Transcript No Slide Title

The 2nd International AIDS Society Conference
on HIV Pathogenesis and Treatment
July 13-16, 2003; Paris, France
Selected and summarized by
Douglas J. Ward, MD
Dupont Circle Physicians Group
Washington, DC
Supported by an unrestricted educational grant from
Highlights of 2nd IAS Conference on HIV Pathogenesis and
Treatment
New Data On:
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Salvage therapy
Approaches to initial/early therapy
Complications of antiretroviral therapy
Preventing mother-to-child HIV transmission
HIV drug resistance
New and investigational drugs
Salvage Therapy (1)
Enfuvirtide (ENF) – 48-Week Data
48-week data were presented from the TORO 1 and TORO 2 studies,
which enrolled heavily treatment-experienced patients:
• median 12 previous antiretrovirals including all 3 available classes
• median baseline viral load 5.1 log10 copies/mL and CD4+ cell count 92
cells/mcL
Patients were randomized to receive:
• an optimized background antiretroviral regimen (OB) of 3-5 agents
based on genotypic and phenotypic resistance tests (total n = 334), or
• OB plus ENF 90 mg twice daily by subcutaneous injection (total n =
661)
24-week data previously presented
Abstract LB2.
Salvage Therapy (1) Continued
Enfuvirtide (ENF) – 48-Week Data
The results show that ENF (versus OB only) can be administered safely,
durably and with sustained virologic effects in heavily pretreated patients:
• % patients achieving < 400 copies/mL at 48 weeks: 30.4 vs 12 (P < .0001)
• Median time (weeks) to virologic failure: 32 vs 11 (P < .0001)
• Local injection-site reactions were observed in > 90% of ENF patients
– Cause of discontinuation in 4.4%
• Increased incidence of bacterial pneumonia observed in the ENF arm (6.6 vs
0.6 events per 100 person-years)
– Relationship to ENF unexplained
Abstract LB2.
Salvage Therapy (2)
Enfuvirtide (ENF) – Predictors of Response in TORO 1 & 2 Trials
A separate multiple logistic regression analysis of 24-week data.
Four characteristics were identified that positively influenced response to ENF:
• viral load < 100,000 copies/mL at baseline
• CD4+ cell count > 100 cells/mcL at baseline
• prior experience with < 10 antiretrovirals
• > 2 active agents in the OB
In the presence of all 4 factors, patients had an 80% chance of achieving viral
suppression to < 50 copies/mL.
Abstract 116.
Salvage Therapy (3)
Factors Contributing to HAART Success – PLATO Collaboration
• 2488 patients from 13 HIV cohorts with viral load > 1000 copies/mL for > 4
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months
All had received NRTIs, NNRTIs, and PIs, sequentially or in combination
Baseline: CDC/C, 52%; median CD4+ cell count, 199 cells/mcL; median
viral load (VL), 4.5 log10 copies/mL; median duration ART/ HAART 4.7/2.5
years, respectively
At 2 years, 17% (95% CI: 15-19) had experienced virologic success (viral
load < 500 copies/mL, and remaining < 1000 for > 6 months)
Independent predictors (Cox regression) of success: more recent calendar
year (related to new agents and physician experience), adding 1-2 new
drugs
Negative predictors: being off therapy, time off PIs with VL > 1000
Abstract 576.
Salvage Therapy (3) Continued
Factors Contributing to HAART Success
Independent predictors of virologic success
Calendar year (reference: 1996/1997)
1998
1999
2000+
Being off treatment
Hazard ratio (95% CI)
1.7 (1.1-2.7)
2.6 (1.6-4.1)
6.8 (4.0-11.4)
0.09 (0.03-0.25)
Adding 1 new PI
3.0 (2.3-3.9)
Adding 2 new PIs simultaneously
4.1 (3.1-5.4)
Adding 1 new NRTI
1.4 (1.1-1.8)
Adding 2 new NRTIs
2.4 (1.5-4.0)
Adding a new NNRTI
1.5 (1.2-2.0)
Baseline viral load (per log10 higher)
0.69 (0.59-0.81)
Ever achieved viral load < 500 until baseline
1.5 (1.2-2.0)
Time on PIs with viral load > 1000 (per year)
0.49 (0.37-0.66)
Abstract 576.
Salvage Therapy (4)
Multi-PI Regimens in Heavily Treatment-Experienced Patients – ATV/r vs
ATV+SQV vs LPV/r (BMS 045)
A randomized, open-label trial comparing:
• once-daily atazanavir (ATV) + ritonavir (r)
• once-daily ATV + saquinavir (SQV)
• twice-daily lopinavir (LPV) + r
Enrolled patients had at least 2 regimen failures, which included drugs from all
3 antiretroviral classes.
Abstract 118.
Salvage Therapy (4) Continued
24-week response to double PIs
ATZ/r
ATV + SQV
LPV/r + SQV
n
120
115
123
Mean drop in viral load
(log10 copies/mL)
1.86
1.52
1.89
< 400 copies/mL (%)
64
44
62
< 50 copies/mL (%)
39
23
42
CD4+ gain (cells/mcL)
83
59
90
ATZ = atazanavir, LPV = lopinavir, r = 100 mg of ritonavir, SQV = saquinavir.
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Virologic efficacy was comparable in all arms. Both ATV groups had
significantly better cholesterol and triglyceride levels after 24 weeks than the
group taking LPV/r.
Saquinavir dose in ATV/SQV is likely insufficient.
Abstract 118.
Approaches to Initial/Early Therapy (1)
Triple-NRTI Regimens: ACTG 5095
A randomized, double-blind-label trial enrolling 1147 ART-naive patients:
• Mean baseline viral load: 4.85 log10 copies/mL; mean baseline CD4+ cell
count: 238 cells/mcL
• Patients randomized to Combivir + efavirenz (EFV), Trizivir + EFV, or
Trizivir
• Data Safety Monitoring Board stopped Trizivir (alone) arm after 32 weeks
due to virologic failure rates
Abstract 41.
Approaches to Initial/Early Therapy (1) Continued
Virologic Failure Rates in ACTG 5095
Regimen
Virologic Failure*, n (%)
EFV arms (combined unblinded data)
85 (11)
Trizivir arm
82 (21)†
*Virologic failure defined as confirmed viral load > 200 copies/mL after 16 weeks of
treatment.
†P
< .001
• Higher failure rate seen in patients with viral load both < and > 100,000
copies/mL
Abstract 41.
Approaches to Initial/Early Therapy (2)
Triple-NRTI Regimens: 3TC + ABC + TDF Once Daily
• Pilot study of lamivudine (3TC) + abacavir (ABC) + tenofovir (TDF), all given
once daily (dosing ABC once daily remains investigational)
• 19 ART-naive patients. Mean baseline CD4+ cell count and viral load were
273 cells/mcL and 82,381 copies/mL, respectively
• 14 of 19 (73.7%) patients experienced virologic failure; 9 of 14 (64.3%) had
significant resistance mutations, including 4 with both M184V and K65R
Abstract 43.
Approaches to Initial/Early Therapy (3)
Induction-Maintenance Strategy
• 448 ART-naive patients; median baseline CD4+ cell count and viral load were 210
cells/mcL and 5.08 log10 copies/mL, respectively
• All patients received induction therapy with Trizivir + efavirenz (EFV) for 48 weeks
• 166 (37%) of patients discontinued, more than half due to adverse events associated
with quadruple therapy
• Viral suppression to < 50 copies/mL was achieved in 90% of patients who remained
on therapy at 48 weeks
• The 282 patients were randomized 1:1 to continue original regimen or switch to
simplified maintenance therapy with Trizivir alone
The investigators will study whether this approach to NRTI-only, “step-down” therapy is
practicable.
Abstract 42.
Approaches to Initial/Early Therapy (4)
Treatment Simplification
• Prospective, open-label study of 355 NNRTI-naive patients with sustained
virologic suppression (< 400 copies/mL) on a PI-based regimen
• Patients were randomized to continue (C) on their current treatment
(usually including either nelfinavir or indinavir) or change to once-daily (OD)
efavirenz/didanosine/emtricitabine (FTC), taken as 5 tablets in 1 nighttime
administration
• Over 1 year, 36 patients discontinued therapy, equally distributed between
the OD and C groups
• Of the remaining patients, 93% in the OD arm and 95% in the C arm
maintained virologic suppression
• 45% of OD patients experienced HDL increases > 57.7 mg/dL (1.5 mM),
compared with 18% of patients receiving PI-based therapy
Abstract 37.
Approaches to Initial/Early Therapy (5)
Alternating Therapy (SWATCH Study)
The SWATCH study was designed to evaluate whether the development of
resistance can be delayed by proactively switching ARV regimens.
• 161 patients were randomized to receive stavudine (d4T) + didanosine (ddI)
+ efavirenz (EFV) or zidovudine (ZDV) + lamivudine (3TV) + nelfinavir
(NFV), or were assigned to alternate between the 2 regimens every 3
months (regimens A, B and C, respectively)
• Baseline CD4+ cell counts and plasma viral loads were comparable in all
arms
• Data from A and B arms pooled for analysis vs arm C
Abstract LB5.
Approaches to Initial/Early Therapy (5) Continued
Alternating Therapy (SWATCH Study)
• At 48 weeks, there was no difference between arms in CD4+ cell count
increases, adverse events, or adherence
• There was a significantly lower rate of virologic failure and development of
resistance-associated mutations among patients receiving regimen C
compared with patients receiving regimens A or B:
– Rate of virologic failure (HIV RNA > 400 copies/mL) was 1.2 vs 4.8 events/1000
person-weeks (P = .01)
– Of 15 cases of virologic breakthrough in the pooled A and B treatment arms, 12
(79%) exhibited evidence of drug resistance
– No (0%) cases of virologic breakthrough in the C treatment arm showed any
evidence of drug resistance
Abstract LB5.
Complications of ARV Therapy (1)
Incidence/Risk Factors for Severe Adverse Events (SAEs) on PIs
• Multicenter cohort of 1155 patients started on PIs between May 1997 and
June 1998; median follow-up 23 months (2037 patient-years)
• Grade 3-4 events (except lipodystrophy) prospectively reported; validated by
2 experts
• 550 SAEs reported; 235 and 169 related to ART and PI, respectively
• 20% occurred in first 1 month of therapy; 51% in first 4 months
Abstract 56.
Complications of ARV Therapy (1) Continued
Risk Factors for SAEs on PIs
Factor resulting in risk for SAE
Hazard ratio* (95% CI)
P value
Creatine clearance < 70 mL/min
2.11 (1.21-3.67)
.007
Increased ASAT (per 100 UI/L)
1.6 (1.31-1.96)
.0001
Hepatitis B and/or C coinfection
2.56 (1.76-3.72)
.0001
HIV RNA > 100,000 copies/mL
1.54 (1.06-2.25)
.03
Indinavir initiation at baseline
1.69 (1.16-2.44)
.008
*Multivariate proportional hazard model
Abstract 56.
Complications of ARV Therapy (2)
Baseline Predictors of Change in Body Fat at 48 Weeks After Switching
d4T ABC or AZT (TARHEEL Study)
• Patients with viral load < 400; stavudine (d4T)-containing ART for > 6 months; with
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lipoatrophy, hyperlactatemia, or both
d4T switched to abacavir (ABC) (n = 86) or zidovudine (ZDV) (n = 32); DEXA/CT
assessed  in body fat
Changes in Body Fat Distribution (results by DEXA)
Body area
Body Fat , g (%)
Arms
239 (35.3%)
Legs
269 (12%)
Trunk
859 (16.4%)
In multivariate logistic regression analysis:
• Decrease in visceral abdominal fat (CT) associated with baseline lactate, visceral fat
• Increase in subcutaneous abdominal fat (CT) associated with baseline BMI
Abstract 51.
Adverse Events of ARV Therapy (3)
Rosiglitazone for Patients With Hyperinsulinemia and Lipoatrophy
• Patients with lipoatrophy and hyperinsulinemia
• First 3 months: patients randomized to rosiglitazone 4 mg/d or placebo
• Next 3 months (open-label): all patients received rosiglitazone 8 mg/d
• Insulin markers primary study end point
Abstract 50.
Adverse Events of ARV Therapy (3) Continued
Changes in Markers of Hyperinsulinemia and Lipoatrophy
Measure
Rosiglitazone, 4 mg
Placebo
Change in glucose utilization, mg glucose/kg LBM
per minute
+1.7
-0.4*
Change in total cholesterol, mg/dL
+25
-16
Change in subcutaneous adipose tissue (SAT), %
+15
<1
*P < .02
• Significant self-reported improvement in lipoatrophy, even during blinded
phase of trial
• During open-label period, insulin sensitivity among rosiglitazone-treated
patients continued to show improvement (P = .01), as did SAT
Abstract 50.
Preventing Mother-to-Child HIV Transmission
The SIMBA (Stopping Infection from Mother-to-child via Breastfeeding in
Africa) Trial
• HIV-infected pregnant women received zidovudine (ZDV) +didanosine (ddI)
from the 36th week of gestation until 1 week after delivery
• 397 infants were randomized to receive once-daily lamivudine (3TC) or
nevirapine (NVP) until 1 month after breastfeeding was stopped; breast milk
was the only source of nutrition to the infant
• Overall, there were 30 cases of HIV infection (7.6% transmission); 24 cases
resulted from intrauterine transmission; 3 cases were probably due to
transmission during delivery
• Of the remaining 370 infants at risk of becoming infected, only 3 (0.8%)
became HIV-positive
• Both 3TC and NVP were equally effective
• No significant drug-related toxicity was observed
Abstract LB7.
HIV Drug Resistance
Primary Drug Resistance – The CATCH Study
• The CATCH study evaluated the rate of primary drug resistance in a number of
European countries and Israel
• Isolates from over 1600 patients were genotyped
• Overall rate of genotypic resistance was 9.6%
• NRTIs had the highest rate (6.7%), followed by NNRTIs (2.6%) and PIs (2.2%)
• 1.7% of isolates demonstrated multiclass resistance
• The most common mutations are significant in conferring reduced susceptibility to
agents such as:
– Zidovudine and stavudine (M41V, T215F/Y)
– NNRTIs (K103N)
– PIs (M46I, G48V, I84V)
• A higher rate of primary resistance was observed in subtype B vs non-B isolates
(11.3% vs 3.3%, P < .001)
Abstract LB1.
Data on Selected New and Investigational Agents
Agent/Stage of
Development
Drug
Class
Abstract
No.
Comment
SPD754 (Phase
I/II)
NRTI
LB15
All of 4 doses (400-1600 mg) were well tolerated,
and produced mean reductions in viral load of up to
1.65 log. Has potent activity against isolates with
most of the common NRTI resistance mutations
except for Q151M.
GW433908 (908),
Phase 3
PI
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48-week studies: 908/RTV (1400 mg/200 mg QD +
NRTIs, n = 322): No APV-associated mutations
detected. PI & 3TC resistance significantly  in
908/RTV arm compared with NFV arm.
Atazanavir
(Reyataz), FDA
licensed
PI
LB13
Metabolic substudy of the pivotal BMS-043 trial
demonstrated no significant differences in body fat
distribution vs efavirenz.
Data on Selected New and Investigational Agents
(continued)
Agent/Stage of
Development
Drug
Class
Abstract
No.
Comment
Atazanavir
(Reyataz), FDA
licensed
PI
543
48-week results of patients who had switched from a BID
PI-based regimen to a QD regimen of ATV/3TC/d4T XR. 22
subjects were well suppressed prior to switching. 18
patients completed 1 year of QD therapy. Virologic
suppression was maintained, mean CD4+ cell counts
increased by 86 cells/mcL and lipid profiles improved. No
acceleration in decay of cells harboring proviral DNA was
observed, however.
Tipranavir ,
Phase 3
PI
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This study calculated the inhibitory quotients (IQs) of the
TPV/r combination in patients with previous experience with
all 3 ARV classes. Patients with IQ of > 50 had reduced
virologic response. 67% of patients reached IQ> 50.
TMC114,
Phase 2
PI
LB16
50 patients on a failing PI regimen substituted TMC114 at 1
of 3 doses along with low-dose (100 mg) ritonavir. After 14
days, the median reduction in viral load was 1.13-1.5 log.
Gastrointestinal upset was the most common side effect. A
small number of patients had AST elevations.