•  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 (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: 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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• 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: 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 (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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• 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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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

• 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.

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

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• 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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• 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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• 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.

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•  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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• 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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• 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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• 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 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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• 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 (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)

• 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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• 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.

• 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