Maraviroc Use Research Articles

Clinical use, efficacy, and durability of maraviroc for antiretroviral therapy in routine care: A European survey.

ObjectivesThe study aimed to survey maraviroc use and assess effectiveness and durability of maraviroc-containing antiretroviral treatment (ART) in routine practice across Europe.MethodsData were retrieved from 26 cohorts in 8 countries comprising adults who started maraviroc in 2005–2016 and had ≥1 follow-up visit. Available V3 sequences were re-analysed centrally for tropism determination by geno2pheno[coreceptor]. Treatment failure (TF) was defined as either virological failure (viral load >50 copies/mL) or maraviroc discontinuation for any reason over 48 weeks. Predictors of TF were explored by logistic regression analysis. Time to maraviroc discontinuation was estimated by Kaplan-Meier survival analysis.ResultsAt maraviroc initiation (baseline), among 1,381 patients, 67.1% had experienced ≥3 ART classes and 45.6% had a viral load <50 copies/mL. Maraviroc was occasionally added to the existing regimen as a single agent (7.3%) but it was more commonly introduced alongside other new agents, and was often (70.4%) used with protease inhibitors. Accompanying drugs comprised 1 (40.2%), 2 (48.6%) or ≥3 (11.2%) ART classes. Among 1,273 patients with available tropism data, 17.6% showed non-R5 virus. Non-standard maraviroc use also comprised reported once daily dosing (20.0%) and a total daily dose of 150mg (12.1%). Over 48 weeks, 41.4% of patients met the definition of TF, although the 1-year estimated retention on maraviroc was 82.1% (95% confidence interval 79.9–84.2). Among 1,010 subjects on maraviroc at week 48, the viral load was >50 copies/mL in 19.9% and >200 copies/mL in 10.7%. Independent predictors of TF comprised a low nadir CD4 count, a detectable baseline viral load, previous PI experience, non-R5 tropism, having ≥3 active drugs in the accompanying regimen, and a more recent calendar year of maraviroc initiation.ConclusionsThis study reports on the largest observation cohort of patients who started maraviroc across 8 European countries. In this overall highly treatment-experienced population, with a small but appreciable subset that received maraviroc outside of standard treatment guidelines, maraviroc was safe and reasonably effective, with relatively low rates of discontinuation over 48 weeks and only 2 cases of serum transaminase elevations reported as reasons for discontinuation.

Efficacy and safety of long-term maraviroc use in a heterogeneous group of HIV-infected patients: A retrospective cohort study

Since the registration of maraviroc (MVC) as an antiretroviral agent in 2008, only studies with a follow-up time of <5 years have been published. Therefore, little is known about its long-term safety and efficacy in clinical practice. In this cohort study, data on long-term follow-up of MVC treatment in routine practice were analysed. A retrospective cohort study was conducted at University Medical Centre Utrecht with a follow-up period up to almost 10 years. The efficacy and tolerability of MVC-containing antiretroviral therapy (ART) was analysed in human immunodeficiency virus type 1 (HIV-1)-infected patients. The cohort consisted of 111 HIV patients who were treated for a median of 11.0 years (IQR 4.0-15.0 years) and with a median of 4 (IQR 2-6) previous ART regimens. The median time of MVC use was 49 months (IQR 21-82 months). Mean CD4+ T-cell counts continued to increase up to 9 years following initiation of MVC. Patients with a detectable viral load (≥50 copies/mL HIV-RNA) at the start of MVC-containing ART reached high proportions of viral suppression. Only three patients (2.7%) experienced treatment failure despite optimal therapy. Nine patients (8.1%) discontinued MVC owing to intolerance of their ART regimen. Severe laboratory abnormalities were deemed to be unrelated to MVC use. During the 487 person-years of follow-up, 18 patients (16.2%) died. MVC use in this heavily pre-treated cohort was generally well tolerated during long-term follow-up. Furthermore, use of MVC resulted in a good immunological and virological response in clinical practice.

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.

Use of maraviroc in patients with undetectable viral load: efficacy, tolerance and predictors of viral response in MARAVIROC-cohort study.

IntroductionNo controlled clinical trials had studied the role of maraviroc (MRV) in fully suppressed patients [1].Materials and MethodsMRV-cohort is an observational, retrospective, multicentric (27 sites) large cohort study of patients starting MRV in clinical practice under different circumstances, with at least 48 weeks of follow-up. For the present analysis we selected all those patients starting with an HIV-RNA<50 copies/mL. Demographics, baseline CD4 cell count, past history of antiretroviral treatment (ART), tropism, reasons for MRV use, MRV based therapy and change/end of MRV use were assessed. Paired analysis of lipid, hepatic and kidney profile changes and univariate and multivariate analyses of HIV-RNA<50 copies/mL at 48 weeks were explored.ResultsWe included 247 out of 667 subjects from the entire cohort. At study entry, their median age was 47 years, 23% were women, 31% MSM, 49% had CDC category C, median CD4+ counts were 468 cells/mm3, 46% were HCV+ and 4.5% AgHBs+. Tropism information was available in 197 (94% R5). Median length of prior ARTV was 10.7 years, with exposure to a median of three drug families. Main reasons for prescribing MRV were: toxicity 38%, inmunodiscordance 23%, simplification 19% and admission in a clinical trial 10.4%. MRV based therapies used were MRV+2NRTIs 9%, MRV+PI 46%, MRV+PI+other 40% and MRV+other 5%. At 48 weeks, 23% of patients had changed or finished MRV therapy due to toxicity 2.4%, virological failure 2%, immunological failure 1.2%, simplification 3,2%, trial requirement 9.7%, medical decision 2.8%, treatment suspension 1.2% and unknown 0.4%. At 48 weeks, no significant changes were observed in lipid, hepatic or kidney profiles, and 85% of patients remained with HIV-RNA<50 copies/mL. Focusing on viral response univariate and multivariate models did not show any significant baseline variable explaining viral failure.ConclusionsIn clinical practice MRV was used, mostly in R5 positive patients, with adequate efficacy and tolerance, but important number of patients changed due to non-clinical reasons. In this scenario neither reason for use of MRV nor MRV-based therapy explained viral failure.

Reactivation of hepatitis B virus infection associated with maraviroc use in an HIV-infected patient

Reactivation of hepatitis B virus infection associated with maraviroc use in an HIV-infected patient

P41: The effects of maraviroc use on liver fibrosis progression: hyaluronic acid reduction in HIV/HCV coinfected patients in MAICOL study, 48‐week analysis

P41: The effects of maraviroc use on liver fibrosis progression: hyaluronic acid reduction in HIV/HCV coinfected patients in MAICOL study, 48‐week analysis

Long-term maraviroc use as salvage therapy in HIV-2 infection

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Maraviroc: the First Chemokine Coreceptor 5 Inhibitor

HIV viral entry occurs via viral interaction with host cell CD4 receptors and a second coreceptor, most commonly chemokine coreceptor (CCR)5. As a result, CCR5 antagonists have been developed to block HIV entry into CD4+ cells, thereby inhibiting viral replication. The first CCR5 inhibitor approved for use in the treatment of HIV was maraviroc. Maraviroc has been shown to be successful in reducing HIV replication in both antiretroviral treatment-experienced and treatment-naive populations. Since maraviroc is only efficacious against CCR5-tropic HIV virus, it is imperative to perform viral tropism testing prior to initiation of maraviroc. The currently available enhanced sensitivity Trofile™ assay (Monogram Biosciences, CA, USA) is the reference standard of tropism tests. Although it is highly sensitive, it remains a barrier to maraviroc use because it is expensive and has a long turnaround time. The development of simpler tropism assays may allow for more widespread use of maraviroc in the future. At present, maraviroc remains a highly useful drug in the management of HIV-infected persons infected with CCR5-tropic viruses.

Profile of maraviroc: a CCR5 antagonist in the management of treatment-experienced HIV patients

Maraviroc is the first and, so far, the only licensed representative of the class of chemokine receptor type 5 (CCR5) inhibitors used for the treatment of human immunodeficiency virus (HIV) infection. Its safety and efficacy were demonstrated in several clinical trials, and its use was approved in 2007 by the responsible authorities. Some specific issues are correlated with maraviroc and its use. It is the only drug in the antiretroviral armamentarium, which does not interact with the viral enzymes but with a human receptor. Hence, it is able to be long-term effective only if the infecting virus uses, exclusively, the CCR5 receptor. Occurrence and detection of the CCR5 tropism are some of the great challenges of maraviroc use in treatment-experienced patients. Although up to 80% of naive patients harbor CCR5-tropic virus, the occurrence of CXCR4 or other tropisms increases with the duration of HIV infection and treatment. Nonetheless, maraviroc is a potent medication for eligible patients and helps to improve the outcome of antiretroviral treatment (ART) of HIV infection.

Baseline CD4+T-cell counts and weighted background susceptibility scores strongly predict response to maraviroc regimens in treatment-experienced patients

Maraviroc-containing regimens are known to achieve virological suppression in many treatment-experienced patients. This study aimed to evaluate a more rigorous methodological approach to resistance-response analysis in large clinical studies and to better establish which subpopulations of patients were most likely to benefit from maraviroc by refining and extending previous subgroup analyses from the MOTIVATE studies. Individual weighted optimized background therapy (OBT) susceptibility scores were calculated by combining genotypic or phenotypic resistance testing with prior drug use information. Virological response (HIV-1 RNA<50 copies/ml at week 48) using each of these methods was compared with a commonly used method of counting active drugs. Baseline predictors of virological response, including weighted or unweighted scoring, maraviroc use, baseline CD4(+) T-cell count, HIV-1 plasma viral load and tropism, were assessed by logistic regression modelling. Genotypic or phenotypic weighted methods were similarly predictive of virological response and better than counting active drugs. Weighted scoring and baseline CD4(+) T-cell count were the strongest predictors of virological response (P<0.0001): ≈70% of maraviroc patients with a weighted score ≥2 had a virological response, rising to ≈80% when the baseline CD4(+) T-cell count was ≥50 cells/mm(3). Approximately 80% of patients with a CD4(+) T-cell count ≥50 cells/mm(3) receiving maraviroc with the equivalent of at least two fully active agents achieved HIV-1 RNA<50 copies/ml at week 48 in the MOTIVATE studies. Genotypic and phenotypic weighted scores were similarly predictive of virological response.

Maraviroc for Treatment‐Naive Patients with HIV‐1 Infection: Is the Glass Half Empty or Half Full?

In 2007, the US Food and Drug Administration (FDA) approved maraviroc for the treatment of human immunodeficiency virus type 1 (HIV-1) infection, making it the first (and to date only) CCR5 antagonist available for clinical use. Approval stipulated that maraviroc be used only in treatment-experienced patients who have viremia with a virus using the CCR5 receptor (R5 virus)—the latter being a critical limitation because maraviroc has no antiviral activity against non– CCR5-using viruses. Because a substantial proportion of treatment-experienced patients harbor these strains—roughly 50% in surveys using the original tropism assay [1]—maraviroc use thus far has been necessarily limited. Unlike in treatment-experienced patients, R5 viruses are the dominant type in transmission and predominate early during HIV disease, with an estimated 80% of untreated patients having R5 strains [2]. It is therefore plausible that maraviroc would have its greatest role earlier during HIV disease, especially among

Maraviroc and CD4+ cell count recovery in patients with virologic suppression and blunted CD4+ cell response

We wish to comment on the recent Editorial review on maraviroc by Soriano et al.[1]. Their suggestion that the drug could be used for managing the subset of patients unable to show an adequate CD4 cell recovery despite achieving sustained virological suppression with highly-active antiretroviral therapy (HAART) [1] has been tested in a recent nonrandomized, prospective, open-label, proof-of-concept pilot study with a minimum follow-up of 150 days, where maraviroc 300 mg was added to an ongoing HAART regimen in nine HIV-infected individuals on stable HAART with HIV-1 RNA less than 50 copies/ml for at least 1 year and a stable CD4+ cell count of less than 250 cells/mm3[2]. Although two patients showed dramatic increases in CD4 cell counts (+112 and +130), the average change was +14 cells for all patients, and was not statistically significant (P > 0.39). Obviously, further studies with a longer follow-up will be required to eventually demonstrate a significant effect of maraviroc. Importantly, Soriano et al.[1] failed to discuss possible drawbacks of maraviroc use in certain HIV-infected individuals. A significant increase in CCR5Δ32 allele prevalence has been found in patients with tickborne encephalitis (TBE, an often fatal infection caused by the TBE virus, TBEV), compared with that in patients with non-TBE aseptic meningoencephalitis and in healthy control individuals seronegative for TBEV [3]. In addition, functional CCR5 seems to be required to prevent symptomatic disease after infection with West Nile virus (WNV), an RNA flavivirus that can cause neuroinvasive disease, particularly in patients with impaired cellular immunity [4]. Indeed CCR5 is specifically required for central nervous system leukocyte trafficking for the purpose of viral clearance, as shown in mouse models [5]. We think that attention needs to be drawn to this possible caveat of maraviroc use, considering the diffusion of TBEV in Eastern Europe, a region where HIV infection is still on the rise, and of WNV in USA. Acknowledgements None of the authors have any conflict of interest. Massimiliano Lanzafame, Emanuela Lattuada and Sandro Vento contributed to the concept and writing of the article. All authors have read and approved the text.

Maraviroc: A coreceptor CCR5 antagonist for management of HIV infection

The mechanism of action, pharmacology, pharmacokinetics, clinical efficacy, drug interactions, adverse effects, dosage and administration, cost, and role in therapy of maraviroc are reviewed. Maraviroc is the first CCR5 coreceptor antagonist to receive marketing approval from the Food and Drug Administration (FDA) for the treatment of CCR5-tropic human immunodeficiency virus (HIV) infection as part of an optimized antiretroviral regimen in treatment-experienced patients. As 50% or more of treatment-experienced patients may be infected with CXCR4-tropic virus, a tropism assay should be performed before initiating maraviroc therapy. The majority of evidence supporting maraviroc's use comes from two studies of HIV-infected, treatment-experienced patients. Pooled analysis from these two studies revealed that twice-daily maraviroc decreased HIV-1 RNA by 1.84 log copies/mL, compared with 0.78 log copy/mL with placebo. Forty-six percent of subjects attained an HIV-1 RNA concentration of <50 copies/mL, compared with only 17% with placebo. In a trial of treatment-naive HIV-infected individuals, maraviroc failed to show noninferiority to efavirenz. Maraviroc is metabolized by cytochrome P-450 isoenzyme 3A4 and is subject to interactions with inhibitors and inducers of that isoenzyme, such as the protease inhibitors (except tipranavir), efavirenz, and rifampin. Resistance has been reported with maraviroc, but specific mechanisms are still poorly understood. The most common adverse effects reported with maraviroc were diarrhea, nausea, fatigue, and headache. Available data support the use of maraviroc, the first CCR5 antagonist to receive FDA marketing approval, as part of an optimized antiretroviral regimen in treatment-experienced patients infected with CCR5-tropic HIV.