Year 2002 Paper two: Questions supplied by Jo 1

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1 Year 2002 Paper two: Questions supplied by Jo 1 Question 9 A 37 year old man with known human immunodeficiency virus (HIV) infection for 10 years presents with severe renal colic for which he has no prior history. Tests performed 2 weeks before have shown a normal full blood count and biochemistry screen (including serum calcium), CD 4+ T cell lymphocyte count of 36 cells/mm 3, HIV RNA concentration (viral load) of 83,000 copies/ml. His medications include zidovudine (AZT), lamivudine (3TC), indinavir, azithromycin and dapsone. The most likely cause for his renal colic is: A) HIV associated opportunistic infection B) HIV associated malignancy C) HIV associated hypercalciuria D) Adverse drug reaction E) Unrelated to HIV infection or therapy Answer: Learning issues - Natural history of HIV - Renal disease in HIV patient - Anti retrovirals, drug classes and common side effects - Prophylaxis Natural history of HIV - Primary infection: 50% asymptomatic, 50% develop acute HIV syndrome with flu-like symptoms and lymphadenopathy - Initial viral load does not appear to be related to degree of disease progression - Set point of steady state plasma viremia after 1 year correlates well with degree of disease progression - Chronic infection persists in untreated patient for a median of 10 years before clinical illness - CDC case definition of AIDS: any HIV infected person with CD4 < 200/microL, regardless of symptoms - Long term survivor: if remain alive > 20 years after initial infection, in most there would be disease progression - Long term non-progressor: infected for > 20 years with normal CD4 counts and plasma HIV RNA < 50 copies/ml without anti-viral therapy (noted strong associations with HLA B57 and HLA B27) Renal disease in HIV patient 1) HIV associated nephropathy - 90% cases in African American and Hispanics (also more severe) - Seen in children, first described in IVDU - Leading cause of ESRF in HIV population - Proteinuria - HT and oedema rare - Renal biopsy: 80% FSGS, 50% mesangial proliferation - Some responsive to high dose steroids 2) Drug toxicity - Directly nephrotoxic: amphotericin,pentamidine, adefovir, tenofovir - Most common: indinavir associated renal calculi (10% of patients receiving indinavir), ranges from asymptomatic haematuria to renal colic, treat with hydration 3) Urinary tract infections (opportunistic or otherwise)

2 Year 2002 Paper two: Questions supplied by Jo 2 4) Urinary tract malignancies - increased risk of malignancies in HIV population - mainly KS and NHL - no particular mention of increased risk of urological cancers - KS can affect any organ but not particularly the urinary tract Goals of treatment 1) Maximal viral suppression 2) Sustain rise in CD4 counts 3) Improve morbidity and mortality 4) Prevention of resistance + compliance 5) Minimisation of side effects Indications for treatment 1) Acute HIV syndrome (primary infection) 2) Chronic infection - Symptomatic (regardless of CD4 count and viral load) - Asymptomatic (CD4 count < 350 and decreasing or viral load > copies/ml) 3) Post-exposure prophylaxis - Percutaneous risk 0.3% - Mucous membrane exposure 0.09% - Through intact skin/ other body fluids eg urine: cases documented but risk < 0.09% Drug Class Mechanism of Action Examples and side effects Reverse transcriptase inhibitors 1) Nucleoside (NRTI) (-udines and osines) Block HIV replication at point of RNA dependant DNA synthesis 1) and 2) inhibit a variety of DNA polymerases including that of human mitochondria 1) NRTI eg zidovudine (AZT) - mitochondrial toxicity with lactic acidosis, fatty liver, myopathy, pancreatitis - initial fatigue/ N+V and headache tends to subside eg didanosine - painful sensory neuropathy in 30% (resolves with durg cessation) - pancreatitis at higher doses 10% eg stavudine - antagonistic with zidovudine - fatty liver and neuropathy eg lamivudine - best tolerated, often used with AZT - strains resistant to lamivudine have enhanced sensitivity to other nucleosides 2) Nucleotide eg abacavir - hypersensitivity reaction in 4% - stop drug as rechallenge can be fatal

3 Year 2002 Paper two: Questions supplied by Jo 3 2) Nucleotide eg tenofovir - renal impairment with hyperphosphataemia - increases in vivo levels of didanosine (needs dose reduction) 3) Nonnucleoside (NNRTI) Generally 3) are more selective for HIV 1 reverse transcritptase thus less side effects, often used in salvage regimens Drug interactions as involved with cytochrome p4503a4 3) NNRTI - eg neviparine, delavirdine, efavirenz - no activity against HIV 2 - maculopapular rash in 1 st few weeks - fatal hepatotoxicity - vivid dreams and lightheadedness with efavirenz (take nocte) - nevirapine induces p450 - delavirdine inhibits p450 - efavirenz unpredictable Protease inhibitors (-avirs) except abacavir which is a NRTI Used together with reverse transcriptase inhibitors - can suppress viral load to <50/mL > 5 years Many drug interactions Absolute contraindications - benzodiazepines (prolonged sedation), use propafol - lovastatin (rhabdomyolosis), use pravastatin - ciscapride (prolong QT, torsades) - most antihistamines except loratidine Hepatic cytochrome p450 3A4 - Ritonavir potent competitive inhibitor of these enzymes - Saquinar, indavinar etc metabolised by these enzymes - Thus baby dose ritonavir used as pharmacological boosting - Ritonavir seldom used alone in full doses as poorly tolerated (GIT and neuropathy) Indinavir - 1 st PI used in triple therapy - Nephrolithiasis in 4% - Asymptomatic indirect hyperbilirubinaemia 10% - Dose reduce in liver cirrhosis Nelfinavir and amprenavir - unique reistance profiles and GIT side effects - nelfinavir resistance with D30N substitution as viruses with this mutation are more sensitive to other PIs (so good initial PI - Amprenavir resistance with single amino acid substitution (good salvage drug): fatal skin reaction in 1%

4 Year 2002 Paper two: Questions supplied by Jo 4 Atazanavir - may not be associated with as severe lipid effects as other PI Entry inhibitors Trials on going - CCR5 inhibitors - Integrase inhibitors Interferes with virus binding to target cell CD4 receptor/ co-receptor (CCR5 or CXR4), or affects viral fusion Fusion inhibitor - enfuvirtide T20 - binds to viral envelope and prevents fusion of viral and host membrane - twice daily C/S injection - 98% injection site reactions - increased risk of bacterial pneumonia Lipodystrophy syndrome - fat wasting/ accumulation, high lipids, glucose intolerance +/- insulin resistance Prophylaxis Immunisations Hepatitis B vaccine (3 doses) Hepatitis A vaccine (2 doses) Influenza virus (annual) Pneumococcal vaccine (Strep pneumoniae) When Anti HBc and antihbs negative Anti HAV negative Chronic HBV Chronic HCV All All when CD4 > 200 For prevention of severe/ frequent occurrences Disease What to use Herpes simplex Acyclovir 200mg TDS Candida Fluconazole 200mg BD Other prophylaxis Disease What Alternative PCP Bactrim DS Pentamidine neb - when CD4 < 200 Dapsone > 200 for 6/12 TB - high exposure - skin test >5mm Isoniazid + Pyridoxine If isoniazid resistant, use Rifampicin or rifambutin MAC - when CD4 < 50 - prior disemminated disease > 100 for 6/12 Toxoplasmosis gondii - Ig G positive Azithromycin or clarithromycin Rifambutin Bactrim DS Dapsone + leucovorin + pyrimethamine

5 Year 2002 Paper two: Questions supplied by Jo 5 - CD4 < 100 If prior encephalitis, use Sulfadiazine + pyrimethamine + leucovorin Varicella zoster (exposed) Varicella zoster - no previous disease immunoglobulin IM within 96 - no immunisation hours Cryptococcus neoformans Fluconazole oral Amphotericin IV 3x/week CMV - prior end organ disease >100 for 6/12 Ganciclovir oral/iv Foscarnet Itraconazole oral Doses and duration vary dependant on what end organ affected Histoplasma Itraconazole Amphoterecin weekly IV Coccidiodes immitis Fluconazole Amphotericin weekly IV Salmonella - prior bacteraemia Cirpofloxacin oral Itraconazole oral

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