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Background:  The Division of Antiviral Drug Products granted traditional approval (October 2004) for enfurvitide (ENF) in the treatment of HIV-1 infection in ART-experienced patients based upon the superior efficacy of ENF add-on to optimized background over optimized background alone in 2 pivotal clinical trials (T20-301 and -302). As part of the safety review, we examined the effect of injection site reactions (ISR) and ENF injection on subject tolerability. 

Methods:  We reviewed the New Drug Application 21-481 for ISR data, describing the following:  demographics, ISR measurements, adverse events, discontinuations, and concomitant medications/interventions related to ISR or ENF injection. Analyses at 48 weeks of study are shown for pooled T20-301 and -302 data in the ENF and the optimized background arm.

Results:  The average age of the safety population (n = 663) was 42 years, 90% male, and 89% white. The median baseline log HIV-1 RNA = 5.2 copies /mL (3.5 to 6.7), and baseline CD4⁺ cell count = 89 cells/mL (1 to 994). The mean number of prior ART use was 12 with mean duration at 7 years. Using modified ACTG criteria for vaccine reactions for ISR measurement, 98% of subjects had at least one ISR with 96% (639 of 663) having pain or discomfort (10.6% had severe grade); induration (90% with 57% severe), erythema (91%, 32%), nodules or cysts (80%, 23%), pruritus (65%, 3%), and ecchymosis (48%, 6%). Average duration of individual ISR was 3 to 7 days in 41% and > 7 days in 24%. The number of ISR per subject at any one time was 6 to 14 ISR in 26%. Infections (including abscesses and cellulitis) were reported in 1.7%. Forty-five (7%) subjects discontinued study due to injection reactions (4% for ISR and 3% for ENF). A quarter of the patients (n = 156) used various interventions (n = 292 times total) to treat ISR with n = 29 using 3 or more interventions. The most frequent uses were non-narcotic analgesics (n = 46 subjects, 76 times), oral antihistamines (n = 40, 56x), and topical steroids (n = 28, 43x). 

Conclusions:  ENF intolerability due to ISR/ENF injection was a major safety issue in the review of NDA 21-481.  Almost all subjects experienced ISR with many experiencing severe grades. A number of subjects discontinued due to difficulties with ISR/ENF injection. A variety of concomitant medications and interventions were used to alleviate the ISR. These results are in the setting of a clinical trial environment.  It is possible that difficulties related to ISR/ENF injection may be higher in the general population. Continued studies and initiatives to improve ISR/ENF injection are warranted.

Keywords: enfurvitide; injection site reactions; tolerability