supported by an unrestricted educational grant from
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TREATMENT HIGHLIGHTS OF THE. XV International AIDS Conference. July 11-16, 2004, Bangkok, Thailand. Selected and summarized by Douglas J. Ward, MD, FACP Dupont Circle Physicians Group, Washington, DC. Supported by an unrestricted educational grant from. CONTENTS. - PowerPoint PPT PresentationTRANSCRIPT
Supported by an unrestricted educational grant from
July 11-16, 2004, Bangkok, Thailand
TREATMENT HIGHLIGHTS OF THE
Selected and summarized by
Douglas J. Ward, MD, FACPDupont Circle Physicians Group, Washington, DC
XV International AIDS XV International AIDS ConferenceConferenceXV International AIDS XV International AIDS ConferenceConference
CONTENTSCONTENTS
XV International AIDS ConferenceXV International AIDS ConferenceXV International AIDS ConferenceXV International AIDS Conference
New Agents
New Data on Current Drugs
New and Novel Approaches to Therapy
Complications of HIV Infection and Therapy
HIV Prevention
Other Studies
The abstracts of the XV International AIDS Conference are available online in
eJIAS: eJournal of the International AIDS Society
Oral presentation: 445
Late breakers: 40
Poster presentation: 1110
Poster exhibition: 5086
CD-ROM: 2960
8,641 accepted abstracts
A. Basic Science
B. Clinical Care
C. Epidemiology and Prevention
D. Social and Economic Issues
E: Policy and Program Implementation
Theme of the XV International AIDS Conference:
5 Program Tracks
19,843 participants
Conference FactsConference Facts
from 152 countries
Medscape is the official provider of online
conference coverage (HIV science and medicine)
and continuing medical education activities based
on the XV International AIDS Conference.
www.ejias.org www.medscape.com/hiv-aidshome
Tipranavir in Patients With Highly PI-Resistant HIV (BI1182.51)Design
296 patients with highly PI-resistant HIV•>/= 3 protease mutations at codons 33, 82, 84, 90
Patients randomized to receive•tipranavir (TPV)/r + optimized background regimen (OBR)•amprenavir (APV)/r, saquinavir SQV/r, or lopinavir (LPV)/r + OBR
TPV added to other PI regimens after 2 weeks
Results
HIV RNA changes at 2 weeks (log10 copies/mL)
•TPV: -1.15
•Other arms: -0.2 to - 0.4
Decreases in plasma concentrations of PIs with addition of TPV
•Cmin: SQV: 84%, APV: 51%, LPV: 45%
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Walmsley et al, WeOrB1236www.medscape.com
New Agents: TipranavirNew Agents: Tipranavir
NRTIs = nucleoside reverse transcriptase inhibitors
Reverset (d4FC) in Treatment-Experienced Patients1
SPD7542,3
Background•Cytidine analog with potent in vitro activity against wild-type and resistant viruses•Half life: ~17 hours•No mitochondrial activity in vitro •In treatment-naive patients, 10-day monotherapy associated with mean HIV RNA
reductions of >1.5 log10 copies/mL (previously reported)•10-day results were reported for 8 patients on failing regimens
Treatment-experienced patients•D-d4FC 200 mg was added to patients’ current regimen •4 patients had > 3 TAMs•5 patients’ failing regimens included tenofovir, 5 included lamivudine•Mean HIV RNA reduction: 0.8 log10 copies/mL
In vitro activity and PK data•Cytidine analog with good activity against wild-type and resistant viruses•Additive or synergistic with most antivirals, antagonistic with 3TC•No plasma interaction with lamivudine•Intracellular SPD-triphosphate levels reduced 6-fold by lamivudine•No effect on 3TC-triphosphate by SPD
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] 3Holdich et al, TuPeB4625www.medscape.com
2Bethell et al, WePeA5642
1Murphy et al, MoOrB1056
New Agents: NRTIsNew Agents: NRTIs
Abacavir Safety and Efficacy: ZODIAC
Subset of 200 subjects (out of 770) genotyped at baseline• 13 had single mutation• 2 had double mutations• None of 17 virologic failures at week 48 had baseline resistance• 6 K103N and 1 M184V mutations at baseline: none failed
13 patients with non-clade B virus• None with virologic failure
ZODIAC: Safety1
ZODIAC: Baseline Resistance and Efficacy2
Abacavir once-daily vs twice-daily + once-daily EFV and 3TCPreviously reported equivalent efficacySafety analysis:• No difference in adverse events• Abacavir hypersensitivity: 7% twice daily vs 9% once daily (NS)
New Data on Current DrugsNew Data on Current Drugs
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] 2Moyle et al, WePeB5698www.medscape.com
1Hernandez et al, TuPeB4521
Tenofovir (TDF): Renal Toxicity
TDF vs stavudine (d4T) + EFV/3TC No difference between groups in creatinine, phosphorus, proteinuria, glycosuria
Gilead 903 -- 3-Year Data1
Kaiser Permanente2
Mild Renal Dysfunction and TDF3
199 patients on TDF >/= 3 months at 5 medical centers Subtle increase in mean creatinine No increase in proteinuria or hypophosphatemia
Cross-sectional study of patients treated with (n = 74) or without (n = 84) TDF
•Other factors associated with renal dysfunction (diabetes mellitus, hypertension)
excluded
34% vs 21% had decreased glomerular filtration rate (by cystatin C clearance)
36% vs 16% had proteinuria
Renal toxicity of TDF is still ill-defined, but probably does exist
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] 3Mauss et al, WePeB5941www.medscape.com
1Stazweski et al, WePeB5917
2Horberg et al, WePpB2066
New Data on Current DrugsNew Data on Current Drugs
CONTEXT: FosAPV/r vs LPV/r in PI-Experienced Patients
Open label, randomized study of fosAPV/r vs LPV/r Patients had failed 1-2 PI-based regimens fosAPV/r: 700 mg/100 mg twice daily or 1400 mg/200 mg once daily + 2 NRTIs
• Once-daily arm performed less well and not included in analysis• Once-daily dosing not recommended in experienced patients
Viable NRTI backbone based on genotype
Results (48 Weeks)
Fosamprenavir/Ritonavir (fosAPV/r) vs Lopinavir/Ritonavir (LPV/r)
New Data on Current DrugsNew Data on Current Drugs
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Elston et al, MoOrB1055 www.medscape.com
Baseline LPV/r (n = 103) fosAPV/r (n = 107)
Mean HIV RNA (log10 copies/mL) 4.13 4.13
Mean CD4 count (cells/mcL) 234 292
LPV/r fosAPV/r
HIV RNA change (log10
copies/mL)-1.76 -1.49
% < 50 copies/mL 50 46
CONTEXT (Continued)
Virologic failures: LPV/r: 29, fosAPV/r: 28
Response rate (% of patients) by baseline mutation:
In presence of 46 or 90, virologic failure predicted by number of PI mutations or phenotype of randomized PI
Insufficient virologic failures to determine phenotypic clinical cut-off
Resistance Analysis
New Data on Current DrugsNew Data on Current Drugs
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Elston: MoOrB1055 www.medscape.com
PI = protease inhibitor
fosAPV/r LPV/r
D30N 95 94
M46I/L 50 50
L90M 52 61
Lopinavir/Ritonavir Monotherapy: IMANI-1
30 treatment-naive patients enrolled in this open label pilot study•Mean HIV RNA: 262,000 copies/mL (17/30 had VL > 100,000 copies/mL)•Mean CD4+ count: 170 cells/mcL (13/30 had CD4+ counts < 50 cells/mL )•No primary drug resistance
Patients < 70 kg and > 70 kg received 3 and 4 LPV/r capsules twice daily Intensification with SQV or TDF/3TC was allowed at any point
20 of 30 patients completed 48 weeks of LPV/r monotherapy Mean CD4+ cell increase = 317 cells/mcL
• No significant toxicity
• No protease resistance identified
48-Week Results
Baseline Characteristics and Treatment Schedule 1
AT (n = 20) ITT (n = 30)
HIV RNA < 400 copies/mL 20 (100%) 20 (67%)
HIV RNA < 50 copies/mL 18 (90%) 18 (60%)
Reasons for noncompletion included adverse events (2), virologic failure (2), nonadherence (2), and factors unrelated to the study (4)
New and Novel Approaches to Therapy
New and Novel Approaches to Therapy
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] J C Gathe et al, MoOrB1057www.medscape.com
Lopinavir/Ritonavir Monotherapy: The “OK” StudyLopinavir/Ritonavir Monotherapy: The “OK” Study LPV/r Monotherapy Simplification (The “OK” Study)
42 patients on LPV/r + 2 NRTIs; viral load < 50 copies/mL for > 6 months Randomized to continue current regimen or switch to LPV/r monotherapy Preliminary 24-week results:
• All triple-therapy patients < 50 copies/mL
• 3 virologic failures in monotherapy group
• Virologic failures had shortest period undetectable (all < 9 months)
New and Novel Approaches to Therapy
New and Novel Approaches to Therapy
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Arribas et al, TuPeB4486www.medscape.com
Continuous vs Intermittent Therapy (HIV-NAT 0014)
74 Thai patients on SQV/r-based therapy
Randomized to
Results (108 Weeks)
Continuous therapy or“One week on/One week off”CD4-guided therapy: stop therapy until CD4+ cell count < 350 cells/mcL, then resume until > 500• At 96 weeks, resume continuous therapy for 12 weeks
Viral load < 50 copies/mL; CD4+ cell count > 350 cells/mcLSubstantial previous NRTI therapy
New and Novel Approaches to TherapyNew and Novel Approaches to TherapyNew and Novel Approaches to TherapyNew and Novel Approaches to Therapy
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Ananworanich et al, WeOrB1283www.medscape.com
“One week on/One week off” arm prematurely discontinued due to high virologic failure rate (35%)• Differs from other trials of similar regimen - ? because of previous NRTI treatment• All resuppressed to < 50 copies/mL after resumption of same regimen continuously
Continuous vs Intermittent Therapy: HIV-NAT 0014 (Continued)
All patients in CD4-guided group resuppressed to < 50 copies/mL with an additional 12 weeks of therapy
No differences in adverse events, lipodystrophy, quality of life CD4-guided intermittent therapy may be a viable strategy, particularly in
resource-limited areas
Results (108 Weeks)
New and Novel Approaches to TherapyNew and Novel Approaches to Therapy
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Ananworanich et al, WeOrB1283www.medscape.com
CD4-Guided Continuous P Value
CD4 > 350, % 100 96
↓ CD4, cells/mcL 154 4
Viral load < 400, % 91 100
Viral load < 50, % 59 96
Time on treatment, % 54 100
Intermittent Therapy: FOTO Trial
Design and Patients
Results (24 Weeks)
Advantages of FOTO
Median follow-up: 42 weeks (range, 8-48)Patients with HIV RNA < 400 copies/mL: 24
•17/17 on NNRTI-based regimens (10 EFV, 7 NVP)•7/9 on PI-based regimens
Patients with virologic failure (> 400 copies/ML): 2•Both on LPV/r-based regimens
Patients reported strong preference for intermittent therapy28% reduction in medication use
“Five Days On, Two Days Off” therapy design parallels work week26 patients on various PI- or NNRTI-based regimens
•CD4+ cell count > 200 cells/mcL•HIV RNA < 75 copies/mL for 3 months
New and Novel Approaches to TherapyNew and Novel Approaches to Therapy
Cohen et al, TuPeB4575MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]www.medscape.com
Induction/Maintenance Therapy: ESS40013
If viral load < 50 copies/mL at weeks 36 and 48, randomized to continue all 4 drugs or discontinue EFV• Only 63% of patients were eligible for randomization
448 treatment-naive patients initially treated with AZT/3TC/ABC + EFV
96-week (end of maintenance phase) results
Maintenance with AZT/3TC/ABC may be better tolerated and less toxic than continued 4-drug therapy, but may be at the expense of potency.
New and Novel Approaches to TherapyNew and Novel Approaches to Therapy
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Markowitz et al, LbOrB14www.medscape.com
AZT/3TC/ABC AZT/3TC/ABC+ EFV
Viral load < 50, % 77 79*
Virologic failures, n 16 8*
Pts with mutations, n 8 16
Perfect adherence, % 89 80
Δ cholesterol @ wk 48, mg/dL -22 +3
Drug-related AEs, % 6 15
3TC Monotherapy After Treatment Interruption
The M184V mutation associated with 3TC resistance causes a decreased viral fitness and may be beneficial to maintain after treatment interruption
Concept
50 patients
Preliminary Results (24 Weeks)
Lower replication capacity in 3TC groupSlower reversion to wild-type virus in 3TC group
Failing therapy (viral load > 1000 copies/mL) with known M184V mutation CD4+ cell count > 500 cells/mcL Randomized to stop all medication or to continue 3TC monotherapy (300 mg/day)
to maintain M184V
New and Novel Approaches to TherapyNew and Novel Approaches to Therapy
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Castagna et al, WeOrB1286www.medscape.com
3TC No 3TC
CD4 < 350 cells/mcL 7/25 13/25
↑ VL, log10 copies/mL 0.6 1.2
↓ CD4, cells/mcL 73 153
Improved CD4 Counts with Prednisolone Uncontrolled observational trial of prednisolone 5 mg/day 56 treatment-naive patients
• 0.5-11.5 years prednisolone treatment
• CD4+ >/= 300 cells/mcL (mean, 565 cells/mcL)
Compared with 135 untreated patients in same clinic • Mean CD4+, 612 cells/mcL
Results
86 patients with prednisolone during STI vs 41 withoutCD4+ decrease of 0.47 cell/mcL per day with prednisolone vs 0.77 withoutNonsignificant trend toward lower viral load with prednisoloneMechanism of benefit not investigated
•Related to decreased immune activation
CD4+ increased 44.4 cells/mcL per year in first 6 years•Compared with 49.7 cells/mcL decrease in untreated patients
•Significant decrease in number on therapy over time
Prednisolone During STI
New and Novel Approaches to TherapyNew and Novel Approaches to Therapy
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Ulmer et al,TuPeB4582www.medscape.com
Cardiovascular Risk of HAART
3-year prospective analysis of cardiovascular risk in patients on PI-, NVP-, or EFV-based HAART
Evaluated carotid intima-media thickness (CIMT) by ultrasound, coronary artery calcium (CAC) by CT, and brachial artery reactivity (BAR)• Complete lipid profile, C-reactive protein, homocysteine; social and
HIV factors also evaluated
• PI group had more advanced HIV disease
No difference at baseline in CIMT or BAR• Significant increase in baseline CAC in PI group (controlled for other risk factors for coronary
artery disease)
No difference between groups in preliminary 1-year follow-up• Significant increase in all groups in CIMT, compared with expected increase in general
population
Study Summary
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Pierone et al, ThOrB1365www.medscape.com
Complications of HIV Infection and TherapyComplications of HIV Infection and Therapy
NRTI Substitution With Tenofovir (TDF) for Toxicity
902 patients switched to TDF; 771 with 24-week follow-up
Patients switched from:• 68% stavudine
• 13% didanosine
• 12% zidovudine
Lipoatrophy improved in 16% (no change in 84%)
Neuropathy resolved in 29%, improved in additional 33%
Improvement also seen in anemia, liver function elevations, and hypertriglyceridemia
No data provided on antiviral efficacy
Prospective Study of Causes of NRTI Drug Switch
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]Miralles Alvarez et al,
WePeB5880www.medscape.com
Complications of HIV Infection and TherapyComplications of HIV Infection and Therapy
Miscellaneous Complications
Survey of the French Hospital Database on HIV 122 cases of osteonecrosis among > 56,000 patients Only associated factor in multivariate analysis was time on antiretroviral
therapy
Emtricitabine (FTC) hyperpigmentation (Mondou et al, WePeB5916)
Pregnancy complications (Suy et al, ThOrB1359):
Gynecomastia (Biglia et al, ThOrB1357):
Osteonecrosis (Mary-Krause et al, ThOrB1358):
2% to 4% in clinical trials Most commonly on palms/soles; also nails, tongue
True gynecomastia in 1.8% of 2275 males in Barcelona, Spain, database•Slightly more than expected in population
In multivariate analysis associated with:•Lipoatrophy, hepatitis C, low free testosterone•Zidovudine, stavudine, or efavirenz use (but not time on therapy)
472 pregnancies evaluated 1985-2003• Dramatic increase in preeclampsia (0.4% to 6.4%) and fetal death (0% to 4.2%) in
2001-2003 period• Only associated HIV factor was time on antiretroviral therapy• However, no mother-to-child transmission during this period
Complications of HIV Infection and TherapyComplications of HIV Infection and Therapy
Prevention of Mother-to-Child HIV Transmission (MTCT) sdNVP at delivery has been shown to reduce MTCT, but frequently results in
NVP resistance in mothers In this trial from South Africa, mothers and infants were randomized to:
• sdNVP or• sdNVP plus Combivir (zidovudine/lamivudine) for 4 days (CBV4) or
• sdNVP plus Combivir for 7 days (CBV7)
Single-Dose Nevirapine (sdNVP) “Plus”
Preliminary Results (First 61 Patients)
Various NNRTI mutations; no NRTI mutations seen4/68 (6%) of infants infectedAddition of Combivir to sdNVP reduces the development of resistance, but optimal duration of therapy remains uncertain
HIV Prevention: MTCTHIV Prevention: MTCT
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] McIntyre et al, LbOrB09www.medscape.com
sdNVP CBV4 CBV7
% NPV resistance 50 5 13
Median HIV RNA: 32,600 copies/mLMedian CD4+ cell count: 318 cells/mcL
Prevalence and Predictive Factors of Coreceptor Tropism
Phenosense assay for tropism in 861 patient• 265 assay failures
80% CCR5 (R5); 20% CXCR4 (X4) or dual tropic• Viral load significantly higher in X4/dual tropic
• CD4+ cell count lower in X4/dual tropic
R5 predicted by viral load < 5000 copies/mL and CD4+ cell count
> 300 cells/mcL (89%) X4 poorly predicted by viral load > 100,000 copies/mL and CD4+ cell
count < 50 cells/mcL (55%)
Coreceptor tropism is associated with disease progression and will be an important consideration in use of coreceptor antagonists
Other StudiesOther Studies
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Moyle et al, WePeB5725www.medscape.com