The Primary Care of HIV Infection and AIDS:

1

Initiation of Antiretroviral Therapy Another Look
J. Kevin Carmichael, MD
JK Carmichael, MD.Presented at IASUSA/RWCA
Clinical Conference, June 2005.
The International AIDS SocietyUSA
2
Treatment Responses in First Yearof HAART
Improving Over Time

• 4143 subjects from 5 clinic cohorts in Europe and
  Canada
• Treatment-naive started HAART between 1996 and
  2002
• ? risk of virologic failure, ? median CD4
  increase in later years

150
Median CD4 increase
with gt 500 copies/mL
100
90
127
125
121
120
119
80
70
97
60
With VL gt 500 on ART
50
40
30
24.8
23.0
17.3
20
12.4
10
8.4
8
10
0
1996
1997
1998
1999
2000
2001
2002
Lampe F, et al. CROI 2005 Abstract 593
3
When To Start Treatment? Summary of Current
Guidelines
4
Evolution of a more conservative approach to ART

• We know the drugs work well and that the immune
  system can recover to some degree
• Eradication is unlikely in chronically infected
  persons
• Risk of AIDS and death is low when treatment
  started gt200 cells
• Side effects and complexity of regimens reduce
  quality of life
• Lifelong adherence is difficult and sub-optimal
  adherence leads to regimen failure
• Continued regimen failure leads to viral
  resistance
• Long term toxicities of successful treatment
  remain problematic
• Cost of therapy

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Why early therapy remains attractive

• Easier to achieve and maintain viral control
• Preserve immune function
• Improve tolerability in healthier/younger
  patients
• Prevent emergence of X4 tropic virus
• Prevent complications less linked to CD4
• ADC, Non Hodgkins Lymphoma, neuropathy, etc.
• Preserve option of intermittent therapy
• Potentially decrease transmission

6
Total deaths and of deaths not on ART El Rio
Special Immunology Associates
7
Factors Guiding Choice of Initial Regimen

• Patient factors
• CD 4 and viral load
• Co-morbidity including MTB, HBV, liver disease,
  depression or mental illness, cardiovascular
  disease, chemical dependency
• Pregnancy or pregnancy potential
• Drug interactions
• Adherence potential
• Tolerance Potency
• Regimen forgiveness
• Adverse drug effects
• Short-term and long-term
• Resistance pattern predicted in virologic failure

8
Guidelines for NNRTI Component

• Preferred/Recommended
• Efavirenz
• Avoid EFV if in first trimester or in women
  trying to conceive who are not using effective
  and consistent contraception
• CNS side-effects may limit use in some patients
• EFV metabolism may be slowed in some African
  Americans
• Nevirapine
• Recommended in selected patients by IAS-USA
• Alternative in DHHS Guidelines in women with CD4
  lt250 or men with CD4 lt 400.

• DHHS Guidelines 4-7-2005 www.aidsinfo.nih.gov
• IAS-USA Guidelines JAMA 2004292251-265

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Guidelines for PI Component

• Preferred/Recommended
• Lopinavir-r
• DHHS preferred with ZDV 3TC or FTC
• Atazanavir-r, Indinavir-r, Saquinavir-r
• Recommended along with LPV-r in the IAS-USA 2004
  guidelines
• Alternatives
• Fosamprenavir-r or Atazanavir or Nelfinavair or
  Fosamprenavir (DHHS only)
• ATV must be boosted with use of TDF

• DHHS Guidelines 4-7-2005 www.aidsinfo.nih.gov
• IAS-USA Guidelines JAMA 2004292251-265

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Efficacy of triple-drug ART Virologic and
immunologic response by drug class

• ART-naïve patients in clinical trials 19942004
• 13,147 patients in 49 studies

Week 48 response by drug class

Week 48 HIV RNA lt50 c/mL by treatment arm
plt0.01 vs NRTI and PI plt0.05 vs PI plt0.01
vs NNRTI, NRTI, and PI plt0.05 vs NRTI

• Caveats
• Cross-study comparison
• CD4 responses may be impacted by lower baseline
  CD4 counts in recent studies
• Wide range of patient numbers (n32405)

Response ()
Bartlett J, et al. 12th CROI, Boston 2005, 586
11
Guidelines for NRTI Backbones

• Preferred/Recommended
• ZDV or TDF 3TC or FTC
• Concerns for nephrotoxicity with TDF
• Alternative
• ABC or DDI or D4T 3TC or FTC
• Avoid D4T with DDI
• TDF increases DDI levels so DDI dose must be
  reduced and there are concerns about using these
  drugs together
• ABC hypersensitivity

• DHHS Guidelines 4-7-2005 www.aidsinfo.nih.gov
• IAS-USA Guidelines JAMA 2004292251-265

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A Comparison of NRTI FDCs
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Initiation of ART Conclusions

• Initiation and choice of initial therapy must
  still be tailored to the individual
• Tolerability equals potency
• Data strongly support starting therapy before CD4
  count falls below 200
• Resistance testing of pregnant, acutely or
  recently infected patients is recommended before
  treatment
• Resistance testing of chronically infected
  persons should be considered based on prevalence
  especially if considering a NNRTI

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Initiation of ART Conclusions

• Current data and guidelines support the use of
  either an NNRTI or a BPI (boosted protease
  inhibitor) in combination with ZDV or TDF and 3TC
  or FTC
• The role of alternative regimens will become
  clearer as data emerge
• ACTG 5202 (ABC/3TC or TDF/FTC with ATV-r or EFV)
• EPZ 104057 (ABC/3TC or TDF/FTC with QD LPV-r)