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anti-CMV drugs.pptx
- 1. Drugs for treatment of CMV
- 2. Outline • Background • Ganciclovir and valganciclovir • Foscarnet • Cidofovir 2
- 3. Background • CMV causes congenital infections & disease in immunocompromised pts • Retinitis, colitis, esophagitis, encephalitis, pneumonitis • Usually, disease when CD4 count is low • During pre-ART era ~25% developed CMV retinitis • Prevalence in Ethiopia • 94.4% +ve for IgG, 4·0% for CMV IgM in blood donors • 88.5% +ve for IgG and 15% +ve for IgM in pregnant • 1.3% +ve for IgM in newborn 3
- 4. Ganciclovir/Valganciclovir • Valganciclovir prodrug converted to ganciclovir • Analog of the nucleoside guanosine • Converted IC to ganciclovir 5'-monophosphate by viral kinase, encoded by CMV gene UL97 • Cellular kinases catalyze formation of ganciclovir diphosphate & triphosphate • Present in 10x greater conc in CMV or HSV-infected cells than uninfected cells 4
- 5. Ganciclovir/Valganciclovir… • Ganciclovir is inhibitor of nucleotide incorporation • Preferential to viral than cellular DNA polymerase • Poor substrate for chain elongation • Primarily used in treating CMV infections • In vitro synergy with Foscarnet against CMV • Inhibits the replication of HSV-1 & 2, EBV, VZV, HHV-6, and herpes simian B virus • Drug of choice for symptomatic herpes simian B virus disease, including CNS infections 5
- 6. Ganciclovir/Valganciclovir… • Antiviral agents preferred for Rx of HSV infections • Acyclovir, valaciclovir famciclovir, • Resistance with continued use • Mutations in the UL97-encoded phosphotransferase • Alterations in UL54-encoded viral DNA polymerase • UL97= moderate resistance, no cross-resistance • UL97 + UL54 = high degree of res & cross-resistance • Cidofovir and Foscarnet 6
- 7. Ganciclovir/Valganciclovir… • Ganciclovir is excreted, unmodified, in the urine with a plasma t1/2 of 2-4hrs • IC t1/2 of ganciclovir triphosphate is 16.5 hours • Dosage adjustment in impaired renal function • Valganciclovir, L-valyl ester of ganciclovir • Well absorbed after oral administration • Rapidly hydrolyzed in the intestinal wall and liver • bioavailability of ganciclovir from valganciclovir = ~60% • 900 mg oral valganciclovir = 5 mg/kg IV ganciclovir 7
- 8. Ganciclovir/Valganciclovir… Toxicity • Bone marrow suppression • Particularly leukopenia • CMV itself could cause BM depression • Not used when neutro. < 500/µL, platelet < 25,000/µL • Renal insufficiency • low risk from ganciclovir • Ganciclovir and imipenem may increase risk of seizure 8
- 9. Foscarnet • For treatment of ganciclovir-resistant CMV • Pyrophosphate analog • Binds reversibly near the pyrophosphate-binding site of DNA polymerase • Blocks cleavage of pyrophosphate moiety from deoxynucleotide triphosphates • Halting DNA chain elongation • Mammalian DNA polymerase requires a 100-fold greater conc. than to block CMV replication 9
- 10. Foscarnet… • Clinical use • Exclusively to treat CMV infections, and acyclovir resistant HSV & VZV • Also Inhibits herpes family viruses, HBV, and HIV • Cause of resistance; mutations in viral DNA pol. • Poor oral bioavailability, administered IV • Vitreous levels approximate those in plasma • CSF levels average 66% of those in plasma 10
- 11. Foscarnet… • Not significantly metabolized and is excreted solely by the kidneys • dose adjustment in patients with renal insufficiency • Renal insufficiency • ~27% of people develop reduction in renal function • Direct tubular damage • Including nephrogenic diabetes insipidus • Concomitant saline administration = reduced incidence 11
- 12. Foscarnet… • Electrolyte disturbance • Hypocalcemia = complex formation with free Ca+2 • Hypomagnesemia leading to hypocalcemia & hypokalemia • Seizure, genital ulcerations, anemia, nausea 12
- 13. Cidofovir • Nucleotide mainly used for CMV retinitis in HIV pts • Cytidine analog, inhibits viral DNA polymerase • Incorporation of drug disrupts further chain elongation • Not phosphorylated by a viral kinase • Mechanism of resistance • Mutations in the viral DNA polymerase gene • Unaffected by mutations in CMV phosphotransferase • Which confer resistance to ganciclovir • Prolonged therapy with ganciclovir cause DNA polymerase mutations; cross-resistance to cidofovir 13
- 14. Cidofovir… • > 80 % excreted unchanged in urine within 24hrs • contraindicated in proteinuria (2+ or greater) or baseline serum creatinine greater than 1.5 mg/dL • t1/2 in serum 2.4-3.2hrs, but IC 24-65 hours • used every two weeks • Most important adverse effects; renal toxicity • Creatinine and urine protein checked within 48 hours prior to each dose, reduced or avoided • ~50% of pts developed either • Proteinuria, ↑ creatinine, ↓ creatinine clearance 14
- 15. Cidofovir… • Pts should receive 1 lt of saline prior to dose • Repeat 1lt if pts tolerate either during or immediately following the drug • Also, probenecid 2g PO 3hrs prior, 1g 2hrs and 8h following cidofovir 15
- 16. THANK YOU ! 16
Editor's Notes
- Structure activity relations (SAR)
- Structure activity relations (SAR)
- human herpes virus 6 (HHV-6),
- One study of 76 AIDS patients with cytomegalovirus (CMV) retinitis treated initially with ganciclovir reported resistance in 11 percent of patients at six months of treatment and 28 percent at nine months
- Ganciclovir is given primarily as an intravenous formulation rather than orally because of its poor bioavailability (ie, 6 percent) that is only modestly increased by food A sustained-release ganciclovir intraocular implant is also available for the treatment of CMV retinitis. Ganciclovir intraocular implants, while avoiding systemic side effects, can be associated with complications of ophthalmologic surgery, such as endophthalmitis and intravitreal bleeding, and may increase the risk of early retinal detachment
- The usual dose of ganciclovir for induction therapy is 5 mg/kg every 12 hours followed by 5 mg/kg as a single daily infusion for maintenance therapy The duration of therapy will depend on the host and the severity of disease. Generally speaking, the duration of induction is 14 to 21 days in the HIV-infected host with invasive infection while the induction period is 7 to 14 days in the transplant patient with invasive disease. In patients able to take and absorb oral medications, valganciclovir is a reasonable alternative to intravenous (IV) ganciclovir for both induction and maintenance therapy The dosing of valganciclovir , in adult patients with normal renal function, is 900 mg twice daily for 21 days during induction therapy followed by single daily dosing during maintenance therapy pregnancy category C substance
- Foscarnet = trisodium phosphonoformate
- Sequestration in bone with gradual release accounts for the fate of an estimated 10-20% of a given dose Dose-limiting toxicities are nephrotoxicity and symptomatic hypocalcemia
- Other electrolyte disturbances that may occur include hypophosphatemia, hypercalcemia, and hyperphosphatemia it is unclear whether seizure reflects direct toxicity, drug-induced hypocalcemia, or underlying conditions This problem, combined with the requirement for concomitant hydration and need for electrolyte monitoring, make this drug more difficult to administer than ganciclovir These lesions are reversible and potentially preventable with careful urinary hygiene
- Approximately 50 percent of patients receiving cidofovir in clinical trials developed either proteinuria (2+ or greater), increased serum creatinine (rise of at least 0.4 mg/dL) or decreased creatinine Renal dysfunction is usually reversible with discontinuation of the drug
- Nausea and vomiting are common side effects of probenecid and may be reduced by giving the drug with food or by administration of antiemetics. Rash is also common and management with an antihistamine and/or acetaminophen may be appropriate [ 8 ]. Neutropenia has been observed in approximately 20 percent of patients receiving cidofovir [ 8 ]; it is more difficult to establish causality for this finding given its common appearance in advanced AIDS