Medical timeline

• Observation or research idea Y0 • Pilot study - design, ethics approval, screen enroll 1-2 years - run study, preliminary analysis +6 months • Conference abstract +6 months • Write up paper, submit to publication +6 months • Published data +6 months • Guidelines and clinical practice ??? Total 3-4 years

S.Collins: HIV i-Base

TAC training - March 2006 Medical timeline

• Observation or research idea Y0 • Pilot study - design, ethics approval, screen enroll 1-2 years - run study, preliminary analysis +6 months • Conference abstract +6 months • Write up paper, submit to publication +6 months • Published data +6 months • Guidelines and clinical practice ??? Total 3-4 years

S.Collins: HIV i-Base

TAC training - March 2006 ARV drug pricing

1987: 1996: One drug $12,000 2000: $12,000 3-drugs $2,700 generic (AZT) 1989: 3-drugs One drug $8,000 1991: 2000: (AZT) One drug $900 $5,000 generic (AZT) 3-drug March 2001: ~$700 generic and brand

April 2002: $209 Oct 2003 generic $140 3-drug generic 3-drug

Single Drug NVP-based triple combination - generic vs brand

S.Collins: HIV i-Base

TAC training - March 2006 -based combination: 1996 Indinavir: Every 8 hours. No food for 2 hours before AND 2 hours after (ie12 hours fasted through each day). PLUS drink 2 litres water to minimise risk of kidney stones 3TC: Every 12 hours; d4T: Every 12 hours

1996: $12,000 3-drugs

8am 12am 4pm 12pm 6am 10am 2pm 6pm 10pm 2am NO FOOD S.Collins: HIV i-Base or DRINK

TAC training - March 2006 -based combination: 1995 Saquinavir (INVIRASE)*: Every 8 hours. Serious issued with absorption (originally recommended to take with grapefruit juice to boost levels. All patients in the Netherlands doubled the saquinavir dose. ddI: 4 large chewable tablets, once daily. Taken on an empty stomach, with no food for 2 hours afterwards. AZT: One capsule every 12 hours * NOTE: when FORTOVASE, the new formulation of saquinavir was approved in 1997 the dose increased to

6am 8am 12am 4pm 12pm 4am 8am NO FOOD or DRINK S.Collins: HIV i-Base

TAC training - March 2006 Saquinavir-based combination: 1998 Saquinavir (FORTOVASE): Approved as 6 capsules every 8 hours but in practice generally given as 8 capsules every 12 hours. This did not overcome the issue of absorption, which required boosting by . Manufacturers of each drug promote research showing why higher doses of their respective drugs was the preferred dose. FORTOVASE was discontinued in 2006. ddI: 4 large chewable tablets, once daily. Taken on an empty stomach, with no food for 2 hours afterwards. AZT: One capsule every 12 hours

8am 12am 12pm 6am 10am NO FOOD or DRINK S.Collins: HIV i-Base

TAC training - March 2006 First-line combination: 2006

Efavirenz: one 600mg capsule, once daily at night + Truvada: one tablet, once daily ** OR : one 600mg capsule, once daily at night + Kivexa: one tablet, once daily

** A single pill, once-daily combination of efavirenz + Truvada has been filed with the FDA and is expected to be approved in 2006/7.

12pm DON’T TAKE WITH HIGH FAT MEAL S.Collins: HIV i-Base

TAC training - March 2006 20 Approved ARVs in US/Europe different access in Western countries

1997  AZT 1987  efavirenz 1998  ddI 1991  1998  ddC 1992  1999  d4T 1994  2000  3TC 1995  tenofovir 2001  saquinavir 1995  T-20 2003  indinavir 1996  2004  ritonavir 1996  2004  1996  FTC 2004  1997

S.Collins: HIV i-Base

TAC training - March 2006 Co-Formulations and combinations

Generic (via India etc) US/Europe

 AZT+3TC  AZT+3TC  d4T+3TC  AZT+3TC+abacavir  AZT+3TC+abacavir

 abacavir+3TC  AZT+3TC+nevirapine  d4T+3TC+nevirapine  Tenofovir+FTC  Kaletra (lopinavir/r)  Kaletra (lopinavir/r)

 ddI+3TC+efavirenz - KIT

S.Collins: HIV i-Base

TAC training - March 2006 ARV approval timeline (FDA*) delavirdine** nelfinavir saquinavir atazanavir, (fortovase) fosamprenavir, 3TC, saquinavir efavirenz, FTC (invirase) abacavir AZT ddI lopinavir/r**

84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06

amprenavir** ddC** d4T T-20 indinavir, tenofovir , * FDA approval often ~ 6 months before EMEA ritonavir, lopinavir/r ** drugs/formulations that are no longer used in U.S. nevirapine (Meltrex) S.Collins: HIV i-Base

TAC training - March 2006 Approx patent expiry dates

delavirdine efavirenz ritonavir 3TC nevirapine nelfinavir AZT abacavir lopinavir tenofovir

2005 2008 2011 2014 2017

ddC d4T saquinavir indinavir T-20 ddI

S.Collins: HIV i-Base

TAC training - March 2006 HIV Drug Pipeline Compounds

Nukes: Entry inhibitors: PIs: (1) attachment inhibitors tipranavir - PIII PRO 542 and BMS 806 Reverset (D-D4FC) (2) co-receptor antagonists of TMC 125 CXCR4 (T-22, PA-14 and TAK-779 and CCR5 T-22, PA-14 and TAK-779 Amdoxovir (DAPD) (3) fusion inhibitors (T-1249) GS 7340 (tenofovir prodrug)

Other targets: NNRTIs: Microbicides - PIII Integrase Vaccines Inhibitors TMC 125 S1360 - GSK PreExposure L-870,810 - Merck Prophylaxis TMC 278 ()

S.Collins: HIV i-Base

TAC training - March 2006 Recent HIV Drug Pipeline

fosamprenavir CCR5 inhibitors: Nelfinavir (625mg) capravirine (??) Zerit XR tipranavir (vasculitis) BMS-806

? 2003 2004 2005 2006 2007 2008

New Targets: Fuzeon FTC TMC-114 DAPD (T-20) Reverset Integrase (lens problems) atazanavir Inhibitors S1360 Meltrex ritonavir L-870,810 (non-refrigerated)

S.Collins: HIV i-Base

TAC training - March 2006 Recent promising failures Development stopped after clinical studies due to toxicity (T), efficacy (E) or formulation (F)

• dOTC - monkeys died • DMP450 - efficacy • DPC-681- toxicity • TMC 126 - dropped • DPC-684 - toxicity • TMC 120 - dropped • DPC 817- toxicity • DPC 961- suicidal paients • adefovir - kidney toxicity • (MKC442) - efficacy • lodenesine - liver toxicity • MK914 - kidney toxicity • capravirine - efficacy (2005) • nelfinavir 625mg form. (2004) • aplaviroc - liver toxicity • d4T ER - formulation (2004) • reverset - pancreatic tox (2006) • DAPD, amdoxovir (2004)

S.Collins: HIV i-Base

TAC training - March 2006