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Therapeutic Options

Therapeutic Options. New Options & New Challenges James A Zachary MD LSU Health Sciences Center HIV Outpatient Clinic 11 April 2005. http://HIVManagement.org. http://HIVInfo.us. Objectives. Review of principles of antiretroviral therapy Review of antiretrovirals Newer agents

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Therapeutic Options

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  1. Therapeutic Options New Options & New Challenges James A Zachary MDLSU Health Sciences CenterHIV Outpatient Clinic11 April 2005

  2. http://HIVManagement.org

  3. http://HIVInfo.us

  4. Objectives • Review of principles of antiretroviral therapy • Review of antiretrovirals • Newer agents • Strategies for naïve and experienced antiretroviral therapy

  5. http://aidsinfo.nih.gov/

  6. Principles of Therapy • There is no latent stage of HIV infection • CD4 lymphocyte counts and HIV viral load determinations are critical to successful therapy • Treatment should be individualized

  7. Principles of Therapy • There is no latent stage of HIV infection • CD4 lymphocyte counts and HIV viral load determinations are critical to successful therapy • Treatment should be individualized

  8. Lab Monitoring of Therapy • CD4 lymphocytes = immunity • HIV RNA PCR or HIV double-stranded DNA = viral load • equilibrium between viral replication vs clearance of virus and inhibition of replication

  9. Principles of Therapy • There is no latent stage of HIV infection • CD4 lymphocyte counts and HIV viral load determinations are critical to successful therapy • Treatment should be individualized

  10. Individualization of Therapy • Clinical factors • Laboratory factors • Psychosocial factors

  11. Individualization of Therapy • Clinical factors: date of primary infection, history of treatment (drugs, intolerances, response), body weight, kidney and liver disease, drug interactions, absorption issues • Laboratory factors • Psychosocial factors

  12. Individualization of Therapy • Clinical factors • Laboratory factors: CD4, viral load, liver enzymes, Cr, hematologic parameters (WBC, hemoglobin) • Psychosocial factors

  13. Individualization of Therapy • Clinical factors • Laboratory factors • Psychosocial factors: support system, mental health, adherence to medical therapy in the past, access to care, understanding of disease process, relationship with medical providers, literacy

  14. Principles of Therapy • Combination therapy is always utilized. • It is important to consider resistance issues. • Antiretrovirals should be administered at optimal dosing and dosing frequencies.

  15. Combination Therapy * Especially stavudine

  16. Combination Therapy

  17. Combination Therapy *April 72004: alternative regimen – women CD4<250 cells/mm3 or men CD4 < 400 cell/mm3

  18. Antiretroviral Toxicity • NRTI • Mitochondrial: d4T, ddC, ddI • Hematologic: AZT • PI • GI: nelfinavir, ritonavir, lopinavir • Hepatic: indinavir, ritonavir atazanavir • Lipodystrophy: lopinavir, indinavir, boosted PIs • NNRTI • Rash: nevirapine, delavirdine • Hepatic: nevirapine >> efavirenz • CNS: efavirenz

  19. Antiretrovirals with Hepatitis B Activity • Tenofovir (TDF) • Lamivudine (3TC) • Emtricitabine (FTC)

  20. Antiretrovirals Regimens to Avoid • Monotherapy • Dual therapy • Triple nukes • Abacavir + tenofovir + lamivudine • Didanosine + tenofovir + lamivudine • Tenofovir + 2NRTI

  21. Antiretrovirals Regimens to Avoid • Amprenavir oral solution • Pregnant women • Children < 4 years age • Hepatic or renal dysfunction • Concomitant metronidazole or disulfiram • Amprenavir + fosamprenavir • Amprenavir soln + ritonavir soln

  22. Antiretrovirals Regimens to Avoid • Atazanavir + indinavir: hyperbilirubinemia • Didanosine + stavudine: mito toxicity • Didanosine + zalcitabine: mito toxicity • Stavudine + zalcitabine: mito toxicity • Efavirenz in first trimester of pregnancy and women of childbearing potential: teratogenicity

  23. Antiretrovirals Regimens to Avoid • Emtricitabine + lamivudine: duplicate mechanism of action • Lamivudine + zalcitabine: decreased intracellular phosphorylation of both drugs • Nevirapine: increased toxicity • Women CD4 > 250 cells/mm3 • Men CD4 > 400 cells/mm3 • NNRTI + didanosine + tenofovir: high failure rate

  24. Antiretrovirals Regimens to Avoid • Hard gel saquinavir (Invirase) as the sole PI: inadequate drug levels • Zidovudine + stavudine: antagonistic in vitro and in vivo • Didanosine + tenofovir?: blunted CD4 increase

  25. Principles of Therapy • Combination therapy is always utilized. • It is important to consider resistance issues. • Antiretrovirals should be administered at optimal dosing and dosing frequencies.

  26. HIV Resistance • A virus is defined by its ability to develop resistance! • HIV resistance testing • Initiation of therapy • newly infected • partner of someone on therapy • recent vertical transmission • Failing regimen: subtherapeutic drug levels for whatever reason*

  27. Complex of HIV-1 Reverse Transcriptase with an RNA-DNA Duplex Clavel, F. et al. N Engl J Med 2004;350:1023-1035

  28. HIV-1 Protease Dimer Binding with a Protease Inhibitor (Panel A) and A Drug-Sensitive (Wild-Type) Protease Juxtaposed against a Drug-Resistant Protease (Panel B) Clavel, F. et al. N Engl J Med 2004;350:1023-1035

  29. HIV Resistance Testing • Baseline? • Lack of virologic suppression • Must be done while patient is on therapy • Genotype vs phenotype

  30. Principles of Therapy • Combination therapy is always utilized. • It is important to consider resistance issues. • Antiretrovirals should always be administered at optimal dosing and dosing frequencies.

  31. Optimized Dosing • Adherence ~ dosing frequency, side effects, possible side effects, refrigeration requirements, meal dependence • Clinical variables ~ body weight, potency of drugs, bioavailability, penetration of drugs into compartments, hepatic and renal clearance, drug interactions, toxicities

  32. Optimized Adherence • Lower pill burden • Combination formulations • Combivir • Trizivir • Truvada • Epzicom • Protease inhibitor boosting • Once-a-day and twice-a-day drugs • Drugs with less toxicity

  33. Combination Drugs

  34. Protease Inhibitor Boosting • Ritonavir inhibits hepatic metabolism of most protease inhibitors • Decreases pill burden • Decreases dosing frequency • Decrease meal dependence

  35. Protease Inhibitor Boosting • Increased potential for non-PI drug interactions • Increases possibility of hyperlipidemia and central fat redistribution

  36. Protease Inhibitor Boosting • Once-a-day boosted PIs • Fosamprenavir 1400 mg + ritonavir 200 mg • Amprenavir 1600 mg + ritonavir 100 mg • Hard gel cap saquinavir 1600 mg + ritonavir 100-200 mg • Atazanavir 2x150 mg + ritonavir 100 mg

  37. Protease Inhibitor Boosting • Twice-a-day PI boosting • Amprenavir + ritonavir • Hard gel caps or soft gel caps saquinavir 1000 mg bid + ritonavir 100 mg bid • Fosamprenavir 700 mg bid + ritonavir 100 mg bid • Indinavir 800 mg bid + ritonavir 100-200 mg bid

  38. Once-A-Day NRTIs • Emtricitabine (FTC) • Tenofovir (TDF) • Didanosine EC (ddI) • Lamivudine (3TC) • Abacavir

  39. NNRTI Atazanavir/r Fosamprenavir/r abacavir/lamivudine tenofovir/emtricitabine or lamivudine didanosine + emtricitabine abacavir + didanosine abacavir + tenofovir abacavir + emtricitabine Once-A-Day Menu 2005

  40. Once-A-Day NNRTIs • Efavirenz • Nevirapine: slightly increased toxicity (hepatic, rash)

  41. Principles of Therapy • Make changes in therapy cautiously • Women and children should be treated as aggressively as male adults. • Primary HIV infection should be treated within the first 6 months.

  42. Changes in TherapyMany variables should considered be at the time alteration of treatment • Adherence issues • Genotypic and phenotypic resistance and cross-resistance issues • Pharmacokinetic issues • Toxicity issues • Availability • Strategic planning for patient and lifestyle

  43. Principles of Therapy • Make changes in therapy cautiously • Women and children should be treated as aggressively as male adults. • Primary HIV infection should be treated within the first 6 months.

  44. Principles of Therapy • Make changes in therapy cautiously • Women and children should be treated as aggressively as male adults. • Primary HIV infection should be treated within the first 6 months.

  45. Principles of Therapy • HIV infected persons should always be considered infectious • Expert consultation just as in other areas of medicine may be helpful.

  46. Principles of Therapy • HIV infected persons should always be considered infectious • Expert consultation just as in other areas of medicine may be helpful.

  47. Case 1 • 22 year old with new dx HIV presents to ED with PCP, oral thrush, weight loss of 15 lbs/3 mos, O2 sat 90% on RA • CD4 41 • HIV VL > 750,000 copies/cc • WBC 2.4, AGC 1200, hgb 12.5, MCV 88 • LDH 450, AST 55, ALT 45, alb 3.1, INR 1.1

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