Lamivudine/Zidovudine

Physiological changes during pregnancy can have a significant impact on antiretroviral pharmacokinetics (PK), which may result in reduced drug efficacy. Here we describe the PK of darunavir/ritonavir (DRV/r) 800/100 once daily in a cohort of pregnant women undergoing routine therapeutic drug monitoring (TDM) as well as transplacental passage of DRV by measuring and comparing cord blood and maternal blood samples at delivery.

Pregnant HIV-positive women received DRV/r as part of routine pre-natal care. Demographic and clinical data were collected. DRV plasma concentrations [DRV] were determined in the first (T1), second (T2) and third (T3) trimester and at postpartum (PP). The target concentration was 550 ng/ml. Where possible, paired maternal and cord blood samples were taken at delivery.

A total of 33 women were enrolled. Samples were taken 14–20 h post-dose and measured concentrations were extrapolated to 24 h post-dose. At the time nearest to delivery, all but four had undetectable plasma viral loads (pVL). [DRV] were determined in 1 (T1); 14 (T2); 32 (T3) and 29 (PP). 1 sample was <550 ng/ml at T2, 6 at T3 and 3 at PP. [DRV] were significantly lower at T2/T3 relative to PP.

[DRV] in T2 and T3 were 36–55% when compared with PP. However, DRV PK in pregnancy were not associated with a lack of virological suppression at delivery as of the 33 patients enrolled in this study, 31 had no HIV transmission from mother to child. Data regarding two candidates were not available as they delivered in a separate health-care facility.

A 30-year-old woman of sub-Saharan Africa origin attended our clinic in October 2016 for the follow-up of an HIV-1 infection. A treatment with combivir/nevirapine was initiated in her country years ago. Laboratory testing indicated a detectable viral load (1420 copies/ml) and genotype testing demonstrated combined nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor resistances with preserved protease-inhibitor sensitivity. CD4+ T cells count was 396 cells/μl (18.3%). A combination therapy with darunavir/cobicistat and dolutegravir (DTG) was initiated on 25 January 2017. One month later, viral load was undetectable (<20 copies/ml). No adverse effect was reported. Twenty-eight weeks after treatment switch, the patient attended the outpatient clinic complaining of tremor of both arms since 5 days. Physical examination revealed grade 2 rigidity on the Unified Parkinson's Disease Rating Scale (UPDRS) [1] of both arms along with tremor of both arms, more severe for the right arm (Video 1, https://links.lww.com/QAD/B410). A light tremor of the lower limbs was also noted. There was no gait instability nor walking abnormalities. Body weight was 75 kg. DTG was stopped and switched to raltegravir 800 mg 1x/d, while darunavir/cobicistat was continued. Six days after DTG discontinuation, tremor of the left arm was no longer observed, but there was a persistence of tremor of the right arm (Video 2, https://links.lww.com/QAD/B411). A brain MRI did not show any brain nor vascular lesion. A dopamine transporter (DAT) single photon emission computerized tomography was performed and revealed no abnormalities. Thyroid function tests were within normal range. The patient did not take other medications apart from antiretroviral therapy and did not report consumption of recreative drugs. Viral load after switch remained undetectable. Three months after treatment switch, minimal tremor of the right arm was still present, but rigidity of the upper limbs was no longer observed (Video 3, https://links.lww.com/QAD/B412). Six months after treatment switch, physical examination was normal with absence of tremor and rigidity. Various cohort studies recently reported a higher rate of discontinuation due to neuropsychiatric events associated with DTG than other integrase strand transfer inhibitors (INSTIs) (namely, raltegravir and elvitegravir). The discontinuation rate ranged from 1.7% to 6%. Discontinuation was mainly observed within the 6 first months of initiation and was higher in women [2,3]. Sleep disturbances and insomnia are the most frequent neuropsychiatric adverse events, but tremors have also been reported [2]. Interestingly, the occurrence of DTG adverse event has been shown to be related to DTG concentrations [4] and increased DTG exposure has been observed in a patient switched from ritonavir to cobicistat [5]. In the present case, the following points suggest a causality link between DTG exposure and the symptoms observed: occurrence of the symptoms within the first months of DTG exposure in a patient without previous neurological disease, a decrease and a progressive resolution of the symptoms after DTG cessation, absence of degenerative lesions at brain MRI that could explain the symptoms of the patient and a normal DAT scan that excludes disease associated with abnormalities of DAT such as Parkinson's disease. The mechanisms associated with DTG neurotoxicity remain unknown. Interestingly, a recent study suggests that extrapyramidal side effects of antipsychotics, which resemble the clinical manifestations of our patient, might be correlated to the kinetics of binding to dopamine D2 receptors [6]. Moreover, dopamine signalling has also been involved in the regulation of the circadian cycle [7]. As stated above, sleep disturbances are the most frequent neuropsychiatric side effect of DTG, suggesting a possible interaction between DTG and dopamine metabolism. The present case adds to the cumulative evidence that DTG may cause significant neurological adverse events, including movement abnormalities, and that a switch to other INSTI is well tolerated and associated with resolution of the symptoms. Acknowledgements Conflicts of interest There are no conflicts of interest.