Elisa Colella

Maraviroc as intensification strategy in HIV-1 positive patients with deficient immunological response: an Italian randomized clinical trial.

Background Immunological non-responders (INRs) lacked CD4 increase despite HIV-viremia suppression on HAART and had an increased risk of disease progression. We assessed immune reconstitution profile upon intensification with maraviroc in INRs. Methods We designed a multi-centric, randomized, parallel, open label, phase 4 superiority trial. We enrolled 97 patients on HAART with CD4+<200/µL and/or CD4+ recovery ≤25% and HIV-RNA<50 cp/mL. Patients were randomized 1:1 to HAART+maraviroc or continued HAART. CD4+ and CD8+ CD45+RA/RO, Ki67 expression and plasma IL-7 were quantified at W0, W12 and W48. Results By W48 both groups displayed a CD4 increase without a significant inter-group difference. A statistically significant change in CD8 favored patients in arm HAART+maraviroc versus HAART at W12 (p=.009) and W48 (p=.025). The CD4>200/µL and CD4>200/µL + CD4 gain ≥25% end-points were not satisfied at W12 (p=.24 and p=.619) nor at W48 (p=.076 and p=.236). Patients continuing HAART displayed no major changes in parameters of T-cell homeostasis and activation. Maraviroc-receiving patients experienced a significant rise in circulating IL-7 by W48 (p=.01), and a trend in temporary reduction in activated HLA-DR+CD38+CD4+ by W12 (p=.06) that was not maintained at W48. Conclusions Maraviroc intensification in INRs did not have a significant advantage in reconstituting CD4 T-cell pool, but did substantially expand CD8. It resulted in a low rate of treatment discontinuations. Trial Registration ClinicalTrials.gov NCT00884858 http://clinicaltrials.gov/show/NCT00884858

Maraviroc intensification for HIV-1-positive immunological non-responders (INRs) despite virological suppression during HAART

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

Efficacy, Tolerability and Virological Consequences of Long-Term Use of Unboosted Atazanavir Plus 2 NRTIs in HIV-Infected Patients

PURPOSE Switch to unboosted atazanavir (ATV) is an attractive option due to convenience and tolerability in HIV-positive patients. With limited available data we investigated the determinants of long-term efficacy and the consequences of virological failure of unboosted atazanavir-based regimens. METHODS Retrospective analysis in two Italian large outpatient clinics including demographic, immunovirological, resistance and pharmacokinetic data. RESULTS 249 patients receiving atazanavir (400 mg once-daily) plus 2 NRTIs were included; 163 were males (65.5%) and median age was 47 years (42-51.5). Median CD4+ T-cell count was 396/uL (261-583); 146 (58.6%) presented a viral load < 50 copies/mL. Over a median follow up of 157 weeks (106-203) 193 patients (77.5%) were still on treatment with 10 (4%) and 2 (0.8%) stopping for virological failure or toxicity, respectively. Ten patients with virological failure presented newly selected resistance associated mutations (RAMs) for NRTIs (2/10) or ATV (4/10, one I50L). Total cholesterol and triglycerides showed significant decreases at 48 [-4 mg/dL and -41 mg/dL] and 96 weeks [-14 mg/dL and -54 mg/dL] as compared to baseline. At multivariate analysis a genotypic sensitivity score ≤ 1, atazanavir RAMs > 1 and suboptimal adherence were independently associated with virological failure; in lamivudine/emtricitabine-treated patients the presence of M184V (without other NRTI RAMs) was not associated with virological failure. CONCLUSION Unboosted-atazanavir containing regimens were efficacious (with uncommon virological failures) and well-tolerated (with improvements in lipid profile over time) treatments in HIV-positive patients. Isolated M184V in lamivudine/emtricitabine recipients was not associated with higher failure rates supporting the use of functional ATV-based dual therapies as maintenance strategies.

Effectiveness, durability, and safety of darunavir/ritonavir in HIV-1-infected patients in routine clinical practice in Italy: a postauthorization noninterventional study

Current antiretroviral (ARV) therapy for the treatment of human immunodeficiency virus (HIV-1)-infected patients provides long-term control of viral load (VL). Darunavir (DRV) is a nonpeptidomimetic protease inhibitor approved for use with a ritonavir booster (DRV/r). This study evaluated the effectiveness of DRV/r in combination with other ARV agents in routine clinical practice in Italy. In this descriptive observational study, data on utilization of DRV/r, under the conditions described in the marketing authorization, were collected from June 2009 to December 2012. Effectiveness (VL <50 copies/mL), tolerability, and durability in four patient groups (two DRV/r-experienced, one ARV-experienced DRV/r-naïve, and one ARV-naïve) were analyzed. Secondary objectives included immunological response, safety, and persistence/discontinuation rates. In total, 875 of 883 enrolled patients were included in the analysis: of these, 662 (75.7%) completed the follow-up until the end of 2012 and 213 (24.3%) withdrew from the study earlier. Initial DRV dose was 600 mg twice daily (67.1%) or 800 mg once daily (32.9%). Only 16 patients (1.8%) withdrew from the study due to virological failure. Virological response proportions were higher in patients virologically suppressed at study entry versus patients with baseline VL ≥50 copies/mL in each ARV-experienced group, while there was no consistent difference across study groups and baseline VL strata according to baseline CD4+ cell count. CD4+ cell count increased from study entry to last study visit in all the four groups. DRV/r was well tolerated, with few discontinuations due to study-emergent nonfatal adverse events (3.0% overall, including 2.1% drug-related) or deaths (3.0% overall, all non-drug-related); 35.3% of patients reported ≥1 adverse events. These observational data show that DRV/r was effective and well tolerated in the whole patient population described here. The DRV/r-containing regimen provided viral suppression in a high percentage of patients in all groups, with low rates of discontinuation due to virological failure.

Treatment outcome in HIV+ patients receiving 3- or 4-drug regimens during PHI

The optimal timing and modality of therapeutic intervention during early phases of HIV infection is still debated; in our prospective observational study we evaluated immunological and virological outcome in HIV+ patients treated during acute or recent HIV infection.

Factors involved in continuance of atazanavir-based regimens: Results from a cohort of HIV1-positive patients.

We evaluated predictive factors involved in durability and therapeutic failure of atazanavir (ATV)-based antiretroviral regimens with or without ritonavir (r) in real life setting. This retrospective study of HIV-1-positive patients evaluated the factors related to ATV continuance and the time-dependent probability of therapeutic failure (HIV-RNA >200 copies/mL and concomitant discontinuation of ATV). We also investigated the rate of therapeutic failure and the variations in total bilirubin levels from starting unboosted ATV-based regimens. The study involved 1030 patients: 183 treatment-naïve patients (17.8%) started ATV/r (17 subsequently switched to unboosted ATV); 653 (63.4%) switched to ATV/r from previous antiretroviral regimens (121 subsequently switched to unboosted ATV); and 194 (18.8%) switched to unboosted ATV from previous ATV-free regimens. The median ATV follow-up was 28 months (interquartile range 7-56). The risk of ATV discontinuation was significantly lower in patients switched to unboosted ATV from ATV/r (HR 0.45; p < 0.0001). The discontinuation of ATV correlated with female gender (HR 1.26; p = 0.035), use of a zidovudine/didanosine/stavudine containing backbone (HR 1.8; p = 0.004), and a baseline CD4+ cell counts of <200/μL (HR 1.54; p = 0.003), the last of which was also associated with a higher risk of therapeutic failure (HR 2.42; p = 0.001). Total bilirubin levels were significantly lower in the patients switching from ATV/r to unboosted ATV. Unboosted ATV-based therapies are safe and effective options in patients whose immuno-virological conditions are stable, and allow the long-term survival of ATV-containing regimens.

Factors involved in treatment durability and immunological recovery in a cohort of HIV-positive patients receiving atazanavir-based regimens.

Since antiretroviral therapy must be taken lifelong, persistence and safety have become the goals to achieve. Protease inhibitors, in particular atazanavir (ATV) with or without ritonavir (r), represent a highly prescribed class in real life long‐term treatment.

Predictive factors of therapeutic success of a HAART regimen including atazanavir with or without ritonavir in HIV-infected patients

To evaluate the factors that may influence the persistence and the virological failure of an atazanavir (ATV)‐containing antiretroviral regimen. We conducted a retrospective cohort study in HIV‐positive patients (pts) who were being followed at the Infectious Diseases Division, University of Milan. Data regarding viral load, CD4 lymphocytes and the blood chemistry parameters were collected at 1st, 3rd, 6th months from the beginning of therapy and then every six months. Factors related to persistence of therapy with ATV and virological failure (HIV‐RNA>50cp/mL after six months) were evaluated with Kaplan‐Meier curve, Cox model and logistic regression. 574 pts were evaluated: 480 experienced therapy with ATV with ritonavir (ATV/r) (80 naïve), 218 with unboosted ATV (5 naïve) and 124 with both regimens. At baseline: median age of 43 years (IQR 39–48), CD4+median count 418 cell/mm3 (IQR 277–606), VL<50cp/mL in 370 pts (54.4%), and median duration of infection 12 years (IQR 6–18). The median duration of therapy was 21 months (IQR 7–49) in pts treated with ATV/r and 22 months (IQR 8–44) with unboosted ATV. We observed a borderline significant difference for the persistence of the regimen between the two groups (p=0.05) that disappears after removing the suspensions for simplification. Pts treated with ritonavir (OR=1.563; 95% CI 1.058–2.308, p=0.025) and with a backbone containing AZT‐ddI‐d4T (OR=3.34; 95% CI 1.873–5.956, p<0.001) had an increased risk of therapy suspension, whereas starting therapy with ATV in recent years resulted protective (OR=0.741; 95% CI 0.678–0.809, p<0.001). The suspension for toxicity was not significantly different between pts treated with ATV/r and unboosted ATV. No significant difference between the two therapies was observed regarding virological failure. Of note, pts with an elevated VL at baseline (OR 1.234; 95% CI 1.065–1.429, p=0.005) and male gender (OR 1.667; 95% CI 1.06–2.621, p=0.027) were at elevated risk of failure, whereas a backbone containing AZT‐ddI‐d4T (OR 0.356; 95% CI 0.196–0.638, p=0.001) and a recent year of starting ATV (OR 0.64; 95% CI 0.579–0.71, p<0.001) are protective factors. No significant difference between pts treated with ATV/r or unboosted was observed regarding the induction of hyperbilirubinemia of ACTG grade III and IV. Treatment with unboosted ATV can last longer than that with ATV/r without an increased risk of therapeutic failure. A comparable safety profile was seen for pts who received ATV/r or unboosted ATV.

Analysis of determinants of long-term efficacy of unboosted atazanavir-based regimens in the clinical setting

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