Session B: HIV Antiretrovirals

1. Session B: HIV Antiretrovirals Pre-departure Orientation 23 January 2007

2. GOALS Review Kenyan ART guidelines Discuss WHO 2006 guidelines Review individual ARV agents Toxicity Side effects Monitoring considerations Review principles of therapy switch For side effects For adverse events Case Studies

3. Available ANTIRETROVIRALS: U.S. NRTI (nucleoside analogs) Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Zalcitabine DDC Tenofovir TDF NNRTI (non-nucleosides) Delavirdine DLV Efavirenz EFV Nevirapine NVP Protease Inhibitor Amprenavir APV Atazanavir ATV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV Darunavir TMC-114 Fusion Inhibitor Enfuvirtide T-20 Integrase Inhibitors

4. Selecting HAART regimen: US Full access to all antiretroviral agents Which specific combo depends on Existing comorbidities, lab abnormalities Genotype (transmitted resistance) Patient preferences Once-daily dosing; pill burden considerations Wide variation in combos prescribed Benefits: tailor-fit; option to switch

5. Selecting HAART regimen: RLS Limited access to all antiretroviral agents Generally, one-size-fits all: Cheap generics make ART ‘roll-out’ possible Algothrithmic approach enable rapid scale-up But this results in limited options, essentially…. Triomune for all, unless: Contraindication to any component Treatment of active TB Pregnancy considerations Treatment-limiting SAE/toxicity

6. Constructing an Antiretroviral Regimen for Initial Therapy: a US-based approach

7. Constructing a HIV Antiretroviral regimen Key principle: 3 active drugs 2 NRTI + NNRTI or PI “Nuc” backbone + either PI or NNRTI AKA: Two scoops rice + chicken or beef Choosing a regimen Step 1: Decide: NNRTI or PI Step 2: Pick a NRTI ”backbone” Choose components based on toxicity Take into account side effect, pill burden, patient preference, and cost

11. Recommended first-line regimens in TZ I d4T+3TC+NVP, (All in one tablet: Fixed Dose Combination (FDC): Triomune 40 twice daily (> 60 kg body weight). Triomune 30 twice daily (< 60 kg body weight). NB: For new patients use Nevirapine only once a day (half dose) for first 2 weeks by giving 1triomune in the evening and d4t and 3TC separate tablets in the morning II AZT+3TC+NVP Zidovudine and Lamivudine and Nevirapine, each twice daily NB: For new patients use Nevirapine only once a day (half dose) for first 2 weeks

12. Recommended first-line regimens in TZ, continued III d4T+3TC+EFV Stavudine and Lamivudine twice daily and Efavirenz 600 mg once daily at night IV AZT+3TC+EFV Zidovudine and Lamivudine twice daily and Efavirenz once daily at night. Indications to change antiretroviral therapy within first line regime are to be determined by prescribing doctor: (see next slide)

13. Recommended second-line regimens in Kenya ABC + ddI + LPV/r Abacavir and Lopinavir/ritonavir two times a day and Didanosine once a day on empty stomach ABC + TDF + LPV/r

14. Learning ARVs for Kenya Goals Monitoring for SAFETY ARVs have many toxicities Toxicity depend on ARV class Some ARVs have fatal toxicities Switching therapy Some clients cannot tolerate their ART regimen Side effects Toxicity Failure Knowing how a HIV regimen is put together allows you to make intelligent and safe changes.

15. How to learn ARVS Divide individual ARVs into 3 classes NRTI NNRTI PI Learn the “class effects” Each class of ARVs have common toxicities If you can remember which class an ARV belongs to, you can remember which toxicities to watch for Learn individual drugs Learn any other unique properties of each drug. Knowing each drug well is one of the most important parts of being a good HIV care and treatment provider!

16. NRTI Nucleoside/tide Reverse Transcriptase Inhibitors (mimics Adenosine, Thymidine, Guanine, or Cytosine)

17. NRTI: class effects All may cause: Mitochondrial toxicity Lactic acidosis Pancreatitis Peripheral Neuropathy Lipodystrophy Hepatotoxicity

18. NRTI tips How to recognize a NRTI 3 letters or numbers AZT, 3TC, DDI, D4T, ABC, TDF Generic name usually end in “ine” Zidovudine, lamividine, didanosine, stavudine NRTI Exceptions: abacavir, tenofovir end in “vir” but are NRTIs NNRTI Exceptions: nevirapine, delavirdine are NNRTI but end in “ine” NRTI = “Backbone” of ART Foundation of most ART combinations “Two scoops of rice” plus chicken or beef Two NRTI (rice) PLUS Chicken (NNRTI) or Beef (PI)

19. NRTIs Essential part of any ART combination Less drug-drug interactions Availability in resource-limited settings Individual drugs with unique side effects/toxicities Class effect: Lactic acidosis Mitochondrial toxicity Peripheral neuropathy Lipodystrophy Hepatotoxicity

20. 3TC (lamivudine/Epivir) Toxicity Few Hepatitis B exacerbation Side Effects Few; class effect Dosing 150mg bid or 300mg qd Renal dosing available Special Considerations Hepatitis B

21. D4T (stavudine/Zerit) Toxicity Lipoatrophy Peripheral neuropathy Pancreatitis Lactic acidosis Side Effects Gen well-tolerated Dosing 40mg bid (if >60kg) 30mg bid (if <60kg)

27. AZT (zidovudine/Retrovir) Toxicity Anemia Neutropenia Thrombocytopenia Myopathy Side Effects Nausea/vomiting Headache Dizziness Dosing 300mg bid

28. DDI (didanosine/Videx) Toxicity Lactic acidosis Peripheral neuropathy Pancreatitis Lipodystrophy Side Effects GI Dosing If EC, 400mg QD (<60kg: 250mg qd) If reg tabs, 200mg bid (<60kg:125 bid/250qd) Empty stomach

29. ABC (abacavir/Ziagen) Toxicity FATAL hypersensitivity Rash Fever GI (nausea/vomiting) Respiratory (SOB) Hypotension Death on re-challenge Class effect Side Effects Nausea, other GI Dosing 300mg bid or 600mg qd Co-formulated with 3TC as Epzicom

30. TDF (tenofovir/Viread) Toxicity Renal failure Renal Tubular Necrosis Hypophosphatemia Hepatitis B exacerbation Side Effects Gen well-tolerated Dosing 300mg QD Avoid in borderline renal dysfunction Fanconi’s syndrome (rare) Renal dosing necessary Special Considerations Hepatitis B

31. NNRTI NON-nucleoside Reverse Transcriptase Inhibitors (blocks RT directly, NOT a nucleoside-analogue)

32. NNRTI: class effects All may cause: Rash Hepatotoxicity

33. NNRTIs Ease (low pill burden) Tolerability Less metabolic effects fat maldistribution, dyslipidemia Availability in resource-limited settings Prone to resistance single mutation Cross resistance among NNRTIs Rash; hepatotoxicity Potential drug interactions (CYP450)

34. NVP (nevirapine/Viramune) Toxicity Hepatotoxicity (can be fatal) Cases of fulminant hepatitis ? death Usually within 6 wks Not in PMTCT Increased risk in women 12-fold risk: women, CD4>250 4-fold risk: men, CD4>400 Rash (can be fatal) Stevens-Johnson (erythema multiforme major) Toxic epidermal necrolysis Mild rash COMMON Side Effects Well-tolerated Dosing Lead-in dosing: 200mg daily x 2 weeks, then 200mg bd

36. EFV (efavirenz/Sustiva) Toxicity Rash Hepatitis Teratogenic Not for use in women of childbearing potential Side Effects CNS Insomnia/Somnolence Vivid dreams “Spacey”, poor concentration Gen. ? after 1-2 wks Dosing 600 mg qd

37. P I Protease Inhibitors (binds/disables viral protease enzyme)

38. PI: class effects All may cause: Hyperlipidemia Hyperglycemia Fat redistribution CYP 3A4 inhibitors multiple drug-drug interactions

39. Protease Inhibitors High potency Longest prospective data (durability) Esp. in advanced AIDS Less susceptible to resistance from virus “Salvage” therapy when NNRTI fails Metabolic complications fat maldistribution, dyslipidemia, insulin resistance Drug interactions (CYP3A4) High cost Limited availability

40. Ritonavir (RIT/Norvir) Toxicity Hepatotoxicity Hyperlipidemia Hyperglycemia/ insulin resistance Drug-drug interactions! Potent inhibition CYP3A4 Increases levels of other PIs Must check interactions Side Effects GI Nausea/vomiting Diarrhea Abdominal pain Dosing “boosting” 100-200mg qd Approved 1996Approved 1996

41. KAL (lopinavir+rit/Kaletra) Toxicity Hyperlipidemia Hyperglycemia/ insulin resistance Drug-drug interactions Side Effects GI Nausea/vomiting Diarrhea Abdominal pain Dosing 3 tabs bid (400/100mg) Other Most potent ARV Hard to develop resistance (>5 major PI-associated mutations ? efficacy)

42. Constructing a HIV Antiretroviral regimen 2 NRTI + NNRTI or PI Exception: 3 NRTI in special circumstances only Choose components based on toxicity Take into account side effect, pill burden, patient preference, and cost Always need 3 active drugs!

45. Putting it all together Cases in Treatment with ART

46. Algorithm for selecting first line treatment

47. Case 1: Switching for complications 34 yo Kenyan woman WHO IV, CD4 45 HIV wasting, chronic diarrhea Exam: cachexia, conjunctival pallor Labs: HgB 7 WBC 1.2 (40% PMN, 59% lymph, 1% eos) Plt 140k Remaining normal OK to start Kenyan first-line therapy? What if you are in South Africa? First-line is efavirenz/3TC/AZT

48. Case 2: Switching for Complications 45 yo man WHO III, CD4 170 Prurigo, onychomycosis, and oral hairy leukoplakia and treated thrush Pre-ART labs: all normal Started on Triomune 4-months later, hospitalized for severe abdominal pain, nausea, vomiting, dehydration, inability to tolerate oral solids/liquids Differential diagnosis? What is your work-up?

49. Case 2 Hospital labs: CBC, chemistry, LFT nl Lipase 600 Clinical course: ART stopped Hydration, electrolyte support Discharged 3 days later When the patient returns, would you resume ART? If so, with what combination?

50. Case 3 45 yo Ugandan woman In 2002 ago was WHO III Weight loss (75kg ? 66kg) Recurrent thrush, vaginal candidiasis Zoster with post-herpetic neuralgia Social: administrative assistant Limited income, can spend up to 25,000 TSH on medications Advised to purchase generic Triomune Triomune is NVP/3TC/D4TTriomune is NVP/3TC/D4T

51. Started Triomune October 2002 4 months later, weight 66kg ? 70kg 8 months later, no more recurrence of thrush 1 yr later, weight 74kg 3 yrs later, weight 74 kg Complains “I am starting to like a man….I think I look strange in the face” Fat loss in thighs and face. Otherwise feels well. Lipoatrophy in a woman.Lipoatrophy in a woman.

52. Case 7: Switching for complications 33 yo Tanzanian woman Spouse also HIV+ WHO Stage III, CD4 180 Sexually active, cannot afford condoms Complains of chronic cough for 2 months Exam: thrush Labs: all within normal parameters CXR: “clear” OK to start Triomune?

53. Case 7 Started on Triomune Tolerated well, no problems 3 weeks later Cough increased Fever Weight loss Differential diagnosis? Exam: Rales in RLL and LUL CXR: R apical infiltrate and LLL diffuse opacity, hilar lymphadenopathy not seen on prior CXR Labs: WNL Course of Action?

54. Case 7 Diagnostics Sputum for AFB Given Amoxicillin No improvement AFB smear+ What should you do now? Start anti-TB therapy? Continue Triomune? Stop Triomune? Replace Triomune? Drug interaction: Rifampin decrease NVP Use EFV+3TC+D4T Must provide birth control while on EFV

56. Rifampicin + Efavirenz YES. But optimal dosage unclear. Rifampin decreases EFV 28% Unclear if dose adjustment needed Spanish study: ?EFV from 600mg to 800mg overcomes PK1 Descriptive studies supporting both 600 and 800 mg dose2,3

57. Rifampicin + Nevirapine UNCLEAR. More data needed. Rifampin decreases NVP 31% to 58% Little clinical data Small Spanish cohort (n=32): 74% with virologic suppression at 15 months1 More studies needed Esp. in resource-limited settings

58. Rifampicin + PI’s NOT RECOMMENDED Rifampicin decrease protease inhibitor levels 70-90% Rifampicin induces hepatic enzyme cytochrome P450 3A4 Results in MARKED INCREASE in metabolism of protease inhibitors Few clinical studies on PI + rifampicin Kaletra (lopinavir/ritonavir): variable Cmin. Saquinavir/ritonavir tried

59. PI’s in TB: Additive Toxicity SQV/rit 1600/200 has been tried1 High dose PI “boosted” with ritonavir Ritonavir used to increase PI levels by inhibiting CYP3A4 3/20 with viral rebound, all with low Cmin High hepatotoxicity with RIF + SAQ/RIT Reported February 2005 in Dear Doctor letter Phase I study: RIF 600mg + SAQ 1000mg + RIT 100mg 11/28 (39.3%) developed hepatotoxicity Transaminases up to 20x upper limit normal Ritonavir + rifampin ? additive hepatotoxicity

60. Summary Points HIV potentiates TB. TB accelerates HIV Treating HIV-TB coinfection is complex Many clinical questions remain Rifampicin decreases levels of PI and NNRTI NRTI levels unchanged. Additive toxicity with some ARVs and TB therapy ARV recommendation in TB therapy EFV 600mg or 800mg is best option NVP not well studied, levels decreased somewhat PIs levels decreased significantly Additive toxicity Beware of hepatotoxicity, failure due to insufficient levels

61. Algorithm for selecting first line treatment

62. Summary Understand Toxicity of Individual ARV If symptoms develop, consider each individual ARV and what it can cause Also consider non-ART related causes Therapy switch For Toxicity of Complication of ART OK to switch within class NVP ? EFV D4T ? AZT or ABC NVP should NOT be switched for D4T, AZT, DDI, ABC!