Background
Shortening the duration of tuberculosis (TB) treatment is a WHO priority. The ACTG Clo-Fast trial compared a 3-month regimen of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose (3HPZEC), to the standard 6-month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in drug-susceptible TB (DS-TB). Skin hyperpigmentation is a major concern with clofazimine-containing regimens, but detailed assessments have been rarely described.
Methods
Participants with DS-TB were randomized to 3HPZEC or HRZE (2:1 ratio). Skin colorimetric measurements (CL-400; Courage+Khazaka) at upper inner arm and median of four facial triangulated anatomic locations were assessed at weeks 8, 13, 26 and 65, along with participant-reported changes in skin pigment and distress related to these changes (from 0 [no change/distress] to 10 [most change/distress]). Colorimetric measurements were described by delta E (ΔE), the standardized difference between two colors as perceived by the human eye (with ΔE<1 unnoticeable and ΔE>5 obvious at a glance).
Results
Of 89 participants from Malawi, South Africa, Zimbabwe, India, Haiti and Thailand randomized, 85 had hyperpigmentation assessments completed. Median age was 33 years (IQR 26, 39); 78% male; 28% living with HIV. At end of treatment (EOT: 3HPZEC week 13; HRZE week 26), there was significantly greater skin darkening with 3HPZEC vs HRZE, both at the inner arm (median ΔE 5.3 vs 3.7; p=0.002) and face (median ΔE 5.0 vs 3.4; p<0.001). At EOT, greater proportions of 3HPZEC vs HRZE participants had obvious darkening (ΔE> 5) for the inner arm (55% vs 23%) and face (51% vs 14%), and 55% vs 24% reported non-zero scores for skin color change and 33% vs 2% reported non-zero distress scores (Figure). By week 65, the proportion reporting non-zero distress score was low for both treatments (6% vs 8%) and median ΔE values (3.2 vs 2.9; p=0.47) did not differ significantly. No treatment discontinuations in either Arm were attributed to skin color changes.
Conclusions
As expected, a 3-month clofazimine-containing regimen caused significantly greater skin color changes by both objective colorimetric and participant subjective assessment, and associated distress, than HRZE at EOT. However, skin darkening resolved for most participants following treatment cessation. Future work includes stratification by baseline skin tone and qualitative investigation of stigma.
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