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The CCR5 coreceptor may be a therapeutic target to block HIV infection. HIV-1–infected patients who had received previous antiretroviral treatment were enrolled in one of two phase 3, placebo-controlled, double-blind international studies of treatment with maraviroc (a CCR5 antagonist). Maraviroc significantly lowered the HIV-1 viral load and increased the CD4 cell count at 48 weeks. The CCR5 coreceptor may be a therapeutic target to block HIV infection. In two studies, maraviroc (a CCR5 antagonist) significantly lowered the HIV-1 viral load and increased the CD4 cell count at 48 weeks. For the past decade, treatment of human immunodeficiency virus type 1 (HIV-1) has consisted of a multiple-drug regimen targeting one or more of three HIV-1 proteins: reverse transcriptase, protease, and the glycoprotein envelope subunit gp41. 1 Although these antiretroviral combinations are successful in suppressing viral replication and delaying disease progression, drug resistance and toxic effects may occur. 2 – 4 There is therefore a need for better-tolerated, convenient antiretroviral agents with reduced toxicity and activity against multidrug-resistant viruses. Agents with novel mechanisms of action provide options for patients with drug-resistant virus. 4 CC chemokine receptor 5 (CCR5) is an attractive therapeutic target, since people . . .

Background. BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529, which inhibits human immunodeficiency virus type 1 (HIV-1) infection by binding to gp120 and interfering with the attachment of virus to CD4+ T-cells. Methods. Fifty HIV-1-infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068. Results. The maximum median decrease in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log₁₀ copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding-adjusted 90% inhibitory concentration (inhibitory quotient), were linked with antiviral response. BMS-663068 was generally well tolerated. Conclusions. Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted.

Enfuvirtide (T-20) is a peptide that binds to glycoprotein 41 and inhibits the entry of human immunodeficiency virus type 1 (HIV-1) into CD4+ cells. In this randomized, open-label trial, patients who were treated with enfuvirtide plus an optimized antiretroviral regimen had significantly greater reductions in viral load and greater increases in CD4+ cell counts. Eosinophilia was a common finding; bacterial pneumonia was more common in enfuvirtide-treated patients. Data on safety and efficacy of the first HIV-1 fusion inhibitor. The durability of suppression of human immunodeficiency virus (HIV) infection with antiretroviral therapy is often limited, for reasons that include poor penetration into protected sites containing a reservoir of HIV, 1 , 2 drug toxicity, 3 , 4 alterations in the bioavailability and metabolism of antiretroviral drugs (e.g., interactions between drugs), 5 and lack of adherence to complex treatment regimens. 6 , 7 These factors contribute to persistent viral replication in patients receiving therapy, increasing the risk of viral resistance, which can limit future treatment options. 8 , 9 Salvage therapy after viral rebound is more successful if an agent from a class of antiretroviral drugs to which the . . .

In key subgroups of the HIV-infected patients in the MOTIVATE 1 and MOTIVATE 2 studies, a consistent treatment benefit of maraviroc over placebo was seen at 48 weeks. These subgroups include patients with a low baseline CD4 cell count and a high HIV viral load at screening and those receiving no active background antiretroviral agents. In patients in whom maraviroc failed, the CXCR4-using virus was often present at failure. In key subgroups of HIV-infected patients, a consistent treatment benefit of maraviroc over placebo was seen at 48 weeks. These subgroups include patients with a low baseline CD4 cell count and a high HIV viral load at screening and those receiving no active background antiretroviral agents. The CC chemokine receptor 5 (CCR5) antagonist maraviroc has shown potent antiviral activity in vitro and in vivo against the R5 human immunodeficiency virus type 1 (HIV-1). 1 , 2 As reported by Gulick et al. 3 elsewhere in this issue, treatment with maraviroc plus optimized background therapy was associated with significantly greater virologic and immunologic efficacy and had a similar safety profile, as compared with placebo plus optimized background therapy, in the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies at 48 weeks. Subgroup analyses of data from recent trials evaluating new drugs in patients . . .

This randomized study, conducted in Europe and Australia, included 335 patients in the enfuvirtide group and 169 in a control group treated with only an optimized antiretroviral regimen. All patients had previously received multiple anti-HIV regimens. At 24 weeks, there was a greater decrease in the plasma viral load and a greater increase in the CD4+ cell count in the enfuvirtide group. The use of highly active antiretroviral therapy has proved extremely successful over the past several years. 1 , 2 However, in about 50 percent of patients, viral suppression is incomplete, and patients are obliged to switch from one combination of antiretroviral drugs to another to combat resistant virus. 3 Cross-resistance within each of the three classes of approved antiretroviral drugs is extensive and often limits the treatment options for patients who are receiving their third or fourth regimen. 4 – 6 New classes of drugs directed at targets other than the reverse transcriptase or protease would be of great benefit. Enfuvirtide (previously known as T-20) . . .

BackgroundMaraviroc, a CCR5 antagonist, is active against R5 but not X4 or dual- or mixed-tropic strains of human immunodeficiency virus type 1 (HIV-1). A phase 2b study was conducted to determine the safety and efficacy of maraviroc in combination with optimized background therapy in treatment-experienced patients infected with dual- or mixed-tropic HIV-1 MethodsTreatment-experienced patients with an HIV-1 RNA level ⩾5000 copies/mL who had received ⩾3 classes of drugs and/or were infected with virus resistant to 2 drug classes and were infected with non-R5 HIV-1 were randomized to receive optimized background therapy plus maraviroc (once or twice daily) or placebo. The primary end point was change in HIV-1 RNA level from baseline to 24 weeks ResultsAmong 167 patients infected with dual- or mixed-tropic HIV-1, baseline mean HIV-1 RNA levels were >5 log10 copies/mL and median CD4+ cell counts were <50 cells/μL. From baseline to 24 weeks, patients who received placebo demonstrated a mean decrease in HIV-1 RNA levels of 0.97 log10 copies/mL, compared with mean decreases of 0.91 and 1.20 log10 copies/mL for those who received maraviroc once (P=.83) or twice (P=.38) daily, respectively. Mean increases in CD4+ cell counts from baseline were 36 cells/μL for patients who received placebo, 60 cells/μL among patients who received maraviroc once daily, and 62 cells/μL among patients who received maraviroc twice daily. The incidences of serious adverse events were similar among groups ConclusionsIn this exploratory study involving extensively treatment-experienced patients with advanced, non-R5 HIV-1 infection, neither superiority nor noninferiority was statistically demonstrated for either maraviroc dosage compared with placebo at 24 weeks of treatment Trial registrationClinicaltrials.gov identifier NCT00098748

Background Long acting antiretroviral drugs represent a promising approach for chronic treatment of HIV infection. Here, we study the efficacy and safety of albuvirtide (ABT), an HIV-1 fusion inhibitor with a half life of 11–12 days in human. Methods ABT was evaluated in a 7-week, open-label and randomized trial, combining with LPV/r. Twenty HIV-1-infected adults were assigned to two dose groups, receiving ABT (160 or 320 mg) given weekly and LPV/r given twice daily. Results At week 7, the decline of HIV-1 RNA from baseline was 1.9 (1.3–2.3) log 10 and 2.2 (1.6–2.7) log 10 copies/ml, and suppression of HIV-1 RNA to below 50 copies/ml was achieved in 11.1 % (1/9) and 55.6 % (5/9) patients, for the 160 and 320 mg dose group respectively. Conclusion A clear dose-efficacy correlation of ABT was demonstrated. ABT combining with LPV/r is a promising two-drug regimen to be tested in larger patient population.

Background In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm. Methods We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses. Results During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20–11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67–39.6], p < 10 −3 ) were significantly associated with a grade 2 or more ALT elevation during follow-up. Conclusion The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT. Trial registration: ClinicalTrials.gov identifier: NCT00454337

New treatments are needed for multidrug-resistant (MDR) HIV-1 infection. In this single-group, open-label study, ibalizumab, an IgG4 monoclonal antibody that blocks HIV-1 entry by noncompetitively binding CD4, had antiviral activity against MDR HIV-1.

The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post-approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4-tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug-drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus-host disease, and inflammatory diseases.