Initiation of Antiretroviral Therapy

1. Initiation of Antiretroviral Therapy Dr Appolinaire TIAM Technical Director EGPAF-Lesotho

2. When to Start Therapy?

3. Eligibility for ART Adults and Adolescents

4. Criteria for initiation in a specific population

5. Priority population for ART initiation • Those with very low CD4 counts (<200) • Children • Pregnant women • TB patients • Absence of CD4 lab should not delay ART initiation in those in need such as children aged <24months, adults or child stage 3 or 4.

6. HAART and Survival Based on Initial CD4+ Cell Count 0.12 0.10 0.08 0.06 0.04 0.02 0.00 • Modeled data from ART Cohort Collaborative • 10,855 patients included • 934 progressed to AIDS or died • IDUs excluded from model Cumulative Probability of AIDS/Death According to CD4+ Count at Initiation of HAART 101-200 cells/mm3201-350 cells/mm3351-500 cells/mm3 Probability of AIDS or Death 3 0 4 5 1 2 Years Since Initiation of HAART Sterne J, et al. CROI 2006. Abstract 525.

7. When to Start - Consensus • Symptomatic patients that WHO stage 3 or 4 • Treat all • Asymptomatic patients • CD4 Abs: ≤350/mm3 • Regardless of HIV-1-RNA level • When the patient is ready to commit

8. The Initial Regimen

9. First Line for Treatment Naive Adults and Adolescents

11. Mode of Action

12. Substitution in the first line • Co-infection with TB: D-D interaction btw NVP and Rifampicin so EFZ should be substituted for NVP. • For children<3 years of wt<10kgs, give NVP at 200mg/m2. • Severe toxicity grade 3 or 4.

13. Severe toxicities and potential First line substitutions

14. Side effects

15. Adverse Effects of Antiretroviral Drugs • Do occur commonly • Can be a potential barrier to successful therapy • May lead to a reduction in the quality of life • May be an important cause of non-adherence to therapy • REMEMBER: Overall experience in the world has shown that ARV medications are very well tolerated by the vast majority of patients!

16. Outline • Common side effect profiles of each ARV drug (grouped by class) • Serious and rare toxicities of each ARV drug • Recognition & Management strategies • Brief review of long-term complications of PI’s • Food requirements of ARV drugs • Summary / Conclusions

17. Side Effects and Toxicities • Side effects are usually self-limited and not life-threatening, and usually resolve over a short period of time and with symptomatic support. Side effects usually occur early after ARV initiation. • Toxicities are more severe, potentially life-threatening effects of ARVs and can occur at anytime.

18. Potential Toxicities of NRTI Class • AZT Zidovudine Retrovir™ • 3TC LamuvidineEpivir™ • DDI DidanosineVidex™ • D4T StavudineZerit™ • ABC AbacavirZiagen™

19. AZT (Zidovudine) • Most common: • Nausea, vomiting, headaches, fatigue, myalgias • Common: • Macrocytosis -- not significant, but a marker for adherence • Serious: • Anemia and neutropenia • Myositis (elevated CPK) and myopathy • Lactic Acidosis • Other: • Darkening of skin, mucous membranes, nails

20. AZT pigmentation (nail beds)

21. AZT pigmentation of the mucosa

22. AZT pigmentation(hard and soft palate)

23. AZT Anemia • Modification of AZT therapy must be considered when patients have substantial drop in HB (< 7.0 gm/dL) or more than 25% decrease from their baseline. • AZT-induced anemia can occur as early as 2-4 weeks following initiation, but typically occurs after 4-12 weeks, but sometimes later.

24. Severe AZT Anemia • If significant drop in HB from baseline: • STOP AZT  Substitute D4T for AZT • Transfuse if HB < 5.5 gm/dL • Do not treat with AZT again.

25. 3TC (Lamivudine) • Common: • None (well-tolerated) • Less common: • Occasional nausea, headaches, vomiting, and diarrhea • Serious: • Pancreatitis (very rare)

26. D4Tn(Stavudine) Contraindicated with AZT • Common side effects: • Peripheral neuropathy (up to 20%) • Uncommon: • Lethargy, myalgia, headache • Serious: • Liver toxicity, pancreatitis (rare), lactic acidosis (rare)

27. DDI (Didanosine) • Common: • Nausea • Bloating • Diarrhoea • Peripheral neuropathy (up to 20%) • Serious: • Pancreatitis, optic neuritis

28. ABC (Abacavir) • Common: • Hypersensitivity reaction • Serious: • Anaphylactic reaction • Death may occur

29. Recognition of ARV drug inducedPeripheral Neuropathy • ARV drugs implicated: D4T > DDI > > AZT • Need to document presence of PN at baseline visit since HIV alone can cause significant PN, which often improves with ARV therapy. • Typical symptoms (parasthesia, numbness) • Usually in hands / feet (“stocking-glove distribution”) • As progresses, can cause loss of reflexes and vibratory sense • Important to assess how PN affects activities of daily living (walking, sleeping, working, etc.)

30. Management of ARV drug inducedPeripheral Neuropathy • Mild/Moderate PN • Treat side effects and continue same regimen • Treat with amitriptyline (begin at 25 mgs), carbamazepine, phenyton, or gabapentin. • NOTE: [Need to document presence of PN at baseline visit since HIV alone can cause significant PN] • Severe PN • Discontinue causative ARV drugs (D4T and/or DDI) • May take weeks-months for symptoms to resolve even after discontinuing causative ARV drugs

31. Recognition of ARV drug induced Pancreatitis • Symptoms of pancreatitis typically during first 1-6 months • Begins with abdominal pain, nausea and vomiting • More common with DDI, but also rarely reported with 3TC and D4T • Elevated amylase/lipase (asymptomatic hyperamylasemia may be due to parotid/salivary gland source).

32. Management of ARV Drug induced Pancreatitis • Treat abdominal pain, nausea, vomiting. • Bowel rest with IVF’s (stop all ARVs, until pancreatitis resolves); consider imaging with abdominal ultrasound / CT scan. • Do not re-challenge with offending ARV(s) if pancreatitis is confirmed.

33. Lactic Acidosis Syndrome • Entire NRTI class implicated: • Recently described / reported • Probably due to mitochondrial toxicity • Very rare • Presentation is very vague (fatigue, nausea, vomiting, abdominal pain, weight loss, malaise, dyspneoa, and motor weakness)

34. Recognition of Lactic Acidosis Syndrome • Laboratory Clues: • Increased anion gap: Na – [Cl + CO2] • Increased lactic acid (check with a grey-top tube on ice), modest elevation in SGOT/SGPT, and low HCO3 • NOTE: If your lab is not able to perform routine HCO3 on U/E, can run heparinised blood specimen on blood gas analyzer) • Diagnosis: • Above symptoms with elevated lactate level (> 5.0 mmol/L in adults

35. Management of Lactic Acidosis Syndrome • High mortality rate (60%) • Consider administering bicarbonate and vitamin supplements (riboflavin). • Discontinue all ART; administer NRTI-sparing HAART after patient recovers. Consult HIV specialist. • Recovery from elevated lactic acid levels may be prolonged.

36. Efavirenz (EFV) • Nevirapine (NVP) Potential Toxicities of NNRTI Class

37. EFV (Efavirenz) • Common (not class-related): • Central nervous system side effects • Headaches • Light-headedness • Confusion • Sleep disturbances (abnormally vivid dreams) • These side effects typically resolve within the first 14-21 days of treatment

38. EFV (Efavirenz) • Serious (class-related): • Skin rash; progressing to Steven’s Johnson Syndrome • Hepatotoxicity • The above toxicities are less common with EFV than with NVP.

39. EFV (Efavirenz) • EFV is the only ARV absolutely contra-indicated in pregnancy • Not recommended for use in women with child-bearing potential • Safe to administer with ATT medications

40. EFV (Efavirenz) • Other possible side effects: • Lipodystrophy (body habitus changes) • Elevated triglycerides/cholesterol • Breast enlargement

41. NVP (Nevirapine) • Common: • Cutaneous • Skin rash, reported up to 20%, usually appears in the first few weeks to months of therapy. • Progresses to Stevens-Johnson Syndrome (SJS) in < 1.0%. • Less Common: • Liver toxicity(more common than with EFV)

42. Mild NVP Rash • Moderate maculopapular rash is typically on face, trunk, and/or extremities, with or without pruritus. • Usually appears within the first few weeks to months of therapy. • Treat with antihistamines, topical skin creams, and NOT systemic steroids. • Usually resolves within a few weeks. • Safe to continue NVP, but if patient is still on OD dose, do not dose escalate until rash resolves. • Advise patient to return if rash worsens or mucous membrane involvement appears.

43. Severe NVP Rash (1) • Severe Hypersensitivity Reaction • SJS is quite rare, occurs within the first 6-8 weeks of ARV therapy, and can be fatal. • Treat with steroids and stop ALL ARV drugs until patient recovers, and do not re-challenge with NVP.

44. Severe NVP Rash (2) • Any of the following signs/symptoms suggest impending SJS: • Fever • Conjunctivitis • Extensive, moist, peeling rash • Mucous membrane involvement (lip sores/ulcers/swelling, new vaginal lesions) • Patient appears unwell

45. NVP-Related SJS

47. Stevens-Johnson Syndrome

48. Management of NVP-induced Severe Skin Reaction • Discontinue ARVs and all other medications • Treatment: • Prednisone (40-60 mgs, taper) • Chlorpheniramine • Brufen • Paracetamol • Close observation, realizing that patient may deteriorate over next 72-96 hours • After recovery, new ARV regimen may substitute EFV or NFV for NVP. Do not re-challenge with NVP.

49. NNRTI Liver Toxicity • If LFT’s up to 2x upper limit of normal values: WATCH! • If LFT’s ≥ 5x upper limit of normal values: • Stop all medications, including ARVs, and monitor LFTs. • When LFTs have normalized, restart ARVs. • If previously on NVP, substitute EFV or NFV for NVP. • If previously on EFV, substitute NFV for EFV (do not use NVP).

50. Practical Considerations with NVP Treatment • LFTs should be drawn at 2 week follow-up visit after initiation of NVP. • NVP: Need to monitor patients closely during first 6-8 weeks on ART. • If possible, try to avoid simultaneous initiation of NVP with other drugs having potential hepatotoxicity, eg., ATT, IPT, cotrimoxazole. • However, INH and cotrimoxazole may safely be used with NVP.