Highlights of the XIV International AIDS Conference July 7-12, 2002; Barcelona, Spain Selected and summarized by Joseph J. Eron, Jr, MD Associate Professor of Medicine University of North Carolina at Chapel Hill Supported by an unrestricted educational grant from
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Highlights of the XIV International AIDS Conference July 7-12, 2002; Barcelona, Spain
Highlights of the XIV International AIDS Conference July 7-12, 2002; Barcelona, Spain. Selected and summarized by Joseph J. Eron, Jr, MD Associate Professor of Medicine University of North Carolina at Chapel Hill. Supported by an unrestricted educational grant from. - PowerPoint PPT Presentation
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Highlights of the
XIV International AIDS ConferenceJuly 7-12, 2002; Barcelona, Spain
Selected and summarized by
Joseph J. Eron, Jr, MDAssociate Professor of Medicine
University of North Carolina at Chapel Hill
Supported by an unrestricted educational grant from
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 >100,000 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
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)
T-20 + Optimized Regimen Optimized Regimen P value
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
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
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 > 10-fold that of the non-PI group, and
> 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
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
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 > arms > lower trunk > 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
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
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
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 2002;360:119-129.
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 < 200 cells/mm3 associated with highest risk of progression
• Baseline viral load was significant only if > 5.0 log10 copies/mL
• Other risk factors: age > 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 (> 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
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
– HAART resumed if CD4+ cell count < 200 cells/mm3 or by physician/patient decision
Abstract: ThOrB1439
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 < 200 cells