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EACS 2013: Cenicriviroc Shows Good Activity Against HIV, New Formulation May Reduce Dropouts


The dual CCR5/CCR2 inhibitor cenicriviroc demonstrated good antiviral activity and tolerability in a Phase 2 clinical trial, according to a report at the 14th European AIDS Conference (EACS 2013) this week in Brussels. The study had many dropouts, likely due to its complex dosing regimen, but a more user-friendly cenicriviroc formulation has since been developed.

Although modern antiretroviral therapy is highly safe and effective, there is still room for development of new classes of drugs that work in novel ways. Cenicriviroc (formerly TBR-652), developed by Tobira Therapeutics, blocks the CCR5 co-receptor -- one of the gateways HIV uses to enter cells -- as well as CCR2, a receptor that plays a role in inflammatory response.

Judith Feinberg from the University of Cincinnati presented results of a final 48-week analysis from Study 202 (NCT01338883), which compared cenicriviroc versus efavirenz (Sustiva) for previously untreated people with HIV. 

The analysis included 143 treatment-naive HIV positive adults. More than 90% were men, about 60% were white, about 30% were African-American, and the median age was 35 years. At baseline the mean CD4 T-cell count was approximately 400 cells/mm3 and 20% had high viral load (>100,000 copies/mL). Participants were required to have CCR5-tropic virus, meaning it only uses the CCR5 co-receptor.

Participants were randomly assigned (2:2:1) to receive 100 mg or 200 mg cenicriviroc or 600 mg efavirenz, both in combination with tenofovir/emtricitabine (the drugs inTruvada). Although all are once-daily drugs, the study used a complex double-blind/double-dummy design so that everyone took similar looking regimens. At the time of the study cenicriviroc was only available as a 50 mg pill. This meant participants had to take 4 pills (either cenicriviroc or placebo) at breakfast, 1 pill (either efavirenz or placebo) at bedtime, and 1 Truvada pill whenever they chose.

The primary endpoint was the proportion of participants with HIV RNA <50 copies/mL at week 24. These results were presented at the 2013 Retrovirus conference this past spring. The researchers also looked at viral suppression and CD4 cell changes at week 48, emergence of resistance mutations, changes in viral tropism (switching to use the CXCR4 co-receptor) and side effects.

The researchers also looked at immune and inflammatory biomarkers. CCR2 is a receptor that binds to monocyte chemo-attractant protein 1 (MCP-1), a cytokine that promotes monocyte migration. At the Retrovirus conference it was reported that levels of MCP-1 increased in the cenicriviroc arms, indicating that the drug was blocking CCR2. Soluble CD14 is a marker of monocyte activation; Feinberg noted that higher sCD14 levels have been associated with mortality among people with HIV.


  • The study had a high dropout rate, with 29% in the 100 mg cenicriviroc arm, 27% in the 200 mg cenicriviroc arm, and 39% in the efavirenz arm stopping prematurely.
  • The efavirenz arm had far more discontinuations due to adverse events (0%, 2%, and 21%, respectively), a majority of which occurred early.
  • Cenicriviroc was found to be as effective as efavirenz.
  • In the primary intent-to-treat snapshot analysis at 24 weeks, 76% of people taking 100 mg cenicriviroc, 73% taking 200 mg cenicriviroc, and 71% taking efavirenz had undetectable viral load.
  • Response rates fell by week 48 -- primarily attributable to additional dropouts -- to 68%, 64%, and 50%, respectively.
  • Rates of virological failure were 7% with 100 mg cenicriviroc, 11% with 200 mg cenicriviroc, and 4% with efavirenz.
  • CD4 cell gains were somewhat higher in the cenicriviroc arms (211 and 205 cells/mm3) than in the efavirenz arm (147 cells/mm3).
  • 7 people taking cenicriviroc, but none taking efavirenz, showed evidence of nucleoside/nucleotide reverse transcriptase inhibitor or NNRTI resistance mutations; however, deep sequencing revealed that the NNRTI mutations were present prior to starting treatment.
  • 1 person was found to have virus with dual/mixed tropism (using both CCR5 and CXCR4 co-receptors).
  • A majority of study participants experienced some drug-related adverse events: 50% in the 100 mg cenicriviroc arm, 44% in the 200 mg cenicriviroc arm, and 71% taking efavirenz.
  • However, serious adverse events were rare, at 2%, 2%, and 4%, respectively.
  • The most common side effects were the known efavirenz symptoms of abnormal dreams and insomnia (11% each in the efavirenz arm compared with 0%-2% amongst cenicriviroc recipients); rash and nausea were also reported more often by efavirenz recipients (7% each vs 0%-4%).
  • People taking the 200 mg cenicriviroc dose were more likely to develop grade 3 or 4 laboratory abnormalities (21%) than those taking 100 mg cenicriviroc (12%) or efavirenz (14%); this was largely attributable to a 16% rate of elevated creatine phosphokinase in the 200 mg arm.
  • Looking at lipid changes, total cholesterol, LDL "bad" cholesterol, and HDL "good" cholesterol all decreased in the cenicriviroc arms while rising in the efavirenz arm.
  • sCD14 decreased in the cenicriviroc arms and rose in the efavirenz arm at 24 weeks; after that point, however, levels began rising in the cenicriviroc arms as well, eventually leveling off slightly above the baseline level, while continuing to rise in the efavirenz arm.

Based on these findings, the investigators concluded that cenicriviroc is suitable for further development.

Regarding the high dropout rate, Feinberg speculated that people who began experiencing well-known central nervous system side effects associated with efavirenz may have quit the study because if they wanted it they could get the same regimen -- without all the placebos -- in the 1-pill/1-daily Atripla coformulation. "I think the dosing scheme had an impact on how well patients adhered and their desire to stick it out," she said.

The 200 mg cenicriviroc dose was selected based on pharmacokinetic and safety data; this dose can now be given as a single pill. A new fixed-dose combination with lamivudine (3TC or Epivir) and single-tablet regimens are being developed. Phase 3 trials will look at cenicriviroc/lamivudine as a "backbone" alternative to tenofovir/emtricitabine to be used with a guidelines-preferred third drug.



J Feinberg, M Thompson, J Cade, et al. Final Week 48 Analysis of Cenicriviroc (CVC) Compared to Efavirenz (EFV), in Combination with Emtricitabine/Tenofovir (FTC/TDF), in Treatment-naive HIV-1-infected Adults with CCR5-Tropic Virus. 14th European AIDs Conference (EACS 2013). Brussels. October 16-19, 2013. Abstract PS4/1.