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Session B: HIV Antiretrovirals

Session B: HIV Antiretrovirals. Pre-departure Orientation 23 January 2007. Royce C. Lin, MD Assistant Clinical Professor of Medicine University of California, San Francisco Director, AIDS Consult Service Deputy Director, ASPIRE Positive Health Program. HIV/AIDS Division

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Session B: HIV Antiretrovirals

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  1. Session B: HIV Antiretrovirals Pre-departure Orientation 23 January 2007 Royce C. Lin, MD Assistant Clinical Professor of Medicine University of California, San Francisco Director, AIDS Consult Service Deputy Director, ASPIRE Positive Health Program. HIV/AIDS Division San Francisco General Hospital

  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. 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 Available ANTIRETROVIRALS: U.S.

  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 Royce C. Lin, MD Assistant Clinical Professor

  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

  8. Summary: DHHS Guidelines 2006 Chicken Beef Two Scoops Guidelines for the Use of Antiretrovirals in HIV-1 infected Adults and Adolescents 10 October 2006, Department of Health and Human Services, USA

  9. WHO 2006 Guidelines: Summary Table Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-limited Settings: Toward Universal Access. World Health Organisation 2006 Revision.

  10. WHO 2006 Guidelines: Summary Table Majority: D4T + 3TC + NVP in FDC Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-limited Settings: Toward Universal Access. World Health Organisation 2006 Revision.

  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. 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 NRTIs DISADVANTAGES ADVANTAGES

  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)

  22. Malar Wasting of Lipoatrophy

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

  24. 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

  25. 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

  26. 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

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

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

  29. 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) NNRTIs DISADVANTAGES ADVANTAGES

  30. 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

  31. 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

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

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

  34. 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 Protease Inhibitors ADVANTAGES DISADVANTAGES

  35. 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

  36. 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)

  37. 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!

  38. AZT 3TC(or FTC) + D4T (or DDI) ABC NRTI Backbone TDF

  39. AVOID D4T AZT Competitive Inhibition Levels ↓ +  ddI +  Excessive toxicity D4T ddC

  40. Putting it all together Cases in Treatment with ART

  41. Algorithm for selecting first line treatment I. d4T + 3TC + NVP 1st line regimen • Replace d4T with AZT due to: • Peripheral neuropathy and NOanaemia • Replace NVP with EFV due to: • Hepatoxicity • NVP intolerance • TB patient • Replace NVP with EFV due to: • Hepatoxicity • NVP intolerance • TB patient on rifampicin • Replace d4T with AZT due to: • Peripheral neuropathy and NOanaemia II. AZT + 3TC + NVP III. d4T + 3TC +EFV IV. AZT +3TC+ EFV Modified 1st line regimen

  42. 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

  43. 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?

  44. 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?

  45. 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

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