An Overview of HIV Drugs: Past, Present, and Future

1. An Overview of HIV Drugs:Past, Present, and Future Patrick Smollen Dr. Buynak Medicinal Chemistry 5308 20 March 2008

2. What is HIV? • HIV = Human Immunodeficiency Virus • Destroys CD4 cells (T-cells and macrophages) • AIDS = Acquired Immunodeficiency Virus (~10 years after infection) • HIV-1 = Europe, America, Asia • HIV-2 = Africa *http://en.wikipedia.org/wiki/Aids#Diagnosis

3. Advancement of HIV • Progression of HIV*: • Stage I: HIV infection is asymptomatic and not categorized as AIDS • Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections • Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis • Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS. • Symptoms: loss of energy and weight, frequent fevers and sweats, persistent or frequent yeast infections, persistent skin rashes or flaky skin, short-term memory loss, and bodily sores from Herpes infections

4. The History of HIV • 1930s: Researchers believe a form of simian immunodeficiency virus jumped to humans in central Africa. The mutated virus is HIV-1. • 1960s: HIV-2, a viral variant found in West Africa, is thought to have transferred to people from sooty mangabey monkeys • 1964: The first retroviral agent (zidovudine) produced by Horwitz • 1966: Genetic studies of the virus indicate that, in or about 1966, HIV first left Africa, infecting a single person in US. • 1981: AIDS discovered in 5 gay men in LA (originally called GRID for Gay-Related Immune Deficiency)

5. The History of HIV • 1982: Name changed to AIDS (½ of infected persons not gay men) • 1985: HIV recognized as the cause of AIDS • 1985: Zidovudine shows anti-HIV properties and is approved for clinical trials (accepted in 1987 as the 1st drug to treat AIDS) • 1995: First approved protease inhibitors • 1998: First approved RTIs • 2006: Atripola, the 1st tablet consisting of 3 drugs is put on the market, greatly simplifying treatment

6. HIV Today: A Modern Pandemic USA (2005) http://gamapserver.who.int/mapLibrary/Files/Maps/HIVPrevalenceGlobal2006.png

7. How is HIV contracted? ALL CLEAR AHEAD • Sneezing / Coughing • Sharing Glasses • Showers / Pools • Protected Sex • Insects • Kissing* DANGER • Health Care Setting • Tattoos / Piercings • Blood Transfusions • Blood Products • Mother to Child • Oral Sex • Vaginal Sex • Anal Sex • Injecting Drugs

8. The Life Cycle of HIV • Free Virus • Binding and Fusion • Infection • Reverse Transcription • Integration • Transcription • Assembly • Budding • Maturation

9. Introduction to Drugs

10. Entry Inhibitors Maraviroc Enfuviritide

11. Closer Look: Maraviroc • 1st oral entry inhibitor • Blocks coreceptor CCR5 • Resistance from one or more of several mutations in the V3 loop of gp120 or gp160 • Possible Side Effects: Cough, Fever, Dizziness, Headache, Lowered BP, Nausea, and Bladder Irritation

12. Reverse Transcriptase Inhibitors: NRTIs Tenofir Disoproxil • Competitive inhibitors • No effect on host enzymes

13. Closer Look: Zidovudine • 1st approved drug for the treatment of AIDS • Phosphorylated by 3 cellular enzymes to form an active nucleotide triphosphate • Analogue of deoxythymidine where the 3’ hydroxyl is replaced by an azide group • The triphosphate is attached to the growing DNA chain, but cannot be extended. • Side effects may include anemia, nausea, headache, changes in body fat, and discoloration of nails.

14. Reverse Transcriptase Inhibitors: NNRTIs Delavirdine Efavirenz Nevirapine • Noncompetitive inhibitors • Only active against HIV-1 • Easily vulnerable to resistance

15. Closer Look: Efavirenz • Made from X-ray crystallography of the RT binding site • Active against many variants of HIV • Replacing Lys-103 with asparagine (K103N mutation) causes resistance • Standard noncompetitive inhibitor • Possible Side Effects: Insomnia, Depression, Rash, Nausea, and Birth Defects

16. Protease Inhibitors Indinavir Atazanavir Fosamprenavir

17. Closer Look: Fosamprenavir • Increased water solubility and improved oral bioavailability • Metabolized to form amprenavir, which is the active ingredient • Because it must be metabolized, it is time released and requires less dosages (4 instead of 16 pills per day) • Possible Side Effects: Nausea, Vomiting, Diarrhea, Loose Stool, Hyperglycemia, and Fatigue

18. The Future in Treatment • Integrase inhibitors (raltegravir and elvitegravir) in advanced development • CXCR4 inhibitors currently in development for HIV entry blockage • Drugs with a broader spectrum of activity and less vulnerable to induce resistance • More combination drugs like Atripola (efavirenz, tenofovir, emtricitabine) so that treatment can consist of a single pill taken once daily • Making drugs more affordable and available to more people ($1500/month and $618,000/lifetime) http://aids.about.com/od/hivmedicationfactsheets/a/drugcost.htm

19. Vaccines • Preventative • Subunit Vaccines • Recombinant Vector Vaccines • DNA Vaccines • Therapeutic

20. The End Brunton, Lawrence L. et al. Goodman and Gilman’s The Pharmacological Basics of Therapeutics. 11th ed. McGraw-Hill. 2006. pgs 1273-1314. Flexner, Charles. “HIV Drug Development: The Next 25 Years.” Nature. Vol 6. pgs 959-966. Dec 2007. Patrick, Graham L. An Introduction to Medicinal Chemistry. 3rd ed. Oxford University Press. 2005. pgs 450-471.