Real-Life Outcomes of Maraviroc-Based Regimens in HIV-1-Infected Individuals

Abstract

Purpose:

The use of maraviroc in our unit was reviewed with regard to efficacy and safety and also reviewed with regard to how our experience reflects the data presented in clinical trials.

Methods:

We utilized the pharmacy dispensary system to identify any patient dispensed maraviroc and conducted a case note review.

Results:

We identified 27 patients who have been prescribed maraviroc as part of their antiretroviral treatment. In all, 81% were men and 81% were white British. There were 26 treatment-experienced patients and 1 treatment-naive patient. At the time of switching to maraviroc, 17 patients had detectable HIV viral loads and 10 had HIV RNA levels <40 copies/mL. At completion, 6 undetectable patients maintained undetectability and 10 viremically detectable patients achieved viral suppression. Maraviroc was discontinued in 18.5% of patients and the only adverse drug reaction reported was a rash.

Conclusions:

The experience of using maraviroc by our study participants shows similarity in terms of efficacy and safety to the MERIT and MOTIVATE clinical trials.

Introduction

Maraviroc is the first approved drug from a novel class of antiretroviral (ARV) drugs—chemokine receptor 5 (CCR5) antagonists—which block a host protein on the CD4 T cell surface rather than a viral target. ¹ As CCR5 antagonists are not active against C-X-C chemokine receptor type 4 (CXCR4) or dual mixed tropic virus, CCR5 tropism must be confirmed prior to the use of maraviroc. ^2,3

Currently available tropism tests include the phenotypic Trofile assay and the genotypic V3 loop tropism assay. The latter has the advantages of greater accessibility, faster turnaround, and lower cost and can be performed in patients with undetectable or very low HIV RNA levels.

Maraviroc has been shown to be effective in both antiretroviral therapy (ART)-naive and treatment-experienced patients with CCR5 tropic HIV, with a good safety profile even in patients with high cardiac risk factors or comorbidities, such as viral hepatitis or tuberculosis. There is no cross-resistance between maraviroc and other ARV drugs. These characteristics make maraviroc an attractive therapeutic option for use in “real-life” settings, particularly in patients resistant to or intolerant of existing ARV drugs.

We set out to evaluate the efficacy and safety of maraviroc in routine clinical practice.

Methods

Patients on maraviroc-based regimens who had received at least 1 dose of maraviroc were identified using pharmacy records. Demographic, clinical, immunological, and virologic data were collected retrospectively from case notes. Results of HIV RNA and CD4 count from the most recent clinic visit were compared to values prior to switch to maraviroc.

Maraviroc was dosed according to manufacturers’ recommendations, taking into account relevant concomitant medications, ^4,5 that is standard dose of 300 mg twice daily (BID), 150 mg BID if coadministered with a significant cytochrome P450 inhibitor (eg, ritonavir [RTV]), or 600 mg BID if coadministered with a significant CYP 450 inducer (eg, rifampicin).

Background regimes varied in 70% (19 of 27) of patients also receiving a protease inhibitor (PI), 40% (11 of 27) of patients receiving an integrase inhibitor, and 30% (8 of 27) of patients receiving etravirine.

Coreceptor tropism testing was performed in 81% (22 of 27) of patients. Prior to 2010, tropism was determined using the commercial Trofile assay (Monogram Biosciences, San Francisco; n = 16). Tropism testing after 2010 (n = 6) utilized a genotypic v3 loop algorithm performed at The Clinical Virology Department of the Manchester Medical Microbiology Partnership (MMMP), using a false positive rate of 5.75%. ⁶

Results

In all, 27 patients were on maraviroc-based regimens, of whom 81% were men and 81% were white British. Median age at maraviroc initiation was 41 years (range, 20-56 years).

Median nadir and pre-maraviroc initiation CD4 counts were 112 cells/mm³ (range, 10-411 cells/mm³) and 272 cells/mm³ (range, 15-1086 cells/mm³), respectively.

Of all, 20 patients had CCR5 tropic virus, 1 patient had mixed tropism, and 1 patient with undetectable viral load in plasma (<40 copies/mL) failed genotypic tropism testing on a peripheral blood mononuclear cells sample.

Of the 6 patients in whom no tropism test was available prior to their maraviroc regime, 2 became undetectable, 2 maintained undetectability, 1 was lost to follow-up, and 1 patient died. The patient who died had maraviroc initiated during an admission for a respiratory illness from which she did not recover.

There were 26 ART-experienced patients and 1 treatment-naive patient who had commenced maraviroc as part of a clinical study. Those with ≥10 previous regimens accounted for 46.2% (12 of 26) of the cohort. Although the majority of patients (17 of 27) who switched to a maraviroc-containing regimen had detectable viremia on their current ARV regimen, there were 10 patients with HIV viral load <40 copies/mL at the time of switching. Reasons for use of maraviroc in these individuals included toxicity with current ARV drugs and the need for regimen with less potential for drug interactions.

At the completion of follow-up (median, 59 weeks; range, 3-281 weeks), 59% (10 of 17) of the participants with detectable HIV RNA at maraviroc initiation achieved a viral load of <40 copies/mL, while 60% (6 of 10) of those switching with HIV RNA <40 copies/mL maintained undetectable viral loads. Overall, 78% (21 of 27) of patients achieved good virologic response (defined as HIV viral load <40 copies/mL or >1 log drop from baseline) by the end of their follow-up period regardless of whether tropism testing was performed appropriately. There was no difference in the likelihood of a good virological outcome based on whether a PI was included in the background regime or not (P = .32, Fischer exact).

Absolute CD4 counts increased post maraviroc in 78% (21 of 27), remained unchanged in 11% (3 of 27), and decreased in 11% (3 of 27) of the cases.

Maraviroc was discontinued in 18.5% of patients (5 of 27). The reasons noted were poor compliance (2), hypersensitivity skin rash (1), change in coreceptor tropism status (patient did not become undetectable after initiating maraviroc and may have had a treatment interruption) (1), and death attributed to advanced HIV disease (1). Skin rash was observed in a patient on concomitant RTV-boosted darunavir therapy while the change in coreceptor tropism was observed in a patient who was originally tested using the Trofile assay.

Discussion

We evaluated the outcomes of maraviroc-based regimens in routine clinical practice. Our HIV cohort includes a significant proportion of heavily treatment-experienced patients with low nadir CD4 counts. Also relevant is the concern that maraviroc will not be effective in treatment-experienced patients because of a significant percentage carrying non-CCR5 tropic virus (estimates of up to 50% in some studies ⁷ ), and the relative expense of maraviroc with respect to other ARV drugs.

However, when considering salvage regimens, maraviroc does not share any cross-resistance with other ARV drugs, and treatment failure due to the presence of maraviroc-resistant isolates, other than CXCR4 tropic virus, is uncommon, ^{8 –10} making it a favorable choice. If virologic failure occurs, it is suggested that possible mechanisms could include unidentified CXCR4 tropic virus during determination of tropism, coreceptor switching or a mutation of a CCR5 to CXCR4 tropic virus or a phenotypic resistance to maraviroc in a CCR5-tropic variant. In clinical practice, switch from CCR5 tropism to CXCR4 has not been shown to occur with any significant frequency. We observed a change in coreceptor tropism in only 1 patient who failed to become undetectable after initiating maraviroc. Possible reasons for a tropism switch include a suboptimal maraviroc dose and background regime (the patient had been prescribed a boosted PI-containing regime, but it appears the patient omitted their RTV for a while) or incorrect initial classification as CCR5 inhibitor sensitive (the patient had their tropism determined by the original Trofile test which is recognized as having a lower sensitivity for minority CXCR4 variants). ¹¹ Of the 17 of our study patients, 10 (59%) with detectable HIV viral loads, who switched to a maraviroc-containing salvage regimen, achieved HIV RNA levels <40 copies/mL, as compared with 44% in the MOTIVATE 1 and 2 trials (combined data) that utilized an HIV RNA assay with cutoff of 50 copies/mL. Use of CCR5 inhibitors has been reported as being associated with an enhanced immunological response. In MOTIVATE 1 and 2, the increase in CD4 count was higher in patients receiving maraviroc, compared with non-CCR5 inhibitor containing salvage regimens (120 vs 61 cells/mm³, respectively). We observed a median increase in CD4 count of over 100 cells in our cohort post maraviroc. Overall, 78% of our patients had good virologic response to maraviroc, achieving an undetectable viral load (HIV RNA <40 copies/mL) or >1 log drop from baseline, and 75% had an increase in CD4 counts following initiation of maraviroc.

Maraviroc has been well tolerated in clinical trials and was similarly well tolerated by our patients, as evidenced by a discontinuation rate of only 18.5%, compared with 33% in the MERIT study ¹² and 5% in the MOTIVATE trials. In studies the most common 5 adverse drug reactions reported compared with placebo were upper respiratory tract infections (20.0% vs 11.5%), cough and associated symptoms (12.7% vs 4.8%), pyrexia (12.0% vs 8.1%), rash (9.6% vs 4.8%), and musculoskeletal or connective tissue signs and symptoms (8.7% vs 7.7%). Only 1 of our cohort who discontinued maraviroc did so because of an adverse drug reaction, that is rash. Although a potential risk of hepatic toxicity has been raised by the manufacturers, this has not been observed in clinical practice, including our cohort.

In summary, in our cohort of heavily ART-experienced patients, the rates of virological suppression and incidence of adverse drug reactions were similar to the data presented from the MOTIVATE studies. We therefore conclude that maraviroc-based regimens are efficacious and safe to administer under routine clinical conditions.