Antiviral agents vaccines and immunotherapies - part 5 doc

Table 3.8 Clinical Studies and Published Reports that Support the Use of FamciclovirDosage for off-label treatment for herpes labialis Genital herpes regimen dosing is not sufficient fo

Table 3.8 Clinical Studies and Published Reports that Support the Use of Famciclovir

Dosage for off-label

treatment for

herpes labialis

Genital herpes regimen dosing is not sufficient for treatment of herpes labialis Use of higher doses may be necessary to reduce lesion healing time (e.g., 500 mg TID for 5 days).

160

Symptomatic and

asymptomatic viral

shedding in women

For those women with a history

of recurrent genital herpes, famciclovir reduces the frequency and delays the onset of viral shedding.

161

Genital herpes

recurrences

Famciclovir is effective in increasing the time to first recurrence of genital herpes and increasing the number of recurrence-free patients.

7 days, especially among persons

50 years of age and older.

162,163

(continued)

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

Adverse Events

Headache.

Nausea.

Diarrhea.

Increased serum concentrations of penciclovir Serum

concentrations of penciclovir may occur if famciclovir is

163,164

Ophthalmic zoster Famciclovir 500 mg 3 times daily

was well tolerated and demonstrated efficacy similar to acyclovir 800 mg 5 times daily

of HBV after liver transplantation.

170

used concurrently with probenecid (or other drugs icantly eliminated by active renal tubular secretion).Special Considerations

signif-Renal impairment For patients with renal

impair-ment, all regimens in Table 3.9 will require dosage justments

ad-Coadministration with probenecid or other

relat-ed drugs Administration of drugs eliminatrelat-ed by

ac-tive renal tubular secretion with famciclovir may causeincreased serum concentrations of penciclovir

Drug resistance For hepatitis B, five domains (labeled

A–E) have been identified Domains B and E may affectprimary and template positioning Structural changes

in these domains may affect oral resistance to side analogues Famciclovir promotes mutations in the

nucleo-B domain A mutation at position 528 (Leu replaced by

Table 3.9 Treatment Table for Famciclovir

Herpes zoster initiation Famciclovir 500 mg every 8 hours for

7 days, begun at the earliest signs of the disease.

Met or Val) also occurs during lamivudine therapy andmay cause cross-resistance A summary of susceptiblepositions for the B-domain resistance for famciclovir isshown 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 Americaand in some, but not all, European countries (137)

Penciclovir

Introduction

Penciclovir is acyclic nucleoside analogue which has in vitro

activity against HSV-1, HSV-2, and VZV (175) (Fig 3.12) FDAapproval is only for topical treatment of recurrent herpes labi-alis as the oral bioavailability is extremely low Intravenouspenciclovir shows promise for the treatment of mucocutaneousherpes simplex infections in those with immunosuppression

Table 3.10 Nucleotide changes that induce resistance

to famciclovir in genotype A hepatitis B virus

V521L P525L L528M L528V T532S

Fig 3.12 Associated names, structure, and applicability ofpenciclovir

The active form of penciclovir is significantly more stable inHSV-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 viralthymidine kinase and cellular kinases prior to its competitiveinhibition 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 immunocompetentpatients that demonstrates that penciclovir treatment results

in improvement in a variety of facets These improvementswere 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

Treatment

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 ofpenciclovir is negligible

Adverse Events

Adverse events are similar to those of acyclovir and valacyclovir

Table 3.11 Efficacy of Penciclovir in Treating Herpes Labialis

Average healing time

by 0.7 days Average duration of pain by 0.6 days Significantly shortened.

151

Introduction

Ganciclovir, a nucleoside analogue, is used to prevent and treatthe 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, transplantrecipients, 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, hasimproved 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 theactive triphosphate form This triphosphate form becomespart of a newly synthesized DNA chain This inhibits further

Table 3.12 Treatment of Viral Diseases with Penciclovir

Fig 3.14 Associated names, structure, and applicability of ganciclovir

DNA synthesis by inhibiting DNA polymerase and by ing premature chain termination (180–183) (Fig 3.15) Thethymidine kinase (TK) encoded by HSV or VZV has a broadsubstrate specificity that permits interaction by acyclovir organciclovir Phosphorylation of ganciclovir in CMV-infectedcells is dependent upon a protein kinase The role of the kinase

induc-is not completely understood and induc-is under study In HHV-6, asimilar mechanism activates ganciclovir Mutations for drugresistance most often occur in the UL97 gene that affects themonophosphorylation process or the UL54 gene that codes forDNA polymerase in human CMV (184) Graft-versus-host-disease can be prevented when donor T cells are transfected toexpress herpes simplex virus thymine kinase Cells that expressthis enzyme are susceptible to ganciclovir, which opens a newavenue for addressing drug resistance

Clinical Studies and Reports that Support the Use of

Ganciclovir

Oral ganciclovir is available for CMV prophylaxis, but is not

as effective as intravenous treatment Valganciclovir has ter availability (177,178,183,185–193) (Table 3.13)

bet-Treatment

Intravenous ganciclovir is the drug of choice for treatment ofCMV 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 andthe convenience of ambulatory therapy This, however, must bebalanced against the potential of intra-ocular side effects orcontralateral eye infection by CMV (185) Late-onset cytomeg-alovirus disease among organ transplant recipients is commonand the current thought is that antiviral prophylaxis, such aswith ganciclovir, be used preemptively Allograft rejection isoften associated with CMV risk Those patients on ganciclovirmay 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 CMVpneumonia where the best available therapy has a mortality

Table 3.13 Clinical Studies and Reports of Ganciclovir Usage

Bioavailability Oral bioavailability is 8–9%

Needs to be administered by daily intravenous infection.

177,178, 183

CMV retinitis The ocular implant may be used

to treat CMV, although it requires surgical insertion every six months.

185

Foscarnet vs ganciclovir Ganciclovir is preferred due to

less severe side effects.

186 Ganciclovir vs

valganciclovir

Valganciclovir has better oral bioavailability and fewer severe side effects.

EBV-positive tumor in the

positive

immunocompetent

(Phase I/II trial)

Induce latent viral TK gene and enzyme in tumor cells using arginine butyrate, followed by ganciclovir treatment in standard treatment doses.

187

transplant patients is controlled with ganciclovir.

(in vitro)

Ganciclovir shows no toxicity in micromolar concentration.

190 CMV after solid organ

transplantation

Ganciclovir is effective for kidney, liver, heart, and lung transplant recipients as preemptive therapy.

is obtained before beginning maintenance therapy.

193

rate of 45–78%; therefore, post-operative prevention of CMV iscritical (196).

Adverse Effects

Dosage of ganciclovir must often be limited due to:

Bone marrow suppression Bone marrow suppression

may also be accompanied by thrombocytopenia, tropenia, anemia, and granulocytopenia

neu-Retinal toxicity High doses of intravitreal ganciclovir

may cause retinal damage (197)

Also involved may be:

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 expressedphenotypic or genotypic ganciclovir-resistance (198).Special Considerations

Animal studies Ganciclovir was found to be

teratoge-nic, carcinogeteratoge-nic, and mutagenic in animal studies Italso caused aspermatogenesis

Combination therapy with foscarnet In cases of

fail-ure of monotherapy, ganciclovir can be combined withfoscarnet for treatment

Table 3.14 Treatment with Ganciclovir

Monitoring of CMV infection in mised transplant patients The results of quantitative

immunocompro-antigenemia, which uses buffy coat cell preparations,may differ significantly from quantitative PCR, whichuses plasma for the analysis of ganciclovir resistance.Once ganciclovir is initially introduced for treatment ofCMV, quantitative PCR levels drop A subsequent use ofboth quantitative PCR and antigenemia may be indica-tive of the emergence of ganciclovir-resistant CMV Oncefoscarnet is administered, both the PCR and antigene-mia levels drop The results of the quantitative PCR canoften be used to provide pre-emptive treatment beforetraditional clinical indicators appear (199) PCR withplasma performed best in a comparison with seven otherlaboratory 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 hasnot been established (202)

Effect of corticosteroids on efficacy In transplant

pa-tients, corticosteriod use may promote early pp65 genemia rather than emergence of a ganciclovir-resistantvirus Therefore, an immediate switch from ganciclovir

anti-to foscarnet (with more severe side effects) may not bewarranted Instead, dose intensification with ganciclovirshould continue to be the medication of choice (203,204)

Valganciclovir

Introduction

Valganciclovir is used to treat CMV retinitis, an infection ineyes of immunocompromised patients Valganciclovir does notcure CMV, but it can keep symptoms from becoming worse or

cause some improvement Oral valganciclovir has increasedavailability when compared with oral ganciclovir As with allother antivirals, valganciclovir-resistant strains are emerging(205) (Fig 3.16).

Mechanism of Action

Valganciclovir is a valylester prodrug of ganciclovir withapproximately 10 times the bioavailability of oral ganciclovir(Fig 3.17)

Clinical Findings and Reports That Support the Use of Valganciclovir

Valganciclovir has been used to treat CMV retinitis (205)(Table 3.15)

Treatment

Oral tablets are available in the United States Adults shouldtake 900 mg two times a day with food (Table 3.16)

Adverse Effects

Anemia and other blood problems Valganciclovir can

suppress the numbers of white blood cells, increasingthe opportunity for infection Valganciclovir also low-ers blood platelet number which may increase bloodclotting time

Fig 3.16 Associated names, structure, and applicability of valganciclovir

Gastrointestinal Presence of blood in urine or stools,

with stools possibly appearing black or tarry, and ful or difficult urination are common side effects of val-ganciclovir Abdominal pain, diarrhea, nausea, andvomiting are normally less serious side effects

pain-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 takingvalganciclovir

Mucocutaneous Ulcers, sores or white spots may

ap-pear in the mouth, paler than usual apap-pearance of theskin, 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” appearingacross 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

Table 3.15 Published Reports of Valganciclovir Usage

Special Considerations

Concomitant therapy Taking valganciclovir with

didanosine, mycophenolate, or probenecid may increasethe chance of side effects

Pregnant and breast-feeding women Valganciclovir

has not been studied in pregnant women but animalstudies indicate that valganciclovir causes birth de-fects and other problems Men who are taking valgan-ciclovir should use a condom to avoid impregnatingtheir spouse, not only during the course of treatmentbut for at least 90 days following treatment Use ofvalganciclovir during pregnancy should be avoidedwhenever possible

Studies to determine the transfer of valganciclovirfrom nursing mothers to their infants have not beencompleted Valganciclovir is not recommended duringbreast-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 differentside effects or problems in older people

Kidney disease Valganciclovir increases the chances of

side effects as it accumulates in the blood in patientswith kidney disease

Blood diseases Low platelet count, low red blood cell

count, or low white blood cell count may be exacerbated

to treat RSV pneumonia, it is also used to treat strains of enza A and B and Lassa fever, off-label It is emerging as a

influ-possible treatment for adenovirus (206) As summarized byGavin and Katz, adenovirus sites are found throughout thebody as cystitis, pneumonia, enteritis, colitis, hepatitis, nephri-tis, etc., and survival-rate improvements are high enough toconsider IV ribavirin a feasible treatment modality (206) Manyother 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 ofribavirin 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 undergoesdehydration synthesis to form new products (Fig 3.19) Whencells 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 thebroad-spectrum attributes of ribavirin (208) Ribavirin signif-icantly increases the mutation rate of RNA in poliovirus and

Fig 3.18 Associated names, structure, and applicability of ribavirin

reduces viral fitness (Fig 3.20) Thus, an understanding of thein-depth mechanisms of ribavirin activity could contribute tothe development of lethal mutagenesis as an effective antivi-ral strategy

Studies that Support Treatment with Ribavirin

Ribavirin may help treat orthopoxviruses, influenza and chronichepatitis A and B (206,209,210) (Table 3.17)

Treatment

Ribavirin is usually prescribed as an inhalant for infants andsmall children Elderly patients, teenagers, and adults areusually not prescribed ribavirin Ribavirin is readily absorbedwith oral administration and there is a linear relationshipbetween the time of last administration and the dosage.Although the tablets are taken with food, there is insufficientdata 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.Adverse Effects

Unusual tiredness and weakness May occur in

pa-tients taking ribavirin by mouth or injection for Lassafever

Headache Occurs rarely.

Itching, redness, and swelling of the eyes Occurs

rarely

Skin rashes Occurs rarely.

Fig 3.19 Ribavirin bonding to cytosine and uracil

Table 3.17 Studies that Support the Use of Ribavirin

Severe adenovirus disease in

immunocompromised

children

Two of five children recovered, whereas non-treatment would have resulted in five non-recoveries Early intervention (diagnosis via PCR) with ribavirin may make earlier, more effective treatment possible

206

Orthopoxviruses (in vivo) Ribavirin has an

inhibitory activity against orthopox viruses.

209

by injection.

210 Influenza A and B Ribavirin given by aerosol

inhalation

210

Table 3.18 Treatment Modalities for Ribavirin

Chronic hepatitis C Capsules: Must be combined with

Interferon –alpha therapy to be effective (See Table 3.28.)

Respiratory syncytial

virus (RSV)

Inhalation therapy: Dosage for treating infants must be determined by physicians Dosage has not been determined for adults and teenagers Usually not prescribed for the elderly Influenza A and B Given by aerosol inhalation as a fine mist

by using a nebulizer attached to an oxygen hood, tent, or facemask.

Lassa fever Given either orally or by injection

Adenoviruses Intravenous ribavirin can be used as a

compassionate-use medicine in severely immunocompromised patients with adenovirus.

Combination Therapy with Interferon-alpha The

adverse events of this combination therapy are icant and include severe depression with suicidal ten-dencies, hemolytic anemia, suppression of bonemarrow function, pulmonary dysfunction, pancreatitis,and diabetes

signif-Special Considerations

Combination with Interferon-alpha Combination

therapy of ribavirin with interferon alpha has beenshown to be effective in the treatment of hepatitis C.Ribavirin monotherapy is not effective However, theremay 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 arepregnant (or may become pregnant) if they spendtime at the bedside when the inhalation therapy isbeing administered The effect of ribavirin on prena-

tal development has not been tested in humans, but

breast milk containing ribavirin has been shown tocause birth defects and other problems in certain an-imal studies

Hepatic dysfunction In patients with decreased

he-patic function, the pharmacokinetics of ribavirin not be accurately predicted Therefore, the dosage mayneed to be increased for efficacy, but monitored careful-

can-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

NUCLEOTIDE ANALOGS

The derivatives of nucleosides that are monophosphorylatedbelong to the nucleotide analogs Those with antiviral propertiesinclude cidofovir, adefovir, and tenofovir Tenofovir is used to

treat HIV infection and is discussed in Chapter 2, page 62.

Phosphorylation of nucleosides occurs within the plasm of cells that are beginning mitotic division The synthe-sis of bases that contribute to DNA chain elongation is limited

cyto-by the inclusion of nucleotide analogs Mitochondrial polymerase may also be affected

DNA-Cidofovir

Introduction

Cidofovir has received much attention as a therapy for manyviral diseases (Fig 3.21) Although preemptive antiviral ther-apy for CMV infection following allogenic stem cell transplan-tation is recommended as an effective strategy for preventingCMV disease, some studies do not support this hypothesis(211) Cidofovir is considered an option for the treatment ofacyclovir-resistant HSV although it has not been FDA-approved for this purpose However, there is an increasingneed for additional therapies as more herpes viral strains

Fig 3.21 Associated names, structure, and applicability of cidofovir