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Incidence and Risk Factors for Malignancies in Treatment-experienced (TE) Patients in the MOTIVATE Studies of Maraviroc (MVC) + Optimized Background Therapy (OBT): 96-Week Follow-up
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Reported by Jules Levin
IAS July 22 2009 Capetown
Ayman Ayoub1, Sharon Walmsley2, Rafael Campo3, James Goodrich4, Jayvant Heera4, Hernan Valdez5, Natasa Rajicic5, Howard Mayer4
1Pfizer Global Research and Development, Sandwich, UK; 2University of Toronto, Toronto, Canada; 3University of Miami, Miami, FL, USA; 4Pfizer Global Research and Development, New London, CT, USA; 5Pfizer Inc. New York, NY, USA
AUTHOR CONCLUSIONS
Patients receiving MVC had a lower exposure-adjusted incidence of malignancies overall, AIDS-and non-AIDS-defining as well as infection-related malignancies
Non-AIDS-defining malignancies were more frequent than AIDS-defining malignancies in this 96-week retrospective analysis, and most malignancies observed were infection-related
Multivariate analysis showed that increasing CD4+ cell count on treatment was protective, while a higher baseline HIV-1 RNA and increasing age were associated with increased risk of malignancy
MVC-treated patients may have a lower risk for all malignancies, including AIDS-defining and infection-related malignancies, compared to PBO-treated patients
Long-term blinded clinical data from MOTIVATE indicate that MVC is not associated with an increased risk of malignancy over 96 weeks
BACKGROUND
Since the advent of HAART, while the incidence of AIDS-related malignancies has decreased over time, the incidence of non-AIDS-defining malignancies has increased1-3
Many of the non-AIDS defining malignancies are associated with infections1-4
Maraviroc (MVC) is a CCR5 antagonist and the first clinically available antiretroviral agent that acts on a host cell target
Since CCR5 is important in the function of the immune system, an increased incidence of malignancies or infections is a theoretical concern
-Although no clinical or pre-clinical malignancy signals have been detected during the clinical development of MVC, an apparent malignancy excess has been observed during the development of another CCR5 antagonist5
We present the 96-week incidence of malignancies among treatment-experienced (TE) patients who participated in the MOTIVATE trials of MVC versus placebo (PBO)
METHODS
Pooled data from the phase 3 MOTIVATE 1 & 2 studies of treatment-experienced patients randomized 1:2:2 to receive PBO, MVC QD or MVC BID with an optimized background regimen of 3-6 investigator-selected agents
The studies were unblinded when the last enrolled patient reached Week 48, and eligible patients were allowed to roll over onto open-label MVC BID (Figure 1).6,7This resulted in variable patient exposure to blinded, randomized treatment between their individual week 48 visits and the end of blinded therapy (EBT)
Retrospective analysis of malignancies occurring on blinded, randomized treatment
Patients were censored at EBT
The MVC QD and BID arms were pooled for this analysis (n=840)
* OBT = optimized background therapy of 36 ARVs (PK boosting doses of ritonavir not counted as an ARV)
Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients received 300 mg dose of MVC
Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥100,000 copies/mL
Patient eligibility criteria:
·R5 HIV-1 infection
·HIV-1-RNA ≥5,000 copies/mL
·Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks
·Resistance to and/or ≥6 months experience with ≥one ARV from three classes (≥two for protease inhibitors [PIs])
·Descriptive statistics (median and IQR) and risk ratios (95% CI) are presented for unadjusted and exposure-adjusted malignancy incidence through EBT
Adjustment to account for shorter duration of treatment in PBO arm and fewer patients randomized to PBO (1:2:2 PBO:MVC QD:MVC BID)
·First events only were considered and malignancies present at baseline were excluded
·Malignancies were categorized as:
AIDS-defining versus non-AIDS-defining
Infection-related versus non-infection-related
·Potentially related to infection with HPV, HBV, EBV, or HCV4
·Risk factors for malignancies were explored by multivariate hazard ratios using a stepwise Cox Proportional Hazard model
·Difference in the time to an event was evaluated using Kaplan-Meier estimates and a Wilcoxon test for the difference of survival curves
· No significant difference between treatment groups was observed for the time to onset of a first malignancy
Lack of observed difference in time to first malignancy probably related to the different durations of exposure for the two treatment groups
· No differences were observed in time to onset of first infection-related, first non-infection-related, or first non-AIDS-defining malignancy
*522 patient-years of exposure to MVC QD and 551 patient years of exposure to MVC BID
Table 1: Malignancies by Treatment Arm
*Unadjusted incidence
**All on-study malignancy events are listed for patients who had one or more malignancy event on-study
Includes lymphoma, T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma
Table 2: Characteristics by Treatment Arm and Presence of Malignancy
*Outcomes shown at Week 24, the median time to event for patients with on-study malignancies; IQR: interquartile range (1st, 3rd quartiles)
Table 3: Higher Baseline Viral Load and Older Age Associated with Increased Risk of Malignancy; Rise in CD4+ Count On-Treatment Associated with Decreased Risk
HR hazard ratio; NA not applicable; * Stepwise Cox Proportional Hazard model; only terms remaining in the model are presented
Table 4: Lower Exposure-Adjusted Incidence of AIDS-defining and Infection-related Malignancies on MVC
PY Patient-years
Figure 4: Significantly Lower Risk of Overall, AIDS-defining, and Infection-related Malignancies in MVC compared with PBO
* Potentially related to infection with HPV, HBV, EBV, or HCV4
REFERENCES
1.Pantanowitz L, et al. Curr Opin HIV AIDS2009;4:27-34.
2.Pantanowitz L, et al. Curr Opin Oncol2006;18:469-478.
3.Bonnet F, Chene G. Curr Opin Oncol2008;20:534-540.
4.Grulich AE, et al. Lancet 2007;370:59-67.
5.Gulick RM, et al. J Infect Dis2007;196:304-312.
6.Gulick RM, et al. N Engl J Med2008; 359:14291441.
7.Hardy WD, et al. 9th International Congress on Drug Therapy in HIV infection, Glasgow, UK, 913 November, 2008; Abstract O425.
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