Reports

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PRIORITY PRESS - Fifth International AIDS Society (IAS)

Cape Town, South Africa / July 19-22, 2009

The CCR5 (R5) entry inhibitor maraviroc (MVC) blocks cellular entry of R5-tropic HIV-1 by binding to the R5 co-receptor on the cell surface and blocking its interaction with the V₃ loop (gp120 viral envelope). While most HIV viruses use the CCR5 co-receptor as the point of entry, some use the CXCR4 entry, and some may have dual/mixed (R5/X4) virus despite an R5 result with the tropism assay. In clinical trials, the sensitivity of the tropism assay is such that it may allow up to 10% of patients screened as having R5-tropic virus to be really of dual/mixed-tropic virus.

The MERIT (Maraviroc versus Efavirenz Regimens as Initial Therapy) study evaluated the efficacy and safety of MVC in combination with zidovudine/lamivudine (CBV) in comparison with efavirenz (EFV) and CBV in treatment-naive patients with R5 HIV-1 living in both the northern and southern hemispheres. MERIT used the less sensitive Trofile assay, and while MVC efficacy was demonstrated, it was 4.2 % less effective than EFV in attaining HIV RNA <50 copies/mL and non-inferiority to EFV could not be demonstrated.

MERIT-ES: 48-week Re-analysis

In a retrospective analysis of MERIT with a new enhanced-sensitivity Trofile assay (MERIT-ES), 15 % (106 patients) originally identified with CCR5-tropic virus were reclassified as having dual or mixed tropic virus. A post-hoc reanalysis of MERIT, MERIT-ES, excluding patients with non-R5 virus was led by Dr. Mark Nelson, Chelsea and Westminster Hospital, London, UK. Improved response with MVC across the randomization strata at 48 weeks was observed. The improvement was greater in patients with a higher baseline viral load. EFV discontinuations due to adverse effects (AEs) were three times higher than on MVC (13.6% [49/361] vs. 4.2% [15/360], occurred earlier (78% by week 16 vs. 60%) and were more viremic at >50 copies/mL before discontinuation: 69% vs. 60%, respectively. In EFV-treated patients who discontinued due to AEs, 14.3% developed new EFV-associated mutations while no CXCR4-using virus occurred in those discontinuing MVC due to AEs.

Results at 96 Weeks

Continuing with the ES Trofile assay, Dr. Michael Saag, University of Alabama at Birmingham Medical Center, reported on the 96-week results, which randomized R5 HIV-1 patients to MVC 300 mg b.i.d. or EFV 600 mg q.d. A similar rate of response with viral loads of <50 copies/mL by intent-to-treat (ITT) (58.8% and 62.7%) and by time-to-loss of virologic response (TLOVR) (60.5 % and 60.7%) was observed between MVC and respectively). According to the TLOVR analysis, the non-inferiority criteria for MVC compared to EFV were met (Figure 1).

Figure 1.

Notably, the increase in CD4 T-cell count from baseline was significantly greater with MVC than with EFV with a median change of +212 cells/mm³ and +171 cells/mm³, respectively.

Results at 96 weeks yielded no new safety findings and discontinuation due to AEs were reported at 18.5% (n=56) for the EFV-treated cohort vs. 6% (n=22) for the MVC-treated group.

According to Dr. Saag, an added advantage for using MVC as a first-line treatment option in R5-tropic patients included its maintained greater CD4+ cell count and the fact that lipid outcomes favoured the novel agent. More patients on EFV exceeded National Cholesterol Education Program (NCEP) thresholds than those on MVC for total cholesterol (38.7% vs. 10.8%, P<0.0001) and LDL-C >3.4 mmol/L (27.4% vs. 6.3%) and >4.1 mmol/L (9.9% vs. 1.5% both P<0.0001).

The durable response and safety profile of MVC “offer the potential to enhance currently available treatment options for treatment-naïve HIV patients,” concluded Dr. Saag.

MOTIVATE Trials

As CCR5 receptors are located on cholesterol-rich rafts within cell membranes, studies have been conducted to determine whether or not statins influence the efficacy of MVC. A post-hoc analysis of the MOTIVATE studies was conducted to determine the continued efficacy of MVC administered with statins.

The MOTIVATE (Maraviroc Versus Optimized Therapy in Viremic Antiretoviral Treatment Experienced Patients) 1 and 2 studies proved the efficacy of MVC over placebo in triple class-resistant and/or experienced patients with R5 tropism. Results were taken at 48 weeks with changes from baseline in HIV-1 RNA and CD+ cell counts for the combined MVC and PBO treatment groups, stratified by statin use: patients on statins were defined as such if statins were started prior to baseline and they remained on statins throughout the study or stopped no less than 300 days’ post-baseline. Over one hundred (n=103) out of 1049 patients received statins overall with similar proportions in the PBO and MVC groups. At baseline, both the “no statin” (NS) and “statin” (S) groups had similar HIV-1 RNA concentrations across the two treatment arms: 4.9 vs. 4.9 log₁₀ copies/mL (MVC vs. PBO) in NS and 4.6 vs. 4.5 log₁₀ copies/mL in S.

The results from this study revealed that a mean week 48 reduction in HIV-1 RNA was comparable between the two statin groups: -1.7 vs. -0.8 log₁₀ copies/mL (MVC vs. PBO) in NS and -1.9 vs. -0.6 log₁₀ copies/mL in S. Proportions with HIV-1 RNA <50 copies/mL at week 48 (MVC vs. PBO) were 47% vs. 20% and 57% vs. 11% in NS and S, respectively. Median week 48 increases in CD4+ cells (MVC vs. PBO) were 103 vs. 29 cells/mm³ and 75 vs. 11 cells/mm3 for the NS and S groups, respectively.

Investigators reported that no interaction between MVC and statin use was found on the odds of achieving a viral load <50 copies/mL and median changes in CD+ cell counts were broadly comparable between the two groups. On the basis of these results, the researchers concluded that statins do not appear to interfere with the efficacy and non-inferiority of MVC as a R5 entry inhibitor.

Prevention Strategy: The Microbicide Potential

The topical blockade of R5 is a potential prevention strategy in the fight against HIV infection. Dr. Annalene Nel, Paarl, Western Cape, South Africa, presented a preclinical evaluation of MVC, using ex vivo genital and colorectal tissue to determine its suitability as an anti-HIV microbicide. It was assessed for biocompatibility and efficacy (HIV-1_BaL) in TZM-bl cells and human cervical, penile and colorectal tissue explants. Data demonstrated that MVC was able to inhibit HIV-1 infection of genital and colorectal tissue cultured ex vivo and that its potency could be increased through sustained delivery. Dr. Nel concluded that MVC was a good candidate for development as a microbicide in both developed and developing countries.

Summary

Targeting the right population with the appropriate treatments provides enhanced responses. While most HIV patients have the R5 virus, the new ES Trofile assay can better identify those with mixed tropism. In excluding those CXCR4 or mixed tropism patients from analysis in MERIT-ES, it has validated the non-inferiority of MVC to EFV with a comparable durable response. There appears to be a significantly more favourable lipid profile observed with the use of MVC than with EFV and an analysis has shown it maintained efficacy whether or not co-administered it was with a statin. In prevention strategies, ongoing research with topical R5 blockade may help slow the HIV epidemic.