IAS: Maraviroc slightly less effective but more tolerable in treatment-naive patients

HIV-positive patients starting treatment for the first time were slightly less likely to achieve HIV viral loads less than 50 copies/ml with maraviroc (Celsentri) than with efavirenz (Stocrin / Sustiva), according to a late-breaker presentation on Wednesday at the Fourth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention in Sydney.

However, maraviroc led to fewer side effects than efavirenz, and it performed equally well among patients in the Northern hemisphere.

Maraviroc is the first of a new class of drugs, called CCR5 chemokine antagonists, to reach phase III studies. It was approved for treatment-experienced patients in Europe last week. A final decision on US marketing approval for the use of maraviroc in treatment-experienced patients is awaited. In June, the US Food and Drug Administration delayed approval of maraviroc because the agency wanted more information to address potential safety concerns.

Earlier this year, researchers reported that about 45% of highly treatment-experienced patients who added maraviroc to an optimised background regimen achieved viral loads below 50 copies/ml, compared with about 25% of those who added placebo.

The findings presented in Sydney were from a study of maraviroc in treatment-naive patients.

The MERIT trial recruited HIV-positive individuals who had been screened for viral tropism. Different strains of HIV can use one of two co-receptors to enter cells: CCR5 or CXCR4. Since maraviroc blocks the CCR5 co-receptor, the study only enrolled patients who were found to have exclusively CCR5-tropic virus.

The study recruited 721 individuals (29% women) with an average age of about 37 years. Nearly 400 were from the Northern hemisphere and just over 300 were from the Southern hemisphere countries of Argentina, Australia and South Africa.

Participants were randomly assigned to receive either maraviroc or efavirenz. All participants also received a nucleoside reverse transcriptase inhibitor backbone of AZT plus 3TC, using the Combivir fixed-dose combination pill.

The MERIT study was originally designed to compare once-daily and twice-daily dosing of maraviroc with once-daily efavirenz, but the once-daily maraviroc arm was stopped in January 2006 after an interim analysis by the trial’s Data and Safety Monitoring Board found that patients in the once-daily arm were more likely to experience virological failure. These patients were not included in the analysis presented in Sydney.

Baseline characteristics were similar in the maraviroc and efavirenz arms. Slightly over half were white and about 35% were black. At study entry, all participants had viral loads of at least 2000 copies/ml, with a median of about 70,000 copies/ml (4.8log₁₀ copies/ml). The median CD4 cell count was about 250 cells/mm³.

The combined primary endpoint was the proportion of patients achieving viral loads below 400 copies/ml and below 50 copies/ml at week 48. On the first measure, the study showed a statistically non-inferior outcome for maraviroc: 70.6% of patients in the maraviroc arm achieved viral loads below 400 copies/ml, compared with 73.1% in the efavirenz arm.

However, using the more sensitive measure, maraviroc was found to be inferior: 65.3% of patients in the maraviroc arm achieved viral loads below 50 copies/ml, compared with 69.3% in the efavirenz arm. However, the cut-off for non-inferiority was stringent, and presenter Michael Saag of the University of Alabama in the United States said the results “fell just short” of the target.

Analysing patients according to baseline viral load, the investigators found a substantial difference between efavirenz and maraviroc in those with high viral load (above 100,000 copies/ml). While 66.6% of the efavirenz group achieved viral load below 50 copies/ml, 59.6% of the maraviroc group achieved viral load below 50 copies/ml. In those with viral load below 100,000 copies, viral suppression rates were very similar (71.6% EFV vs 69.6% MVC).

When the participants were analysed separately by geographical region, the study found that patients in the Northern hemisphere taking maraviroc and efavirenz were equally likely to achieve viral loads below 50 copies/ml (68.0% and 67.8%, respectively).

But in the Southern hemisphere there was a clear difference: 62.1% taking maraviroc and 71.0% taking efavirenz achieved viral loads below 50 copies/ml, and it was this difference that was reflected in the overall combined results.

Maraviroc-treated patients experienced a greater mean CD4 cell increase of 170 cells/mm³, compared with 144 cells/mm³ in the efavirenz group, but the clinical relevance of this small difference is not clear.

Overall, participants taking both drugs were equally likely to stop taking them prematurely: 26.9% for maraviroc and 25.2% for efavirenz.

However, the reasons for discontinuation differed in the two arms. Patients taking maraviroc were significantly more likely to experience virological failure during the 48-week follow-up period, most of which occurred early on. Whilst 11.9% stopped maraviroc for this reason, only 4.2% did so in the efavirenz arm.

Maraviroc, however, was better tolerated. Just 4.2% of maraviroc-treated patients stopped therapy due to adverse events, compared with 13.6% in the efavirenz arm. Further, significantly more efavirenz-treated patients experienced serious (grade 3 or 4) adverse events. As expected patients taking efavirenz were more likely to experience neuropsychiatric side effects such as dizziness and abnormal dreams. Those taking maraviroc had somewhat more nose and throat infections, and more bronchitis.

There were fewer malignancies reported in the maraviroc-treated group (one case) compared with the efavirenz group (four cases). This is an important observation, because a previous study of another CCR5 chemokine antagonist, vicriviroc, has found eight cases of cancer in patients receiving the drug. Although that study’s Data and Safety Monitoring Board concluded that there was no causal link between vicriviroc and the cancers, concerns persist about the potential long-term side-effects of altering chemokine activity in the human body.

Similar proportions of patients in the maraviroc and efavirenz arms experienced severe (grade 3 or 4) liver enzyme increases, which were uncommon in both groups. This also addresses an outstanding concern, since GlaxoSmithKline abandoned the development of its CCR5 antagonist after a number of cases of severe liver toxicity were reported in treatment-naïve HIV-positive study participants.

With regard to blood fat changes, patients taking efavirenz had larger increases in total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides, which are associated with a greater risk of cardiovascular disease. However, this group also had a larger increase in protective high-density lipoprotein (HDL) cholesterol.

In a discussion following the presentation, Dr. Saag said it was unclear why the results differed in the Northern and Southern hemispheres – given that the data are less than 30 days old and are still being analysed – but he suggested this might be due to difference in HIV clades in the regions or in the accuracy of test results.

Another question arising from this study is to what extent patients with mixed-tropic virus (a mixed population of CCR5-tropic and CXCR4-tropic strains) might have slipped through the screening test due to the lack of sensitivity of the Trofile assay used for tropism detection.