Single-Dose Dolutegravir Safe in Kids With HIV Receiving Preventive TB Treatment

Children with HIV on dolutegravir (Tivicay)-based antiretroviral therapy (ART) can safely receive the standard prophylactic tuberculosis (TB) treatment without needing to up their dolutegravir dose, the phase I/II DOLPHIN-KIDS study suggested.

Among 41 children who received a single dose of dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) and the standard TB treatment of rifapentine and isoniazid, 95% remained virally suppressed and dolutegravir trough concentrations dropped below the predetermined threshold of 64 ng/mL in only two children, reported Nicole Salazar-Austin, MD, ScM, of the Johns Hopkins University School of Medicine in Baltimore, at the Conference on Retroviruses and Opportunistic Infectionsopens in a new tab or window.

Two children with a clearly detectable viral load during the study re-suppressed following adherence counseling, Salazar-Austin said, adding that strong adherence counseling and support for families and children is crucial during TB treatment.

Tom Jacobs, PhD, of Radboud University Medical Center in Nijmegen, the Netherlands, told MedPage Today that he was glad to see this study because “children are usually left behind when it comes to these kinds of innovations.”

“With all the fixed-dose combinations of dolutegravir-based ART regimens now coming to the market, we think the single-dose dolutegravir tablets for kids will be phased out, unfortunately, and then we need to find other effective ways to administer dolutegravir with either TB treatment or preventive TB treatment,” Jacobs said. “This is a fantastic first step to show that once-daily dolutegravir is possible, so I think it’s going to have major programmatic implications.”

The WHO recommends dolutegravir as a first- and second-line ART for children living with HIV, and the preferred tuberculosis prevention regimen for all ages is rifapentine and isoniazid once weekly for 12 weeks (3HP). However, two enzymes induced by rifapentine metabolize dolutegravir. Since children metabolize faster than adults, Salazar-Austin and her team hypothesized that children may need twice-daily dolutegravir while on 3HP to offset the effects of rifapentine, which would present adherence challenges.

She and her team conducted a single-arm pharmacokinetic and safety trial to determine whether it was possible for children to receive 3HP with only a single daily dose of dolutegravir, as in adults. Based on simulations run from 17 participants, the safety monitoring committee deemed a single dolutegravir dose to be acceptable when given with 3HP if the lower 95% confidence interval of the observed C_trough of dolutegravir was greater than 158 ng/mL and all dolutegravir trough values were greater than 64 ng/mL.

The study enrolled 41 children who weighed at least 10 kg, were virally suppressed on dolutegravir and two NRTIs, and were receiving 3HP. Just over half were ages 2 to 5 years, 29% were 6 to 11 years, and 17% were 12 to 17 years; 54% were boys. Under a third of the children (29%) weighed less than 14 kg, 37% weighed 14 to 19 kg, and 34% weighed 20 kg or more. The mean CD4 percentage in children under 6 years old was 34.6%, and the mean absolute CD4 count in children 6 and older was 1,090 cells/mm³.

Among the three cases with detectable viral loads, one was a 4-year-old who had a viral load of 160 copies/mL in the third week of 3HP but achieved viral suppression after adherence counseling by the end of the study. Another was a 12-year-old with a viral load of 2,310 copies/mL at the end of the study who re-suppressed after adherence counseling. The third was a 4-year-old who had less than 200 copies/mL based on a test that’s 1:5 dilution increased the lower limit of detection to less than 200 copies/mL.

To assess pharmacokinetics, the researchers sampled for dolutegravir on the day before starting 3HP at 0, 1, 2, 4, 8, 23, and 24 hours after the dolutegravir dose. Three days after the third dose of 3HP, they sampled 1 hour before the dolutegravir dose and at 0, 1, 2, 4, and 8 hours post-dose. They also sampled at 11 and 12 hours after a dolutegravir dose at 1 and 5 days after the third 3HP dose.

One of the two participants with a C_trough of dolutegravir below 64 ng/mL had 79% adherence based on pill count but remained virally suppressed during the study. The other was the 12-year-old who was re-suppressed by study’s end, who had 100% adherence by pill count. Because of these two cases, contributing to a fifth percentile of distribution of 75 ng/mL — below the 158 ng/mL threshold — the pharmacokinetics criteria was not met.

“We asked whether time-limited and infrequent drops in dolutegravir concentration are clinically relevant given the high affinity dolutegravir has for its target and if all participants receiving daily dolutegravir were virally suppressed at study completion,” Salazar-Austin said, noting that they concluded that the regimen was safe and well-tolerated, with no serious drug-related adverse events and no treatment discontinuations.

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