Reduction in Preterm Delivery and Neonatal Mortality after the Introduction of Antenatal Cotrimoxazole Prophylaxis among HIV‐Infected Women with Low CD4 Cell Counts

Walter, Jan; Mwiya, Mwiya; Scott, Nancy A.; Kasonde, Prisca; Sinkala, Moses; Kankasa, Chipepo; Kauchali, Shuaib; Aldrovandi, Grace M.; Thea, Donald M.; Kuhn, Louise

doi:10.1086/508996

Cited by 44 publications

(34 citation statements)

References 38 publications

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“…Discrepancies between studies may be linked to patient and practice heterogeneity, as HIV disease stage, HIV-1 RNA load, and CD4 count are all potential confounders of timing of ART initiation in pregnancy and adverse pregnancy outcomes. For instance, women with advanced HIV infection are more likely to deliver prematurely and to receive ART early during pregnancy (38). In the current study, there were six (32%) preterm deliveries, which is consistent with other reports (23,36).…”

Section: Discussionsupporting

confidence: 92%

Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Else

Douglas

Dickinson

et al. 2012

Antimicrob Agents Chemother

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Lopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC 0 -12 ) and maximum concentration were ϳ15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.A ntiretroviral therapies (ARTs), with the exception of zidovudine, are unlicensed for use in pregnancy. However, they are widely used, in accordance with national and international guidelines, both for maternal treatment and for the prevention of HIV mother-to-child transmission (MTCT). Multiple physiological changes which can impact the pharmacokinetics (PKs) of these agents occur during pregnancy; therefore, studies in pregnancy are required to ensure appropriate dosing and avoid unnecessary toxicity or treatment failure. Protease inhibitors (PIs) are widely used during pregnancy for both treatment and prevention of MTCT due to their efficacy, lack of CD4 count-dependent toxicity, and short half-lives (t 1/2 s). However, plasma concentrations of certain protease inhibitors have repeatedly been shown to be significantly reduced during the third trimester, with some concerns over efficacy (37).Lopinavir (LPV)-ritonavir (RTV), or LPV/r, is used during pregnancy,...

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Section: Discussionsupporting

confidence: 92%

Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Else

Douglas

Dickinson

et al. 2012

Antimicrob Agents Chemother

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“…3,22–41 One paper reported the results of several studies in a single paper, 26 one study reported data in two separate publications, 3042 and data from another, unpublished study, was reported in a review article. 36 Two studies reported data from the Danish national pregnancy registry during overlapping time periods: one reported the risk of miscarriage among all births, 22 the other reported the risk of congenital anomalies among live births.…”

Section: Resultsmentioning

confidence: 99%

“…1,2 For HIV-infected pregnant women, the use of prophylactic cotrimoxazole is associated with a reduction in preterm delivery and neonatal mortality in their HIV-exposed infants. 3 Since 2006, the World Health Organization (WHO) has recommended that cotrimoxazole prophylaxis should be provided to all HIV-infected individuals with a CD4 cell count <350 per mm 3 , particularly in resource-limited settings where bacterial infections and malaria are prevalent. 4 …”

Section: Introductionmentioning

confidence: 99%

Safety of Cotrimoxazole in Pregnancy

Ford

Shubber

Jao

et al. 2014

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Introduction Cotrimoxazole is widely prescribed to treat a range of infections and for HIV-infected individuals it is administered as prophylaxis to protect against opportunistic infections. Some reports suggest that fetuses exposed to cotrimoxazole during early pregnancy may have an increased risk of congenital anomalies. We carried out this systematic review in order to update the evidence of cotrimoxazole safety in pregnancy. Methods Three databases and one conference abstract site were searched in duplicate up to 31 October, 2013 for studies reporting adverse maternal and infant outcomes among women receiving cotrimoxazole during pregnancy. This search was updated in MEDLINE via PUBMED to 28 April 2014. Studies were included irrespective of HIV-infection status or the presence of other co-infections. Our primary outcome was birth defects of any kind. Secondary outcomes included spontaneous abortions, terminations of pregnancy, stillbirths, preterm deliveries, and drug-associated toxicity. Results 24 studies were included for review. There were 232 infants with congenital anomalies among 4196 women receiving cotrimoxazole during pregnancy, giving an overall pooled prevalence of 3.5% (95% CI 1.8–5.1%; τ2 0.03). Three studies reported 31 infants with neural tube defects, giving a crude prevalence of 0.7% (95%CI 0.5–1.0%) with most data (29 neural tube defects) coming from a single study. The majority of adverse drug reactions were mild. The quality of the evidence was very low. Conclusions The findings of this review support continued recommendations for cotrimoxazole as a priority intervention for HIV-infected pregnant women. It is critical to improve data collection on maternal and infant outcomes.

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“…At the individual level, nutritional and micronutrient support for women and infants may reduce infant mortality rates, as demonstrated by a recent study in Tanzania showing the benefit of maternal vitamin D replacement for infant survival [19]. Other interventions include prophylactic vaccinations, use of bed nets in areas where malaria is prevalent, and the provision of prophylactic sulfamethoxazoletrimethoprim to HIV-infected women in pregnancy and to infected infants [20,21].…”

Section: (See the Article By Kuhn Et Al On Pages 437-44)mentioning

confidence: 99%