Title: Highlights of the XIV International AIDS Conference July 7-12, 2002; Barcelona, Spain
1Highlights 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
2T-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
3T-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
4Tenofovir 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
5Tenofovir 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?
6ACTG 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
7ACTG 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
8ACTG 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
9PIs 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
10PIs 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
11FRAM 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
12FRAM 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
13Same-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
14Same-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
15Risk 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.
16Risk 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
17Discontinuing 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
18Discontinuing 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)
19Update 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
20CLASS 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
21CLASS 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