Class-specific Characteristics: Nucleoside Reverse Transcriptase Inhibitors (nRTIs)
  •  Nucleoside Reverse Transcriptase Inhibitors (nRTIs)-inhibit HIV reverse transcriptase & slow/prevent HIV replication
  •  Taken in two or three doses per day without regard for meals (except for didanosine (Videx, ddI), which may be taken once daily on an empty stomach)
  •  All nRTIs may cause a rare, but potentially fatal lactic acidosis with hepatic steatosis syndrome

 

Zidovudine (ZDV)
  • Zidovudine (azidothymidine, AZT):
    • activation by phosphorylation to the 5'-triphosphate derivative; phosphorylated by three cellular kinases;
    • active drug is a competitive inhibitor of deoxythymidine triphosphate;
    • active drug also chain-terminates proviral DNA synthesis.
  •  Activity (in vitro) against: HIV-1, HIV-2, human T cell lymphotrophic viruses;
    • weaker activity: hepatitis B virus, Epstein-Barr virus.
  • Resistance: reverse transcriptase gene mutations;
    • resistance more frequent in advanced HIV infection;
    • Mutations at certain codons associated with 100-fold reduction in viral susceptibility to zidovudine.
    • Multiple mutations result in additive loss of drug susceptibility.
  • Oral and IV formulations available
  • Significant first pass effect results in a bioavailability of about 65%.
    •  Hepatic disease (cirrhosis) reduces the clearance significantly and requires dosage adjustment.
    •  Renal disease may also require dosage adjustment.

 Zidovudine: Clinical Use

  • Zidovudine inhibits HIV-1 replication and may decrease of the rate of disease progression and may prolong survival.
  • Effective in treating: HIV encephalopathy; HIV thrombocytopenia;
  • Zidovudine (Retrovir, AZT, azidothymidine) may be hidden in combination with any other nRTIs [except for stavudine (Zerit, d4T)]
    • Zidovudine (Retrovir, AZT, azidothymidine) plus stavudine (Zerit, d4T) causes antagonism
  • Resistance to zidovudine (Retrovir, AZT, azidothymidine): increasing in newly infected patients & those previously treated with the drug.
  • Effective in prevention of mother to newborn transmission of HIV.
  • Combination of zidovudine with other agents, including additional reverse transcriptase inhibitor or protease inhibitor appears to enhance antiviral activity while decreasing development of resistance.
  • ZDV is beneficial for AIDS patients-- probably associated with prolonged survival and decreases in frequency and severity of opportunistic infections.
  • ZDV was also shown beneficial in clinical trials involving patients with less severe disease, including patients with early symptomatic disease or asymptomatic patients with CD4 counts < 500 per ml.
  •  ZDV monotherapy is inferior to its use in combination with other antiretroviral drugs.
    • Generally, monotherapy is no longer recommended in view of the success of combination protocols.
  •  Possibly due to the development of resistance, ZDV clinical efficacy diminishes after 12-18 months.
  • The rationale for ZDV administration in combination with other agents is that such combinations may diminish or modify the emergence of resistant viral strains.
  • Zidovudine plus lamivudine often with a protease inhibitors -- recommended for HIV prevention after a needle stick or sexual exposure.-Morbidity and Mortality Weekly Report, 47, RR7: 1, 1998
  • ZDV available in combination with lamivudine as Combivir.
  • ZDV not associated with fetal malformations, if taken after first trimester pregnancy (medical letter 12/12/97)

 Zidovudine: Adverse reactions

  • Most common: myelosuppression (anemia, neutropenia) -- myelosuppression may be worse is the zidovudine is administered with other drugs that the also cause bone marrow suppression.
  • Lactic acidosis -- rare, but can be fatal.
  • transient adverse reactions, resolving with continued use, include GI intolerance, headache, insomnia.
  • Less frequent side effects: thrombocytopenia, myopathy, acute cholestatic hepatitis:
  • High-dose zidovudine therapy may cause CNS effects: confusion, anxiety,tremulousness.

 Zidovudine: Drug-Drug Interactions

  • Zidovudine dosage adjustment required if coadministered with drugs that inhibit hepatic glucuronidation (and probenecid (Benemid), naproxen (Naprosyn, Aleve), phenytoin (Dilantin), beta-lactam antibiotics, phenobarbital, ethinyl estradiol)
  • Increase zidovudine toxicity may also be caused by concurrent administration of drugs that are hepatically metabolized (acetaminophen, cimetidine (Tagamet), methadone, sulfonamides, benzodiazepines)
  • Zidovudine administration may decrease levels of the anti-epileptic drug phenytoin (Dilantin)-- requiring serum phenytoin level monitoring.

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Lamivudine (3TC) (Epivir)
  • Lamivudine: nucleoside analog; activity against (1) HIV-1 (including zidovudine-resistant strains) and (2) hepatitis B. virus.
  • Best tolerated of the nRTIs
  • An increase in viral loads when lamivudine (Epivir, 3TC) his part of a combination regimen may be indicative of lamivudine (Epivir, 3TC)-resistance
  • Since lamivudine (Epivir, 3TC) is effective against hepatitis B virus, lamivudine (Epivir, 3TC) discontinuation may cause a hepatitis flareup.
  • Not licensed as monotherapy.
  • synergistic with zidovudine against HIV-1
  • requires intracellular tri-phosphorylation for activation
  • effective orally; bioavailability > 80 % .
  • low body weight or renal dysfunction mandates dosage adjustment.
  •  side effects(mild): headache, fatigue, gastrointestinal upset, insomnia; and pancreatitis in children (rarely)

  • Approved by FDA for treating chronic hepatitis B
    • 56% of patients improved his logically; 72% of patients had normalization of serum aminotransferase activity
    • Serum conversion to anti-HBeAg: 16% after one year, 27% after two years of treatment
    • Long-term (90 weeks) treatment with lamivudine (Epivir, 3TC) reduces hepatitis B virus reinfection in orthotopic liver transplant recipients {treatment begins 4 weeks prior to transplant}

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Didanosine (ddI) (Videx)
  • Synthetic analog of deoxyadenosine, used in combination with zidovudine (Retrovir, AZT, azidothymidine) or stavudine (Zerit, d4T) plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor
  • Combination of didanosine (Videx, ddI) plus zalcitabine (Hivid, ddc): not recommended-overlapping toxicities
  • Used mainly in combination with stavudine or zidovudine plus a protease inhibitor or non-nucleoside agent.
  • phosphorylated active derivative competitively inhibits HIV reverse transcriptase and also interferes with viral replication by chain termination.
  • mutation responsible for ddI resistance may restore zidovudine susceptibility but may lead to cross-resistance with zalcitabine.
  • Oral administration. Elimination by glomerular filtration and tubular secretion.
    • Dosage adjustment may be required with low creatinine clearance.
  • ddI: effective in slowing HIV disease progression
  • Drug-Drug interactions: Didanosine (Videx, ddI) interferes with absorption of drugs which require gastric acidity, e.g.:
    • dapsone
    • ketoconazole (Nizoral)
    • doxycycline (Vibramycin, Doryx)
    • fluoroquinones
    • delavirdine (Rescriptor)
    • indinavir (Crixivan) & anothers
  •  Major clinical adverse effect:dose-dependent pancreatitis (risk factors for pancreatitis included alcoholism and hypertriglyceridemia)
    • Likelihood of pancreatitis may be enhanced by concurrent stavudine (Zerit, d4T) use
  •  Treatment-limiting toxicity: painful, nose-related peripheral neuropathy, pancreatitis (noted above), gastrointestinal disturbances.
  •  Severe lactic acidosis and retinal depigmentation may occur
  •  coadministration of ddI with fluoroquinones or tetracycline: low antibiotic serum levels due chelation.
  •  other adverse effects: peripheral neuropathy, hepatic toxicity, hematocytopenias, CNS toxicity (headache, irritability)
  •  ddI: increased uric acid may cause gout.

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Zalcitabine (ddC)
  • Zalcitabine: pyrimidine nucleoside: inhibits HIV-1 replication; requires activation by intracellular tri-phosphorylation; competitive inhibitor of reverse transcriptase.
  • prolonged therapy: resistance with decreased susceptibility to zalcitabine, didanosine, and lamivudine.
  • Least potent of nucleoside analogs.
  • Effective in treating HIV infection; oral route to administration only; bioavailability > 80 percent.
  •  adverse effects: dose-dependent persistent and severe peripheral neuropathy (especially in diabetic patients); pancreatitis, esophageal ulceration, headache, nausea, rash, stomatitis, fever.

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Stavudine (Zerit, d4T)
  • Stavudine (d4T): thymidine analog; activity requires intracellular tri-phosphorylation.
  • Antiviral activity: competitive inhibitor of HIV-1 reverse transcriptase; chain termination.
  • oral route administration; high bioavailability ( greater than 80 percent);
  • Used in initial combination treatment and and treatment failure all of zidovudine (Retrovir, AZT, azidothymidine)-containing protocols
  • Generally well tolerated
  • Adverse effects: major dose limiting toxicity-- peripheral sensory neuropathy, which often than disappears upon drug discontinuation. Less common toxicities: pancreatitis, arthralgias.
  • Combination of stavudine (Zerit, d4T) with zidovudine (Retrovir, AZT, azidothymidine) not recommended; they appear to be antagonistic (in vivo and in vitro)
  • renal insufficiency requires dosage adjustment;
  • multiple mutation sites associated with decreased antiviral activity.

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Abacavir (Ziagen)
  • For previously untreated patients: abacavir (Ziagen) +zidovudine (Retrovir, AZT, azidothymidine) & lamivudine (Epivir, 3TC) increased CD4 levels and lowered plasma HIV RNA to undetectable levels
  • HIV strains resistant to zidovudine (Retrovir, AZT, azidothymidine) & lamivudine (Epivir, 3TC) may be resistant to abacavir (Ziagen)
  • Response to abacavir (Ziagen) may be significantly reduced in patients with previous, extensive exposure to anti-HIV nucleoside treatment
  •  Adverse Effects:
    • severe hypersensitivity reaction {fever, gastrointestinal symptoms, rash, malaise} following about 11 days of therapy: frequency = 5%
    • A second exposure to abacavir (Ziagen) results and more severe reactions including respiratory distress, hypertension, & death

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Class-specific Characteristics: Non-Nucleoside Reverse Transcriptase Inhibitors (nnRTIs)

Non-Nucleoside Reverse Transcriptase Inhibitors (nnRTIs)

  • Combination of nnRTIs with nRTIs or protease inhibitors is at least additive in reducing IGIV replication (in vitro)
  • In patients without previous anti-HIV therapy, nnRTIs combined with two nRTIs may reduce HIV RNA levels and increase CD4 counts
  • HIV strains exhibiting resistance to nRTIs and protease inhibitors remain sensitive to nnRTIs{cross-resistance is common within the nnRTI group}
    • Rapid resistance development: give nnRTIs
  •  Adverse Effects:
    • rash-may be severe
    • nevirapine (Viramune): associated with Stevens-Johnson syndrome
    • nnRTIs metabolized by hepatic cytochrome P450 systems: many drug-drug interactions including those involving protease inhibitors.
    • Concurrent use of nevirapine (Viramune) or delavirdine (Rescriptor) with rifampin (Rimactane): not recommended

 

Nivirapine (Viramune)
  • Non-nucleoside reverse transcriptase inhibitor. -- In vitro, acts synergistically with nucleosides.
  • HIV resistant strains develop quickly if nivirapine is used alone or with only one nucleoside.
  • Binds to regions outside the active site, inducing a conformational change -- inactive enzyme.
  • Licensed for use with nucleoside analogues.
  • Nivirapine (in patients without previous therapy) in combination with zidovudine and didanosine for up to one-year was more effective then zidovudine plus didanosine alone (as estimated by increasing CD4 T cell counts and decreasing HIV RNA to "undetectable" levels.
  •  Main toxicities:
    • macropapular rash -- may progress to Stevens Johnson's syndrome
    • elevations in hepatic enzyme levels
  •  Combination treatment with nucleoside analogues -- increases in CD4 T cell counts and decreases in viral load greater than obtained by nucleoside treatment alone.
  • Other non-nucleoside reverse transcriptase inhibitor available: Delavirdine (Rescriptor)-- cross resistant with nivirapine;
    • used alone or with only one other drug -- rapid resistance.
Efavirenz (Sustiva)
  • Approved September 18, 1998--once daily anti-HIV/AIDS non-nucleoside reverse transcriptase inhibitor.
  • Clinical trials suggest that efavirenz + zidovudine + 3TC was as effective as indinavir + zidovudine + 3TC in treatment naive patient groups.
    • Within 6 months nearly all patients in both groups had a viral loads of < 400 copies/ml.
  • Efavirenz may be first-line therapy when combined with NRTIs.
  • Abacavir (Ziagen), another non-nucleoside reverse transcriptase inhibitor has received, November 2, 1998, a recommendation by the FDA Antiviral Drug Products Advisory Committee for accelerated approval.

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*attribution: The Hopkins HIV Report, Sept. 1998 (http://hopkins-aids.edu/publications/report/sept98_5.html);

 

Delavirdine (Rescriptor)
  • Delavirdine (Rescriptor) raises protease inhibitor levels and unlike other nnRTIs
  • Rash-less frequent/severe with delavirdine (Rescriptor) compared other nnRTIs

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Class-specific Characteristics: Protease Inhibitors
  • In patients with advanced HIV disease, use of protease inhibitors improve clinical condition and prolonged survival
  •  Protease inhibitor suppress HIV in vivo.
  •  Cross-resistance between protease inhibitors may be a concern
  •  Use of two new protease inhibitors in combination regimens may be recommended even when resistance to multiple other drugs (including protease inhibitors} has developed
  •  All protease inhibitors cause:
    •  gastrointestinal disturbance
    •  increased aminotransferase enzyme activity
  • Protease inhibitor use has been associated with:
    •  increased bleeding in patients with hemophilia
    •  hyperglycemia
    •  worsening or new onset of diabetes
    •  insulin resistance
    •  fat wasting and redistribution
    •  hyperlipidemia
  •  Protease inhibitors: metabolized by hepatic cytochrome P450 enzyme systems, leading to drug-drug interactions, which are common and sometimes severe
  •  Rifampin (Rimactane) which decreases protease inhibitor effect should usually be avoided

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Indinavir (Crixivan)
  • Specific inhibitor of HIV-1 protease: Viral Protease is essential for infectious virion production.
  • Oral route of administration; excellent bioavailability.
  • Full doses result in potent HIV inhibition in lymph nodes & serum
  • Major use: in low doses with minimal intrinsic antiviral activity to increase same concentrations & reduce dosage frequency of other protease inhibitors
  • Resistance: protease amino acids substitutions;Many indinavir-resistant viral strains are cross resistant to saquinavir (Fortovase) and ritonavir (Norvir).
  •  Adverse effects: most common -- hyperbilirubinemia and nephrolithiasis. Less common: thrombocytopenia, nausea, diarrhea, irritability.
    • Low dose usage make adverse reactions less common
    • Unusual side effects include:
      • circumoral & peripheral paresthesias
      • altered taste
      • drug-interactions
  • Crystalluria with dysuria and pain without nephrolithiasis also occurs.
    •  Adequate hydration essential to prevent nephrolithiasis.
  • Indinavir (Crixivan) and ritonavir (Norvir)-- substrates and inhibitors for cytochrome P450 CYP3A4 isoenzyme:
    • as a result, drug-drug interactions are common.
    • For example, indinavir serum levels go up in the presence of antifungal azoles (CYP3A4 inhibitors) and down in the presence of rifampin (Rimactane) or rifabutin (Mycobutin) (CYP3A4 inducers)

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Amprenavir (Agenerase)
  • Overview: Fifth and newest protease inhibitor to become available {amprenavir (Agenerase); indinavir (Crixivan); nelfinavir (Viracept); ritonavir (Norvir); saquinavir (Fortovase)
    •  Approval:
      • in combination with other drugs for HIV-infected adults & children
      • Usually combined with at least two nucleoside reverse transcriptase inhibitors
  • Pharmacokinetics:
    • Rapid gastrointestinal tract absorption
    • May be taken with or without food {fatty foods reduce absorption-should be avoided}
    • Metabolize mainly by CYP3A4 enzymes(hepatic)-mostly fecal excretion
      • Hepatic insufficiency may result in elevated serum concentration (2X)
  • HIV-viral Resistance
    • Viral strains resistant to other protease inhibitors may be sensitive to amprenavir (Agenerase)
  •  Adverse Effects:
    • Most common: nausea, diarrhea, vomiting, oral/perioral paresthesias, ranch
    • Other side effects: rash (1%-severe rash, including Stevens-Johnson syndrome; 3% of patients with rash required drug discontinuation)
    • Adverse effects common to other protease inhibitors: hyperglycemia; increased aminotransferase enzyme activity; changed body fat distribution
  •  Drug Interactions:
    • Package insert suggests not giving amprenavir (Agenerase) with drugs metabolized by CYP3A4 such as:
      • midazolam (Versed), triazolam (Halcion), bepridil (Vascor), ergotamine, dihydroergotamine, cisapride (Propulsid)
    • Serious toxicity could result with concurrent administration involving amprenavir (Agenerase) and:
      • amiodarone (Cordarone), systemic lidocaine (Xylocaine), quinidine, warfarin (Coumadin), tricyclic antidepressants, rifabutin (Mycobutin), cholesterol-lowering ("statins")
    • Drugs which induce CYP3A4 lowers amprenavir (Agenerase) serum concentrations, e.g.:
      • rifampin (Rimactane) -- 90% reduction in amprenavir (Agenerase) levels & 40% reduction of serum amprenavir (Agenerase) with concurrent efavirenz (EFV; Sustiva).
  • Conclusions:
    • Possibly effective against some HIV strains that a become resistant to other protease inhibitors
    • May offer no advantage over other protease inhibitors
    • twice a day-dosing; few food restrictions; perhaps less well tolerated compared to other protease inhibitors
    • Large number of capsules required (16/day) raise the issue of compliance
      • dosage (adult) 1200 mg/twice a day; available capsules 50 & 150 mg.
The Medical Letter, "Amprenavir: A New HIV Protease Inhibitor", 41 (Issue 1057) July 16, 1999., The Medical Letter, Inc, New Rochelle, N.Y.; "Drugs for HIV Infection", Leading Medical Letter, volume 42 (issued 1069), January 10, 2000, published by The Medical Letter, Inc., NewRochelle, New York.

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Lopinavir (ABT-378)
  •  A new protease inhibitor (available through expanded access trial)
  •  Highly potent, in vitro, particularly in combination with low dose ritonavir (Norvir)
  •  Lopinavir (ABT-378)/ritonavir (Norvir)combination: well tolerated- mild gastrointestinal disturbances and headache

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Ritonavir (Norvir)
  • potent inhibitor of HIV-1 protease, high bioavailability, oral administration.
  • Produces high concentrations in serum and lymph nodes.
  • Even in patients with extensive previous treatment protocols, addition of ritonavir decreased incidence of clinical progress and death.
  •  Most common adverse effect: gastrointestinal disturbances, parathesias, hypertriglyceridemia, altered taste, elevated hepatic aminotransferase levels.to
  •  Major limitation of ritonavir use is due to significant and numerous drug interactions.
    • Ritonavir is metabolized by the hepatic P450 cytochrome oxidase system (CYP3A and others).
      • Many drugs increased CYP3A activity and therefore increase ritonavirr clearance, reducing its plasma concentration.
      • Alternatively, ritonavir may increase the plasma concentration of other drugs: examples include erythromycin estolate (Ilosone), lidocaine (Xylocaine), clonazepam (Klonopin), ondansetron (Zofran), carbamazepine (Tegretol), and saquinavir (Fortovase).
  •  Ritonavir (Norvir)contains alcohol, as a result, coadministration of disulfram (Anabuse) is contraindicated.

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Saquinavir (Fortovase)-soft gel formulation
  • Synthetic peptide-like substrate analog that inhibits HIV-1 protease, preventing viral poly-protein cleavage.
  • Saquinavir: highly active against HIV, including zidovudine-resistant strains.
  • Acts synergistically with zidovudine (Retrovir, AZT, azidothymidine), didanosine (Videx, ddI), zalcitabine (Hivid, ddc).
  •  Saquinavir action is an additive to or synergistic with reverse transcriptase drugs.
  • Little evidence of cross-resistance between saquinavir and other viral protease inhibitors.
  • Oral route of administration;poor bioavailability.
  • Generally well tolerated.
  •  Many drug-drug interactions: saquinavir levels increase in the presence of ketoconazole (Nizoral) or ritonavir (Norvir) or when the drug is taken with grapefruit juice.
  •  Multiple drug interactions due to saquinavir (Fortovase) interaction with cytochrome P450 enzyme systems.

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Nelfinavir mesylate (Viracept)
  • Probably most commonly used protease inhibitor since it is comparatively well tolerated
  • Approved March 1997 for adult or pediatric HIV infection.
  • Approval based in part on finding that in 300 patients, not previously having received antiretroviral treatment, a zidovudine (Retrovir, AZT, azidothymidine), lamivudine (Epivir, 3TC), and nelfinavir combination decreased viral load by 98% and increased CD4 T cell counts by 150 cells per microliter.
  • Main side effect: mild diarrhea, that typically results with continued use

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Amantadine (Symmetrel) and Rimantadine(Flumadine)
  •  Amantadine and and its derivative rimantadine inhibit uncoating of influenza A viral RNA, preventing replication.
  •  Clinical Use:Both drugs are effective in preventing influenza A infection in high-risk patients and lessen clinical symptoms.
    • If started (orally) before influenza A exposure, amantidine (Symmetrel) or amantidine (Symmetrel): 70%-90% effective in preventing influenza.
    • If treatment is initiated within two days following illness onset,duration of symptom/fevers reduced
    • Prophylaxis:
      •  Amantidine (Symmetrel) or rimantadine (Flumadine) has been used to control institutional influenza outbreaks.
      •  These drugs also used to protect high-risk patients who were immunized after an influenza epidemic had begun
      •  Prophylaxis for immunodeficient patients {poor responders to influenza vaccine; patients for whom influenza vaccine contradicted}
    •  not effective against influenza B
  • Both drugs reduce symptom duration.
  • Resistance:
    • observed influenza A cross resistance to both amantidine (Symmetrel) and rimantadine (Flumadine)
    • resistant viruses still susceptible to oseltamivir (Tamiflu) & zanamivir (Relenza)
  • Adverse Effects:
    • Most common side effects: gastrointestinal intolerance, CNS effects (nervousness, lightheadedness, difficulty in concentrating, especially in the elderly).
      •  Effects diminish after first week; disappear upon drug discontinuation
    • Seriousness of CNS effects related to:
      •  age (worse in elderly)
      •  renal insufficiency (drugs cleared by kidney)
      •  anticholinergic drug therapy
      •  presence of psychiatric illness
    • Rimantadine (Flumadine):
      •  similar to amantidine (Symmetrel) in gastrointestinal side effects
      •  reduce CNS side effects
      •  hepatic metabolism precedes renal excretion; nor acquired to reduce dosage unless creatinine clearance < 10 ml/min
    • Use in pregnancy:
      •  Amantidine (Symmetrel) & rimantadine (Flumadine): contraindications
  •  Amantadine dosage: reduce in patients over 65 years old and in patients with renal dysfunction.
    • Main excretory pathway: in the urine
    • reduce dosage when creatinine clearance < 50 ml/min.

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Fomivirsen (Vitravene)
  • Antisense oligonucleotide
  • Clinical use:
    • intravitreal treatment of CMV retinitis in HIV-infected patients who are either non-responders to other drugs or who cannot tolerate other drugs
    • Should not be administered to patients previously treated with cidofovir (Vistide) or in the preceding two-four weeks
  •  Adverse Effects:
    •  iritis
    •  vitritis
    •  increased intraocular pressure, vision changes
  • Resistance:has not been observed

 

Interferons
  •  Interferons (IFNs): endogenous proteins -- virus-nonspecific antiviral actions (interacts with cellular metabolic processes having to do with RNA and protein synthesis)
  •  Three classes: IFN-alpha (type I, leukocyte), IFN-beta(type I, fibroblast), IFN-gamma (type II, immune).
  •  Potent cytokines: antiproliferative, immunomodulatory, antiviral actions.
  •  Enzyme induction by interferons:
    • protein kinase that phosphorylates and elongation factor that inhibits peptide chain initiation.
    • oligoisoadenylate synthase -- activation of an RNAase and degradation of viral mRNA;
    • phosphodiesterase -- degrades terminal nucleotides of tRNA, inhibiting peptide growth .
  • Clinical use: Interferons -
    • IFN-alpha for chronic hepatitis B. and C
    • AIDS-associated Kaposi's sarcoma
    • Laryngeal papillomatosis.
    • Use in Hepatitis B or C:
      • Parenteral IFN-alpha: may produce clinical remission in some patients
      • IFN-alpha preparations:
        •  interferon alfa con-1 (Infergen)
        •  interferon alfa-2b (Intron A)
        •  interferon alfa-n3 (Alferon N)
        •  interferon alfa-2b (Intron A) in combination with oral ribavirin (Rebetron)
      • Effectiveness: in about one-third of adults & children with chronic hepatitis B, interferon treatment:
        •  causes loss of hepatitis B antigens
        •  causes sustained histological improvement
        •  results in a return to normal aminotransferase enzyme activity the (adults): reduced risk of progressive liver disease
        •  in patient with hepatitis D (hepatitis Delta virus, which occurs in patients infected with hepatitis B)-- respond to high-dose IFN-alpha therapy; but relapse is common
      • Effectiveness-hepatitis C
        •  All forms of IFN-alpha: similar effectiveness in treating hepatitis C
        •  Chronic hepatitis C-following 6 months interferon alfa:
          • response rate-biochemical normalization in 15%-20%; loss of hepatitis C virus RNA in 10%-20%
        •  Chronic hepatitis C-following 12 months inteferon alfa treatment:
          • response rate-biochemical normalization in 20%-30%
        •  Probably reduces hepatocellular carcinoma risk in patients with chronic hepatitis C
        •  Combination therapy involving interferon + ribavirin (Rebetron): better response rate than with interferon or ribavirin (Rebetron) alone.
  •  Adverse Effects:
    • IM or subcutaneous injection: influenza-like syndrome (particularly week 1 of treatment)
Factors Limiting Interferon High-Dose/Chronic Therapy

bone marrow suppression

fatigue (significant)

myalgia

weight loss

increased bacterial infection susceptibility

increased aminotransferase activity

alopecia

hypo/hyperthyroidism, possible cardiotoxicity

psychiatric symptoms

  • Dosage reduction required in 10%-40% of patients treated for chronic hepatitis B virus {in 5% of patients discontinuation of interferon therapy is required)
  • Autoimmune chronic hepatitis & other on amine diseases (e.g. thyroiditis): worsened by interferon treatment

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Ribavirin
  • Synthetic nucleoside, Guanosine analog -- phosphorylated by host cell enzymes
    • may interfere with guanosine triphosphate synthesis

Possible Mechanisms of Action

  • Interferes with capping of viral messenger RNA
  • Inhibits viral RNA-dependent polymerase (only certain viruses)
  • Inhibits replication of many DNA and RNA viruses, including influenza A and B, parainfluenza, paramyxoviruses, respiratory syncytial virus.
  • IV ribavirin beneficial in treating Lassa fever and other viral hemorrhagic fevers.
  •  Clinical Use:
    • Ribavirin (Virazole) aerosol:
      •  reduced morbidity in children hospitalized with respiratory syncytial virus bronchiolitis and pneumonia
      •  not for use in infants
    • For hepatitis C-- in combination with IFN-alpha and oral ribavirin (Rebetron): higher response rates than interferon or ribavirin (Rebetron) alone
    • IV ribavirin:reduce mortality and lesson fever in hemorrhagic fever with renal symptoms caused by hanta virus
    • May be beneficial in treating severe measles pneumonitis.
  • Adverse Effects:
    •  Contraindicated in pregnancy (pregnant women should not be exposed to aerosol ribavirin (Virazole))
    •  Compromise in respiratory function (acute deterioration): ribavirin (Virazole) aerosol in infants and in adults with bronchospastic respiratory disease
    •  Systemic ribavirin: incidence of hemolytic anemia
    •  Oral ribavirin (Rebetron) + interferon = increased incidence of cough, rash pruritis compared to interferon monotherapy
      •  Combination most likely to be discontinued because of psychiatric disturbances (including depression)
  •  Systemic ribavirin administration is associated with a dose-dependent anemia and bone marrow suppression
  •  contraindicated pregnancy: possible teratogenicity.

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Oseltamivir (Tamiflu)
  • Oral neuraminidase inhibitor
  • Initiate treatment within 36 hours of influenza A or B onset: reduced severity and symptom duration
    • may decrease incidence of upper respiratory tract complications
  • Prophylaxis:
    •  75% effective in preventing disease
    •  87% effective in preventing culture-proven influenza

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Dolan, R., Antiviral Chemotherapy. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1078-1079.
Safrin, S. and Chambers, H. F Antiviral Agents, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 795-799
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1845-1854.
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Drugs for non-HIV viral infection. The Medical Letter, 1999, vol. 41 (Issue 1067) December 3, 1999
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