Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents

1. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents III - Initiation of Therapy AETC NRC Slide Set Version 1.0, February 2001

2. Disclaimer These slides were developed using the most recent treatment guideline information at the time of production. However, in the rapidly changing field of HIV care this information could become out of date quickly. The user is encouraged to compare the date of this slide set with the date of the most recent guidelines. Also, it is intended that these slides be used, as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC NRC

3. III. Initiation of Therapy:Contents • Goals of Therapy and Tools to Achieve Them • ART in the chronically HIV infected • Treatment options • Adherence • Drug interactions • Toxicities

4. Goals of Therapy • Eradication of HIV? Not yet… “…in spite of plasma RNA below detection there is evidence of genetic evolution in reservoirs.”

5. Maximal and durable suppression of viral load Restoration and/or preservation of immunologic function Improvement of quality of life Reduction of HIV-related morbidity and mortality Maximize adherence Rational sequencing of therapy Preservation of future treatment options Use of resistance testing in selected clinical settings Goals of Therapy and Tools To Achieve Goals

6. Before Initiating Therapy... • Confirm HIV results • Complete H&P • CBC, chemistry profile • CD4 and T lymphocyte count • Plasma HIV RNA measurement • Assess “readiness” for rx & adherence • Additional tests

7. VDRL PPD Chest x-ray Hepatitis A,B,C serology Gynecology exam with pap smear Ophthalmology exam (CD4+ T cell <100) Toxoplasma titer CMV serology (if indicated by history) Before Initiating TherapyAdditional Tests

8. Considerations in Initiating Therapy HIV Asymptomatic • Theoretical benefit • No proven long-term clinical benefit for CD4 >200 cells/ml3 • Expert opinion advises initiation of therapy for CD4 <350 cells/ml3 at any viral load • Consider the viral load when > 350 cells/ml3 CD4+ T cell • The “downside” of antiretroviral regimens

9. Considerations in Initiating Therapy HIV Asymptomatic • Willingness of patient to begin and the likelihood of adherence • Degree of immunodeficiency • Plasma HIV RNA • Risk of disease progression • Potential risks and benefits

10. Indications for ART in the Chronically HIV-Infected Patient TREAT ALL (regardless of viral load) • Symptomatic (AIDS, severe symptoms) • Asymptomatic, CD4+ <200 cells/mm3 • Asymptomatic, CD4+ >200/mm3 but <350 cells/ mm3 * * Treatment should generally be offered, though controversy exists

11. Indications for ART in the Chronically HIV-Infected Patient TREAT • Asymptomatic • CD4+ >350/mm3 • HIV RNA>30,000(bDNA)/55,000(RT-PCR)* * Some experts would recommend initiating therapy, recognizing that the 3 year risk of developing AIDS in untreated patients is >30%. In the absence of very high levels of plasma HIV RNA, some would defer therapy and monitor the CD4+ and level of plasma HIV RNA more frequently. Clinical outcomes data after initiating therapy are lacking.

12. Indications for ART in the Chronically HIV-Infected Patient DEFER TREATMENT • Asymptomatic • CD4+ cells > 350/mm3 • HIV RNA <30,000(bDNA)/55,000(RT-PCR)* * Many experts would defer therapy and observe, recognizing that the 3 year risk of developing AIDS in untreated patients is <15%.

13. Indications for ART in the Chronically HIV-Infected Patient • Clinical benefit has been demonstrated for patients w/ CD4 <200 mm3. However, most experts would offer therapy at a CD4 threshold <350 mm3. • All decisions should be based on prognosis for disease-free survival in the absence of treatment, as determined by the CD4 count and viral load (Table V), the potential benefits and risks of therapy (Table IV), and the willingness of the patient to accept therapy. For further information, see text.

14. NRTI Abacavir ABC Didanosine ddI Lamivudine 3TC Stavudine d4T Zidovudine ZDV Zalcitabine ddC Trizivir TRZ NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP PI Amprenavir AMP Indinavir IND Lopinavir LOP Nelfinavir NLF Ritonavir RIT Saquinavir SAQ soft gel SGC hard gel HGC Current Medications & Abbreviations

15. Column A Efavirenz Indinavir Nelfinavir Ritonavir + Saquinavir (SGC or HGC)* Ritonavir + Lopinavir** Ritonavir + Indinavir*** Column B Stavudine + Lamivudine Stavudine + Didanosine Zidovudine + Lamivudine Zidovudine + Didanosine Initial TreatmentStrongly Recommended One Choice Each From Column A and B * Saquinavir-SGC, soft-gel capsule (Fortovase): Saquinavir-HGC, hard-gel capsule (Invirase) ** Co-formulated as Kaletra *** Based largely on expert opinion

16. Column A Abacavir Amprenavir Delavirdine Nelfinavir + Saquinavir-SGC Nevirapine Ritonavir Saquinavir-SGC Indinavir Column B Didanosine + Lamivudine Zidovudine + Zalcitabine Initial TreatmentAlternative Recommendation One Choice Each From Column A and B • CONTRAINDICATED • ART monotherapy* • Zidovudine and Stavudine • * exception for prevention of perinatal transmission (see ACOG guidelines)

17. Column A Saquinavir-HGC** Column B Stavudine + Zidovudine Zalcitabine + Lamivudine Zalcitabine + Stavudine Zalcitabine + Didanosine Not Recommended* • *All monotherapies, whether from column A or B. Zidovudine or Nevirapine monotherapy may be considered for prophylactic use in pregnant women with a low viral load and high CD4+ T cell count to prevent perinatal transmission • **Use of Saquinavir-HGC (Invirase) is not recommended unless in combination with ritonavir

18. ADVANTAGES Documented clinical, virologic and immunologic efficacy Benefit despite viral breakthrough Resistance requires multiple mutations Targets HIV at two steps of viral replication Preserves NNRTI use DISADVANTAGES May be difficult to use and adhere to May have long-term side effects (lipodystrophy, insulin resistance and hyperlipidemia) Mild to severe inhibition of cytochrome P450 Cross resistance with other PIs PI-Based HAART Regimen

19. ADVANTAGES Sparing of PI-related side effects Generally easier to use and adhere to Fewer drug-drug interactions Preserves PIs for later use DISADVANTAGES Clinical endpoints unknown Resistance - single or few mutations Cross resistance across entire NNRTI class NNRTI-Based HAART Regimen

20. ADVANTAGES Easier to use and adhere to Spares PI and NNRTI side effects Limited cross resistance within the class Drug interactions are manageable Preserves PI and NNRTI class DISADVANTAGES Clinical endpoints are unknown Long-term virologic efficacy with high baseline viral load may be suboptimal Triple NRTI-Based HAART Regimen • Some side effects being attributed to protease inhibitor therapy, such as lipodystrophy, have not been proven to be strictly associated with the use of protease inhibitor-containing regimens. Lipodystrophy has also been described uncommonly in patients on NRTIs alone and in patients on no antiretroviral therapy.

21. The Advantage of Sequencing Drugs • To extend the overall long-term effectiveness of the available therapy options • Delay the risk of certain side effects uniquely associated with a single class of drugs • Anticipates up to 50% of failure rate and preserves future treatment options

22. Adherence • “The achilles heel of HAART” • G. Friedland • “Drugs don’t work if people don’t take them.” • C. Everett Koop

23. Adherence • The “rule” of thirds… • 1/3 take medication as prescribed • 1/3 are intermittently adherent • 1/3 take little or no medication

24. Who Will Be Adherent? • Age, race, sex, socioeconomic level educational level, socioeconomic status, and a past history of alcoholism or drug use are not reliable predictors of poor adherence • Active drug use or alcoholism, unstable housing, mental illness, and major life crises ARE predictors of poor adherence

25. Adherence – Predicting Success • The more severe the symptoms or illness the better adherence • Improved adherence if patients believe in efficacy of treatment

26. Predicting Poor Adherence • Active drug use or alcoholism • Unstable housing, mental illness, and major life crises

27. Adherence – Keep It Simple • Once daily therapy - 90% adherence • Twice daily therapy - 80% adherence • Three or more times daily - 65% adherence

28. Improving Adherence • A trusting provider-patient relationship • Education • Development of treatment plan with patient • Social support network • Simple regimen

29. NRTIs Zidovudine – HA, GI, bone marrow suppression Didanosine – GI intolerance, pancreatitis Stavudine – peripheral neuropathy Zalcitabine - peripheral neuropathy Abacavir – HA, GI, hypersensitivity reaction NNRTIs Nevirapine - rash, liver Delavirdine - rash Efavirenz – teratogenic in primates, CNS, rash PIs Indinavir – nephrolithiasis Ritonavir – GI intolerance Nelfinavir – diarrhea Amprenavir – GI intolerance Lopinavir - diarrhea Adverse Effects

30. Drug Interactions - IART and Other Medications • PIs and many lipid lowering agents • Anti-Mycobacterials, especially rifampin • Psychotropics – midazolam, triazolam • Ergot Alkaloids • Antihistamines – astemizole • Viagra • Methadone • Herbs - St. John’s Wort

31. Drug Interactions - IIART Classes and Dose Alterations • Efavirenz and single PIs • Efavirenz + ritonavir + PI • Renal failure: d4T + 3TC

32. Overlapping Toxicities • Peripheral neuropathy • didanosine, isoniazid, stavudine, zalcitabine • Bone marrow suppression • cidofavir, dapsone, zidovudine, hydroxyurea • Hepatotoxicity • efavirenz, isoniazid, NRTIs, nevirapine • Pancreatitis • didanosine, pentamidine, ritonavir, cotrimoxazole

33. Web Sites to Access the Guidelines • www.aids-etc.org • www.hivatis.org