Brief Report: Suboptimal Lopinavir Exposure in Infants on Rifampicin Treatment Receiving Double-dosed or Semisuperboosted Lopinavir/Ritonavir: Time for a Change

Jacobs, Tom; Mumbiro, Vivian; Chitsamatanga, Moses; Namuziya, N.; Passanduca, Alfeu; Domínguez‐Rodríguez, Sara; Tagarro, Alfredo; Nathoo, Kusum; Nduna, B.; Ballesteros, Álvaro; Madrid, Lola; Mujuru, Hilda; Chabala, Chishala; Buck, W Chris; Rojo, Pablo; Burger, David M.; Moraleda, Cinta; Colbers, Angela

doi:10.1097/qai.0000000000003168

Cited by 1 publication

(2 citation statements)

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“…Dolutegravir and rifampicin are widely recognized as the preferred components for treating HIV and TB, respectively, with well-established pharmacokinetics, efficacy, and safety in infants when given in the absence of the other drug [ 6 , 26 ]. Furthermore, the options for appropriate alternative ART for infants receiving rifampicin-based TB treatment are limited due to suboptimal pharmacokinetic outcomes or limited drug availability [ 4 , 27 , 28 ]. Hence, cotreatment with rifampicin and dolutegravir is preferred for treatment of infants with HIV-associated TB [ 4 , 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…All infants needed to be on dolutegravir treatment for at least 14 days and rifampicin for at least 30 days. Exclusion criteria for this substudy included the use of concomitant medications known to have DDIs with dolutegravir, grade 4 anemia or likelihood of progressing to grade 4 anemia at the day of sampling, and vomiting within 4 hours of drug administration [ 16 ]. The EMPIRICAL trial protocol, including the pharmacokinetic substudies, was approved by local ethics committees and national ethical and regulatory authorities.…”

Section: Methodsmentioning

confidence: 99%

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Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial

Jacobs,

Mumbiro,

Cassia

et al. 2023

Clinical Infectious Diseases

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Introduction We evaluated dolutegravir pharmacokinetics in infants with HIV receiving dolutegravir twice-daily with rifampicin-based TB-treatment compared to once-daily without rifampicin. Methods This pharmacokinetic substudy was nested in the EMPIRICAL trial for infants with HIV admitted with severe pneumonia. Infants aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir twice-daily with rifampicin or once-daily without rifampicin were eligible. Six bloodsamples were taken over 12 (twice-daily dosing) or 24 hours (once-daily dosing). Dolutegravir pharmacokinetic parameters were calculated and compared for infants with and without rifampicin, and HIV viral load data and adverse events (AEs) were reported descriptively. Results 27/30 enrolled infants on dolutegravir had evaluable pharmacokinetic curves. The median (IQR) age was 7.1 (6.1-9.9) months, weight was 6.3 (5.6-7.2) kilograms, 21/27 (78%) received rifampicin, and 11/27 (41%) were female. Geometric mean ratios comparing dolutegravir twice-daily with rifampicin versus once-daily without rifampicin were AUC0–24h 0.91 (95%CI 0.59-1.42); Ctrough 0.95 (0.57-1.59); Cmax 0.87 (0.57-1.33). 1/21 infants receiving rifampicin versus 0/6 without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. Dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. 5/82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB-treatment completion, HIV viral load was <1,000 copies/mL in 76% and 100% of infants, and undetectable in 35% and 20% of infants with and without rifampicin, respectively. Conclusion Dolutegravir twice-daily in infants receiving rifampicin-based TB-treatment resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.

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