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