Maraviroc Monotherapy May Be Less Effective Than Combination ART PrEP

Although maraviroc-containing HIV pre-exposure prophylaxis (PrEP) regimens did not increase gut-associated lymphoid tissue (GALT) CD4⁺ T-cell activation that might limit its acceptability as a PrEP agent, maraviroc monotherapy may be less effective than combination antiretroviral therapy (ART) PrEP regimens, according to a study published in AIDS.¹

As part of the HIV Prevention Trials Network 069/AIDS Clinical Trials Group 5305, this tissue substudy aimed to determine whether ART exposure was associated with ex vivo suppression of HIV infection in colorectal explants.

Researchers evaluated changes in GALT T-cell phenotype associated with 4 ART PrEP regimens: maraviroc-alone, maraviroc+emtricitabine, maraviroc+tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate+emtricitabine. Samples were collected at baseline, week 24, and week 48, and after a 1-week washout period (week 49).

Of the 59 men who have sex with men enrolled in the tissue substudy, 55 had the CCR5 chemokine receptor wild-type genotype and 4 were heterozygous, although heterozygosity was not associated with greater suppression of CCR5-tropic HIV viral replication.

Exposure to maraviroc was not associated with increased expression of CD4⁺/CCR5⁺

HIV target T cells. Compared with baseline, the participants in the maraviroc-alone group showed median 0.6 log₁₀ pg/mL cumulative p24 antigen reduction at week 24 (P =.03), but no change at week 48 (P =.48). In contrast, there were significant ex vivo viral suppression in all 3 combination ART groups at both weeks 24 and 48, ranging from 1.4 to 1.8 log₁₀ pg/mL (all P <.02). This remained true at week 49, but the level of suppression was less than at week 48.

In generalized estimating equation analysis, when compared with the standard PrEP regimen (tenofovir disoproxil fumarate+emtricitabine) control group, the maraviroc-alone group demonstrated a much smaller p24 reduction (P =.00001). The 2 maraviroc combination regimens also trended toward statistical significance with cumulative p24 values intermediate between the standard PrEP and maraviroc-alone regimens (both P =.08).

The lack of pharmacodynamic effect with maraviroc has been summarized in other studies,^2-4 in 1 of which,⁴ the study authors demonstrated that explant tissue lost approximately 60% of maraviroc within 1 hour of culture. As such, researchers stressed that the negative explants findings in this substudy may “reflect a technical challenge (such as loss of drug from explant tissue prior to infection), rather than an intrinsic failure of [maraviroc] antiretroviral potency.” They noted that “this issue will be further investigated in the CHARM-03 study [ClinicalTrials.gov identifier: NCT02346084], a Phase 1 pharmacokinetics/pharmacodynamic study in which explant pharmacokinetics was characterized in snap-frozen explant tissue as well as in tissue that had been cultured for 2 hours.”

References

1. McGowan I, Wilkin T, Landovitz RJ, et al. The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM. AIDS. 2019;33(2):237-246.

2. Fletcher P, Herrera C, Armanasco N, Nuttall J, Shattock RJ. Short communication: limited anti-HIV-1 activity of maraviroc in mucosal tissues. AIDS Res Hum Retroviruses. 2016;32(4):334-338.

3. Fox J, Tiraboschi JM, Herrera C, et al. Brief report: pharmacokinetic/pharmacodynamic investigation of single-dose oral maraviroc in the context of HIV-1 pre-exposure prophylaxis. J Acquir Immune Defic Syndr. 2016;73(3):252-257.

4. Coll J, Molto J, Boix J, et al. Single oral dose of maraviroc does not prevent ex-vivo HIV infection of rectal mucosa in HIV-1 negative human volunteers. AIDS. 2015; 29(16):2149-2154.