Transcript 11th CROI: Antiretroviral Therapy Highlights

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
XV 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
Conference Facts
Theme of the XV International AIDS Conference:
19,843 participants
from 152 countries
8,641 accepted abstracts
5 Program Tracks
Oral presentation: 445
Late breakers: 40
Poster presentation: 1110
Poster exhibition: 5086
CD-ROM: 2960
The abstracts of the XV International AIDS
Conference are available online in
eJIAS: eJournal of the
International AIDS Society
www.ejias.org
A. Basic Science
B. Clinical Care
C. Epidemiology and Prevention
D. Social and Economic Issues
E: Policy and Program Implementation
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.medscape.com/hiv-aidshome
New Agents: Tipranavir
Tipranavir in Patients With Highly PI-Resistant HIV (BI1182.51)
Design

296 patients with highly PI-resistant HIV
•

Patients randomized to receive
•
•

>/= 3 protease mutations at codons 33, 82, 84, 90
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%
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Walmsley et al, WeOrB1236
New Agents: NRTIs
Reverset (d4FC) in Treatment-Experienced Patients1
 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
SPD7542,3

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
NRTIs = nucleoside reverse transcriptase inhibitors
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
1Murphy
et al, MoOrB1056
2Bethell
et al, WePeA5642
3Holdich
et al, TuPeB4625
New Data on Current Drugs
Abacavir Safety and Efficacy: ZODIAC
ZODIAC: Safety1



Abacavir once-daily vs twice-daily + once-daily EFV and 3TC
Previously reported equivalent efficacy
Safety analysis:
•
•
No difference in adverse events
Abacavir hypersensitivity: 7% twice daily vs 9% once daily (NS)
ZODIAC: Baseline Resistance and Efficacy2

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
1Hernandez
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
2Moyle
et al, TuPeB4521
et al, WePeB5698
New Data on Current Drugs
Tenofovir (TDF): Renal Toxicity
Gilead 903 -- 3-Year Data1


TDF vs stavudine (d4T) + EFV/3TC
No difference between groups in creatinine, phosphorus, proteinuria, glycosuria
Kaiser Permanente2



199 patients on TDF >/= 3 months at 5 medical centers
Subtle increase in mean creatinine
No increase in proteinuria or hypophosphatemia
Mild Renal Dysfunction and TDF3

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
1Stazweski
2Horberg
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
3Mauss
et al, WePeB5917
et al, WePpB2066
et al, WePeB5941
New Data on Current Drugs
CONTEXT: FosAPV/r vs LPV/r in PI-Experienced Patients
Fosamprenavir/Ritonavir (fosAPV/r) vs Lopinavir/Ritonavir (LPV/r)



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
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
Results (48 Weeks)
HIV RNA change (log10
copies/mL)
% < 50 copies/mL
www.medscape.com
LPV/r
fosAPV/r
-1.76
-1.49
50
46
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Elston et al, MoOrB1055
New Data on Current Drugs
CONTEXT (Continued)
Resistance Analysis

Virologic failures: LPV/r: 29, fosAPV/r: 28
Response rate (% of patients) by baseline mutation:


fosAPV/r
LPV/r
D30N
95
94
M46I/L
50
50
L90M
52
61
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
PI = protease inhibitor
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Elston: MoOrB1055
New and Novel Approaches to Therapy
Lopinavir/Ritonavir Monotherapy: IMANI-1
Baseline Characteristics and Treatment Schedule 1

30 treatment-naive patients enrolled in this open label pilot study
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•
•


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
48-Week Results
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
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
AT (n = 20)
ITT (n = 30)
HIV RNA < 400 copies/mL
20 (100%)
20 (67%)
HIV RNA < 50 copies/mL
18 (90%)
18 (60%)
www.medscape.com
Reasons for noncompletion included
adverse events (2), virologic failure (2),
nonadherence (2), and factors unrelated
to the study (4)
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
J C Gathe et al, MoOrB1057
New and Novel Approaches to Therapy
Lopinavir/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)
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Arribas et al, TuPeB4486
New and Novel Approaches to Therapy
Continuous vs Intermittent Therapy (HIV-NAT 0014)
74 Thai patients on SQV/r-based therapy
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
Viral load < 50 copies/mL; CD4+ cell count > 350 cells/mcL
Substantial previous NRTI therapy
Randomized to



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
Results (108 Weeks)

“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
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Ananworanich et al, WeOrB1283
New and Novel Approaches to Therapy
Continuous vs Intermittent Therapy: HIV-NAT 0014 (Continued)
Results (108 Weeks)
CD4 > 350, %
↓ CD4, cells/mcL
Viral load < 400, %
Viral load < 50, %
Time on treatment, %



CD4-Guided
100
154
91
59
Continuous
96
4
100
96
54
100
P Value
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
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Ananworanich et al, WeOrB1283
New and Novel Approaches to Therapy
Intermittent Therapy: FOTO Trial
Design and Patients
 “Five Days On, Two Days Off” therapy design parallels work week
 26 patients on various PI- or NNRTI-based regimens
• CD4+ cell count > 200 cells/mcL
• HIV RNA < 75 copies/mL for 3 months
Results (24 Weeks)
 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
Advantages of FOTO
 Patients reported strong preference for intermittent therapy
 28% reduction in medication use
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Cohen et al, TuPeB4575
New and Novel Approaches to Therapy
Induction/Maintenance Therapy: ESS40013
448 treatment-naive patients initially treated with AZT/3TC/ABC + EFV

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
96-week (end of maintenance phase) results
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
6
15
Drug-related AEs, %
 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.
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Markowitz et al, LbOrB14
New and Novel Approaches to Therapy
3TC Monotherapy After Treatment Interruption
Concept

The M184V mutation associated with 3TC resistance causes a decreased viral
fitness and may be beneficial to maintain after treatment interruption
50 patients



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
Preliminary Results (24 Weeks)


3TC
No 3TC
CD4 < 350 cells/mcL
7/25
13/25
↑ VL, log10 copies/mL
0.6
1.2
↓ CD4, cells/mcL
73
153
Lower replication capacity in 3TC group
Slower reversion to wild-type virus in 3TC group
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Castagna et al, WeOrB1286
New and Novel Approaches to Therapy
Improved CD4 Counts with Prednisolone

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Uncontrolled observational trial of prednisolone 5 mg/day
56 treatment-naive patients
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•
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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
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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



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86 patients with prednisolone during STI vs 41 without
CD4+ decrease of 0.47 cell/mcL per day with prednisolone vs 0.77 without
Nonsignificant trend toward lower viral load with prednisolone
Mechanism of benefit not investigated
•
Related to decreased immune activation
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Ulmer et al,TuPeB4582
Complications of HIV Infection and Therapy
Cardiovascular Risk of HAART
Study Summary

3-year prospective analysis of cardiovascular risk in patients on PI-, NVP-, or EFVbased HAART

Evaluated carotid intima-media thickness (CIMT) by ultrasound, coronary artery
calcium (CAC) by CT, and brachial artery reactivity (BAR)
•
•

No difference at baseline in CIMT or BAR
•
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Complete lipid profile, C-reactive protein, homocysteine; social and
HIV factors also evaluated
PI group had more advanced HIV disease
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
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Pierone et al, ThOrB1365
Complications of HIV Infection and Therapy
NRTI Substitution With Tenofovir (TDF) for Toxicity
Prospective Study of Causes of NRTI Drug Switch

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
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Miralles Alvarez et al,
WePeB5880
Complications of HIV Infection and Therapy
Miscellaneous Complications
Osteonecrosis (Mary-Krause et al, ThOrB1358):



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
Gynecomastia (Biglia et al, ThOrB1357):

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)
Pregnancy complications (Suy et al, ThOrB1359):

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
Emtricitabine (FTC) hyperpigmentation (Mondou et al, WePeB5916)


2% to 4% in clinical trials
Most commonly on palms/soles; also nails, tongue
HIV Prevention: MTCT
Prevention of Mother-to-Child HIV Transmission (MTCT)
Single-Dose Nevirapine (sdNVP) “Plus”


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)
Preliminary Results (First 61 Patients)


Median HIV RNA: 32,600 copies/mL
Median CD4+ cell count: 318 cells/mcL
% NPV resistance



sdNVP
CBV4
CBV7
50
5
13
Various NNRTI mutations; no NRTI mutations seen
4/68 (6%) of infants infected
Addition of Combivir to sdNVP reduces the development of
resistance, but optimal duration of therapy remains uncertain
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
McIntyre et al, LbOrB09
Other Studies
Prevalence and Predictive Factors of Coreceptor Tropism
Coreceptor tropism is associated with disease progression
and will be an important consideration in use of coreceptor antagonists

Phenosense assay for tropism in 861 patient
•

80% CCR5 (R5); 20% CXCR4 (X4) or dual tropic
•
•

265 assay failures
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%)
www.medscape.com
MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]
Moyle et al, WePeB5725