Impact of Dolutegravir-Based Antiretroviral Therapy on Piperaquine Exposure following Dihydroartemisinin-Piperaquine Intermittent Preventive Treatment of Malaria in Pregnant Women Living with HIV

Abstract

Dihydroartemisinin-piperaquine, an artemisinin-based combination therapy, has been identified as a promising agent for intermittent preventive treatment of malaria in pregnancy. However, in pregnant women living with HIV (PLWH), efavirenz-based antiretroviral therapy (ART) significantly reduces the plasma exposure of piperaquine. In an open-label, nonrandomized, fixed-sequence, pharmacokinetic study, we compared piperaquine plasma concentrations in 13 pregnant women during a 3-day treatment course of dihydroartemisinin-piperaquine when coadministered with efavirenz-based versus dolutegravir-based ART in the second or third trimester of pregnancy. Piperaquine concentrations were measured over a 28-day period, while on efavirenz-based ART and after switching to dolutegravir-based ART. Noncompartmental analysis was performed, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were generated to compare piperaquine pharmacokinetic parameters between these two treatment periods. Compared with efavirenz-based ART, coadministration of dihydroartemisinin-piperaquine and dolutegravir-based ART resulted in a 57% higher overall piperaquine exposure (area under the concentration-time curve from 0 to 672 h [AUC_{0-672 h}]) (GMR, 1.57; 90% CI, 1.28 to 1.93). Piperaquine's day 7 concentrations were also 63% higher (GMR, 1.63; 90% CI, 1.29 to 2.11), while day 28 concentrations were nearly three times higher (GMR, 2.96; 90% CI, 2.25 to 4.07). However, the maximum piperaquine concentration (C_max) remained similar (GMR, 1.09; 90% CI, 0.79 to 1.49). Dihydroartemisinin-piperaquine was well tolerated, with no medication-related serious adverse events observed in this small study. Compared with efavirenz-based ART, a known inducer of piperaquine metabolism, dolutegravir-based ART resulted in increased overall piperaquine exposure with pharmacokinetic parameter values that were similar to those published previously for pregnant and nonpregnant women. Our findings suggest that the efficacy of dihydroartemisinin-piperaquine will be retained in pregnant women on dolutegravir. (The study was registered on PACTR.samrc.ac.za [PACTR201910580840196].).

Keywords: HIV; antiretroviral therapy; dihydroartemisinin-piperaquine; intermittent preventive treatment; malaria; piperaquine; pregnancy.

FIG 1

Participant flow chart.

FIG 2

Plasma piperaquine concentration-time profile following coadministration of dihydroartemisinin-piperaquine with efavirenz (EFV)-based antiretroviral therapy (solid line) and with dolutegravir (DTG)-based antiretroviral therapy (dashed line) in 13 pregnant women. Data are presented on a semilogarithmic plot as medians and interquartile ranges.

FIG 3

Study design. A fixed-sequence study switching from efavirenz- to dolutegravir-based antiretroviral therapy. Intense plasma pharmacokinetic sampling of piperaquine was conducted in two sequences: when participants were on efavirenz-based antiretroviral therapy (sequence 1) and when they were on dolutegravir-based antiretroviral therapy (sequence 3) following a 4-week lead-in period from the time of switching from efavirenz- to dolutegravir-based antiretroviral therapy.