Highlights of the XIV International AIDS Conference July 7-12, 2002; Barcelona, Spain

1
Highlights of theXIV International AIDS
ConferenceJuly 7-12, 2002 Barcelona, Spain

• Selected and summarized byJoseph J. Eron, Jr, MD
• Associate Professor of MedicineUniversity of
  North Carolina at Chapel Hill

Supported by an unrestricted educational grant
from
2
T-20 Phase 3 Studies in Highly Experienced
Patients

• Study Outline
• Two studies TORO 1 (Americas) and TORO 2 (Europe
  and Asia)
• Highly treatment-experienced subjects
• Median 7.4 yrs prior therapy
• 75 prior AIDS-defining illness
• Median plasma HIV-1 RNA gt100,000 copies/mL
• Median CD4 cell count 100 cells/mm3
• Over 600 subjects, randomized to change therapy
  to either
• New regimen optimized by genotype or phenotype,
  or
• Optimized regimen plus T-20
• Primary end point change in plasma HIV-1 RNA
• 24 weeks follow-up

Abstracts LbOr19A/B
3
T-20 Phase 3 Studies in Highly Experienced
Patients (2)

• Results at Week 24
• Significantly greater CD4 cell count increases
  in the T-20 arms
• Injection-site reactions were the most frequent
  AE on T-20, although overall discontinuation
  rates between treatment arms were similar

Study Viral Load Reduction (log10 copies/mL) Viral Load Reduction (log10 copies/mL) Viral Load Reduction (log10 copies/mL)
Study T-20 Optimized Regimen Optimized Regimen P value
TORO 1 -1.70 -0.76 lt .001
TORO 2 -1.43 -0.65 lt .001
4
Tenofovir DF in Treatment-Naive Subjects

• Study Outline
• Gilead 903 study randomized, double-blind,
  placebo-controlled
• Treatment-naive subjects (N 600)
• plasma HIV-1 RNA level gt 5000 copies/mL (median
  81,300)
• any CD4 cell count (median 279)
• Randomized to initiate therapy with either
• tenofovir DF (QD) and stavudine placebo (BID), or
• stavudine (BID) plus tenofovir DF (QD)
• each combined with open-label efavirenz (QD)
  lamivudine (BID)

Abstract LbOr17
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Tenofovir DF in Treatment-Naive Subjects

• Results at Week 48
• Equivalent virologic and immunologic outcomes
• HIV-1 RNA lt 50 copies/mL in 81 to 82 of both
  arms (ITT, MF)
• CD4 cell count increases of 167-169 cells/mm3 in
  both arms
• Similar rates of adverse effects
• More peripheral neuropathy on stavudine
• Lactic acidosis 3 on stavudine, none on
  tenofovir DF
• Triglycerides 74 mg/dL on stavudine no change
  on tenofovir DF
• Cholesterol 53 mg/dL on stavudine 25 mg/dL on
  tenofovir DF
• Question Resistance pattern after TDF/3TC/EFV
  failure?
• Will K65R mutation appear more commonly in
  previously naive patients?
• Question Long-term effects of regimens on
  metabolic parameters, eg, fat redistribution,
  bone density?

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ACTG 384 Head-to-Head Comparison of 6 Initial
Regimens

• Study Outline
• Factorial design
• Zidovudine/lamivudine (ZDV/3TC) vs
  stavudine/didanosine (d4T/ddI) as NRTI backbones
• Efavirenz (EFV) vs nelfinavir (NFV) vs both as
  the additional agent(s)
• Comparison of sequential 3-drug vs single 4-drug
  therapy

First-line Regimen Second-line Regimen
Stavudine didanosine efavirenz Zidovudine lamivudine nelfinavir
Stavudine didanosine nelfinavir Zidovudine lamivudine efavirenz
Zidovudine lamivudine efavirenz Stavudine didanosine nelfinavir
Zidovudine lamivudine nelfinavir Stavudine didanosine efavirenz
Stavudine didanosine efavirenz nelfinavir Not applicable
Zidovudine lamivudine efavirenz nelfinavir Not applicable
Abstracts LbOr20A/B
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ACTG 384 Head-to-Head Comparison of 6 Initial
Regimens (2)

• Primary End point
• Time to failure after exposure to all 3 classes,
  ie
• Time to failure of the 4-drug regimen
• Time to failure of the second 3-drug regimen
• Baseline Characteristics
• N 980
• 72 male, 47 white
• Median baseline CD4 cell count 278 cells/mm3
• Median baseline plasma HIV-1 RNA level 4.9
  log10 copies/mL
• Median follow-up 28 months

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ACTG 384 Head-to-Head Comparison of 6 Initial
Regimens (3)

• Results
• Factorial design thwarted by interactions between
  the regimen components
• Activity of efavirenz differed with ZDV/3TC vs
  d4T/ddI
• Activity of ZDV/3TC differed with nelfinavir vs
  efavirenz
• In the arms receiving sequential 3-drug regimens
• Time to first failure was substantially longer
  with ZDV/3TC/EFV
• Time to second failure appeared substantially
  longer if either the first or second 3-drug
  regimen was ZDV/3TC/EFV
• Comparing sequential 3-drug vs single 4-drug
  regimens
• No additional benefit from receiving nelfinavir
  with ZDV/3TC/EFV
• Significantly more toxicity from d4T/ddI vs
  ZDV/3TC backbone
• No significant differences in CD4 cell count
  responses
• Results strongly support use of ZDV/3TC/EFV as
  initial therapy and suggest that the ddI/d4T
  backbone may be suboptimal

9
PIs Associated With More Cardiac Events Than
NNRTIs

• Study Outline
• Multicenter, randomized trial in Italy
• 776 patients treated with a PI-containing regimen
• 775 patients treated with a non-PI regimen
• End points new myocardial infarction or
  new-onset angina
• Baseline Characteristics
• Average age 36 years
• Median CD4 cell count at baseline 325
  cells/mm3 (range, 170-850)
• 87 smokers
• Follow-up
• After 3 years, 587 PI and 621 non-PI patients
  remained on original regimen

Abstract WeOrB1307
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PIs Associated With More Cardiac Events Than
NNRTIs (2)

• Results
• 23 episodes of new heart disease in PI group
• 6 transmural MI, 6 non-Q-wave MI, 11 new-onset or
  unstable angina
• 2 episodes of new heart disease in non-PI group
• 1 MI, 1 angina
• Highly statistically significant difference in
  heart disease-free survival between arms
• Incidence of heart disease in PI group gt 10-fold
  that of the non-PI group, and gt 50-fold that of
  the general population
• Heart disease associated with lipodystrophy signs
  (OR 26.9), elevated lipids (OR 14.2), smoking
  (OR 9.7), male sex, and HIV treatment.
• Nonblinded study, so the risk of an ascertainment
  bias (ie, cardiac events were sought more
  carefully in PI-treated patients) should be kept
  in mind

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FRAM Study Defining Lipodystrophy

• Study Outline
• Aim Compare randomly selected HIV-infected
  subjects and healthy controls and identify
  statistically significant differences and any
  linkages between components of lipodystrophy
• Three types of evaluation
• Self-report re body habitus changes
• Clinical evaluation of presence/degree of visible
  lipoatrophy
• Body composition measures including whole-body
  MRI and DEXA scanning
• N about 1200 HIV-infected subjects from 16 US
  clinics and 300 controls
• Subjects and controls were well matched for
  baseline characteristics, but subjects were
  lighter than controls
• This report focused on only a subset of enrolled
  men, not all subjects

Abstract TuOrB1140
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FRAM Study Defining Lipodystrophy (2)

• Initial Results
• Subjects were more likely to have lipoatrophy
  when compared with controls, by all 3 measures
• Nonuniform pattern of subcutaneous lipoatrophy
• Loss from legs gt arms gt lower trunk gt upper trunk
  
• Visceral adipose tissue nonsignificantly lower in
  subjects vs controls
• No linkage between changes in amounts of
  subcutaneous vs visceral fat
• No significant difference in prevalence of
  buffalo hump in subjects vs controls
• Rates of accumulation of visceral fat or buffalo
  hump fat could not be compared in this
  cross-sectional study

13
Same-Clade Superinfection Research and Health
Implications

• Case Report
• Anecdotal case described by Bruce Walker (Mass
  Gen)
• Subject enrolled in primary infection study
• Early initiation of HAART followed by sequential
  STIs
• Detailed longitudinal virologic and immunologic
  evaluations
• Evidence of superinfection
• Subject initially controlled replication
  off-therapy for several months after final STI
• Subject had HIV-1-specific cytotoxic T
  lymphocytes directed at multiple epitopes
• Viral load increased after 1 month
• Genotyping indicated acquisition of a clade B
  virus that appeared genetically distinct from
  original infecting virus
• Patient admitted episode of unprotected sex
• No immunologic control of new virus patient
  declined clinically despite some shared CTL
  epitopes between the initial and probable
  superinfecting HIV-1 variants

Abstract WeOrA197
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Same-Clade Superinfection Research and Health
Implications (2)

• Implications
• Immune responses that were able to control
  initial strain could not prevent acquisition or
  control replication of a closely related second
  strain
• Alarming implications for vaccine research,
  currently focused on generating HIV-specific
  immune responses
• Superinfection with different HIV strains appears
  possible
• Superinfected strain may be more
  pathogenic/drug-resistant
• Reinforces importance of prevention counselling
  of infected patients

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Risk Factors for Progression in Naive Patients
Starting HAART

• Study Outline
• Pooled analysis of data from 12,574 patients in
  13 cohort studies
• Intention-to-treat analysis of subjects starting
  3-drug therapy, 80 with 2 NRTIs plus 1 PI
• Baseline characteristics
• Median age 38 years
• 21 CDC stage 3 disease
• Median CD4 cell count 250 cells/mm3
• Mean plasma HIV-1 RNA 4.9 log10 copies/mL
• Follow-up 24,310 person-years
• 870 patients experienced at least 1 AIDS event
• 344 died
• 1094 either developed AIDS or died

Abstract TuOrB1140 Lancet 2002360119-129.
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Risk Factors for Progression in Naive Patients
Starting HAART (2)

• Results
• Risk of progression/death at 1, 2, or 3 years
  estimated based on baseline CD4 cell count, log
  HIV-1 RNA, age, transmission group, and CDC stage
• Baseline CD4 cell count lt 200 cells/mm3
  associated with highest risk of progression
• Baseline viral load was significant only if gt 5.0
  log10 copies/mL
• Other risk factors age gt 50 years
  injection-drug use CDC stage 3 disease
• Viral load at month 6 of therapy was a
  significant factor at all levels.
• Comments
• Optimal CD4 cell count (gt 200) for therapy
  initiation remains unknown
• Factors such as age, IDU, and high viral load may
  weigh toward early therapy
• Interactive risk calculator available online
• http//www.art-cohort-collaboration.org

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Discontinuing HAART in Prematurely Treated
Patients

• Study Overview
• Views on initiating HAART have recently become
  more conservative many patients now on treatment
  would not have met current criteria for starting
• Should such patients discontinue HAART?
• Johns Hopkins cohort of patients who interrupted
  HAART
• N 101
• 44 prematurely treated 30 toxicity/nonadheren
  ce 8 virologic failure
• HAART resumed if CD4 cell count lt 200 cells/mm3
  or by physician/patient decision

Abstract ThOrB1439
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Discontinuing HAART in Prematurely Treated
Patients (2)

• Predictors of Successful Interruption
• 33/101 patients resumed HAART
• 25 had rising HIV-1 RNA 24 had falling CD4
  cell count 24 had both
• Resumers had lower mean CD4 cell count and less
  viral suppression at time of interruption
• Pre-HAART CD4 cell count (but not viral load)
  was strongest predictor of duration of
  interruption
• 7-fold greater likelihood of resumption if
  pre-HAART CD4 cell count lt 200 cells mm3 (P
  .001), compared with pre-HAART baseline CD4 cell
  count gt 500 cells/mm3
• 4-fold greater likelihood if pre-HAART CD4 cell
  count 200-350 cells/mm3 (P .015)
• Patients who met current guidelines for therapy
  at time of interruption were 3-fold more likely
  to resume therapy than those who did not (P
  .004)

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Update HIV Eradication by HAART Is Impossible

• Updated data from Siliciano (Johns Hopkins)
• One important reservoir HIV-infected resting T
  cells
• Transcriptionally silent, so invisible to immune
  surveillance
• Unaffected by current drugs
• Replenished by cell division, not from viral
  replication
• Half-life is at least 6 months, so decay rate is
  measured in decades
• No decrease in decay rate in optimally treated,
  chronically infected patients with no blips of
  viremia
• Even if this reservoir could be flushed, others
  exist
• However, long-term suppression appears possible
• In patients with long-term suppression, virus
  released into circulation is wild-type
• No resistance even to drugs with low genetic
  barrier in many patients with long-term
  suppression

Abstract MoOr103
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CLASS Study of First-Line Regimens

• Study Outline
• Study of antiretroviral sequencing initial ITT
  analysis of 3 first-line regimens
• Abacavir/lamivudine/efavirenz (ABC/3TC/EFV)
• Abacavir/lamivudine/amprenavir/ritonavir
  (ABC/3TC/APV/RTV)
• Abacavir/lamivudine/stavudine (ABC/3TC/d4T)
• Planned interim analysis at 48 weeks
• Baseline Characteristics
• N 291
• 70 were black or Hispanic
• Mean baseline viral load 4.19 log10 copies/mL
  42 gt 100,000 copies/mL
• 35 had CD4 cell counts lt 200 cells/mm3
• 28 had CDC stage B or C disease

Abstract TuOrB1189
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CLASS Study of First-Line Regimens (2)

• Results
• Suppression to lt 50 copies/mL highest in the
  efavirenz arm
• 76 vs 52 (APV/RTV) and 62 (d4T) P .047
• Efavirenz also superior if baseline viral load gt
  100,000 copies/mL
• 77 lt 50 copies/mL vs 53 and 55
• Similar increases in CD4 cell count
• 26 (9) premature discontinuations only 5 (2)
  due to AEs
• 6 abacavir hypersensitivity
• Comments
• RT mutation pattern in failures with ABC/3TC
  backbone will be instructive
• Importance of regimen convenience cannot be
  underestimated
• Similar comparisons should be undertaken with
  more compact PIs, eg, fosamprenavir or
  atazanavir