1. ARV overview and toxicity Dr Francois Venter Reproductive Health Research Unit University of the Witwatersrand

2. HAART experience Current HAART experience Future safety and efficacy < 9 years

3. ddI d4T AZT 3TC 2 Nukes Non-nuke Efavirenz/ nevirapine Protease Kaletra Failure – VL>5000

4. Guidelines….Americans 1996- 2000 ► All symptomatic patients (CD4/VL not an issue) ► For chronic infection: - CD4<500 or - CD4<500 or - viral load>10 000 – 20 000 - viral load>10 000 – 20 000

6. So when to start? Critical questions… ► Can HIV be eradicated with HAART? ► Better virological outcomes with earlier treatment? ► Better immunological responses with earlier treatment? ► Lower drug toxicity with earlier treatment? ► Are there better clinical outcomes?

8. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? ► Better immunological responses with earlier treatment? ► Lower drug toxicity with earlier treatment? ► Are there better clinical outcomes?

9. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? ► Better immunological responses with earlier treatment? ► Lower drug toxicity with earlier treatment? ► Are there better clinical outcomes?

12. So, to get maximum viral suppression… ► Viral load not an issue ► CD4<200 not ideal, but not bad ► CD4<50 definitely less effective ► CD4 200-350 and above 350 – get equivalent responses

13. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? NO ► Better immunological responses with earlier treatment? ► Lower drug toxicity with earlier treatment? ► Are there better clinical outcomes?

14. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? NO ► Better immunological responses with earlier treatment? ► Lower drug toxicity with earlier treatment? ► Are there better clinical outcomes?

15. Immunological outcomes… ► Need quantitative and qualitative outcome ► CD4 is rough but robust marker ► The lower the CD4, the less recovery occurs

16. Immunology cont… ► AIDS 2001; 15;983 ICONA trial: ► CD4 rise 280 if started >350, ► CD4 rise 281 if CD4 201-350, and ► CD4 rise 186 if<200 ► Almost no difference in VL undetectable

17. Immunology cont… ► Ann Intern Med 2000;133:401 – 17% patients only had virological response

18. Immunology cont… ► But: even with no CD4 response - significant benefit (Lancet 1999;353:863 – 20.1% vs 55% OI rate if no HAART)

19. Immunology cont… ► Ideal: initiate before critical CD4 reached

20. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? NO ► Better immunological responses with earlier treatment? YES ► Lower drug toxicity with earlier treatment? ► Are there better clinical outcomes?

21. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? NO ► Better immunological responses with earlier treatment? YES ► Lower drug toxicity with earlier treatment? ► Are there better clinical outcomes?

22. Drug toxicity… ► In general – the lower the CD4, the higher the incidence of short-term toxicity ► BUT – the long-term toxicity is the most worrying: lipodystrophy a major reason for change in guidelines; lactic acidosis emerging as problem ► Delay=more short term toxicity, but delays onset of long term toxicity

23. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? NO ► Better immunological responses with earlier treatment? YES ► Lower drug toxicity with earlier treatment? Short term YES, long term NO ► Are there better clinical outcomes?

24. So when to start? Critical questions… ► Can HIV be eradicated with HAART? NO ► Better virological outcomes with earlier treatment? NO ► Better immunological responses with earlier treatment? YES ► Lower drug toxicity with earlier treatment? YES and NO ► Are there better clinical outcomes with earlier treatment?

30. BUT….. ► All retrospective data ► Some discordance from the data ► Blacks and women under-represented ► ?role age, women ► What happens at 3,5, 10 years? ► None of it from Africa ► Does starting later increase risk of TB? When all think alike, no one is thinking - Lippman

31. Side effects Dr Francois Venter Reproductive Health Research Unit

32. Johannesburg Hospital ► 1 st 350 patients: 1 st 10 weeks ► 44% significant side effects ► Dizziness, confusion, rash, bad dreams, peripheral neuropathy, anaemia ► 10 stopped! Rash, peripheral neuropathy, dizziness ► IRIS is a problem - ?side effects…

33. Teratogenicity ► “Safe” vs “unknown” ► C vs B: ► For SA: nevirapine vs efavirenz – we’ll find out fast ► Do NOT confuse teratogenicity with maternal toxicity (lactic acidosis)

34. Non Nucleoside RTI’s ► Nevirapine and Efavirenz - Rash ► Common - up to 20% ► Stevens Johnson Syndrome - Liver Toxicity : up to 20% of pts on NVP, 2x higher in females, can be fatal. LFTs must be done - Rash - Neuropsychiatric

35. GIT ► All manner ► Pancreatitis – all the d’s

36. MARROW SUPPRESSION ► All NRTI’s  Most common with AZT  Effect of uncontrolled HIV  Other causes e.g. infections, nutritional, autoimmune, drugs and infiltrations Investigations: Full Blood count & smear Reticulocyte count, coombs Vitamin B12, Red cell folate, Iron studies Bone marrow aspirate, trephine and TB culture

37. NEUROPATHY  Predominantly axonal degeneration  EMG  Exclude ► Drugs (INH, Metronidazole, Dapsone) ► Alcohol, Diabetes, Hypothyroidism ► B12 deficiency  Treatment : 1. Stop drugs; 2. Rx underlying pathology; 3. Avoid trauma; 4. Analgesia ►

38. Lactic Acidosis ► d4T, all the others ► Clinical Symptoms and Signs Loss weight Nausea, Vomiting Abdominal discomfort Extreme Fatigue Hyperventilation Liver failure and Pancreatitis

39. MYOPATHY  ?  Mostly AZT  Proximal myopathy

40. Protease Inhibitors ► Lipodystrophy  Fat redistribution  Raised triglycerides and cholesterol  Elevated blood sugar ► General symptoms are moderately severe and relatively common ► Nephrolithiasis (Indinavir >30%)

41. Common side effects and HAART… ► Diabetes ► Hypertension ► Raised cholesterol, decreased HDL, raised LDL ► Endothelial dysfunction ► Lipodystrophy, with increased intra- abdominal fat

42. Prescription pad Dr WDF Venter, Physician 27 Eton Road, Parktown, 2193 (011) 717 2810 7 October 2005 Re: Mr John Smit Discovery Super-duper Vitality Xtra member 100234 Please provide: 1) Trizovir 1 BD 2) Atenolol 100 mg/d 3) Aspirin 150mg/d 4) Perindopril 4 mg/d 5) Pravastatin 1/d Regards WDF Venter FCP (SA), DTM&H 6) Metformin 850mg/d 7) Glicazide 80mg BD 8) Bezalip 1 BD 9) Prozac 20mg/d 10) Viagra 25mg PRN

44. Abdominal MRI Scans Control SubjectIncreased VAT SAT

45. What Are the Treatment Options? ► Lifestyle changes  Exercise  Diet ► Lipid-lowering agents  Fibric acid derivatives  Statins ► Drugs  Growth hormone  Anabolic steroids  Dietary supplements ► Hypoglycemic agents  Thiazolidinediones  Metformin ► Surgical interventions  Surgical removal/liposuction  Facial implants  Fat transfer techniques

48. “The drugs are toxic. The disease is toxicer.” – Dr Francesca Conradie

49. The END…

51. Drug interactions

52. WHAT IS THE PATIENT TAKING ? ► Prescription ? ► Non-prescription ? - OTC drugs antacids, analgesics, H2-antagonists - Alternative medicines eg St John’s Wort - Illicit drugs

53. ANTI-INFECTIVES - Antiretrovirals: AZT & d4T, ddI & IDV, ddC & 3TC. - Antibiotics: Clarithromycin & PIs & NNRTIs, Ciprofloxacin and ddI Rifampicin & Pis and NNRTIs also ddI, AZT Rifampicin & Pis and NNRTIs also ddI, AZT - Antifungals: Fluconazole & AZT, Ketoconazole/Itraconazole & PIs and NNRTIs also ddI

54. ANTICONVULSANTS - carbamazepine, phenytoin, phenobarbitone AVOID ALL PI’s and NNRTIs - Valproate AVOID AZT AND RTV

55. COLDS AND ALLERGY AGENTS Eg Preparations containing astemizol, loratidine, promethazine and terfenadine. AVOID WHEN ON Pis and NNRTIS

56. GASTROINTESTINAL AGENTS - Antacids, H2-antagonists, proton pump inhibitors Must be given 1-2 hours after ddI, IDV

57. CARDIOVASCULAR AGENTS - Lipitor/Zocor: AVOID Pis or change to Pravastatin - Ca antagonists: AVOID Pis - Warfarin: AVOID Pis and NNRTIs

58. HYPOGLYCAEMICS - Sulphonylureas - Metformin AVOID RITONAVIR

59. HOMEOPATHIC St John’s Wort Garlic Pills Grapefruit juice