Principles of HIV Therapy Simple is Better!

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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
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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

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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
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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 lt100
Total 3.1 million
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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 1524 year olds

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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
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Projected changes in life expectancy in selected
African countries with high HIV prevalence,
19952000
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
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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
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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
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Who Should be Treated

• HIV ELISA positive, confirmed with Western blot
• HIV RNA gt55,000 copies/ml
• CD4 lt350 cells/mm3
• Special considerations
• Pregnant women
• Acute HIV infection
• Exposed healthcare workers

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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

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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)

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Currently Available Drugs

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

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Currently Available Drugs

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

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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?

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ABC of HIV Therapy

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

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Choice of Initial Regimen
2 NRTI 1 PI
2 NRTI 1 NNRTI
3 NRTI 3rd NRTI is abacavir
2 NRTI 1 nucloeotide RTI (tenofovir)
2 NRTI 2 PI (ritonavir as booster)
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Choice of Initial Regimen

• NRTIs
• AZT 2 tab
• Epivir 2 tab
• Zerit 2 tab
• Videx (DDI) 1 tab (new EC formulation)
• Hivid (DDC) I dont ever use it
• Abacavir 2 tab
• Tenofovir 1 tab
• Combivir (AZT Epivir) 2 tab
• Trizivir (AZT Epivir Abacavir) 2 tab

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Choice of Regimen

• PIs
• Indinavir (6 or 12 cap)
• Nelfinavir (10 tab)
• Ritonavir (dont even go there)
• Saquinavir soft gel (18 cap)
• Amprenavir (16 cap)
• Lopinavir/ritonavir (6 cap)

• NNRTIs
• Nevirapine (Viramune) (2 tab)
• Efavirenz (Sustiva) (3 cap)
• Delavradine (Rescriptor) (6 or 12)

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Complexity of Regimens
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Final Regimen

• Trizivir 2 tab
• Combivir ABC 4 tab
• Combivir NEV 4 tab
• Combivir EFV 5 tab/cap
• D4t EPI EFV 7 tab/cap

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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

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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

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What Non-Adherence Can Do
Paterson Ann Int Med 200013321-30
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Are Simple Regimens As Effective?

• COMBINE Study
• ZDVEpivirNEV vs. ZDVEpivirNelfinavir
• CNA3014
• Combivirabacavir vs. Combivirindinavir
• CNAF3007
• Combivirabacavir vs. combivirnelfinavir

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Adherence at Week 24 in CNA3014
74
56
Percentage of Subjects
45
25
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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
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TORO 1 Demographics and Baseline Characteristics
ENFOB OB Total (N326) (N165)
(N491) 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
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TORO 1 Primary Study Endpoint HIV-1 RNA Log
Change from Baseline at Week 24
ENF (T-20) OB
OB alone
0
N165
N326
Change from BL(log10 copies/ml)
-0.76
-1
-1.70
-2
(Delta0.93 Plt0.0001)
Least Squared Means Log Change from Baseline -
Intent-to-Treat Population (LOCF)
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TORO 1 CD4 Cell Count Change from Baseline at
Week 24
100
76
P0.0001
Change from BL (Cells/mm3)
50
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0
OB alone
ENF (T-20) OB
Least Squared Means Change from Baseline
Intent-to-Treat Population (LOCF)
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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

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Averting Failure

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

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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

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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

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Summary

• When to start treatment
• CD4lt350
• VLgt 55,000
• Choice of initial regimen
• 3 drugs
• Appropriate prophylaxis
• Primary PCP, MAC
• Secondary PCP, MAC, Toxo, candidiasis, CMV, etc.