Person:

Coit, Julia

Background: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question. Methods/Design The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0–24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %. Discussion Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems. Trial registration This trial was registered with clinicaltrials.gov (registration number: NCT01408914) on 2 August 2011.

On average, the Peruvian population is among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvians, and identify a novel, population-specific, missense variant in FBN1 (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency=4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). This is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin-1, a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals homozygous for G1297 compared to individuals homozygous for E1297. Moreover, we show that E1297G locus is under positive selection in non-African populations, and the E1297 variant shows subtle evidence of positive selection within the Peruvian population specifically. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, suggesting that short stature might be the result of adaptation to factors associated with the coastal environment in Peru.