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PRIORITY PRESS - 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

San Francisco, California / September 12-15, 2009

Efficacy was once the single most important criterion for evaluating antiretroviral therapies (ARTs) because of the limited treatment options and the potential for a fatal outcome when HIV control could not be sustained. However, there is now a broad array of agents in six antiretroviral classes that permit other considerations, particularly safety, to assume a more important role in treatment selection. New data from recent additions to the ART classes have suggested that the newer options may provide significant advantages over older agents in regard to both immediate tolerability and long-term safety.

MERIT Lipid Analysis at 96 Weeks

“In newly generated data from MERIT (Maraviroc versus Efavirenz Regimens as Initial Therapy), increases in LDL-C, triglycerides and total cholesterol were all greater in those patients randomized to efavirenz relative to maraviroc, and a higher proportion of patients on efavirenz experienced lipid levels above those recommended by the National Cholesterol Education Panel [NCEP] guidelines,” reported Dr. Adriano Lazzarin, San Raffaele Scientific Institute, Milan, Italy. “Overall, maraviroc is lipid-neutral.”

In fact, the CCR5 inhibitor maraviroc has generally been neutral for adverse events overall. In the placebo controlled trials, there was no difference in discontinuation rates for adverse events between maraviroc and control patients, and the only adverse events more common to the CCR5 inhibitor in the currently recommended dose than placebo was fever (6% vs. 2%; P=0.04) and headache (5% vs. 2%, P=0.03). In the phase III MERIT study, which compared maraviroc to efavirenz in treatment-naive patients when both were combined with zidovudine (AZT) and lamivudine (3TC), the rate of discontinuations attributed to an adverse event was 13.2% in the efavirenz group vs. 4.2% in the CCR5 inhibitor group.

Findings from VICTOR-E1

Similar results have been reported with vicriviroc (VCV), a CCR5 inhibitor in development that has now entered phase III studies. In the newly reported 96-week results from the phase II VICTOR-E1 (Vicriviroc in Combination Treatment with Optimized antiretroviral Regimen in Experienced subjects) study, tolerability has been a prominent feature. Initially, the double-blind VICTOR-E1 study randomized treatment-experienced patients to 20 mg VCV, 30 mg VCV, or placebo in combination with a ritonavir-boosted protease inhibitor (PI/r) plus optimized background therapy (OBT). At the end of the 48 weeks, both doses of VCV were active and well tolerated, but the 30-mg dose was selected for further development.

The 96-week results are based on an open-label extension study that enrolled 85 individuals who had participated in the double-blind portion of VICTOR-E1. As in the MERIT study, there was a small but steady increase in the proportion of patients with a viral load <50 copies/mL and <400 copies/mL over the course of follow-up. This sustained viral control was accompanied by a steep increase in CD4 cell count rising from a mean of 366 cells/mm³ at the time of entry into the extension study to a mean of 422 cells/mm³ at the end of 96 weeks. Sustained viral control is anticipated with all ARTs, but the safety of CCR5 inhibitors has been an important feature.

“VCV was generally well tolerated in this highly treatment-experienced population with no apparent VCV-related toxicities,” reported a team of investigators that included Dr. Edwin DeJesus, Orlando Immunology Center, Florida. “No grade 3 or 4 changes from baseline occurred for any laboratory parameter measured, including liver function tests.”

Virologic Response with CCR5 Inhibitors

With CCR5 inhibitors, high rates of efficacy appear to be assured by confirming the presence of CCR5- tropic HIV. Due to insensitive measures for CCR5, which along with CXCR4 is one of the two co-receptors employed by HIV to bind to and infect target cells, the initial analyses of MERIT placed maraviroc at a slight disadvantage to efavirenz for undetectable viremia at 48 weeks. However, when CXCR4 infections that had been missed by previous screening methods were excluded, maraviroc was at least as effective as efavirenz. This has been further supported by new 96-week analyses that evaluated efficacy by several subgroups, including HIV clade (B or C), race, and gender.

“Maraviroc and efavirenz demonstrated generally similar virologic response rates across subgroups,” stated Dr. William D. Hardy, Cedars-Sinai Medical Center, Geffen School of Medicine, UCLA, Los Angeles, California. Although black patients (53.5% vs. 61%), particularly from the southern hemisphere, and clade C patients (53.3% vs. 67.7%) were more likely to have HIV levels <50 copies/mL on efavirenz relative to maraviroc at 96 weeks, Dr. Hardy reported that reasons other than efficacy, such as compliance, appear responsible. In fact, the rate of discontinuations for lack of efficacy did not differ for these or any other subgroups. According to Dr. Hardy, “No influence of clade, race or gender on time to loss of virologic response outcome on maraviroc was seen in a multivariate analysis which excluded non-virologic discontinuations.”

The more conspicuous difference between therapies for all subgroups was the discontinuation rate for adverse events. Whether white (22.4% vs. 7.8%), black (9.3% vs. 2.6%), clade B (22.9% vs. 8.5%), clade C (6.1% vs. 2.9%), male (16.9% vs. 6.4%) or female (12.2% vs. 5.5%), discontinuation rates for adverse events were higher on efavirenz. This was an unexpected development because efavirenz is generally well tolerated compared to many PIs.

As Dr. Lazzarin reported in his analysis of the lipid findings, “Whether maraviroc will be associated with decreased progression of atherosclerosis in humans as seen in the mouse model remains to be determined.” However, he added that maraviroc “may offer an advantage in patients in whom cardiovascular risk is an issue.”

Immune Reconstitution

In addition to safety, one of the features of the CCR5 inhibitors has been their greater relative improvement in immune reconstitution. In the MERIT study, the rise in the CD4+ cell counts has favoured maraviroc over efavirenz at all time points, including 48 weeks (170 vs. 144 cells/mm³) and 96 weeks (207 vs. 171 cells/mm³). In a new study attempting to explore mechanisms for this difference, the advantage of maraviroc was found to be even greater for those with a baseline viral load greater than 100,000 copies/mL (227 vs. 178 cells/mm³) than in those with a lower baseline HIV RNA (190 vs. 167 cells/mm³). This difference may be due to discrepancies in immune activation.

“Immune activation is a predictor and likely driver of HIV disease progression, decreasing immune activation by maraviroc may decrease CD4+ T cell turnover and increase their numbers,” explained Dr. Nicholas T. Funderburg, Case Western Reserve University, Cleveland, Ohio. “Compared with efavirenz-treated patients, maraviroc-treated patients had earlier modest decrease in several markers of immune activation and inflammation.”

For example, high-sensitivity C-reactive protein (hs-CRP) levels actually increased on efavirenz by week 48 of the study but were unchanged in those taking maraviroc. Interleukin-6 concentrations declined precipitously by week 4 on maraviroc and levels remained below those on efavirenz, which exerted only a mild reduction in this measure of inflammation, over the course of the study. Although the ability of CCR5 inhibitors to raise CD4+ cell counts more than would be anticipated by its antiviral activity alone may very well be due to other mechanisms, relative differences in immune activation and suppression of inflammation appear to be important.

“These observations do not prove that the greater immune reconstitution is related to maraviroc’s effect on markers of immune activation or inflammation, but the observed differences with efavirenz are consistent with that theory,” Dr. Funderburg told delegates.

Summary

The relative safety of the CCR5 inhibitors appears to be a distinguishing characteristic from other ART classes. Tolerability data with the currently available agent, maraviroc, are further supported by a relatively low risk of laboratory abnormalities, including lipid changes, over long-term follow-up. Although VCV is at an earlier stage of development, there are now long-term data to suggest similar freedom from short- and long-term adverse events. The clinical significance of the relative advantage for immune reconstitution with these agents is unclear but future results will be closely followed in the control of HIV in both treatment-naive and treatment-experienced patients.