1. HIV and AIDS Global: 40M HIV positive 25M AIDS deaths from ‘80 (60% sub-Saharan Africa) 80+% male Canada:63K HIV positive 16K AIDS deaths since 1980 (83% male) BC:13K HIV positive 3K AIDS deaths since 1980

2. AIDS and HIV Cases in Canada over the past 30 years

3. THE HIV VIRUS Disease discovered in 1981; virus discovered 1983 RETROVIRUS – Normally DNA is used to form RNA in the host cell In HIV, RNA forms DNA in the host cell It is a cell parasite, can only live in a cell, uses host material to reproduce It is a piece of RNA packaged in a protein with a fatty envelope. It attacks our T4 cells, preventing defense against other viruses, bacteria

4. Symptoms: fever, cough, headache, sweats In 6-12 weeks blood tests +ve for HIV Disease (AIDS) can switch on at any time: swollen lymph nodes, tiredness, loss of weight, abdominal discomfort, diarrhea, fevers, itching, attack by opportunistic infections (pneumonia is most common in Canada) TREATMENT Three main types 1) REVERSE TRANSCRIPTASE INHIBITORS 2) PROTEASE INHIBITORS 3) ENTRY INHIBITORS coming now: Integration inhibitors and Maturation inhibitors

6. 1) REVERSE TRANSCRIPTASE INHIBITORS RNA/DNA Made of Nucleotides:

7. These provide the templates for making proteins (we will see this in detail under proteins): each set of 3-bases provides a template or code for a single amino-acid in a protein so if the virus can be tricked by feeding useless mimics of these nucleotides, it might produce a useless protein or not even produce one prevents the virus from building new DNA from its RNA, and they are thus called REVERSE TRANSCRIPTASE INHIBITORS

8. AZTDDI DDC mimics: thymidine guanosine cytidine AzidothymidineDideoxyinosine Dideoxycytidine [zidovudine, Retrovir] [didanosine, Videx] [zalcitabine, Hivid] 5 x 100mg 2 x 200mg 3 x 0.7 mg /day cocktails work better: eg. 0.75 mg DDC + 200 mg AZT every 8 h

9. AZT was first made in 60's as an anti-cancer drug (same mechanism) but it did not work BUT it does work for the HIV virus Approved in 1987: Burroughs-Welcome stock rose $3B overnight! DOSE then was 1.2 g/day ($8000/yr), now about 500 mg/day (at the same cost!)

10. AZT SIDE EFFECTS: supressed bone marrow production, low white cell counts, anaemia, nausea, headaches, muscle wasting DDI is less active BUT less toxic, so less side effects: peripheral nerve damage - feet tingle (About 40% cannot tolerate AZT) In Canada: didanosine (DDI), lamivudine (3TC); stavudine (d4T), zalcitabine (DDC) zidovudine (AZT) 3TC = Heptovir = 3-thia( )-dideoxycytidine d4T = Zerit = 3-deoxy-thymidine-ene ( )

11. ACYCLOVIR [ZOVIRAX] HERPES VIRUS INHIBITOR for HIV, AZT + ZOVIRAX works better than AZT alone For herpes (lips or genitals): cream (50 mg/g) or oral: 200 mg/4 h (5x per day) for 10 days Herpes: famciclovir, valacyclovir, valganciclovir, ribavirin

12. 2) PROTEASE INHIBITORS: Inhibit the enzyme that cleaves the viral large proteins in to new ones used for assembly atazanivir fosamprenavir lopinavir darunavir

13. Use about 800mg every 8 h; $10-15,000/y Most cocktails knock down the virus levels rapidly in 1 st two weeks, more slowly after that Cannot stop drugs, even for one day! Cocktails have advantage of reducing resistance. Relenza (zanamivir), and Tamiflu (oseltamavir) for FLU are also protease inhibitors (not effective against H5N1):

14. 3) ENTRY (FUSION) INHIBITORS Glycoproteins on virus (GP41 and GP120) bind to surface protein receptors (CD4 and CCR5) on T-cell facilitating cell fusion and virus entry

15. Enfurvitide: 36-peptide chain that binds to GP41 and prevents it binding to CCR5 Approved drugs in this class Maraviroc (Selzentry) by Pfizer: binds directly to CCR5 and blocks fusion appears quite safe for long term use

16. Maturation Inhibitor: disrupts protein protecting virus core Virus budding inhibitors –yet to come Integration Inhibitor: stops integration of viral dna into host cell’s dna to replicate virus – not in other cells raltegravir (Isentress) from Merck approved FDA Oct 07 Other strategies being explored