Background Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. MethodsIn this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0-14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181.Findings Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) or efavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33-77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1•64, 95% CI 1•31-2•06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0•013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16•4% vs 3•3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions.Interpretation Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential.Funding Unitaid.

Grapefruit juice and grapefruit product consumption have potential health benefits; however, their intake is also associated with interactions with certain drugs, including calcium channel blockers, immunosuppressants and antihistamines. The primary mechanism through which interactions are mediated is mechanism-based intestinal cytochrome P450 3A4 inhibition by furanocoumarins resulting in increased bioavailability of administered medications that are substrates. Grapefruit products have also been associated with interactions with P-glycoprotein (P-gp) and uptake transporters (e.g. organic anion-transporting polypeptides [OATPs]). Polyphenolic compounds such as flavonoids have been proposed as the causative agents of the P-gp and OATP interactions. The mechanisms and magnitudes of the interactions can be influenced by the concentrations of furanocoumarins and flavonoids in the grapefruit product, the volume of juice consumed, and the inherent variability of specific enzymes and transporter components in humans. It is therefore challenging to predict the extent of grapefruit product-drug interactions and to compare available in vitro and in vivo data. The clinical significance of such interactions also depends on the disposition and toxicity profile of the drug being administered. The aim of this review is to outline the mechanisms of grapefruit-drug interactions and present a comprehensive summary of those agents affected and whether they are likely to be of clinical relevance.

ObjectiveTo evaluate the prevalence, type and severity of prescribing errors observed between grades of prescriber, ward area, admission or discharge and type of medication prescribed.DesignWard-based clinical pharmacists prospectively documented prescribing errors at the point of clinically checking admission or discharge prescriptions. Error categories and severities were assigned at the point of data collection, and verified independently by the study team.SettingProspective study of nine diverse National Health Service hospitals in North West England, including teaching hospitals, district hospitals and specialist services for paediatrics, women and mental health.ResultsOf 4238 prescriptions evaluated, one or more error was observed in 1857 (43.8%) prescriptions, with a total of 3011 errors observed. Of these, 1264 (41.9%) were minor, 1629 (54.1%) were significant, 109 (3.6%) were serious and 9 (0.30%) were potentially life threatening. The majority of errors considered to be potentially lethal (n=9) were dosing errors (n=8), mostly relating to overdose (n=7). The rate of error was not significantly different between newly qualified doctors compared with junior, middle grade or senior doctors. Multivariable analyses revealed the strongest predictor of error was the number of items on a prescription (risk of error increased 14% for each additional item). We observed a high rate of error from medication omission, particularly among patients admitted acutely into hospital. Electronic prescribing systems could potentially have prevented up to a quarter of (but not all) errors.ConclusionsIn contrast to other studies, prescriber experience did not impact on overall error rate (although there were qualitative differences in error category). Given that multiple drug therapies are now the norm for many medical conditions, health systems should introduce and retain safeguards which detect and prevent error, in addition to continuing training and education, and migration to electronic prescribing systems.