Vicriviroc effective in treatment-experienced patients, but malignancy questions remain unanswered

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A second CCR5 antagonist, vicriviroc, may also be safe and effective in treatment-experienced patients with CCR5-tropic virus, according to a late breaker study presented at the Sixteenth International AIDS Conference in Toronto on Thursday August 17th.

Although studies of this drug in patients who had not taken anti-HIV therapy before were stopped by manufacturer Schering-Plough in October 2005 due to poor responses, an AIDS Clinical Trials Group study in 118 patients with treatment experience continued.

ACTG A5211 recruited individuals with viral load above 5,000 copies/ml with CCR5-tropic virus who were taking a ritonavir-boosted protease inhibitor. Ritonavir increases the level of vicriviroc in the blood.

Glossary

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.

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.

tropism

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).

lymphoma

A type of cancer that starts in the tissues of the lymphatic system, including the lymph nodes, spleen, and bone marrow. In people who have HIV, certain lymphomas, such as Burkitt lymphoma, are AIDS-defining conditions.

Participants were randomised to receive one of three doses of vicriviroc (5, 10 or 15mg once daily) or placebo for 14 days, after which they added a background regimen that had been optimised by resistance testing. Participants were followed for a further 22 weeks.

In October 2005 the study’s data and safety monitoring committee recommended that the 5mg arm of the study be stopped after it became evident that participants in this arm were experiencing sub-optimal virologic responses and coreceptor switches to a predominantly CXCR4-tropic virus population. The 5mg arm in the vicriviroc treatment-naïve study was stopped at the same time. Participants in the 5mg arm in the treatment-experienced study were switched to the 15mg arm.

The investigators found that all three doses of vicriviroc brought about greater decreases in viral load than placebo after two weeks of adding the drug to the patients failing treatment regimens (p

After two weeks, the background regimen was optimised, and follow-up continued for a further 22 weeks. At the end of this phase of the study, the patients taking vicriviroc continued to have greater viral load reductions than those taking placebo, ranging from 1.51 to 1.68 log10, compared to 0.29 log10 in the placebo group (p

This was mirrored by greater CD4 cell count rises (84, 142 and 142 cells/mm3), compared to a fall of 9 cells/mm3 in the patients taking placebo.

Although all participants had CCR5-tropic virus at the time of screening for study entry, early changes occurred in 12 patients who already mixed CCR5/CXCR4-tropic virus at the time the study began, Further changes in tropism occurred during the 14 day monotherapy phase: seven patients in the 5mg arm experienced tropism switches, three in the 10mg arm, two in the 15mg arm and only one in the placebo arm.

The changes in tropism prior to initiation of treatment allowed investigators to compare the virologic response in the ten patients with mixed-tropic virus at baseline and those with exclusively CCR5-tropic virus populations. In the mixed tropism group viral load fell by a mean of 0.77 log, while in the CCR5-tropic group it fell by a mean of –1.83 log (p=0.01).

Although the rates of serious side-effects were similar across all four arms, five cases of lymphoma or adenocarcinoma were seen. Several of these cases occurred in patients with a previous history of malignancy:

  • One case of non-Hodgkin’s lymphoma in a patient with a history of Hodgkin’s disease.
  • One case of Hodgkin’s disease in a patient with a previous history of this condition.

Three other malignancies – non-Hodgkin’s lymphoma, Hodgkins disease and gastric adenocarcinoma – were diagnosed in three other patients receiving vicriviroc.

However two malignancies – a case of multiple squamous cell carcinomas and a case of localised perianal squamous cell carcinoma – were diagnosed in patients who were not taking vicriviroc (one in the placebo group and one who had stopped taking vicriviroc a month previously due to lack of efficacy).

“The relationship of vicriviroc to malignancy is uncertain,” said investigator Trip Gulick.

References

Gulick R et al. ACTG 5211: phase II study of the safety and efficacy of vicriviroc in HIV-infected treatment-experienced subjects. Sixteenth International AIDS Conference, Toronto, abstract THLB0217, 2006.