2. Principles of HIV Therapy Simple is Better! Adeel A. Butt, MD Assistant Professor of Medicine and Infectious Diseases University of Pittsburgh Director, VAPHS HIV-ID Clinics Center for Health Equity Research and Promotion

3. Objectives To tell you why we should care To tell you why the care is not optimal To share with you how some of us feel how this may be improved To describe when to initiate treatment and some initial regimens Principles of HIV Therapy

5. 00002-E-4 – 1 December 2002 Estimated number of adults and children newly infected with HIV during 2002 Total: 5 million Western Europe 30 000 North Africa & Middle East 83 000 Sub-Saharan Africa 3.5 million Eastern Europe & Central Asia 250 000 East Asia & Pacific 270 000 South & South-East Asia 700 000 Australia & New Zealand500 North America 45 000 Caribbean 60 000 Latin America 150 000

6. 00002-E-5 – 1 December 2002 Estimated adult and child deaths from HIV/AIDS during 2002 Total: 3.1 million Western Europe 8 000 North Africa & Middle East 37 000 Sub-Saharan Africa 2.4 million Eastern Europe & Central Asia 25 000 East Asia & Pacific 45 000 South & South-East Asia 440 000 Australia & New Zealand<100 North America 15 000 Caribbean 42 000 Latin America 60 000

7. 00002-E-6 – 1 December 2002 About 14 000 new HIV infections a day in 2002 - More than 95% are in developing countries - 2000 are in children under 15 years of age - About 12 000 are in persons aged 15 to 49 years, of whom: almost 50% are women about 50% are 15–24 year olds

8. Estimated adult and child deaths due to HIV/AIDS from the beginning of the epidemic to end 1999 Western Europe 210 000 North Africa & Middle East 70 000 Sub-Saharan Africa 13.7 million Eastern Europe & Central Asia 17 000 East Asia & Pacific 40 000 South & South-East Asia 1.1 million Australia & New Zealand 8 000 North America 450 000 Caribbean 160 000 Latin America 520 000 Total: 16.3 million Over 20 million dead by now

9. Projected changes in life expectancy in selected African countries with high HIV prevalence, 1995–2000 Source: United Nations Population Division, 1996 1955196019651970197519801985199019952000 Average life expectancy at birth, in years 65 60 55 50 45 40 35 Zimbabwe Zambia Uganda Botswana Malawi

10. Goals of Antiretroviral Therapy Control of viral replication Prevention or delay of progressive immunodeficiency Delayed progression to AIDS Prolonged Survival Decreased selection of resistant virus

11. Treatment Impact: CD4 Cell Count and Plasma HIV-1 RNA Level 150 100 50 0 -50 -100 -150 -200 CD4 + Cell Count Plasma HIV-1 RNA 1985198619871988198919901991199219931994199519961997 Monotherapy Double RTI Combinations Highly Active Antiretroviral Therapy Years +

12. Who Should be Treated HIV ELISA positive, confirmed with Western blot HIV RNA >55,000 copies/ml CD4 <350 cells/mm 3 Special considerations: Pregnant women Acute HIV infection Exposed healthcare workers

13. Highly Active Antiretroviral Therapy Four approved classes of drugs in the HAART regimens Nucleoside and nucleotide reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Fusion inhibitors

14. Currently Available Drugs Nucleoside analogue reverse transcriptase inhibitors Zidovudine (AZT, Retrovir) Lamivudine (3TC, Epivir) Stavudine (D4T, Zerit) Didanosine (DDI, Videx) Zalcitabine (DDC) Abacavir (Ziagen) Nucleotide … Tenofovir (Viread)

15. Currently Available Drugs Non-nucleoside reverse transcriptase inhibitors Nevirapine (viramune) Delavridine (rescriptor) Efavirenz (sustiva) Fusion Inhibitors Enfuvirtide (T-20)

16. Currently Available Drugs Protease Inhibitors Indinavir (crixivan) Nelfinavir (viracept) Ritonavir (norvir) Saquinavir soft gel (fortovase) Amprenavir (agenerase) Lopinavir/ritonavir (kaletra) Amprenavir/ritonavir

17. What is the Best Initial Treatment What we know Two is better than one Three is better than two What we are trying to find out Is four better than three???? IS THERE A GOLD STANDARD?

18. ABC of HIV Therapy Here is what I am NOT going to talk about All previous HIV Studies Details and comparisons of all regimens

19. Choice of Initial Regimen 2 NRTI1 PI 2 NRTI1 NNRTI 3 NRTI3 rd NRTI is abacavir 2 NRTI1 nucloeotide RTI (tenofovir) 2 NRTI2 PI (ritonavir as booster)

20. Choice of Initial Regimen NRTIs AZT – 2 tab Epivir – 2 tab Zerit – 2 tab Videx (DDI) – 1 tab (new EC formulation) Hivid (DDC) – I don’t ever use it Abacavir – 2 tab Tenofovir – 1 tab Combivir (AZT + Epivir) – 2 tab Trizivir (AZT + Epivir + Abacavir) – 2 tab

21. Choice of Regimen NNRTIs Nevirapine (Viramune) (2 tab) Efavirenz (Sustiva) (3 cap) Delavradine (Rescriptor) (6 or 12) PIs Indinavir (6 or 12 cap) Nelfinavir (10 tab) Ritonavir (don’t even go there) Saquinavir soft gel (18 cap) Amprenavir (16 cap) Lopinavir/ritonavir (6 cap)

22. Complexity of Regimens

23. Final Regimen Trizivir – 2 tab Combivir + ABC – 4 tab Combivir + NEV – 4 tab Combivir + EFV – 5 tab/cap D4t + EPI + EFV – 7 tab/cap

24. Why Does Treatment Fail? Intolerance Infection with a resistant virus Malabsorption NON-ADHERENCE TOPS THE LIST Rates of adherence have a direct correlation with success of HAART 1 Near perfect viral suppression in DOT trials 2

25. Reasons for Non-Adherence Psychiatric issues Drug use Social circumstances Privacy issues Adverse events COMPLEXITY Number of pills, number of doses, food restrictions, drug interactions

26. What Non-Adherence Can Do Paterson Ann Int Med 2000;133:21-30

27. Are Simple Regimens As Effective? COMBINE Study ZDV+Epivir+NEV vs. ZDV+Epivir+Nelfinavir CNA3014 Combivir+abacavir vs. Combivir+indinavir CNAF3007 Combivir+abacavir vs. combivir+nelfinavir

28. Adherence at Week 24* in CNA3014 Percentage of Subjects 56% 25% 74% 45%

29. Enfuvirtide (ENF, T-20) in Combination with an Optimized Background (OB) Regimen vs. OB Alone in Patients with Prior Experience or America and Brazil (TORO 1) Resistance to Each of the Three Classes of Approved Antiretrovirals (ARVs) in North

30. TORO 1: Demographics and Baseline Characteristics ENF+OBOBTotal (N=326) (N=165) (N=491) Baseline RNA 5.25.25.2 (median, log 10 ) Baseline CD4+ cell count 768780 (median, cells/mm 3 ) Prior ARVs (median)121212 Years ARV use (median)7.07.17.0 Prior ADEs (N, %)273 (84%)148 (90%)421 (86%) PSS at entry (mean)1.71.81.7

31. TORO 1: Primary Study Endpoint HIV-1 RNA Log Change from Baseline at Week 24 -1.70 -0.76 -2 0 (Delta=0.93 P<0.0001) Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF) OB alone ENF (T-20) + OB N=165N=326 Change from BL (log 10 copies/ml)

32. 76 32 0 50 100 Change from BL (Cells/mm 3 ) TORO 1: CD4+ Cell Count Change from Baseline at Week 24 P=0.0001 Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF) OB aloneENF (T-20) + OB

33. Averting Failure — Promote Adherence HAART has increased long-term survival of patients with HIV – Before HAART, median survival: 8 to 10 years – After HAART, median survival: may be 36 years Drug “holidays” or treatment interruptions result in rapid viral rebound within 2 to 3 weeks of treatment discontinuation Simplification of dosing regimens to twice or once daily may improve long-term adherence

34. Averting Failure Initiate therapy at the optimal time Patient factors, viral load, CD4 Simplify regimens Provide support Social, medical, psychiatric, rehabilitation

35. active depression, risk factor for HIV other than male-male sex, nonwhite race, low income, lower level of education, psychiatric disorders active alcoholism Other Factors Associated with Poor Adherence

36. Summary Chose patients to treat carefully With appropriate treatment, HIV is quite controllable, like any other chronic disease Missing a couple of doses a week may mean losing the game Less is better, when it comes to the number of pills

37. Summary When to start treatment CD4<350 VL> 55,000 Choice of initial regimen 3 drugs Appropriate prophylaxis Primary: PCP, MAC Secondary: PCP, MAC, Toxo, candidiasis, CMV, etc.