11% with zidovudine monotherapy/single-dose nevirapine) [57]. The randomized studies above are two of few studies that have been able to look at individual PIs. One additional analysis from the APR of 955 live births exposed to lopinavir/ritonavir reported a

PTD rate of 13.4% [58]. A retrospective study from the UK reported a PTD GDC-0068 mw rate of 10% in 100 women taking ritonavir-boosted atazanavir in pregnancy, of whom 67% had conceived on their regimen [34]. The data regarding HAART, individual components of HAART and PTD remain conflicting. Some studies suggest that PIs, in particular ritonavir-boosted PIs, are associated with an increased risk of PTD but this is not confirmed by others. There is a

need for a randomized study of sufficient power to explore these issues further and the Promoting Maternal and Infant Survival Everywhere (PROMISE) study (NCT01061151), with 6000 women either randomly allocated to a PI-based combination regimen or zidovudine monotherapy will hopefully provide some answers to these important questions. 5.2.4 No routine dose alterations are recommended for ARVs during pregnancy if used at adult licensed doses with the exception of darunavir, which should be dosed twice daily. Grading: 1C Consider third-trimester TDM particularly if combining tenofovir AZD2281 in vivo and atazanavir. Grading: 1C If dosing off licence, consider switching to standard dosing throughout pregnancy or regular TDM. Grading: 1C Physiological changes that occur even during the first trimester of pregnancy may affect the kinetics of drug absorption, distribution, metabolism and elimination, thereby affecting the drug dosing. Gastrointestinal transit time becomes prolonged; body water and fat increase throughout gestation and there are accompanying increases in cardiac output, ventilation, and liver and renal blood flow; plasma protein concentrations Adenosine decrease, notably albumin

and α1 acid glycoprotein; renal sodium reabsorption increases; and changes occur in the metabolic enzyme pathway in the liver, including changes in cytochrome P450. Caution should be exercised if women fall pregnant on unlicensed doses and consideration given to performing TDM to assess trough levels, or reverting to licensed dosing, often twice per day, during pregnancy. The pharmacokinetics of most NRTIs (zidovudine [59], stavudine [60], lamivudine [61], abacavir [62]) are not significantly affected by pregnancy and dose adjustment is not required. Renal excretion of didanosine is increased in pregnancy, but dose alteration is probably not required [63]. Tenofovir concentrations in the third trimester were reported to be reduced by about 15% compared with postpartum, but trough levels are adequate [64] although in a population-based study of tenofovir use, pregnant women appear to have 39% more clearance than non-pregnant women [65].