In a French study, transmission rates with dual therapy (zidovudine and lamivudine) to both the neonate and mother (1.6%) were lower than zidovudine monotherapy reported in historical controls (6.8%; OR 0.22; 95% CI 0.2–0.5) [259]. The strength of recommendation is proportionate to the estimated risk of transmission. Thus, benefit of additional neonatal DNA Damage inhibitor therapy is anticipated at higher VLs, in circumstances

where resistance is suspected or confirmed and where VL is increasing despite treatment. As with the recommendations regarding PLCS at VLs <400 HIV RNA copies/mL, favourable trends can be considered in the risk assessment. Despite the lack of evidence for its use, NSHPC data indicate a trend towards increasing use of triple-neonatal PEP. When an infant has been started on triple-combination PEP because find more the maternal VL is >50 HIV RNA copies/mL at 36 weeks and subsequently a delivery maternal VL is <50 HIV RNA copies/mL, then it is reasonable to simplify the infant PEP to monotherapy. Most neonates born in the UK to mothers known to have HIV will be exposed to ART in utero, during delivery and

after birth for the first 4 weeks of life. The range of cARTs to which neonates are being exposed in utero continues to increase. Neonatal drug metabolism is generally slower than that of older infants or children and premature neonates have even less efficient metabolism. Owing to a lack of neonatal pharmacokinetic and efficacy studies and suitable formulations, ART dosing regimens remain restricted to a small proportion of the ARV drugs currently manufactured (Table 1). Small pharmacokinetic studies have been performed (zidovudine [260], lamivudine [261],[262], tenofovir [139], emtricitabine [263]) and dosing regimens are available for most of the nucleoside analogues and for abacavir from age 1 month [264], while limited study of didanosine in neonates suggests that the pharmacokinetics are highly variable [108]. The pharmacokinetics of nevirapine in neonates has been

described in more ASK1 detail [72],[74],[265-267]. Pharmacokinetic-supported dosing is available for the PIs nelfinavir [261] and ritonavir-boosted lopinavir (based on HIV-1 infected infants initiating therapy in the first 6 weeks of life) [268-270] and a study that included some infants treated from birth [271]. However, evidence of adrenal suppression has been documented in some neonates treated with lopinavir/ritonavir, particularly when preterm [272], in addition to case reports of cardiac, renal and neurological toxicity, especially in, but not restricted to, premature infants, and including one death during PEP with lopinavir/ritonavir [273]. No effects have been observed with maternal lopinavir/ritonavir in the absence of neonatal dosing. It remains unclear whether these effects are related to lopinavir/ritonavir specifically or could be seen with other ritonavir-boosted PIs.