1. Update on HIV Therapy Elly T Katabira, FRCP Department of Medicine Makerere University Medical School Scaling up Treatment Programs: Issues, Challenges & Best Practices Dakar, Senegal, December 2, 2008

2. The early days of HIV care • Diagnosis of HIV infection was clinical • Emphasis on care was on: • Management of opportunistic infections and cancers • Early diagnosis • Prompt and effective treatment • Psychosocial support • Palliative care • Minimise stigma • Health education on prevention

3. The early HIV related Guidelines • First international guidelines by WHO and CDC • Targeting resource limitted settings • AIDS case surveillance definition • October 1985, Bangui, CAR • Public Health experts + CDC representation • Revised 1994 • HIV serology optional – when available

4. The early HIV related Guidelines • Other guidelines followed including: • WHO clinical staging system • Management of opportunistic infections • HIV prevention • On PMTCT • At the work place • Home care and counseling • ART • IAS-USA • WHO

5. “Slim Disease”/Wasting

6. Kaposi’s sarcoma

7. Kaposi’s sarcoma before and after chemotherapy

8. Early days of antiretroviral therapy • AZT and monotherapy • Premature termination of the studies • Toxicity and short-lived response • Dual therapy of NRTIs • d4T, ddI, ddC • Better than monotherapy but not good enough • Considered suitable for sub-Saharan Africa • Triple therapy and the PIs – 1996 • The basis of the current ART strategies

9. Development of International Guidelines • Generated by a panel of experts in the relevant fields • Regional representation • Often evidence or consensus based or both • Published research • Clinical or field experience • Subject to regular review • When new evidence become available

10. Major contentions of ART guidelines • When to start ART • Early vs delayed start • What criteria to use • Clinical + CD4 count or viral load or both • WHO or CDC staging – for adults and children • What to use as first line therapy • Triple nukes and which ones • Use of PIs as first line

11. HIV-1 lifecycle Entry Viral protease RNA RNA Proteins Reversetranscriptase RT RNA RNA DNA DNA RT DNA DNA DNA DNA Provirus Integrase

12. Continued Evolution of HAART 25 drugs and counting First NNRTI approved First once-daily ARV approved First boosted PIapproved First fusion inhibitor approved First integrase inhibitor approved 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Number of new approved ARV agents(1996–2007) 1 2 5 0 2 2 1 2 2 1 1 1 First proteaseinhibitor (PI)approved First fixed-dose (dual) combination approved First fixed-dose (triple) combination approved First HAART fixed-dosecombination approved First CCR5 antagonist approved ARV, antiretroviral; CCR, chemokine receptor (C–C motif); NNRTI, non-nucleaoside reverse transcriptase inhibitor; PI, protease inhibitor www.emea.europa.eu/; http://www.fda.gov/bbs/topics/NEWS/2006/NEW01408.html

13. We have better and more tolerable therapy It appears we have: • Less short term toxicity-diarrhoea, dyslipidemia • Less long term toxicities such as lipodystrophy • Better formulations • easier to take • lower pill burdens-one pill once a day • no refrigeration

14. So why should HIV-Infected Patients Be Offered Earlier Treatment? Better tolerability and less toxicity of therapy Better chance of normalising CD4 count Lower risk of developing resistance Fewer OIs and deaths Preventing Non-AIDS defining events

15. Don't wait until its too late • In Patients presenting with OIs including tuberculosis it is important to start ARVs as soon as is practicable • Toxicity, adherence and IRIS are important but outweighed by the morbidity and mortality in those that don't start HIV treatment Dean et al AIDS. 2002;16;75-83 ,Lawn s et al CROI 2007 abstract 81, Zolopa A, et al. CROI 2008. Abstract 142.

16. Once on therapy then Don't Stop! The SMART study Plus DART and Trivacan

17. New Classes of drugs Integrase inhibitors-Raltegravir CCR5 antagonists- Maraviroc

18. HIV-1 lifecycle Entry Viral protease RNA RNA Proteins Reversetranscriptase RT RNA RNA DNA DNA RT DNA DNA DNA DNA Provirus Integrase

19. What is the place of new drugs in HIV treatment experienced patients? A new Paradigm Now we should aim for viral load undetectability The likelihood of reaching an HIV-1 RNA level lower than 50 copies/mL is highest if more than 2 active drugs are in a regimen and a new class is used Hammer et al. JAMA (2006) 296:827–43

20. What is the place of new drugs in HIV Naive Patients? • CCR5 inhibitors- Maraviroc didn't match up to Efavirenz but some Virological failures driven by the innacuracy of the tropism test used • Integrase plus nucleosides? -Good 96 week data but need large comparative study • Nucleoside sparing- boosted PI and integrase? • Trial planned in Europe by NEAT network using an efavirenz, tenofovir, FTC reference arm to look at these 2 latter approaches • Also studies are underway to evaluate 2 NNRTIs as well Hammer et al. JAMA (2006) 296:827–43