Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies

Catriona John Waitt, Paul Garner, Laura Jayne Bonnett, Saye Hock Khoo, Laura Jayne Else, Catriona John Waitt, Paul Garner, Laura Jayne Bonnett, Saye Hock Khoo, Laura Jayne Else

Abstract

Objectives: The objectives of this study were to summarize antiretroviral drug concentrations in breast milk (BM) and exposure of breast-fed infants.

Methods: This was a systematic review of pharmacokinetic studies of HIV-positive women taking antiretrovirals that measured drugs in BM. The quality of pharmacokinetic and laboratory methods was assessed using pre-defined criteria. Pooled ratios and 95% CIs were calculated using the generalized inverse variance method and heterogeneity was estimated by the I(2) statistic. PubMed Central, SCOPUS and LactMed databases were searched. No date or language restrictions were applied. Searches were conducted up to 10 November 2014. Clinical relevance was estimated by comparing ingested dose with the recommended therapeutic dose for each drug.

Results: Twenty-four studies were included. There was substantial variability in the clinical and laboratory methods used and in reported results. Relative to maternal plasma (MP), NRTIs accumulate in BM, with BM : MP ratios (95% CI estimates) from 0.89 to 1.21 (14 studies, 1159 paired BM and MP samples). NNRTI estimates were from 0.71 to 0.94 (17 studies, 965 paired samples) and PI estimates were from 0.17 to 0.21 (8 studies, 477 paired samples). Relative to the recommended paediatric doses, a breast-fed infant may ingest 8.4% (95% CI 1.9-15.0), 12.5% (95% CI 2.6-22.3) and 1.1% (95% CI 0-3.6) of lamivudine, nevirapine and efavirenz, respectively, via BM.

Conclusions: Transfer to untreated infants appears quantitatively important for some NRTIs and NNRTIs. The pharmacokinetic methods varied widely and we propose standards for the design, analysis and reporting of future pharmacokinetic studies of drug transfer during breastfeeding.

Keywords: ARV; PK; mother-to-child transmission.

© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
Information sources and search strategy.
Figure 2.
Figure 2.
Forest plot of BM : MP ratios for NNRTIs. Mean (SD) BM : MP ratios are illustrated for each drug. Where studies reported drug levels measured at different infant ages (representing different sampling times post-partum), these are represented as a separate line. The vertical line indicates a BM : MP ratio of 1, where BM and MP levels are equal. Pooled statistics are shown by the diamond and the I2 statistic is indicated. NVP, nevirapine; EFV, efavirenz; ETR, etravirine; NR, not reported; NaN, not a number; NA, not available. *Conference proceeding.
Figure 3.
Figure 3.
Forest plot of BM : MP ratios for NRTIs. Mean (SD) BM : MP ratios are illustrated for each drug. Where studies reported drug levels measured at different infant ages (representing different sampling times post-partum), these are represented as a separate line. The vertical line indicates a BM : MP ratio of 1, where BM and MP levels are equal. Pooled statistics are shown by the diamond and the I2 statistic is indicated. 3TC, lamivudine; ZDV, zidovudine; d4T, stavudine; ABC, abacavir; NR, not reported; NA, not available. *Conference proceeding.
Figure 4.
Figure 4.
Forest plot of BM : MP ratios for PIs. Mean (SD) BM : MP ratios are illustrated for each drug. Where studies reported drug levels at different infant ages (representing different sampling times post-partum), these are represented as a separate line. The vertical line indicates a BM : MP ratio of 1, where BM and MP levels are equal. Pooled statistics are shown by the diamond and the I2 statistic is indicated. LPV, lopinavir; NFV, nelfinavir; RTV, ritonavir; IDV, indinavir; ATV, atazanavir; NR, not reported; NA, not available. *Conference proceeding.
Figure 5.
Figure 5.
Forest plot of IP : BM ratios for all drugs where infant concentrations were detectable, grouped according to drug class. Where studies reported drug levels at different infant ages, these are represented as a separate line. Pooled statistics are shown by the diamond and the I2 statistic is indicated. EFV, efavirenz; NVP, nevirapine; 3TC, lamivudine; ZDV, zidovudine; LPV, lopinavir; RTV, ritonavir; NR, not reported; NA, not available. *Conference proceeding.
Figure 6.
Figure 6.
‘Dose’ via BM to a fully breast-fed 3 kg infant, as a percentage of recommended paediatric dose. Pooled statistics are shown by the diamond and the I2 statistic is indicated. EFV, efavirenz; NVP, nevirapine; 3TC, lamivudine; d4T, stavudine; ZDV, zidovudine; LPV, lopinavir; RTV, ritonavir; NaN, not a number. *Conference proceeding.

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