which blocks both CCR5 and CCR2 receptors on immune cells, is effective against
HIV, better tolerated than current antiretrovirals and has immunomodulatory
activity that may reduce inflammation, according to a presentation yesterday at
the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
development by Tobira Therapeutics, cenicriviroc (formerly TBR-652) blocks
CCR5, one of the two co-receptors HIV uses to enter T-cells. It also interferes
with CCR2, a receptor that binds to monocyte chemo-attractant protein 1 (MCP-1), a
cytokine that promotes migration of monocytes.
Though not fully understood, CCR2 plays a role in inflammation and is
implicated in a range of conditions including liver fibrosis, metabolic
syndrome and cardiovascular disease. A growing body of evidence indicates that
chronic inflammation plays a role in a
variety of non-AIDS-related conditions that help explain why HIV-positive people still
have higher mortality than age-matched HIV-negative people.
Joseph Gathe from Therapeutic Concepts in Houston, Texas, described
findings from Study 202, an ongoing, phase IIb study on
cenicriviroc versus efavirenz (Sustiva orStocrin). The trial will last 48
weeks; Gathe presented data from a 24-week primary analysis.
This dose-finding study included 143 antiretroviral-naive adults who
were tested to ensure that they had exclusively CCR5-tropic (using only the
CCR5 co-receptor) virus. Although more than 90% of participants were men, the group
was racially/ ethnically diverse, with about 60% white, 30% African American
and 25% Latino/Hispanic. The average CD4 cell count was approximately 400
cells/mm3 and about 20% had a high viral load (100,000 copies/ml or
more) at baseline.
Participants were randomly allocated (2:2:1) to receive 100mg or 200mg once-daily
cenicriviroc or 600mg once-daily efavirenz, both with co-formulated
When the study was started only a 50mg cenicriviroc pill was available,
requiring people to take two or four cenicriviroc or matching placebo tablets
with a meal in the morning, one efavirenz tablet or placebo at bedtime and Truvada
At 24 weeks similar proportions of participants in all arms achieved
undetectable HIV RNA (< 5 copies/ml) in an intent-to-treat analysis: 76%
with 100mg cenicriviroc, 73% with 200mg cenicriviroc and 71% with efavirenz.
However, virological non-response rates were significantly higher in the
cenicriviroc groups compared with the efavirenz group (12, 14 and 4%,
respectively). Gathe explained that this was largely attributable to missing
24-week data (counted as failure) because several participants discontinued
treatment ahead of schedule. Likelihood of non-response did not differ
according to baseline viral load, but there was a trend toward decreased response
among people with lower 'trough' or minimum drug concentrations.
Five participants in the cenicriviroc arms developed
nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) mutations in the
cenicriviroc arms, and out of six people tested, one showed a tropism switch,
changing from exclusively CCR5-tropic to dual/mixed tropic (using CXCR4 as well
as CCR5) virus.
CD4 cell gains were good across treatment groups - 147, 170 and 135
cells/mm3, respectively – with a trend toward
a larger increase in the cenicriviroc arms.
The researchers also looked at immune and inflammatory biomarkers to
assess the drug's effect on CCR2. Levels of MCP-1 (the ligand or binding
partner of CCR2) on monocytes increased in a dose-related fashion among
cenicriviroc recipients – suggesting that the
drug was indeed blocking the natural ligand – but remained stable
in the efavirenz arm.
Levels of soluble CD14 (sCD14), a marker of monocyte activation,
decreased in both cenicriviroc arms whilst increasing in the efavirenz arm.
Gathe explained that higher sCD14 was an independent predictor of all-cause
death in the SMART treatment interruption trial.
Cenicriviroc was generally safe and well tolerated. Adverse events were
less common among cenicriviroc recipients and there were no serious adverse events
or deaths observed in any study arm. One person (2%) discontinued cenicriviroc
due to adverse events, compared with 18% who stopped efavirenz.
In general, no meaningful differences in laboratory safety were observed
across arms. However, 14% of patients in the 200mg cenicriviroc group had grade
3-4 creatine phosphokinase (CPK) elevations,
which returned to normal after the end of treatment. Total and LDL ('bad')
cholesterol decreased among people taking cenicriviroc whilst rising among
efavirenz recipients. HDL ('good') cholesterol also fell but by a
smaller amount, resulting in a more favourable ratio.
"When used in combination with [Truvada]
in treatment-naive HIV-1+ adults with CCR5-tropic virus, both once-daily cenicriviroc
doses were effective, resulted in fewer discontinuations due to adverse events
compared with [efavirenz] and decreased total and LDL cholesterol", the
researchers concluded. "The effect of cenicriviroc on sCD14 merits further
evaluation in clinical trials".
Gathe acknowledged that the regimen used in
this study was complex and difficult to adhere
to, and is "probably not a reliable component of modern
HAART". The larger number of dropouts among cenicriviroc recipients – which led to the
higher failure rate – may have been in
part attributable to the difficulty of the regimen. Since that time, however, a
higher-dose single tablet has been developed and fixed-dose combinations with
other agents are in development.
In the future, the success of HIV treatment may be
assessed based not just on viral load reduction and CD4 cell increases, Gathe
suggested at a CROI press conference, but also on whether it has beneficial
effects on other endpoints beyond HIV control.