpox.


InternalMed_Harrison

InternalMed_Harrison. The most widespread use of acyclovir is in the treatment of genital HSV infections. IV or oral acyclovir or oral valacyclovir has shortened the duration of symptoms, reduced virus shedding, and accelerated healing when used for the treatment of primary genital HSV infections. Oral acyclovir and valacyclovir have also had a modest effect in treatment of recurrent genital HSV infections. However, the failure of treatment of either primary or recurrent disease to reduce the frequency of subsequent recurrences has indicated that acyclovir is ineffective in eliminating latent infection. Documented chronic oral administration of acyclovir for up to 6 years or of valacyclovir for up to 1 year has reduced the frequency of recurrences markedly during therapy; once the drug is discontinued, lesions recur. In one study, suppressive therapy with valacyclovir (500 mg once daily for 8 months) reduced transmission of HSV-2 genital infections among discordant couples by 50%. A modest effect on herpes


InternalMed_Harrison

InternalMed_Harrison. recur. In one study, suppressive therapy with valacyclovir (500 mg once daily for 8 months) reduced transmission of HSV-2 genital infections among discordant couples by 50%. A modest effect on herpes labialis (i.e., a reduction of disease duration by 1 day) was seen when valacyclovir was administered upon detection of the first symptom of a lesion at a dose of 2 g every 12 h for 1 day. In AIDS patients, chronic or intermittent administration of acyclovir has been associated with the development of HSV and VZV strains resistant to the action of the drug and with clinical failures. The most common mechanism of resistance is a deficiency of the virus-induced thymidine kinase. Patients with HSV or VZV infections resistant to acyclovir have frequently responded to foscarnet.


InternalMed_Harrison

InternalMed_Harrison. With the availability of the oral and IV forms, there are few indications for topical acyclovir, although treatment with this formulation has been modestly beneficial in primary genital HSV infections and in mucocutaneous HSV infections in immunocompromised hosts.


InternalMed_Harrison

InternalMed_Harrison. Overall, acyclovir is remarkably well tolerated and is generally free of toxicity. The most frequently encountered form of toxicity is renal dysfunction because of drug crystallization, particularly after rapid IV administration or with inadequate hydration. Central nervous system changes, including lethargy and tremors, are occasionally reported, primarily in immunosuppressed patients. However, whether these changes are related to acyclovir, to concurrent administration of other therapy, or to underlying infection remains unclear. Acyclovir is excreted primarily unmetabolized by the kidneys via both glomerular filtration and tubular secretion. Approximately 15% of a dose of acyclovir is metabolized to 9-[(carboxymethoxy)methyl]guanine or other minor metabolites. Reduction in dosage is indicated in patients with a CrCl of <50 mL/min. The half-life of acyclovir is ~3 h in normal adults, and the peak plasma concentration after a 1-h infusion of a dose of 5 mg/kg is 9.8 μg/mL.


InternalMed_Harrison

InternalMed_Harrison. is indicated in patients with a CrCl of <50 mL/min. The half-life of acyclovir is ~3 h in normal adults, and the peak plasma concentration after a 1-h infusion of a dose of 5 mg/kg is 9.8 μg/mL. Approximately 22% of an orally administered acyclovir dose is absorbed, and peak plasma concentrations of 0.3–0.9 μg/mL are attained after administration of a 200-mg dose. Acyclovir penetrates relatively well into the cerebrospinal fluid (CSF), with concentrations approaching half of those found in plasma.


InternalMed_Harrison

InternalMed_Harrison. Acyclovir causes chromosomal breakage at high doses, but its administration to pregnant women has not been associated with fetal abnormalities. Nonetheless, the potential risks and benefits of acyclovir should be carefully assessed before the drug is used in pregnancy.


InternalMed_Harrison

InternalMed_Harrison. Valacyclovir exhibits three to five times greater bioavailability than acyclovir. The concentration-time curve for valacyclovir, given as 1 g PO three times daily, is similar to that for acyclovir, given as 5 mg/kg IV every 8 h. The safety profiles of valacyclovir and acyclovir are similar, although thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome has been reported in immunocompromised patients who have received high doses of valacyclovir (8 g/d). Valacyclovir is approved for the treatment of herpes zoster, of initial and recurrent episodes of genital HSV infection, and of herpes labialis in immunocompetent adults as well as for suppressive treatment of genital herpes. Although it has not been extensively studied in other clinical settings involving HSV or VZV infections, many consultants use valacyclovir rather than oral acyclovir in settings where only the latter has been approved because of valacyclovir’s superior pharmacokinetics and more convenient dosing schedule.


InternalMed_Harrison

InternalMed_Harrison. Cidofovir is a phosphonate nucleotide analogue of cytosine. Its major use is in CMV infections, but it is active against a broad range of herpesviruses, including HSV, human herpesvirus (HHV) types 6A and 6B, HHV-8, and certain other DNA viruses such as polyomaviruses, papillomaviruses, adenoviruses, and poxviruses, including variola (smallpox) and vaccinia. Cidofovir does not require initial phosphorylation by virus-induced kinases; the drug is phosphorylated by host cell enzymes to cidofovir diphosphate, which is a competitive inhibitor of viral DNA polymerases and, to a lesser extent, of host cell DNA polymerases. Incorporation of cidofovir diphosphate slows or terminates nascent DNA chain elongation. Cidofovir is active against HSV isolates that are resistant to acyclovir because of absent or altered thymidine kinase and against CMV isolates that are resistant to ganciclovir because of UL97 phosphotransferase mutations. CMV isolates resistant to ganciclovir on the basis of UL54


InternalMed_Harrison

InternalMed_Harrison. absent or altered thymidine kinase and against CMV isolates that are resistant to ganciclovir because of UL97 phosphotransferase mutations. CMV isolates resistant to ganciclovir on the basis of UL54 mutations are usually resistant to cidofovir as well. Cidofovir is usually active against foscarnet-resistant CMV, although cross-resistance to foscarnet has been described.


InternalMed_Harrison

InternalMed_Harrison. Cidofovir has poor oral availability and is administered intravenously. It is excreted primarily by the kidney and has a plasma half-life of 2.6 h. Cidofovir diphosphate’s intracellular half-life of >48 h is the basis for the recommended dosing regimen of 5 mg/kg once a week for the initial 2 weeks and then 5 mg/kg every other week. The major toxic effect of cidofovir is proximal renal tubular injury, as manifested by elevated serum creatinine levels and proteinuria. The risk of nephrotoxicity can be reduced by vigorous saline hydration and by concomitant oral administration of probenecid. Neutropenia, rashes, and gastrointestinal tolerance may also occur.


InternalMed_Harrison

InternalMed_Harrison. IV cidofovir has been approved for the treatment of CMV retinitis in AIDS patients who are intolerant of ganciclovir or foscarnet or in whom those drugs have failed. In a controlled study, a maintenance dosage of 5 mg/kg per week administered to AIDS patients reduced the progression of CMV retinitis from that seen at 3 mg/kg. Intravitreal cidofovir has been used to treat CMV retinitis but has been associated with significant toxicity. IV cidofovir has been reported anecdotally to be effective for treatment of acyclovir-resistant mucocutaneous HSV infections. Likewise, topically administered cidofovir is reportedly beneficial against mucocutaneous HSV infections in HIV-infected patients. Anecdotal use of IV cidofovir has been described in disseminated adenoviral infections in immunosuppressed patients and in genitourinary infections with BK virus in renal transplant recipients; however, its efficacy, if any, in these circumstances is not established.


InternalMed_Harrison

InternalMed_Harrison. CMX-001 (brincidofovir) is an ester prodrug of cidofovir that can be administered orally and may be less nephrotoxic than IV cidofovir. It is being evaluated for prevention of CMV infection in stem cell transplant recipients and for treatment of BK nephropathy and adenovirus infections.


InternalMed_Harrison

InternalMed_Harrison. Fomivirsen is the first antisense oligonucleotide approved by the FDA for therapy in humans. This phosphorothioate oligonucleotide, 21 nucleotides in length, inhibits CMV replication through interaction with CMV messenger RNA. Fomivirsen is complementary to messenger transcripts of the major immediate early region 2 (IE2) of CMV, which codes for proteins regulating viral gene expression. In addition to its antisense mechanism of action, fomivirsen may exert activity against CMV through inhibition of viral adsorption to cells as well as direct inhibition of viral replication. Because of its different mechanism of action, fomivirsen is active against CMV isolates that are resistant to nucleoside or nucleotide analogues, such as ganciclovir, foscarnet, or cidofovir. Antiviral Chemotherapy, Excluding Antiretroviral Drugs


InternalMed_Harrison

InternalMed_Harrison. Antiviral Chemotherapy, Excluding Antiretroviral Drugs Fomivirsen has been approved for intravitreal administration in the treatment of CMV retinitis in AIDS patients who have failed to respond to other treatments or cannot tolerate them. Injections of 330 mg for two doses 2 weeks apart, followed by maintenance doses of 330 mg monthly, significantly reduce the rate of progression of CMV retinitis. The major toxicity is ocular inflammation, including vitritis and iritis, which usually responds to topically administered glucocorticoids.


InternalMed_Harrison

InternalMed_Harrison. An analogue of acyclovir, ganciclovir is active against HSV and VZV and is markedly more active than acyclovir against CMV. Ganciclovir triphosphate inhibits CMV DNA polymerase and can be incorporated into CMV DNA, whose elongation it eventually terminates. In HSV-and VZV-infected cells, ganciclovir is phosphorylated by virus-encoded thymidine kinases; in CMV-infected cells, it is phosphorylated by a viral kinase encoded by the UL97 gene. Ganciclovir triphosphate is present in tenfold higher concentrations in CMV-infected cells than in uninfected cells. Ganciclovir is approved for the treatment of CMV retinitis in immunosuppressed patients and for the prevention of CMV disease in transplant recipients. It is widely used for the treatment of other CMV-associated syndromes, including pneumonia, esophagogastrointestinal infections, hepatitis, and “wasting” illness.


InternalMed_Harrison

InternalMed_Harrison. Ganciclovir is available for IV or oral administration. Because its oral bioavailability is low (5–9%), relatively large doses (1 g three times daily) must be administered by this route. Oral ganciclovir has largely been supplanted by valganciclovir, which is the l-valyl ester of ganciclovir. Valganciclovir is well absorbed orally, with a bioavailability of 60%, and is rapidly hydrolyzed to ganciclovir in the intestine and liver. The area under the curve for a 900-mg dose of valganciclovir is equivalent to that for 5 mg/kg of IV ganciclovir, although peak serum concentrations are ~40% lower for valganciclovir. The serum half-life is 3.5 h after IV administration of ganciclovir and 4.0 h after PO administration of valganciclovir. Ganciclovir is excreted primarily by the kidneys in an unmetabolized form, and its dosage should be reduced in cases of renal failure. Ganciclovir therapy at the most commonly used initial IV dosage—i.e., 5 mg/kg every 12 h for 14–21 days—can be changed to


InternalMed_Harrison

InternalMed_Harrison. form, and its dosage should be reduced in cases of renal failure. Ganciclovir therapy at the most commonly used initial IV dosage—i.e., 5 mg/kg every 12 h for 14–21 days—can be changed to valganciclovir (900 mg PO twice daily) when the patient can tolerate oral therapy. The maintenance dose is 5 mg/kg IV daily or five times per week for ganciclovir and 900 mg by mouth once a day for valganciclovir. Dose adjustment in patients with renal dysfunction is required. Intraocular ganciclovir, given by either intravitreal injection or intraocular implantation, has also been used to treat CMV retinitis.


InternalMed_Harrison

InternalMed_Harrison. Ganciclovir is effective as prophylaxis against CMV-associated disease in organ and bone marrow transplant recipients. Oral ganciclovir administered prophylactically to AIDS patients with CD4+ T cell counts of <100/μL has provided protection against the development of CMV retinitis. However, the long-term benefits of this approach to prophylaxis in AIDS patients have not been established, and most experts do not recommend the use of oral ganciclovir for this purpose. As already mentioned, valganciclovir has supplanted oral ganciclovir in settings where oral prophylaxis or therapy is considered. The administration of ganciclovir has been associated with profound bone marrow suppression, particularly neutropenia, which significantly limits the drug’s use in many patients. Bone marrow toxicity is potentiated in the setting of renal dysfunction and when other bone marrow suppressants, such as zidovudine or mycophenolate mofetil, are used concomitantly.


InternalMed_Harrison

InternalMed_Harrison. Resistance has been noted in CMV isolates obtained after therapy with ganciclovir, especially those from patients with AIDS or from patients receiving prolonged ganciclovir therapy after organ transplantation. Such resistance may develop through a mutation in either the viral UL97 gene or the viral DNA polymerase. Ganciclovir-resistant isolates are usually sensitive to foscarnet (see below) or may be sensitive to cidofovir, depending on the mechanism of resistance (see above).


InternalMed_Harrison

InternalMed_Harrison. Famciclovir is the diacetyl 6-deoxyester of the guanosine analogue penciclovir. This agent is well absorbed orally, has a bioavailability of 77%, and is rapidly converted to penciclovir by deacetylation and oxidation in the intestine and liver. Penciclovir’s spectrum of activity and mechanism of action are similar to those of acyclovir. Thus, penciclovir usually is not active against acyclovir-resistant viruses. However, some acyclovir-resistant viruses with altered thymidine kinase or DNA polymerase substrate specificity may be sensitive to penciclovir. This drug is phosphorylated initially by a virus-encoded thymidine kinase and subsequently by cellular kinases to penciclovir triphosphate, which inhibits HSV-1, HSV-2, VZV, and EBV as well as hepatitis B virus (HBV). The serum half-life of penciclovir is 2 h, but the intracellular half-life of penciclovir triphosphate is 7–20 h—markedly longer than that of acyclovir triphosphate. The latter is the basis for the less frequent


InternalMed_Harrison

InternalMed_Harrison. of penciclovir is 2 h, but the intracellular half-life of penciclovir triphosphate is 7–20 h—markedly longer than that of acyclovir triphosphate. The latter is the basis for the less frequent (twice-daily) dosing schedule for famciclovir than for acyclovir. Penciclovir is eliminated primarily in the urine by both glomerular filtration and tubular secretion. The usually recommended dosage interval should be adjusted for renal insufficiency.


InternalMed_Harrison

InternalMed_Harrison. Clinical trials involving immunocompetent adults with herpes zoster showed that famciclovir was superior to placebo in eliciting the resolution of skin lesions and virus shedding and in shortening the duration of postherpetic neuralgia; moreover, administered at 500 mg every 8 h, famciclovir was at least as effective as acyclovir administered at an oral dose of 800 mg five times daily. Famciclovir was also effective in the treatment of herpes zoster in immunosuppressed patients. Clinical trials have demonstrated its effectiveness in the suppression of genital HSV infections for up to 1 year and in the treatment of initial and recurrent episodes of genital herpes. Famciclovir is effective as therapy for mucocutaneous HSV infections in HIV-infected patients. Application of a 1% penciclovir cream reduces the duration of signs and symptoms of herpes labialis in immunocompetent patients (by 0.5–1 day) and has been approved for that purpose by the FDA. Famciclovir is generally well


InternalMed_Harrison

InternalMed_Harrison. cream reduces the duration of signs and symptoms of herpes labialis in immunocompetent patients (by 0.5–1 day) and has been approved for that purpose by the FDA. Famciclovir is generally well tolerated, with occasional headache, nausea, and diarrhea reported in frequencies similar to those among placebo recipients. The administration of high doses of famciclovir for 2 years was associated with an increased incidence of mammary adenocarcinomas in female rats, but the clinical significance of this effect is unknown.


InternalMed_Harrison

InternalMed_Harrison. Foscarnet (phosphonoformic acid) is a pyrophosphate-containing compound that potently inhibits herpesviruses, including CMV. This drug inhibits DNA polymerases at the pyrophosphate binding site at concentrations that have relatively little effect on cellular polymerases. Foscarnet does not require phosphorylation to exert its antiviral activity and is therefore active against HSV and VZV isolates that are resistant to acyclovir because of deficiencies in thymidine kinase as well as against most ganciclovir-resistant strains of CMV. Foscarnet also inhibits the reverse transcriptase of HIV and is active against HIV in vivo.


InternalMed_Harrison

InternalMed_Harrison. Foscarnet is poorly soluble and must be administered intravenously via an infusion pump in a dilute solution over 1–2 h. The plasma half-life of foscarnet is 3–5 h and increases with decreasing renal function because the drug is eliminated primarily by the kidneys. It has been estimated that 10–28% of a dose may be deposited in bone, where it can persist for months. The most common initial dosage of foscarnet—60 mg/kg every 8 h for 14–21 days—is followed by a maintenance dose of 90–120 mg/kg once a day.


InternalMed_Harrison

InternalMed_Harrison. Foscarnet is approved for the treatment of CMV retinitis in patients with AIDS and of acyclovir-resistant mucocutaneous HSV infections. In a comparative clinical trial, the drug appeared to be about as efficacious as ganciclovir against CMV retinitis but was associated with a longer survival period, possibly because of its activity against HIV. Intraocular foscarnet has been used to treat CMV retinitis. In addition, foscarnet has been employed to treat acyclovir-resistant HSV and VZV infections as well as ganciclovir-resistant CMV infections, although resistance to foscarnet has been reported in CMV isolates obtained during therapy. Foscarnet has also been used to treat HHV-6 infections in immunosuppressed patients.


InternalMed_Harrison

InternalMed_Harrison. The major form of toxicity associated with foscarnet is renal impairment. Thus renal function should be monitored closely, particularly during the initial phase of therapy. Because foscarnet binds divalent metal ions, hypocalcemia, hypomagnesemia, hypokalemia, and hypoor hyperphosphatemia can develop. Saline hydration and slow infusion appear to protect the patient against nephrotoxicity and electrolyte disturbances. Although hematologic abnormalities have been documented (most commonly anemia), foscarnet is not generally myelosuppressive and can be administered concomitantly with myelosuppressive medications.


InternalMed_Harrison

InternalMed_Harrison. Trifluridine is a pyrimidine nucleoside active against HSV-1, HSV-2, and CMV. Trifluridine monophosphate irreversibly inhibits thymidylate synthetase, and trifluridine triphosphate inhibits viral and, to a lesser extent, cellular DNA polymerases. Because of systemic toxicity, trifluridine’s use is limited to topical therapy. Trifluridine is approved for treatment of HSV keratitis, against which trials have shown that it is more effective than topical idoxuridine but similar in efficacy to topical vidarabine. The drug has benefited some patients with HSV keratitis who have failed to respond to idoxuridine or vidarabine. Topical application of trifluridine to sites of acyclovir-resistant HSV mucocutaneous infection has also been beneficial in some cases.


InternalMed_Harrison

InternalMed_Harrison. Vidarabine is a purine nucleoside analogue with activity against HSV-1, HSV-2, VZV, and EBV. Vidarabine inhibits viral DNA synthesis through its 5′-triphosphorylated metabolite, although its precise molecular mechanisms of action are not completely understood. IV-administered vidarabine has been shown to be effective in the treatment of herpes simplex encephalitis, mucocutaneous HSV infections, herpes zoster in immunocompromised patients, and neonatal HSV infections. Its use has been supplanted by that of IV acyclovir, which is more effective and easier to administer. Production of the IV preparation has been discontinued by the manufacturer, but vidarabine is available as an ophthalmic ointment, which is effective in the treatment of HSV keratitis.


InternalMed_Harrison

InternalMed_Harrison. Maribavir is a benzimidazole that inhibits CMV and EBV. This drug inhibits the CMV UL97 kinase and does not require intracellular phosphorylation for its antiviral activity. Its mechanism of action involves blocking viral DNA synthesis and virion egress. Maribavir is orally administered and has been associated with taste disturbance and diarrhea. In phase 3 studies, it was not efficacious in the prevention of CMV infection in recipients of hematopoietic stem cell and adult liver transplants. However, when used at somewhat higher doses, it may be efficacious for the treatment of refractory or resistant CMV infections in transplant recipients.


InternalMed_Harrison

InternalMed_Harrison. Letermovir is an investigational drug with activity against CMV. It is a dihydroquinozoline that acts through inhibition of the viral terminase enzyme complex. This mechanism of action differs from that of ganciclovir, foscarnet, and cidofovir, which inhibit viral DNA polymerase; therefore, letermovir is active against CMV isolates that are resistant to those drugs. It is orally administered and is reportedly well tolerated. Letermovir is being evaluated as prophylaxis against CMV in hematopoietic stem cell recipients.


InternalMed_Harrison

InternalMed_Harrison. Inhibition of the helicase-primase heterotrimeric complex of HSV-1 and HSV-2 represents a novel mechanism of action of amenamevir and pritelivir. These drugs are being assessed for prevention and treatment of HSV genital infection. The efficacy of amenamevir, administered as a single oral dose of 1200 mg for recurrent genital herpes, was comparable to that of valacyclovir given for 3 days. Pritelivir has a long half-life (up to 80 h) and was studied in a placebo-controlled trial of suppression of genital HSV infections. Compared with placebo, pritelivir—a loading dose followed by either a daily oral dose of 75 mg for 4 weeks or a weekly dose of 400 mg for 4 weeks—reduced HSV shedding and days of genital lesions. Additional clinical studies of the helicase-primase inhibitors of HSV are planned.


InternalMed_Harrison

InternalMed_Harrison. Lamivudine is a pyrimidine nucleoside analogue that is used primarily in combination therapy against HIV infection (Chap. 226). Its activity against HBV is attributable to inhibition of the viral DNA polymerase. This drug has also been approved for the treatment of chronic HBV infection. At doses of 100 mg/d given for 1 year to patients positive for hepatitis B e antigen (HBeAg), lamivudine is well tolerated and results in suppression of HBV DNA levels, normalization of serum aminotransferase levels in 40–75% of patients, and reduction of hepatic inflammation and fibrosis in 50–60% of patients. Loss of HBeAg occurs in 30% of patients. Lamivudine also appears to be useful in the prevention or suppression of HBV infection associated with liver transplantation. Resistance to lamivudine develops in 24% of patients treated for 1 year and is associated with changes in the YMDD motif of HBV DNA polymerase. Because of the frequency of development of resistance, lamivudine has been largely


InternalMed_Harrison

InternalMed_Harrison. in 24% of patients treated for 1 year and is associated with changes in the YMDD motif of HBV DNA polymerase. Because of the frequency of development of resistance, lamivudine has been largely supplanted by less-resistanceprone drugs for the treatment of HBV infection.


InternalMed_Harrison

InternalMed_Harrison. Adefovir dipivoxil is the oral prodrug of adefovir, an acyclic nucleotide analogue of adenosine monophosphate that is active against HBV, HIV, HSV, CMV, and poxviruses. It is phosphorylated by cellular kinases to the active triphosphate moiety, which is a competitive inhibitor of HBV DNA polymerase and results in chain termination after incorporation into nascent viral DNA. Adefovir is administered orally and is eliminated primarily by the kidneys, with a plasma half-life of 5–7.5 h. In clinical studies, therapy with adefovir at a dose of 10 mg/d for 48 weeks resulted in normalization of serum alanine aminotransferase (ALT) levels in 48–72% of patients and improved liver histology in 53–64%; it also resulted in a 3.5to 3.9-log10 reduction in the number of HBV DNA copies per milliliter of plasma. Adefovir was effective in treatment-naïve patients as well as in those infected with lamivudineresistant HBV. Resistance to adefovir appears to develop less readily than that to lamivudine,


InternalMed_Harrison

InternalMed_Harrison. plasma. Adefovir was effective in treatment-naïve patients as well as in those infected with lamivudineresistant HBV. Resistance to adefovir appears to develop less readily than that to lamivudine, but adefovir resistance rates of 15–18% have been reported after 192 weeks of treatment and may reach 30% after 5 years. This agent is generally well tolerated. Significant nephrotoxicity attributable to adefovir is uncommon at the dose used in the treatment of HBV infections (10 mg/d) but is a treatment-limiting adverse effect at the higher doses used in therapy for HIV infections (30–120 mg/d). In any case, renal function should be monitored in patients taking adefovir, even at the lower dose. Adefovir is approved only for treatment of chronic HBV infection.


InternalMed_Harrison

InternalMed_Harrison. Tenofovir disoproxil fumarate is a prodrug of tenofovir, a nucleotide analogue of adenosine monophosphate with activity against both retroviruses and hepadnaviruses. In both immunocompetent and immunocompromised patients (including those co-infected with HIV and HBV), tenofovir given at a dose of 300 mg/d for 48 weeks reduced HBV replication by 4.6–6 log10, normalized ALT levels in 68–76% of patients, and improved liver histopathology in 72–74% of patients. Resistance develops uncommonly during ≥2 years of therapy, and tenofovir is active against lamivudine-resistant HBV. The safety profile of tenofovir is similar to that of adefovir, but nephrotoxicity has not been encountered at the dose used for HBV therapy. Tenofovir is approved for the treatment of HIV and chronic HBV infections. For a more detailed discussion of tenofovir, see Chap. 226.


InternalMed_Harrison

InternalMed_Harrison. Entecavir is a cyclopentyl 2′-deoxyguanosine analogue that inhibits HBV through interaction of entecavir triphosphate with several HBV DNA polymerase functions. At a dose of 0.5 mg/d given for 48 weeks, entecavir reduced HBV DNA copies by 5.0–6.9 log10, normalized serum aminotransferase levels in 68–78% of patients, and improved histopathology in 70–72% of patients. Entecavir inhibits lamivudineresistant viruses that have M550I or M550V/L526M mutations but only at serum concentrations 20or 30-fold higher than those obtained with the 0.5-mg/d dose. Thus, higher doses of entecavir (1 mg/d) are recommended for the treatment of patients infected with lamivudineresistant HBV. Development of resistance to entecavir is uncommon in treatment-naïve patients but does occur at unacceptably high rates


InternalMed_Harrison

InternalMed_Harrison. Antiviral Chemotherapy, Excluding Antiretroviral Drugs (43% after 4 years) in patients previously infected with lamivudineresistant virus. Entecavir-resistant strains appear to be sensitive to adefovir and tenofovir.


InternalMed_Harrison

InternalMed_Harrison. Entecavir is highly bioavailable but should be taken on an empty stomach because food interferes with its absorption. The drug is eliminated primarily in unchanged form by the kidneys, and its dosage should be adjusted for patients with CrCl values of <50 mL/min. Overall, entecavir is well tolerated, with a safety profile similar to that of lamivudine. As with other anti-HBV treatments, exacerbation of hepatitis may occur when entecavir therapy is stopped. Entecavir is approved for treatment of chronic hepatitis B, including infection with lamivudineresistant viruses, in adults. Entecavir has some activity against HIV-1 (median effective concentration, 0.026 to >10 μM) but should not be used as monotherapy in HIV-positive patients because of the potential for development of HIV resistance due to the M184V mutation.


InternalMed_Harrison

InternalMed_Harrison. Telbivudine is a β-l enantiomer of thymidine and is a potent, selective inhibitor of HBV. Its active form is telbivudine triphosphate, which inhibits HBV DNA polymerase and causes chain termination but has little or no activity against human DNA polymerase. Administration of telbivudine at an oral dose of 600 mg/d for 52 weeks to patients with chronic hepatitis B resulted in reduction of HBV DNA by 5.2–6.4 log10 copies/mL along with normalization of ALT levels in 74–77% of recipients and improved histopathology in 65–67% of patients. Telbivudineresistant HBV is generally cross-resistant with lamivudine-resistant virus but is usually susceptible to adefovir. After 2 years of therapy, resistance to telbivudine was noted in isolates from 22% of HBeAgpositive patients and in those from 9% of HBeAg-negative patients.


InternalMed_Harrison

InternalMed_Harrison. Orally administered telbivudine is rapidly absorbed; because it is eliminated primarily by the kidneys, its dosage should be reduced in patients with a CrCl value of <50 mL/min. Telbivudine is generally well tolerated, but increases in serum levels of creatinine kinases as well as fatigue and myalgias have been observed. As with other anti-HBV drugs, hepatitis may be exacerbated in patients who discontinue telbivudine therapy. Telbivudine has been approved for the treatment of adults with chronic hepatitis B who have evidence of viral replication and either persistently elevated serum aminotransferase levels or histopathologically active disease, but it has not been widely used because of the frequency of development of resistance, as noted above. IFNs are cytokines that exhibit a broad spectrum of antiviral activities as well as immunomodulating and antiproliferative properties. IFNs are not available for oral administration but must be given IM, SC, or


InternalMed_Harrison

InternalMed_Harrison. IV. Early studies with human leukocyte IFN demonstrated an effect in the prophylaxis of experimentally induced rhinovirus infections in humans and in the treatment of VZV infections in immunosuppressed patients. DNA recombinant technology has made available highly purified α, β, γ, and λ IFNs that have been evaluated in a variety of viral infections. Results of such trials have confirmed the effectiveness of intranasally administered IFN in the prophylaxis of rhinovirus infections, although its use has been associated with nasal mucosal irritation. Studies have also demonstrated a beneficial effect of intralesionally or systemically administered IFNs on genital warts. The effect of systemic administration consists primarily of a reduction in the size of the warts, and this mode of therapy may be useful in persons who have numerous warts that cannot easily be treated by individual intralesional injections. However, lesions frequently recur after either intralesional or systemic IFN


InternalMed_Harrison

InternalMed_Harrison. may be useful in persons who have numerous warts that cannot easily be treated by individual intralesional injections. However, lesions frequently recur after either intralesional or systemic IFN therapy is discontinued.


InternalMed_Harrison

InternalMed_Harrison. IFNs have undergone extensive study in the treatment of chronic HBV infection. The administration of standard IFN-α2b (5 million units daily or 10 million units three times a week for 16–24 weeks) to patients with stable chronic HBV infection resulted in loss of markers of HBV replication, such as HBeAg and HBV DNA, in 33–37% of cases; 8% of patients also became negative for hepatitis B surface antigen. In most patients who lose HBeAg and HBV DNA markers, serum aminotransferases return to normal levels, and both shortand long-term improvements in liver histopathology have been described. Predictors of a favorable response to standard IFN therapy include low pretherapy levels of HBV DNA, high pretherapy serum levels of ALT, a short duration of chronic HBV infection, and active inflammation in liver histopathology. Poor responses are seen in immunosuppressed patients, including those with HIV infection.


InternalMed_Harrison

InternalMed_Harrison. In pegylated IFNs, IFN alphas are linked to polyethylene glycol. This linkage results in slower absorption, decreased clearance, and more sustained serum concentrations, thereby permitting a more convenient, once-weekly dosing schedule; in many instances, pegylated IFN has supplanted standard IFN. After 48 weeks of treatment with 180 μg of pegylated IFN-α2a, HBV DNA was reduced by 4.1–4.5 log10 copies/mL, with normalization of serum ALT levels in 39% of patients and improved histology in 38%. Response rates were somewhat higher when lamivudine was administered with pegylated IFN-α2a. Adverse effects of IFN are common and include fever, chills, myalgia, fatigue, neurotoxicity (manifested primarily as somnolence, depression, anxiety, and confusion), and leukopenia. Autoantibodies (e.g., antithyroid antibodies) can also develop. IFN-α2b and pegylated IFN-α2a are approved for the treatment of patients with chronic hepatitis B. Data supporting the therapeutic efficacy of pegylated


InternalMed_Harrison

InternalMed_Harrison. antithyroid antibodies) can also develop. IFN-α2b and pegylated IFN-α2a are approved for the treatment of patients with chronic hepatitis B. Data supporting the therapeutic efficacy of pegylated interferon-α2b in HBV infection have been published; the drug has not been approved for this indication in the United States but has been approved for treatment of chronic HBV infection in other countries.


InternalMed_Harrison

InternalMed_Harrison. Several IFN preparations, including IFN-α2a, IFN-α2b, IFNalfacon-1, and IFN-αm1 (lymphoblastoid), have been studied as therapy for chronic HCV infections. A variety of monotherapy regimens have been studied, of which the most common for standard IFN is IFN-α2b or -α2a at 3 million units three times per week for 12–18 months. The addition of oral ribavirin to IFN-α2b—either as initial therapy or after failure of IFN therapy alone—results in significantly higher rates of sustained virologic and/or serum ALT responses (40–50%) than are obtained with monotherapy. Comparative studies indicate that pegylated IFN-α2b or -α2a therapy is more effective than standard IFN treatment against chronic HCV infection. The combination of SC pegylated IFN and oral ribavirin results in sustained virologic responses (SVRs) in 42–51% of patients with HCV genotype 1 infection and in 76–82% of patients with genotype 2 or 3 infection. Ribavirin appears to have a small antiviral effect in HCV infection but may


InternalMed_Harrison

InternalMed_Harrison. (SVRs) in 42–51% of patients with HCV genotype 1 infection and in 76–82% of patients with genotype 2 or 3 infection. Ribavirin appears to have a small antiviral effect in HCV infection but may also be working through an immunomodulatory effect in combination with IFN. Optimal results with ribavirin appear to be associated with weight-based dosing. Prognostic factors for a favorable response include an age of <40 years, a short duration of infection, low levels of HCV RNA, a lesser degree of liver histopathology, and infection with HCV genotypes other than 1. IFN-alfacon, a synthetic “consensus” α interferon, appears to produce response rates similar to those elicited by standard IFN-α2a or -α2b alone. In 2014, the approval of a polymerase inhibitor, sofosbuvir, and a second-generation protease inhibitor, simeprevir, led to revised recommendations for treatment of hepatitis C with triple combinations of pegylated IFN, ribavirin, and one of these two drugs, depending on the viral


InternalMed_Harrison

InternalMed_Harrison. protease inhibitor, simeprevir, led to revised recommendations for treatment of hepatitis C with triple combinations of pegylated IFN, ribavirin, and one of these two drugs, depending on the viral genotype (see below and Table 215e-1).


InternalMed_Harrison

InternalMed_Harrison. IFN-α and pegylated IFN-α are active against hepatitis D, but high doses are required (9 million units three times per week for 48 weeks). IFN-α elicited an SVR in 25–30% of patients, whereas pegylated IFN-α had a variable effect, evoking an SVR in 17–43% of patients. However, long-term biochemical and histologic improvements have been seen, even in the absence of sustained inhibition of viral replication. Sofosbuvir is the prodrug of a uridine nucleoside inhibitor of the HCV RNA NS5B polymerase. Its metabolism to the active uridine nucleoside triphosphate results in chain termination. Sofosbuvir is active against all HCV genotypes (1–6) and has a median effective concentration (EC50) of 0.7–2.6 μM against NS5B. Resistance to sofosbuvir is conferred by an S282T substitution in NS5B, but clinically expressed resistance to treatment has only rarely been encountered in patients who receive sofosbuvir.


InternalMed_Harrison

InternalMed_Harrison. Sofosbuvir is administered orally and is unaffected by food. After oral administration, plasma concentrations of sofosbuvir and of its active metabolite peak in 0.5–2 h and 2–4 h, respectively. Approximately 61–65% of sofosbuvir is bound in plasma proteins, but very little of the active metabolite is bound. Both sofosbuvir and its active metabolite are cleared renally, with t1/2 values of 0.4 h and 27 h, respectively. Sofosbuvir is relatively free from clinically significant drug interactions, although P‐glycoprotein inducers can reduce sofosbuvir concentrations. Sofosbuvir is generally well tolerated and has not been associated with significant toxicity. The most common side effects in recipients of sofosbuvir have been attributable to concomitant administration of IFN and ribavirin in combination clinical trials (see below).


InternalMed_Harrison

InternalMed_Harrison. Sofosbuvir has been studied in a variety of controlled and open‐label clinical trials. In late 2013, the results of these trials led to its recommendation—in triple combination with pegylated IFN and ribavirin—as first-line treatment for chronic hepatitis due to HCV genotypes 1, 4, 5, and 6, in which SVRs among treatment‐naïve patients were 89–97%. For HCV genotypes 2 and 3, IFN‐free regimens consisting of sofosbuvir and ribavirin have been recommended, with SVRs among treatment‐naïve patients of 93% for genotype 2 and 61% for genotype 3. BOCEPREVIR, TELAPREVIR


InternalMed_Harrison

InternalMed_Harrison. BOCEPREVIR, TELAPREVIR This drug class is specifically designed to inhibit the 3/4A (NS3/4A) HCV protease. These agents resemble the HCV polypeptide and, when processed by the viral protease, form a covalent bond with the catalytic NS3 serine residues, block further activity, and prevent proteolytic cleavage of the HCV polyprotein into NS4A, NS4B, NS5A, and NS5B proteins. Boceprevir and telaprevir are linear ketoamide compounds that are active against HCV genotype 1 (1b > 1a) and much less so against genotypes 2 and 3. These first-generation protease inhibitors received approval for combination therapy (with IFN and ribavirin) for genotype 1 infection. Neither boceprevir nor telaprevir is now recommended for the treatment of hepatitis C. These drugs have been supplanted by sofosbuvir and by simeprevir, a second‐generation protease inhibitor with improved pharmacokinetic properties, fewer drug–drug interactions, and less overall toxicity (see below).


InternalMed_Harrison

InternalMed_Harrison. Simeprevir is a second‐generation NS3/4A protease inhibitor with antiviral activity against genotype 1 (1b > 1a); the EC50 is 9.4 nM in an HCV genotype 1b replicon. The NS3 polymorphism Q80K, which is present in approximately one‐third of patients carrying HCV genotype 1b, increases the EC50 by elevenfold and results in clinical resistance to simeprevir. Thus, testing for Q80K should be carried out if treatment with simeprevir is being considered. Cross‐resistance occurs between simeprevir and the first‐generation protease inhibitors boceprevir and telaprevir.


InternalMed_Harrison

InternalMed_Harrison. Simeprevir is orally administered as a 150-mg capsule, and its bioavailability is increased by administration with food. The serum concentration peaks 4–6 h after oral administration. The drug’s elimination half-life is 10–13 h in healthy individuals and 41 h in patients with hepatitis C. Simeprevir is nearly entirely bound by plasma proteins and cleared by biliary excretion. Because there is no renal excretion, dose adjustments are not required in the presence of renal dysfunction. Simeprevir is metabolized by hepatic CYP3A and therefore should not be used in patients with decompensated liver function.


InternalMed_Harrison

InternalMed_Harrison. Because of its metabolism by cytochrome P450 3A (CYP3A), simeprevir interacts with drugs that induce or inhibit CYP3A, and these interactions may concomitantly increase or reduce plasma concentrations of simeprevir. Administration of simeprevir may also increase plasma concentrations of drugs that are substrates for hepatic organic anion‐transporting polypeptide 1B1 or 1B3 or for P glycoprotein transporters. Toxicity observed during clinical trials with simeprevir included photosensitivity (usually mild or moderate) in 28% of recipients and reversible hyperbilirubinemia (both conjugated and unconjugated), which was generally mild to moderate. Most of the other adverse effects that were seen in clinical trials with simeprevir were attributable to concomitant administration of IFN and ribavirin.


InternalMed_Harrison

InternalMed_Harrison. Simeprevir has been recommended as a component of alternative treatment—in combination with pegylated IFN and ribavirin—of chronic infection with HCV genotypes 1 and 4. Daily simeprevir, daily ribavirin, and weekly pegylated IFN for 12 weeks followed by another 12 weeks of pegylated IFN and ribavirin resulted in an SVR of 80% in the absence of the Q80K variant. In general, simeprevir‐based triple therapy appeared to be 10% less likely to yield an SVR than sofosbuvirbased therapy and more likely to cause adverse effects. However, for prior nonresponders or partial responders to pegylated IFN, the IFN‐free regimen of simeprevir, sofosbuvir, and ribavirin shows promise.


InternalMed_Harrison

InternalMed_Harrison. Next-generation direct-acting antivirals against HCV inhibitors are under active development. These agents include second-generation inhibitors of NS3/4, NS5B polymerase inhibitors, and inhibitors of NS5A (a membrane-associated phosphoprotein that is part of the HCV RNA replication complex). These investigational agents are making progress toward IFN-free regimens, shorter courses of therapy, improved tolerability, and reduction of resistance. For updated information, readers should consult http://www.hcvguidelines.org/. Antiviral Chemotherapy, Excluding Antiretroviral Drugs Herpes simplex virus Infections Lawrence Corey DEFINITION Herpes simplex viruses (HSV-1, HSV-2; Herpesvirus hominis) produce a variety of infections involving mucocutaneous surfaces, the central nervous system (CNS), and—on occasion—visceral organs. Prompt 216 sEC TIOn 12 InFECTIOns duE TO dnA vIRusEs recognition and treatment reduce the morbidity and mortality rates associated with HSV infections.


InternalMed_Harrison

InternalMed_Harrison. The genome of HSV is a linear, double-strand DNA molecule (molecular weight, ~100 × 106) that encodes >90 transcription units with 84 identified proteins. The genomic structures of the two HSV subtypes are similar. The overall genomic sequence homology between HSV-1 and HSV-2 is ~50%, whereas the proteome homology is >80%. The homologous sequences are distributed over the entire genome map, and most of the polypeptides specified by one viral type are antigenically related to polypeptides of the other viral type. Many type-specific regions unique to HSV-1 and HSV-2 proteins do exist, however, and a number of them appear to be important in host immunity. These type-specific regions have been used to develop serologic assays that distinguish between the two viral subtypes. Either restriction endonuclease analysis or sequencing of viral DNA can be used to distinguish between the two subtypes and among strains of each subtype. The variability of nucleotide sequences from clinical strains


InternalMed_Harrison

InternalMed_Harrison. endonuclease analysis or sequencing of viral DNA can be used to distinguish between the two subtypes and among strains of each subtype. The variability of nucleotide sequences from clinical strains of HSV-1 and HSV-2 is such that HSV isolates obtained from two individuals can be differentiated by restriction enzyme patterns or genomic sequences. Moreover, epidemiologically related sources, such as sexual partners, mother-infant pairs, or persons involved in a common-source outbreak, can be inferred from such patterns.


InternalMed_Harrison

InternalMed_Harrison. The viral genome is packaged in a regular icosahedral protein shell (capsid) composed of 162 capsomeres (see Fig. 214e-1). The outer covering of the virus is a lipid-containing membrane (envelope) acquired as the DNA-containing capsid buds through the inner nuclear membrane of the host cell. Between the capsid and lipid bilayer of the envelope is the tegument. Viral replication has both nuclear and cytoplasmic phases. Initial attachment to the cell membrane involves interactions of viral glycoproteins C and B with several cellular heparan sulfate–like surface receptors. Subsequently, viral glycoprotein D binds to cellular co-receptors that belong to the tumor necrosis factor receptor family of proteins, the immunoglobulin superfamily (nectin family), or both. The ubiquity of these receptors contributes to the wide host range of herpesviruses. HSV replication is highly regulated. After fusion and entry, the nucleocapsid enters the cytoplasm and several viral proteins are released from


InternalMed_Harrison

InternalMed_Harrison. contributes to the wide host range of herpesviruses. HSV replication is highly regulated. After fusion and entry, the nucleocapsid enters the cytoplasm and several viral proteins are released from the virion. Some of these viral proteins shut off host protein synthesis (by increasing cellular RNA degradation), whereas others “turn on” the transcription of early genes of HSV replication. These early gene products, designated α genes, are required for synthesis of the subsequent polypeptide group, the β polypeptides, many of which are regulatory proteins and enzymes required for DNA replication. Most current antiviral drugs interfere with β proteins, such as viral DNA polymerase. The third (γ) class of HSV genes requires viral DNA replication for expression and encodes most structural proteins specified by the virus.