Suchergebnisse

BackgroundHere we report 96‐ and 144‐week follow‐up data from VERxVE, which demonstrated that NVP XR (400 mg QD) was non‐inferior to NVP IR (200 mg BID), each on a backbone of emtricitabine/tenofovir at 48 weeks.MethodsVERxVE was a double‐blind, double‐dummy, non‐inferiority study in adults with screening viral‐load (VL) >1000 copies/mL and CD4+ cell count <400 cells/mm3 (males) and <250 cells/mm3 (females). Randomization was stratified by baseline VL (copies/mL), ≤100,000 or >100,000. Primary endpoint was confirmed virologic response (<50 copies/mL) at Week 48. Cochran's statistic incorporating baseline‐VL strata tested non‐inferiority of XR efficacy to IR. Secondary endpoints included 144‐week sustained virologic response and safety.Results1011 patients were randomized and treated; 736 (NVP XR: 378, NVP IR: 358) completed 144 weeks. Virologic response was 63.6% for NVP XR and 58.5% for NVP IR (adjusted difference of 4.8% [95% CI: −1.1%, 10.8%] favoring NVP XR). No significant differences were seen in changes in CD4+ T cell counts from baseline, virologic failures, and total discontinuation rates between treatment arms regardless of demographic or baseline characteristics.













48 Weeks
96 Weeks
144 Weeks



NVP IR 200 mg BID
NVP XR 400 mg QD
NVP IR 200 mg BID
NVP XR 400 mg QD
NVP IR 200 mg BID
NVP XR 400 mg QD




% Virologic response
75.9
81.0
66.6
69.3
58.5
63.6


Change from baseline in CD4+ Count (cells/mm3)
207
213
257
275
286
317


Virologic failures (%)
5.9
3.2
10.7
11.1
15.8
15.1


Discontinuation rate (%)
19.2
16.6
26.1
23.6
29.2
25.1


Discontinuations due to AEs
8.3
6.3
9.5
8.3
10.7
8.5




ConclusionsNVP XR continued to demonstrate non‐inferior virologic efficacy to NVP IR in prior treatment‐naïve HIV infected patients out to week 144. NVP XR continued to be well‐tolerated with a safety profile similar to NVP IR.

Purpose of the studyGood penetration of antiretroviral drugs to the seminal plasma may be associated with a decrease in viral replication and play an important role in the prevention of sexual transmission of HIV. We present data from a series of HIV‐infected ARV‐experienced patients receiving etravirine‐containing regimens, in whom etravirine concentrations and viral loads were determined in blood plasma and seminal plasma. The objective was to determine etravirine concentrations and HIV‐1 viral load (VL) in blood plasma (BP) and seminal plasma (SP) of HIV‐infected patients.MethodsTen HIV‐1 adult antiretroviral‐experienced patients receiving an etravirine‐containing regimen for at least 1 month were enrolled. Semen and blood samples were both collected around 12–24 h after the last etravirine dose, depending on once‐daily or twice‐daily dosing, respectively. HPLC/MS/MS was used to determine etravirine concentrations, and HIV‐1 VL was determined by real‐time PCR (limit of detection, VL 40 copies/mL).ResultsTen blood and twenty semen samples were collected. Median (range) CD4 count was 502 cells/mm3 (252–817) and median (range) BP VL was<40 copies/mL (40–362). Median (range) time on etravirine was 52 weeks (12–124). Median (range) BP etravirine concentration was 452.5 ng/mL (258–751). Median (range) SP etravirine concentration was 62.9 ng/mL (31.2–166), and values were above the protein‐free IC50 range (0.39–2.4 ng/mL) in all cases. Median (range) etravirine SP:BP ratio was 0.16 (0.07–0.26). SP VL was<40 copies/mL in all patients, whereas BP VL was detectable in one patient with poor adherence to treatment.












Patient
SP (ng/ml)
BP (ng/ml)
SP VL (copies/ml)
BP VL (copies/ml)
SP:BP
Concomitant ARV




1
31.2
375
<40
<40
0.08
DRVr/TDF


2*
57.1
307
<40
<40
0.18
3TC/ABC


3*
36.9
506
<40
<40
0.07
TDF/FTC


4*
60.6
399
<40
<40
0.15
3TC/ABC


5
68.1
258
<40
<40
0.26
LPVr/TDF


6*
104
414
<40
<40
0.25
3TC/ABC


7
107
491
<40
362
0.21
DRVr/TDF/FTC


8*
65.3
592
<40
<40
0.11
TDF/FTC


9
52.2
518
<40
<40
0.1
DRVr


10
166
751
<40
<40
0.22
TDF/FTC


Median
62.9
452.5
<40
<40
0.16






Patients taking ETR once a day.

ConclusionsTotal etravirine concentrations in male genital secretion are modest, reaching only 16% of the BP concentration, but nevertheless, more than 10 times above the wild type IC50 range.

Purpose of the studyOur aim was to evaluate factors associated with progression to AIDS/death in HIV‐infected naïve pts initiating cART with low CD4 counts.MethodsAdult HIV‐infected ARV‐naïve pts with CD4 <200 who initiated NNRTI or PI‐containing regimens between 1998 and 2009, were included. Primary end point was progression to AIDS (a first episode or a new AIDS‐defining condition in pts with prior AIDS) or death. Kaplan‐Meier curves were used to determine progression‐free survival and multivariate Cox regression models were used to identify independent predictive factors of progression to AIDS/death.Summary of resultsWe included 1427 patients (80% men, median age 38 years, 25% IDU, 37% AIDS, 20% HCV) between 1998 and 2009. At baseline (BL), median (range) CD4 and viral load (VL) was 77 (1–199) cells/µL and 170,000 (19–8,750,000) copies/mL, respectively. After a median follow‐up 4.6 years, 70% of pts reached CD4>200/µL, 65.2% reached undetectable VL and 268 (19%) pts progressed to AIDS/death during follow‐up. The probability of AIDS/death at 5 years was 76%, 34%, 3% and 3%, in pts with BL CD4<100/VL>5 log and CD4<200/VL detectable during FU, BL CD4<100/ VL>5 log and CD4<200/VL undetectable during FU, BL CD4<100 and/or VL>5 log and CD4>200/VL undetectable during FU and BL CD4>100/ VL<5 log and CD4>200/VL undetectable during FU, respectively. In the multivariate analysis, several variables were associated with AIDS/death: CD4< 200 during FU (HR 10.89, p<0.001), detectable VL during FU (HR 3.49, p<0.001), age>50 years (HR 1.75, p=0.001), prior AIDS (HR 1.71, p<0.001) and BL VL>5 log (HR 1.45, p=0.011). If only pts without prior AIDS (n=895) were analyzed, the variables independently associated with AIDS/death were: CD4<200 during FU (HR 9.90, p<0.001), detectable VL during FU (HR 2.78, p<0.001) and BL VL>5 log (HR 1.62, p=0.016).ConclusionsIn immunosuppressed patients initiating cARV therapy, not reaching CD4>200/µL during FU was the strongest variable associated with progression to AIDS/death. VL at BL and mainly at follow up also played a role in patient outcome.

Purpose of the studyFew clinical trials have compared non‐nucleoside reverse transcriptase inhibitors (NNRTI) and ritonavir‐boosted protease inhibitors (PI/r) as initial combined antiretroviral therapy (cART) for HIV‐1‐infected patients with high plasma viral load (pVL), and non‐conclusive results have been reported. We compared the effectiveness between NNRTI and PI/r as first‐line cART for HIV‐1‐infected patients with high pVL.MethodsObservational retrospective study of 664 consecutive treatment‐naïve HIV‐1‐infected patients with pVL (HIV‐1 RNA) >100,000 copies/mL who initiated NNRTI or PI/r‐based cART between 2000–2010 in three University hospitals. Only currently preferred or alternative regimens in clinical guidelines were included. Primary endpoint: percentage of therapeutic failures at week 48. Virologic failure was defined as: a) lack of virologic response (<1 log RNA HIV‐1 decrease in first 3 months); b) RNA HIV‐1 >50 c/mL at week 48; c) confirmed rebound >50 c/ml after a previous value <50 c/mL. Intent‐to‐treat (ITT noncompleter=failure) and on‐treatment (OT) analyses were performed.Results62% of patients initiated NNRTI‐regimens (83% efavirenz) and 38% PI/r‐regimens (62% lopinavir/). Baseline characteristics: male 83%; median age 39 yrs; median CD4 count: 212/µL (NNRTI 232 vs PI/r 177, p=0.028); pVL 5.83 log10 c/mL (NNRTI 5.43 vs PI/r 5.55, p=0.007); AIDS 24% (NNRTI 21% vs PI/r 29%, p=0.015). NRTI backbones were tenofovir plus 3TC or FTC in 72%. The percentage of therapeutic failure was higher in the PI/r group (ITT NC=F 26% vs 18%, p=0.012) with no differences in virologic failures (PI/r 5%, NNRTI 6%, p=0.688). The rate of treatment changes due to toxicity and/or voluntary discontinuations was higher in the PI/r group (15% vs 8%, p=0.008). A multivariate analysis adjusted for age, gender, CD4 count, VL and AIDS showed NNRTI vs PI/r as the only variable associated with treatment response (OR 0.61, 95% CI 0.41–0.88). Median pVL and rate of resistance at virologic failure were higher in patients receiving NNRTI (3.97 vs 2.49 log copies/mL, p<0.001 and 62% vs 12%, p=0.004, respectively).ConclusionsInitial NNRTI‐regimens showed higher effectiveness compared with PI/r‐regimens in HIV‐1‐infected patients with high pVL, although virologic failure rates were low and comparable. Resistance emergence was more frequent and pVL higher in patients failing NNRTI. However, more patients initiating PI/r‐based regimens changed or discontinued therapy.

Purpose of the studyATV/r or DRV/r plus TDF/FTC are recommended for first‐line therapy due at least in part to their clinical tolerability and scarce metabolic effects. We investigated whether both regimens might differ regarding plasma lipids, insulin resistance (HOMA‐IR), and estimated glomerular filtration rate (MDRD).MethodsMulticentre, randomized, clinical trial (ATADAR Study, NCT01274780). Primary end‐point: 24‐week change in total cholesterol. Secondary end‐points: changes in lipids other than total cholesterol, HOMA‐IR, and MDRD; clinical tolerability; and efficacy. We assumed that patients assigned to DRV/r would have an increase in plasma total cholesterol<21 mg/dL, which was the difference between lopinavir/r and ATV/r in CASTLE study. Fasting plasma lipids, glucose, insulin, and creatinine were measured at baseline, and 4, 12, and 24 weeks. Analyses were by intent‐to‐treat.Summary of results180 patients were randomized (ATV/r=91, DRV/r=89), 95% Caucasian, and 8% co‐infected with hepatitis C virus. At baseline (mean, SD): age 36 (9) years; plasma log HIV RNA 4.8 (0.7); CD4 334 (189) cells/mm3; triglycerides 107 (62), total cholesterol 158 (32), LDL cholesterol 97 (28), HDL cholesterol 39 (11) mg/dL, and glucose 84 (13) mg/dL; HOMA‐IR 2.47 (3.46); and MDRD 108 (21) mL/min/1.73 m2. At 24 weeks, total cholesterol (mean, SD) changed +7.26 (26.76) mg/dL with ATV/r and +11.47 (25.85) mg/dL with DRV/r (estimated difference ATV/r minus DRV/r −4.21 (95% CI−12.11 to +3.69), P=0.2944), thus confirming our primary hypothesis. Changes (mean, SD) in triglycerides were roughly similar: +16.29 (61.76) mg/dL with ATV/r and +18.40 (64.24) mg/dL with DRV/r (P=0.8261), but there were trends to more favourable changes in LDL (−2.14 [21.45] vs +3.14 [21.97] mg/dL, P=0.1160) and HDL cholesterol (+5.50 [10.36] vs +3.88 [8.42] mg/dL, P=0.2625), and total‐to‐HDL cholesterol ratio (−1.16 [6.38] vs −0.14 [0.86], P=0.0652) with ATV/r than with DRV/r. There were small, non‐significant decreases in HOMA‐IR (ATV/r −0.17 [2.48] vs DRV/r −0.70 [3.38], P=0.3785) and MDRD (ATV/r −7 [22] vs DRV/r −6 [15] mL/min/1.73 m2, P=0.6652). 6 ATV/r and 3 DRV/r patients had their study drugs discontinued because of adverse effects (P=0.4967). 7 additional patients in each arm had confirmed HIV RNA >50 copies.ConclusionsThere were trends to more favourable changes in LDL and HDL cholesterol and particularly total‐to‐HDL cholesterol ratio at 24 weeks with ATV/r than with DRV/r.

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK