ARV overview and toxicity

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

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

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

4. Guidelines….Americans 1996-2000 • All symptomatic patients (CD4/VL not an issue) • For chronic infection: - CD4<500 or - 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 • 1st 350 patients: 1st 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 HIV Clinic 2005 6)Metformin 850mg/d 7)Glicazide 80mg BD 8)Bezalip 1 BD 9)Prozac 20mg/d 10)Viagra 25mg PRN

44. Abdominal MRI Scans SAT SAT Control Subject Increased VAT

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

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

49. The END…