Suchergebnisse

Novel strategies with NRTIs‐sparing regimen in antiretroviral naïve HIV‐infected patients are currently used in clinical trials [1]. We previously presented preliminary results of this study [2] and here we present the 48‐weeks final results. Prospective, open‐label, randomised (1:1), multicenter, proof‐of‐concept trial. HIV‐infected naïve patients were assigned to once daily maraviroc (MVC) plus lopinavir/ritonavir (LPV/r) or to tenofovir/emtricitabine (TDF/FTC) plus LPV/r. Objectives of the study were the 48‐weeks virological and immunological efficacy. Data were collected at baseline (BL) and at 4, 12, 24, 36 and 48 weeks. T cell subsets from frozen peripheral blood mononuclear cells collected at BL, 4 and 48 weeks were also evaluated. ANOVA for repeated measures performed and Greenhouse‐Geisser probabilities calculated. Results reported as median (Q1–Q3) or frequency (%). Fifty patients (26 in MVC group and 24 in TDF/FTC group) were enrolled and reached week 48. Similar BL characteristics were observed in the two study groups; age: 39.1 (34.2–44) years, 2/50 (4%) females, infected since 2.9 (0.8–5.3) years, CD4+ nadir 266 (242–315) cells/µL, BL CD4+ 295 (260–369) cells/µL; CD4% 18.6 (14.6–23), HIV‐RNA 4.4 (3.9–4.8) log10 copies/mL. At W48, all patients in MVC group and 22/24 (96%) in TDF/FTC group had HIV‐RNA<50 copies/ml (p=0.225). CD4+ trend during follow‐up was different between the two groups (p=0.046) with a higher CD4 gain of 286 (183–343) vs 199 (125–285) cells/mL in MVC and TDF/FTC, respectively (p=0.033). In MVC vs TDF/FTC group, we observed a higher expression of CCR5+CD4+ T cells [W48 change: +7.5% (−4.5/11) vs −5.4 (−15.1/−0.5), p=0.016] and a higher increase of CD4+ effector memory [W48 change: +1.6% (0.7/4.8) vs ‐4.4 (−13.5/−0.2), p=0.007]. No significant variations in naïve and central memory CD4+ T cells. Treatment was well tolerated, without grade 3 or 4 adverse events. No significant difference between the two groups as for the 48‐weeks trend of bone marrow function, AST, ALT and CPK values, creatinine value, glicyde profile (fasting glucose, fasting insuline) and lipid profile (total cholesterol, LDL and HDL cholesterol, tryglicerides). Results are shown in Table 1. In naïve‐patients, virological efficacy and tolerability of a NRTIs‐sparing regimen with maraviroc and lopinavir/ritonavir was similar to conventional treatment in addition to a better immunological recovery, in particular of the Effector Memory CD4+ cells subset.















Baseline
Week 12
Week 24
Week 36
Week 48
p‐valuea




CD4+ cells/mm3
MVC+LPV/r
292 (261–359)
438 (381–500)
517 (432–620)
533 (457–682)
614 (455–709)
0.046



TDF/FTC+LPV/r
297 (257–373)
450 (354–511)
496 (367–568)
470 (402–568)
505 (419–705)



CD4%
MVC+LPV/r
19.5 (16.3–24.3)
24 (18–29.5)
26.2 (22.2–29)
28.2 (21.3–32.2)
27.7 (21.6–33)
0.718



TDF/FTC+LPV/r
18.8 (14.3–22.3)
24.7 (18.4–26.2)
25.2 (21.3–30.1)
24.9 (21.5–31.6)
25.7 (22.1–30.2)



CD4/CD8 ratio
MVC+LPV/r
0.35 (0.25–0.48)
0.45 (0.3–0.62)
0.54 (0.4–0.67)
0.66 (0.4–0.82)
0.72 (0.47–0.93)
0.316



TDF/FTC+LPV/r
0.33 (0.26–0.4)
0.44 (0.33–0.55)
0.51 (0.39–0.66)
0.52 (0.48–0.7)
0.54 (0.49–0.72)



HIV‐RNA log10 copies/ml
MVC+LPV/r
4.42 (4.07–4.84)
1.56 (1.56–1.56)
1.56 (1.56–1.56)
1.56 (1.56–1.56)
1.56 (1.56–1.56)
0.188



TDF/FTC+LPV/r
4.41 (3.84–4.76)
1.56 (1.56–1.56)
1.56 (1.56–1.56)
1.56 (1.56–1.56)
1.56 (1.56–1.56)



Haemoglobin (g/dL)
MVC+LPV/r
14.7 (13.7–15.1)
14 (13.5–14.6)
14.3 (13.7–14.9)
14.1 (13.3–15.1)
14.5 (13.6–15.2)
0.357



TDF/FTC+LPV/r
14.1 (13.8–14.9)
14.4 (13.5–15.1)
14.8 (13.5–15.3)
14.7 (13.7–15.3)
14.7 (13.6–15.2)



White blood cell (109/mm3)
MVC+LPV/r
5 (4.6–5.6)
5.6 (5.2–6.9)
5.8 (4.8–7.2)
5.9 (5–7.7)
5.9 (5–7.5)
0.806



TDF/FTC+LPV/r
4.5 (3.9–5.2)
4.3 (4.3–6.5)
5.1 (4.5–7.1)
5.1 (4.3–6.8)
5.5 (4.4–6.7)



Cholesterol (mg/dl)
MVC+LPV/r
178 (149–204)
–
202 (177–233)
–
218 (167–260)
0.794



TDF/FTC+LPV/r
160 (144–194)
–
189 (157–239)
–
199 (164–239)



Tryglicerides (mg/dl)
MVC+LPV/r
91 (64–126)
–
193 (113–254)
–
170 (105–270)
0.825



TDF/FTC+LPV/r
91 (66–148)
–
159 (106–203)
–
147 (110‐187)



Glucose (mg/dl)
MVC+LPV/r
84 (78–91)
–
86 (75–89)
–
84 (76–93)
0.200



TDF/FTC+LPV/r
81 (75–89)
–
85 (79–92)
–
82 (77–88)



Insulin (U/L)
MVC+LPV/r
5.7 (4–10.2)
–
7 (5.1–8.4)
–
6.8 (5.8–10.8)
0.554



TDF/FTC+LPV/r
7.2 (5.7–14.6)
–
6.8 (5.7–10)
–
5.8 (5.3–9.3)



Creatinine (mg/dl)
MVC+LPV/r
0.83 (0.77–0.95)
0.79 (0.72–0.85)
0.78 (0.69–0.87)
0.78 (0.71–0.86)
0.81 (0.75–0.87)
0.149



TDF/FTC+LPV/r
0.83 (0.78–0.98)
0.88 (0.79–1)
0.85 (0.75–0.93)
0.85 (0.77–0.92)
0.85 (0.74–0.95)

Purpose of the studyTo assess the impact of lamivudine (3TC) monotherapy in failing patients with multidrug‐resistant HIV and limited therapeutic options.MethodsProspective, open‐label, multicenter, randomised (1:1), pilot study. HIV‐1 failing pts with M184V mutation, HBsAg negative were assigned to 3TC 300mg QD for 24 weeks followed by a new regimen for 24 weeks (Arm A) or to a new regimen for 48 weeks (Arm B). The new HAART regimen was decided before randomisation in both groups, based on clinical history, genotype and viral tropism. Primary endpoint was the proportion of pts with HIV‐RNA<50 copies/mL (VS) at week 48 (W48). ITT and OT analysis performed. Results described by median (IQR).Summary of results109 screened, 34 screening failures, 75 randomised, 72 initiated the assigned treatment [38 and 34 pts in Arm A and B, respectively]: 69% males; age: 47.4 (43.2–51.9) years; years of HIV infection: 17 (14–23); nadir CD4+: 150 (47–231) cells/μL. Similar baseline demographic and clinical characteristics were found in Arm A vs Arm B [CD4+: 413 (294–550) vs 377 227–520) cells/µL; HIV‐RNA: 3.94 (2.89–4.43) vs 3.66 (2.78–4.20) log10copies/mL; number of mutations: 9 (5–13) vs 9 (3–19); R5‐virus: 67% vs 50%; new regimen GSS: 2 (2–3) vs 2 (2–2); 60% vs 56% pts included in the new regimen at least two of the following drugs: DRV/r, MVC, RAL, ETR, T‐20]. At W48, pts with VS were 15/38 (39%) vs 17/34 (50%) in Arm A and B, respectively (ITT: P=0.477). In Arm A, 25/38 (66%) completed the 24‐weeks of monotherapy and 21 reached week 48 vs 27 pts in Arm B (P=0.045). Pts with VS were 15/21 (71%) vs 17/27 (63%) in Arm A and B, respectively (OT: P=0.758). VS according to nadir CD4+, screening HIVRNA and GSS of the new regimen shown in 1. SAEs occurred in 4 (11%) and 2 (6%) in Arm A and B, respectively; all but 1 in Arm A unrelated to the regimen; 4 CDC events: 3 oral candidiasis and 1 recurrence of CMV infection in Arm A; 1 oral candidiasis in Arm B. W48 CD4 change from baseline was: ITT:−4 (−108/+56) and 53 (−37/+110) cells/L (P=0.735); OT: 8 (−62/+58) and 68 (−24/+148) cells/L in arm A and B, respectively (P=0.500). Mutations associated with resistance at W48 were 4 (0–7) and 7 (2–13) in Arm A and B, respectively (P=0.031). R5 virus at W48: Arm A=55% vs Arm B=29% (P=0.124).ConclusionsUse of 3TC monotherapy was associated with greater discontinuation. It may be considered in patients without effective therapeutic options to favour virological efficacy of the subsequent regimen.

Virological success according to Nadir CD4+, screening HIVRNA and GSS of the new regimen.










ITT ANALYSIS


Characteristic
Strata
Percent of patients with HIV‐RNA < 50 copies/mL at week 48 in Arm A
Percent of patients with HIV‐RNA < 50 copies/mL at week 48 in Arm B
P‐value
Breslow‐Day Test P‐value




Nadir Cd4+(cells/μL)
<200
10/24 42%
10/24 42%
0.999
0.173



≥200
5/14 (36%)
7/10 (70%)
0.214



Screening HIV‐RNA
51–10000
15/26 (58%)
15/26 (58%)
0.999
0.092


   (copies/mL)
>10000
0/12
2/8 (25%)
0.147



New Regimen GSS
<2
3/7 (43%)
3/8 (38%)
0.999
0.479



≥2
12/31 (39%)
14/26 (54%)
0.294



OT Analysis



Characteristic
Strata
Percent of patients with HIV‐RNA < 50 copies/mL at week 48 in Arm A
Percent of patients with HIV‐RNA < 50 copies/mL at week 48 in Arm B
P‐value
Breslow‐Day Test P‐value


Nadir Cd4+(cells/μL)
<200
10/12 (83%)
10/19 (53%)
0.128
0.027



≥200
5/9 (56%)
7/8 (88%)
0.294



Screening HIV‐RNA
51–10000
15/17 (88%)
15/22 (68%)
0.251
0.052


   (copies/mL)
>10000
0/4 (0%)
2/5 (40%)
0.444



New Regimen GSS
<2
3/4 (75%)
3/5 (60%)
0.999
0.816



≥2
12/17 (71%)
14/22 (64%)
0.740

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