Epstein-Barr virus (EBV) is found in human mucosal epithe- lial cells and B lymphocytes. Other cell types may also be infected. Burkitt’s lymphoma, originally identiﬁed in Africa, was found to be due to Epstein-Barr virus, named after its two discoverers (4). Epstein-Barr virus later became associated with not only African Burkitt’s lymphoma, but Hodgkin’s dis- ease and nasopharyngeal carcinoma (5,6). Infectious mononu- cleosis is the most common manifestation of EBV. Infectious mononucleosis has a large public health impact on young col- lege students and military recruits. Both are populations liv- ing in close quarters, exposed to many new people, and where mucosal contact via oral secretions may occur. Symptoms present in >50% of patients include fever, pharyngitis and sore throat, lymphadenopathy, malaise, headache, and splenome- galy. Complications involve the neurological, respiratory, car- diac, hematological, hepatic and renal systems. There is a rash in 10% of the cases (7). EBV-associated lymphoprolifera- tive diseases and malignancies occur as solid tumors (nasopharyngeal carcinoma and cervical lymphadenopathy), B-cell lymphoproliferative disorders (Hodgkin’s lymphoma, Burkitt’s lymphoma, and lymphoproliferative disease in the immunocompromised), and T-cell lymphoproliferative disorders (oral lymphoma in HIV-infected patients, angiocentric cutane- ous lymphoma including papules, nodules, bullae, panniculitis, histiocytoid cutaneous lymphoma, and vesiculopapular lesions of the face) (8). In HIV-positive persons, oral hairy leukopenia (OHL) is a benign focus of hyperplasia. EBV is sometimes iden- tiﬁed in breast tumors (9–11). EBV has a latent circular genome and a linear genome. OHL develops when the linear genome replicates via a viral polymerase. Antiviral agents which inhibit this enzyme are an effective therapy for OHL. These include: 1) high doses of acyclovir (800 mg ﬁve times/day); 2) valacyclovir and famciclovir (with better bioavailability); and 3) ganciclovir, foscarnet or cidofovir for HIV-infected patients with CMV (OHL seems to improve at the same time).
A variety of cutaneous manifestations may occur with CMV mononucleosis syndrome, congenital CMV infection, and coin- fection of HIV with CMV. In vitro, CMV infection shows sen- sitivity to many of the antiviral agents used to treat HSV and VZV. CMV infection can be life-threatening to neonates, transplant recipients, and HIV-positive patients. CMV retini- tis requires particular attention to prevent blindness. CMV replicates by rolling-circle replication. For CMV to replicate requires eleven genetically determined proteins to be in place. These proteins are contained within a variety of related mol- ecules: DNA polymerase, a polymerase-associated protein, single-stranded DNA binding protein, helicase primase, transactivators, and two unknown functions (12). This speciﬁc- ity provides a number of molecular targets for potential antiviral drug development and intervention. As with many viruses, transmission is relatively simple and may occur through intrau- terine infection from primary-infected mothers, perinatal infec- tion from breast milk, postnatal infection primarily from saliva and/or sexual contact, blood transfusions, and organ transplan- tation. Laboratory diagnoses of active CMV infection include PCR, histopathology, isolation of the virus, antigen detection, and serological assays. CMV can be prevented by utilizing seronegative blood for transfusions, especially for pregnant women and immunocompromised patients. Day care centers may be the reservoir for transmission of CMV among a variety of individuals. CMV is asymptomatic in most cases, but saliva, a saliva-coated toy, or eating utensils (fomites) may spread the disease among teethers, droolers, and toddlers. Children may then infect siblings, pregnant mothers or day care workers. Infected workers risk transmittal to the children. Since this mode of transmission occurs within the realm of daycare cen- ters, daycare workers must be careful to utilize appropriate hand washing and other good hygiene practices.
Exposure to CMV appears to be a life-long event. The per- centage of women with IgG antibodies against CMV increases as their ages increase. Approximately 40% of women under the age of 16 have IgG antibodies against CMV compared with nearly 80% of those women over 41 years of age (13). CMV in the immunosuppressed can also have serious conse- quences. Studies indicate that seronegative CMV transplant recipients can acquire CMV from organs of seropositive donors (14). CMV has been associated with thrombotic microangiopathy in HIV-infected patients (15,16). Vaccines for better protection are needed and are being developed and tested. The antivirals, ganciclovir, valganciclovir, foscarnet, cidofovir, and fomivirsen, are FDA approved for treatment of CMV. These currently available drugs have issues of toxicity, modest efﬁcacy and poor oral bioavailability. New compounds being tested include novel inhibitors of protein kinase and viral proteins of DNA origin. Certain non-nucleosides also can inhibit the viral process (17).
Human Herpesvirus 8 (HHV-8)
Kaposi’s sarcoma (KS) occurs as four main types. Classic Kaposi’s sarcoma occurs in elderly Mediterranean men or those of Ashkenazi Jewish descent. An endemic form affects persons of all ages in tropical Africa. The two most common forms seen in the medical profession are an immunosuppressive form in organ transplant recipients and the AIDS-associated form. Mediterranean, Jewish, Arabic, or African ancestry is often associated with KS in organ transplant recipients. In Africa, where endemic KS is the cause of up to 10% of all his- tologically proven malignancies, sexual transmission is believed to be the most common mode of transmission. Perin- atal transmission from mother to child is also suspected (18). Kaposi’s sarcoma, prior to the introduction of highly active antiretroviral therapy (HAART), affected nearly 20% of patients with AIDS (19–21), and was primarily treated with destructive therapies similar to those used with HPV. Radia- tion therapy and chemotherapy were also used. The develop- ment of alitretinoin, a gene expression regulator, has shown promise in treating Kaposi’s sarcoma with a topical, at-home therapy. However, alitretinoin is not as effective for the large fungating lesions, but it could be combined with chemother- apy for treatment of large tumors. Antiherpes drugs seem to be more effective as a preventive drug for KS in HHV-8 infected immunosuppressed persons than as a therapy for active KS. KS is composed of large latently infected spindle cells. These antiviral drugs seem to block the lytic phase of viral replication which occurs when HHV-8 is establishing itself in the dermis (22–25). Interferon-alpha is currently FDA-approved for treatment of Kaposi’s sarcoma (26).
Human Papillomavirus (HPV)
HPV is the most commonly sexually transmitted disease in the United States. HPV expresses itself as genital warts or lesions on the cervix and the virus has been directly connected to the development of cervical cancer (27). There are over 100 genotypes of HPV with genotypes 16 and 18 most commonly associated with the development of cervical cancer (Fig. 3.4).
Fig. 3.4 Relational map of human papillomaviruses by genotypes.
The prevalence of genotypes worldwide demonstrates isola- tion by distance with additional pockets of introduced geno- types or mutations occurring overtime. Sexual behavior and possibly fomite contamination are leading causes of transmis- sion. Electrocautery and laser therapy present a risk to the surgeon and other medical staff as HPV DNA is contained in the smoke caused by the procedure (28).
The genetic make-up of the infected person may affect development of cervical dysplasia or neoplasia. There appears to be genetic propensity to develop either long-term infection leading to cervical cancer (if left untreated) or automatic clearing of the infection (experienced by the majority of women). Other lesions indicate HPV infection, including, but not limited to, plantar warts, common warts, ﬂat or planar warts (29,30), epidermodysplasia verruciformis, other ano- genital diseases, respiratory papillomatosis (especially in chil- dren), and other mucosal papillomas (Fig. 3.4).
While treatment with antiviral drugs is needed to help those already infected, vaccine development is also needed as a preventive method. Most treatments for HPV have been ablative— trichloroacetic acid, podophyllotoxin, cryotherapy, laser ablation, surgical excision, and electrosurgery/cautery. Not only can genital warts be treated with antiviral drugs, but some of the therapies may prove effective in treating com- mon warts. Imiquimod users have a 56% complete response rate with a 13% relapse rate for the treatment of anogenital warts (31,32). Interferon-alpha is also FDA approved for the treatment of HPV (i.e., condyloma acuminatum).
Molluscum Contagiosum Virus (MCV) and other Poxviruses
Currently, no antiviral agents are FDA-approved for treatment of MCV lesions. Most lesions are treated with cytodestructive methods. There are reports of various antiviral agents having some efﬁcacy in treating MCV, but more thorough investiga- tions and clinical studies are needed. In HIV-positive patients, antiretroviral agents, such as highly active antiretroviral ther- apy (HAART), improve the immune system and contribute to the success of additional antiviral drugs (33,34).
Two other poxviruses have gained recent attention: small- pox as a bioterrorism threat and monkeypox as a hitchhiker to the United States on the Gambian pouched rat with subsequent infection of U.S.-endemic prairie dogs being sold as pets. The handlers of the pet prairie dogs then developed monkeypox. Monkeypox was initially identiﬁed as a poxvirus in laboratory primates before it was linked to an orthopoxvirus from central and western Africa. It is a rare zoonosis and isolation of most cases makes vaccine development unlikely. However, the poten- tial for animal to animal and human to human transmission (Fig. 3.5) may stimulate development of new vaccines or addi- tional antiviral therapy. Prior to this event in the summer of
2003, monkeypox transmission was only by monkeys and squir- rels to humans and human to humans subsequently. Skinning or handling wild animals and consumption of incompletely cooked wild monkey meat was thought to be the primary route of transmission. Smallpox vaccination reduces susceptibility to monkeypox and lessens the severity of the disease (33).
Initially variolation with pustule ﬂuid or scab material was used to protect against smallpox. Reﬁnements in vaccine development led to the eradication of epidemic smallpox.
Recent advances in smallpox vaccine development and adminis- tration are discussed in chapter 4 (Vaccines). A possible treatment for complications from vaccination is vaccinia immune globulin. Cidofovir has antipoxvirus effects and the potential to treat vac- cinia and smallpox (34). Ribavirin displays modest antiviral activ- ity against cowpox. Triﬂuridine is used to treat ocular keratitis.
Hepatitis B Virus (HBV)/Hepatitis C Virus (HCV)
HBV and HCV have similar treatments and are sensitive to sim- ilar drugs. Both hepatitis B and C have the potential to develop fatal sequellae, such as cirrhosis of the liver and hepatocellular carcinoma. Injection drug use accounts for 21% of the known cases in the United States and Western Europe (35). The primary means for HBV transmission is through blood or blood products, sexual contact or perinatal exposure. Fomites, such as contami- nated dental instruments, acupuncture needles, tattoo needles, and other invasive medical instruments, may also transmit hep- atitis B. Travelers are subject to infection, particularly those in third-world countries. Transfusion and dialysis are other modes of transmission. Seven genotypes, encompassing 12 subtypes, have been described. Nearly 5% of the world’s population has chronic HBV infection (36). The incubation period for HBV ranges from 60 to 180 days. Patients may experience jaundice and, perhaps, liver failure (37,38). Unfortunately, patients may not know they have HBV until they present with ascites, bleed- ing esophageal variances, or encephaly (39). Biochemically, serum bilirubin and aminotransferase levels are used for initial diagnosis but serological and virological conﬁrmation is required. Necrotizing vasculitis and polyarteritis nodosa are associated with HBV infections, and are linked to cryoglobuline- mia (35,40,41). Chronic infection may occur in hemodialysis, dia- betic, and elderly stroke or head injury patients with very high rates (43–59%) of chronic infection after an acute exposure. HIV positive patients are also at greater risk. Treatment of symptoms without knowledge of the presence of HBV can be problematic as many drugs are potentially hepatotoxic.
With better diagnostics for HCV infection, it is estimated that 3.9 million Americans (1.8% of the population) are infected with HCV (42) with over 170 million infected worldwide.
The genome displays genetic heterogeneity which makes it less likely to activate the human immune system. Appropriate animal models for HCV are lacking and mechanistic molecu- lar studies of replication have been limited. Humans may be multiply infected overtime and there may be a failure to develop a high rate of immunity after the initial infection occurs (43,44). As with other hepatitis infections, clinical man- ifestations do not occur until the disease has become chronic. The presence of ﬁbrosis is the end stage of hepatitis C over time and is predictive of progression to cirrhosis. HCV progresses over a period of 10–30 years from infection to liver cirrhosis. There are six deﬁnite genotypes with subtypes of each geno- type. Leukocytoclastic vasculitis, lichen planus, poryphyria cutanea tarda, and polyarteritis nodosa have been linked to chronic HBV and/or HCV infections (39,45,46). Prevention via modiﬁcation of risky behaviors, passive immunoprophy- laxis, and immunization (i.e., HBV) are the best strategy. Edu- cation and information campaigns to reduce the transmission of hepatitis B and vaccines have been effective in reducing the numbers of cases of hepatitis B in the United States (35). Cur- rently approved treatments for hepatitis B include interferon- alpha, adefovir, and lamivudine. Lamivudine is discussed in chapter 2 Page 48. Hepatitis C treatments are pegylated (PEG) interferon-alpha, and PEG-interferon-alpha + ribavirin. Currently available drugs have issues of toxicity, modest efﬁ- cacy, and poor oral bioavailability. New compounds being tested include novel inhibitors of protein kinase, viral protease, and viral proteins of DNA origin. Certain non-nucleosides also can inhibit the viral process (17).
Inﬂuenza is responsible for pandemic or worldwide outbreaks of new strains of ﬂu that originate in localized geographic areas. The advent of world travel has opened every country’s door to a sudden invasion of new inﬂuenza strains at a moment’s notice. Fortunately, faster and better communica- tions about the disease—prevention, clinical manifestations, treatment, etc.—assist with harnessing resources to prevent further spread. Animals, particularly those domesticated for
agricultural use, are often the culprit, such as the swine inﬂu- enza virus that was responsible for the 1918 pandemic with
40 million deaths worldwide. There are three inﬂuenza viruses: A, B, and C. Only A is subdivided and only ﬁve of those subtypes are known to affect humans. A and B have eight dif- ferent RNA segments; C has only seven.
Rapid detection of inﬂuenza in pediatric patients is important for early therapy. The use of an enzyme-linked immunosorbent assay can detect inﬂuenza A. The end result is that this rapid detection system decreases the use of ancil- lary tests and indiscriminate use of antibiotics (47). On the other hand, for adults, clinical modeling indicates that testing strategies for inﬂuenza before prescribing antivirals is more expensive than just prescribing the antiviral. Running tests for inﬂuenza are more costly and less effective when the prob- ability of inﬂuenza exceeds 30% (48).
Human inﬂuenza virus may co-infect with an animal strain to produce new pandemic strains, much as hybridiza- tion occurs among higher level organisms. In this case, how- ever, replication occurs and the new viral strain has few, if any, enemies. Each strain requires a new set of antibodies to be produced for future resistance.
Pandemic inﬂuenza viruses are characterized by rapid onset and easy dissemination of infection. The short (only days) incubation periods accompanied by high levels of virus in respi- ratory secretions at the onset of illness create multiple waves of infection. Hands or fomites may also spread inﬂuenza (49).
Factors which contribute to the spread of an inﬂuenza virus are travelers, seasonally by geographic area, and initia- tion of school in the fall. Mortality rates are highest in the eld- erly and the very young, particularly those with respiratory or cardiovascular disease. Nursing home outbreaks require spe- cial care and a number of recommendations have been made to avoid major outbreak catastrophes (49–51). Nosocomal infec- tions occur where there are high concentrations of people.
Inﬂuenza outbreaks vary by the proportional activity of the three subtypes. Dramatic changes occur in those propor- tions annually. Thus, this year’s vaccine combination may not be effective for the following years. The ancestral genetic origin
of pandemic strains is often avian. A limitation on vaccina- tions for inﬂuenza is the “drift” (proportional reassortment) of wild virus strains each year (52). For example, the composi- tion of the 2002–2003 vaccine was
A/Moscow/10/99 (H3N3)- like, A/Ner Caledonia/20/99 (H1N1)-like, and B/Hong Kong/
330/2001-like strains (53).
Treatment of inﬂuenza is symptomatic and antiviral. Ventilation may be necessary. Antivirals such as amantadine, ramantadine, oseltamivir and zanamivir are effective. Ribavi- rin is under investigation as is interferon-alpha (54–56).
Respiratory Syncytial Virus (RSV)
Respiratory syncytial virus (RSV) is the most common cause of inﬂammation in the small airways in the lung and pneumonia in infants and small children. Most children have had RSV by the age of 3 (57). RSV is seasonal and peaks in February. Native Americans and Alaskan natives seem to be more susceptible (58).
RSV is a labile paramyxovirus that causes human cell fusion-the syncytial effect. Two strains, A and B, cause either asymptomatic illness (Type B) or more clinical illness (Type A).
Babies who are born premature and are less than 6 weeks of age, with congenital problems, such as heart disease, chronic lung disease, and immunodeﬁciency, are at high risk. Other con- tributing factors are lower socioeconomic states, crowded living conditions, presence of secondary cigarette smoke, older siblings in the home, and daycare attendance. Breast-fed infants seem to be at less risk than their bottle-fed counterparts.
Children with runny noses (rhinorrhea), wheezing and coughing, low-grade (102°F) or higher (104°F) fever (if coin- fected), and nasal ﬂaring may have RSV. RSV can be positively identiﬁed by using direct antigen tests that provide a positive response in little over an hour. RSV has been indicated as a risk factor for asthma development. An antiviral, such as ribavirin, inhibits replication during the viral replication stage (54–57).
Rhinovirus infection has been responsible for years for the com- mon cold, which was treated symptomatically. Rhinovirus has also been associated with complications, such as acute sinusitis, otitis media, acute bronchitis, and pneumonia. Rhinovirus is also associated with the development of asthma and cystic ﬁbrosis exacerbations in children.
Rhinosinusitis involves the nasal passages, paranasal sinuses, naso- and oropharynx, Eustachian tubes, middle ear, larynx, and large airways. Systemic involvement is usually mild in adults. Rhinovirus infections in immunocompromised patients, as with other infections, are more serious when com- bined with multiple infections.
Adults who are taught the characteristics of allergic rhin- itis and cold are able to distinguish between the two (59).
Symptomatic and anti-inﬂammatory treatment includes decongestants, fever relief, cough cessation, etc., but does not cure the infection. Antivirals identiﬁed for their potential use- fulness include interferon α to reduce viral replication. Capsid binding agents and 3 C protease inhibitors are being evaluated. Pleconaril and AG7088 are under investigation in clinical trials.
The (non-antiretroviral) nucleoside analogs include acyclovir, valacyclovir, famciclovir, penciclovir, ganciclovir, and valganci- clovir as well as ribavirin. Nucleoside analogs are important antivirals in the therapy of HIV and herpesvirus infections.
Most nucleoside analogue antivirals have the capacity to induce chromosomal aberrations, but these aberrations are not evident in gene arrays. Genotoxicity is being investigated in this group but, thus far, there is no conclusive evidence that nucleoside analogs cause tumors in humans. Antiviral nucleo- sides for HIV therapy, in addition to being highly effective, may also cause side effects that become serious enough to con- sider alternative therapies (60).
Acyclovir, an analog of 2′-deoxyguanosine, has become the most widely prescribed antiviral in the world since its intro- duction in 1983 (Fig. 3.6). Acyclovir does not appear to alter
Fig. 3.6 Associated names, structure, and applicability of acyclovir.
the development of long-term immunity to varicella zoster virus when administered for the treatment of chickenpox in otherwise healthy patients. A limiting factor is considered to be its poor bioavailability. Viral resistance to acyclovir is not a major concern in normal clinical practice, but has occurred in a few patients with immunosuppression. There are conﬂicting studies as to whether acyclovir treatment in AIDS patients is associated with prolonged survival. Use of highly active anti- retroviral therapy (HAART) has virtually eliminated further studies of acyclovir as an agent for prolonged survival in AIDS patients.
Mechanisms of Action
Acyclovir is ﬁrst phosphorylated to acyclovir monophosphate by the virus-speciﬁc enzyme, thymidine kinase (Fig. 3.7). Host cellular enzymes further phosphorylate the compound to con- vert it to its active triphosphate form (61). The ﬁnal product inactivates viral DNA polymerase which leads to irreversible inhibition of further viral DNA synthesis (62–65). Acyclovir potency against HSV-1 replication can vary among cell lines. It has been suggested that the effect of acyclovir is due to pro- ﬁcient phosphorylation of acyclovir and/or a favorable dGTP/ acyclovir triphosphate level in macrophage cells (66).
Studies to Support Use of Acyclovir Acyclovir has been extensively studied for treatment of many viral diseases. Studies of interest are shown in Table 3.4 (64,65,67–120).
Acyclovir can be administered topically, orally or intrave- nously with few adverse events (Table 3.5). Acyclovir is consid- ered to be safe and well-tolerated with a 20 year history of usage, although its bioavailability (15–20%) is a limiting fac- tor. Acyclovir is effective in decreasing severity in chickenpox (121,122). Acyclovir 5% ointment is used to treat initial herpes genitalis and limited mucocutaneous herpes simplex virus infections in immunocompromised patients. Acyclovir in oint- ment form is used cutaneously and should not be applied to the eye. Acyclovir is noncarcinogenic and nonteratogenic (i.e., class B) (123).
Intravenous acyclovir is more readily assimilated and can be used for serious or disseminated infections. Immuno- compromised patients with HSV or VZV infections who develop chickenpox, disseminated herpes zoster, severe cases of trigeminal zoster (particularly ophthalmic zoster), eczema herpeticum (Kaposi’s varicelliform eruption), herpes encepha- litis, and neonatal herpes may be treated with intravenous acyclovir. During administration of intravenous acyclovir, ade- quate ﬂuid intake by patients is important and renal insufﬁ- ciency may require dosage adjustments.
Acyclovir and its related analogs are ideal for treating and suppressing genital herpes and related HSV episodes.
Treatment should be initiated for a variety of reasons. These are summarized in Table 3.5. The argument is that the therapy is based on reducing the available time of exposure to others, thus preventing transmission, and the suppression of painful lesions.
Once therapy is needed to control HSV infection, there are a number of therapies available, depending upon the age and immune status of the patient.
In general, acyclovir is well tolerated by most patients, whether administered topically, orally, or intraveneously. There are few rare adverse events present, if they occur at all. These are:
Nausea. Vomiting. Diarrhea. Headache.
Central nervous system. If patients have a preexisting renal impairment, treatment with acyclovir may in- duce nephrotoxicity or neurotoxicity. One patient, treated for suspected viral meningoencephalitis with acyclovir, began to improve until right arm myoclonia developed followed by a progressive comatose state. Acyclovir neurotoxicity should be suspected if continu- ing treatment with acyclovir is accompanied by worsen- ing neurological status. High plasma and CSF acyclovir levels can conﬁrm the toxicity. Hemodialysis may be ef- fective in reducing levels of acyclovir. Measuring blood creatinine permits prompt dosage adjustment (124).
Crystalluria. Adverse reactions of crystalluria include urinary insufﬁciency, elevated serum creatinine, and altered renal function that may lead to acute tubular necrosis. Risks that promote crystal development are dehydration, high dose of acyclovir and rapid induction rate (125). Crystalluria may occur in patients if the in- fusion rate for the administration of intravenous acy- clovir occurs too rapidly. Therefore it is important that each dose of acyclovir be administered evenly during a one-hour period. Crystalline formation may cause renal impairment which is usually reversible. In at least one incidence, discontinuation of acyclovir resulted in reso- lution of crystalluria with 24 hours with no evidence of renal toxicity (126).
Phlebitis and infusion-site inﬂammation. Both phle- bitis and inﬂammation at the infusion site may be caused by the intravenous administration of acyclovir.
Acyclovir-resistant herpes simplex virus. Labora- tory isolates and clinical specimens reveal that the
frequency of acyclovir resistance ranges from 7.5 ×10 −4 to 15 × 10−4 and are not signiﬁcantly different (127,128).
Acyclovir-resistent varicella-zoster infection in HIV- positive patients. Acyclovir resistance has been repor- ted in HIV-positive patients who are coinfected with VZV (129–132).
Pregnant women and breast-fed infants. Data from the treatment of 1000 pregnant women who received acyclovir before or during early pregnancy indicates that there was no increase in rates of miscarriage or in birth defects of the offspring. However, it is recom- mended that acyclovir be given to pregnant women only if the beneﬁt outweighs the risk to the fetus. Acyclovir may concentrate in breast milk as it has been shown that breast milk acyclovir concentrations may be 0.6 to 4.1 times greater than the drug concentra- tion in the corresponding maternal plasma (89). The amount of acyclovir exposure to breast-fed infants de- pends upon the maternal dose of acyclovir and quan- tity of milk ingested. In mothers who received acyclovir in dosages ranging from 200–800 mg ﬁve times daily, the level of acyclovir in the infants equated to a dosage of 0.2 mg/kg/day to 0.731 mg/kg/day (89–91). This quantity is less than the dosage indicated for infants with herpes encephalitis (30 mg/kg/day) that is given intravenously.
Transfer of antiviral agents to breast milk may provide therapeutic beneﬁts in reducing the vertical transmis- sion of viruses and clinical sequelae in the breast-feeding infant (133).
Probenicid coadministration. If probenicid is coad- ministered with intravenous acyclovir, there may be an increased half-life and systemic exposure of acyclovir, requiring dose adjustments.
Coadministration with antiretrovirals. Acyclovir, famciclovir, and valacyclovir are all safe and effective in HIV seropositive patients and have no negative in- teractions with HAART (134,135).
Fig. 3.8 Associated names, structure, and applicability of valacyclovir.
Valacyclovir is a prodrug of acyclovir with signiﬁcantly improved bioavailability (136) (Fig. 3.8). Once absorbed, over 99% of the dosage is hydrolyzed by valacyclovir hydrolase to acyclovir. The oral bioavailability of valacyclovir is 3–5 times that of acyclovir, but the bioavailability of valacyclovir remains lower than that of famiciclovir. The increased bio- availability provides valacyclovir with the beneﬁt of less fre- quent dosing, a boon for those who tend to forget to take medications. Valacyclovir was approved by the FDA in 1995 for use in the treatment of herpes simplex viruses and vari- cella zoster virus infections. A variety of off-label uses is also known. It is likely that valacyclovir will eventually replace acy- clovir for treatment of HSV or VZV infections in HIV-positive or other immunocompromised persons (137).
Mechanism of Action
Valacyclovir is the L-valyl ester and prodrug of acyclovir. The conversion of valacyclovir to acyclovir by valacyclovir hydro- lase translates into higher blood levels of acyclovir (Fig. 3.9). The metabolism and mechanism of action are identical to that of acyclovir. The greater afﬁnity (100 times greater than that of penciclovir triphosphate) of acyclovir triphosphate for viral DNA polymerase is such that viral DNA chain termination
requires less concentrations of acyclovir. Acyclovir and valacy- clovir are obligate viral DNA terminators. It is unknown if there is any importance to the relationship between the greater viral DNA polymerase afﬁnity and obligate/condi- tional viral DNA chain termination.
Clinical Studies to Support the Use of Valacyclovir
Valacyclovir is used to treat HSV, VZV, and (occasionally) CMV (136,138–150) (Table 3.6). Valacyclovir is considered to be as effective as acyclovir and famciclovir, with more conve- nient dosing than with acyclovir.
Valacyclovir is administered orally with limited adverse events, similar to acyclovir and famciclovir. In addition, the increased bioavailability of valacyclovir means that patients only take medications 2–3 times per day rather than 5 times (with acyclovir). Table 3.7 highlights treatment options for HSV-1 and -2 and VZV.
Like acyclovir, side effects do not differ signiﬁcantly from those of the placebo. There are a few rare adverse effects such as:
Thrombotic microangiopathy (TMA). Thrombotic microangiopathy, similar to thromboic thrombocy- topenic purpura/hemolytic uremic syndrome (TTP/ HUS), may occur in immunosuppressed patients who have received high dosages of valacyclovir (8 g/day) for extended periods of time when used for suppression of CMV. Valacyclovir has not been shown to be the cause of the TMA as rates seen in this study were similar to those of all patients with advanced HIV disease. Of 18 patients, eight developed TMA during treatment with the study drug, whereas 10 patients developed TMA af- ter it had been discontinued for a median of 8 weeks.
This syndrome has not been observed in healthy pa- tients who received doses of 3 g/day nor has it been seen in HIV-positive patients receiving valacyclovir for suppression of genital herpes.
Probenecid and cimetidine coadministration. Coad- ministration of valacyclovir with probenecid causes re- duced renal clearance of acyclovir. Dosage adjustments are not necessary unless renal impairment exists and is not clinically signiﬁcant in patients with normal re- nal function.
Neurologic toxicity. Valacyclovir very rarely may cause neurotoxicity as its bioavailability is 54% compared with
20% for acyclovir. Valacyclovir hydrolyzes to acyclovir following systemic exposure and may cause unexpected overdoses, but clinical manifestations are rare (148).
Treating Bell’s Palsy
Antivirals bind to viral enzymes so the viruses do not repli- cate. Adverse effects of valacyclovir are rare but can include headache, nausea, diarrhea, constipation, and dizziness (149,
150) (see Table 3.6). When treatment begins within 3 days of onset of paralysis caused by Bell’s palsy, patients treated with acyclovir have less neural degeneration and more favorable recoveries (150). Therefore, valacyclovir is being studied for this indication.
Famciclovir, an oral prodrug of penciclovir expresses the highest bioavailability (77%) of the nucleoside analogues. Like acyclovir, famciclovir, a diacetyl-6-deoxy analog, is effec- tive against HSV-1, HSV-2, and VZV (Fig. 3.10). It is approved for the treatment of herpes zoster and for the episodic treat- ment and suppression of recurrent genital herpes in other- wise healthy adults. Originally FDA-approved in 1995, famciclovir has been found to signiﬁcantly reduce the pain, burning, tenderness, and tingling of recurrent genital herpes and its metabolite, penciclovir, is used for therapy of herpes labialis (151). For the immunocompromised, famciclovir is an effective treatment for herpes zoster although famciclovir,
like valacyclovir, is not currently approved for the treatment of herpes zoster in this population (152). Famciclovir can be used to treat ophthalmic zoster (153) as well as shorten zoster-associated pain (154).
Mechanisms of Action
Famciclovir is a guanine analog that is also classiﬁed as a purine analog, a modiﬁed cyclic or acyclic sugar. Famciclovir is metabolized to the active agent, penciclovir triphosphate. In hepatitis B guanine analogs inhibit priming by binding to tyrosine at the priming site of the polymerase. They also inhibit DNA elongation of both strands of DNA of the virus. Although elongation is initiated, it is terminated only two or three nucleotides later. Famciclovir is a prodrug, and its deacytylation and oxidation form, penciclovir, is the active antiviral form (Fig. 3.11). D-famciclovir is more potent than l- famciclovir (155). Once it is rapidly metabolized to penciclovir by the gastrointestinal tract, blood, and liver, the remaining metabolism is identical to that of acyclovir (156).
Clinical Studies and Published Reports to Support the Use of
Famciclovir studies often compare the efﬁcacy of famciclovir with acyclovir (153,157–170) (Table 3.8). For herpes zoster, famciclovir generally is as effective or more effective than acy- clovir. Famciclovir is also useful in both immunosuppressed and immunocompetent patients. Aoki, in a review, cites the use of famciclovir in the treatment of both HIV-negative and HIV-positive patients for the management of recurring genital herpes (HSV) (171). In the treatment of VZV adult patients, famciclovir is usually prescribed at 500 mg orally three times a day in the USA and 250 mg three times daily in most other countries. Famciclovir and valacyclovir are preferred over oral acyclovir for the treatment of zoster in otherwise healthy adults (172). In a comparison study to treat Chinese patients with hepatitis B, lamivudine was signiﬁcantly more effective than famciclovir (173).
Dosages for treatment vary according to the disease treated, the severity of an outbreak, and the recurrence rate of out- breaks as shown in Table 3.9.
Headache. Nausea. Diarrhea.
Increased serum concentrations of penciclovir. Serum concentrations of penciclovir may occur if famciclovir is
used concurrently with probenecid (or other drugs signif- icantly eliminated by active renal tubular secretion).
Renal impairment. For patients with renal impair- ment, all regimens in Table 3.9 will require dosage ad- justments.
Coadministration with probenecid or other relat- ed drugs. Administration of drugs eliminated by ac- tive renal tubular secretion with famciclovir may cause increased serum concentrations of penciclovir.
Drug resistance. For hepatitis B, ﬁve domains (labeled A–E) have been identiﬁed. Domains B and E may affect primary and template positioning. Structural changes in these domains may affect oral resistance to nucleo- side analogues. Famciclovir promotes mutations in the B domain. A mutation at position 528 (Leu replaced by
Met or Val) also occurs during lamivudine therapy and may cause cross-resistance. A summary of susceptible positions for the B-domain resistance for famciclovir is shown in Table 3.10.
Approval. Famciclovir has been approved for the episodic therapy and for chronic suppression of recurring HSV as well as treatment of herpes zoster in North America and in some, but not all, European countries (137).
Penciclovir is acyclic nucleoside analogue which has in vitro activity against HSV-1, HSV-2, and VZV (175) (Fig. 3.12). FDA approval is only for topical treatment of recurrent herpes labi- alis as the oral bioavailability is extremely low. Intravenous penciclovir shows promise for the treatment of mucocutaneous herpes simplex infections in those with immunosuppression.
The active form of penciclovir is signiﬁcantly more stable in HSV-infected cells (in vitro half-life of 10–20 hours) when com- pared to acyclovir (0.7 to 1 hour) (174).
Mechanisms of Action
Like acyclovir, penciclovir must be phosphorylated by viral thymidine kinase and cellular kinases prior to its competitive inhibition of viral DNA polymerase (Fig 3.13). However, pen- ciclovir is not an obligate DNA-chain terminator like acyclovir (175,176).
Clinical Studies to Support the Use of Penciclovir
There is only one major study involving immunocompetent patients that demonstrates that penciclovir treatment results in improvement in a variety of facets. These improvements were observed at all stages of a herpes labialis outbreak: pro- drome, erythema, papule, and vesicle. Table 3.11 (151) high- lights the parameters measured and analyzed.
Herpes labialis lesions may be treated with topical cream (Table 3.12). Treatment should be initiated as early as possi- ble during the course of an outbreak. The systemic uptake of penciclovir is negligible.
Adverse events are similar to those of acyclovir and valacyclovir.
Ganciclovir, a nucleoside analogue, is used to prevent and treat the manifestations of CMV in immunocompromised patients (177–179). This is important as CMV infection in immunocom- petent individuals tends to be brief and self-limited. However, CMV can be severe and life-threatening in neonates, transplant recipients, and HIV-positive patients. Oral ganciclovir is avail- able for CMV prophylaxis, but it is not considered to be as effec- tive as other means. Valganciclovir a prodrug of ganciclovir, has improved bioavailability. Ganciclovir may also have in vitro efﬁ- cacy against EBV (HHV-4) replication (Fig. 3.14).
Mechanism of Action
The viral-encoded phosphotransferase (thymidine kinase) monophosphorylates ganciclovir, a nucleoside analogue, to the active triphosphate form. This triphosphate form becomes part of a newly synthesized DNA chain. This inhibits further
DNA synthesis by inhibiting DNA polymerase and by induc- ing premature chain termination (180–183) (Fig. 3.15). The thymidine kinase (TK) encoded by HSV or VZV has a broad substrate speciﬁcity that permits interaction by acyclovir or ganciclovir. Phosphorylation of ganciclovir in CMV-infected cells is dependent upon a protein kinase. The role of the kinase is not completely understood and is under study. In HHV-6, a similar mechanism activates ganciclovir. Mutations for drug resistance most often occur in the UL97 gene that affects the monophosphorylation process or the UL54 gene that codes for DNA polymerase in human CMV (184). Graft-versus-host- disease can be prevented when donor T cells are transfected to express herpes simplex virus thymine kinase. Cells that express this enzyme are susceptible to ganciclovir, which opens a new avenue for addressing drug resistance.
Clinical Studies and Reports that Support the Use of
Oral ganciclovir is available for CMV prophylaxis, but is not as effective as intravenous treatment. Valganciclovir has bet- ter availability (177,178,183,185–193) (Table 3.13).
Intravenous ganciclovir is the drug of choice for treatment of CMV in transplant recipients or AIDS patients (194) (Table 3.14). The ocular implant of ganciclovir for treatment of CMV retini- tis provides a better clinical outcome for disease regression and the convenience of ambulatory therapy. This, however, must be balanced against the potential of intra-ocular side effects or contralateral eye infection by CMV (185). Late-onset cytomeg- alovirus disease among organ transplant recipients is common and the current thought is that antiviral prophylaxis, such as with ganciclovir, be used preemptively. Allograft rejection is often associated with CMV risk. Those patients on ganciclovir may beneﬁt from extended and/or enhanced antiviral prophy- laxis (195). Stem cell transplantation (SCT) has similar chal- lenges in that SCTs are at increased risk of developing CMV pneumonia where the best available therapy has a mortality
rate of 45–78%; therefore, post-operative prevention of CMV is critical (196).
Dosage of ganciclovir must often be limited due to:
Bone marrow suppression. Bone marrow suppression may also be accompanied by thrombocytopenia, neu- tropenia, anemia, and granulocytopenia.
Retinal toxicity. High doses of intravitreal ganciclovir may cause retinal damage (197).
Also involved may be: Renal insufﬁciently. Neutropenia.
Fever. Rash. Headache.
Irritation and phlebitis. Irritation and phlebitis may occur at the infusion site.
Nausea. May occur with arginine butyrate combined with ganciclovir to treat Epstein-Barr tumors.
Ganciclovir resistance. A recent study demonstrated that 26 of 210 patients with CMV retinitis expressed phenotypic or genotypic ganciclovir-resistance (198).
Animal studies. Ganciclovir was found to be teratoge- nic, carcinogenic, and mutagenic in animal studies. It also caused aspermatogenesis.
Combination therapy with foscarnet. In cases of fail- ure of monotherapy, ganciclovir can be combined with foscarnet for treatment.
Monitoring of CMV infection in immunocompro- mised transplant patients. The results of quantitative antigenemia, which uses buffy coat cell preparations, may differ signiﬁcantly from quantitative PCR, which uses plasma for the analysis of ganciclovir resistance. Once ganciclovir is initially introduced for treatment of CMV, quantitative PCR levels drop. A subsequent use of both quantitative PCR and antigenemia may be indica- tive of the emergence of ganciclovir-resistant CMV. Once foscarnet is administered, both the PCR and antigene- mia levels drop. The results of the quantitative PCR can often be used to provide pre-emptive treatment before traditional clinical indicators appear (199). PCR with plasma performed best in a comparison with seven other laboratory assays. This permitted pre-emptive treat- ment with ganciclovir (200).
Arginine butyrate/ganciclovir treatment of EB tumors. Arginine butyrate/ganciclovir treatment does not appear to activate HIV transcription rates (187).
Pregnant women. Only limited studies have been done, but no large-scale safety data exists (201).
Neonates and pediatric patients. Ganciclovir has been used effectively in pediatric transplant patients, but safety of use in neonates with CMV infection has not been established (202).
Effect of corticosteroids on efﬁcacy. In transplant pa- tients, corticosteriod use may promote early pp65 anti- genemia rather than emergence of a ganciclovir-resistant virus. Therefore, an immediate switch from ganciclovir to foscarnet (with more severe side effects) may not be warranted. Instead, dose intensiﬁcation with ganciclovir should continue to be the medication of choice (203,204).
Valganciclovir is used to treat CMV retinitis, an infection in eyes of immunocompromised patients. Valganciclovir does not cure CMV, but it can keep symptoms from becoming worse or
Fig. 3.16 Associated names, structure, and applicability of valganciclovir.
cause some improvement. Oral valganciclovir has increased availability when compared with oral ganciclovir. As with all other antivirals, valganciclovir-resistant strains are emerging (205) (Fig. 3.16).
Mechanism of Action
Valganciclovir is a valylester prodrug of ganciclovir with approximately 10 times the bioavailability of oral ganciclovir (Fig. 3.17).
Clinical Findings and Reports That Support the Use of
Valganciclovir has been used to treat CMV retinitis (205) (Table 3.15).
Oral tablets are available in the United States. Adults should take 900 mg two times a day with food (Table 3.16).
Anemia and other blood problems. Valganciclovir can suppress the numbers of white blood cells, increasing the opportunity for infection. Valganciclovir also low- ers blood platelet number which may increase blood clotting time.
Gastrointestinal. Presence of blood in urine or stools, with stools possibly appearing black or tarry, and pain- ful or difﬁcult urination are common side effects of val- ganciclovir. Abdominal pain, diarrhea, nausea, and vomiting are normally less serious side effects.
Respiratory distress or infection. Cough, hoarseness, troubled breathing, nasal congestion, sore throat, chills, fever, lower back or side pain, unusual bleeding, bruising, or fatigue could be seen if a patient is taking valganciclovir.
Mucocutaneous. Ulcers, sores or white spots may ap- pear in the mouth, paler than usual appearance of the skin, pinpoint red macules on skin, or allergic (hive- like) swelling or itching are indicators of adverse ef- fects of valganciclovir.
Ophthalmological. Seeing ﬂashes of light, ﬂoating spots before the eyes, or a “veiled curtain” appearing across the ﬁeld of vision can be indicators of side effects of valganciclovir.
Neurological. Rare but serious side effects may be con- fusion, illogical thinking, seizures, or false sensations. Agitation may also occur.
Concomitant therapy. Taking valganciclovir with didanosine, mycophenolate, or probenecid may increase the chance of side effects.
Pregnant and breast-feeding women. Valganciclovir has not been studied in pregnant women but animal studies indicate that valganciclovir causes birth de- fects and other problems. Men who are taking valgan- ciclovir should use a condom to avoid impregnating their spouse, not only during the course of treatment but for at least 90 days following treatment. Use of valganciclovir during pregnancy should be avoided whenever possible.
Studies to determine the transfer of valganciclovir from nursing mothers to their infants have not been completed. Valganciclovir is not recommended during breast-feeding because it may cause unwanted effects in nursing babies.
Pediatric use. No studies have been done on pediatric patients.
Elderly. No studies have been done on elderly patients and it is not known if valganciclovir causes different side effects or problems in older people.
Kidney disease. Valganciclovir increases the chances of side effects as it accumulates in the blood in patients with kidney disease.
Blood diseases. Low platelet count, low red blood cell count, or low white blood cell count may be exacerbated by valganciclovir.
Severe viral pneumonia—respiratory syncytial virus RSV—in children can be effectively treated by ribavirin. Ribavirin is a broad-spectrum antiviral nucleoside. In addition to being used to treat RSV pneumonia, it is also used to treat strains of inﬂu- enza A and B and Lassa fever, off-label. It is emerging as a
Fig. 3.18 Associated names, structure, and applicability of ribavirin.
possible treatment for adenovirus (206). As summarized by Gavin and Katz, adenovirus sites are found throughout the body as cystitis, pneumonia, enteritis, colitis, hepatitis, nephri- tis, etc., and survival-rate improvements are high enough to consider IV ribavirin a feasible treatment modality (206). Many other viruses respond to ribavirin, including hepatitis A, B, and C, particularly when combined with pegylated interferon- alpha (for more information, refer to ribavirin-PEG-interferon, page 213). Ribavirin is a white crystalline powder with high solubility in water and limited solubility in anhydrous alcohol. Figure 3.18 shows the structure of ribivarin.
Mechanisms of Action
Ribavirin, a broad-spectrum antiviral nucleoside (guanosine) analog, phosphorylates easily. Although the mechanisms of ribavirin remain unclear (207), ribavirin appears to be a non- speciﬁc antiviral with most of its efﬁcacy due to incorporation of the ribavirin into the viral genome. Ribavirin undergoes dehydration synthesis to form new products (Fig. 3.19). When cells are exposed to ribavirin, there is a reduction in intracel- lular guanosine triphosphate—a requirement for translation, transcription, and replication in viruses and a reason for the broad-spectrum attributes of ribavirin (208). Ribavirin signif- icantly increases the mutation rate of RNA in poliovirus and
Fig. 3.19 Ribavirin bonding to cytosine and uracil.
reduces viral ﬁtness (Fig. 3.20). Thus, an understanding of the in-depth mechanisms of ribavirin activity could contribute to the development of lethal mutagenesis as an effective antivi- ral strategy.
Studies that Support Treatment with Ribavirin
Ribavirin may help treat orthopoxviruses, inﬂuenza and chronic hepatitis A and B (206,209,210) (Table 3.17).
Ribavirin is usually prescribed as an inhalant for infants and small children. Elderly patients, teenagers, and adults are usually not prescribed ribavirin. Ribavirin is readily absorbed with oral administration and there is a linear relationship between the time of last administration and the dosage. Although the tablets are taken with food, there is insufﬁcient data to determine the effect of different types of diets (high fat, high protein, vegetarian, etc.) on ribavirin absorption. Dos- ages and types of administration are shown in Table 3.18.
Unusual tiredness and weakness. May occur in pa- tients taking ribavirin by mouth or injection for Lassa fever.
Headache. Occurs rarely.
Itching, redness, and swelling of the eyes. Occurs rarely.
Skin rashes. Occurs rarely.
Fig. 3.20 Mechanisms of action of ribavirin. Ribavirin is a nucleoside analog that readily phosphorylates to ribavirin triphosphate. Ribavirin is incorporated into the viral genome by binding to cytosine and uracil.
Combination Therapy with Interferon-alpha. The adverse events of this combination therapy are signif- icant and include severe depression with suicidal ten- dencies, hemolytic anemia, suppression of bone marrow function, pulmonary dysfunction, pancreatitis, and diabetes.
Combination with Interferon-alpha. Combination therapy of ribavirin with interferon alpha has been shown to be effective in the treatment of hepatitis C. Ribavirin monotherapy is not effective. However, there may be severe adverse effects (see the preceding sec- tion). For example, patients with autoimmune hepati- tis become worse when treated with this therapy.
Allergies. Some patients are allergic to ribavirin. The possibility exists that children who are allergic to food, preservatives, dyes, or other substances may also be al- lergic to ribavirin.
Pregnancy. Ribavirin for inhalation therapy for very young children may cause exposure to women who are pregnant (or may become pregnant) if they spend time at the bedside when the inhalation therapy is being administered. The effect of ribavirin on prena- tal development has not been tested in humans, but breast milk containing ribavirin has been shown to cause birth defects and other problems in certain an- imal studies.
Hepatic dysfunction. In patients with decreased he- patic function, the pharmacokinetics of ribavirin can- not be accurately predicted. Therefore, the dosage may need to be increased for efﬁcacy, but monitored careful- ly to reduce adverse effects.
Breast milk. In animal studies, ribavirin passes to the offspring through breast milk and can cause problems in nursing animals and the young. There have been no tests on humans.