Safety and efficacy of CMX001 as salvage therapy for severe adenovirus infections in immunocompromised patients

Abstract

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

Figure 1

Change in adenovirus VL between cidofovir and CMX001 treatment. The median change in log10 VL on cidofovir treatment (before receipt of CMX001) was 0.08 (range, −2.14 to 4.66) (P = .95). The median change in log10 VL for CMX001 treatment was −2.71 (range, −5.63 to 1.1) (P = .001). The median was connected over time.

Figure 2

Change in adenovirus VL (log10) and change in ALC after initiation of CMX001 to week 8 of therapy. The median was connected over time. The median change in log10 VL (upper part of the graph) was −1.78 (range, −2.91 to 0.46) from week 0 to week 1 (P = .002), −1.77 (range, −4.65 to 0.36) from week 0 to week 2 (P = .0007), −1.89 (range, −4.65 to 1.42) from week 0 to week 4 (P = .002), −2.6 (range, −5.81 to 1.34) from week 0 to week 6 (P = .006), and −3.06 (range, −7.81 to −1.54) from week 0 to week 8 (P = .004). The median change in ALC (lower part of the graph) was 40 (range, −100 to 4100) from week 0 to week 1 (P = .01), 100 (range, −100 to 5300) from week 0 to week 2 (P = .02), 300 (range, −300 to 5100) from week 0 to week 4 (P = .059), 164.5 (range, −300 to 4700) from week 0 to week 6 (P = .094), and 577 (range, −300 to 1300) from week 0 to week 8 (P = .094).

Figure 3

Overall survival after starting therapy for disseminated adenovirus in responders and nonresponders to CMX001 (n = 13). Median survival was 196 days in the complete responders and 54.5 days in the nonresponders (P = .04).