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Treatment of HIV

Treatment of HIV. DR Sara Woods GUIDE Registrar St James’s Hospital. Number of people living with HIV/AIDS. Total 33.6 Million Adults 32.4 Million Women 14.8 Million Children < 15 years 1.2 Million. AIDS Deaths in 1999. Total 2.6 Million

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Treatment of HIV

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  1. Treatment of HIV DR Sara Woods GUIDE Registrar St James’s Hospital

  2. Number of people living with HIV/AIDS Total 33.6 Million Adults 32.4 Million Women 14.8 Million Children < 15 years 1.2 Million

  3. AIDS Deaths in 1999 Total 2.6 Million Adults 2.1 Million Women 1.1 Million Children < 15 years 470,000

  4. HIV Infection in Ireland

  5. Goal of Antiretroviral Therapy To  the length/quality of life by • Reducing the Viral Load (VL) • Preventing infection of new cells • Preventing further damage to the immune system ( CD4) AIM:VL<50 copies/ml and CD4>>200

  6. BHIVA Guidelines When to start therapy? • VL >30,000 & CD4 350-500 • CD4 <350 • Symptomatic Starting Tx early • Drug toxicities • Drug resistance/limit future drug options Delayed Treatment • Limit capacity for immune restoration

  7. Antiretroviral Agents (HAART) Divided into 4 groups • Nucleoside reverse transcriptase inhibitors (NRTIs) • Protease Inhibitors (PIs) • Non- nucleoside reverse transcriptase inhibitors (NNRTIs) • Fusion Inhibitors

  8. Antiretroviral Therapy

  9. NRTIs • 1st drugs licensed • Backbone of HAART • Similar in structure to nuclesides present in HIV RNA • During viral replication – become incorporated into the genome, competing with cellular nucleosides • Bring about chain termination & incomplete replication

  10. Zidovudine (AZT) Dose: 300mg -1000mg daily Metabolism – hepatic and renal Reduces risk of vertical transmission of HIV Good CNS penetration Side Effects Bone Marrow Suppression Nausea Headache Insomnia Myalgia Lamivudine (3TC) Dose 150mg BD 90% renal excretion Hepatitis B Side Effects Pancreatitis Abnormal LFTs Peripheral neuropathy Headache

  11. Emtricitabine (FTC) Dose 200mg OD Take with/without food. CrCl <50ml/min – dose adjustment Hepatitis B Side Effects Headaches, diarrhoea, nausea  CK – muscle pain & weakness  Tg,  blood sugar,  WCC & RBC Disturbance of liver, kidney & pancreas Tenofovir (TEN) Dose 245mg OD Take with food Hepatitis B Side Effects Hypophosphatemia Diarrhoea, nausea, vomiting Pancreatitis Renal failure, acute renal failure, proximal tubulopathy

  12. Protease Inhibitors Act on the HIV Protease Enzyme – prevent production of essential proteins. Benefits: • Dramatic decline in clinical progression of HIV disease/related deaths followed PI introduction in 1996 Drawback: • Pill Burden • Long term metabolic complications Cholesterol/Lipodystrophy Syndrome/Diabetes • Food/fluid restrictions • DRUG INTERACTIONS

  13. Ritonavir (RTN) Dose Escalation 600mg bd 50% discontinuation rate Side Effects N/V/D Perioral/Peripheral Neuropathy Malaise Fever Atazanavir Azapeptide PI Superior lipid profile to other PIs Dose: 400mg OD Or 300mg OD Ataz/100mg OD Ritonavir Boosted if coprescribed with Ten or EFV or previous PI exposure With food Side effects Diarrhoea, nausea, vomiting (taken with RTN)

  14. Tipranavir Novel nonpeptidic PI Active against HIV 1 strains which demonstrate resistance to other PIs Dose: 500mg Bd Tip/200mg Bd Ritonavir Side Effects Diarrhoea, nausea, vomiting (taken with RTN) Atazanavir Azapeptide PI Superior lipid profile to other PIs Dose: 400mg OD Or 300mg OD Ataz/100mg OD Ritonavir Boosted if coprescribed with Ten or EFV or previous PI exposure With food Side effects Diarrhoea, nausea, vomiting (taken with RTN)

  15. Drug Interactions - PIs • PIs metabolised by CYP 450 isoenzyme system • Coadministration of enzyme inducers may  levels of PIs – risk of resistance (eg Rifampicin) • Coadministration of enzyme inhibitors may  levels of Pis – risk of toxicity • PIs inhibit CYP3A4 –  levels of other drugs RTN>>IND=NFV=AMP>>SQV (eg/Pethidine/Antiepileptics) • Some PIs induce isoenzymes  levels of other drugs (eg Methadone/O.C.)

  16. NNRTIs • Act on reverse transcriptase enzyme –preventing HIV RNA from being processed • Simplier to take than PIs/no food restrictions • Resistance develops quickly – interclass resistance • ?delayed toxicities

  17. Nevirapine (NVP) Dose: 200mg OD x 14/7, then 200mg BD Metabolised by and inducer of CYP 450 Side Effects Rash Fever Nausea Hepatotoxicity Efavirenz (EFV) Dose 600mg OD Induces and inhibits CYP 450 Teratogen Side Effects Dizziness/Headache Insomnia Increased Dreaming Irritability Decreased Concentration

  18. Drug Interactions NNRTIs • NNRTIs metabolised by CYP 450 isoenzyme system • Coadministration of enzyme inducers may  levels of NNRTIs -  risk of resistance • Coadministration of enzyme inhibitors may  levels of NNRTIs – risk of toxicity • NNRTIs induce isoenzymes  levels of other drugs

  19. Patient Monitoring • Baseline – VL/CD4/FBC/LFTs • 1 Month – VL/CD4/FBC/LFTs • Then every 3 Months – VL/CD4/FBC/LFTs

  20. Virologic Failure • VL > 50copies/ml on 2 occasions more than one month apart Reasons • ? Patient Adherence(<95%)/Intolerance • ? Pharmacological Issues • ? Poor Pharmacokinetics Perform Resistance Test and change therapy accordingly

  21. HIV ResistanceReduced Susceptibility of Virus to ART • Virus replicates in the presence of drugs – can result in development of mutations • Results in changes in structure/function of protease & RT enzymes –less susceptible to drugs

  22. HIV Resistance Testing • Two types -both require VL > 1000copies/ml Phenotypic Assay: • Measures ability of a HIV isolate from patient to grow in presence of specific drugs • Time consuming & expensive Genotypic Assay: • RT/Protease genes from patients virus sequenced to determine mutations within these genes • Insensitive to presence of minor variants

  23. Genital Wart Therapies Clearance Rate Recurrence Rate Podophyllin 38-79% 21-65% Surgical Excision 89-93% 19-22% Electrodesiccation 94% 25% CO2 Laser 72-97% 6-49% Cryotherapy 70-96% 25-39% Interferons 36-53% 21-25% Beutner K, Am J Med, 1997.

  24. Patient Applied Therapies Clearance rate Recurrence rate Imiquimod 40-77% 13% Podophyllotoxin 68-88% 16-34% 5-FU* 68-97% 0-8% * No longer recommended Beutner K, Am J Med, 1997.

  25. Trichomonas vaginalis • Treatment – • Rx; Metronidazole 2g stat dose • Rx; Metronidazole 400mg bd x 5/7 • Contraindicated in first trimester • Treat Partner

  26. Bacterial Vaginosis • Treatment – Metronidazole 400mg BD x 5d • Avoid alcohol as possibilty of a disulfiram-like reaction BV normal increasing pH increasing symptoms

  27. Treatment of chlamydia • Azithromycin 1g po stat. • Doxycycline 100mg bd x 7/7 • In pregnancy / breastfeeding: Erythromycin 500mg bd x 14/7 • Contact tracing concordance rate 65% of F contacts [80% if epididymitis], 53% M contacts • Test of cure

  28. NSU • Treatment – Azithromycin 1g stat dose or Doxycycline 100mgs BD x 7d Alternative regimens Erythromycin 500mgs QDS x 7 days or 250mgs QDS x 14d or Olfloxacin 300mgs BD x 7d

  29. Gonorrhoea • IM Ceftriaxone 250mg stat • Screening for other STD • Contact tracing • Pregnancy / Breastfeeding - Ceftriaxone 250mg im stat. • Contact tracing concordance rates: 78% F contacts, 86% M • Test of cure

  30. Herpes simplex genitalis • HSV-1 and 2 • Symptomatic primary infection in adult life, as likely to be HSV-1 as HSV-2 • Antivirals Valcyclovir 500mg bd x 5/7- acute attack Valcyclovir 500mg od x 1 year –suppression Acyclovir 200mg five times day - pregnancy • Saline baths/Analgesia/Local anaesthetic/Counselling • May require admission and suprapubic catheterisation

  31. Treatment of syphillis Benzathine penicillin 2.4MU once/week x 3 weeks If allergic - doxycycline 200mg od x 14d or erythromycin 500mg QDS x 14d

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