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Antiviral drugs final

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Antiviral drugs final

  1. 1. Antiviral drugs
  2. 2. Virus-Introduction • Viruses are obligate intracellular parasites • Their replication depends primarily on synthetic processes of the host cell • Effective antiviral agents inhibit virus-specific replicative events or preferentially inhibit virus-directed rather than host cell-directed nucleic acid or protein synthesis
  3. 3. Viral replication and sites of antiviral drug action
  4. 4. Classification of Antiviral Drugs CLASSES DRUGS 1. Anti-Herpes virus Idoxuridine, Trifluridine Acyclovir, Valacyclovir, Famciclovir Ganciclovir, Valganciclovir Cidofovir Foscarnet Fomivirsen 2. Anti-influenza virus Amantadine, Rimantadine Oseltamivir, Zanamivir 3. Anti-Hepatitis virus/Nonselective antiviral drugs a. Primarily for Hepatitis B Lamivudine, Adefovir dipivoxil, Tenofovir b. Primarily for Hepatitis C Ribavirin, Interferon α
  5. 5. CLASSES DRUGS 4. Anti-retrovirus a. Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine (AZT), Didanosine, Stavudine Lamivudine, Abacavir, Emtricitabine Tenofovir (Nt RTI) b. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine, Efavirenz, Delavirdine c. Protease inhibitors Ritonavir, Atazanavir, Indinavir, Nelfinavir Saquinavir, Amprenavir, Lopinavir d. Entry (Fusion) inhibitor Enfuvirtide e. CCR5 receptor inhibitor Maraviroc f. Integrase inhibitor Raltegravir
  6. 6. 1. Anti-Herpes Virus Acyclovir  Mechanism of action: Acyclovir Herpes virus specific thymidine kinase Acyclovir monophosphate Cellular kinases Acyclovir triphosphate Inhibits herpes virus DNA polymerase competitively Gets incorporated in viral DNA and stops lengthening of DNA strand; the terminated DNA inhibits DNA- polymerase irreversibly
  7. 7. Acyclovir  Pharmacokinetics: • About 20% of an oral dose of acyclovir is absorbed • Less plasma protein bound • Primarily excreted unchanged in urine both by glomerular filtration and tubular secretion • It accumulates in patients with renal failure • Its plasma half life is 2-3 hours
  8. 8. Acyclovir  Uses: • Genital Herpes simplex Primary disease Recurrent disease • Mucocutaneous H. simplex • H. simplex encephalitis (type-1 virus) • H. simplex keratitis • Herpes zoster • Chickenpox  Adverse effects: • Topical: stinging and burning sensation after each application • Oral: Headache, nausea, malaise and some CNS effects • Intravenous: Rashes, sweating, emesis, and fall in BP(in few) • Dose dependent decrease in GFR (in renal failure)
  9. 9. Valacyclovir • An ester prodrug of acyclovir • Improved oral bioavailability due to active transport by peptide transporters in the intestine • Drug of choice in herpes zoster • High-dose can cause gastrointestinal problems and thrombotic thrombocytopenia purpura in patients with AIDS • An ester prodrug of penciclovir • Used as an alternative to acyclovir for genital or orolabial herpes and herpes zoster • Side effects are headache, nausea, loose motions, itching, rashes and mental confusion
  10. 10. Ganciclovir • An analogue of acyclovir • Active against all herpes viruses- H. simplex, H. zoster, EBV and CMV • Its active metabolite attains higher concentration inside CMV cells (plasma t1/2 >24 hrs)  Adverse effects: • Systemic toxicity is high ( bone marrow toxicity, rash, fever, vomiting, neuropsychiatric disturbances) • Note: Used only for prophylaxis and treatment of severe CMV infections in immunocompromised patients
  11. 11. Cidofovir  Mechanism of action:  It inhibits viral DNA synthesis. Its phosphorylation is not dependent on viral enzymes (viral phosphokinase) and is converted to the active diphosphate by cellular enzymes.  Cidofovir diphosphate does not preferentially accumulate in virus infected cells, but remains intracellularly for long periods to inhibit viral DNA polymerase  Pharmacokinetics: • Available in intravenous, intravitreal (injection into the eye's vitreous humor between the lens and the retina), and topical administration
  12. 12. Cidofovir  Uses: • CMV-induced retinitis in patients with AIDS  Adverse effects: • Dose related kidney damage • Neutropenia, metabolic acidosis, uveitis and ocular hypotony also occur • Note: Probenecid must be coadministered with cidofovir to reduce the risk of nephrotoxicity, but probenecid itself causes rash, headache, fever, and nausea  Contraindications: • Patients with preexisting renal impairment • Patients taking concurrent nephrotoxic drugs, including NSAIDS
  13. 13. Foscarnet • It is not a purine or pyrimidine analog; phosphonoformate pyrophosphate derivative and does not require activation by viral (or human) kinases • CMV retinitis in immunocompromised hosts • Acyclovir-resistant HSV and herpes zoster infections  Mechanism of action:  It reversibly inhibits viral DNA and RNA polymerases, thereby interfering with viral DNA and RNA synthesis
  14. 14. Foscarnet  Pharmacokinetics: • Poorly absorbed orally; intravenously • Must also be given frequently to avoid relapse when plasma levels fall • It is dispersed throughout the body; >10% enters the bone matrix • Excreted into the urine  Adverse effects: • Nephrotoxicity, anemia, nausea, and fever • Hypocalcemia and hypomagnesemia • Hypokalemia, hypo- and hyperphosphatemia • Seizures and arrhythmias
  15. 15. 2. Anti-influenza virus Amantadine • Its antiviral activity is strain specific = inhibits replication of influenza A virus but not influenza B  Mechanism of action:  It acts at uncoating as well as viral assembly in viral replication  Blocks the viral membrane matrix protein, M2, which functions as a channel for hydrogen ion  This channel is required for the fusion of the viral membrane with the cell membrane that ultimately forms the endosome (during internalization of the virus by endocytosis)
  16. 16. Amantadine  Pharmacokinetics: • Well absorbed orally and excreted unchanged in urine over 2-3 days  Adverse effects: • Nausea, anorexia, insomnia, dizziness, nightmares, lack of mental concentration • Hallucinations (rarely) • Ankle edema (local vasoconstriction)
  17. 17. Amantadine  Uses: • Prophylaxis of influenza A2 during an epidemic or seasonal influenza (~ 2 months) • Treatment of influenzal (A2) illness  Reduction in fever, congestion, cough and quicker recovery  Parkinsonism  Contraindications: • Epilepsy and other CNS disease; gastric ulcer, pregnancy
  18. 18. Rimantadine • Methyl derivative of amantadine • More potent, longer acting (t½ 30 hours) and better tolerated • Side effects is lower • Oral bioavailability is higher and it is largely metabolized by hydroxylation followed by glucuronide conjugation • Metabolites are excreted in urine
  19. 19. Oseltamivir • Influenza A (amantadine sensitive as well as resistant), H5N1 (bird flu), nH1N1 (swine flu) strains and influenza B • An ester prodrug; rapidly and nearly completely hydrolysed during absorption in intestine and by liver to the active form oseltamivir carboxylate ( an oral bioavailability of ~ 80%) • Active metabolite is excreted unchanged by the kidney • t½ of 6–10 hours
  20. 20. Oseltamivir  Mechanism of action:  Neuraminidase enzyme Release of progeny virions from the infected cell Spread of the virus in the body  Uses: • Prophylaxis and treatment of influenza A, swine flu, bird flu and influenza B Oseltamivir
  21. 21. Oseltamivir  Side effects: • Nausea and abdominal pain (gastric irritation) • Headache, weakness, sadness, diarrhoea, cough, and insomnia • Skin reactions • Influenza A (including amantadine-resistant, nH1N1, H5N1 strains) and influenza B virus neuraminidase inhibitor • Low oral bioavailability; t½ of 2–5 hours  Containdication: Asthmatics ( bronchospasms)
  22. 22. 3. Anti-Hepatitis Virus/ Nonselective Antiviral Drugs • Hepatitis A, B, C, D, and E viruses replicate in and destruct hepatocytes • Hepatitis B and C are the most common causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma • Hepatitis B virus (HBV) is a DNA virus, can integrate into host chromosomal DNA to establish permanent infection • Hepatitis C virus (HCV) is a RNA virus
  23. 23. Lamivudine • An inhibitor of both hepatitis B virus (HBV) DNA polymerase and human immunodeficiency virus (HIV) reverse transcriptase • First line drug for chronic hepatitis B • Chronic treatment decreased plasma HBV DNA levels, improved biochemical markers, and reduced hepatic inflammation  Mechanism of action:  It must be phosphorylated by host cellular enzymes to the triphosphate (active) form  This compound competitively inhibits HBV DNA polymerase at concentrations that have negligible effects on host DNA polymerase
  24. 24. Adefovir dipivoxil  Mechanism of action:  It is phosphorylated to adefovir diphosphate incorporated into viral DNA termination of further DNA synthesis prevents viral replication  Both decreased viral load and improved liver function • Indicated in chronic hepatitis B, also in lamivudine- resistant cases and in concurrent HIV infection • Its plasma t½ is 7 hours; intracellular t½ of the diphosphate is upto 18 hours
  25. 25. Adefovir dipivoxil  Adverse effects: • Sore throat, headache, weakness, abdominal pain and flu syndrome • Nephrotoxicity ( higher doses and in those with preexisting renal insufficiency ) • Lactic acidosis ( patients receiving anti-HIV drugs )
  26. 26. Ribavirin • Broad-spectrum antiviral activity • Influenza A and B, respiratory syncytial virus (in children only) and many other DNA and double stranded RNA viruses • Oral ribavirin is commonly used in chronic hepatitis C  Mechanism of action: • Its mono- and triphosphate derivatives generated intracellularly inhibit GTP and viral RNA synthesis
  27. 27. Ribavirin • Oral bioavailability ~50% • Partly metabolized and eliminated • Accumulates in the body on daily dosing and persists months after discontinuation • Long term t½ is > 10 days  Adverse effects: • Anaemia, bone marrow depression hemolysis; CNS and GI disturbances • Teratogenic • Aerosol can cause bronchospasm and irritation of mucosae
  28. 28. Interferon • Cytokines produced by host cells in response to viral infections and other inducers • Three types of human IFNs (α, β and γ) are known to have antiviral activity  Mechanism of action:  Induction of host cell enzymes that inhibit viral RNA translation degradation of viral mRNA and tRNA  Interferon receptors are JAK-STAT tyrosine protein kinase receptors which on activation phosphorylate cellular proteins  These then migrate to the nucleus and induce transcription of ‘interferon-induced- proteins’ which exert antiviral effects
  29. 29. Interferon  Uses: • Chronic hepatitis B • Chronic hepatitis C • AIDS-related Kaposi’s sarcoma • Condyloma acuminata • H. simplex, H. zoster and CMV
  30. 30. Interferon  Pharmacokinetics: • Not active orally; administered intralesionally, subcutaneously, or intravenously • High cellular uptake and metabolism by the liver and kidney; less plasma level • Negligible renal elimination occurs
  31. 31. Interferon  Adverse effects: • Flu-like symptoms: fatigue, aches and pains, malaise, fever, dizziness, anorexia, nausea, taste and visual disturbances develop few hours after each injection, but become milder later • Neurotoxicity: numbness, neuropathy, altered behaviour, mental depression, tremor, sleepiness, rarely convulsions • Myelosuppression: dose dependent neutropenia, thrombocytopenia • Thyroid dysfunction (hypo as well as hyper) • Hypotension, transient arrhythmias, alopecia and liver dysfunction.
  32. 32. Interferon  Drug interaction: • It interferes with hepatic drug metabolism • Toxic accumulations of theophylline • It may also potentiate the myelosuppression caused by other bone marrow depressing agents ( zidovudine )
  33. 33. ANTI-RETROVIRUS DRUGS • Aim of anti-HIV therapy is to cause maximal suppression of viral replication for the maximal period of time that is possible • ARV drugs are always used in combination of at least 3 drugs and regimens have to be changed over time due to development of resistance • Life long therapy is required
  34. 34. ANTI-RETROVIRUS DRUGS Established targets for anti-HIV attack: (1)Chemokine coreceptor (CCR5) on host cells which provide anchorage for the surface proteins of the virus (2)Fusion of viral envelope with plasma membrane of CD4 cells through which HIV- RNA enters the cell (3)HIV reverse transcriptase: Which transcripts HIV-RNA into proviral DNA (4)HIV-integrase: Viral enzyme which integrates the proviral DNA into host DNA (5) HIV protease: Which cleaves the large virus directed polyprotein into functional viral proteins
  35. 35. Nucleoside reverse transcriptase inhibitors (NRTIs)  Zidovudine: • is a thymidine analogue (azido- thymidine, AZT), the prototype NRTI • after phosphorylation in the host cell—zidovudine triphosphate selectively inhibits viral reverse transcriptase in preference to cellular DNA polymerase Single-stranded viral RNA Virus directed reverse transcriptase (inhibited by zidovudine triphosphate) Double-stranded proviral DNA
  36. 36. ZIDOVUDINE  Pharmacokinetics: • The oral absorption of AZT is rapid, but bioavailability is ~65% • It is quickly cleared by hepatic glucuronidation (t1⁄2 1 hr); 15–20% of the unchanged drug along with the metabolite is excreted in urine • Plasma protein binding is 30% and CSF level is ~50% of that in plasma • It crosses placenta and is found in milk
  37. 37. ZIDOVUDINE  Adverse effects: • Anaemia and neutropenia are the most important and dose-related adverse effects • Nausea, anorexia, abdominal pain, headache, insomnia and myalgia are common at the start of therapy, but diminish later • Myopathy, pigmentation of nails, lactic acidosis, hepatomegaly, convulsions and encephalopathy are infrequent
  38. 38. ZIDOVUDINE  Interactions: • Paracetamol increases AZT toxicity, probably by competing for glucuronidation • Azole antifungals also inhibit AZT metabolism • Other nephrotoxic and myelosuppressive drugs and probenecid enhance toxicity • Stavudine and zidovudine exhibit mutual antagonism by competing for the same activation pathway
  39. 39. ZIDOVUDINE  Uses: • Zidovudine is used in HIV infected patients only in combination with at least 2 other ARV drugs • It is one of the two optional NRTIs used by NACO for its first line triple drug ARV regimen • AZT also reduces neurological manifestations of AIDS and new Kaposi’s lesions do not appear • AZT, along with two other ARV drugs is the standard choice for post-exposure prophylaxis of HIV, as well as for mother to offspring transmission
  40. 40. DIDANOSINE • Is a purine nucleoside analogue which after intracellular conversion to didanosine triphosphate competes with ATP for incorporation into viral DNA, inhibits HIV reverse transcriptase and terminates proviral DNA • Antiretroviral activity of didanosine is equivalent to AZT • Use has declined due to higher toxicity than other NRTIs
  41. 41. STAVUDINE • A thymidine analogue • By utilizing the same thymidine kinase for activation, AZT antagonises the effect of stavudine and the two should not be used together • Should also not be combined with didanosine, because both cause peripheral neuropathy • Frequent peripheral neuropathy, lipodystrophy, lactic acidosis, and rarely pancreatitis are the serious adverse effects which have restricted its use
  42. 42. LAMIVUDINE • Deoxycytidine analogue, is phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as HBV DNA polymerase • Its incorporation into DNA results in chain termination • Most human DNA polymerases are not affected and systemic toxicity of 3TC is low • Oral bioavailability of 3TC is high and plasma t1⁄2 longer (6–8 hours)
  43. 43. LAMIVUDINE • Used in combination with other anti-HIV drugs, and appears to be as effective as AZT • Synergises with most other NRTIs for HIV, and is an essential component of all first line triple drug NACO regimens for AIDS • Side effects are few—fatigue, rashes , abdominal pain • Pancreatitis and neuropathy are rare • Hematological toxicity does not occur
  44. 44. ABACAVIR • Guanosine analogue , potent , acts after intracellular conversion to carbovir triphosphate • Hypersensitivity reactions such as rashes, fever, abdominal pain, bowel, upset, flu-like respiratory and constitutional symptoms • Lypodystrophy is least likely • Avoidance of alcohol is advised
  45. 45. TENOFOVIR • Is the only nucleotide analogue ,relatively newer • Due to good tolerability profile, it is included in first line regimens • Tenofovir containing regimens have been found at least as effective and less toxic as other first line regimens • NACO includes tenofovir in its first line 3 drug regimen as an alternative when either zidovudine or nevirapine/efavirenz cannot be used due to toxicity/contraindication
  46. 46. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  Nevirapine (NVP) and Efavirenz (EFV) • are nucleoside unrelated compounds which directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation • are more potent than AZT on HIV-1, but do not inhibit HIV-2 • they should always be combined with 2 other effective drugs • Cross- resistance between NVP and EFV is common
  47. 47. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  Nevirapine (NVP) and Efavirenz (EFV) • enzyme inducers, and cause autoinduction of their own metabolism • Nevirapine is started at a lower dose (200 mg/day); the dose is doubled after 2 weeks when its blood levels go down • Rifampin induces NVP metabolism and makes it ineffective, but has little effect on EFV levels • Either NVP or EFV is included in the first line triple drug regimen used by NACO
  48. 48. NEVIRAPINE • Rashes are the commonest adverse effect, followed by nausea and headache • Occasionally skin reactions are severe • NVP is potentially hepatotoxic
  49. 49. EFAVIRENZ • Side effects are headache, rashes, dizziness, insomnia and a variety of neuropsychiatric symptoms • Contraindicated in pregnancy and in women likely to get pregnant, since it is teratogenic • Because of its longer plasma t1⁄2, occasional missed doses of EFV are less damaging
  50. 50. Retroviral protease inhibitors (PIs) • Acts at a late step in HIV replication, i.e. maturation of the new virus particles when the RNA genome acquires the core proteins and enzymes • Bind to the active site of protease molecule, interfere with its cleaving function, and are more effective viral inhibitors than AZT • Because they act at a late step of viral cycle, they are effective in both newly as well as chronically infected cells
  51. 51. Retroviral protease inhibitors (PIs) • Nelfinavir, lopinavir and ritonavir induce their own meta- bolism • metabolism of PIs is induced by rifampin and other enzyme inducers rendering them ineffective • patient acceptability and compliance are often low • most prominent adverse effects of PIs are gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial tingling, numbness and rashes
  52. 52. Retroviral protease inhibitors (PIs) • lipodystrophy , dyslipidaemia and insulin resistance are of particular concern • Diabetes may be exacerbated • Indinavir crystalises in urine and increases risk of urinary calculi
  53. 53. Retroviral protease inhibitors (PIs)  Atazanavir (ATV) • is administered with light meal which improves absorption, while acid suppressant drugs decrease its absorption • Bioavailability and efficacy of ATV is improved by combining with RTV • Dyslipidaemia and other metabolic complications are minimal with ATV • jaundice occurs in some patients without liver damage due to inhibition of hepatic glucuronyl transferase
  54. 54. Retroviral protease inhibitors (PIs)  Indinavir (IDV) • Is to be taken on empty stomach • g.i. intolerance is common • excess fluids must be consumed to avoid nephrolithiasis • Hyperbilirubinaemia occurs • less frequently used now  Nelfinavir (NFV) • Is to be taken with meals • Often produces diarrhoea and flatulence; lower clinical efficacy than other PIs
  55. 55. Retroviral protease inhibitors (PIs)  Ritonavir (RTV) • Is potent • Drug interactions, nausea, diarrhoea, paresthesias, fatigue and lipid abnormalities are prominent • more commonly employed in a low dose  Saquinavir (SQV) • Two types of formulations (hard gel and soft gel capsules) have been produced • tablet load is large and side effects are frequent; photosensitivity can occur
  56. 56. Retroviral protease inhibitors (PIs)  Lopinavir: • Available only in combination with RTV to improve bioavailability, though it is itself a CYP3A4 inhibitor • Diarrhoea, abdo- minal pain, nausea and dyslipidaemias are more common • Dose needs to be increased by 1/3rd if either NVP or EFV is used concurrently
  57. 57. Entry (fusion) Inhibitor-Enfuvirtide • HIV derived synthetic peptide • binds to HIV 1 envelope transmembrane glycoprotein(gp41) involved in fusion of viral and cellular membranes entry of virus into host cell is blocked • Not active against HIV 2 • Pharmacokinetics:  Administered s.c twice daily  Used as add on drug in earlier regimens • Adverse reactions:  Local nodule/ cyst at injection site
  58. 58. CCR5 receptor inhibitor-Maraviroc • Targets the host cell chemokine -CCR5 receptor and blocks it attachment and entry of virus is inhibited • Has no effect on CXCR4 receptor tropic HIV strains • Adverse reactions:  impaired immune surveillance  Increased risk of infection/malignancy
  59. 59. Integrase inhibitor-Raltegravir • Inhibits the viral enzyme integrase • HIV Integrase nicks the host chromosomal DNA and integrates the proviral DNA with it • Active against both HIV 1 and 2 and causes improved CD4 cell count • Uses:  As a component of initial triple drug regimen along with 2NRTIs • Adverse effect: myopathy
  60. 60. HIV treatment principles and guidelines • Monotherapy is contraindicated • HAART: highly active antiretroviral therapy with a combination of 3 or more drugs is indicated • Greater the supression of viral replication, lesser is the chance of emergence of drug resistant virus
  61. 61. Initiating antiretroviral therapy • The US Department of Health and Human Services guidelines (2010) recommend instituting ART to: 1. All symptomatic HIV disease patients. 2. Asymptomatic patients when the CD4 cell count falls to 350/μl or less. 3. All HIV patients coinfected with HBV/HCV requiring treatment 4. All pregnant HIV positive women. 5. All patients with HIV-nephropathy.
  62. 62. Initiating antiretroviral therapy contd.. • In addition to above, the current NACO guidelines give priority in treatment to: 1. All HIV-positive persons in WHO-clinical stage 3 and 4 2. All persons who tested HIV positive 6–8 years ago 3. Patients with history of pulmonary TB and/ or Herpes zoster 4. HIV infected partners of AIDS patients. 5. All HIV positive children < 15 years of age
  63. 63. First line antiretroviral therapy Preferred regimen 1. Lamivudine + Zidovudine + Nevirapine Alternative regimens 1.Lamivudine + Zidovudine + Efavirenz 2.Lamivudine + Stavudine + Efavirenz 3. Lamivudine + Stavudine + Nevirapine Other options 1.Lamivudine + Tenofovir + Nevirapine 2. Lamivudine + Tenofovir + Efavirenz 3.Lamivudine + Zidovudine + Tenofovir Recommended by National AIDS control Organization
  64. 64. First line therapy • All regimen should have 2 NRTI+ 1NNRTI and treatment is life long • Efavirenz is indicated for patient with hepatic dysfunction and concurrently taking rifampin. It is contraindicated in pregnancy • PI containing regimen: 2NRTI+PI or NRTI+NNRTI +PI(low dose ritonavir boosted PIs are used) • Development of drug toxicity: no dose reduction  Either entire regimen should be interrupted  Or the offending drug should be changed
  65. 65. First line therapy contd… • Institution of HAART with latent or partially treated opportunistic infection causes immune reconstitution syndrome • Safe drugs in pregnancy :  Zidovudine  Lamivudine  Nevirapine  Nelfinavir  Saquinavir
  66. 66. Changing a failing regimen • An ART regimen is considered to have failed when:  Plasma HIV-RNA count is not rendered undectable (<50 copies/μl) with in 6 months therapy  Repeated detection of virus in plasma after initial supression to undectable levels despite continuation of drug regimen  Clinical deterioration,fall in CD4 cell count,serious opportunistic infection while continuing drug therapy
  67. 67. Second line regimen • Drugs with known overlapping viral resistance should not be used. 1. Indinavir should not be substituted for nelfinavir or saquinavir 2. Efavirenz should not be replaced by nevirapine • Viral resistance testing is recommended for selecting the salvage regimen • A boosted PI is nearly always included
  68. 68. List of second line regimens (NACO) NRTI component Standard regimen 1. Lopinavir 2. Atazanavir 1. Tenofovir + Abacavir 2. Didanosine + Abacavir 3. Tenofovir + Zidovudine 4. Tenofovir + Lamivudine 3.Saquinavir 4.Indinavir 5.Nelfinavir Special circumstances 1. Didanosine + Zidovudine 2. Didanosine + Lamividine
  69. 69. Antiretroviral combination to be avoided 1.Zidovudine + stavudine Pharmacodynamic antagonism Stavudine + didanosine Increased toxicity ( neuropathy, lactic acidosis ) Lamivudine + didanosine Clinically not additive
  70. 70. Prophylaxis of HIV infection 1.Post- exposure prophylaxis: Drugs used Comments A .Basic (2 drug) regimen for low risk Both for 4 weeks Zidovudine ( 300mg) + twice daily Lamivudine ( 150 mg) Twice daily B. Expanded ( 3 drugs) regimen for high risk Both for 4 weeks Zidovudine (300 mg )+ lamivudine ( 150 mg ) Twice daily Indinavir( 800 mg) (or another PI) Thrice daily
  71. 71. Post exposure prophylaxis(PEP) •Aim is to supress local viral replication prior to dissemination to abort infection •PEP should be started within 1-2 hours of exposure a) Basic regimen:  Asymptomatic HIV +ve source with low HIV-RNA titre and high CD4 cell count  Exposure is through mucous membrane, superficial scratch or solid needle b) Expanded regimen:  symptomatic HIV +ve source with high HIV-RNA titre or low CD4 cell count  Exposure is through large area contact of longer duration with mucus membrane or large bore hollow needle, deep puncture.
  72. 72. Prophylaxis of HIV infection 2.Prophylaxis after sexual intercourse: the same method as for needle stick 3. Perinatal HIV prophylaxis: • Vertical transmission: Highest rate of transmission (2/3rd) through placenta ,during delivery or breast feeding • HIV positive mother (not on ART) : should take 3 drug ART, continue through delivery and into postnatal period. • First line NACO regimen for pregnant women: Zidovudine + Lamivudine + Nevirapine • Nevirapine : higher risk of hepatotoxicity in women with CD4 cell count > 250 cells /μl • Efavirenz is teratogenic particularly in 1st trimester
  73. 73. Perinatal HIV prophylaxis • For HIV +ve women not on ART : 1. Zidovudine (300 mg BD) started at 2nd trimester and continued through delivery to postnatal period with treatment of neonate for 6 month reduce the transmission by 2/3rd 2. AZT started during labour and then to infant is substantially protective
  74. 74. Thank you !!!

Editor's Notes

  • Viral replication consists of several steps: (1) adsorption to and penetration into susceptible host cells; (2) uncoating of viral nucleic acid; (3) synthesis of early regulatory proteins, eg, nucleic acid polymerases; (4) synthesis of RNA or DNA; (5) synthesis of late, structural proteins; (6) assembly (maturation) of viral particles; and (7) release from the cell
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