February 16, 2018
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Combining HIV drug dolutegravir with TB therapy causes ‘serious toxicities’

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A study examining pharmacokinetic interactions between the first-line HIV drug dolutegravir and a once-weekly tuberculosis regimen was terminated early after NIH researchers found that the combined use of the treatments led to “unexpected and serious toxicities” in healthy participants.

Although the study enrolled only a small number of participants, Kristina M. Brooks, PharmD, of the Clinical Pharmacokinetics Research Unit at the NIH’s Clinical Center, and colleagues reported in Clinical Infectious Diseases that their findings suggest coadministration of dolutegravir and isoniazid-rifapentine — a latent TB treatment often administered to patients coinfected with HIV — “should be done cautiously, ideally in a clinical research setting.”

The researchers assigned four healthy adult participants with no evidence of HIV or TB to receive 50 mg of dolutegravir once-daily for 4 days, then in combination with a once-weekly TB regimen containing 900 mg of isoniazid, 900 mg of rifapentine and 50 mg of pyridoxine.

The TB regimen is usually administered for 3 months, according to the researchers. However, 19 days into the study, two of the participants developed an influenza-like syndrome. One of the participants required hospitalization for 24 hours.

Laboratory results revealed multiple abnormalities among both patients who developed influenza-like symptoms. The researchers identified elevated transaminase levels and a temporal association between elevated cytokine levels, specifically interferon-gamma, chemokine ligand 10 and C-reactive proteins, and symptom onset.

Data further showed that the dolutegravir area under the curve (AUC) decreased 46% (90% CI, 0.27-1.10) 48 to 72 hours after the second dose of TB treatment was administered. Meanwhile, isoniazid AUCs were approximately 67% to 92% higher in participants who developed toxicities.

“Though not the original intent, this study provides important insights into potential mechanisms resulting in the adverse events seen in subjects receiving once-weekly isoniazid-rifapentine with dolutegravir,” the researchers concluded. “Further studies are needed to carefully evaluate the safety and efficacy of dolutegravir-based regimens when coadministered with isoniazid-rifapentine, especially given the recent availability of generic dolutegravir in countries with high TB burden, and the desire to use this once-weekly regimen in patients living with HIV.”

In the United States, rifapentine is sold under the brand name Priftin (Sanofi-Aventis), and dolutegravir is sold under the brand name Tivicay (ViiV Healthcare). – by Stephanie Viguers

Disclosures: The authors report no relevant financial disclosures.