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 >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

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

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 > 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

5. Tenofovir DF in Treatment-Naive Subjects Results at Week 48 • Equivalent virologic and immunologic outcomes: • HIV-1 RNA < 50 copies/mL in 81% to 82% of both arms (ITT, M=F) • 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?

6. 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 Abstracts: LbOr20A/B

7. 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

8. 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

10. 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

11. 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

12. 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

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

14. 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

15. 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; Lancet2002;360:119-129.

16. 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

17. 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/nonadherence; 8% virologic failure • HAART resumed if CD4+ cell count < 200 cells/mm3 or by physician/patient decision Abstract: ThOrB1439

18. 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 mm3 (P = .001), compared with pre-HAART baseline CD4+ cell count > 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)

19. 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

20. 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% > 100,000 copies/mL • 35% had CD4+ cell counts < 200 cells/mm3 • 28% had CDC stage B or C disease Abstract: TuOrB1189

21. CLASS Study of First-Line Regimens (2) Results • Suppression to < 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 > 100,000 copies/mL • 77% < 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