1. Preparing for HAART Cyril Goshima, M. D. Monday April 4, 2005

2. Prior to Considering HAART for Your Communities  HIV Testing with Confirmatory Tests must be available.  Certain Minimal Tests must be available e.g. CBC  At least two Classes of Antiviral Medications must be available on an ongoing basis.  Providers trained in HIV Care

3. Indications for ART  World Health Organization  DHHS Guidelines  IAS-USA Guidelines

4. WHO Staging System for HIV Infection & Disease in Adults & Adol escents  Clinical Stage I Asymptomatic Asymptomatic Generalized Lymphadenopathy Generalized Lymphadenopathy  Clinical Stage II Wt. loss <10%of BW Wt. loss <10%of BW Minor mucocutaneous manifestations e.g. onychomycosis, seb. derm., prurigo, angular cheilitis Minor mucocutaneous manifestations e.g. onychomycosis, seb. derm., prurigo, angular cheilitis Herpes Zoster within the last 5 yrs. Herpes Zoster within the last 5 yrs. Recurrent URI e.g. bacterial sinusitis Recurrent URI e.g. bacterial sinusitis And/or performance scale 2: symptomatic, normal activity And/or performance scale 2: symptomatic, normal activity

5. WHO Staging System  Clinical Stage III Wt. loss > 10% of BW Wt. loss > 10% of BW Unexplained chronic diarrhea > 1 mo. Unexplained chronic diarrhea > 1 mo. Unexplained prolonged fever (intermittent or chronic) > 1 mo. Unexplained prolonged fever (intermittent or chronic) > 1 mo. Oral Candidiasis Oral Candidiasis Oral Hairy Leucoplakia Oral Hairy Leucoplakia Pulmonary TB Pulmonary TB Severe Bacterial infections e.g. pneumonia Severe Bacterial infections e.g. pneumonia And/or performance scale 3: bedridden < 50 % of the day during last month And/or performance scale 3: bedridden < 50 % of the day during last month

6. WHO Staging System  Clinical Stage IV HIV Wasting Syndrome HIV Wasting Syndrome Opportunistic Infections Opportunistic Infections Any disseminated endemic mycosis Any disseminated endemic mycosis Non-typhoid Salmonella Septicemia Non-typhoid Salmonella Septicemia Extra-pulmonary TB Extra-pulmonary TB Lymphoma Lymphoma Kaposi’s Sarcoma Kaposi’s Sarcoma HIV encephalopathy HIV encephalopathy And/or performance scale 4: bedridden > 50% of the day during last mo. And/or performance scale 4: bedridden > 50% of the day during last mo.

7. WHO Recommendations for Starting ART in Adults and Adolescents  Documented HIV Infection  If CD4 testing is available WHO Stage IV disease, irrespective of CD4 WHO Stage IV disease, irrespective of CD4 WHO Stage III disease, CD4 < 350 WHO Stage III disease, CD4 < 350 WHO Stage I or II disease, CD4 < or = 200 WHO Stage I or II disease, CD4 < or = 200

8. WHO Recommendations for Starting ART in Adults & Adolescents  CD4 Testing Unavailable WHO Stage IV disease, irrespective of TLC WHO Stage IV disease, irrespective of TLC WHO Stage III disease, irrespective of TLC WHO Stage III disease, irrespective of TLC WHO Stage II disease with TLC < or = 1200 WHO Stage II disease with TLC < or = 1200 WHO Stage I, ART not recommended WHO Stage I, ART not recommended  Viral Load is considered not necessary  TLC is a useful marker of prognosis & survival in combination with clinical staging

9. DHHS Guidelines for Initiating ART in Adults and Adolescents Clinical CD4 Count Viral Load Recomm. Sym./AIDSAnyAnyTreat Asymp./AIDS<200AnyTreat Asymp. >200, 200, <350Any Offer esp. VL >20K Asymp.>350>100KConsider Asymp.>350<100KDefer

10. DHHS Guidelines for Initiating ART in Adults & Adolescents  Guidelines for initiating ART in pregnant women are different depending on the stage of pregnancy.  If a pregnant woman needs ART for her health then, ART should be started irregardless of the trimester. EFV should be avoided and NVP should be used with caution or avoided in women with CD4 >250.  Delaying ART until after 10-12 wks. gestation.

11. IAS-USA Guidelines-2004 for Initiating ART in Adults/Adoles. ClinicalCD4 Viral Load Recomm. Symp./AIDSAnyAnyTreat <200AnyTreat 200-350 >50K, * Consider 350-500 >100K, * Consider >500Monitor

12. IAS-USA Guidelines 2004 Initiating Therapy  * other criteria for considering therapy is a more rapid decline in CD4 by 100 in a year

13. Comparison of the Guidelines for Initiating ART  Clinical staging important Severe symptoms or AIDS Defining Conditions Severe symptoms or AIDS Defining Conditions  Evidence of significant immunological suppression CD4 cut off around 350 CD4 cut off around 350  Considerations for the pregnant women Timing, medications to be avoided Timing, medications to be avoided

14. Initial ART Regimens  WHO for Resource Limited Settings Usage in Pregnancy: NVP+3TC+d4T or AZT, avoid EFV Usage in Pregnancy: NVP+3TC+d4T or AZT, avoid EFV Usage with TB Co-Infection: EFV+3TC+d4T or AZT, avoid NVP with incr. LFT Usage with TB Co-Infection: EFV+3TC+d4T or AZT, avoid NVP with incr. LFT AZT use more costly with the addition of Hct monitoring. AZT use more costly with the addition of Hct monitoring. NVP+3TC+d4T and NVP+3TC+AZT available in fixed dose combination NVP+3TC+d4T and NVP+3TC+AZT available in fixed dose combination

15. Initial ART  DHHS Guidelines – 2004 Preferred NNRTI-Based Regimens: Preferred NNRTI-Based Regimens: EFV+(3TC or FTC)+(AZT or TDF), except in pregnant women or women with pregnancy potentialEFV+(3TC or FTC)+(AZT or TDF), except in pregnant women or women with pregnancy potential 3TC+AZT is in a fixed combination pill, Epzicom3TC+AZT is in a fixed combination pill, Epzicom FTC+TDF is in a fixed combination pill, TruvadaFTC+TDF is in a fixed combination pill, Truvada Preferred PI-Based Regimens: Preferred PI-Based Regimens: LPVr+(3TC or FTC)+AZTLPVr+(3TC or FTC)+AZT

16. Initial ART  DHHS Guidelines – 2004 cont’d Alternative NNRTI-Based Regimens: Alternative NNRTI-Based Regimens: EFV+(3TC or FTC)+other NRTIEFV+(3TC or FTC)+other NRTI NVP+(3TC or FTC)+other NRTINVP+(3TC or FTC)+other NRTI Alternative PI-Based Regimens: Alternative PI-Based Regimens: Other PI+(3TC or FTC)+other NRTIOther PI+(3TC or FTC)+other NRTI Many PI are boosted with RTV, except NFVMany PI are boosted with RTV, except NFV

17. Initial ART  IAS-USA Guidelines – 2004 NNRTI Component: NNRTI Component: EFV, NVP for selected pts.EFV, NVP for selected pts. NNRTI Component to be used with NRTI componentNNRTI Component to be used with NRTI component PI Component PI Component ATZr, SQVr, LPVr, IDVr (r=boosted with RTV)ATZr, SQVr, LPVr, IDVr (r=boosted with RTV) PI Component to be used with NRTI ComponentPI Component to be used with NRTI Component NRTI Component: NRTI Component: (AZT or TDF)+(3TC or FTC)(AZT or TDF)+(3TC or FTC) ddI+FTCddI+FTC

18. Initial ART  IAS-USA Guidelines – 2004 Alternative PI Components: FAPr, ATZ, NFV Alternative PI Components: FAPr, ATZ, NFV Alternative NRTI Components: ABC+3TC, ddI+3TC, AZT+ABC, d4T+3TC Alternative NRTI Components: ABC+3TC, ddI+3TC, AZT+ABC, d4T+3TC  Both DHHS and IAS-USA Guidelines list AZT+3TC+ABC in a fixed combination as an alternative in special circumstances

19. Regimens or Components of ART That Are Not Recommended  Monotherapy  Two-Agent Drug Combinations  TDF+3TC+ABC or TDF+3TC+ddI  AZT+3TC+ABC (Trizivir)  ATV+IDV (hyperbilirubinemia)  AZT+d4T (antagonistic)  Combination of “d” drugs

20. Regimens or Components of ART That Are Not Recommended  EFV in Pregnancy (teratogenic in non- human primates)  d4T+ddI in Pregnancy (lactic acidosis)  FTC+3TC (no benefit)  2 NNRTI (increase in side effects)

21. Adherence  Adherence is the most important factor in the success of ART.  Barriers to achieving adherence: Readiness to beginning treatment Readiness to beginning treatment Pill “burden” Pill “burden” Side Effects Side Effects Dosing Schedule, Storage & Food Requirements Dosing Schedule, Storage & Food Requirements

22. Adherence  Barriers to Achieving Adherence: Co-Morbid Conditions e.g. TB, Hepatitis, Mental Illness, Active Substance Use Co-Morbid Conditions e.g. TB, Hepatitis, Mental Illness, Active Substance Use Specific Cultural Issues Specific Cultural Issues Lack of Family, Community, Country Support Lack of Family, Community, Country Support

23. When to Change Therapy  Clinical Failure: HIV-related event 3 or more months after start of ART excluding reconstitution syndromes. WHO: Stg. III, IV.  Immunologic Failure: Failure to increase CD4 25-50 cells during the first year of ART. WHO: return to pre-treatment baseline or fall >50%.  Virologic Failure: Failure to achieve VL <400 by 24 wks. or <50 by 48 wks.  Criteria for children are different.

24. What to Change to?  Change at least 2 and at best all 3 ARV.  Try to avoid the use of 3 classes of ARV together, i.e. NRTI + NNRTI + PI.  Dual PI therapy is an option.  Mega-HAART: whatever the patient can tolerate.  Better to be on ART than not.

25. What to Change to?  Special Considerations: Women of child bearing age Women of child bearing age Pts. on TB therapy Pts. on TB therapy Hepatitis B Co-Infection: hepatitis flare if stop 3TC, FTC, TDF Hepatitis B Co-Infection: hepatitis flare if stop 3TC, FTC, TDF  Resistance Testing Where available Where available

26. Any Questions?