Effect of dihydroartemisinin/piperaquine for malaria intermittent preventive treatment on dolutegravir exposure in pregnant women living with HIV.

BACKGROUND: In sub-Saharan Africa, the burdens of malaria and HIV infections overlap. In settings with moderate-to-high malaria transmission intensity, pregnant women living with HIV (PLWH) require both ART and malaria intermittent preventive treatment (IPTp). Dihydroartemisinin/piperaquine has been identified as a promising alternative to sulfadoxine/pyrimethamine for IPTp. However, another antimalarial drug, artesunate/amodiaquine, similar to dihydroartemisinin/piperaquine, was previously shown to reduce dolutegravir exposure in non-pregnant adults.
OBJECTIVES: To investigate the effect of dihydroartemisinin/piperaquine on dolutegravir plasma exposure in pregnant women on dolutegravir-based ART.
METHODS: We conducted an open-label, non-randomized, fixed-sequence, pharmacokinetic study in PLWH in Malawi. Dolutegravir concentrations were measured over a 24 h period, before and after the recommended 3 day treatment dose of dihydroartemisinin/piperaquine in 12 pregnant women in their second or third trimester. Non-compartmental analysis was performed, and geometric mean ratios (GMRs) and 90% CIs were generated to compare dolutegravir pharmacokinetic parameters between the two treatment periods.
RESULTS: Co-administration of dihydroartemisinin/piperaquine and dolutegravir increased dolutegravir's overall exposure (AUC0-24) and Cmax by 30% (GMR 1.30; 90% CI 1.11-1.52) and 31% (GMR 1.31; 90% CI 1.13-1.51), respectively. The dolutegravir trough (C24) concentration increased by 42% (GMR 1.42; 90% CI 1.09-1.85). The combined treatments were well tolerated with no serious adverse events observed.
CONCLUSIONS: Dihydroartemisinin/piperaquine may be administered with dolutegravir-based ART in pregnant women as the modest increase in dolutegravir exposure, similar to pharmacokinetic parameter values published previously, ensures its efficacy without any clinically significant adverse events observed in this small study.

Introduction

In sub-Saharan Africa, malaria and HIV infections are endemic.[1] Pregnant women who are infected with malaria are at increased risk of adverse outcomes including maternal anaemia, severe malaria and low-birth-weight and stillbirth deliveries, with these adverse outcomes more frequent in pregnant women living with HIV (PLWH).[2] Preventing malaria in PLWH is, therefore, a key priority.

The WHO recommends intermittent preventive therapy during the second and third trimesters of pregnancy (IPTp) in moderate-to-high intensity malaria transmission settings. This involves administering standard antimalarial treatment doses regularly during pregnancy. In pregnant women who are not living with HIV, the WHO recommends the sulphonamide-based therapy sulfadoxine/pyrimethamine (SP). However, the efficacy of SP is being undermined by increasing SP resistance.[3] PLWH cannot receive SP for IPTp if they are taking another sulphonamide-based combination, trimethoprim/sulfamethoxazole (co-trimoxazole), to prevent opportunistic infections. Therefore, IPTp with dihydroartemisinin/piperaquine is being investigated as add-on therapy to co-trimoxazole in PLWH.[4,5]

Dihydroartemisinin/piperaquine is an artemisinin-based combination therapy (ACT), comprising dihydroartemisinin for rapidly suppressing any existing parasite load and piperaquine for clearing any remaining parasites and providing protection against new infections, given its long elimination half-life (t½).[6] In non-pregnant Ugandan adults, the related ACT artesunate/amodiaquine was found to reduce dolutegravir exposure by 24% and trough concentrations by 42%,[7] although these remained above the purported minimum efficacious dolutegravir concentration of 300 ng/mL;[8] the mechanism of this interaction is unknown. Piperaquine, like amodiaquine, is a 4-aminoquinoline,[9] and may thus also reduce dolutegravir exposure. We assessed whether a 3 day treatment course of dihydroartemisinin/piperaquine altered plasma dolutegravir exposure in PLWH in Malawi.

Materials and methods

Study design, pharmacokinetic sampling and assay

An open-label, non-randomized, fixed-sequence, pharmacokinetic study was conducted between December 2019 and July 2020 in PLWH in Malawi. Consenting pregnant women on efavirenz-based ART were switched to a dolutegravir-based ART regimen from 16 weeks of gestation. They remained on this new regimen for 4 weeks (Sequence 1) to allow efavirenz enzyme induction effects to wane. The first dihydroartemisinin/piperaquine dose was observed, as were doses of dolutegravir-based ART and dihydroartemisinin/piperaquine on the last (third) day of dihydroartemisinin/piperaquine treatment. Blood samples for dolutegravir concentrations were collected at the same timepoints before (Sequence 2) and after (Sequence 3) co-administration of dolutegravir-based ART and dihydroartemisinin/piperaquine (Figure S1, available as Supplementary data at JAC Online). Dolutegravir plasma concentrations were quantified using LC-MS/MS at the University of Cape Town, South Africa. For further details, see Texts S1 and S2. Routine antenatal care continued in parallel with all study procedures.

A sample size of 14 participants was calculated to have 80% power to detect a change in AUC outside the FDA limits for bioequivalence.[10] Assuming 10% loss to follow-up, 16 participants were planned for recruitment. The study was registered on PACTR.samrc.ac.za (PACTR201910580840196) and research ethics committee approval was granted by the Malawi College of Medicine, University of Cape Town, and Liverpool School of Tropical Medicine, UK.

Safety assessments

Participants were followed up from enrolment until 28 days after dihydroartemisinin/piperaquine co-administration. At scheduled and unscheduled visits, symptom-directed history and examination were conducted. All adverse effects were graded and independently assessed by two physician investigators for any relationship to co-administration of dihydroartemisinin/piperaquine and dolutegravir-based ART. HIV viral load was measured prior to, and repeated 28 days after, dihydroartemisinin/piperaquine dosing to assess whether participants remained virologically suppressed.

Statistical analysis

Data from Sequences 2 and 3 were analysed using non-compartmental analysis. Pharmacokinetic parameters were estimated for AUC to 24 h post-dose (AUC0–24), t½, Cmax and Tmax. Dolutegravir’s CL/F was calculated using the equation CL/F = dose/AUC0–24, while trough concentrations (C24) were estimated from the sample collected just before the next dolutegravir dose. Pharmacokinetic data were log-transformed to calculate the geometric mean ratio (GMR) and 90% CIs of Sequence 3 to Sequence 2 parameters. Changes in pharmacokinetic parameters between the two sequences were considered statistically significant when the 90% CI of the GMR did not cross the value of 1.[10] Since isoniazid is known to inhibit CYP3A4,[11] a minor metabolic pathway for dolutegravir, post hoc analyses were stratified by concomitant isoniazid use to explore any impact on plasma dolutegravir exposure. Analyses were performed using Stata version 15.1.

Results

Study profile

Twenty pregnant women were screened for eligibility and 13 were recruited. Twelve participants had quantifiable plasma dolutegravir concentrations at all required timepoints (Figure S2). The median (range) gestational age during Sequence 2 was 28 (24–33) weeks. Four participants were receiving TB prophylaxis with isoniazid and pyridoxine, initiated when they started ART, in line with the national HIV treatment policy at that time (Table S1).

Pharmacokinetics of dolutegravir

Dolutegravir exposure was increased when co-administered with dihydroartemisinin/piperaquine, with the AUC0–24 and Cmax increased by 30% (GMR 1.30; 90% CI 1.11–1.52) and 31% (GMR 1.31; 90% CI 1.13–1.51), respectively. Dolutegravir C24 values were 42% higher (GMR 1.42; 90% CI 1.09–1.85) during co-administration with dihydroartemisinin/piperaquine (Figure 1 and Table 1).

Figure 1.

Plasma dolutegravir (DTG) concentration–time profile following administration of DTG-based ART alone (red line) and with a treatment course of dihydroartemisinin/piperaquine (+ DP; black line) in 12 pregnant women. Data are presented as median (IQR). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Table 1.

Dolutegravir (DTG) exposure when administered alone (as DTG-based ART) compared with co-administration with dihydroartemisinin/piperaquine (+ DP)

Pharmacokinetic parameter	GM (90% CI), N = 12		GMR (90% CI) Sequence 3/Sequence 2	P value[a]
	DTG-based ART + DP (Sequence 3)	DTG-based ART only (Sequence 2)
AUC0–24 (ng·h/mL)	43 659 (39 939–47 726)	33,555 (29 479–38 196)	1.30 (1.11–1.52)	0.004
C max (ng/mL)	3270 (3030–3529)	2504 (2213–2832)	1.31 (1.13–1.51)	0.001
C 24 (ng/mL)[b]	701 (593–830)	495 (404–606)	1.42 (1.09–1.85)	0.008
T max (h)	2.6 (2.1–3.3)	2.3 (1.8–3.1)	1.13 (0.80–1.61)	0.379
t ½ (h)	9.9 (8.8–11.1)	9.0 (8.2–9.9)	1.10 (0.95–1.27)	0.063
CL/F (L/h)	1.15 (1.05–1.25)	1.49 (1.31–1.70)	0.77 (0.66–0.90)	0.004

GM, geometric mean. Bold represents statistical significance.

Paired t-test.

One participant had an implausible DTG C24 due to dosing prior to the 24 h sample. This value was imputed from the previous pre-dose concentration.

Impact of isoniazid prophylaxis

The four participants on isoniazid had higher dolutegravir exposure at baseline (Table S2). In the eight participants not on isoniazid, dolutegravir exposure increased by 38% (GMR 1.38; 90% CI 1.13–1.70) following co-administration with dihydroartemisinin/piperaquine. However, in those on isoniazid, dolutegravir exposure remained similar when dihydroartemisinin/piperaquine was co-administered with dolutegravir-based ART (GMR 1.15; 90% CI 0.93–1.43).

Treatment-emergent adverse events and viral load changes

A total of 16 adverse events occurred in the 13 participants enrolled. All these events were assessed as mild, with the exception of one incident of catheter site pain, which was assessed to be of moderate severity as paracetamol was given. Two events were suspected to be associated with co-administration of dihydroartemisinin/piperaquine and dolutegravir-based ART: nausea that developed 10 min after drug administration and resolved within 1 h of onset, and a pruritic rash that started 2 h after co-administration of study drugs and resolved within 1 day of onset (Table S3). Neither of these events were associated with higher dolutegravir exposure. In all 13 participants enrolled, viral load remained below 50 copies/mL throughout the study.

Discussion

We investigated the impact of the promising antimalarial for IPTp, dihydroartemisinin/piperaquine, on the pharmacokinetic profile of dolutegravir when co-administered in PLWH. Dihydroartemisinin/piperaquine modestly increased dolutegravir’s overall exposure, resulting in pharmacokinetic parameter values similar to those published previously, without any clinically significant adverse events observed in this small study. These findings are reassuring and suggest that dihydroartemisinin/piperaquine IPTp can be safely administered with dolutegravir-based ART without reducing dolutegravir exposure (as previously reported with the related antimalarial amodiaquine[7]).

The mechanism behind the increased dolutegravir exposure when co-administered with dihydroartemisinin/piperaquine is unclear, but this could be driven by improved bioavailability or reduced clearance. Both piperaquine and dolutegravir are substrates of cytochrome P450 3A4 (CYP3A4) enzymes.[12] However, inhibition of CYP3A4 is an unlikely mechanism as piperaquine is not known to inhibit CYP3A4, and strong inhibitors of CYP3A4, e.g. cobicistat, do not increase dolutegravir exposure significantly.[13] We hypothesize that the increased dolutegravir exposure could be due to dihydroartemisinin/piperaquine inhibiting efflux transporters involved in dolutegravir clearance. Dolutegravir is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP) transporters.[14] Mefloquine, an aminoquinoline similar to piperaquine, inhibits P-glycoprotein;[15] thus, this is a plausible mechanism. In vitro mechanistic studies are warranted.

Dolutegravir exposure, when administered with dihydroartemisinin/piperaquine, falls within a range previously described in pharmacokinetic studies during pregnancy.[16,17] In these studies, dolutegravir exposure was well tolerated, suggesting that the modest increase observed in our study is unlikely to be associated with safety concerns. Furthermore, this increase could help ensure dolutegravir’s efficacy; C24 values during co-administration with dihydroartemisinin/piperaquine were above the purported minimum effective concentration of 300 ng/mL in all study participants.[8]

Our study has limitations. Firstly, due to the small sample size, we were unable to accurately assess the impact of isoniazid on dolutegravir exposure when co-administered with dihydroartemisinin/piperaquine; adequately powered, prospective pharmacokinetic studies are needed to investigate this question. Secondly, our participants received dihydroartemisinin/piperaquine for IPTp, as part of another study (PACTR201910580840196),[18] 6 weeks before its co-administration with dolutegravir. However, a significant carry-over effect was unlikely as our participants were initially on efavirenz-based ART, which enhances piperaquine metabolism by induction of CYP3A4[19] and reduces piperaquine’s t½ in pregnant women to a mean of 6 days.[20] Thirdly, this study was not designed to investigate any potential impact of modestly increased dolutegravir exposure on long-term effects including maternal weight gain and metabolic syndrome.

The combination of dolutegravir-based ART and dihydroartemisinin/piperaquine was well tolerated in this study, with no observed serious adverse events or changes in HIV viral load. Adverse events were mild to moderate and consistent with previously approved drug labels for both treatments.

In conclusion, dihydroartemisinin/piperaquine can be administered with dolutegravir-based ART in PLWH, as the modest increase in dolutegravir exposure, similar to pharmacokinetic parameter values published previously, ensures its efficacy without any safety concerns observed in this small study.

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