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Principles of HIV Therapy Simple is Better!

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. Member of Academic Research Council

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Principles of HIV Therapy Simple is Better!

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  1. Principles of HIV TherapySimple 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 Member of Academic Research Council A non-profit organization dedicated to improving medical education and fostering research

  2. Principles of HIV Therapy 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

  3. Estimated number of adults and childrennewly infected with HIV during 2002 Eastern Europe & Central Asia 250 000 Western Europe 30 000 North America 45 000 East Asia & Pacific 270 000 North Africa & Middle East 83 000 South & South-East Asia 700 000 Caribbean 60 000 Sub-Saharan Africa 3.5 million Latin America 150 000 Australia & New Zealand 500 Total: 5 million

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

  5. 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

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

  7. Projected changes in life expectancy in selected African countries with high HIV prevalence, 1995–2000 65 60 55 50 45 40 35 Average life expectancy at birth, in years Botswana Zimbabwe Zambia Uganda Malawi 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 Source: United Nations Population Division, 1996

  8. 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

  9. Treatment Impact: + CD4 Cell Count and Plasma HIV-1 RNA Level 150 100 50 Cell Count 0 Plasma HIV-1 RNA -50 + CD4 -100 -150 -200 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 Years Highly Active Antiretroviral Monotherapy Therapy Double RTI Combinations

  10. Who Should be Treated • HIV ELISA positive, confirmed with Western blot • HIV RNA >55,000 copies/ml • CD4 <350 cells/mm3 • Special considerations: • Pregnant women • Acute HIV infection • Exposed healthcare workers

  11. 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

  12. 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)

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

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

  15. 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?

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

  17. Choice of Initial Regimen

  18. 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

  19. 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) Choice of Regimen

  20. Complexity of Regimens

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

  22. 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 HAART1 • Near perfect viral suppression in DOT trials2

  23. 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

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

  25. 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

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

  27. 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

  28. TORO 1: Demographics and Baseline Characteristics ENF+OB OB Total (N=326) (N=165) (N=491) Baseline RNA 5.2 5.2 5.2(median, log10) Baseline CD4+ cell count 76 87 80(median, cells/mm3) Prior ARVs (median) 12 12 12 Years ARV use (median) 7.0 7.1 7.0 Prior ADEs (N, %) 273 (84%) 148 (90%) 421 (86%) PSS at entry (mean) 1.7 1.8 1.7

  29. TORO 1: Primary Study Endpoint HIV-1 RNA Log Change from Baseline at Week 24 ENF (T-20) + OB OB alone 0 N=326 N=165 Change from BL(log10 copies/ml) -0.76 -1 -1.70 -2 (Delta=0.93 P<0.0001) Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF)

  30. TORO 1: CD4+ Cell Count Change from Baseline at Week 24 100 76 P=0.0001 Change from BL (Cells/mm3) 50 32 0 ENF (T-20) + OB OB alone Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF)

  31. 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

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

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

  34. 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

  35. 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.

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