1 / 81

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

helki
Télécharger la présentation

Therapeutic Options

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related