Antiviral agents vaccines and immunotherapies - part 5 doc

General (Non-antiretroviral) Antiviral Drugs 163 Table 3.8 Clinical Studies and Published Reports that Support the Use of Famciclovir Topic Findings Reference 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). 157 Efficacy in reducing number of recurrences of genital herpes Famciclovir delays the time of the first recurrence of genital herpes. The number of patients remaining lesion free was 3 times higher in famciclovir than in placebo recipients. 158,159 Comparison of famciclovir with acyclovir for treatment of HSV in HIV-positive patients Both acyclovir and famciclovir are well tolerated, generally safe to use, and effective 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. 159,160 Suppression of HSV reactivation in HIV- positive patients Famciclovir treatment of 500 mg twice daily for 8 weeks significantly reduces symptoms and viral shedding. 161 Herpes zoster in immunocompetent patients; reduction of postherpetic neuralgia Famciclovir is effective at reducing PHN when used 500 mg t.i.d. for 7 days, especially among persons 50 years of age and older. 162,163 (continued) 164 Antiviral Agents Treatment 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 Table 3.8 (Continued) Topic Findings Reference Rapid resolution of zoster-associated pain Famciclovir is as effective and more convenient than acyclovir for rapid resolution of zoster- associated pain. 163,164 Ophthalmic zoster Famciclovir 500 mg 3 times daily was well tolerated and demonstrated efficacy similar to acyclovir 800 mg 5 times daily 153 Ramsey Hunt syndrome A 7–10 day course of famciclovir (500 mg 3 times daily) combined with 3–5 days of oral prednisone (60 mg/day) is effective against VZV-mediated Ramsey Hunt syndrome. 112,165 Treatment of herpes zoster in immunosuppressed patients Famciclovir is safe and effective. 166 Hepatitis B virus (HBV) Only limited in vivo effect on HBV. 167–169 HBV disease in liver transplant recipients and recurrent HBV disease Famciclovir administered independently seems to be of limited efficacy in the treatment of HBV after liver transplantation. 170 General (Non-antiretroviral) Antiviral Drugs 165 used concurrently with probenecid (or other drugs signif- icantly eliminated by active renal tubular secretion). Special Considerations 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 Table 3.9 Treatment Table for Famciclovir Symptom Treatment Herpes zoster initiation Famciclovir 500 mg every 8 hours for 7 days, begun at the earliest signs of the disease. Chickenpox in adolescents and adults Famciclovir 500 mg every 8 hours for 7 days. Episodic treatment of genital herpes Famciclovir 125 mg twice daily for 5 days. Chronic suppressive treatment of recurrent genital herpes Famciclovir 250 mg twice daily for 1–2 years, followed by a reevaluation of patient’s recurrences. Recurrent orolabial or genital herpes in HIV- positive patients. Famciclovir 500 mg twice daily for 7 days. Initial outbreak of HSV in HIV-positive patients 250–750 mg t.i.d. for 5–10 days Recurrent anogenital herpes in HIV-positive patients with CD4 + counts of <200 × 10 6 cells/ml 500 mg twice daily for 7 days is as effective as acyclovir 400 mg 5 times daily for 7 days. 166 Antiviral Agents 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 Introduction 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. 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 of penciclovir. General (Non-antiretroviral) Antiviral Drugs 167 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. 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 of penciclovir is negligible. Adverse Events Adverse events are similar to those of acyclovir and valacyclovir. Table 3.11 Efficacy of Penciclovir in Treating Herpes Labialis Topic Findings Reference In immunocompetent patients: a. Healing time b. Pain duration c. Viral shedding Topical 1% penciclovir decreases: Average healing time by 0.7 days Average duration of pain by 0.6 days Significantly shortened. 151 168 Antiviral Agents Fig. 3.13 Phosphorylation of penciclovir to inactivate viral DNA polymerase. General (Non-antiretroviral) Antiviral Drugs 169 Ganciclovir Introduction 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 Table 3.12 Treatment of Viral Diseases with Penciclovir Symptom Treatment Herpes labialis lesions (immunocompetent patients) Apply topical 1% penciclovir cream to herpes labialis lesions every 2 hours while awake for 4 days to reduce healing time, pain duration, and viral shedding. Fig. 3.14 Associated names, structure, and applicability of ganciclovir. 170 Antiviral Agents 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 Ganciclovir 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). Treatment 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 General (Non-antiretroviral) Antiviral Drugs 171 Fig. 3.15 Phosphorylation of ganciclovir to inactivate viral DNA polymerase. 172 Antiviral Agents Table 3.13 Clinical Studies and Reports of Ganciclovir Usage Topic Findings Reference Bioavailability Oral bioavailability is 8–9%. Needs to be administered by daily intravenous infection. 183 Treatment and prevention of CMV in immunocompromised patients Ganciclovir is usually administered intravenously because of poor oral bioavailability. 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 HHV-6 HHV-6 reactivation in transplant patients is controlled with ganciclovir. 188 CMV with acute lymphoblastic leukemia Ganciclovir can be used to manage CMV infection. 189 Cytotoxicity in retinas (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. 191 Globulin plus ganciclovir to treat CMV in a solid organ transplant patient Oral ganciclovir given preemptively reduces invasion of tissue by CMV- associated disease. 192 CMV retinitis intravitreal vs intravenous therapy Induction therapy should be prolonged until complete inactivation of CMV retinitis is obtained before beginning maintenance therapy. 193 [...]... dyspepsia However the reports between those receiving adefovir and the placebo were not significantly different Pre- and post-liver transplant patients reported some additional concerns that may be important on 194 Antiviral Agents a case-by-case basis: changes in serum creatinine and serum phosphorus, pruritus and rash, abnormal liver functions, and some respiratory complications Discontinuation of adefovir... on adefovir before the FDA gave approval, and are shown in Table 3.21 ( 252 – 255 ) Fig 3.24 Mechanism of action of adefovir 192 Antiviral Agents General (Non-antiretroviral) Antiviral Drugs 193 Table 3.21 Reports that Support Use of Adefovir Topic Findings Reference Chronic hepatitis B Loss of serum HBV DNA and HBcAg after 12 weeks therapy with adefovir Long-term treatment not associated with toxicity... Ribavirin is a broad-spectrum antiviral nucleoside In addition to being used to treat RSV pneumonia, it is also used to treat strains of influenza A and B and Lassa fever, off-label It is emerging as a General (Non-antiretroviral) Antiviral Drugs 179 Fig 3.18 Associated names, structure, and applicability of ribavirin possible treatment for adenovirus (206) As summarized by Gavin and Katz, adenovirus... treatment with adefovir Safety and efficacy of adefovir in HIVpositive (advanced) patients 253 254 255 Treatment Adefovir is administered as an oral tablet Each table contains 10 mg of adefovir dipivoxil and a number of inactive ingredients In laboratory studies, 0.2–0. 25 µM of adefovir achieved a 50 % reduction in viral DNA synthesis Adefovir is excreted by glomular filtration and active tubular secretion... triphosphate—a requirement for translation, transcription, and replication in viruses and a reason for the broad-spectrum attributes of ribavirin (208) Ribavirin significantly increases the mutation rate of RNA in poliovirus and 180 Antiviral Agents 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... Insufficient studies have been done to establish safety and effectiveness Overdosage Doses of adefovir of 50 0 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated General (Non-antiretroviral) Antiviral Drugs 1 95 with gastrointestinal side effects In case of overdose, the patient should be monitored for evidence of toxicity and standard supportive treatment used, as necessary HIV For... Phosphorylation of cidofovir to inactivate viral DNA polymerase 186 Antiviral Agents General (Non-antiretroviral) Antiviral Drugs 187 Table 3.19 Studies and Reports of Cidofovir Usage Topic CMV retinitis in AIDS patients HHV-8 Kaposi’s sarcoma HSV HPV Poxviruses Perianal condylomata in HIV-positive patient (HPV) Use of cidofovir for CMV, preemptive therapy and secondary preemptive therapy Use of alkoxyalkyl or... therapeutic agents for viral infections, cancer, inflammatory, and cardiovascular diseases Some drawbacks of antisense drugs include low-binding to active sites and toxic side effects ( 256 ) Oligonucleotides may be inhibitors of HIV ( 257 ) It still remains a challenge for oligonucleotides to provide efficient and specific antisense activity with reduced toxicity Fomivirsen is an example of an antisense drug 196 Antiviral. .. CMV retinitis ( 258 –260) (Table 3.22) Treatment Treatment for CMV-retinitis is shown in Table 3.23 Adverse Effects In AIDS patients, pigmentary retinopathy, alterations in the electro-retinogram, rings of over-or under-pigmented retinal epithelium around the cornea (bull’s-eye maculopathy), and cataracts have been reported Other common adverse effects are: Ocular inflammation Vitreitis and/ or iritis may... can keep symptoms from becoming worse or General (Non-antiretroviral) Antiviral Drugs 1 75 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 (2 05) (Fig 3.16) Mechanism of Action Valganciclovir is a . genotype A hepatitis B virus V521L P525L L528M L528V T532S Fig. 3.12 Associated names, structure, and applicability of penciclovir. General (Non-antiretroviral) Antiviral Drugs 167 The active. acyclovir 400 mg 5 times daily for 7 days. 166 Antiviral Agents Met or Val) also occurs during lamivudine therapy and may cause cross-resistance. A summary of susceptible positions for the B-domain resistance. outbreak of HSV in HIV-positive patients 250 – 750 mg t.i.d. for 5 10 days Recurrent anogenital herpes in HIV-positive patients with CD4 + counts of <200 × 10 6 cells/ml 50 0 mg twice daily