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.

/pdf/maraviroc-a-review-of-its-use-in-hiv-infection-and-beyond-2qa7yv1ied.pdf

Maraviroc: a review of its use in HIV infection and beyond

Purpose of reviewWith continued improvements to the antiviral efficacy and tolerability of antiretroviral therapy, long-term safety of antiretroviral therapy has become paramount. Low bone mineral density and fragility fractures are more common in HIV-infected individuals than in the general populat

Tenofovir and bone health

Purpose of reviewBecause of antiretroviral therapy (ART), people are living with HIV infection longer than ever before. As this patient group ages, it is expected that medical comorbidities such as osteoporosis and fragility fractures will increase. The purpose of this review is to address the epide

Bone loss in HIV: a contemporary review

Author(s): Gulick, Roy M; Wilkin, Timothy J; Chen, Ying Q; Landovitz, Raphael J; Amico, K Rivet; Young, Alicia M; Richardson, Paul; Marzinke, Mark A; Hendrix, Craig W; Eshleman, Susan H; McGowan, Ian; Cottle, Leslie M; Andrade, Adriana; Marcus, Cheryl; Klingman, Karin L; Chege, Wairimu; Rinehart, Alex R; Rooney, James F; Andrew, Philip; Salata, Robert A; Magnus, Manya; Farley, Jason E; Liu, Albert; Frank, Ian; Ho, Ken; Santana, Jorge; Stekler, Joanne D; McCauley, Marybeth; Mayer, Kenneth H | Abstract: BackgroundMaraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis.MethodsPhase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat.ResultsAmong 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations.ConclusionsMVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis.Clinical trials registrationNCT01505114.

/pdf/phase-2-study-of-the-safety-and-tolerability-of-maraviroc-3hp94no2ec.pdf

Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305).

BackgroundWe conducted a systematic review and meta-analysis (CRD#42017070552) to quantify the impact of oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on bone mineral density (BMD) and...

The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis.

Background. There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)–containing ART.

Methods. This was a double-blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) >1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1:1), stratified by VL <100 000 or ≥100 000 copies/mL and age <30 or ≥30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X-ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population.

Results. We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log10 copies/mL and CD4 count was 390 cells/µL. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of −1.51% [−2.93%, −0.11%] vs −2.40% [−4.30%, −1.32%] for TDF (P < .001). Lumbar spine BMD decline was also less with MVC (median −0.88% vs −2.35%; P < .001). Similar proportions of subjects in both arms achieved VL ≤50 copies/mL in as-treated and ITT analyses.

Conclusions. MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss.

Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT01400412","term_id":"NCT01400412"}}NCT01400412.

/pdf/less-bone-loss-with-maraviroc-versus-tenofovir-containing-45u3ovrugp.pdf

Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study

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Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study