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Antiretroviral-Experienced HIV-1-Infected Patients Treated with Maraviroc: Factors Associated with Virological Response.

ABSTRACT: There are few data on the clinical and virological factors associated with the virological response (VR) of maraviroc (MVC) in clinical practice. This study aimed to identify factors associated with the VR to MVC-containing regimens in 104 treatment-experienced but CCR5 inhibitor-naive HIV-1 patients. VR was defined at month 3 (M3) as HIV-1 RNA viral load (VL) <50 copies/ml. The impact on VR of age, sex, baseline tropism, HIV subtype (B vs. non-B), nadir CD4 cell count and CD4 cell count, baseline VL, genotypic susceptibility score of treatment, once or twice daily treatment, presence of raltegravir in optimized background therapy, and MVC concentrations was investigated. Median baseline VL was 3.3 log10 copies/ml (range 1.7-6.0 log10 copies/ml) and CD4 cell count was 299 cells/mm(3) (range 7-841 cells/mm(3)). At M3, 53.8% of patients were responders. In univariate analysis, a better efficacy of the MVC-containing regimen was associated with a high CD4 cell count (p=0.0069) and there was a trend for low baseline VL, high nadir CD4 cell count, and HIV subtype (B versus non-B). Only low baseline VL remained significantly associated with better VR in the multivariate analysis. This study demonstrated a VR of an optimized antiretroviral treatment including MVC in clinical practice similar to that observed in clinical trials. The factors associated with VR were higher baseline CD4 cell count in univariate analysis and lower baseline VL in multivariate analysis.

SUBMITTER: Soulie C

PROVIDER: S-EPMC4426320 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Antiretroviral-Experienced HIV-1-Infected Patients Treated with Maraviroc: Factors Associated with Virological Response.

Soulie Cathia C Peytavin Gilles G Charpentier Charlotte C Lambert-Niclot Sidonie S Sayon Sophie S Visseaux Benoit B Simon Anne A Katlama Christine C Yazdanpanah Yazdan Y Descamps Diane D Calvez Vincent V Marcelin Anne-Geneviève AG

AIDS research and human retroviruses 20141217 5

There are few data on the clinical and virological factors associated with the virological response (VR) of maraviroc (MVC) in clinical practice. This study aimed to identify factors associated with the VR to MVC-containing regimens in 104 treatment-experienced but CCR5 inhibitor-naive HIV-1 patients. VR was defined at month 3 (M3) as HIV-1 RNA viral load (VL) <50 copies/ml. The impact on VR of age, sex, baseline tropism, HIV subtype (B vs. non-B), nadir CD4 cell count and CD4 cell count, baseli ...[more]

PMID: 25420695

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Project description:IntroductionLimited data are available on the durability and effectiveness of maraviroc in routine clinical practice. We assessed the durability of maraviroc-containing regimens during a 30-month period, as well as their immunovirological and clinical efficacy, according to viral tropism in treatment-experienced individuals with viral load (VL) >50 copies/ml in the French Hospital Database on HIV.MethodsVirological success was defined as VL<50 copies/ml, immunological success as a confirmed increase of at least 100 CD4 cells/mm3 measured twice at least one month apart, and clinical failure as hospitalization for a non-AIDS event, an AIDS event, or death. Multivariable Cox regression models adjusted for potential confounders were used to assess the influence of viral tropism on durability, the immunovirological responses, and clinical outcome.Results356 individuals started maraviroc with VL>50 copies/ml of whom 223 harbored R5 viruses, 44 non-R5 viruses and 89 viruses of unknown tropism. Individuals with non-R5 viruses were more likely than individuals with R5 viruses to discontinue maraviroc (75% vs 34%, p<0.0001). At 30 months, the estimated rates of virological and immunological success were respectively 89% and 51% in individuals with R5 viruses and 48% and 23% in individuals with non-R5 viruses. In multivariable analysis, non-R5 viruses were associated with a lower likelihood of both virological success (hazard ratio (HR): 0.42; 95% confidence interval (CI), 0.25-0.70) and immunological success (HR: 0.37; 95% CI, 0.18-0.77). No difference in clinical outcome was found between individuals with R5 and non-R5 viruses. The effectiveness of maraviroc-containing regimens in individuals with unknown viral tropism was not significantly different from that in individuals with R5 viruses. A limitation of the study is the absence of genotypic susceptibility score.ConclusionIn this observational study, maraviroc-containing regimens yielded high rates of viral suppression and immunological responses in individuals with R5 viruses in whom prior regimens had failed.

Project description:BackgroundHIV management remains concerning and even more challenging in the frame of comorbidities like malnutrition that favors disease progression and mortality in resource-limited settings (RLS).ObjectiveTo describe the nutritional parameters of antiretroviral therapy (ART) recipients (without nutritional support) with respect to CD4 count and virological failure.MethodsA cross-sectional study was conducted from October to December 2018 among 146 consenting participants enrolled in two health facilities of the East-Region of Cameroon. Socio-demographic data, basic clinical information and treatment history were collected; blood samples were collected by venipuncture for laboratory analysis (HIV-1 viral load, CD4 Tcells measurement and biochemical analysis) performed at the "Chantal Biya" International Reference Center", Yaounde, Cameroon. The nutritional profile was assessed by using anthropometric and biochemical parameters. Data were analyzed using Excel 2016, Graph pad prism version 6; Spearman correlation and Kruskal-Wallis test were used; with p<0.05 considered statistically significant.ResultsMedian [IQR] age was 42 [33-51] years, 76.0% (111/146) were female and median [IQR] duration on ART was 54 [28-86] months. Of these participants, 11.6% (17/146) were underweight based on the body mass index and 4.7% (7/146) were at the stage of advanced weight loss. According to immunovirological responses, 44.5% (65/146) were immunocompromised (CD4<500 cell/μl) and 75.3% (110/146) had an undetectable viremia (<40 copies/mL). CD4 count inversely correlated with total protein concentration (r = -0.18, p = 0.005**). Viremia was inversely correlated with albumin (r = -0.21; p = 0.047*), nutritional risk index (r = -0.28; p = 0.013*), total cholesterol (r = -0.27; p = 0.007**), and positively correlated with total protein (r = 0.27; p<0.001**) concentrations.ConclusionIn this RLS, with patients having about five years of ART-experience, malnutrition appears to be driven mainly by a poor BMI, indicating that about one of ten patients falls within this severe condition. However, the largely normal nutritional profiles should be interpreted with caution, considering local realities and food support programs in place. The present outcomes highlight the need for monitoring nutritional status of people receiving ART in RLS, toward the design of optimal food interventions.

Project description:Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency-reversing potential of maraviroc and the mechanisms involved, we performed a phase II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (EudraCT registration no. 2012-003215-66). All patients completed full maraviroc dosing and follow-up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signaling pathways involved in the viral reactivation. An increase in HIV-1 transcription in resting CD4+ T cells, estimated by levels of HIV-1 unspliced RNA, was observed. Moreover, activation of the NF-κB transcription factor was observed in these cells. To elucidate the mechanism of NF-κB activation by maraviroc, we have evaluated in HeLa P4 C5 cells, which stably express CCR5, whether maraviroc could be acting as a partial CCR5 agonist, with no other mechanisms or pathways involved. Our results show that maraviroc can induce NF-κB activity and that NF-κB targets gene expression by CCR5 binding, since the use of TAK779, a CCR5 inhibitor, blocked NF-κB activation and functionality. Taking the results together, we show that maraviroc may have a role in the activation of latent virus transcription through the activation of NF-κB as a result of binding CCR5. Our results strongly support a novel use of maraviroc as a potential latency reversal agent in HIV-1-infected patients.IMPORTANCE HIV-1 persistence in a small pool of long-lived latently infected resting CD4+ T cells is a major barrier to viral eradication in HIV-1-infected patients on antiretroviral therapy. A potential strategy to cure HIV-1-infection is the use of latency-reversing agents to eliminate the reservoirs established in resting CD4+ T cells. As no drug has been shown to be completely effective so far, the search for new drugs and combinations remains a priority for HIV cure. We examined the ability of maraviroc, a CCR5 antagonist used as an antiretroviral drug, to activate latent HIV-1 in infected individuals on antiretroviral therapy. The study showed that maraviroc can activate NF-κB and, subsequently, induce latent HIV-1-transcription in resting CD4+ T cells from HIV-1-infected individuals on suppressive antiretroviral therapy. Additional interventions will be needed to eliminate latent HIV-1 infection. Our results suggest that maraviroc may be a new latency-reversing agent to interfere with HIV-1 persistence during antiretroviral therapy.

Dataset Information

Antiretroviral-Experienced HIV-1-Infected Patients Treated with Maraviroc: Factors Associated with Virological Response.

Publications

Antiretroviral-Experienced HIV-1-Infected Patients Treated with Maraviroc: Factors Associated with Virological Response.

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