Maraviroc raises CD4 counts in patients with mixed-tropism virus, may offer value for highly treatment-experienced

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The experimental CCR5 antagonist maraviroc is safe and well tolerated in patients infected with HIV variants that use both the CCR5 and CXCR4 co-receptors to enter CD4 T-cells, according to a study presented on Thursday at the Sixteenth International AIDS Conference in Toronto.

In addition to the CD4 receptor, HIV also binds to a second ‘co-receptor’ on the surface of T-cells before it can get through the cell membrane. While most patients have HIV that uses the CCR5 co-receptor, a minority of patients have HIV that uses the alternative CXCR4 co-receptor. However, these strains of HIV are associated with low CD4 cell counts, rapid disease progression and the development of AIDS or death. CXCR4 variants begin to emerge as the CD4 count falls, and studies suggest that they become the dominant population of viruses in people with advanced HIV disease (CD4 cell counts below 200 cells/mm3). A minority of variants may use both CCR5 and CXCR4 co-receptors to gain entry to cells.

Maraviroc is designed to block HIV’s attachment to the CCR5 co-receptor. Although it has shown promising results in early trials, experts are concerned that using the drug in patients infected with both CCR5- and CXCR4-using (‘R5- and X4-tropic’) strains of HIV could lead to selection of X4-tropic strains. This could result in falls in CD4 cell count and rapid disease progression.

Glossary

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

tropic

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

strain

A variant characterised by a specific genotype.

 

To assess the risk of this occurring, investigators from maraviroc’s manufacturer, Pfizer randomised 186 treatment-experienced patients to receive once- or twice-daily doses of the drug or placebo, together with an optimised background regimen. All of the patients had a mixture of R5-and X4-tropic strains of HIV, or ‘dual-tropic’ strains that could use both co-receptors to enter CD4 T-cells.

Patients in the study were highly treatment-experienced; 51% in the placebo group and 61% and 55% in the once and twice-daily dosing groups had to include T-20 (enfuvirtide, Fuzeon) in their background regimen in order to assemble a viable drug combination, and 29% of the placebo group, 36% of the once-daily group and 23% of the twice daily group had no or only one active drug in their background regimen at baseline.

The participants also had very advanced HIV disease, further underlining their need to assemble an effective antiretroviral regimen. The median CD4 cell count was around 40 cells/mm3 in each group, although it is interesting to note that the stated range of CD4 counts showed that some participants in the study had been diagnosed with mixed-tropic virus at very high CD4 cell counts (650 cells/mm3 in the placebo arm and 615 cells/mm3 in the twice daily arm.

After 24 weeks, viral loads fell from an average of over 100,000 copies/ml by 0.91 log10 in the once-daily maraviroc group, and by 1.20 log10 in the twice-daily group. The placebo group’s viral loads fell by 0.97 log10. These differences were not statistically significant. A trend towards a greater viral load decrease in maraviroc-treated patients was evident among those who also received enfuvirtide, where viral load fell by -1.26 log in the once daily group and -1.44 log in the twice daily group, compared to -0.89 log in the placebo group.

There was also no substantial difference in the proportion of patients who achieved viral load below 400 or 50 copies/ml between the three study arms.

In contrast, CD4 cell counts rose in both maraviroc arms, by 60 cells/mm3 in the once-daily arm and 62 cells/mm3 in the twice-daily arm, whereas they rose by only 35 cells/mm3 in the placebo arm.

In patients who only had CXCR4-tropic virus detectable at the time of virologic failure, the CD4 cell difference was much greater. While patients with CXCR4-tropic virus in the once-daily group had an average 48 CD4 cell increase and the twice-daily group had a 33 cell increase, those with exclusively CXCR4 virus who experienced virologic failure lost an average of 102 cells/mm3 by the end of the follow-up period.

The three arms had similar rates of severe side-effects, treatment discontinuations and deaths, demonstrating that maraviroc is safe for use in treatment-experienced patients. There were also no cases of lymphoma or adenocarcinoma, two types of cancer that have been linked to use of the CCR5 antagonist vircriviroc in a phase II study also reported at the conference.

References

Mayer H et al. Safety and efficacy of maraviroc (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. Sixteenth International AIDS Conference, Toronto, abstract THLB0215, 2006.