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, FACP Dupont Circle Physicians Group, Washington, DC XV International AIDS XV International AIDS Conference Conference
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Supported by an unrestricted educational grant from
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 Presentation
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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
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
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
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
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)
“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
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
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
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
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